CA2262434A1 - Substituted pyridines and biphenyls as anti-hypercholesterinemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents - Google Patents
Substituted pyridines and biphenyls as anti-hypercholesterinemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents Download PDFInfo
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- CA2262434A1 CA2262434A1 CA002262434A CA2262434A CA2262434A1 CA 2262434 A1 CA2262434 A1 CA 2262434A1 CA 002262434 A CA002262434 A CA 002262434A CA 2262434 A CA2262434 A CA 2262434A CA 2262434 A1 CA2262434 A1 CA 2262434A1
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- substituted
- alkyl
- phenyl
- diisopropyl
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Abstract
Substituted pyridines of formula (IA) are produced by reaction of suitably substituted pyridylaldehydes with Grignard or Witting reagents, and the resulting products are appropriately reduced. The pyridines of formula (IA) are suitable as active compounds in pharmaceutical products, particularly in pharmaceutical products for the inhibition of cholesterol ester transfer proteins. 3-Heteroalkyl-aryl-substituted pyridines of formula (IB) are produced from pyridines which are correspondingly protected at the hydroxy group and correspondingly substituted. The compounds of formula (IB) according to the invention are suitable as active compounds in pharmaceutical products, particularly pharmaceutical products for the treatment of hyperlipoproteinemia. Substituted pyridines and benzenes of formula (IC) are produced by procedures disclosed herein, and are useful as active ingredients in pharmaceutical products, particularly pharmaceutical products for inhibition of the glucagon receptor, leading to treatment of glucagon-mediated conditions such as diabetes.
Description
DEMANDES OU BR~VETS VO~UM~NEUX
I A PRÉSENTE PARTIE DE CEI I E DENIANDE OU CE BREVFI
COMPRE~YD PLUS D'UN TOME.
CECI EST LE TOME /--DE_,~
NO~E: Pour les tomes additionels, veuillez cantacter le Bureau canadier~ des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE
THAN ONE VOLUME
, Tt11S IS VOLUME ~ OF ~Z
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NO~E: Fcr additional vclumes please c~ntact~the Canadian Patent Off~ce SUBSTITUTED PYRlDlNES AND BJPHENYLS AS AN~ HypERcHoLEsTERlNEMlc~ ANTI-HYPERLIPOPROTEINEMIC AND ANT~-HYPE~RGLYCEMIC AGENTS
Field This application relates to substituted biaryl compounds which inhibit 5 cholesterol ester transfer proteins (CETPs), stimulate reverse cholesterol transport, and inhibit the action of glucagon.
Baclc~round The present invention concerns certain substituted pyridines, processes for the production thereof, and the use thereof in pharmaceutical products. It also concerns certain substituted biphenyls, processes for their production, pharmaceutical compositions containing them, and methods for their use.
7-(polysubstituted pyridyl) hept-6-enoates for the treatment of ~5 arteriosclerosis, lipoproteinemia, and hyperlipoproteinemia are known from US 5 169 857. In addition, the production of 7-(4-aryl-3-pyridyl)-3,5-dihydroxy-hept-6-enoate is described in EP 325 130.
Glucagon is a peptide hormone whose main function is to increase hepatic glucose production. Insulin, on the other hand, functions to decrease glucose 20 production. Together, these two hormones are necessary for maintaining a correct level of glucose in the blood.
Diabetes is a complex disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Diabetes is also associated with elevated glucagon levels. The heterogeneous nature of the disease requires 25 different strategies to address the different abnormalities in metabolism found in affected individuals.
In the diabetic state (all forms of Type I and Type IT), hyperglycemia often is associated with elevated glucagon levels. Accordingly, a means of treating all forms of diabetes is to block the glucagon receptor with a suitable antagonist, 30 thereby inhibiting glucose production by the liver and reducing glucose levels in the patient.
Glucagon receptor antagonists, materials which block the action of endogenous glucagon, are known to have many and varied applications. Among these applications are the following:
W 098t04528 PCT~US97/13248 0 1. Treatment of hyperglycemia associated with diabetes of any cause and associated with any other diseases or conditions. A glucagon receptor antagonistcan be used either alone or in combination with any other therapies to treat hyperglycemia.
I A PRÉSENTE PARTIE DE CEI I E DENIANDE OU CE BREVFI
COMPRE~YD PLUS D'UN TOME.
CECI EST LE TOME /--DE_,~
NO~E: Pour les tomes additionels, veuillez cantacter le Bureau canadier~ des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE
THAN ONE VOLUME
, Tt11S IS VOLUME ~ OF ~Z
.
NO~E: Fcr additional vclumes please c~ntact~the Canadian Patent Off~ce SUBSTITUTED PYRlDlNES AND BJPHENYLS AS AN~ HypERcHoLEsTERlNEMlc~ ANTI-HYPERLIPOPROTEINEMIC AND ANT~-HYPE~RGLYCEMIC AGENTS
Field This application relates to substituted biaryl compounds which inhibit 5 cholesterol ester transfer proteins (CETPs), stimulate reverse cholesterol transport, and inhibit the action of glucagon.
Baclc~round The present invention concerns certain substituted pyridines, processes for the production thereof, and the use thereof in pharmaceutical products. It also concerns certain substituted biphenyls, processes for their production, pharmaceutical compositions containing them, and methods for their use.
7-(polysubstituted pyridyl) hept-6-enoates for the treatment of ~5 arteriosclerosis, lipoproteinemia, and hyperlipoproteinemia are known from US 5 169 857. In addition, the production of 7-(4-aryl-3-pyridyl)-3,5-dihydroxy-hept-6-enoate is described in EP 325 130.
Glucagon is a peptide hormone whose main function is to increase hepatic glucose production. Insulin, on the other hand, functions to decrease glucose 20 production. Together, these two hormones are necessary for maintaining a correct level of glucose in the blood.
Diabetes is a complex disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Diabetes is also associated with elevated glucagon levels. The heterogeneous nature of the disease requires 25 different strategies to address the different abnormalities in metabolism found in affected individuals.
In the diabetic state (all forms of Type I and Type IT), hyperglycemia often is associated with elevated glucagon levels. Accordingly, a means of treating all forms of diabetes is to block the glucagon receptor with a suitable antagonist, 30 thereby inhibiting glucose production by the liver and reducing glucose levels in the patient.
Glucagon receptor antagonists, materials which block the action of endogenous glucagon, are known to have many and varied applications. Among these applications are the following:
W 098t04528 PCT~US97/13248 0 1. Treatment of hyperglycemia associated with diabetes of any cause and associated with any other diseases or conditions. A glucagon receptor antagonistcan be used either alone or in combination with any other therapies to treat hyperglycemia.
2. Treatment of impaired glucose tolerance (IGT).
3. Treatment of insulin resistance syndromes including those due to obesity, polycystic ovarian syndrome, "Syndrome X", drugs and hormones, endocrinopathies and genetic syndromes.
4. To decrease free fatty acid levels and treat conditions associated with elevated free fatty acids levels such as insulin resistance, obesity, all or part of Syndrome X, Type I and II diabetes, hyperlipidemias and elevated hepatic glucoseoutput associated with insulin resistance, Type I and Type II diabetes, obesity, and Syndrome X.
5. To treat conditions associated with genetic defects in insulin action due to alterations in insulin receptor structure and function or alterations in postreceptor signal transduction. To treat diabetes associated with anti-insulin antibodies, drug induced diabetes, diabetes associated with endocrinopathies anddiabetes associated with genetic syndromes.
6. To treat gestational diabetes mellitus.
7. To treat autoimmune and non autoimmune causes of Type I diabetes including those due to known genetic defects of the beta cell, pancreatic diseases, drug or toxin induced beta cell dysfunction, endocrinopathies, infectious causes, malnutrition associated and idiopathic Type I diabetes.
8. To prevent and treat diabetic ketoacidosis and decrease hepatic ketone body production 9. To treat hyperglycemia of exercise in diabetes.
10. To reduce fasting and postprandial glucose.
11. Treatment of insulin resistance in liver, muscle, and fat.
12. Treatment of conditions of hyperlipidemia.
13. To treat glucagonomas and all other conditions associated with elevated glucagon levels.
14. To treat conditions of increased futile cycling of glucose in the liver.
15. To increase insulin secretion.
16. To decrease glucose toxicity.
W098/045~8 PCTrUS971132q8 0 17. To decrease the renal prostaglandin response to protein and amino acids.
18. To decrease elevated GFR and albumin clearance due to diabetes or proteins or amino acids.
19. To decrease renal albumin clearance and excretion.
20. To treat acute pancreatitis.
- 21. To treat cardiovascular disease including causes of increased cardiac contractility.
22. To treat cardiac hypertrophy and its consequences.
23. As a diagnostic agent and as a diagnostic agent to identify patients having a defect in the glucagon receptor.
24. Treatment of gastrointestinal disorders, treatment of decreased gut motility.
25. As a therapy to increase gastric acid secretions.
26. To reverse intestinal hypomobility due to glucagon administration.
27. To reverse catabolism and nitrogen loss in states of negative nitrogen balance and ~roLeill wasting including all causes of Type I and Type II diabetes, fasting, AIDS, cancer, anorexia, aging and other conditions.
28. To treat any of the above conditions or diseases in post-operative or operative period.
29. To decrease satiety and increase energy intake.
Glucagon receptor antagonists of the prior art, such as those described in W 09518153-A and references cited therein, are predominantly peptide analogues of glucagon. They are susceptible to the actions of endogenous proteases, may precipitate antibody production and immune reactions and can be difficult and expensive to manufacture. Such peptides are usually unsuitable for oral delivery.
One non-peptide glucagon receptor antagonist has been reported (Collins, et al; BioMed. Chem Le~t. 1992,2,915-918). This quinoxaline derivative, CP-99,711, was shown to inhibit glucagon binding and glucagon action in rat liver membrane at micromolar concentrations.
It would be desirable to have inhibitors of CETP which possess valuable pharmacological properties that are superior to those of the state of the art.
Certain of the substituted pyridine compounds of the invention are highly effective W098/04528 PCT~US97/13248 O inhibitors of cholesterol ester transfer proteins (CETP) and stimulate reversecholesterol transport. They cause a reduction in LDL cholesterol levels in the blood, while at the same time increasing HDL cholesterol levels. They can therefore be used for the treatment of hyperlipoproteinemia or arteriosclerosis.
It would also be desirable to have readily prepared non-peptidic glucagon 5 receptor antagonists which are metabolically more stable than peptidic antagonists of the prior art, and which afford good activity and bioavailability. Certain of the substituted pyridine compounds as well as the substituted biphenyls of the invention are highly effective inhibitors of the glucagon receptor. Accordingly,these compounds may be used to treat glucagon-mediated conditions such as those 10 listed above.
The present invention concerns substituted biaryl compounds which fall 15 within the three general formulae (IA), (IB), and (IC) shown below. The definitions of these general formulae are given broadly in the following text. In the subsequent detailed description sections, each of these broad general formulae is discussed in more detail in terms of its prere~,~d and most preferred molecular constituents, procedures for making, examples of particular materials made, testing 20 procedures, and results obtained.
It should be noted that in the text below, and in the subsequent detailed description sections~ the definitions of the various constituent and substituentgroups apply only to the particular subset of the compounds of the invention then under consideration. The same symbols may have different definitions in 25 connection with the other subsets of compounds.
The present invention concerns substituted pyridines of the general formula (LA), T~ D
J~,l (lA) L N E
30 in which A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, W 098/04528 PCT~US97113248 0 acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula NRlR2, wherein R1 and R2 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms, D stands for straight-chain or branched alkyl with up to 8 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 8 carbon atoms, which is optionally substituted by cycloalkyl with 3 to 8 carbon atoms, or stand for cycloalkyl with 3 to 8 carbon atoms, or E has the above-mentioned meaning and L in this case stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR3R4, wherein R3 and R4 are identical or different and have the meaning given above for R1 and R2 or E stands for straight-chain or branched alkyl with up to 8 carbon atoms, or s WO 98/04528 PCTrUS97/13248 0 stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR5R6, wherein R5 and R6 are identical or different and have the meaning given above for R1 and R2 and L in this case stands for straight-chain or branched alkoxy with up to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbon atoms, T stands for a radical of the formula R7--X-- or Rs V
wherein R7 and R8 are identical or different and denote cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms, or denote a 5- to 7-member aromatic, optionally benzo-condensed, heterocyclic compound with up to 3 heterocyclic atoms from the 2~ series S, N and/or O, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by halogen, trifluoromethyl, or trifluoromethoxy, and/or the rings are substituted by a group of the formula -NR11R12, wherein W098104528 PCTrUS97113248 0 R11 and R12 are identical or different and have the meaning given above for R1 and R2, X denotes a straight or branched alkyl chain or alkenyl chain with 2 to 10 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, R9 denotes hydrogen, and R10 denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 5 carbon atoms, or a radical of the formula -NR13R14, wherein R13 and R14 are identical or different and have the meaning given above for R1 and R2, or R9 and R10 form a carbonyl group together with the carbon atom, and the salts thereof.
The present invention also concerns substituted pyridines of general formula (lB) A
Rl-E-V- D~ CH20H
L N T
in which A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, WO 98/04528 PCTrUS97113248 0 trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR2R3 and/or-WR4, wherein R2 and R3 are the same or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms, W denotes an oxygen or sulfur atom, R4 denotes aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, trifluoromethyl, trifluoromethoxy, hydroxy, or by straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each, D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 8 carbon atoms, or E stands for a bond, 25 V stands for an oxygen or sulfur atom or for a group of the formula -NR5-, wherein R5 denotes hydrogen or straight-chain or branched alkyl with up to 6 carbon atoms or phenyl, R~- stands for cycloalkyl with 3 to 6 carbon atoms, or stands for aryl with 6 to 10 carbon atoms or for a 5- to 7-member, optionally benzocondensed, saturated or unsaturated, mono-, bi-, or tricyclic heterocyclic compound with up to 4 carbon atoms from the series S, N, and/or O, W O g8/017X PCTrUS97113248 0 in which the heterocycles, also via the N function in the case of nitrogen-containing rings, are optionally substituted up to 3 times in an identical manner or differently by halogen, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, by aryl with 6 to 10 carbon atoms, or by an optionally benzo-condensed, aromatic 5- to 7-member heterocyclic compound with up to 3 heterocyclic atoms from the series S, N, and/or O, and/or are substituted by a group of the formula -oR6, -SR7, -SO2R8, or -NR9R10, wherein R6, R7, and R~ are identical or different and denote aryl with 6 to 10 carbon atoms, which in turn is substituted up to 2 times in an identical manner or differently by phenyl or halogen or by straight-chain or branched alkyl with up to 4 carbon atoms, R9 and R10 are identical or different and have the above-indicated meaning of R2 and R3, L and T are identical or dirrelellt and stand for trifluoromethyl or straight-chain or branched alkyl with up to 8 carbon atoms, which are optionally substituted by cycloalkyl with 3 to 7 carbon atoms, or by aryl with 6 to 10 carbon atoms, which in turn can be substituted up to 2 times in an identical manner or differently by halogen, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or L and/or T stand for cycloalkyl with 3 to 7 carbon atoms or stand for aryl with 6 to 10 carbon atoms or for a 5- to 7-member, saturated, partially unsaturated, or unsaturated heterocyclic compound with up to 3 heterocyclic atoms from the series S, N and/or O, with binding in the case of - 35 a nitrogen atom also being possible via this atom, with the heterocycles optionally being substituted up to 3 times in an identical manner or differently by halogen, nitro, trifluoromethyl, trifluoromethoxy, or by WO98104Q8 PCTnUS97113248 0 straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, and the salts thereof.
This invention also relates to compounds having glucagon receptor antagonistic activity and the general formula (IC) shown below.
Ar Jl --1 (IC) In general formula IC, the groups X, R1a, R1b, R2, R3, and Ar have the following meanings:
X represents N or CR8.
R8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl-(C1-~3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5. The substituents on the substituted phenyl or substituted alkyl R8 groups are from 1 to 3 of, for example, hydroxy, fluoro, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(cl-c3)-alkoxy~ (C1-C6)-alkanoyloxy, (C1-C6~-alkoxycarbonyl, carboxy, formyl, or -NR4R5.
The groups R4 and R5 are independently hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalky~-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substi~ted naphthyl-(Cl-C6)-alkyl The substitutents on ~e substituted phenyl or substituted naphthyl R4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
R4 and R5 may be joined together to form -(CH2)rA(CH2)S- wherein the subscripts r and s are independently 1 to 3 and A is CHR6, NR6, O, or S(O)n in which n is 0, 1, or 2; and R6 is hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(C1-C6)-alkyl.
R1a and R1b are independently trifluoromethyl, (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C2-Clo)-alkenyl~ substituted (C2-C1o)-alkenyl, (C2-Clo)-alkyn WO 98/04528 PCT~US97113248 0 substituted (c2-clo)-alkynylJ (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (cl-c6) alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl Rla and Rlb groups are independently from 1 to 3 of, for example, -oR4, -C(o)R4, -co2R4~ -C(o)NR4R5, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (Cl-C4)-alkyl, or 5 (Cl-C4)-alkoxy groups.
R2 is (Cl-Clo)-alkyl, substituted (Cl-Clo)-alkyl, (C2-Clo)-alkenyl, substituted (C2-Clo)-alkenyl, (C2-Clo)-alkynyl, substituted (C2-Clo)-alkynyl, (C3-C6)-cycloalkyl-(Cl-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(Cl-C6)-alkyl. The substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and 10 substituted cycloalkyl R2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(o)NR4R5, or -S(o)mR7 wherein m is 0, 1, ar 2. ~he substituents on the substituted phenyl R2 substituent group are from 1 to 3 of, for example, halogen, (Cl-C4)-alkyl, or (Cl-C4)-alkoxy.
R7 is (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cl-C6)-alkyl, 15 substituted phenyl-(Cl-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Cl-C6)-alkyl, substituted pyridyl-(Cl-C6) alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cl-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (Cl-C6)-alkyl, (Cl-C6)-alkoxy,20 nitro, cyano, or hydroxy.
R2 and Rlb may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and Rlb are attached.
R3 is hydroxy, trifluoroacetyl, (Cl-C6)-alkanoyl, substituted (Cl-C6)-alkyl, or substituted (C3-C6)-alkenyl. The substitutents on the substituted alkyl and 25 substituted alkenyl R3 groups are from 1 to 3 hydroxy or trifluoromethyl groups.
Ar is an optionally substituted aromatic or heteroaromatic ring. Examples of possible Ar groups are: phenyls, naphthyls, pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls. The optional substitutents on t~.e group Ar are 30 independently 1 to 3 of, for example, halogen, (Cl-C6)-alkyl, substituted (Cl-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -oR4, -C(o)R4, -oC(o)R4,-Co2R4,-NR4R5,-C(o)NR4R5~ or -S(o)mR7. The substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on 3~ Ar are from 1 to 3 of, for example, halogen, hydroxy, -NR4R~, phenyl, or W 098104528 PCTrUS97113248 0 substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4) alkyl, or (C1-C4) alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
The invention also relates to a pharmaceutical product containing the substituted pyridines according to general formula (IA) and, if appropriate, a pharmacologically tolerable formulation adjuvant. It further relates to such pharmaceutical product for the inhibition of cholesterol ester transfer proteins, and to the use of the claimed substituted pyridines for the production of pharmaceutical products, and to use of the claimed substituted pyridines for the production of cholesterol ester transfer ~rolei~l inhibitors.
The invention further relates to a pharmaceutical product containing the substituted pyridines 3-heteroalkyl-aryl-substituted pyridines according to general formula (IB) and, if appropriate, a pharmacologically tolerable formulation adjuvant. It further relates to such pharmaceutical product for the treatment ofhyperlipoproteinemia, and to the use of the ~l~ime-l substituted pyridines for the production of pharmaceutical products, and to use of the claimed substituted pyridines for the production of pharmaceutical products for the treatment of hyperlipoproteinemia .
The invention also relates to a pharrnaceutical composition for use in treating a glucagon-mediated condition, which comprises: a compound having glucagon receptor antagonistic activity and a structure within general structural formula IC, plus a pharmaceutically acceptable carrier.
The invention further relates to a method for treating a glucagon-mediated condition which comprises administering to a subject an effective amount of a compound having glucagon receptor antagonistic activity and a structure within general structural formula IC.
O Detailed ~l~s~nption with l~fer~lce to c~"~ ds of ~eneral formula (IA) The substituted pyridines according to the invention can also occur in the form of the salts thereof. In general, salts with organic or inorganic bases or acids are mentioned here.
Within the context of the present invention, physiologically safe salts are ~refeLled. Physiologically safe salts of the compounds according to the invention can be salts of substances according to the invention with mineral acids, carboxylic acids, or sulfonic acids. Salts with, for example, hydrochloric acid, hydrobromic 10 acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid, or benzoic acid are particularly preferred.
Physiologically safe salts can also be metallic or ammonium salts of the compounds according to the invention that possess a free carboxyl group. For example, sodium salts, potassium salts, magnesium salts, or calcium salts, as well as ammonium salts, that are derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, 20 dimethylaminoethanol, arginine, lysine, ethylenediamine, or 2-phenyl-ethylamine are particularly preferred.
The compounds according to the invention can exist in stereoisomeric forms, which either behave like an image and mirror image (enantiomers) or do not 25 behave like an image and mirror image (diastereomers). The invention concernsboth enantiomers or diastereomers or the mixtures thereof. These mixtures of enantiomers and diastereomers can be separated in the known manner into stereoisomerically homogeneous components.
Within the context of the invention, the heterocyclic compound, which is optionally benzo-condensed, stands in general for a saturated or unsaturated, 5-to 7-member, preferably 5- to 6-member, heterocyclic compound that can contain up to 3 heteroatoms from the series S, N, and/or O. Indolyl, isoquinolyl, quinolyl,benzothia~olyl, benzolb]thiophene, benzo[b]furanyl, benzoxazolyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl, or piperidyl are cited as examples. Quinolyl, pyridyl, indolyl, benzothiazolyl, or benzoxazolyl are preferred.
Compounds of the general formula (IA) are ~le~lred, in which 5 A stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula NRlR2 ~0 wherein R1 and R2 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 4 carbon atoms, D stands for straight-chain or branched alkyl with up to 6 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 6 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or E has the above-mentioned meaning and ~0 L in this case stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR3R4,~5 WO ~8~ 2~ PCTrUS971~3248 0 wherein R3 and R4 are identical or different and have the meaning given above for R1 and R2 5 or E stands for straight-chain or branched alkyl with up to 5 carbon atoms, or stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, 1~ trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR5R6, wherein R5 and R6 are identical or different and have the meaning given above for R1 and R2 and L in this case stands for straight-chain or branched alkoxy with up to 6 carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy, 25 T stands for a radical of the formula R9 Rl~
R7--X or Rs V
wherein R7 and R8 are identical or different and denote cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, or denote naphthyl, phenyl, pyridyl, quinolyl, indolyl, benzothiazolyl, or benzoxazolyl, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoro-methoxy, fluorine, chlorine, bromine, hydroxy, carboxyl, by straight-chain or W 03~ 2~ PCTrUS97/13248 0 branched alkyl, alkoxy, or alkoxycarbonyl with up to 5 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn by substituted by fluorine, chlorine, bromine, trifluoromethyl, or trifluoromethoxy, and /or the rings are optionally substituted by a group of the formula _NRllR12, wherein R11 and R12 are identical or different and have the meaning given above for R1 and R2, X denotes a straight or branched alkyl chain or alkenyl chain with 2 to 8 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, R9 denotes hydrogen, and R10 denotes hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 4 carbon atoms, or a radical of the formula -wherein R13 and R14 are identical or different and have the meaning given above for R1 and R2, or R9 and R10 form a carbonyl group together with the carbon atom, 3~ and the salts thereof.
O Compounds of the general formula (IA) are particularly preferred, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, triffuoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, D stands for straight-chain or branched alkyl with up to 5 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 5 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or E has the above-mentioned meaning and L in this case stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, or 30 E stands for straight-chain or branched alkyl with up to 4 carbon atoms, or stands for phenyl, which is optionally substituted up to 2 times in an identicalmanner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, and 0 L in this case stands for straight-chain or branched alkoxy with up to 5 carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy, T stands for a radical of the formula R7 X Rs V
or wherein R7 and R8 are identical or different and denote cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, or denote phenyl, pyridyl, quinolyl, indolyl, naphthyl, benzothiazolyl, or benzoxazolyl, which are optionally substituted up to 2 times in an identical manner or dir~erelllly by trifluoromethyl, trifluoromethoxy, fluorine, chlorine, bromine, hydroxy, carboxyl, by straight-chain or branched alkyl, alkoxy, or alkoxycarbonyl with up to 4 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by fluorine, chlorine, bromine, trifluoromethyl, or trifluoromethoxy, X denotes a straight or branched alkyl chain with 2 to 6 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, R9 denotes hydrogen, and R10 denotes hydrogen, fluorine, chlorine, bromine, azido, amino, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 3 carbon atoms,~0 or R9 and R10 form a carbonyl group together with the carbon atom, 35 and the salts thereof.
W098/045~8 PCTrUS971132q8 0 17. To decrease the renal prostaglandin response to protein and amino acids.
18. To decrease elevated GFR and albumin clearance due to diabetes or proteins or amino acids.
19. To decrease renal albumin clearance and excretion.
20. To treat acute pancreatitis.
- 21. To treat cardiovascular disease including causes of increased cardiac contractility.
22. To treat cardiac hypertrophy and its consequences.
23. As a diagnostic agent and as a diagnostic agent to identify patients having a defect in the glucagon receptor.
24. Treatment of gastrointestinal disorders, treatment of decreased gut motility.
25. As a therapy to increase gastric acid secretions.
26. To reverse intestinal hypomobility due to glucagon administration.
27. To reverse catabolism and nitrogen loss in states of negative nitrogen balance and ~roLeill wasting including all causes of Type I and Type II diabetes, fasting, AIDS, cancer, anorexia, aging and other conditions.
28. To treat any of the above conditions or diseases in post-operative or operative period.
29. To decrease satiety and increase energy intake.
Glucagon receptor antagonists of the prior art, such as those described in W 09518153-A and references cited therein, are predominantly peptide analogues of glucagon. They are susceptible to the actions of endogenous proteases, may precipitate antibody production and immune reactions and can be difficult and expensive to manufacture. Such peptides are usually unsuitable for oral delivery.
One non-peptide glucagon receptor antagonist has been reported (Collins, et al; BioMed. Chem Le~t. 1992,2,915-918). This quinoxaline derivative, CP-99,711, was shown to inhibit glucagon binding and glucagon action in rat liver membrane at micromolar concentrations.
It would be desirable to have inhibitors of CETP which possess valuable pharmacological properties that are superior to those of the state of the art.
Certain of the substituted pyridine compounds of the invention are highly effective W098/04528 PCT~US97/13248 O inhibitors of cholesterol ester transfer proteins (CETP) and stimulate reversecholesterol transport. They cause a reduction in LDL cholesterol levels in the blood, while at the same time increasing HDL cholesterol levels. They can therefore be used for the treatment of hyperlipoproteinemia or arteriosclerosis.
It would also be desirable to have readily prepared non-peptidic glucagon 5 receptor antagonists which are metabolically more stable than peptidic antagonists of the prior art, and which afford good activity and bioavailability. Certain of the substituted pyridine compounds as well as the substituted biphenyls of the invention are highly effective inhibitors of the glucagon receptor. Accordingly,these compounds may be used to treat glucagon-mediated conditions such as those 10 listed above.
The present invention concerns substituted biaryl compounds which fall 15 within the three general formulae (IA), (IB), and (IC) shown below. The definitions of these general formulae are given broadly in the following text. In the subsequent detailed description sections, each of these broad general formulae is discussed in more detail in terms of its prere~,~d and most preferred molecular constituents, procedures for making, examples of particular materials made, testing 20 procedures, and results obtained.
It should be noted that in the text below, and in the subsequent detailed description sections~ the definitions of the various constituent and substituentgroups apply only to the particular subset of the compounds of the invention then under consideration. The same symbols may have different definitions in 25 connection with the other subsets of compounds.
The present invention concerns substituted pyridines of the general formula (LA), T~ D
J~,l (lA) L N E
30 in which A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, W 098/04528 PCT~US97113248 0 acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula NRlR2, wherein R1 and R2 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms, D stands for straight-chain or branched alkyl with up to 8 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 8 carbon atoms, which is optionally substituted by cycloalkyl with 3 to 8 carbon atoms, or stand for cycloalkyl with 3 to 8 carbon atoms, or E has the above-mentioned meaning and L in this case stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR3R4, wherein R3 and R4 are identical or different and have the meaning given above for R1 and R2 or E stands for straight-chain or branched alkyl with up to 8 carbon atoms, or s WO 98/04528 PCTrUS97/13248 0 stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR5R6, wherein R5 and R6 are identical or different and have the meaning given above for R1 and R2 and L in this case stands for straight-chain or branched alkoxy with up to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbon atoms, T stands for a radical of the formula R7--X-- or Rs V
wherein R7 and R8 are identical or different and denote cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms, or denote a 5- to 7-member aromatic, optionally benzo-condensed, heterocyclic compound with up to 3 heterocyclic atoms from the 2~ series S, N and/or O, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by halogen, trifluoromethyl, or trifluoromethoxy, and/or the rings are substituted by a group of the formula -NR11R12, wherein W098104528 PCTrUS97113248 0 R11 and R12 are identical or different and have the meaning given above for R1 and R2, X denotes a straight or branched alkyl chain or alkenyl chain with 2 to 10 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, R9 denotes hydrogen, and R10 denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 5 carbon atoms, or a radical of the formula -NR13R14, wherein R13 and R14 are identical or different and have the meaning given above for R1 and R2, or R9 and R10 form a carbonyl group together with the carbon atom, and the salts thereof.
The present invention also concerns substituted pyridines of general formula (lB) A
Rl-E-V- D~ CH20H
L N T
in which A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, WO 98/04528 PCTrUS97113248 0 trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR2R3 and/or-WR4, wherein R2 and R3 are the same or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms, W denotes an oxygen or sulfur atom, R4 denotes aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, trifluoromethyl, trifluoromethoxy, hydroxy, or by straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each, D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 8 carbon atoms, or E stands for a bond, 25 V stands for an oxygen or sulfur atom or for a group of the formula -NR5-, wherein R5 denotes hydrogen or straight-chain or branched alkyl with up to 6 carbon atoms or phenyl, R~- stands for cycloalkyl with 3 to 6 carbon atoms, or stands for aryl with 6 to 10 carbon atoms or for a 5- to 7-member, optionally benzocondensed, saturated or unsaturated, mono-, bi-, or tricyclic heterocyclic compound with up to 4 carbon atoms from the series S, N, and/or O, W O g8/017X PCTrUS97113248 0 in which the heterocycles, also via the N function in the case of nitrogen-containing rings, are optionally substituted up to 3 times in an identical manner or differently by halogen, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, by aryl with 6 to 10 carbon atoms, or by an optionally benzo-condensed, aromatic 5- to 7-member heterocyclic compound with up to 3 heterocyclic atoms from the series S, N, and/or O, and/or are substituted by a group of the formula -oR6, -SR7, -SO2R8, or -NR9R10, wherein R6, R7, and R~ are identical or different and denote aryl with 6 to 10 carbon atoms, which in turn is substituted up to 2 times in an identical manner or differently by phenyl or halogen or by straight-chain or branched alkyl with up to 4 carbon atoms, R9 and R10 are identical or different and have the above-indicated meaning of R2 and R3, L and T are identical or dirrelellt and stand for trifluoromethyl or straight-chain or branched alkyl with up to 8 carbon atoms, which are optionally substituted by cycloalkyl with 3 to 7 carbon atoms, or by aryl with 6 to 10 carbon atoms, which in turn can be substituted up to 2 times in an identical manner or differently by halogen, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or L and/or T stand for cycloalkyl with 3 to 7 carbon atoms or stand for aryl with 6 to 10 carbon atoms or for a 5- to 7-member, saturated, partially unsaturated, or unsaturated heterocyclic compound with up to 3 heterocyclic atoms from the series S, N and/or O, with binding in the case of - 35 a nitrogen atom also being possible via this atom, with the heterocycles optionally being substituted up to 3 times in an identical manner or differently by halogen, nitro, trifluoromethyl, trifluoromethoxy, or by WO98104Q8 PCTnUS97113248 0 straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, and the salts thereof.
This invention also relates to compounds having glucagon receptor antagonistic activity and the general formula (IC) shown below.
Ar Jl --1 (IC) In general formula IC, the groups X, R1a, R1b, R2, R3, and Ar have the following meanings:
X represents N or CR8.
R8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl-(C1-~3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5. The substituents on the substituted phenyl or substituted alkyl R8 groups are from 1 to 3 of, for example, hydroxy, fluoro, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(cl-c3)-alkoxy~ (C1-C6)-alkanoyloxy, (C1-C6~-alkoxycarbonyl, carboxy, formyl, or -NR4R5.
The groups R4 and R5 are independently hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalky~-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substi~ted naphthyl-(Cl-C6)-alkyl The substitutents on ~e substituted phenyl or substituted naphthyl R4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
R4 and R5 may be joined together to form -(CH2)rA(CH2)S- wherein the subscripts r and s are independently 1 to 3 and A is CHR6, NR6, O, or S(O)n in which n is 0, 1, or 2; and R6 is hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(C1-C6)-alkyl.
R1a and R1b are independently trifluoromethyl, (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C2-Clo)-alkenyl~ substituted (C2-C1o)-alkenyl, (C2-Clo)-alkyn WO 98/04528 PCT~US97113248 0 substituted (c2-clo)-alkynylJ (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (cl-c6) alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl Rla and Rlb groups are independently from 1 to 3 of, for example, -oR4, -C(o)R4, -co2R4~ -C(o)NR4R5, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (Cl-C4)-alkyl, or 5 (Cl-C4)-alkoxy groups.
R2 is (Cl-Clo)-alkyl, substituted (Cl-Clo)-alkyl, (C2-Clo)-alkenyl, substituted (C2-Clo)-alkenyl, (C2-Clo)-alkynyl, substituted (C2-Clo)-alkynyl, (C3-C6)-cycloalkyl-(Cl-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(Cl-C6)-alkyl. The substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and 10 substituted cycloalkyl R2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(o)NR4R5, or -S(o)mR7 wherein m is 0, 1, ar 2. ~he substituents on the substituted phenyl R2 substituent group are from 1 to 3 of, for example, halogen, (Cl-C4)-alkyl, or (Cl-C4)-alkoxy.
R7 is (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cl-C6)-alkyl, 15 substituted phenyl-(Cl-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Cl-C6)-alkyl, substituted pyridyl-(Cl-C6) alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cl-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (Cl-C6)-alkyl, (Cl-C6)-alkoxy,20 nitro, cyano, or hydroxy.
R2 and Rlb may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and Rlb are attached.
R3 is hydroxy, trifluoroacetyl, (Cl-C6)-alkanoyl, substituted (Cl-C6)-alkyl, or substituted (C3-C6)-alkenyl. The substitutents on the substituted alkyl and 25 substituted alkenyl R3 groups are from 1 to 3 hydroxy or trifluoromethyl groups.
Ar is an optionally substituted aromatic or heteroaromatic ring. Examples of possible Ar groups are: phenyls, naphthyls, pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls. The optional substitutents on t~.e group Ar are 30 independently 1 to 3 of, for example, halogen, (Cl-C6)-alkyl, substituted (Cl-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -oR4, -C(o)R4, -oC(o)R4,-Co2R4,-NR4R5,-C(o)NR4R5~ or -S(o)mR7. The substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on 3~ Ar are from 1 to 3 of, for example, halogen, hydroxy, -NR4R~, phenyl, or W 098104528 PCTrUS97113248 0 substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4) alkyl, or (C1-C4) alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
The invention also relates to a pharmaceutical product containing the substituted pyridines according to general formula (IA) and, if appropriate, a pharmacologically tolerable formulation adjuvant. It further relates to such pharmaceutical product for the inhibition of cholesterol ester transfer proteins, and to the use of the claimed substituted pyridines for the production of pharmaceutical products, and to use of the claimed substituted pyridines for the production of cholesterol ester transfer ~rolei~l inhibitors.
The invention further relates to a pharmaceutical product containing the substituted pyridines 3-heteroalkyl-aryl-substituted pyridines according to general formula (IB) and, if appropriate, a pharmacologically tolerable formulation adjuvant. It further relates to such pharmaceutical product for the treatment ofhyperlipoproteinemia, and to the use of the ~l~ime-l substituted pyridines for the production of pharmaceutical products, and to use of the claimed substituted pyridines for the production of pharmaceutical products for the treatment of hyperlipoproteinemia .
The invention also relates to a pharrnaceutical composition for use in treating a glucagon-mediated condition, which comprises: a compound having glucagon receptor antagonistic activity and a structure within general structural formula IC, plus a pharmaceutically acceptable carrier.
The invention further relates to a method for treating a glucagon-mediated condition which comprises administering to a subject an effective amount of a compound having glucagon receptor antagonistic activity and a structure within general structural formula IC.
O Detailed ~l~s~nption with l~fer~lce to c~"~ ds of ~eneral formula (IA) The substituted pyridines according to the invention can also occur in the form of the salts thereof. In general, salts with organic or inorganic bases or acids are mentioned here.
Within the context of the present invention, physiologically safe salts are ~refeLled. Physiologically safe salts of the compounds according to the invention can be salts of substances according to the invention with mineral acids, carboxylic acids, or sulfonic acids. Salts with, for example, hydrochloric acid, hydrobromic 10 acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid, or benzoic acid are particularly preferred.
Physiologically safe salts can also be metallic or ammonium salts of the compounds according to the invention that possess a free carboxyl group. For example, sodium salts, potassium salts, magnesium salts, or calcium salts, as well as ammonium salts, that are derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, 20 dimethylaminoethanol, arginine, lysine, ethylenediamine, or 2-phenyl-ethylamine are particularly preferred.
The compounds according to the invention can exist in stereoisomeric forms, which either behave like an image and mirror image (enantiomers) or do not 25 behave like an image and mirror image (diastereomers). The invention concernsboth enantiomers or diastereomers or the mixtures thereof. These mixtures of enantiomers and diastereomers can be separated in the known manner into stereoisomerically homogeneous components.
Within the context of the invention, the heterocyclic compound, which is optionally benzo-condensed, stands in general for a saturated or unsaturated, 5-to 7-member, preferably 5- to 6-member, heterocyclic compound that can contain up to 3 heteroatoms from the series S, N, and/or O. Indolyl, isoquinolyl, quinolyl,benzothia~olyl, benzolb]thiophene, benzo[b]furanyl, benzoxazolyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl, or piperidyl are cited as examples. Quinolyl, pyridyl, indolyl, benzothiazolyl, or benzoxazolyl are preferred.
Compounds of the general formula (IA) are ~le~lred, in which 5 A stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula NRlR2 ~0 wherein R1 and R2 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 4 carbon atoms, D stands for straight-chain or branched alkyl with up to 6 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 6 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or E has the above-mentioned meaning and ~0 L in this case stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR3R4,~5 WO ~8~ 2~ PCTrUS971~3248 0 wherein R3 and R4 are identical or different and have the meaning given above for R1 and R2 5 or E stands for straight-chain or branched alkyl with up to 5 carbon atoms, or stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, 1~ trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR5R6, wherein R5 and R6 are identical or different and have the meaning given above for R1 and R2 and L in this case stands for straight-chain or branched alkoxy with up to 6 carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy, 25 T stands for a radical of the formula R9 Rl~
R7--X or Rs V
wherein R7 and R8 are identical or different and denote cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, or denote naphthyl, phenyl, pyridyl, quinolyl, indolyl, benzothiazolyl, or benzoxazolyl, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoro-methoxy, fluorine, chlorine, bromine, hydroxy, carboxyl, by straight-chain or W 03~ 2~ PCTrUS97/13248 0 branched alkyl, alkoxy, or alkoxycarbonyl with up to 5 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn by substituted by fluorine, chlorine, bromine, trifluoromethyl, or trifluoromethoxy, and /or the rings are optionally substituted by a group of the formula _NRllR12, wherein R11 and R12 are identical or different and have the meaning given above for R1 and R2, X denotes a straight or branched alkyl chain or alkenyl chain with 2 to 8 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, R9 denotes hydrogen, and R10 denotes hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 4 carbon atoms, or a radical of the formula -wherein R13 and R14 are identical or different and have the meaning given above for R1 and R2, or R9 and R10 form a carbonyl group together with the carbon atom, 3~ and the salts thereof.
O Compounds of the general formula (IA) are particularly preferred, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, triffuoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, D stands for straight-chain or branched alkyl with up to 5 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 5 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or E has the above-mentioned meaning and L in this case stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, or 30 E stands for straight-chain or branched alkyl with up to 4 carbon atoms, or stands for phenyl, which is optionally substituted up to 2 times in an identicalmanner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, and 0 L in this case stands for straight-chain or branched alkoxy with up to 5 carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy, T stands for a radical of the formula R7 X Rs V
or wherein R7 and R8 are identical or different and denote cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, or denote phenyl, pyridyl, quinolyl, indolyl, naphthyl, benzothiazolyl, or benzoxazolyl, which are optionally substituted up to 2 times in an identical manner or dir~erelllly by trifluoromethyl, trifluoromethoxy, fluorine, chlorine, bromine, hydroxy, carboxyl, by straight-chain or branched alkyl, alkoxy, or alkoxycarbonyl with up to 4 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by fluorine, chlorine, bromine, trifluoromethyl, or trifluoromethoxy, X denotes a straight or branched alkyl chain with 2 to 6 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, R9 denotes hydrogen, and R10 denotes hydrogen, fluorine, chlorine, bromine, azido, amino, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 3 carbon atoms,~0 or R9 and R10 form a carbonyl group together with the carbon atom, 35 and the salts thereof.
' CA 02262434 1999-01-28 W 098/04528 PCT~US97/13248 Compounds according to the invention of the general formula (LA) are most prefell~d, in which A stands for phenyl, which is optionally substituted by fluorine, chlorine, or methyl.
Furthermore, a process for the production of compounds according to the invention of the general formula (IA) has been discovered, characterized by the fact that compounds of the general formula (II) or (III) O H C~R1 s T~C H O
15 in which A, E, L, and T have the above-mentioned meanings, and R15 stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms, are either first reacted, using the Grignard or Wittig reaction, in an inert solvent, 25 with further derivatization optionally being carried out according to the customary methods, and then are reduced in inert solvents, or, in the case of compounds of the general formula (III), direct reductions arecarried out, optionally via several steps.
The compounds according to the invention can be explained, for example, by - means of the following reaction diagram:
Furthermore, a process for the production of compounds according to the invention of the general formula (IA) has been discovered, characterized by the fact that compounds of the general formula (II) or (III) O H C~R1 s T~C H O
15 in which A, E, L, and T have the above-mentioned meanings, and R15 stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms, are either first reacted, using the Grignard or Wittig reaction, in an inert solvent, 25 with further derivatization optionally being carried out according to the customary methods, and then are reduced in inert solvents, or, in the case of compounds of the general formula (III), direct reductions arecarried out, optionally via several steps.
The compounds according to the invention can be explained, for example, by - means of the following reaction diagram:
OHC~,COOCH3 O N~ MgBr Grignard reaction ~
F ~ H3 D~ b F
F
F ~ OH
~'1~'",~
b o CA 02262434 l999-0l-28 W 098/04528 PCTrUS97/13248 O H C~COOC2H5 n-BuLi\ F
'~ ~
~N H0 ~J
1 J~COOC2H5 CH30 N '~/
dehydration /
PTS /
~/ F
N ~
~0 ~ ~ COOC2H5 CH30 N ~ F
DIBAL-~ ,J~, ~,J
o Suitable solvents are ethers, such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, or cyclohexane, or petroleum fractions, or halocarbons, such as 5 dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, or trichloroethylene, or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, - dimethyl sulfoxide, dimethyl formamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is likewise possible to use mixtures of said solvents. Dichloromethane is preferred.
W 098104528 PCTrUS97113248 Suitable organometallic reagents are systems such as Mg/bromobenzene trifluoride and p-trifluoromethylphenyllithium. The Mgtbromobenzene trifluoride system is preferred.
The reductions and derivatizations are carried out according to the above-mentioned methods.
In general, the reductions are carried out in ethers, such as dioxane, tetrahydrofuran, or diethyl ether, or in hydrocarbons, such as benzene, hexane, or toluene. Toluene and tetrahydrofuran arepreferred.
Suitable reductants are complex metal hydrides, such as lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutylaluminum hydride, dimethoxymethylaluminate sodium salt, or sodium-1~ bis-(2-methoxyethoxy)-dihydroaluminate (Red-Al). Diisobutyl-aluminum hydride and dimethoxymethylaluminate sodium salt are preferred.
The reductant is generally added in a quantity ranging from 4 moles to 10 moles, preferably from 4 moles to 5 moles, relative to 1 mole of the compound tobe reduced.
The reduction generally takes place within a temperature range of -78~C to +50~C, preferably from -78~C to O~C, and most preferably at -78~C, depending on the choice of both the reductant and the solvent.
The reduction generally takes place at normal pressure, but it is also possible to work at increased or reduced pressure.
However, the reductions can also be carried out with reductants that are suitable for the reduction of ketones to hydroxy compounds. Particularly suitable in this regard is reduction using metal hydrides or complex metal hydrides in inert solvents, if a~pro~riate in the presence of a trialkyl borane. Preferably, the reduction is carried out using complex metal hydrides, such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkyl borohydride, or lithium aluminum hydride. More particularly preferably, the reduction is carried out using sodium borohydride in the presence of triethylborane .
W O~ 2~ PCTrUS97113248 The reaction can also take place via hydrogenation. The hydrogenation takes place according to the customary methods using hydrogen in the presence ofnoble metal catalysts, such as Pd/C, Pt/C, or Raney nickel in one of the above-mentioned solvents, preferably in alcohols such as methanol, ethanol, or propanol, within a temperature range of -20~C to +100~C, preferably from 0~C to +50~C, at normal pressure or elevated pressure.
As derivatizations, the following types of reactions are cited by way of examples: oxidations, reductions, hydrogenations, halogenation, Wittig reactions/Grignard reactions, and amidation/sulfoamidation.
The customary strong basic compounds can be used as auxiliary agents.
Among these are, preferably, organolithium compounds, such as n-butyllithium, sec-butyllithium, tert-butyllithium, or phenyllithium, or amides, such as lithium diisopropylamide, sodium amide, or potassium amide, or lithiurn hexamethylsilylamide, or alkali hydrides, such as sodium hydride or potassium hydride. Particularly preferably, n-butyllithium, or sodium hydride are used.
Furthermore, the customary inorganic bases are suitable bases. Among these are, ~ref~dbly, alkali hydroxides or alkaline earth hydroxides, such as sodium hydroxide, potassium hydroxide, or barium hydroxide, or aLkali carbonates, such as sodium carbonate, potassium carbonate, or sodium hydrogen carbonate. Particularly ~refelably, sodium hydroxide or potassium hydroxide are used.
Alcohols, such as methanol, ethanol, propanol, butanol, or tert-butanol, are also suitable solvents for the individual reaction steps. Tert-butanol is preferred.
It may possibly be necessary to carry out several reaction steps under a protective gas atmosphere.
The halogenation generally takes place in one of the above-mentioned chlorinated hydrocarbons, whereby methylene chloride is preferred.
Diethylamino sulfur trifluoride (DAST) or SOCl2, for example, are suitable halogenation agents.
W O 98/04528 PCTrUS97tl3248 0 The halogenation generally takes place within a temperature range of -78~C
to +50~C, preferably from -78~C to 0~C, and most preferably at -78~C, depending on the choice of both the halogenation agent and the solvent.
The halogenation generally takes place at normal pressure, but it is also possible to work at increased or reduced pressure.
The customary reagents are suitable as Wittig reagents. 3-Trifluoro-methylbenzyl triphenylphosphonium bromide is prerelled.
One of the above-mentioned bases are generally suitable as bases, ~rerelably Li-bis-(triethylbutyl)amide.
The base is introduced in a quantity ranging from 0.1 mole to 5 moles, preferably from 0.5 mole to 2 moles, relative to 1 mole of the starting compound.
The reaction using Wittig reagents is generally carried out within a temperature range of 0~C to 150~C, ~refeldbly at 25~C to 40~C.
In general, the Wittig reactions are carried out at normal pressure.
However, it is also possible to carry out the process at reduced pressure or high pressure (e.g., within a range from 0.5 to 5 bar).
Compounds of the general formula (II) in the case wherein L is other than alkoxy/cyclooxy (L') are known or can be produced by processing compounds of the general formula (IV) A
R16o2C~Co2R17 1 ~ (IV) L' N E
H
in which A, E, and L' have the above-mentioned meanings, R16 and R17 are identical or different and stand for straight-chain or branched alkyl with up to 4 carbon atoms, WO 98J'~'r~% PCTAUS97/13248 0 in inert solvents with oxidants, and selectively reducing the alkoxycarbonyl function (Co2Rl7) to the hydroxy function 5 in a second step.
Suitable solvents for the oxidation are ethers, such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylol, hexane, or cyclohexane, or petroleum fractions, or halocarbons, such 10 as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, or trichloroethylene, or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethyl formamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is likewise possible to use a mixture of said solvents. Dichloromethane is preferred.
Suitable oxidants are, for example, 2,3-dichloro-5,6-dicyanobenzoquinone, pyridinium chlorochromate (PCC), osmium tetroxide, and manganese dioxide. For the above-mentioned step, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is preferred.
The oxidant is introduced in a quantity ranging from 1 mole to 10 moles, preferably from 2 moles to 5 moles, relative to 1 mole of the compound of the general formula (IV).
The oxidation generally takes place within a temperature range of -50~C to +100~C, preferably from 0~C to room temperature.
The oxidation generally takes place at normal pressure. However, it is also possible to carry out the oxidation at increased or reduced pressure.
1,4-Dihydropyridine-3,5-dicarboxylic acid esters of the general formula (IV) are known and can be produced according to known methods.
The reaction is generally carried out at normal pressure. However, it is also - 35 possible to carry out the process at reduced pressure or high pressure (e.g., within a range of 0.5 to 5 bar).
WOg8104528 PCTrUS97/13248 0 Compounds of the general formula (II) in the case wherein L is alkoxy/cyclooxy (L') are known and can be produced by first oxidizing compounds of the general formula (V) R 1 8O2C~,CO2R t g O ~' N E
H
in which A and E have the above-mentioned meanings and R18 and R19 have the meaning given above for R16 and R17 and are identical to or different from these, with ceric(IV) ammonium nitrate into compounds of the general formula (VI) A
R1 8O2C~CO2R 19 (VI) O N E
H
in which A, E, R18, and R19 have the above-mentioned meanings, then, by reaction with alkylation agents of the general formula (VII) R20_y (VII) 25 in which R20 stands for cycloalkyl with 3 to 8 carbon atoms, or stands for straight-chain or branched alkyl with up to 8 carbon atoms, 0 and Y stands for halogen, preferably for bromine or iodine, in inert solvents and in the presence of a base, converting them into compounds of 5 the general formula (VIII) A
R 1 8O2C~CO2R 19 11 (vm R200~N~ E
in which A, E, R1~, R19, and R20 have the above-mentioned meanings, and finally, as described above, carrying out a selective reduction with diisobutylaluminum hydride of the alkoxycarbonyl group -CO2R18 to the 15 hydroxymethylene function, followed by an oxidation to the corresponding aldehyde, likewise as described above, preferably with PCC.
The individual reaction steps each take place in one of the above-mentioned solvents and/or bases; preferably, the oxidation is carried out with ceric(IV) 20 ammonium nitrate in acetonitrile, the alkylation is carried out with dimethylformamide and sodium hydride, and the reduction is carried out in toluene within a temperature range of -30~C to 100~C, at normal pressure, and, if applicable, under a protective gas atmosphere.
Compounds of the general formulas (V) and (VII) are known in and of themselves or can be produced according to the customary methods.
Compounds of the general formulas (VI) and (VIII) are known in part or are novel and can therefore be produced according to the above-mentioned process.
Compounds of the general formula (III) are novel and are produced by converting compounds of the general formula (IX) WO 98104528 PCTrUS97/13248 T~C02R2 1 1' ~ (~) o L N E
in which A, E, L, and T have the above-mentioned meanings 5 and R21 denotes a straight-chain or branched alkoxycarbonyl with up to 3 carbon atoms, 10 first by reduction of the alkoxycarbonyl function, into compounds of the general formula (Ia) A
T~,CH20 H
,L ~ (Ia) L N E
in which 15 A, E, L, and T have the above-mentioned meanings, and in a second step, oxidizing the hydroxymethyl function into the aldehyde according to the above-mentioned conditions, preferably with pyridinium chlorochromate (PCC).
The individual reaction steps are generally carried out within a temperature range of -10~C to +160~C, preferably 0~C to +100~C, and at normal pressure.
Compounds of the general formula (IX) are produced analogously to the 25 methods described above for the production of compounds of the general formula (II).
Compounds of the general formula (Ia) are also novel and can be produced as described above.
O Compounds of the general formulas (L~) and (Ia) according to the invention have an unforeseeable pharmacological spectrum of action.
Compounds of the general formulas (L~) and (Ia) according to the invention possess valuable pharmacological properties that are superior to those of the state of the art; in particular, they are highly effective inhibitors of cholesterol ester transfer proteins (CETP) and stimulate reverse cholesterol transport. The active~ compounds according to the invention cause a reduction in LDL cholesterol levels in the blood, while at the same time increasing HDL cholesterol levels. They cantherefore be used for the treatment of hyperlipoproteinemia or arteriosclerosis.
The invention additionally concerns the combination of compounds according to the invention with a glucosidase and/or amylase inhibitor for the treatment of familial hyperlipidemia, obesity (adiposis), and diabetes mellitus.Within the context of the invention, glucosidase and/or amylase inhibitors are, for example, acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose (MDL-73945), tendamistat, AI-3688, testatin, pradimicin-Q, and salbostatin.
The combination of acarbose, miglitol, emiglitate, or voglibose and one of the above-mentioned compounds of the general formula (L~) according to the invention is preferred.
The pharmacological action of the substances according to the invention was determined in the following test:
CETP Inhibition Test 1. Obtainin~ CETP
CETP is obtained in partially purified form from human plasma by difl~lelllial centrifugation and column chromatography and is used for testing. In so doing, human plasma is adjusted with NaBr to a density of 1.21 g per ml and is centrifuged for 18 h at 50,000 rpm at 4~C. The bottom fraction (d > 1.21 g/ml) is applied to a Sephadex(~) Phenyl-Sepharose 4B (Pharmacia) column, washed with 0.15 m NaCl/0.001 m TrisHCl, pH 7.4, and then eluted with dist. water. The CETP-active fractions were pooled, dialyzed against 50 mM Na acetate, pH 4.5, and applied to a CM-Sepharose~) (Pharmacia) column. They were then eluted with a WO 98/04~28 PCTAUS9?/13248 0 linear gradient (0-1 M NaCl). The pooled CETP fractions were dialyzed against 10 mM TrisHCl, pH 7.4, and were then further purified by chromatography over a Mono Q(~ column (Pharmacia).
2. Obtainins~ Radioactively Ta~ed HDL
50 ml of fresh human EDTA plasma was adjusted with NaBr to a density of 1.12 and centrifuged at 4~C for 1~ h at 50,000 rpm in the Ty 65 rotor. The upperphase was used to obtain cold LDL. The lower phase was dialyzed against 3x4 l ofPDB buffer (10 mM Tris/HCl, pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN3).
20 ~ll 3H cholesterol (Du Pont NET-725; 1 -,uC/~l dissolved in ethanol) was subsequently added per 10 ml of dialysis residue volume and incubated for 72 h at 37~C under N2 The sediment was then adjusted with NaBr to a density of 1.21 and centrifuged in the Ty 65 rotor for 18 h at 50,000 rpm at 20~C. The upper phase was obtained and the lipoprotein fractions were purified by gradient centrifugation. In so doing, the isolated, tagged lipoprotein fraction was adjusted with NaBr to a density of 1.26. Every 4 ml of this solution was covered in centrifuge tubes (SW 40 rotor) with 4 ml of a solution with a density of 1.21 and 4.5 ml of a solution with a density of 1.063 (density solutions from PDB buffer and NaBr) and then centrifuged for 24 h at 38,000 rpm and 20~C in the SW 40 rotor. The intermediate layer between the densities 1.063 and 1.21 that contained the tagged HDL was dialyzed against 3x100 volumes of PDB buffer at 4~C.
The dialysis residue contained radioactively tagged 3H-CE-HDL, which was adjusted to approx. 5X106 cpm per ml and used for the test.
3. Conductin~ the Test In order to test the CETP activity, the transfer of 3H cholesterol ester from human HD lipoproteins to biotinylated LD lipoproteins was measured.
The reaction was ended by adding Streptavidin-SPA(~) beads (Amersham), and the transferred radioactivity was determined directly in the liquid scintill~*on counter.
In the test batch, 10 ~ll HDL-3H cholesterol ester ~~ 50,000 cpm) was incubated for 18 h at 37~C with 10 ,ul biotin-LDL (Amersham) in 50 mM HEPES /
0.15 m NaCl / 0.1% bovine serum albumin / 0.05% NaN3, pH 7.4, with 10 ~Ll CETP
(1 mg/ml) and 3 ~l solution of the substance to be tested (dissolved in 10% DMSO /
W0~8'~ -~X PCTAUS97113248 0 1% BSA). Then 200 ~l of the SPA-Streptavidin bead solution (Amersham TRKQ
7005) was added, and the mixture was further incubated for 1 h under agitation and subsequently measured in the scintillation counter. Corresponding incubations with 10 ,ul buffer, 10 ~ll CETP at 4~C, and 10 ~ll CETP at 37~C served as controls.
The transferred activity in the control batches with CETP at 37~C was 5 assessed as 100% transfer. The substance concentration in which this transfer was reduced by half was indicated as an ICso value.
CETP inhibitory activity of the following compounds:
~x~ ,leNo. ICso (,uM) 7 0.6 24 1.0 Syrian golden hamsters from the company's own breeding were anesthetized after fasting for 24 h (0.80 mg/kg atropine, 0.80 mg/kg Ketavetg) s.c., 30' later 50 mg/kg Nembutal i.p.). The jugular vein was then exposed and cannulated. The test substance was dissolved in a suitable solvent (as a rule, Adalat placebo solution: 60 g glycerin, 100 ml H2O, ad 100 ml PEG-400) and administered to the animals via a PE catheter inserted into the jugular vein. The control animals received the same volume of solvent without any test substance. The vein was then ligated and the wound closed up. At different intervals--up to 24 hours after administration of the test substance--blood was drawn from the animals by 20 puncture of the retroorbital venous plexus (approx. 250 ~ll). Coagulation wascompleted by incubating at 4~C overnight, then the blood was centrifuged for 10 minutes at 6000 g. The cholesterol and triglyceride content in the serum obtained in this manner was determined using modified commercially available enzyme tests (cholesterol enzymatic 14366 Merck, triglyceride 14364 Merck). The serum was 25 diluted in a suitable manner with physiological saline solution.
100 ~l serum dilution was mixed with 100 ~l test substance in 96-hole perforated plates and incubated 10 minutes at room temperature. The optical density was then determined with an automatic plate reader at a wavelength of 492 30 nM (SLT-Spectra). The triglyceride/cholesterol concentration contained in the samples was determined using a parallel-measured standard curve.
O The determination of the HDL cholesterol content was carried out afterprecipitation of the lipuproleins containing Apo B by means of a reagent mixture(Sigma 352~ HDL cholesterol reagent) according to the manufacturer's instructions.
In alLem~ g to determine oral efficacy, the test substance, which was dissolved in DMSO and suspended in 0.5% methylcellulose, was administered orallyto Syrian golden hamsters from the company's own breeding via a pharyngeal tube. The control animals received identical volumes of solvent without any testsubstance. Feed was then withheld from the animals and blood was drawn at dirr~ t intervals--up to 24 hours after administration of the substance--via puncture of the retroorbital venous plexus. It was further processed as described above.
The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions, and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. In this connection, the therapeutically active compound should be present in each case in a concentration of about 0.5% to 90% by weight, i.e., in amounts that are sufficient to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds using solvents and /or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, organic solvents can be used, if appropriate, as auxiliary solvents.
The administration takes place in a customary manner, preferably orally or pal~nlelally~ in particular, perlingually or intravenously.
In the case of parenteral use, solutions of the active compound can be employed using suitable liquid excipients.
In general, it has proved advantageous in intravenous administration to administer amounts of about 0.001 to 1 mg/kg, ~rererably about 0.01 to 0.5 mg/kgof body weight, to attain effective results, and in oral administration, the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.
W O 981'~ PCTAUS97113248 O In spite of this, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type o~ administration route, individual behavior toward the medication, the type of formulation thereof, and the time orinterval at which administration takes place. Thus, in some cases it may be suffi~iPnt to manage with less than the minimum amount previously mentioned, whereas in other cases the upper limit mentioned must be exceeded. If larger amounts are administered, it may be advisable to divide these into several individual doses over the day.
Startin~ C~ ul-ds Example I
Diethyl 4-(4-fluorophenyl)-6-isopropyl-~lH)-pyrid-2-one-3,5-dicarboxylate H5C200C $~,cooc2H5 149 g (0.395 mmol) of diethyl 3,4-dihydro-4-(~fluorophenyl)-6-isopropyl-(lH)-pyrid-2-one-3,5-dicarboxylate is dissolved in 800 ml of acetonitrile, mixed with 475 g (0.867 mol) of ceric(IV) ammonium nitrate dissolved in 500 ml of H20, and subsequently stirred for 3 h. The aqueous phase is extracted two times with ethyl acetate. The combined ethyl acetate phases are washed with salt water, dried, and concentrated. The residue is mixed with isopropanol immediately thereafter, whereby crystallization is started by cooling with ice. The product is drawn off by suction and dried in a high vacuum.
Yield: 58.8 g (39.6% of theory) Rf = 0.5 (toluene / ethyl acetate 1:1) ~ 30 W 098/04528 PCTrUS97/13248 0 Example II
Diethyl 4-(4-fluorophenyl)-6-is~Ioyyl-2-methoxy-3,5-dicarboxylate H5C200C~,COOC2H5 1.72 mg (42.9 mmol; 1.61 eq.) of sodium hydride (60% dispersion in mineral oil) is added to 10 g (26.6 mmol) of the compound from Example I dissolved in 40 g of DMF, and the mixture is suspended in 30 ml at -20~C. Afterwards, the suspension is heated to +30~C, 3.3 ml (53.2 mmol; 2 eq.) of methyl iodide is added, and it is heated for 2.5 hours to 80~C -100~C. The reaction solution is mixed with 500 ml ethyl acetate and 300 ml H2O, and the aqueous layer is separated off and extracted one time with ethyl acetate. The combined ethyl acetate phases are washed with water and saline solution, dried, and concentrated. The crude product is dissolved in 20 ml of toluene and chromatographed over 200 ml of silica gel 60 using toluene 15 as the eluant.
Yield: 10 g (96.4% of theory) Rf = 0.28 (toluene) Example III
Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxy-3-hydroxymethyl-pyridine-5-carboxylate HO ¢~
~COOc2H5 H3CO N~
W O ~8/'~'28 PCTrUS97/13248 500 mg (1.284 mmol) of the compound from Example II in 40 g of toluene p.a. is mixed under argon at -78~C with 3.21 ml (3.852 mmol) of diisobutylaluminum hydride (DIBAL-H, 1.2 molar in toluene). The mixture is stirred 30 min at -78~C, and the batch is allowed to stand overnight at -30~C in the 5 refrigerator. It is further cooled to -70~C, 20% potassium sodium tartrate solution is added, and the mixture is extracted with ethyl acetate. The organic layer is dried with Na2SO~ and concentrated.
Yield: 287 mg (64.5% of theory) Rf = 0.41 (toluene / ethyl acetate 9:1) Example IV
Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxy-3-formyl-pyridine-5-carboxylate OHC~b,COOc2H5 H3CO N~
F ~ H3 D~ b F
F
F ~ OH
~'1~'",~
b o CA 02262434 l999-0l-28 W 098/04528 PCTrUS97/13248 O H C~COOC2H5 n-BuLi\ F
'~ ~
~N H0 ~J
1 J~COOC2H5 CH30 N '~/
dehydration /
PTS /
~/ F
N ~
~0 ~ ~ COOC2H5 CH30 N ~ F
DIBAL-~ ,J~, ~,J
o Suitable solvents are ethers, such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, or cyclohexane, or petroleum fractions, or halocarbons, such as 5 dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, or trichloroethylene, or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, - dimethyl sulfoxide, dimethyl formamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is likewise possible to use mixtures of said solvents. Dichloromethane is preferred.
W 098104528 PCTrUS97113248 Suitable organometallic reagents are systems such as Mg/bromobenzene trifluoride and p-trifluoromethylphenyllithium. The Mgtbromobenzene trifluoride system is preferred.
The reductions and derivatizations are carried out according to the above-mentioned methods.
In general, the reductions are carried out in ethers, such as dioxane, tetrahydrofuran, or diethyl ether, or in hydrocarbons, such as benzene, hexane, or toluene. Toluene and tetrahydrofuran arepreferred.
Suitable reductants are complex metal hydrides, such as lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutylaluminum hydride, dimethoxymethylaluminate sodium salt, or sodium-1~ bis-(2-methoxyethoxy)-dihydroaluminate (Red-Al). Diisobutyl-aluminum hydride and dimethoxymethylaluminate sodium salt are preferred.
The reductant is generally added in a quantity ranging from 4 moles to 10 moles, preferably from 4 moles to 5 moles, relative to 1 mole of the compound tobe reduced.
The reduction generally takes place within a temperature range of -78~C to +50~C, preferably from -78~C to O~C, and most preferably at -78~C, depending on the choice of both the reductant and the solvent.
The reduction generally takes place at normal pressure, but it is also possible to work at increased or reduced pressure.
However, the reductions can also be carried out with reductants that are suitable for the reduction of ketones to hydroxy compounds. Particularly suitable in this regard is reduction using metal hydrides or complex metal hydrides in inert solvents, if a~pro~riate in the presence of a trialkyl borane. Preferably, the reduction is carried out using complex metal hydrides, such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkyl borohydride, or lithium aluminum hydride. More particularly preferably, the reduction is carried out using sodium borohydride in the presence of triethylborane .
W O~ 2~ PCTrUS97113248 The reaction can also take place via hydrogenation. The hydrogenation takes place according to the customary methods using hydrogen in the presence ofnoble metal catalysts, such as Pd/C, Pt/C, or Raney nickel in one of the above-mentioned solvents, preferably in alcohols such as methanol, ethanol, or propanol, within a temperature range of -20~C to +100~C, preferably from 0~C to +50~C, at normal pressure or elevated pressure.
As derivatizations, the following types of reactions are cited by way of examples: oxidations, reductions, hydrogenations, halogenation, Wittig reactions/Grignard reactions, and amidation/sulfoamidation.
The customary strong basic compounds can be used as auxiliary agents.
Among these are, preferably, organolithium compounds, such as n-butyllithium, sec-butyllithium, tert-butyllithium, or phenyllithium, or amides, such as lithium diisopropylamide, sodium amide, or potassium amide, or lithiurn hexamethylsilylamide, or alkali hydrides, such as sodium hydride or potassium hydride. Particularly preferably, n-butyllithium, or sodium hydride are used.
Furthermore, the customary inorganic bases are suitable bases. Among these are, ~ref~dbly, alkali hydroxides or alkaline earth hydroxides, such as sodium hydroxide, potassium hydroxide, or barium hydroxide, or aLkali carbonates, such as sodium carbonate, potassium carbonate, or sodium hydrogen carbonate. Particularly ~refelably, sodium hydroxide or potassium hydroxide are used.
Alcohols, such as methanol, ethanol, propanol, butanol, or tert-butanol, are also suitable solvents for the individual reaction steps. Tert-butanol is preferred.
It may possibly be necessary to carry out several reaction steps under a protective gas atmosphere.
The halogenation generally takes place in one of the above-mentioned chlorinated hydrocarbons, whereby methylene chloride is preferred.
Diethylamino sulfur trifluoride (DAST) or SOCl2, for example, are suitable halogenation agents.
W O 98/04528 PCTrUS97tl3248 0 The halogenation generally takes place within a temperature range of -78~C
to +50~C, preferably from -78~C to 0~C, and most preferably at -78~C, depending on the choice of both the halogenation agent and the solvent.
The halogenation generally takes place at normal pressure, but it is also possible to work at increased or reduced pressure.
The customary reagents are suitable as Wittig reagents. 3-Trifluoro-methylbenzyl triphenylphosphonium bromide is prerelled.
One of the above-mentioned bases are generally suitable as bases, ~rerelably Li-bis-(triethylbutyl)amide.
The base is introduced in a quantity ranging from 0.1 mole to 5 moles, preferably from 0.5 mole to 2 moles, relative to 1 mole of the starting compound.
The reaction using Wittig reagents is generally carried out within a temperature range of 0~C to 150~C, ~refeldbly at 25~C to 40~C.
In general, the Wittig reactions are carried out at normal pressure.
However, it is also possible to carry out the process at reduced pressure or high pressure (e.g., within a range from 0.5 to 5 bar).
Compounds of the general formula (II) in the case wherein L is other than alkoxy/cyclooxy (L') are known or can be produced by processing compounds of the general formula (IV) A
R16o2C~Co2R17 1 ~ (IV) L' N E
H
in which A, E, and L' have the above-mentioned meanings, R16 and R17 are identical or different and stand for straight-chain or branched alkyl with up to 4 carbon atoms, WO 98J'~'r~% PCTAUS97/13248 0 in inert solvents with oxidants, and selectively reducing the alkoxycarbonyl function (Co2Rl7) to the hydroxy function 5 in a second step.
Suitable solvents for the oxidation are ethers, such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylol, hexane, or cyclohexane, or petroleum fractions, or halocarbons, such 10 as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, or trichloroethylene, or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethyl formamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is likewise possible to use a mixture of said solvents. Dichloromethane is preferred.
Suitable oxidants are, for example, 2,3-dichloro-5,6-dicyanobenzoquinone, pyridinium chlorochromate (PCC), osmium tetroxide, and manganese dioxide. For the above-mentioned step, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is preferred.
The oxidant is introduced in a quantity ranging from 1 mole to 10 moles, preferably from 2 moles to 5 moles, relative to 1 mole of the compound of the general formula (IV).
The oxidation generally takes place within a temperature range of -50~C to +100~C, preferably from 0~C to room temperature.
The oxidation generally takes place at normal pressure. However, it is also possible to carry out the oxidation at increased or reduced pressure.
1,4-Dihydropyridine-3,5-dicarboxylic acid esters of the general formula (IV) are known and can be produced according to known methods.
The reaction is generally carried out at normal pressure. However, it is also - 35 possible to carry out the process at reduced pressure or high pressure (e.g., within a range of 0.5 to 5 bar).
WOg8104528 PCTrUS97/13248 0 Compounds of the general formula (II) in the case wherein L is alkoxy/cyclooxy (L') are known and can be produced by first oxidizing compounds of the general formula (V) R 1 8O2C~,CO2R t g O ~' N E
H
in which A and E have the above-mentioned meanings and R18 and R19 have the meaning given above for R16 and R17 and are identical to or different from these, with ceric(IV) ammonium nitrate into compounds of the general formula (VI) A
R1 8O2C~CO2R 19 (VI) O N E
H
in which A, E, R18, and R19 have the above-mentioned meanings, then, by reaction with alkylation agents of the general formula (VII) R20_y (VII) 25 in which R20 stands for cycloalkyl with 3 to 8 carbon atoms, or stands for straight-chain or branched alkyl with up to 8 carbon atoms, 0 and Y stands for halogen, preferably for bromine or iodine, in inert solvents and in the presence of a base, converting them into compounds of 5 the general formula (VIII) A
R 1 8O2C~CO2R 19 11 (vm R200~N~ E
in which A, E, R1~, R19, and R20 have the above-mentioned meanings, and finally, as described above, carrying out a selective reduction with diisobutylaluminum hydride of the alkoxycarbonyl group -CO2R18 to the 15 hydroxymethylene function, followed by an oxidation to the corresponding aldehyde, likewise as described above, preferably with PCC.
The individual reaction steps each take place in one of the above-mentioned solvents and/or bases; preferably, the oxidation is carried out with ceric(IV) 20 ammonium nitrate in acetonitrile, the alkylation is carried out with dimethylformamide and sodium hydride, and the reduction is carried out in toluene within a temperature range of -30~C to 100~C, at normal pressure, and, if applicable, under a protective gas atmosphere.
Compounds of the general formulas (V) and (VII) are known in and of themselves or can be produced according to the customary methods.
Compounds of the general formulas (VI) and (VIII) are known in part or are novel and can therefore be produced according to the above-mentioned process.
Compounds of the general formula (III) are novel and are produced by converting compounds of the general formula (IX) WO 98104528 PCTrUS97/13248 T~C02R2 1 1' ~ (~) o L N E
in which A, E, L, and T have the above-mentioned meanings 5 and R21 denotes a straight-chain or branched alkoxycarbonyl with up to 3 carbon atoms, 10 first by reduction of the alkoxycarbonyl function, into compounds of the general formula (Ia) A
T~,CH20 H
,L ~ (Ia) L N E
in which 15 A, E, L, and T have the above-mentioned meanings, and in a second step, oxidizing the hydroxymethyl function into the aldehyde according to the above-mentioned conditions, preferably with pyridinium chlorochromate (PCC).
The individual reaction steps are generally carried out within a temperature range of -10~C to +160~C, preferably 0~C to +100~C, and at normal pressure.
Compounds of the general formula (IX) are produced analogously to the 25 methods described above for the production of compounds of the general formula (II).
Compounds of the general formula (Ia) are also novel and can be produced as described above.
O Compounds of the general formulas (L~) and (Ia) according to the invention have an unforeseeable pharmacological spectrum of action.
Compounds of the general formulas (L~) and (Ia) according to the invention possess valuable pharmacological properties that are superior to those of the state of the art; in particular, they are highly effective inhibitors of cholesterol ester transfer proteins (CETP) and stimulate reverse cholesterol transport. The active~ compounds according to the invention cause a reduction in LDL cholesterol levels in the blood, while at the same time increasing HDL cholesterol levels. They cantherefore be used for the treatment of hyperlipoproteinemia or arteriosclerosis.
The invention additionally concerns the combination of compounds according to the invention with a glucosidase and/or amylase inhibitor for the treatment of familial hyperlipidemia, obesity (adiposis), and diabetes mellitus.Within the context of the invention, glucosidase and/or amylase inhibitors are, for example, acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose (MDL-73945), tendamistat, AI-3688, testatin, pradimicin-Q, and salbostatin.
The combination of acarbose, miglitol, emiglitate, or voglibose and one of the above-mentioned compounds of the general formula (L~) according to the invention is preferred.
The pharmacological action of the substances according to the invention was determined in the following test:
CETP Inhibition Test 1. Obtainin~ CETP
CETP is obtained in partially purified form from human plasma by difl~lelllial centrifugation and column chromatography and is used for testing. In so doing, human plasma is adjusted with NaBr to a density of 1.21 g per ml and is centrifuged for 18 h at 50,000 rpm at 4~C. The bottom fraction (d > 1.21 g/ml) is applied to a Sephadex(~) Phenyl-Sepharose 4B (Pharmacia) column, washed with 0.15 m NaCl/0.001 m TrisHCl, pH 7.4, and then eluted with dist. water. The CETP-active fractions were pooled, dialyzed against 50 mM Na acetate, pH 4.5, and applied to a CM-Sepharose~) (Pharmacia) column. They were then eluted with a WO 98/04~28 PCTAUS9?/13248 0 linear gradient (0-1 M NaCl). The pooled CETP fractions were dialyzed against 10 mM TrisHCl, pH 7.4, and were then further purified by chromatography over a Mono Q(~ column (Pharmacia).
2. Obtainins~ Radioactively Ta~ed HDL
50 ml of fresh human EDTA plasma was adjusted with NaBr to a density of 1.12 and centrifuged at 4~C for 1~ h at 50,000 rpm in the Ty 65 rotor. The upperphase was used to obtain cold LDL. The lower phase was dialyzed against 3x4 l ofPDB buffer (10 mM Tris/HCl, pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN3).
20 ~ll 3H cholesterol (Du Pont NET-725; 1 -,uC/~l dissolved in ethanol) was subsequently added per 10 ml of dialysis residue volume and incubated for 72 h at 37~C under N2 The sediment was then adjusted with NaBr to a density of 1.21 and centrifuged in the Ty 65 rotor for 18 h at 50,000 rpm at 20~C. The upper phase was obtained and the lipoprotein fractions were purified by gradient centrifugation. In so doing, the isolated, tagged lipoprotein fraction was adjusted with NaBr to a density of 1.26. Every 4 ml of this solution was covered in centrifuge tubes (SW 40 rotor) with 4 ml of a solution with a density of 1.21 and 4.5 ml of a solution with a density of 1.063 (density solutions from PDB buffer and NaBr) and then centrifuged for 24 h at 38,000 rpm and 20~C in the SW 40 rotor. The intermediate layer between the densities 1.063 and 1.21 that contained the tagged HDL was dialyzed against 3x100 volumes of PDB buffer at 4~C.
The dialysis residue contained radioactively tagged 3H-CE-HDL, which was adjusted to approx. 5X106 cpm per ml and used for the test.
3. Conductin~ the Test In order to test the CETP activity, the transfer of 3H cholesterol ester from human HD lipoproteins to biotinylated LD lipoproteins was measured.
The reaction was ended by adding Streptavidin-SPA(~) beads (Amersham), and the transferred radioactivity was determined directly in the liquid scintill~*on counter.
In the test batch, 10 ~ll HDL-3H cholesterol ester ~~ 50,000 cpm) was incubated for 18 h at 37~C with 10 ,ul biotin-LDL (Amersham) in 50 mM HEPES /
0.15 m NaCl / 0.1% bovine serum albumin / 0.05% NaN3, pH 7.4, with 10 ~Ll CETP
(1 mg/ml) and 3 ~l solution of the substance to be tested (dissolved in 10% DMSO /
W0~8'~ -~X PCTAUS97113248 0 1% BSA). Then 200 ~l of the SPA-Streptavidin bead solution (Amersham TRKQ
7005) was added, and the mixture was further incubated for 1 h under agitation and subsequently measured in the scintillation counter. Corresponding incubations with 10 ,ul buffer, 10 ~ll CETP at 4~C, and 10 ~ll CETP at 37~C served as controls.
The transferred activity in the control batches with CETP at 37~C was 5 assessed as 100% transfer. The substance concentration in which this transfer was reduced by half was indicated as an ICso value.
CETP inhibitory activity of the following compounds:
~x~ ,leNo. ICso (,uM) 7 0.6 24 1.0 Syrian golden hamsters from the company's own breeding were anesthetized after fasting for 24 h (0.80 mg/kg atropine, 0.80 mg/kg Ketavetg) s.c., 30' later 50 mg/kg Nembutal i.p.). The jugular vein was then exposed and cannulated. The test substance was dissolved in a suitable solvent (as a rule, Adalat placebo solution: 60 g glycerin, 100 ml H2O, ad 100 ml PEG-400) and administered to the animals via a PE catheter inserted into the jugular vein. The control animals received the same volume of solvent without any test substance. The vein was then ligated and the wound closed up. At different intervals--up to 24 hours after administration of the test substance--blood was drawn from the animals by 20 puncture of the retroorbital venous plexus (approx. 250 ~ll). Coagulation wascompleted by incubating at 4~C overnight, then the blood was centrifuged for 10 minutes at 6000 g. The cholesterol and triglyceride content in the serum obtained in this manner was determined using modified commercially available enzyme tests (cholesterol enzymatic 14366 Merck, triglyceride 14364 Merck). The serum was 25 diluted in a suitable manner with physiological saline solution.
100 ~l serum dilution was mixed with 100 ~l test substance in 96-hole perforated plates and incubated 10 minutes at room temperature. The optical density was then determined with an automatic plate reader at a wavelength of 492 30 nM (SLT-Spectra). The triglyceride/cholesterol concentration contained in the samples was determined using a parallel-measured standard curve.
O The determination of the HDL cholesterol content was carried out afterprecipitation of the lipuproleins containing Apo B by means of a reagent mixture(Sigma 352~ HDL cholesterol reagent) according to the manufacturer's instructions.
In alLem~ g to determine oral efficacy, the test substance, which was dissolved in DMSO and suspended in 0.5% methylcellulose, was administered orallyto Syrian golden hamsters from the company's own breeding via a pharyngeal tube. The control animals received identical volumes of solvent without any testsubstance. Feed was then withheld from the animals and blood was drawn at dirr~ t intervals--up to 24 hours after administration of the substance--via puncture of the retroorbital venous plexus. It was further processed as described above.
The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions, and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. In this connection, the therapeutically active compound should be present in each case in a concentration of about 0.5% to 90% by weight, i.e., in amounts that are sufficient to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds using solvents and /or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, organic solvents can be used, if appropriate, as auxiliary solvents.
The administration takes place in a customary manner, preferably orally or pal~nlelally~ in particular, perlingually or intravenously.
In the case of parenteral use, solutions of the active compound can be employed using suitable liquid excipients.
In general, it has proved advantageous in intravenous administration to administer amounts of about 0.001 to 1 mg/kg, ~rererably about 0.01 to 0.5 mg/kgof body weight, to attain effective results, and in oral administration, the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.
W O 981'~ PCTAUS97113248 O In spite of this, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type o~ administration route, individual behavior toward the medication, the type of formulation thereof, and the time orinterval at which administration takes place. Thus, in some cases it may be suffi~iPnt to manage with less than the minimum amount previously mentioned, whereas in other cases the upper limit mentioned must be exceeded. If larger amounts are administered, it may be advisable to divide these into several individual doses over the day.
Startin~ C~ ul-ds Example I
Diethyl 4-(4-fluorophenyl)-6-isopropyl-~lH)-pyrid-2-one-3,5-dicarboxylate H5C200C $~,cooc2H5 149 g (0.395 mmol) of diethyl 3,4-dihydro-4-(~fluorophenyl)-6-isopropyl-(lH)-pyrid-2-one-3,5-dicarboxylate is dissolved in 800 ml of acetonitrile, mixed with 475 g (0.867 mol) of ceric(IV) ammonium nitrate dissolved in 500 ml of H20, and subsequently stirred for 3 h. The aqueous phase is extracted two times with ethyl acetate. The combined ethyl acetate phases are washed with salt water, dried, and concentrated. The residue is mixed with isopropanol immediately thereafter, whereby crystallization is started by cooling with ice. The product is drawn off by suction and dried in a high vacuum.
Yield: 58.8 g (39.6% of theory) Rf = 0.5 (toluene / ethyl acetate 1:1) ~ 30 W 098/04528 PCTrUS97/13248 0 Example II
Diethyl 4-(4-fluorophenyl)-6-is~Ioyyl-2-methoxy-3,5-dicarboxylate H5C200C~,COOC2H5 1.72 mg (42.9 mmol; 1.61 eq.) of sodium hydride (60% dispersion in mineral oil) is added to 10 g (26.6 mmol) of the compound from Example I dissolved in 40 g of DMF, and the mixture is suspended in 30 ml at -20~C. Afterwards, the suspension is heated to +30~C, 3.3 ml (53.2 mmol; 2 eq.) of methyl iodide is added, and it is heated for 2.5 hours to 80~C -100~C. The reaction solution is mixed with 500 ml ethyl acetate and 300 ml H2O, and the aqueous layer is separated off and extracted one time with ethyl acetate. The combined ethyl acetate phases are washed with water and saline solution, dried, and concentrated. The crude product is dissolved in 20 ml of toluene and chromatographed over 200 ml of silica gel 60 using toluene 15 as the eluant.
Yield: 10 g (96.4% of theory) Rf = 0.28 (toluene) Example III
Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxy-3-hydroxymethyl-pyridine-5-carboxylate HO ¢~
~COOc2H5 H3CO N~
W O ~8/'~'28 PCTrUS97/13248 500 mg (1.284 mmol) of the compound from Example II in 40 g of toluene p.a. is mixed under argon at -78~C with 3.21 ml (3.852 mmol) of diisobutylaluminum hydride (DIBAL-H, 1.2 molar in toluene). The mixture is stirred 30 min at -78~C, and the batch is allowed to stand overnight at -30~C in the 5 refrigerator. It is further cooled to -70~C, 20% potassium sodium tartrate solution is added, and the mixture is extracted with ethyl acetate. The organic layer is dried with Na2SO~ and concentrated.
Yield: 287 mg (64.5% of theory) Rf = 0.41 (toluene / ethyl acetate 9:1) Example IV
Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxy-3-formyl-pyridine-5-carboxylate OHC~b,COOc2H5 H3CO N~
21.3 g (0.0988 mol, 3.8 eq.) of pyridinium chlorochromate (PCC) is added to a solution of 9.07 g (0.026 mol) of the compound from Example m in 400 ml CH2Cl2 in the presence of neutral Al2O3 (10.07 g = 0.0988 mol), and the mixture is stirred 20 for 1 h at room temperature. It is drawn off by suction over silica gel and subsequently washed with CH2Cl2, then the filtrate is concentrated in a vacuum and chromatographed on silica gel 60 (500 ml) using toluene / ethyl acetate (8:2).
Yield: 8.88 g (98.4% of theory) Rf = 0.62 (toluene / ethyl acetate 9:1) O l~dlllylC V
Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxy-3-[2-(benzoxazol-2-yl)-1-hydroxy-ethyl]-pyridine-5-carboxylate N Otl¢~
¢~oJ~,COOC2H5 C H30 N ~
400 mg (3 mmol) of 2-methylbenzoxazole dissolved in 5 g THF p.a. is cooled under argon to -78~C. 1.83 ml (3 mmol) of n-butyllithium (1.6 molar in hexane) is added to this, and the mixture is stirred for 120 min at -78~C. 1.036 g (3 mmol) of the compound from Example IV is then added by drops at -78~C; the mixture ~s 10 stirred for 10 min at -78~C and overnight until it reaches room temperature. After adding 50 ml of water, it is extracted by shaking with 100 ml of ethyl acetate. The aqueous phase is separated off, washed two times with saline solution, dried over Na2SO4, and concentrated. The residue is chromatographed on 60 ml of silica gel using toluene and toluene / ethyl acetate (8:2). The concentrated fractions are dried 15 in a high vacuum.
Yield: 450 mg (31.4% of theory) Rf = 0.22 (toluene / ethyl acetate 9:1) Example VI
Ethyl 4-(4-fluorophenyl)-~isopropyl-2-methoxy-3-[2-(benzoxazol-2-yl)-ethenyl]-pyridine-5-carboxylate F
~OC2H5 WO 98/04528 PCTrUS97/13248 0 100 mg (0.209 mmol) of the compound from Example V is boiled in 10 g toluene p.a. under argon in the presence of 25 mg (0.131 mmol) of p-toluenesulfonic acid hydrate for 6 h under reflux, and afterwards the mixture isstirred at room temperature overnight. The reaction solution is then applied to a column filled with 40 ml of silica gel and consecutively eluted with toluene andtoluene / ethyl acetate (9.5:0.5). The desired fractions are concentrated and dried in a high vacuum.
- Yield: 91 mg (94.6% of theory) Rf = 0.59 (toluene / ethyl acetate 9:1) Example VII
Diethyl 1,~dihydro-2,6-diisopropyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylate H5C20 oC~,COOC2H5 ~N~
528 g (2 mol) of (E/Z)-4-carboxymethyl-5-(4-fluorophenyl)-2-methyl-pent-4-en-3-one and 350 g (2 mol) of 90% ethyl 3-amino-4-methyl-pent-2-enoate are stirred in 1800 ml ethanediol overnight at a bath temperature of 200~C. The mixture is cooled slowly and poured into a large glass beaker at approx. 80~C. After further cooling to 0~C, the solution is drawn off by suction from the precipitated sediment, then the sediment is washed well with ice cold ethanol and dried in a desiccator.
The ethanol solution is concellLldled~ and the residue together with the ethanediol mother liquor is extracted four times with 1.5 l ether each time. The combined ether phases are washed three times each with 500 ml of 10% hydrochloric acid and once each with 500 ml of saturated sodium hydrogen carbonate solution and water,dried over magnesium sulfate, filtered, and allowed to stand overnight at room temperature. The solution is drawn off by suction from the precipitated sediment, - subsequently washed with ice cold ethanol, and dried in a desiccator. The ethanol solution and the ether mother liquor are concentrated together in a vacuum to a W O 98101~2~ PCTrUS97/13248 0 volume of approx. 2 l, allowed to stand overnight again, and drawn off by suction from the precipitated sediment.
Total yield: 556.9 g (69.1% of theory) 1H-NMR (CDCl3): ~ = 1.1 - 1.3 (m, 18H); 4.05 - 4.25 (m, 6H); 5.0 (s, lH); 6.13 (s, lH); 6.88 (m, 20H); 7.2 (m, 2H) ppm.
Example VIII
Diethyl 2,6-diisopropyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate ¢~
H5C200C~COOC2H5 \~ N~
171.7 g (0.757 mol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone is added to a solution of 304.8 g (0.757 mol) of the compound from Example VII in 2 l of dichloromethane, and the mixture is stirred overnight at room temperature. The 15 mixture is drawn off by suction over diatomaceous earth and subsequently washed well with dichloromethane. After concentration of the dichloromethane phase to avolume of approx. 800 ml, it is chromatographed on a column (2 kg of silica gel 70-230 mesh) with dichloromethane.
Yield: 222 g (73.4% of theory) lH-NMR (CDCl3): ~ = 0.98 (t, 6H); 1.41 (d, 12H); 3.1 (m, 2H); 4.11 (q, 4H);
7.04 (m, 2H); 7.25 (m, 2H) ppm.
WO 3~ 7~ PCTrUS97/13248 0 Example IX
Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-hydroxymethylpyridine-5-carboxylate ¢~
H o~cooc2H5 ~' ~
257 ml (0.9 mol) of a 3.5 molar solution of sodium-bis-(2-methoxy-ethoxy)dihydroaluminate is steadily added by drops under nitrogen to a solution of 120 g (0.3 mol) of the compound from Example VIII in 800 ml of dried tetrahydrofuran at room temperature, and the mixture is subsequently stirred for 5 10 h. After cooling to 0~C, 500 ml of water is carefully added by drops, the phases are separated, and the aqueous phase is extracted three times with 250 ml ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated in a vacuum. Theresidue is mixed with petroleum ether, drawn off by suction, and dried in a 15 desiccator.
Yield: 69.1 g (64.2% of theory) 1H-NMR (CDCl3): ~ = 0.95 (t, 3H); 1.31 (m, 12H); 3.05 (m, lH); 3.48 (m, lH);
3.95 (q, 2H); 4.93 (d, 2H); 7.05 - 7.31 (m, 4H) ppm.
20 Example X
Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-formyl-pyridine-5-carboxylate OHC~,COOC2H5 WO 98104528 PCTrUS97/13248 0 14.18 g (0.139 mol) of neutral Al2O3 and 29.96 g (0.13 mol) of pyridinium ch}orochromate (PCC) are added to a solution of 25.0 g (0.0695 mol) of the compound from Example IX in 500 ml CH2Cl2 and the mixture is stirred for 1 h at room temperature. It is drawn off by suction over silica gel and subsequently washed with CH2Cl2, and the filtrate is concentrated in a vacuum, whereby the product precipitates out.
Yield: 20 g (80.48% of theory) lH-NMR (DMSO-d6): ~ = 0.92 (t, 3H); 1.39 (dd, 6H); 3.02 - 3.13 (m, lH); 3.75 -3.86 (m, lH); 3.95 - 4.05 (q, 2H); 7.32 (m, 4H); 9.8 (s, lH) ppm.
Example XI
Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-[(4-fluorophenyl)hydroxymethyl]-pyridine-5-carboxylate HO ~J
~ 3. ~ oc2H5 10.0 g (27.98 mmol) of aldehyde from Example X is cooled to -70~C in 100 g THF p.a. under argon, 33.6 ml (33.58 mmol, 1.2 eq.) of p-fluorophenyl magnesium bromide solution is added by drops at -70~C, and the mixture is then stirred foranother 2 h at -70~C. The reaction solution is mixed with 200 ml of conc. NH4Cl solution, the cooling bath is removed, and the solution is adjusted with 1 molarHCl, pH = 6. After extraction with 400 ml of CH2Cl2 and drying over Na2SO4, the organic phase is concentrated in a vacuum and the rigid foam is crystallized using n-heptane.
Yield: 8.97 g (70.7% of theory) Rf = 0.18 (toluene) 0 Example XII
Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-[(4-fluorophenyl)-chloromethyl]-pyridine-5-carboxylate Cl ¢~
F {~l OC2H5 907 mg (2 mmol) of the compound from Example XI is dissolved in 20 g of CH2C12 p.a. and cooled under argon at -40~C, and 0.44 ml (6 mmol) SOC12 are added. The solution is stirred for 1.5 h from -40~C to -5~C and afterwards agitated in 50 ml of ethyl acetate / 40 ml of NaHC03 solution. The organic phase is separated off, dried over Na2SO4, concentrated in a vacuum, and chromatographed on diatomaceous earth using toluene.
Yield: 89g mg (95% of theory) Rf - 0.79 (toluene) Example XIII
3-Ethyl 5-methyl 3,4-dihydro-4-(4-fluorophenyl)-6-p-fluorophenyl-(lH)-pyrid-2-20 one-3,5-dicarboxylate H5C200C~,COOCH3 O N~
H ~F
W098t04528 PCTrUS97113248 30.69 g (115.3 mmol) of ethyl 1-carboethoxy-2-(4-fluorophenyl)-propenate, 22.5 g (115.3 mmol) of methyl 3-amino-3-(4-fluorophenyl)-acrylate, 115 mg of sodium methylate, and 0.6 ml of ethanol are stirred for 48 h at a bath temperature of 140~C. The reaction mixture is absorbed in ethyl acetate, washed three times 5 with water, dried over Na2SO4, and concentrated in a vacuum.
Yield: 43.2 g (90.2% of theory) Rf = 0.26 (toluene / ethyl acetate 9:1) Example XIV
3-Ethyl 5-methyl 4-(4-fluorophenyl)-6-p-fluorophenyl-(lH)-pyrid-2-one-3,5-dicarboxylate H5C200C~,COOCH3 H ~ F
Analogously to Example I, 1.00 g (0.2407 mol) of the compound from Example XIII is stirred with 277 g (0.506 mol) of ceric(IV) ammonium nitrate in 600 ml of acetonitrile and 600 ml of water for 3 h at room temperature. After extraction with ethyl acetate, the residue is crystallized from isopropanol.
Yield: 28.59 g (28.7% of theory) Rf = 0.16 (toluene / ethyl acetate 8:2) WO 98/0~528PCT~US9711~248 O I~xa,~,ylc XV
3-Ethyl 5-methyl4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3,5-dicarboxylate ¢~
H5C200C~,~ ~,COOCH3 O J'N ~
Following the instructions in Example II, 5.0 g (0.0121 mol) of the mixture from Example XIV in 20 ml of DMF is reacted in the presence of 0.783 g (0.0196 mol) of 60% NaH with 3.61 g (0.0242 mol) of cyclopentyl bromide. After chromatography on silica gel using toluene, 5.14 g (88.3% of theory) is obtained.
Rf = 0.34 (toluene) Example XVI
Methyl 4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-hydroxymethyl-15 pyridine-5-carboxylate HO ¢~
~COOCH3 1' ~
Analogously to Example IIl, 3.719 g (7.72 mmol) of the compound from Example XV in 150 g of toluene is stirred with 11.58 ml (11.58 mmol) of DIBAL-H
WO 98104528 PCT~US97113248 O (1.0 molar) for 2.5 h at -78~C. The compound is chromatographed on silica gel first with toluene and then with toluene / ethyl acetate (9:1).
Yield: 1.648 g (48.5% of theory) Rf = 0.45 (toluene / ethyl acetate 9:1) 5 Example XVII
Methyl 4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-formyl-pyridine-5-carboxylate ~ ~i Following the instructions in Example IV, 1.636 g (3.72 mmol) of the compound from Example XVI in 150 ml of CH2Cl2 is stirred with 0.759 g (7.44 mmol) of Al2O3 (neutral) and 1.604 g (7.44 mmol) of PCC for 1.5 h. The crude product is purified by chromatography on silica gel using toluene.
Yield: 1.484 g (91.2% of theory) Rf = 0.59 (toluene / ethyl acetate 9:1) Example XVIII
Methyl 4-t4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-[(naphthyl-2)-hydroxy-methyl]-pyridine-5-carboxylate , . .. ... .. .
W098/04528 PCT~US97113248 H O '~i J
0 ~ F
53.4 mg (2.2 mmol) of magnesium shavings is heated to reflux in 10 ml of THF p.a. under argon. 313 mg (1.51 mmol) of 2-bromonaphthalene dissolved in 15 ml of THF is added to this and the solution is boiled 75 min to reflux in the presence of iodine crystals (= Grignard reagent). 220 mg (0.503 mmol) of the compound from Example XVII is dissolved in 5 ml of THF p.a. and cooled under argon to -70~C, and the Grignard reagent is sprayed in. The batch is subsequently stirred for one hour without cooling. The reaction solution is distributed in ethyl acetate /
ammonium chloride solution, and the organic phase is separated off, washed with NaCl solution, dried, and concentrated. Chromatography is then carried out on silica gel using toluene.
Yield: 261 mg (91.9% of theory) Rf - 0.57 (toluene / ethyl acetate 9:1) Example XIX
Methyl 4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-[(naphthyl-2)-fluoromethyl] -pyridine-5-carboxylate F
' ' r~ H~
W 098/04528 PCTrUS97/13248 0.08 mmol (0.60Z mmol) of diethylamino sulfur trifluoride (DAST) is added to a solution of 227 mg (0.401 mmol) of the compound from Example XVIII in 10 g of CH2Cl2 at -40~C under argon, the cooling bath is removed, and the solution is stirred for 20 min. The reaction solution is subsequently distributed in ethyl acetate 5 / NaHCO3 solution, and the organic layer is dried with Na2SO4 and concentrated in a vacuum. The crude product is chromatographed on silica gel using toluene.
Yield: 224 mg (98.6% of theory) Rf = 0.67 (toluene) Production Examples Example 1 2,6-Diisopropyl-3-p-fluorobenzyl-4-p-fluorophenyl-5-hydroxymethyl-pyridine F
T " I
5.7 g (150 mmol) of LiAlH4 are suspended in 200 ml of THF, heated to 80~C, and mixed by drops with a solution of 23.7 g of the compound from Example XII in150 ml of THF. After being stirred for 5 h, the mixture is cooled, carefully neutralized with 20% Na-K-tartrate solution, and extracted three times with ethyl acetate, and the organic phase is dried, concentrated, and chromatographed over silica gel 60 (toluene).
Yield: 13.6 g (69% of theory) Rf = 0.59 (toluene / ethyl acetate = 9/1) WO 98/04528 PCTIUS97113~48 O The compounds listed in Table 1(A) are produced in analogy to the instructions in Example I:
Table 1(A):
Ex. G Rf Solvent No.
2 OH 0.60 toluene /
J CH ethyl acetate 3 9:1 3 OH 0.74 toluene /
~,CH3 ethyl acetate 9:1 4 OH 0.75 toluene /
~CH3 ethyl acetate 9:1 WO ~ PCT~US97/13248 O ~:x~ le 5 ~(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-[(naphthyl-2)-fluoromethyl]-5-hydroxymethyl-pyridine Cl ~1 O~l ~ F
Analogously to the instructions of Example 1, 182 mg (0.321 mmol) of the compound from Example XIX in 10 ml of THF p.a. is boiled with 18.3 mg (0.481 mmol) of LiAlH4 for 1 h under reflux. The compound is purified by 10 chromatography on silica gel first with toluene and then with toluene / ethyl acetate (9:1).
Yield: 86 mg (49.7% of theory) Rf = 0.47 WO 98l04~28 PCIIUS97/13248 O The compounds listed in Table 2(B) are produced in analogy to the instructions of Example 5:
Table 2(B):
R22~ 0 H
Z~ ~JE
Ex. E R22 z1/Z2 L Rf No. (solvent) 6 cyclo-C6H11 H p-F / HCH(CH3)2 0 59 toluene /
ethyl acetate 9:1 7 CH(CH3)2 NH2 p-F / HCH(CH3)2 0.60 toluene /
ethyl acetate 1:1 8 CH(CH3k SH p-F / HCH(CH3)2 0.31 toluene /
ethyl acetate 9:1 g CH(CH3)2 Cl p-CF3 / HCH(CH3)2 054 toluene /
ethyl acetate 9:1 CH(CH3)2 H 3,4-F2CH(CH3)2 0.26 toluene 11 4-F-C6H4 F p-CF3 / H~CH3 0.48 - toluene /
ethyl acetate 9:1 WO 98l04528 PCTIUS97/13248 0 Table 2(B), contd.
Ex. E R22 z1/Z2 L Rf No. (solvent) 12 CH(CH3)2 F p-F / H CH(CH3)2 0.21 toluene 13 4-F-C6H4 F p~F3 / H (~,rclo-C7H13)O 0.28 petroleum ether /
ethyl acet~te 5:1 Example 14 2-Isopropyl-6-methoxy-4-(4-fluorophenyl)-5-[2-(benzoxazol-2-yl)ethyl]-3-hydroxymethylpyridine 69 mg (0.15 mmol) of the compound from Example VI is dissolved in 5 g of toluene and mixed with 0.6 ml DIBAL-H (1.0 molar in toluene). The mixture is then stirred without a cooling bath for 4 h to +15~C. 30 ml of ethyl acetate and 15 ml of a 20% potassium sodium tartrate solution is added, and the solution is stirred for 10 min. The aqueous layer is separated off, and the organic phase is dried, concentrated, and chromatographed. After chromatography on 20 ml of silica gel using toluene / ethyl acetate (9;1),19 mg (30.2% of theory) is o~tained.
Rf = 0.28 (toluene / ethyl acetate 9:1) WO 98/04528 PCT/US97tl3248 O Detailed description with refer~l,ce to compounds of ~eneral formula (IB) The compounds according to the invention can also occur in the form of the salts thereof. In general, salts with organic or inorganic bases or acids are mentioned here.
Within the context of the present invention, physiologically safe salts are preferred. Physiologically safe salts from the compounds according to the invention can be salts of substances according to the invention with mineral acids, carboxylic acids, or sulfonic acids. Salts with, for example, hydrochloric acid,10 hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid, or benzoic acid are particularly yr~elled.
Physiologically safe salts can also be metallic or ammonium salts of the compounds according to the invention that possess a free carboxyl group. For example, sodium salts, potassium salts, magnesium salts, or calcium salts, as well as ammonium salts, that are derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, 20 dimethylaminoethanol, arginine, lysine, ethylenediamine, or 2-phenylethylamine are particularly preferred.
The compounds according to the invention can exist in stereoisomeric forms, which either behave like an image and mirror image (enantiomers) or do not 25 behave like an image and mirror image (diastereomers). The invention concernsboth enantiomers or diastereomers or the mixtures thereof. These mixtures of enantiomers and diastereomers can be separated in the known manner into stereoisomerically homogeneous components.
Within the context of the invention, the heterocyclic compound, which is optionally benzo-condensed, stands in general for a saturated or unsaturated, 5- to 7-member, and preferably 5- to 6-member, heterocyclic compound that can contain up to 3 heteroatoms from the series S, N, and/or O. Tetrazolyl, isoquinolyl, quinolyl, benzo[b]thiophene, benzo[b]furanyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, pyrinyl, benzothiazolyl, phenoxathinzyl, benzoxazolyl, tetrahydropyrimidyl, pyrazolopyrimidyl, pyrrolyl, thiazolyl, oxazolyl, and imidazolyl are cited as examples. Quinolyl, furyl, pyridyl, tetrahydropyrimidyl, 5 l 0 indolyl, benzothiazolyl, benzoxazolyl, pyrinyl, and pyrazolopyrimidyl are preferred.
This also includes 5- to 7-member saturated heterocyclic compounds bound via N, which can also contain up to 2 oxygen, sulfur, and/or nitrogen atoms as heteroatoms, such as piperidyl, morpholinyl, or piperazine or pyrrolidinyl.
Piperidyl and pyrrolidinyl are particularly ~re~lled.
Compounds of general formula (IB) are preferred, in which A stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR2R3 and/or by a group of the formula -W-R4, wherem R2 and R3 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 4 carbon atoms, W denotes an oxygen or sulfur atom, R4 denotes phenyl or benzyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, hydroxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, 30 D and E are identical or different and stand for a straight-chain or branched alkyl chain w*h up to 6 carbon atoms, or 35 E stands forabond, V stands for an oxygen or sulfur atom or for a group of the formula -NR5, WO 981'~ PCTtUS97113248 wherein R5 denotes hydrogen or straight-chain or branched alkyl with up to 4 carbon atoms or phenyl, R1 stands for cyclopropyl, cyclopentyl, or cyclohexyl, or tetrahydropyrimidyl stands for phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, tetrahydropyrimidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl, pyrazolopyrimidyl, or purine-yl, with the rings, also via the N function in the case of nitrogen-containing rings, being optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 4 carbon atoms each, triazolyl, tetrazolyl, benzoxathiazolyl, or phenyl, and/or by a group of the formula -oR6, -SR7, or -SO2R8, wherein R6, R7, and R8 are identical or different and denote phenyl, which in turn is substituted up to 2 times in an identical manner or diffelelllly by phenyl, fluorine, chlorine, or by straight-chain or branched alkyl with up to 4 carbon atoms, L and T are identical or different and stand for trifluoromethyl, pyrrolidinyl, or for straight-chain or branched alkyl with up to 7 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, naphthyl, or phenyl, which in turn can be substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, - 35 or CA 02262434 l999-0l-28 wog8/a~e~ PCT~US97/13248 0 L and/or T stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or for naphthyl, phenyl, pyridyl, or furyl, which optionally can be substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, and the salts thereof.
Compounds of general formula (IB) are particularly preferred, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 4 carbon atoms each or by benzyloxy, which in turn can be substituted by fluorine or chlorine.
D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 3 carbon atoms, or 25 E stands for a bond, V stands for an oxygen or sulfur atom or for a group of the formula -NR5, wherein R5 denotes hydrogen or straight-chain or branched alkyl with up to 3 carbon atoms, Rl stands for cyclo~roE~yl, cyclopentyl, or cyclohexyl, or tetrahydropyrinidyl stands for phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, tetrahydropyrimidyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, 0 morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl, pyrazolopyrimidyl, or purine-yl, with the rings, also via the N-function in the case of nitrogen-containing rings, optionally being substituted up to 3 times in an identical manner or difl~rently by fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, ~ 5 trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 3 carbon atoms each, triazolyl, tetrazolyl, benzoxathiazolyl, or phenyl, and/or substituted by a group of the formula -oR6, -SR7, or -SO2R8, wherein 1~6, R7, and R8 are identical or different and denote phenyl, which in turn is substituted up to 2 times in an identical manner or di~rerelllly by phenyl, fluorine, chlorine, or is substituted by straight-chain or branched alkyl with up to 3 carbon atoms, L and T are identical or different and stand for trifluoromethyl, pyrrolidinyl, or for straight-chain or branched alkyl with up to 6 carbon atoms, which are optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, which in turn may be substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 4 carbon atoms each, or L and/or T stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for naphthyl, phenyl, or furyl, which are optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 3 carbon atoms each, and the salts thereof.
W 098/04528 PCTrUS97/13248 O The compounds according to the invention of general formula (IB) are particularly preferred, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, methoxy, methyl, or by fluorine- or chlorine-substituted benzyloxy.
Moreover, a process for the production of compounds according to the invention of general formula (IB) has been discovered, characterized in that [A] in the case of V = O
compounds of general formula (II) A
HO-D~ Rl I
~ll ,1 (II) in which A, D, L, and T have the indicated meaning, 20 and R11 stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms or for the group of the formula -CH2-O-Si(CH3)2C(CH3)3, 25 are reacted with compounds of general formula (III) Rl-E-Z (III) in which R1 and E have the indicated meaning and WO 38~ PCT~US97113248 0 Z stands for halogen, preferably chlorine or bromine, in inert solvents, optionally in the presence of bases and/or auxiliary agents, and reductive separation is then carried out, depending on the meaning of the group Rll, or [B] compounds of general formula (II) are first converted by reactions with compounds of general formula (IV) R 1~ S--Cl (IV) in which 15 R12 stands for straight-chain alkyl with up to 4 carbon atoms, into compounds of general formula (V) Rl ~ S--~~ ~ Rl l Il . .1, ~ (V) ~ L~ N T
in which A, D, L, T, R11, and R12 have the indicated meaning, and these are then reacted with compounds of general formula (VI) R1-E-V-H (VI) in which 30 R1, E, and V have the indicated meaning, and reductive separation is carried out, WO ~8/01-2~ PCTrUS97/13248 and optionally, the groups listed under substituents A, L, T, and 1;~l are introduced or varied according to customary methods.
5The processes according to the invention can be explained, for example, by means of the following reaction diagrams:
[A] F
¢~
HO~2C2H5 F3C~=~ F
O~N \~Br ¢~1 F3C~¢~c2H5 ¢~ /H4 F3C~I3~[~,oH F
F3C,~o Si ~J r WO 98/04528 PC~IUS97/13248 [B] F~ FJ~
HO~2c2H5 H3CO2SO~[~2C2H5 F~
(3~'o~2c2Hs ~locki g~OH
F~ HCl/methanol ~0~ ~O~
¢~f C FJ~
F~ H3C~ O~
HO~ J~O- Si W O 98/04528 PCTrUS97113248 [C] F
¢~
H3C--~--O~, $
NH~
~S~,O- Si ¢~
~0- li--De-blocking / <\ ~
HCI/methan~l ~ ~ ~
¦ ~ De-blocking F
N~ ~J HCllm-~th~nQl ¢~
S~, ~ ~,OH
Suitable solvents for this process are inert organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether or tetrahydrofuran, halocarbons such as dichloromethane, trichloromethane, 5 tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane, or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile, or hexamethylphosphoric triamide. It is W0~8/0~8 PCTAUS97113248 0 also possible to use mixtures of the solvents. Dichloromethane, tetrahydrofuran, toluene, or dimethylformamide are particularly preferred.
In general, as auxiliary agents for the process according to the invention, inorganic or organic bases may be used. These preferably include alkali hydroxides 5 such as sodium hydroxide or potassium hydroxide, alkaline earth hydroxides such as barium hydroxide, alkali carbonates such as sodium carbonate or potassium carbonate, alkaline earth carbonates such as calcium carbonate, or alkali or alkaline earth alcoholates such as sodium or potassium ethanolate, sodium or potassium methanolate, or potassium tert-butylate, or organic amines (trialkyl(C1-C6)amines) 10 such as triethylamine, or heterocyclic compounds such as 1,4-diazabicyclo[2.2.2]octane tDABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),pyridine, diaminopyridine, methylpiperidine, or morpholine. It is also possible to use alkali metals such as sodium and hydrides thereof such as sodium hydride as bases. Sodium and potassium carbonate and triethylamine are preferred.
As bases, the usual strongly basic compounds can be used for the individual steps. These preferably include lithium organic compounds such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, or phenyl lithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithiumhexamethylsilyl 20 amide, or alkali hydrides such as sodium hydride or potassium hydride. N-butyl lithium or sodium hydride should preferably be used.
The bases are used in a mixture of 1 mole to 5 moles, and preferably 1 mole to 3 moles, relative to 1 mole of the compound of general formula (II~.
In general, the reaction is carried out in a temperature range of 0~C to 150~C, and prereldbly from +20~C to +110~C.
The reaction can be carried out at normal, increased, or reduced pressure 30 (for example, 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
As derivatizations, the following types of reactions are cited as examples:
oxidations, reductive separation, reductions, hydrogenations, halogenation, 35 Wittig/Grignard reactions, and amidation/sulfoamidation.
6 l W 098t04528 PCT~US97113248 0 Suitable solvents are ethers such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, or cyclohexane, or petroleum fractions, or halocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, or trichloroethylene, or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethyl formamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is also possible to use mixtures of said solvents. Dichloromethane is preferred.
Suitable organometallic reagents are Grignard systems such as Mg/bromobenzotrifluoride and p-trifluoromethylphenyl lithium. The Mg/bromobenzotrifluoride system is ~lefelled.
The reductions and derivatizations are carried out according to the above-mentioned methods.
In general, the reductions are carried out in ethers such as dioxane, tetrahydrofuran, or diethyl ether, or in hydrocarbons such as benzene, hexane, or toluene. Toluene and tetrahydrofuran are ~lefe.led.
Suitable reductants are complex metal hydrides such as lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutyl aluminum hydride, dimethoxymethyl aluminate sodium salt, or sodium-bis(2-methoxyethoxy) dihydroaluminate (Red-Al). Diisobutyl aluminum hydride and dimethoxymethylaluminate sodium salt are ~referred.
The reductant is generally added in the amount of 4 moles to 10 moles, and ~re~lably from 4 moles to 5 moles, relative to 1 mole of the compound to be reduced.
The reduction generally takes place within a temperature range of -78~C to +50~C, preferably from -78~C to 0~C, and particularly preferably at -78~C, depending on the choice of both the reductant and the solvent.
The reduction generally takes place at normal pressure, but it is also possible to work at increased or reduced pressure.
0 However, the reductions can also be carried out with reductants that are suitable for the reduction of ketones to hydroxy compounds. Particularly suitable in this regard is reduction using metal hydrides or complex metal hydrides in inert solvents, if appropriate, in the presence of a trialkyl borane. Preferably, the reduction is carried out using complex metal hydrides such as lithium borohydride, ~ 5 sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylborohydride, or lithium aluminum hydride. More preferably, the reaction is carried out using sodium borohydride in the presence of triethyl borane.
The hydrogenation takes place according to the customary methods using hydrogen in the presence of noble metal catalysts such as Pd/C, Pt/C, or Raney nickel in one of the above-mentioned solvents, preferably in alcohols such as methanol, ethanol, or propanol, within a temperature range of -20~C to +100~C, preferably from 0~C to 50~C, at normal pressure or elevated pressure.
As derivatizations, the following types of reactions are cited by way of examples: oxidations, reductions, hydrogenations, halogenation, Wittig/Grignard reactions, and amidation/sulfoamidation.
The customary strongly basic compounds can be used as bases for the individual steps. These preferably include organolithium compounds such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, or phenyl lithium, or amides such as lithium diisopropylamide, sodium amide, or potassium amide, or lithium hexamethylsilyl amide, or alkali hydrides such as sodium hydride or potassium hydride. n-butyl lithium or sodium hydride are particularly preferred.
Furthermore, the customary inorganic bases are suitable bases. These ~re~lably include alkali hydroxides or alkaline earth hydroxides such as sodium hydroxide, potassium hydroxide, or barium hydroxide, or alkali carbonates such as sodium carbonate, potassium carbonate, or sodiurn hydrogencarbonate. Sodium hydroxide or potassium hydroxide are particularly pre~el,ed.
Alcohols such as methanol, ethanol, propanol, or tert-butanol are also suitable solvents for the individual reaction steps. Tert butanol is ~re~lled.
It may possibly be necessary to carry out several reaction steps under a protective gas atmosphere.
WO 98/04528 PCT~US97113248 0 The halogenations generally take place in one of the above-mentioned chlorinated hydrocarbons, with methylene chloride being ~lef~lled.
Diethylamino sulfur trifluoride (DAST) or SOC12, for example, are suitable halogenation agents.
The halogenation generally takes place within a temperature range of -78~C
to +50~C, preferably from -78~C to 0~C, and particularly preferably at -78~C, depending on the choice of both the halogenation agent and the solvent.
The halogenation generally takes place at normal pressure, but it is also possible to work at increased or reduced pressure.
The customary reagents are suitable as Wittig reagents. 3-Trifluoro-methylbenzyltriphenylphosphonium bromide is preferred.
In general, one of the above-mentioned bases is suitable as a base, preferably Li-bis-(triethylbutyl)amide.
The base is used in an amount of 0.1 moles to 5 moles, ~refelably 0.5 moles 20 to 2 moles, in relation to 1 mole of the parent compound.
The reaction with Wittig reagents is generally carried out in a temperature range of 0~C to 150~C, preferably at 25~C to 40~C.
The Wittig reactions are generally carried out at normal pressure. However, it is also possible to carry out the process at reduced or high pressure (e.g., within a range of 0.5 to 5 bar).
The compounds of general formula (II) are known in part or new and can then be produced from the corresponding dihydropyridines of general formula (VII) Rl302C~Co2Rl4 L N T
.. ......... . . ...
WO g8/04528 PCTIUS97113248 0 in which A, L, and T have the above-indicated meaning, and R13 and R14 are identical or different and denote straight-chain or branched alkyl with up to 4 carbon atoms, through oxidation into the corresponding pyridines and finally depending 10 on the substituents a reduction according to conventional methods can be carried out.
Suitable solvents for the oxidation are ethers such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimethyl ether; or hydrocarbons such as benzene, 15 toluene, xylene, hexane, or cyclohexane, or petroleum fractions, or halocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene,or trichloroethylene, or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is also possible to use a mixture of said 20 solvents. Dichloromethane is preferred.
Suitable oxidants are, for example, 2,3-dichloro-5,6-dicyanobenzoquinone, pyridinium chlorochromate (PCC), osmium tetroxide, and manganese dioxide. For the above-mentioned step, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is 25 yrefe~,ed.
The oxidant is introduced in an amount of 1 mole to 10 moles, preferably 2 moles to 5 moles, relative to 1 mole of the compound of general formula (VII).
The oxidation generally takes place within a temperature range of -50~C to +100~C, preferably from 0~C to room temperature.
The oxidation generally takes place at normal pressure. However, it is also possible to carry out the oxidation at increased or reduced pressure.
The dihydropyridines of general formula (VII) are known per se or can be produced by customary methods.
WO 98/04~28 PCTrUS97/13248 The compounds of general formulas (III), (IV), and (VI) are known per se or can be produced by customary methods.
The compounds of general formula (V) are new or can be manufactured as 5 described above.
The 3-heteroalkyl-aryl-substituted pyridines according to the invention possess valuable pharmacological properties that are superior to those of the state of the art; in particular, they are highly effective inhibitors of cholesterol ester 10 transfer proteins (CETP) and stimulate reverse cholesterol transport. The active compounds according to the invention cause a reduction in LDL cholesterol levelsin the blood, while at the same time increasing HDL cholesterol levels. They cantherefore be used for the treatment of hyperlipoproteinemia or arteriosclerosis.
The invention additionally concerns the combination of compounds according to the invention with a glucosidase and/or amylase inhibitor for the treatment of f~mili~l hyperlipidemia, obesity (adiposis), and diabetes mellitus.Within the context of the invention, glucosidase and/or amylase inhibitors are, for example, acarbose, adiposine, voglibose, miglitol, emigl*ate, MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688, lesLl ali~, pradimicin-Q, and salbostatin.
The com~ination of acarbose, miglitol, emiglitate, or voglibose and one of the above-mentioned compounds of general formula (IB) according to the invention is preferred.
CETP Inhibition Test 1. Obtainin~ CETP
CETP was obtained in partially purified form from human plasma by di~ferenlial centrifugation and column chromatography and was used for testing. In so doing, human plasma was adjusted with NaBr to a density of 1.21 g/ml and was centrifuged for 18 h at 50,000 rpm at 4~C. The bottom fraction (d>1.21 g/ml) was applied to a Sephadex~) Phenyl-Sepharose 4B
(Pharmacia) column, washed with 0.15 m NaCl/0.001 m Tris HCI, pH 7.4, and then eluted with dist. water. The CETP-active fractions were pooled, dialyzed against 50 mM Na acetate, pH 4.5, and applied to a CM-Sepharose(~
Wo~ 1'?8 PCTrUS97/13248 0 (Pharmacia) column. They were then eluted with a linear gradient (0-1 MNaCl). The pooled CETP fractions were dialyzed against 10 mM Tris HCl, pH 7.4, and were then further purified by chromatography over a Mono Q(~) column (Pharmacia).
~ 5 2. Obtainin~radioactivel~-labeled HDL
50 ml of fresh human EDTA plasma was adjusted with NaBr to a density of 1.12 and centrifuged at 4~C for 18 h at 50,000 rpm in the Ty 65 rotor. The upper phase was used to obtain cold LDL. The lower phase was dialyzed against 3 x 4 l PDB buffer (10 mM Tris/HCl, pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN3). 20 ,ul of 3H cholesterol (Du Pont NET-725; 1 -~C/,ul dissolved in ethanol) was subsequently added per 10 m~ of dialysis residue volume and incubated for 72 h at 37~C under N2.
The sediment was then adjusted with NaBr to a density of 1.21 and centrifuged in the Ty 65 rotor for 18 h at 50,000 rpm at 20~C. The upper phase was obtained, and the lipoprotein fractions were purified by gradient centrifugation. In so doing, the isolated, tagged lipoprotein fraction was adjusted with NaBr to a density of 1.26. Every 4 ml of this solution was covered in centrifuge tubes (SW 40 rotor) with 4 ml of a solution with a density of 1.21 and 4.5 ml of a solution with a density of 1.063 (density solutions from PDB buffer and NaBr) and then centrifuged for 24 h at 38,000 rpm and 20~C in the SW 40 rotor. The intermediate layer between the density of 1.063 and 1.21 that contained the labeled HDL was dialyzed against 3 x 100 volumes of PDB buffer at 4~C.
The dialysis residue contained radioactively-labeled 3H-CE-HDL, which was adjusted to approx. 5 x 106 cmp per ml and used for the test.
3. Conductin~ the test In order to test the CETP activity, the transfer of 3H cholesterol ester from human HD lipo~roL~ s to biotinylated LD lipoproteins was measured.
The reaction was ended by adding Streptavidin-SPA(g) beads (Amersham), and the transferred radioactivity was determined directly in the liquid scintillation counter.
In the test batch, 10 ~l of HDL-3H cholesterol ester (~50,000 cpm) was incubated for 18 h at 37~C with 10 ~l of biotin-LDL (Amersham) in 50 mM
HEPES / 0.15 m NaCl / 0.1% bovine serum albumin / 0.05% NaN3, pH 7.4, with 10 ~l of CETP (1 mg/ml) and 3 ~l solution of the substance to be tested WO 98/0452B PCT~US97/13248 O (dissolved in 10% DMSO / 1% BSA). Then, 200 ~1 of the SPA-Streptavidinbead solution (Amersham TI~KQ 7005) was added, and the mixture was further incubated for 1 h under agitation and subsequently measured in the scintillation counter. Corresponding incubations with 10 ~l buffer, 10 ~LI
CETP at 4~C, and 10 ~ll CETP at 37~C served as controls.
The transferred activity in the control batches with CETP at 37~C was assessed as 100% transfer. The substance concentration in which this transfer was reduced by half was indicated as the ICso value.
Syrian golden hamsters from the company's own breeding were anesthetized after fasting for 24 h (0.88 mg/kg atropine, 0.80 mg/kg Ketavet(~ s.c., 30' later 50 mg/kg Nembutal i.p.). The jugular vein was then exposed and cannulated. The test substance was dissolved in a suitable solvent (as a rule, Adalat placebo solution: 60 g glycerin, 100 ml H2O, ad 100 ml PEG-400) and administeredto the animals via a PE catheter inserted into the jugular vein. The control animals received the same volume of solvent without any test substance. The vein was then ligated and the wound closed up. At different intervals--up to 24 h after administration of the test substance blood was drawn from the animals by puncture of the retroorbital venous plexus (approx. 250 ~ll). Coagulation was completed by incubating at 4~C overnight, and the blood was then centrifuged for10 minutes at 6,000 g. The cholesterol and triglyceride content in the serum obtained in this manner was determined using modified commercially-available enzyme tests (cholesterol enzymatic 14366 Merck, triglyceride 14364 Merck). The serum was diluted in a suitable manner with physiological saline solution. 100 ~l serum dilution was mixed with 100 ,ul of test substance in 96-well plates and incubated for 10 minutes at room temperature. The optical density was then determined with an automatic plate reader at a wavelength of 492 nm (SLT-Spectra). Ihe triglyceride/cholesterol concentration contained in the samples was determined using a parallel-measured standard curve.
The deterrnination of the HDL cholesterol content was carried out after precipitation of the lipoproteins containing Apo B by means of a reagent mixture(Sigma 352-4 HDL cholesterol reagent) according to the manufacturer's instructions.
In attempting to determine oral efficacy, the test substance, which was dissolved in DMSO and suspended in 0.5% methylcellulose, was administered orallyto Syrian golden hamsters from the company's own breeding via a pharyngeal WO 38~ 1528 PCT/US97113248 0 tube. The control animals received identical volumes of solvent without any test substance. Feed was then withheld from the animals, and blood was drawn at different intervals--up to 24 h after administration of the substance--via puncture of the retroorbital venous plexus. Further processing was carried out as described above.
The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions, and solutions, using inert, nontoxic, pharmaceutically-suitable excipients or solvents. In this connection, the 10 therapeutically-active compound should be present in each case in a concentration of about 0.5% to 90% by weight, i.e., in amounts that are sufficient to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active 15 compounds using solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, with it being possible, for example, in the case of the use of water as a diluent, to use organic solvents, if appropriate, as auxiliary soIvents.
Administration takes place in a customary manner, preferably orally or 20 parenterally, in particular, perlingually or intravenously.
In the case of parenteral use, solutions of the active compound can be employed using suitable liquid excipients.
In general, it has proved to be advantageous in intravenous administration to administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight, to obtain effective results, and in oral administration, the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.
In spite of this, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of administration route, individual response to the medication, the type of formulation thereof, and the time or interval at which administration takes place. Thus in some cases, it may be sufficient to manage with less than the minimum amount previously mentioned, whereas in other cases, the upper limit mentioned must be exceeded. If larger amounts are administered, it may be advisable to divide these into several individual doses over the day.
W 098/04528 PCTrUS9711324 I. Mobile solvents for thin-layer chromatog~ hy A1 = PE98:EE2 A2 = PE95: EE5 A3 = PE9 :EE1 A4 = PE85:EE15 As = PE8 :EE2 A6 = PE75:EE25 A7 = PE7 :EE3 A8 = PE 65: EE35 Ag = PE 6: EE 4 A1o = PE55:EE45 A11 = PE1 :EE1 A12 = Toluene/ethyl acetate 1/1 A13 = Toluene/ethyl acetate 8/2 A14 = Acetonitrile/water 9/1 PE = petroleum ether; EE = ethyl acetate 20 Example I
1,4-Dihydro-2-cyclopentyl-6-ethyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylic acid-3-methylester-5-ethylester ¢~
H3COOC~ COOC2Hs Il 11 ~N--/
\ I H
6.2 g ~50 mmol~ of 4-fluoroben~aldehyde, 8.5 g (50 mmol) of 3-amino-cyclopenlyl~rop-2-ene-carboxylic methylester, and 7.2 g (50 mmol) of 4-methylacetoacetic ethylester are heated for 18 hours to 130~C while stirring.
30 After cooling to room temperature, chromatography is carried out over silica gel W0~8~'~tCt~ PCTAUS97/13248 0 (200 g of silica gel, 230-400 mesh; d 3.5 cm, mobile solvent ethyl acetate/petroleum etherl :9).
Yield: 2.8 g (14% of theory) Rf (ethyl acetate / petroleum ether 2: 8) = 0.31 ~xa,l,~lc II
2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylic acid-3-methylester- 5-ethylester H3COOC~ ~OC2Hs V
2.8 g (6.98 mmol) of 1,4-dihydro-2-cyclopentyl-6-ethyl-~(4-fluoro-phenyl)pyridine-3,5-dicarboxylic acid-3-methylester-5-ethylester is dissolved in 100 ml of absol. methylene chloride, and after addition of 1.6 g (6.98 mmol) of 2,3-dichloro-5,6-dicyano- p-benzoquinone (DDQ), the mixture is stirred for 1 hour at room temperature. After this, it is drawn off by suction over diatomaceous earth and concentrated in a vacuum. The residue is chromatographed over silica gel (100 g of silica gel, 230-400 mesh, d 3.5 cm, mobile solvent ethyl acetate / petroleum ether 5:95).
Yield: 2.1 g (75.4% of theory) Rf (ethyl acetate / petroleum ether 1:9) = 0.56 H-NMR (CDCl3): ~ = 0.95 (t, 3H); 1.32 (t, 3H); 1.6 - 2.1 (m, 8H); 2.83 (q, 2H);
3.14 (m, lH); 3.53 (s, 3H); 4.02 (q, 2H); 7.0-7.3 (m, 4H) ppm.
Example III and Example IV
2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-3-hydroxymethylpyridine-5-carboxylic acid ethylester (Example III) and 2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-5-hydroxymethylpyridine-3-carboxylic acid methylester (Example IV) W 098/04528 PCT~US97113248 F F
~OC2Hs H CO~C,OH
(III) (IV) Under argon, 2.1 g (5.26 mmol) of 2-cyclopentyl-6-ethyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylic acid-3-methylester5-ethylester is dissolved in 50 ml of absol. toluene. 26.6 ml of diisobutyl aluminum hydride (1 M solution in toluene) is added dropwise to this solution at -60DC. After this, the mixture isstirred for 15 minutes at-60~C, and the reaction solution is then cooled at -30~C for 18 h. After heating to 0~C, 50 ml of water is added, and the resulting sediment is drawn off by suction and washed 4 times with 50 ml of ethyl acetate. The aqueousphase is washed with 100 ml of ethyl acetate, and the combined organic phases are shaken out with 150 ml of saturated sodium chloride solution, dried with sodium sulfate, and concentrated in a vacuum. The residue is chromatographed over silica gel (100 g of silica gel, 230-400 mesh, d 3.5 cm, mobile solvent ethyl acetate /petroleum ether 15:85).
Yield (Example III): 0.263 g (13.5% of theory) Rf (ethyl acetate / petroleum ether 2:8) = 0.42 H-NMR (CDCl3): ~ = 0.95 (t, 3H); 1.28 (t, 3H); 1.6-2.1 (m, 8H); 2.76 (q, 4H);
3.55 (m, lH); 3.97 (q, 4H); 4.48 (d, 2H); 7.0-7.3 (m, 4H) ppm.
Yield (Example IV): 0.907 g (48.3% of theory) Rf (ethyl acetate / petroleum ether 2:8) = 0.32 H-NMR (CDCl3): ~ = 1.32 (t, 3H); 1.6-2.1 (m, 8H); 2.97 (t, 3H); 3.06 (m, lH);
3.45 (s, 3H); 4.45 (d, 2H) ppm.
The compounds shown in Table I(B) are produced analogously to the instructions for Examples I-IV:
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WO 98/04528 PCTrUS97/13248 O Example CXXXIX
2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-3-(3-trifluoromethylbenzyloxy-methyl)-pyridine-5-carboxylic acid ethylester F
~, F3C~Cf ~~C2~5 186 mg (0.5 mmol) of 2-cyclopentyl-6-ethyl-4-(4-fluorophenyl)-3-hydroxy-methylpyridine-5-carboxylic acid ethylester dissolved in 5 ml of absol. dimethylformamide is added dropwise at 0~C while stirring to a suspension of 18 mg (0.5 mmol) of sodium hydride (80%) in 5 ml of dimethyl formamide and subsequently stirred for 30 minutes. After this, 143 mg (0.6 mmol) of trifluoromethylbenzylbromide dissolved in 3 ml of dimethyl formamide is added, and the mixture is stirred for 18 h at room temperature. After addition of 25 ml of water, the mixture is extracted twice with 50 ml of ethyl acetate each time, and the combined ethyl acetate phases are shaken out with 10 ml of saturated sodium chloride solution, dried with sodium sulfate, and concentrated in a vacuum. The residue is chromatographed over silica gel (100 g of silica gel, 230-400 mesh, diameter 3.5 cm, mobile solvent ethyl acetate / petroleum ether 1:9).
Yield: 0.246 g (93.1% of theory) Rf value (ethyl acetate / petroleum ether 1:9) = 0.35 H-NMR (CDCl3): ~ = 0.95 (t, 3H); 1.32 (t, 3H); 1.6-2.1 (m, 8H); 2.78 (q, 4H);
3.44 (m, lH); 3.95 (q, 4H); 4.28 (s, 2H); 4.42 (s, 2H); 7.0-7.6 (m, 8H) ppm.
W098/04528 PCTrUS97/13248 O Example CXL
2,6-Diisopropyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylic acid diethylester F
C2HsOOC~,COOC2Hs 3.8 g (16.4 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone is added to a solution of 6.6 g (16.4 mmol) of 1,4-dihydro-2,6-diisopropyl-4-(~fluorophenyl)pyridine-3,5-dicarboxylic acid diethylester in 200 ml of analysisgrade methylene chloride, and the mixture is then stirred for 1 h at room 10 temperature. After this, it is drawn off by suction over diatomaceous earth, and the methylene chloride phase is extracted 3 times with 100 ml of water each time anddried on magnesium sulfate. After concentrating in a vacuum, the residue is chromatographed on a column (100 g of silica gel, 70-230 mesh, diameter 3.5 cm, with ethyl acetate / petroleum ether 1:9).
Yield: 5.8 g (87.9% of theory) H-NMR (CDCl3): ~ = 0.98 (t, 6H); 1.41 (d, 12H); 31 (m, 2H); 4.11 (q, 4H);
7.04 (m, 2H); 7.25 (m, 2H) ppm.
Example CXLI
2,6-Diisopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-pyridine-3,5-carboxylic acid ethylester ¢~
HOH2C~ COOC2Hs ~~' N~
. , ~ . .
Under nitrogen, 21 ml (80.5 mmol) of a 3.5 molar solution of sodium bis(2-methoxyethoxy)dihydroaluminate in toluene is added to a solution of 9.2 g (23 mmol) of the compound from Example CXL in 100 ml of dried tetrahydrofuran at -10~C to -5~C, and the mixture is stirred for 5 h at room temperature. After cooling ~ 5 to O~C, 100 ml of water is carefully added dropwise, and extraction is carried out 3 times with 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated in a vacuum. The residue is chromatographed on a column (200 g of silica gel, 70-230 mesh, diameter 4.5 cm, with ethyl acetate / petroleum ether 3:7).
Yield: 7.2 g (87.2% of theory) H-NMR (CDCl3): ~ = 0.95 (t, 3H); 1.31 (m, 12H); 3.05 (m, lH); 3.48 (m, lH);
3.95 (q, 2H); 4.93 (d, 2H); 7.05-7.31 (m, 4H) ppm.
Iix~ ,le CXLII
5-(tert-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluoro-phenyl)-pyridine-3-carboxylic acid ethylester (H3C)3C--Si- O--H2C~COOC2Hs ~N~
2.1 g (13.8 mmol) of tert-Butyldimethylsilyl chloride, 1.8 g (27.5 mmol) of imidazole, and 0.05 g of 4-dimethyl-aminopyridine are added to a solution of 4.5 g (12.5 mmol) of the compound from Example CXLI in 50 ml of dimethyl formamide at room temperature. The mixture is stirred overnight at room temperature, 200 ml 25 of water is added, and the mixture is adjusted to a pH of 3 with 1 N hydrochloric acid. The mixture is extracted 3 times with 100 ml of ether each time, and the combined organic phases are washed once with saturated sodium chloride solution,dried over magnesium sulfate, and concentrated in a vacuum. The residue is chromatographed on a column (150 g of silica gel, 70-230 mesh, diameter 4 cm, with 30 ethyl acetate / petroleum ether 1:9).
WO 98104528 PCT~US97113248 0 Yield: 4.2 g (73.7% of theory) Rf = 0.75 (A3) Example CXLIII
3-(tert-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethylpyridine CH3 ¢~:1 (H3C)3C- Si- O--H2C~f OH
~ N \~
IJnder argon, 76.0 ml (0.266 mmol; 3.6 eq.) of a 3.5 molar solution of sodium bis(2methoxyethoxy)dihydroaluminate (Red-Al) in toluene is slowly added to a solution of 35.0 g (0.0738 mmol) of the compound from Example CXLII in 500 ml ofanalysis-grade THF at room temperature, and stirring is then carried out for 3 h.
The reaction solution is mixed under ice cooling with 50 ml of a 20% potassium sodium tartrate solution and extracted with 200 ml of ethyl acetate. The organicphase is washed once with a saturated NaCl solution, dried over Na2SO4, and concentrated in a vacuum. The residue is chromatographed over silica gel 60 withtoluene / ethyl acetate (8:2).
Yield: 30.2 g (94.7% of theory) Rf = 0.71 (toluene / ethyl acetate 8:2) l~xample CXLIV
3-(ter~-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-methylsulfonyloxymethylpyridine wogp/05e~ PCTrUS97/13248 o ¢~ O- Si H3C--I$--o--H2C~
~ O ~N'~/
16.94 g (39.24 mmol) of 3-(tert-butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethylpyridine is dissolved in 220 gof analysis grade CH2Cl2, cooled to -60~C, and mixed dropwise with 11.0 ml (78.48 mmol; 2 eq.) of triethylamine and 6.1 ml (78.48 mmol; 2 eq.) of methanesulfonyl chloride under nitrogen while stirring. Stirring is carried out for 1 h at -60~C to -20~C and for 30 minutes at 0~C. After this, the reaction solution is w~shed wi~cold NaHCO3 solution, dried over Na2SO4, concentrated, dried for 60 min. in a high vacuum, and then stored at -20~C.
Yield: 19.8 g (99% of theory) Rf = 0.77 (toluene / ethyl acetate 8:2) Example CXLV
3-(tert-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-(1-methylimidazole-2-thiomethyl)pyridine N~ S~
1.0 g (1.96 mmol) of 3-(tert-butyldimethylsilyloxymethyl)-2,~diisopropyl-4-(4-fluorophenyl)-5-methylsulfonyloxymethylpyridine is placed in 15 ml of analysis-grade DMF. 0.256 g (2.25 mmol; 1.15 eq.) of 2-mercapto-1-methylimidazole and 0.41 ml (2.35 mmol; 1.2 eq.) of N,N-diisopropylamine are added, and the .
0 mixture is stirred overnight at 60~C. After this, 80 ml of ethyl acetate is added, and the mixture is then successively washed with saturated NaHCO3 solution, 1 N
H2SO4, and saturated NaCl solution. The organic phase is dried over Na2SO4, filtered, and concentrated.
Yield: 0.93 g (89.8% of theory) Rf = 0.35 (toluene / ethyl acetate 8:2) Example CXLVI
3-(tert-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-10 (indolyl-5-aminomethyl)pyridine F
~, 2.0 g (3.92 mmol) of 3-(tert-butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-methylsulfonyloxymethylpyridine is reacted in 20 ml of analysis grade DMF under nitrogen with 0.674 g (5.1 mmol; 1.3 eq.) of 5-aminoindole and 0.82 ml (4.71 mmol) of N,N-diisopropylethylamine analogously to the instructionsof Example CXLII.
Yield: 2.05 g (95.8% of theory) Rf = 0.75 (toluene / ethyl acetate 8:2) Production Examples 25 Example 1 2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-5-hydroxymethyl-3-(3-tri-fluoromethylbenzyloxymethyl)pyridine WO ~81'~ PCTrUS97/13248 F
F3C~f ~,OH
A suspension of 30 mg (0.8 mmol) of lithium aluminum hydride in 10 ml of absol. tetrahydrofuran is heated under argon. After this, 212 mg (0.4 mmol) of 2-cyclopentyl-6-ethyl-4-(4-fluorophenyl)-3-(3trifluoromethylbenzyloxymethyl)-5 pyridine-5-carboxylic acid ethylester dissolved in 10 ml of absolute tetrahydrofuran is added. Next, the mixture is refluxed for 1 h. After cooling to room temperature, 10 ml of a 10% potassium hydroxide solution is added. The resulting sediment is drawn off by suction and boiled off several times with 10 ml of diethyl ether. The combined mother liquors are dried with sodium sulfate, concentrated in a vacu~
10 and chromatographed over silica gel (mobile solvent ethyl acetate / petroleum ether 2:8).
Yield: 149 mg (76.5% of theory) Rf value (ethyl acetate / petroleum ether 2:8) = 0.08 1~-NMR (CDCl3): ~ = 1.32 (t, 3H); 1.6-2.1 (m, 8H); 2.95 (q, 4H); 3.41 (m, lH);
4.16 (s, 2H); 4.38 (s, 2H); 7.0-7.6 (m, 8H) ppm.
Example 2 2,6-Diisopropyl-4-(4-fluorophenyl)-5-(1-methylimidazole-2-thiomethyl)-3-20 hydroxymethylpyridine F
N~ S~ OH
WO 98/04528 PCTlUS97tl3248 0 10 ml of 3 N hydrochloric acid is added to 0.5 g (0.947 mmol) of the compound from Example CXLII dissolved in 10 ml of methanol, and the mixture is stirred for 3 h at room temperature. The mixture is concentrated in a vacuum, covered with a layer of ethyl acetate, and adjusted to a pH of 8.0 with a saturated NaHCO3 solution, and the organic phase is separated off. The aqueous phase is again extracted with ethyl acetate, and the combined organic phases are washed with salt water, dried over Na2SO4, and concentrated.
Yield: 230 mg (58.7% of theory) Rf = 0.76 (toluene / ethyl acetate 1:1) WO 3n/~ PCT~US97/13248 0 The compounds listed in Tables l(B) through 5(B) are produced analogously to the procedures of Examples 1 and 2:
Table l(B):
R~ S~~ OH
--f N ~
Example No. Rl Rf (solvents) N
3 ~~ 0.56(A12) N-N
" ~~ 0.42 (A13) N~ 0.12 (A13) ~ CO2CH3 6 l~l~ 0.62 (A13) ~NH
N J' 0.42 (A14) wo 98/04528 ExampleNo. R1 Rf (solvents) 8 ¢~CO~ 0.54 (A13) 9 ~!~N 0.59 (A13) W~
N=\
~NH 0.23 tA12) ~N~
~I N
0.54 (A12) N J~
12 N~-- 0.5(A12) 13 F3C~J 0.68 (A13) ~W~
14 W~ J 0.71 (A13) o O Example 15 2,6-Diisopropyl-4-(4-fluorophenyl)-5-(indolyl-5-aminomethyl)-3-hydroxy-methylpyridine H 11 ¦
~H~,f OH
~N
Analogously to Example 2, 2.3 g (4.21 mmol) of ~he compound from Exampl~
CXLnI is desilylated in methanol in the presence of 3 N hydrochloric acid.
Yield: 720 mg (39.6% of theory) Rf = 0.48 (A13) The compounds listed in Table 2(B) are synthesized according to these instructions:
W 0~ ?8 PCTAUS97113248 0 Table 2(B):
¢~
R~ N ~~¢~ OH
~ N ~
ExampleNo. R1 Rf (solvents) 16 N 0.46 (A13) 17 Q/\ 0.33 (A13) ~ CH2 18 0.86 tA13) 19 F~J 0.48 (A13) J~--' 0.3~ (A13) MeO2C
21 ~CH3 0 39 (A13) W 098104~28 PCTtUS97tl3248 0 Table 3(B) Rl7 Il I
H~H
R~ E-O--~ OH
L N T
Ex. R17 Rl-E T L Rf (solvent) 22 F 4-F-C6H4 CH(CH3)2 CH(CH3)2 0.43 (A5) 23 F 4-CF3-C6H4 CH(CH3)2 CH(CH3)2 0.40 (A5) 24 F 3-CF3-C6H4 CH(CH3)2 CH(CH3)2 0.47 (A5) F 2-cF3-c6H4 CH(CH3)2 CH(CH3)2 0.41 (A5) 26 F 4-F-C6H4(CH2)2 CH(CH3)2 CH(CH3)2 0.17 (A3) 27 H 2-CF3-C6H4(CH2)2 CH(CH3)2 CH(CH3)2 0.38 (A5) 28 F 2-F-C6H4(CH2)2 CH(CH3)2 CH(CH3)2 0.16 (A3) 29 F 4-cF3-c6H4cHcH3 CH(CH3)2 CH(CH3)2 0.17 (A3) F 3-CF3-C6H4(CH2)2 CH(CH3)2 CH(CH3)2 0.49 (A5) 31 F 3-CF3-C6H4CHCH3 CH(CH3k CH(CH3)2 0 47 (A5) 32 F O NCH2CH2 CH(CH3)2 CH(CH3)2 0.20 ~ (A11) 33 F (4-py~dyl)CH2 CH(CH3)2 CH(CH3)2 0.16 (A9) Ex. R17 R1-E T L Rf ~solvent) 34 F (3-pyridyl)CH2 CH(CH3)2 CH(CH3)2 0.20 (Ag) F (2-pyridyl)CH2 CH(CH3)2 CH(CH3)2 0.38 (A9) 36 F 4-ph-c6H4 CH(CH3)2 CH(CH3)2 0.24 tA4) 37 F 3-Ph-C6H4 CH(CH3)2 CH(CH3)2 0.27 ~A4) 38 F 2-ph-c6H4 CH(CH3)2 CH(CH3)2 0.26 (A4) 39 F 4-F-C6H4(CH2)3 CH(CH3)2 CH(CH3)2 0.14 (A3) F ~ N- C6H4 CH(cH3)2 CH(CH3)2 0.13 N ~/ (A9) 41 F (1-naphthyl)CH2 CH(CH3)2 CH(cH3)2 0.14 (A3) 42 F 2-naphthyl(CH2)2 CH(CH3)2 CH(CH3)2 0.15 (A3) 43 F 1-naphthyl(CH2)2 CH(CH3)2 CH(CH3)2 0.15 (A3) 44 F C6H5 4-F-C6H4 CH(CH3)2 0-54 (A5) F 4-F-c6H4 4-F-c6H4 CH(CH3)2 0.42 (A5) 46 F 4-CF3-C6H4 4-F-c6H4 CH(CH3)2 0.40 (A5) 47 F 3-cF3-c6H4 4-F-C6H4 CH(CH3)2 0-45 (A5) 48 F 2-CF3-C6H4 4-F-c6H4 CH(CH3)2 0 33 (A5) 49 F 4-F-C6H4(CH2)2 4-F-c6H4 CH(CH3)2 0.15 (A3) H 2-CF3-C6H4(CH2)2 4-F-c6H4 CH(CH3)2 0.41 (A5) WO98/04528 PCT~S97/13248 Ex. R17 Rl-E T L Rf ~so1vent) 51 F 2-F-C6H4(CH2)2 ~F-c6H4 CH(CH3)2 0.14 (A3) 52 F 4-cF3-c6H4cHcH3 ~F-C6H4 CH(CH3)2 0.11 (A3) 53 F 3-CF3-C6H4(CH2)2 4-F-C6H4 CH(CH3)2 0 43 (A5) 54 F 3-cF3-c6H4cHcH3 4-F-c6H4 CH(CH3)2 0.42 (A5) F O NCH2CH2 ~F-c6H4 CH(CH3)2 0.48 \___/ (A9) 56 F (2-pyridyl)CH2 4-F-C6H4 CH(CH3)2 0.20 (A9) 57 F (3-pyridyl)CH2 4-F-C6H4 CH(CH3)2 0.19 (A9) 58 F 4-F-C6H4(CH2)3 ~F-C6H4 CH(CH3)2 0 33 (A5) 59 F (~pyridyl)CH2 4-F-C6H4 CH(CH3)2 0.25 (All) F 2-ph-c6H4 4-F-C6H4 CH(CH3)2 0.38 (A5) 61 F 3-Ph-C6H4 4-F-C6H4 CH(CH3)2 0.32 (A5) 62 F 4-Ph-C6H4 4-F-c6H4 CH(CH3)2 0 33 (A5) 63 F 2-naphthyl(CH2) 4-F-C6H4 CH(CH3)2 0 33 (A5) 64 F l-naphthyl(CH2) 4-F-c6H4 CH(CH3)2 0.32 (A5) F 2-naphthyl(CH2)2 4-F-C6H4 CH(CH3)2 0 34 (A5) 66 F l-naphthyl(CH2)2 4-F-c6H4 CH(CH3)2 0 34 (A3) 67 F 4-CF3O-C6H4CH2 4-F-c6H4 CH(CH3)2 0.31 (A5) Ex. R17 Rl-E T L Rf (solvent) 68 F 3-CF3O-C6H4CH2 4-F-c6H4 CH(CH3)20 34 (AS) 69 F 3-CF3-C6H4(CH2)34-F-C6H4 CH(CH3)20.16 (A4) 70 F 4-CF3O-C6H4CH2 4-F-C6H4 cyclo-C5H90.35 (A5) 71 F 3-CF30-C6H4CH2 4-F-C6H4 ~yclo-C5H90.33 (A5) 72 F 3-CF3-C6H4(CH2)34-F-C6H4 cyclo-CsHg0.28 (A4) 73 F 4-F-C6H4O(CH2)24-F-C6H4 cyclo-CsHg0.67 (A7) 74 F 3-cF3-c6H4 4-F-c6H4 cyclo-CsHg0.46 (A5) 75 F 4-CF3-C6H4 4-F-C6H4 cyclo-CsHg0.42 (A5) 76 F 3-CF3-C6H4(CH2)24-F-C6H4 cyclo-CsHg0.42 (A5) 77 F 3-CF3O-C6H4CH23-CF3-C6H4 cyclo-CsHg0.33 (A5) 78 F 3-CF3-C6H4CH2 4-F-C6H4 4-F-C6H4 0.20 (A7) o WO 98,~ ~'2x PCT/US97/13248 0 Table 4(B) R17 H~,H
Rl--E-O~[ 'OH
L N T
Ex. Rl-E T L Rf (solvent) 79 2-CN-C6H4CH2 CH(CH3)2 CH(CH3)2 0.16 (A3) 80 3-CN-C6H4CH2 CH(CH3)2 CH(CH3)2 0.10 (A3) 81 4~cN-c6H4cH2 CH(CH3)2 CH(CH3)2 0.10 (A3) 82 4-F-c6H4cH2 cyclo-C3H5 CH(CH3)2 0.46 (A5) 83 4-F-c6H4cH2 C2H5 CH(CH3)2 0.36 (A5) 84 C6H5CH2 C2H5 CH(CH3)2 0.36 (A5) 85 4-F-c6H4cH2 CH(CH3)2 pyrro~d~n-l-yl 0.10 (A3) 86 3-cF3-c6H4cH2 CH(CH3)2 cyclo-C6H11 0.15 (A3) 87 4-F-C6H4CH2 CH(CH3)2 cyclo-c6Hll 0.15 (A3) 88 4-F-c6H4cH2 CH(cH3)2 2-CH3-C6H4 0.12 (A3) 89 9-F-C6H4CH2 CH(CH3)2 4-Cl-C6H4 0.19 (A3) go 4-F-C6H4CH2 4-F- CH(CH3)2 0.11 C6H4(CH2)2 (A3) 91 3-cF3-c6H4cH2 4-F-c6H4 CF3 0.24 (A5) WOg8/04528 PCTrUS97/13248 Ex. Rl-E T L Rf ~so~vent) 92 ~F-C6H4CH2 4-F-c6H4 CF3 0.25 (A5 93 3-CF3-C6H4CH2 2,4-F2-C6H3 cyclo-CsHg 0.18 (A4) g4 ~CF3-C6H4CH2 2,4-F2-C6H3 cyclo-CsHg 0.22 (A4) o WO~8/~1C~8 PCTrUS97113248 ~ ~ o ~ o ¢ 3 ¢ o ¢ o ¢ o ¢
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W 098/04528 PCT~US97/13248 O Detailed .l~cription with l~fel~l,ce to co.,l~Gul,ds of ~eneral formula (IC) In the above structural formula (IC) the following terms have the indicated meanings:
The term alkyl means alkyl groups which are straight chain or branched and have the designated number of carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, and isohexyl.
The term cycloalkyl means an alkyl group which is in the form of a ring and contains the designated number of carbon atoms. Examples include the cyclo~r~yl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
The term alkoxy means a group in which the alkyl portion is straight or branched and has the designated number of carbon atoms. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, and isohexoxy.
The term alkanoyl means groups of formula -C(O)-alkyl in which the aL~cyl group has the designated number of carbon atoms. Examples include: acetyl, propionyl and butanoyl.
The term alkanoyloxy means groups of formula -OC(O)-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include -OC(O)CH3, -OC(O)C2H5, and -OC(O)C3H7.
The term alkoxycarbonyl means groups of formula -C(O)O-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include -C(O)OCH3, -C(O)OC2H5, and -C(O)OC3H7.
The term cycloalkyl-alkyl means groups in which an alkyl group bears a cycloalkyl substituent, and the cycloalkyl and alkyl portions each contain the designated number of carbon atoms. Examples include -C2H4-C5H9.
The term phenyl-alkyl means groups in which an alkyl group bears a phenyl substituent, and the alkyl portion contains the designated number of carbon atoms.
Examples include-C2H4-C6H5 The term naphthyl-alkyl means groups in which an alkyl group bears a naphthyl substituent, and the alkyl portion contains the designated number of carbon atoms. Examples include -c2H4-cloH7.
The term pyridyl-alkyl means groups in which an alkyl group bears a pyridyl substituent, and the alkyl portion contains the designated number of carbon atoms. Examples include -c2H4-pyridyl.
, , ~ ., ~
. ~
W O3~/01~8 PCT~US97113248 0 The term alkenyl means straight chain or branched groups having the designated number of carbon atoms and containing a carbon-carbon double bond.
Examples include: ethenyl, propen-1-yl, propen-2-yl and penten-1-yl.
The term alkynyl means straight chain or branched groups having the designated number of carbon atoms and containing a carbon-carbon triple bond.
Examples include ethynyl, propyn-1-yl and butyn-1-yl.
The term halogen means the halogen atoms fluorine, chlorine, bromine and iodine.
The term "substituted" is defined implicitly by the exemplary substituents disclosed for the various substituted groups in the above discussion of general formula (IC). These lists of exemplary substituents are not intended to be considered as limiting; those skilled in the art will recognize that other sirnilar substituents can also be employed.
Certain of the above defined terms may occur more than once in the formulae employed herein, and upon such occurrence each term shall be defined independently of the other.
Ple~l,~d and most preferred groups constituting the compounds of general formula (IC) are as follows:
X preferably represents CR8.
When X is CR8, R8 is ~e~ldbly hydrogen, halogen, trifluoromethyl or (C1-C1o) alkyl. R8 is most preferably hydrogen.
Rla and Rlb preferably are independently trifluoromethyl, (C1-C1o)-alkyl, substituted (Cl-Clo)-alkyl, (c2-clo)-alkenyl~ substituted (C2-C1o)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl. R1a and R1b most preferably are independently (Cl-C6)-alkyl or (C2-C6)-alkenyl.
R2 is preferably (C1-C1o)-alkyl, substituted (C1-C10)-alkyl, (C2-C1o)-alkenyl or substituted (C2-C1o)-alkenyl. The substituents on the substituted alkyl and substituted alkenyl R2 groups preferably are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(o)NR4R5, or -S(o)mR7 wherein m is 0,1, or 2. Mostprefeldbly, the substituents are halogen or -S(o)mR7 wherein m=0.
The groups R4 and R~ are preferably independently hydrogen, (C1-C6) alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl. R4 and R5 are most ~ 35 preferably independently hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl.
O When R4 and R5 are joined together to form -(CH2)rA(CH2)s~~ in this linkage it is preferable that the subscripts r and s are independently 1 to 3, and A is CHR6, NR6, O, or S(O)n wherein n is 0, 1, or 2, and R6 is hydrogen, (C1-C6) alkyl, phenyl, or phenyl (C1-C6) alkyl.
R7 is preferably (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, or substituted pyridyl-(C1-C6) alkyl. R7 is most preferably (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl. The substituents on the substituted R7 groups are preferably 1-3 of halogen, trifluoromethyl, or (C1-C6) alkyl.
When R2 and R1b are joined to form an alkylene bridge, this bridge preferably contains 3 or 4 carbon atoms.
R3 is preferably (C1-C6) alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl, wherein the substitutents are preferably from 1 to 3 hydroxyl groups. Most preferably, R3 is substituted (Cl-C6)-alkyl or substituted (C3-C6)-alkenyl where the substitutents are from 1 to 2 hydroxyl groups.
P.erer~llces for the aromatic and heteroaromatic groups Ar of structural formula (IC) are presented below. Compounds of general formula (IC) are further ifie~l into four subsets represented by structural formulae lA, lB, 1C, and lD, which relate respectively to 4-heteroaryl-substituted pyridines, 4-aryl-substituted pyridines, heteroaryl-substituted benzenes, and aryl-substituted benzenes.
The 4-heteroaryl pyridine compounds included within formula (IC) have the formula lA
Ar' R 1 a~ RR2 b lA
wherein R1a and R1b are independently trifluoromethyl, (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C2-C1o)-alkenyl, substituted (C2-C1o)-alkenyl, (C2-C1o)-alkynyl, substituted ~C2-C1Q)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R1a and R1b groups are independently from 1 to 3 of, for l28 ... . . . . . .. . .. . . ... .
W098/04528 PCTrUS97/13248 O example, -oR4, -C(o)R4, -co2R4l -C(o)NR4R5, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (cl-c4)-alkoxy groups.
The groups R4 and R5 are independently hydrogen, (cl-c6)-alkyl~ (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(cl-c6)-alkyl~ substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(cl-c6)-alkyl~ or substituted naphthyl-(C1-C6)-alkyl. The substitutents on the substituted phenyl or substituted naphthyl R4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
R4 and R5 may be joined together to form -(CH2)rA(CH2)S- wherein the subscripts r and s are independently 1 to 3 and A is CHR6, NR6, O, or S(O)n in which n is 0, 1, or 2; and R6 is hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cl-C6)-alkyl.
R2 is (C1-C1Q)-alkyl, substituted (Cl-C1o)-alkyl, (C2-C1o)-alkenyl, substituted (C2-Clo)-alkenyl, (C2-C1o)-alkynyl, substituted (C2-C1o)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl. The substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(o)NR4R5, or -S(o)mR7 wherein m is 0, 1, or 2. The substituents on the substituted phenyl R2 substituent group are from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy.
R7 is (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cl-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cl-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R7 groups are from 1 to 5 of, for example, halogn, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, cyano, or hydroxy.
R2 and R1b may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached.
R3 is hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl R3 groups from 1 to 3 hydroxy or trifluoromethyl groups.
Ar' is an optionally substituted heteroaromatic ring. Examples of possible Ar' groups are pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls. The .
. . _ , . ~
W 098104528 PCT~US97/13248 O optional subsliLul~llts on the group Ar' are independently 1 to 3 of, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -oR4, -C(o)R4, -oC(o)R4, -Co2R4, -NR4R5, -C(o)NR4R~, or -S(o)mR7. The substitutents on the substituted alkyl, substitutedalkenyl, and substituted alkynyl substituent groups on Ar' are from 1 to 3 of, for example, halogen, hydroxy, -NR4R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4) alkyl, or (C1-C4) alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
In formula lA, the preferred and most ~refelled groups R1a, R1b, R2, R3, as well as the additional groups R4, R5, R6, and R7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.
In formula lA, heteroaromatic ring Ar' is preferably selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and thiazolyls, and the optional substitutents on Ar' are pre~ldbly independently from 1 to 3 of, for example, halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -oR4, or -oC(o)R4 where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C1-C4) alkyl. Heteroaromatic ring Ar' is most preferably selected from the group consisting of pyridyls, furanyls and thiophenyls, and the optional substitutents thereon are most ~referably 2~ independently from 1 to 3 of, for example, halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -oR4, or -oC(o)R4 where R4 is hydrogen or (C1-C6) alkyl.
The ~aryl-substituted pyridines included within formula (IC) have the formula lB
Ar"
R1a~ ~ RR2b lB
wherein W O 98/04528 PCTrUS97/13248 0 R1a and R1b are independently trifluoromethyl, (C1-C1o)-alkyl, substituted (C1-C10)-alkyl, (C2-clO)-alkenyl~ substituted (C2-C1o)-alkenyl, (C2-C1o)-alkynyl, substituted (C2-Clo)-alkynyl~ (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R1a and R1b groups are independently from 1 to 3 of, for example, -oR4, -C(o)R4, -co2R4~ -C(o)NR4R5, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy ~ groups.
The groups R4 and R5 are independently hydrogen, (cl-c6)-alkyl~ (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl. The substitutents on the substituted phenyl or substituted naphthyl R4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
R4 and R5 may be joined together to form ~(CH2)rA(CH2)S- wherein the subscripts r and s are independently 1 to 3 and A is CHR6~ NR6~ O, or S(O)n in which n is 0, 1, or 2; and R6 is hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cl-C6)-alkyl.
R2 is (C1-C10)-alkyl, substituted (C1-C1o)-alkyl, (C2-C1o)-alkenyl, substituted (C2-C1o)-alkenyl, (C2-C1o)-alkynyl, substituted (C2-C1o)-alkynyl, (C3-C6)-cycloalkyl-(Cl-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl. The substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(o)NR~R5, or -S(o)mR7 wherein m is 0, 1, or 2. The substituents on the substituted phenyl R2 substituent group are from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy.
R7 is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C~-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy,nitro, cyano, or hydroxy.
R2 and R1b may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached.
WO 9~101C2% PCT/US97/13248 0 R3 is hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl R3 groups are ~rom 1 to 3 hydroxy or trifluoromethyl groups.Ar" is an optionally substituted aromatic ring. Examples of possible Ar"
groups are phenyls and naphthyls. The optional substitutents on the group Ar" are independently 1 to 3 of, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -oR4, -C(o)R4, -oC(o)R4, -Co2R4~ -NR4R5, -C(o)NR4R5, or -S(o)mR7. The substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on Ar" are from 1 to 3 of, for example, halogen, hydroxy, -NR4R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4) alkyl, or (Cl-C4) alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
In formula lB, the ~refe~l~d and most preferred groups R1a, R1b, R2, R3, as well as the additional groups R4, R5, R6, and R7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.
In formula lB, aromatic ring Ar" preferably is a phenyl ring wherein the optional substitutents are preferably independently from 1 to 3 of, for example,halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -oR4 or -~(o)R4, where R4 is hydrogen, (cl-c6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C1-C4) alkyl. Most preferably, the optional substitutents are from 1 to 3 of, for example, halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -oR4 or -oC(o)R4, where R4 is hydrogen or (C1-C6) alkyl.
WO ~ 1e~7~ PCT/US97/13248 O The heteroaryl-substituted benzenes ir~ ef~ within formula (IC) have the formula lC
Ar' Rla/~\ R1b lC
wherein R8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5. The substituents on the substituted phenyl or substituted alkyl R8 groups are from 1 to 3 of, for example, hydroxy, fluoro, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5.
The groups R4 and R5 are independently hydrogen, (Cl-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl. The substitutents on the substituted phenyl or substituted naphthyl R4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
R4 and R5 may be joined together to form -(CH2)rA(CH2)S- wherein the subscripts r and s are independently 1 to 3 and A is CHR6, NR6, O, or S(O)n ~n which n is 0, 1, or 2; and R6 is hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cl-C6)-alkyl.
R1a and R1b are independently trifluoromethyl, (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C2-Clo)-alkenyl~ substituted (C2-Clo)-alkenyl~ (C2-Clo)-alkynyl~
substituted (C2-C1o)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R1a and R1b groups are independently from 1 to 3 of, for example, -oR4, -C(o)R4, -Co2R4~ -C(o)NR4R5, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
R2 is (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C2-C1o)-alkenyl, substituted (C2-C1o)-alkenyl, (C2-C1o)-alkynyl, substituted (C2-C1o)-alkynyl, (C3-C6)-cycloalkyl-(Cl-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(Cl-C6)-alkyl. The WO 98104528 PCT~US97/13248 0 substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C~o)NR4R5, or -S(o)mR7 wherein m is 0, 1, or 2. The substituents on the substituted phenyl R2 substituent group are from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy.
R7 is (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy,nitro, cyano, or hydroxy.
R2 and R1b may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached.
R3 is hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl R3 groups are from 1 to 3 hydroxy or trifluoromethyl groups.Ar' is an optionally substituted heteroaromatic ring. Examples of possible Ar' groups are: pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls. The optional substitutents on the group Ar' are independently 1 to 3 of, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -oR4, -C(o)R4, -oC(o)R4, -Co2R4~ -NR4R5, -C(o)NR4R5, or -S(o)mR7 The substitutents on the substituted alkyl, substituted alkenyl, and substituted all~ynyl substituent groups on Ar' are from 1 to 3 of, for example, halogen, hydroxy, -NR4R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (Cl-C4)-alkyl, or (C1-C4)-alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
In formula lC, the pfere~led and most preferred groups Rla, Rlb, R2, R3, and R8, as well as the additional groups R4, R~, R6, and R7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.
In formula 1C, heteroaromatic ring Ar' is preferably selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and 1~4 ~ . . . .. . ... ~ . ~ ... .... .
WO 98/04528 PCTrUS97/13248 0 thiazolyls, and the optional substitutents on the group Ar' are preferably independently from 1 to 3 of, for example, halogen, (Cl-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -oR4, or -oC(o)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C1-C4) alkyl.
5 Heteroaromatic ring Ar' is most preferably selected from the group consisting of pyridyls, furanyls and thiophenyls, and the optional substitutents thereon are most preferably independently from 1 to 3 of, for example, halogen, (C1-C6) alkyl, (C2-C6) alkenyl, -oR4~ or -oC(o)R4, where R4 is hydrogen or (C1-C6) alkyl.
The aryl-substituted benzenes included within formula (IC) have the formula lD
Ar"
R1a ~ ~1b lD
wherein R8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5. The substituents on the substituted phenyl or substituted alkyl R8 groups are from 1 to 3 of, for example, hydroxy, fluoro, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(cl-c3)-alkoxy~ (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or-NR4R5.
The groups R4 and R5 are independently hydrogen, (cl-c6)-alkyl~ (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl. The substitutents on the substituted phenyl or substituted naphthyl R4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
R4 and R5 may be joined together to form -(CH2)rA(CH2)S- wherein the subscripts r and s are independently 1 to 3 and A is CHR6, NR6, O, or S(O)n in which n is 0, 1, or 2; and R6 is hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cl-C6)-alkyl .
W O 98104528 PCT~US97/13248 O Rla and Rlb are independently trifluoromethyl, (Cl-Clo)-alkyl, substituted (C1-C1o)-alkyl, (c2-clo)-alkenyl~ substituted (C2-Clo)-alkenyl~ (C2-C1o)-alkynyl, substituted (C2-Clo)-alkynyl~ (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R1a and R1b groups are independently from 1 to 3 of, for example, -oR4, -C(o)R4, -co2R4~ -C(o)NR4R~, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (cl-c4)-alkoxy groups.
R2 is (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C2-C10)-alkenyl, substituted (C2-C1o)-alkenyl, (C2-C1o)-alkynyl, substituted (C2-C1o)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl. The substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(o)NR4R5, or -S(o)mR7 wherein m is 0, 1, or 2. The substituents on the substituted phenyl R2 substituent group are from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy.
R7 is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-~C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6) alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cl-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy,nitro, cyano, or hydroxy.
R2 and R1b may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms between the ring carbon atoms to which R2 and R1b are attached.
R3 is hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl. T~e substitutents on the substituted alkyl and substituted alkenyl R3 groups are from 1 to 3 hydroxy or trifluoromethyl groups.Ar" is an optionally substituted aromatic ring. Examples of possible Ar"
groups are phenyls and naphthyls. The optional substitutents on the group Ar areindependently 1 to 3 of, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6~-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -oR4, -C(o)R4, -oc(o)R4~-co2R4~ -NR4R5,-C(o)NR4R5, or -S(o)mR7. The substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on Ar are from 1 to 3 of, for example, halogen, hydroxy, -NR4R~, phenyl, or ,, W098104528 PCT~US97/13248 substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
- 5 In formula lD, the preferred and most preferred groups R1a, R1b, R2, R3, and R8, as well as the additional groups R4, R5, R6, and R7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.
In formula lD, aromatic ring Ar" ~ref~Ldbly is a phenyl ring wherein the optional substitutents are preferably from 1 to 3 of, for example, halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (c2-c6)-alkynyL (C3-C7)-cycloalkyl, cyano, -oR4 or -oC(o)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C1-C4) alkyl. Most preferably, the substitutents are from 1 to 3 of, for example, halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -oR4 or -oC(o)R4, where R4 is hydrogen or (C1-C6) alkyl.
Basic compounds of the invention are generally isolated in the form of their pharmaceutically acceptable acid addition salts derived using inorganic or organic 20 acids. Examples of such materials are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, and malonic acids.Compounds of the invention which contain an acidic functionality such as a carboxyl group can be isolated in the form of pharmaceutically acceptable addition salts derived using inorganic or organic bases. The salt forming ion derived from 25 such bases can be a metal ion such as sodium, potassium, lithium, calcium, magnesium, etc., or an ion of an organic base, such as an ammonium or substituted ammonium ion derived from an amine. Examples of suitable amines for this purpose include ammonia, arylalkylamines such as dibenzylamine and N,N-dibenzylethylenediamine, lower alkylamines such as methylamine, ~-butylamine, 30 procaine, lower alkylpiperidines such as N-ethylpiperidine, cycloalkylamines such as cyclohexylamine or dicyclohexylamine, 1-adamantylamine, benzathine, or salts derived from amino acids such as arginine or lysine.
The present invention also encompasses pharmaceutically acceptable "prodrugs" of the compounds of formula (IC) which form such derivatives. These W O 93/OI¢~X PCT~US97/13248 0 are typically acylated derivatives of alcohol-containing compounds of the invention, though other types of prodrugs are known. Preparation of such derivatives is within the skill of the art.
The inhibitors of the present invention are contemplated for use in veterinary and human applications. For such applications, the active agent(s) are employed in pharmaceutical compositions which comprise the active ingredient(s) plus a pharmaceutically acceptable carrier which contains one or more diluents, fillers, binders, or other excipients, depending on the administration mode and dosage form contemplated. Examples of such agents include carriers such as sucrose, lactose, or starch; lubricating agents such as magnesium stearate;
adjuvants, such as wetting agents; excipients such as cocoa butter or suppository wax; emulsifying and suspending agents, and sweetening, flavoring and perfuming agents and buffering agents.
The pharmaceutical compositions of the invention may also include one or more known antidiabetic agents in addition to a compound of structural formula (IC). Examples of such antidiabetic agents are: a-glucosidase inhibitors such asacarbose or voglibose, insulin sensitizers such as bromocriptine, thiazolidinediones such as troglitazone, insulin secretagogues such as glimepride, sulfonylureas such as glyburide, GLP-1 and its derivatives such as insulinotropin, amylin and its derivatives such as AC-137, calcitonin, insulin and its derivatives such as HOE-901, biguanides such as metformin, aldose reductase inhibitors such as tolrestat, ~3 agonists such as BTA-243, and hypocholesterolemics such as lovastatin.
The method of treating glucagon-mediated conditions by administering a glucagon receptor antagonist of the present invention may be practiced in mammals, including humans, which exhibit such conditions. A typical application is treatment of diabetes.
The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection or implant), nasal, vaginal, rectal, sublin~ual, or topical routes of administration and can be formulated in dosage forms a~ro~riate for each route of administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, eg., lubricating agents such asmagnesium stearate. In the case of capsules, tablets and pills, the dosage forms 13~
W098/04S28 PCTrUS97113248 O may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings such as the ORO~CT/OsmetTM and PULSINCAP~M systems from ALZA and Scherer Drug Delivery Systems.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert 5 diluents commonly used in the art, such as water. Besides such inert diluents,compositions can also include adjuvants, such as wetting agents, emulsifying andsuspending agents, and sweetening, flavoring and perfuming agents.
Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
10 Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain ad~uvants such as preserving, wetting, emulsifying, and dispersing agents. Alternatively intramuscular, intraarticular or subcutaneous depot injection with or without 15 encapsulation of the drug into degradable microspheres e.g., comprising poly(DL-lactide-co-glycolide) may be used to obtain prolonged sustained drug release. For improved convenience of the dosage form it may be possible to use an i.p.
implanted reservoir and septum such as the Percuseal system available from Pharmacia. Improved convenience and patient compliance may also be achieved 20 by the use of either injector pens (e.g. the NovoPen or ~pen) or needle-free jet injectors (e.g. from Bioject, Mediject or Becton Dickinson). Prolonged zero-order or other precisely controlled release such as pulsatile release can also be achieved as needed using implantable pumps with delivery of the drug through a cannula into the synovial spaces. Examples include the subcutaneously implanted osmotic 25 pumps available from ALZA, such as the ALZET osmotic pump.
Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients30 such as cocoa butter or a suppository wax.
- The compounds of this invention can be manufactured into the above listed forrnulations by the addition of various therapeutically inert, inorganic or organic carriers well known to those skilled in the art. Examples of these include, but are not limited to, lactose, corn starch or derivatives thereof, talc, vegetable oils, waxes, 3~ fats, polyols such as polyethylene glycol, water, saccharose, alcohols, glycerin and the like. The formulations may be sterilized by, for example, filtration through a W 098J04~28 PCTfUS97tl3248 0 bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved insterile water, or some other sterile injectable medium immediately before use.
Various preservatives, emulsifiers, dispersants, flavorants, wetting agents, 5 antioxidants, sweeteners, colorants, stabilizers, salts, buffers and the like are also added, as required to assist in the stabilization of the formulation or to assist in increasing bioavailability of the active ingredient(s) or to yield a formulation of acceptable flavor or odor in the case of oral dosing.
The amount of the pharmaceutical composition to be employed will depend 10 on the recipient and the condition being treated. The requisite amount may bedetermined without undue experimentation by protocols known to those skilled in the art. Alternatively, the requisite amount may be calculated, based on a determination of the amount of target receptor which must be inhibited to treat the condition. An effective amount of active ingredient is generally in the range 0.0001 15 mg/kg to 100 mg/kg of body weight.
The treatment method of the invention is not limited to administration of the above-described pharmaceutical composition. Rather, this treatment regimen may be employed in combination with conventional treatments of diabetes (both Type I20 and Type II) or of other conditions which are sometimes found in diabetic subjects.
Thus, for example, treatment may be administered in conjunction with (a) diet restrictions and exercise; (b) insulin, or other drugs used to treat ketoacidosis; (c) any drug used for the treatment of hyperlipidemia, such as lovastatin, or cardiovascular disease, such as enalapril; (d) drugs used to treat diabetic 25 complications, such as epalrestat and (e) drugs that lower body weight, such as dexfenfluramine .
The glucagon receptor antagonists of the invention are useful not only for treatment of the pathophysiological conditions discussed above, but are also useful in other applications such as a diagnostic agent. For example, these compounds 30 can be administered to humans in vivo in the fasting state as a diagnostic tool to directly determine whether the glucagon receptor is functional. Serum samples taken before and after such administration can be assayed for glucose levels;
comparison of the amounts of blood glucose in each of these samples would be a means for directly determining the ability of the patient's glucagon receptor to O modulate hepatic glucose output. Alternatively, compounds of the present invention may be useful for finding new glucagon antagonists. For example, a binding assay employing a radiolabeled derivative (such as 3H) of a compound of formula (IC) would be useful in identifying new compounds that competitively bind to the glucagon receptor. Such an assay is useful in identifying structurally 5 novel antagonists that may offer advantages in ease of chemical modification, selectivity and oral bioavailability.
WO 98/04S28 PCTrUS97/13248 0 The compounds of the present invention may contain asymmetric centers on the molecule, depending upon the nature of the various substituents. Each such asymmetric center will produce two optical isomers. In certain instances, asymmetry may also be present due to restricted rotation about the central bond adjoining the two aromatic rings of the specified compounds. For example, for certain tompounds of Pormula (IC) wherein Ar is taken as substituted phenyl, there exist additional isomers due to restricted rotation about the central aryl-aryl bond, depending on the substitution pattern.
R~ b Rla~ R~b It is intended that all isomers, either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purifiedisomers or racemic mixtures thereof, be included within the ambit of the instantinvention. In the case of compounds of Formula (IC) wherein R3 is taken as 1-hydroxyethyl, it has been found that the isomer in which the hydroxy substituent is lS above the plane of the structure, as seen in Formula Ic, is more active and thus more preferred over the compound in which the hydroxy substituent is below the plane of the structure.
OH Ar H~ R1b WO~W'2~ PCT~US97/13248 0 Representative examples of the nomenclature employed herein are given below:
2,6-Dimethyl-3-hydroxymethyl-4-(3-bromophenyl)-5-isobutylpyridine ~,, Br HO
N
3,5-Di-t-butyl-2-(phenylthio)methyl-6- hydroxymethyl-3',5'-dichloro-1,1'-biphenyl HO~S J~3 The compounds of general formula (IC) of the present invention are prepared as indicated in the following reaction Schemes.
The phenylpyridine compounds of formula (IC) (X= N) are prepared from a common intermediate 6 using the well-known Hantzsch pyridine synthesis, as shown in Scheme 1 (Stout, D. M.; Myers, A. I. Chenl. Rev. 1982, 223).
W098/04~28 PCTrUS97/13248 R~b~CO2Et RlaJ~ AcO-NH4 /cyclohexanre 1a~CO2Et Ar-CHO
Ar Ar EtO2C~CO2Et DDQ / CH2C12 EtO2C~C02Et H R1a N R1b The ketoester 1, (commercially available or prepared according to the procedure of Deslongchamps, Syn~h. Comm., 1976, 6, 169) is treated with an S ammonium salt such as ammonium acetate, in an inert solvent such as cyclohexane capable of forming an azeotrope with water, to give the enamine 2. Compound 2 is then treated with the ketoester ~, which may or may not be identical to the ketoester 1, and an aromatic aldehyde, in a polar solvent such as ethanol, to produce the dihydropyridine 5. Certain substituents on aldehyde 4 may need to beprotected during the Hantzsch pyridine synthesis. A description of suitable protecting groups may be found in: Protective Groups in Or~anic S~nthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991. Oxidation of 5 is achieved by any of several known methods. For example, treatment of 5 with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in a solvent such as methylene chloride (CH2Cl2), or with ceric ammonium nitrate (CAN) in a mixture of solvents such as aqueous acetone, affords the intermediate 6. Separation of unwanted sideproducts and purification of intermediates is achieved by chromatography on silica gel, employing flash chromatography (Still, W.C.; Khan, M.; Mitra, A. J. Org. Chem., 1978, 43, 2923) An alternative Hantzsch pyridine synthesis of the intermediate 6, where R1a and R1b of formula (IC) are identical, can be accomplished following the procedure of Chucholowski (U.S. Patent 4,950,675), Scheme 2. By heating two equivalents ofketoester 1 with ammonium hydroxide and the aldehyde 4 in a polar solvent such as methanol, the dihydropyridine 5 is obtained directly. Compound 5 is oxidized to pyridine 6, according to the procedure described in Scheme 1.
.
WO 98/04528 PCTrUS97/13248 - Ar A
2 ~ Ar CHO ElO2C~C02Et DDQ/cHzcl2 EtO2C~CO2EI
R1aJ~ CO2Et NH40H/MeOH ~1a N R1a Rla~N R1a ~ In Scheme 3, another alternative Hantzsch pyridine synthesis of intermediate 6 is described. Ketoester 1 is condensed with aldehyde 4 by treatment with 5 catalysts such as acetic acid and piperidine without solvent to afford intermediate 7.
Treatment of 7 with ketoester 3 in the presence of a base such as sodium methoxyde, in a polar solvent such as methanol produces the diketone 8.
Cyclization of 8 is achieved by treatment with an ammonium salt such as ammonium acetate in a polar solvent such as acetic acid to afford the previously10 described dihydropyridine 5 (Scheme 1), which is oxidized to the pyridine 6 according to the procedure as indicated in Scheme 1.
o ArRl b J~ C02Et ArCHO I 3 Ar 0 4 ~CO2EtN OM EtO2C~J~C02Et R~ , C02Et o~ R1 a MeOH R 1 a ~lo 0~ Rl b Ar Ar NH40Ac EtO2C~CO2Et DDQ / CH2CI2 EtO2C~
AcOHR1a N Rlb R1a N R1b The synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl and R3 is hydroxymethyl (IIa) is described in Scheme 4.
W O~8J~'2X PCTrUS97/13248 Ar Ar EtO2C~CO2Et Red-AI I THF EtOzc~oH PCC / CH2C12 EtO2C~CHO R Ar 1) LAH ITHF
R1a N R1b THF F~1a NR1b 2) H2, Pd/C
Ar Ar HO ~ R2 HO ~ R2 R1a N R1b R1a N R1b Ila ~b Chemical reducing agents such as sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) in an inert solvent, such as tetrahydrofuran (THF) or diethyl ether 5 (Et2O), can result in a monoreduction of the pyridinediester 6 to give the alcohol 9.
Oxidants such as pyridinium chlorochromate (PCC), in a solvent such as CH2Cl2, convert compound 9 to the aldehyde 10. Wittig reaction with compound 10 and an ylide ~, in an inert solvent such as THF or Et20, affords olefin _ obtained usually, but not always, as a mixture of E and Z isomers . The reagent 11a is 10 prepared from an alkyl triphenyl phosphonium salt, wherein the alkyl group may contain a heteroatom, and a suitable base such as butyllithium or sodium amide, according to known methods (Maercker, A. in Organic l~eactions, Vol. 14, Ed.; Wiley, New York, 1965, Chapter 3). Olefin 12 is successively treated with a reducing agent such as lithium aluminum hydride (LAH), in an inert solvent such as THF or Et20,15 and hydrogen in the presence of a metal catalyst, such as p~ m~ on carbon, in a polar solvent such as ethanol, to afford compounds of formula IIa. ~ some of these compounds, R2 may contain substituents such as alcohol, acetate, ester, carboxylic acid, and amide. These products can be obtained directly by the procedures of Scheme 4, with or without the use of appropriate protecting groups, 20 or by additional steps familiar to those skilled in the art. For example, a primary alcohol can be converted to a carboxylic acid by standard methods of oxidation, WO ~X~ r~X PCTrUS97/13248 0 such as those described by Eisenbraun (Eisenbraun, E. J. Org. Syn. Coll., 1973, 5, 310).
If the Wittig reaction is performed with methoxymethyl triphenyl-phosphonium as ylide (~), followed by treatment with an acid such as hydrochloric acid, the homologous aldehyde 13 is obtained. This can undergo 5 another Wittig reaction to afford olefin 14, (Scheme 5). This known procedure (Wittg, G.; Walter, B.; Kruck, K.-H. Chem. Ber. 1962, 2514) allows one to synthesize extended alkyl chain (R2) analogs of formula IIa, which may not be directly prepared by usual Wittig reaction due to limited availability of the requisite alkyl triphenylphosphonium salt.
Oxidation of the compounds of formula IIa by the method described in Scheme 4 affords intermediates that can be converted to homologues of compounds of formula IIa, containing the -CH2-CH2- linkage between the pyridine nucleus and the hydroxy group (IIb).
Ar =~OMe Ar R
p1a N R1b 2) HCI R1a N Rlb Ar Ar EtO2C ,~ R2 R 1) LAH/THF HO T¦ r R1a~NJ'F~1b 2) H2, PdlC R1a~N ~'R1b 14 lIa Synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl 20 containing a heteroatom such as sulfur and R3 is hydroxymethyl (ma and IIIb), is outlined in Scheme 6. Alcohol 9 is converted to an alkyl halide 15 by treatrnent with a suitable reagent such as dibromotriphenylphosphorane in an inert solvent.
Treatment of 15 with a thiol and a base such as N-methyl morpholine in an inert solvent produces intermediate 16. The sulfur atom of compounds 16 can be 25 oxidized (n = 1 or 2) by any of several known methods. For example, it can be accomplished by treatment of 16 wherein n=0, with an oxidant such as m-chloroperbenzoic acid in a solvent such as CH2Cl2 Chemical reducing agents such WO 98~'~t-~X PCTrUS97/13248 O as lithium aluminum hydride (LAH) in an inert solvent such as tetrahydrofuran or diethyl ether, can reduce the ester 16 to a compound of formula IIIa. Intermediate _ can also react with alcohols following the methods outlined in Scheme 6, to afford compounds of formula IIIc.
Ar Ar EtO2C~OH Ph3P Br2EtO2C~Br R7SHICH2C12 R1a N R1b CH2C12 R1a N R1b N-Me-.,.o.~ " ,e Ar Ar Eto2c~s(o)n-R7 LAH / THF HO~S(o)n-R7 R1a N Rlb R1~ N R1b 16 IIIa Ar Ar HO--~S(O~n--R7 Ho~o~R4 R1a ~ N ~ R1b R1a N R1b Illb I~c The synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl containing a heteroatom such as nitrogen and R3 is hydroxymethyl (IVa), is 10 outlined in Scheme 7. Treatment of 15 with a primary or secondary amine in aninert solvent results in the intermediate 17. Chemical reducing agents such as lithium aluminum hydride in an inert solvent, such as tetrahydrofuran or diethylether, can reduce ester 17 to a compound of formula IVa. Reduction of aldehyde 13 by the method outlined in Scheme 4 affords an intermediate that can be converted15 to homologues of compounds of formula IIIa and IVa, containing the -CH2-CH2-linkage between the pyridine nucleus and the sulfur or nitrogen substituent (IIIb and IVb).
.... . .. .
WO 98/04528 PCTrUS97113248 Ar Ar ,R4 EtO2C~Br R4R5Ntl EtO2C~N~ LAH I THF
R1~ N R1 b CH2C12 R 1 a ~ll N~l R1 b R
R~R1b P' Ar N~
IVa IVb Synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl and R3 is 1-hydroxyethyl (Va), is outlined in Scheme 8. Oxidants such as pyridinium 5 chlorochromate (PCC), are used to convert compounds of formula II to the aldehyde 18. Treatment of 18 with an organometallic reagent such as methyl magnesium bromide or methyl li~ium in an inert solvent such as THF or Et20 affords racemic compounds of formula Va. Chiral 1-hydroxyethyl aryl pyridine derivatives of formula Vb are obtained by resolution of the racemates Va by 10 I~lA~sical methods. For example, resolution can be achieved by formation of diastereomeric adducts of the racemic compounds with optically active reagents such as a-methoxy-a-(trifluoromethyl)phenylacetic acid (Dale, J.A.; Dull, D.L.;
Mosher, H.S. J Org. Chem. 1969, 34, 2543). Alternatively, separation of enantiomers is achieved by HPLC on chiral solid phase. Determination of absolute 15 stereochemistry can be achieved in a number of ways familiar to those skilled in the art, including X-ray analysis of a suitable crystalline derivative, such as a Mosher ester.
Ar Ar HO~R PCC J CH2cl2OHC~R2 CH3Mg~r/THF
R1a N R1b R1a N R1b OH Ar CH3~ R2 Rta N R1b va W098/04528 PCTrUS97/13248 o An alternative synthesis of aryl pyridine derivatives of formula Vb is achieved by treating aldehyde 18 with the anion of methyl toluylsulfoxide 19 to give a diastereomeric mixture of alcohols 20 as shown in Scheme 9 (Blase, F. R.; Le H. Tet. Lett. 1995, 36, 4559). The diastereomers are separated by flash 5 chromatography and treated separately with Raney nickel and hydrogen in ethanol to provide pure enantiomers (>99% enantiomeric excess, e.e.) of the compounds offormula Vb. Alternatively, the chromatographic step is avoided by a two step sequence consisting of (1) oxidation of the mixture 20 with manganese dioxide in an inert solvent, followed by (2) reduction of the ketone with a chemical reductant10 such as LAH, to provide the enantiomerically pure alcohol 21. Treatment of 21 with Raney nickel and hydrogen in a polar solvent provides pure enantiomer (>99% e.e.) of the compounds of formula Vb.
o ~ ,~(S) CH2Li ~~R2 R1a N Rlb THF R1a N R1b 18 20 1 ) Ssparate r~u, ~
\~2) Hz Raney Ni 1) Mno2lcH2cl2 S OH Ar H2 OH Ar 2) LAH/THF, -78 ~s~f X Flaney Ni CH3 ~
R1a N Rlb R1a N Rlb 21 Vb A preferred alternative enantioselective synthesis of aryl pyridine derivatives of formula Vb is shown in Scheme 10. Treatment of the racemic mixture of compounds of formula Va with an oxidant such as pyridinium chlorochromate 20 (PCC), gives the ketone 22. Reduction of 22 with a complex of LAH and N-methylephedrine (Kawasaki, M.; Susuki, Y.; Terashima, S. Chem. Lett. 1984, 239) in an inert solvent, provides the alcohol of formula Vb with an enantiomeric excess of 95%.
WO 98104528 PCT~US97/13248 o SCHEME 10 ~ OH Ar O Ar CH3~R2 PCC/CH2C~> CH J~ ether, -7~ C
R1a N R1b R1a N R1b Va 22 OH Ar CH3~R1b Vb The synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl and R3 is 1,2-dihydroxyalkyl (VI), is described in Scheme 11. A methyl 5 triphenylphosphonium salt is treated with a suitable base such as butyllithiurn in an inert solvent and reacted with intermediate 18 to afford olefin 23. Treatment ofcompound 23 with a suitable oxidant such as osmium tetroxide in a polar solvent such as pyridine gives the compounds of formula VI.
Ar OHC~R2 Ph3P=CHR R ~R2 R1a N R1b T~IF R1a N R1b OsO4 R~
pyridine HO R1a N R1b VI
The synthesis of aryl pyridine derivatives of formula (IC) wherein R2 and Rlb are taken together to form an alkylene bridge and R3 is hydroxymethyl (VIIa), 15 is described in Scheme 12. The ketoester 1, is treated with an aromatic aldehyde and catalysts such acetic acid and piperidine, in ethanol, to afford the a"B-unsaturated ketoester 24. Treatment of 24 with the cyclic ketone 25 and a base such as lithium bis(trimethylsilyl)amide in an inert solvent such as THF affords an intermediate which is treated with ammonium acetate and copper acetate in acetic CA 02262434 l999-0l-28 W 098~04S28 PCTrUS97/13248 O acid to give the pyridine 26. ChPmie~l reducing agents reduce the ester 26 to analogs of formula VIIa. It may be appreciated that these analogs can be used asintermediates to generate new derivatives of formula (IC) wherein R2 and R1b aretaken together and R3 is 1-hydroxyethyl (VIIb) according to the procedures described in Scheme 8.
s Ar-CHO Ar 1) R
4 b co2Et~ R2 R1a Jl C02Et ~ ' ~
AcOH, piperidine 0~ ~ R1 a LiHMDStrtlF
~2) NH40Ac, AcOH
Ar 2 Ar EtO2~ ~ LAHlTHF HO~ R2 ) R1a N~R1b R1a N R1b 26 Vlla OH Ar ~, R2 ~
R1 a ~lN 1 R1 b ) Vllb The synthesis of the aryl pyridine derivative IIa wherein R1b is CH2OH is described in Scheme 13. Alcohol 27 (aryl pyridine IIa in which R1b is CH3) is treated with a trialkylsilyl chloride, such as tert-butyldiphenylsilyl chloride, and a base to yield silyl ether 28. Treatment of 28 with meta-chloroperbenzoic acid in an inert solvent, such as chloroform, provides the N-oxide 29. The N-oxide is treated 15 with acetic anhydride to afford pyridine acetate 30. Treatment of 30 with aqueous methanol in the presence of potassium carbonate, yields alcohol 31. The silyl ether is cleaved with tetrabutylammonium fluoride in THF to provide aryl pyridine derivative 32.
WO 98~O1'2~ PCTAUS97113248 Ar Ar HO~R2 TBDPsclr TBDPSO~R2 mCPBA
Il ,I Imidazole1~ ,J~
Rla ~N CH3 R la~ N CH
Yield: 8.88 g (98.4% of theory) Rf = 0.62 (toluene / ethyl acetate 9:1) O l~dlllylC V
Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxy-3-[2-(benzoxazol-2-yl)-1-hydroxy-ethyl]-pyridine-5-carboxylate N Otl¢~
¢~oJ~,COOC2H5 C H30 N ~
400 mg (3 mmol) of 2-methylbenzoxazole dissolved in 5 g THF p.a. is cooled under argon to -78~C. 1.83 ml (3 mmol) of n-butyllithium (1.6 molar in hexane) is added to this, and the mixture is stirred for 120 min at -78~C. 1.036 g (3 mmol) of the compound from Example IV is then added by drops at -78~C; the mixture ~s 10 stirred for 10 min at -78~C and overnight until it reaches room temperature. After adding 50 ml of water, it is extracted by shaking with 100 ml of ethyl acetate. The aqueous phase is separated off, washed two times with saline solution, dried over Na2SO4, and concentrated. The residue is chromatographed on 60 ml of silica gel using toluene and toluene / ethyl acetate (8:2). The concentrated fractions are dried 15 in a high vacuum.
Yield: 450 mg (31.4% of theory) Rf = 0.22 (toluene / ethyl acetate 9:1) Example VI
Ethyl 4-(4-fluorophenyl)-~isopropyl-2-methoxy-3-[2-(benzoxazol-2-yl)-ethenyl]-pyridine-5-carboxylate F
~OC2H5 WO 98/04528 PCTrUS97/13248 0 100 mg (0.209 mmol) of the compound from Example V is boiled in 10 g toluene p.a. under argon in the presence of 25 mg (0.131 mmol) of p-toluenesulfonic acid hydrate for 6 h under reflux, and afterwards the mixture isstirred at room temperature overnight. The reaction solution is then applied to a column filled with 40 ml of silica gel and consecutively eluted with toluene andtoluene / ethyl acetate (9.5:0.5). The desired fractions are concentrated and dried in a high vacuum.
- Yield: 91 mg (94.6% of theory) Rf = 0.59 (toluene / ethyl acetate 9:1) Example VII
Diethyl 1,~dihydro-2,6-diisopropyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylate H5C20 oC~,COOC2H5 ~N~
528 g (2 mol) of (E/Z)-4-carboxymethyl-5-(4-fluorophenyl)-2-methyl-pent-4-en-3-one and 350 g (2 mol) of 90% ethyl 3-amino-4-methyl-pent-2-enoate are stirred in 1800 ml ethanediol overnight at a bath temperature of 200~C. The mixture is cooled slowly and poured into a large glass beaker at approx. 80~C. After further cooling to 0~C, the solution is drawn off by suction from the precipitated sediment, then the sediment is washed well with ice cold ethanol and dried in a desiccator.
The ethanol solution is concellLldled~ and the residue together with the ethanediol mother liquor is extracted four times with 1.5 l ether each time. The combined ether phases are washed three times each with 500 ml of 10% hydrochloric acid and once each with 500 ml of saturated sodium hydrogen carbonate solution and water,dried over magnesium sulfate, filtered, and allowed to stand overnight at room temperature. The solution is drawn off by suction from the precipitated sediment, - subsequently washed with ice cold ethanol, and dried in a desiccator. The ethanol solution and the ether mother liquor are concentrated together in a vacuum to a W O 98101~2~ PCTrUS97/13248 0 volume of approx. 2 l, allowed to stand overnight again, and drawn off by suction from the precipitated sediment.
Total yield: 556.9 g (69.1% of theory) 1H-NMR (CDCl3): ~ = 1.1 - 1.3 (m, 18H); 4.05 - 4.25 (m, 6H); 5.0 (s, lH); 6.13 (s, lH); 6.88 (m, 20H); 7.2 (m, 2H) ppm.
Example VIII
Diethyl 2,6-diisopropyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate ¢~
H5C200C~COOC2H5 \~ N~
171.7 g (0.757 mol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone is added to a solution of 304.8 g (0.757 mol) of the compound from Example VII in 2 l of dichloromethane, and the mixture is stirred overnight at room temperature. The 15 mixture is drawn off by suction over diatomaceous earth and subsequently washed well with dichloromethane. After concentration of the dichloromethane phase to avolume of approx. 800 ml, it is chromatographed on a column (2 kg of silica gel 70-230 mesh) with dichloromethane.
Yield: 222 g (73.4% of theory) lH-NMR (CDCl3): ~ = 0.98 (t, 6H); 1.41 (d, 12H); 3.1 (m, 2H); 4.11 (q, 4H);
7.04 (m, 2H); 7.25 (m, 2H) ppm.
WO 3~ 7~ PCTrUS97/13248 0 Example IX
Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-hydroxymethylpyridine-5-carboxylate ¢~
H o~cooc2H5 ~' ~
257 ml (0.9 mol) of a 3.5 molar solution of sodium-bis-(2-methoxy-ethoxy)dihydroaluminate is steadily added by drops under nitrogen to a solution of 120 g (0.3 mol) of the compound from Example VIII in 800 ml of dried tetrahydrofuran at room temperature, and the mixture is subsequently stirred for 5 10 h. After cooling to 0~C, 500 ml of water is carefully added by drops, the phases are separated, and the aqueous phase is extracted three times with 250 ml ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated in a vacuum. Theresidue is mixed with petroleum ether, drawn off by suction, and dried in a 15 desiccator.
Yield: 69.1 g (64.2% of theory) 1H-NMR (CDCl3): ~ = 0.95 (t, 3H); 1.31 (m, 12H); 3.05 (m, lH); 3.48 (m, lH);
3.95 (q, 2H); 4.93 (d, 2H); 7.05 - 7.31 (m, 4H) ppm.
20 Example X
Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-formyl-pyridine-5-carboxylate OHC~,COOC2H5 WO 98104528 PCTrUS97/13248 0 14.18 g (0.139 mol) of neutral Al2O3 and 29.96 g (0.13 mol) of pyridinium ch}orochromate (PCC) are added to a solution of 25.0 g (0.0695 mol) of the compound from Example IX in 500 ml CH2Cl2 and the mixture is stirred for 1 h at room temperature. It is drawn off by suction over silica gel and subsequently washed with CH2Cl2, and the filtrate is concentrated in a vacuum, whereby the product precipitates out.
Yield: 20 g (80.48% of theory) lH-NMR (DMSO-d6): ~ = 0.92 (t, 3H); 1.39 (dd, 6H); 3.02 - 3.13 (m, lH); 3.75 -3.86 (m, lH); 3.95 - 4.05 (q, 2H); 7.32 (m, 4H); 9.8 (s, lH) ppm.
Example XI
Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-[(4-fluorophenyl)hydroxymethyl]-pyridine-5-carboxylate HO ~J
~ 3. ~ oc2H5 10.0 g (27.98 mmol) of aldehyde from Example X is cooled to -70~C in 100 g THF p.a. under argon, 33.6 ml (33.58 mmol, 1.2 eq.) of p-fluorophenyl magnesium bromide solution is added by drops at -70~C, and the mixture is then stirred foranother 2 h at -70~C. The reaction solution is mixed with 200 ml of conc. NH4Cl solution, the cooling bath is removed, and the solution is adjusted with 1 molarHCl, pH = 6. After extraction with 400 ml of CH2Cl2 and drying over Na2SO4, the organic phase is concentrated in a vacuum and the rigid foam is crystallized using n-heptane.
Yield: 8.97 g (70.7% of theory) Rf = 0.18 (toluene) 0 Example XII
Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-[(4-fluorophenyl)-chloromethyl]-pyridine-5-carboxylate Cl ¢~
F {~l OC2H5 907 mg (2 mmol) of the compound from Example XI is dissolved in 20 g of CH2C12 p.a. and cooled under argon at -40~C, and 0.44 ml (6 mmol) SOC12 are added. The solution is stirred for 1.5 h from -40~C to -5~C and afterwards agitated in 50 ml of ethyl acetate / 40 ml of NaHC03 solution. The organic phase is separated off, dried over Na2SO4, concentrated in a vacuum, and chromatographed on diatomaceous earth using toluene.
Yield: 89g mg (95% of theory) Rf - 0.79 (toluene) Example XIII
3-Ethyl 5-methyl 3,4-dihydro-4-(4-fluorophenyl)-6-p-fluorophenyl-(lH)-pyrid-2-20 one-3,5-dicarboxylate H5C200C~,COOCH3 O N~
H ~F
W098t04528 PCTrUS97113248 30.69 g (115.3 mmol) of ethyl 1-carboethoxy-2-(4-fluorophenyl)-propenate, 22.5 g (115.3 mmol) of methyl 3-amino-3-(4-fluorophenyl)-acrylate, 115 mg of sodium methylate, and 0.6 ml of ethanol are stirred for 48 h at a bath temperature of 140~C. The reaction mixture is absorbed in ethyl acetate, washed three times 5 with water, dried over Na2SO4, and concentrated in a vacuum.
Yield: 43.2 g (90.2% of theory) Rf = 0.26 (toluene / ethyl acetate 9:1) Example XIV
3-Ethyl 5-methyl 4-(4-fluorophenyl)-6-p-fluorophenyl-(lH)-pyrid-2-one-3,5-dicarboxylate H5C200C~,COOCH3 H ~ F
Analogously to Example I, 1.00 g (0.2407 mol) of the compound from Example XIII is stirred with 277 g (0.506 mol) of ceric(IV) ammonium nitrate in 600 ml of acetonitrile and 600 ml of water for 3 h at room temperature. After extraction with ethyl acetate, the residue is crystallized from isopropanol.
Yield: 28.59 g (28.7% of theory) Rf = 0.16 (toluene / ethyl acetate 8:2) WO 98/0~528PCT~US9711~248 O I~xa,~,ylc XV
3-Ethyl 5-methyl4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3,5-dicarboxylate ¢~
H5C200C~,~ ~,COOCH3 O J'N ~
Following the instructions in Example II, 5.0 g (0.0121 mol) of the mixture from Example XIV in 20 ml of DMF is reacted in the presence of 0.783 g (0.0196 mol) of 60% NaH with 3.61 g (0.0242 mol) of cyclopentyl bromide. After chromatography on silica gel using toluene, 5.14 g (88.3% of theory) is obtained.
Rf = 0.34 (toluene) Example XVI
Methyl 4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-hydroxymethyl-15 pyridine-5-carboxylate HO ¢~
~COOCH3 1' ~
Analogously to Example IIl, 3.719 g (7.72 mmol) of the compound from Example XV in 150 g of toluene is stirred with 11.58 ml (11.58 mmol) of DIBAL-H
WO 98104528 PCT~US97113248 O (1.0 molar) for 2.5 h at -78~C. The compound is chromatographed on silica gel first with toluene and then with toluene / ethyl acetate (9:1).
Yield: 1.648 g (48.5% of theory) Rf = 0.45 (toluene / ethyl acetate 9:1) 5 Example XVII
Methyl 4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-formyl-pyridine-5-carboxylate ~ ~i Following the instructions in Example IV, 1.636 g (3.72 mmol) of the compound from Example XVI in 150 ml of CH2Cl2 is stirred with 0.759 g (7.44 mmol) of Al2O3 (neutral) and 1.604 g (7.44 mmol) of PCC for 1.5 h. The crude product is purified by chromatography on silica gel using toluene.
Yield: 1.484 g (91.2% of theory) Rf = 0.59 (toluene / ethyl acetate 9:1) Example XVIII
Methyl 4-t4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-[(naphthyl-2)-hydroxy-methyl]-pyridine-5-carboxylate , . .. ... .. .
W098/04528 PCT~US97113248 H O '~i J
0 ~ F
53.4 mg (2.2 mmol) of magnesium shavings is heated to reflux in 10 ml of THF p.a. under argon. 313 mg (1.51 mmol) of 2-bromonaphthalene dissolved in 15 ml of THF is added to this and the solution is boiled 75 min to reflux in the presence of iodine crystals (= Grignard reagent). 220 mg (0.503 mmol) of the compound from Example XVII is dissolved in 5 ml of THF p.a. and cooled under argon to -70~C, and the Grignard reagent is sprayed in. The batch is subsequently stirred for one hour without cooling. The reaction solution is distributed in ethyl acetate /
ammonium chloride solution, and the organic phase is separated off, washed with NaCl solution, dried, and concentrated. Chromatography is then carried out on silica gel using toluene.
Yield: 261 mg (91.9% of theory) Rf - 0.57 (toluene / ethyl acetate 9:1) Example XIX
Methyl 4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-[(naphthyl-2)-fluoromethyl] -pyridine-5-carboxylate F
' ' r~ H~
W 098/04528 PCTrUS97/13248 0.08 mmol (0.60Z mmol) of diethylamino sulfur trifluoride (DAST) is added to a solution of 227 mg (0.401 mmol) of the compound from Example XVIII in 10 g of CH2Cl2 at -40~C under argon, the cooling bath is removed, and the solution is stirred for 20 min. The reaction solution is subsequently distributed in ethyl acetate 5 / NaHCO3 solution, and the organic layer is dried with Na2SO4 and concentrated in a vacuum. The crude product is chromatographed on silica gel using toluene.
Yield: 224 mg (98.6% of theory) Rf = 0.67 (toluene) Production Examples Example 1 2,6-Diisopropyl-3-p-fluorobenzyl-4-p-fluorophenyl-5-hydroxymethyl-pyridine F
T " I
5.7 g (150 mmol) of LiAlH4 are suspended in 200 ml of THF, heated to 80~C, and mixed by drops with a solution of 23.7 g of the compound from Example XII in150 ml of THF. After being stirred for 5 h, the mixture is cooled, carefully neutralized with 20% Na-K-tartrate solution, and extracted three times with ethyl acetate, and the organic phase is dried, concentrated, and chromatographed over silica gel 60 (toluene).
Yield: 13.6 g (69% of theory) Rf = 0.59 (toluene / ethyl acetate = 9/1) WO 98/04528 PCTIUS97113~48 O The compounds listed in Table 1(A) are produced in analogy to the instructions in Example I:
Table 1(A):
Ex. G Rf Solvent No.
2 OH 0.60 toluene /
J CH ethyl acetate 3 9:1 3 OH 0.74 toluene /
~,CH3 ethyl acetate 9:1 4 OH 0.75 toluene /
~CH3 ethyl acetate 9:1 WO ~ PCT~US97/13248 O ~:x~ le 5 ~(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-[(naphthyl-2)-fluoromethyl]-5-hydroxymethyl-pyridine Cl ~1 O~l ~ F
Analogously to the instructions of Example 1, 182 mg (0.321 mmol) of the compound from Example XIX in 10 ml of THF p.a. is boiled with 18.3 mg (0.481 mmol) of LiAlH4 for 1 h under reflux. The compound is purified by 10 chromatography on silica gel first with toluene and then with toluene / ethyl acetate (9:1).
Yield: 86 mg (49.7% of theory) Rf = 0.47 WO 98l04~28 PCIIUS97/13248 O The compounds listed in Table 2(B) are produced in analogy to the instructions of Example 5:
Table 2(B):
R22~ 0 H
Z~ ~JE
Ex. E R22 z1/Z2 L Rf No. (solvent) 6 cyclo-C6H11 H p-F / HCH(CH3)2 0 59 toluene /
ethyl acetate 9:1 7 CH(CH3)2 NH2 p-F / HCH(CH3)2 0.60 toluene /
ethyl acetate 1:1 8 CH(CH3k SH p-F / HCH(CH3)2 0.31 toluene /
ethyl acetate 9:1 g CH(CH3)2 Cl p-CF3 / HCH(CH3)2 054 toluene /
ethyl acetate 9:1 CH(CH3)2 H 3,4-F2CH(CH3)2 0.26 toluene 11 4-F-C6H4 F p-CF3 / H~CH3 0.48 - toluene /
ethyl acetate 9:1 WO 98l04528 PCTIUS97/13248 0 Table 2(B), contd.
Ex. E R22 z1/Z2 L Rf No. (solvent) 12 CH(CH3)2 F p-F / H CH(CH3)2 0.21 toluene 13 4-F-C6H4 F p~F3 / H (~,rclo-C7H13)O 0.28 petroleum ether /
ethyl acet~te 5:1 Example 14 2-Isopropyl-6-methoxy-4-(4-fluorophenyl)-5-[2-(benzoxazol-2-yl)ethyl]-3-hydroxymethylpyridine 69 mg (0.15 mmol) of the compound from Example VI is dissolved in 5 g of toluene and mixed with 0.6 ml DIBAL-H (1.0 molar in toluene). The mixture is then stirred without a cooling bath for 4 h to +15~C. 30 ml of ethyl acetate and 15 ml of a 20% potassium sodium tartrate solution is added, and the solution is stirred for 10 min. The aqueous layer is separated off, and the organic phase is dried, concentrated, and chromatographed. After chromatography on 20 ml of silica gel using toluene / ethyl acetate (9;1),19 mg (30.2% of theory) is o~tained.
Rf = 0.28 (toluene / ethyl acetate 9:1) WO 98/04528 PCT/US97tl3248 O Detailed description with refer~l,ce to compounds of ~eneral formula (IB) The compounds according to the invention can also occur in the form of the salts thereof. In general, salts with organic or inorganic bases or acids are mentioned here.
Within the context of the present invention, physiologically safe salts are preferred. Physiologically safe salts from the compounds according to the invention can be salts of substances according to the invention with mineral acids, carboxylic acids, or sulfonic acids. Salts with, for example, hydrochloric acid,10 hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid, or benzoic acid are particularly yr~elled.
Physiologically safe salts can also be metallic or ammonium salts of the compounds according to the invention that possess a free carboxyl group. For example, sodium salts, potassium salts, magnesium salts, or calcium salts, as well as ammonium salts, that are derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, 20 dimethylaminoethanol, arginine, lysine, ethylenediamine, or 2-phenylethylamine are particularly preferred.
The compounds according to the invention can exist in stereoisomeric forms, which either behave like an image and mirror image (enantiomers) or do not 25 behave like an image and mirror image (diastereomers). The invention concernsboth enantiomers or diastereomers or the mixtures thereof. These mixtures of enantiomers and diastereomers can be separated in the known manner into stereoisomerically homogeneous components.
Within the context of the invention, the heterocyclic compound, which is optionally benzo-condensed, stands in general for a saturated or unsaturated, 5- to 7-member, and preferably 5- to 6-member, heterocyclic compound that can contain up to 3 heteroatoms from the series S, N, and/or O. Tetrazolyl, isoquinolyl, quinolyl, benzo[b]thiophene, benzo[b]furanyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, pyrinyl, benzothiazolyl, phenoxathinzyl, benzoxazolyl, tetrahydropyrimidyl, pyrazolopyrimidyl, pyrrolyl, thiazolyl, oxazolyl, and imidazolyl are cited as examples. Quinolyl, furyl, pyridyl, tetrahydropyrimidyl, 5 l 0 indolyl, benzothiazolyl, benzoxazolyl, pyrinyl, and pyrazolopyrimidyl are preferred.
This also includes 5- to 7-member saturated heterocyclic compounds bound via N, which can also contain up to 2 oxygen, sulfur, and/or nitrogen atoms as heteroatoms, such as piperidyl, morpholinyl, or piperazine or pyrrolidinyl.
Piperidyl and pyrrolidinyl are particularly ~re~lled.
Compounds of general formula (IB) are preferred, in which A stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR2R3 and/or by a group of the formula -W-R4, wherem R2 and R3 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 4 carbon atoms, W denotes an oxygen or sulfur atom, R4 denotes phenyl or benzyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, hydroxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, 30 D and E are identical or different and stand for a straight-chain or branched alkyl chain w*h up to 6 carbon atoms, or 35 E stands forabond, V stands for an oxygen or sulfur atom or for a group of the formula -NR5, WO 981'~ PCTtUS97113248 wherein R5 denotes hydrogen or straight-chain or branched alkyl with up to 4 carbon atoms or phenyl, R1 stands for cyclopropyl, cyclopentyl, or cyclohexyl, or tetrahydropyrimidyl stands for phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, tetrahydropyrimidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl, pyrazolopyrimidyl, or purine-yl, with the rings, also via the N function in the case of nitrogen-containing rings, being optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 4 carbon atoms each, triazolyl, tetrazolyl, benzoxathiazolyl, or phenyl, and/or by a group of the formula -oR6, -SR7, or -SO2R8, wherein R6, R7, and R8 are identical or different and denote phenyl, which in turn is substituted up to 2 times in an identical manner or diffelelllly by phenyl, fluorine, chlorine, or by straight-chain or branched alkyl with up to 4 carbon atoms, L and T are identical or different and stand for trifluoromethyl, pyrrolidinyl, or for straight-chain or branched alkyl with up to 7 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, naphthyl, or phenyl, which in turn can be substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, - 35 or CA 02262434 l999-0l-28 wog8/a~e~ PCT~US97/13248 0 L and/or T stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or for naphthyl, phenyl, pyridyl, or furyl, which optionally can be substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, and the salts thereof.
Compounds of general formula (IB) are particularly preferred, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 4 carbon atoms each or by benzyloxy, which in turn can be substituted by fluorine or chlorine.
D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 3 carbon atoms, or 25 E stands for a bond, V stands for an oxygen or sulfur atom or for a group of the formula -NR5, wherein R5 denotes hydrogen or straight-chain or branched alkyl with up to 3 carbon atoms, Rl stands for cyclo~roE~yl, cyclopentyl, or cyclohexyl, or tetrahydropyrinidyl stands for phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, tetrahydropyrimidyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, 0 morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl, pyrazolopyrimidyl, or purine-yl, with the rings, also via the N-function in the case of nitrogen-containing rings, optionally being substituted up to 3 times in an identical manner or difl~rently by fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, ~ 5 trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 3 carbon atoms each, triazolyl, tetrazolyl, benzoxathiazolyl, or phenyl, and/or substituted by a group of the formula -oR6, -SR7, or -SO2R8, wherein 1~6, R7, and R8 are identical or different and denote phenyl, which in turn is substituted up to 2 times in an identical manner or di~rerelllly by phenyl, fluorine, chlorine, or is substituted by straight-chain or branched alkyl with up to 3 carbon atoms, L and T are identical or different and stand for trifluoromethyl, pyrrolidinyl, or for straight-chain or branched alkyl with up to 6 carbon atoms, which are optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, which in turn may be substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 4 carbon atoms each, or L and/or T stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for naphthyl, phenyl, or furyl, which are optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 3 carbon atoms each, and the salts thereof.
W 098/04528 PCTrUS97/13248 O The compounds according to the invention of general formula (IB) are particularly preferred, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, methoxy, methyl, or by fluorine- or chlorine-substituted benzyloxy.
Moreover, a process for the production of compounds according to the invention of general formula (IB) has been discovered, characterized in that [A] in the case of V = O
compounds of general formula (II) A
HO-D~ Rl I
~ll ,1 (II) in which A, D, L, and T have the indicated meaning, 20 and R11 stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms or for the group of the formula -CH2-O-Si(CH3)2C(CH3)3, 25 are reacted with compounds of general formula (III) Rl-E-Z (III) in which R1 and E have the indicated meaning and WO 38~ PCT~US97113248 0 Z stands for halogen, preferably chlorine or bromine, in inert solvents, optionally in the presence of bases and/or auxiliary agents, and reductive separation is then carried out, depending on the meaning of the group Rll, or [B] compounds of general formula (II) are first converted by reactions with compounds of general formula (IV) R 1~ S--Cl (IV) in which 15 R12 stands for straight-chain alkyl with up to 4 carbon atoms, into compounds of general formula (V) Rl ~ S--~~ ~ Rl l Il . .1, ~ (V) ~ L~ N T
in which A, D, L, T, R11, and R12 have the indicated meaning, and these are then reacted with compounds of general formula (VI) R1-E-V-H (VI) in which 30 R1, E, and V have the indicated meaning, and reductive separation is carried out, WO ~8/01-2~ PCTrUS97/13248 and optionally, the groups listed under substituents A, L, T, and 1;~l are introduced or varied according to customary methods.
5The processes according to the invention can be explained, for example, by means of the following reaction diagrams:
[A] F
¢~
HO~2C2H5 F3C~=~ F
O~N \~Br ¢~1 F3C~¢~c2H5 ¢~ /H4 F3C~I3~[~,oH F
F3C,~o Si ~J r WO 98/04528 PC~IUS97/13248 [B] F~ FJ~
HO~2c2H5 H3CO2SO~[~2C2H5 F~
(3~'o~2c2Hs ~locki g~OH
F~ HCl/methanol ~0~ ~O~
¢~f C FJ~
F~ H3C~ O~
HO~ J~O- Si W O 98/04528 PCTrUS97113248 [C] F
¢~
H3C--~--O~, $
NH~
~S~,O- Si ¢~
~0- li--De-blocking / <\ ~
HCI/methan~l ~ ~ ~
¦ ~ De-blocking F
N~ ~J HCllm-~th~nQl ¢~
S~, ~ ~,OH
Suitable solvents for this process are inert organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether or tetrahydrofuran, halocarbons such as dichloromethane, trichloromethane, 5 tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane, or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile, or hexamethylphosphoric triamide. It is W0~8/0~8 PCTAUS97113248 0 also possible to use mixtures of the solvents. Dichloromethane, tetrahydrofuran, toluene, or dimethylformamide are particularly preferred.
In general, as auxiliary agents for the process according to the invention, inorganic or organic bases may be used. These preferably include alkali hydroxides 5 such as sodium hydroxide or potassium hydroxide, alkaline earth hydroxides such as barium hydroxide, alkali carbonates such as sodium carbonate or potassium carbonate, alkaline earth carbonates such as calcium carbonate, or alkali or alkaline earth alcoholates such as sodium or potassium ethanolate, sodium or potassium methanolate, or potassium tert-butylate, or organic amines (trialkyl(C1-C6)amines) 10 such as triethylamine, or heterocyclic compounds such as 1,4-diazabicyclo[2.2.2]octane tDABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),pyridine, diaminopyridine, methylpiperidine, or morpholine. It is also possible to use alkali metals such as sodium and hydrides thereof such as sodium hydride as bases. Sodium and potassium carbonate and triethylamine are preferred.
As bases, the usual strongly basic compounds can be used for the individual steps. These preferably include lithium organic compounds such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, or phenyl lithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithiumhexamethylsilyl 20 amide, or alkali hydrides such as sodium hydride or potassium hydride. N-butyl lithium or sodium hydride should preferably be used.
The bases are used in a mixture of 1 mole to 5 moles, and preferably 1 mole to 3 moles, relative to 1 mole of the compound of general formula (II~.
In general, the reaction is carried out in a temperature range of 0~C to 150~C, and prereldbly from +20~C to +110~C.
The reaction can be carried out at normal, increased, or reduced pressure 30 (for example, 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
As derivatizations, the following types of reactions are cited as examples:
oxidations, reductive separation, reductions, hydrogenations, halogenation, 35 Wittig/Grignard reactions, and amidation/sulfoamidation.
6 l W 098t04528 PCT~US97113248 0 Suitable solvents are ethers such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, or cyclohexane, or petroleum fractions, or halocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, or trichloroethylene, or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethyl formamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is also possible to use mixtures of said solvents. Dichloromethane is preferred.
Suitable organometallic reagents are Grignard systems such as Mg/bromobenzotrifluoride and p-trifluoromethylphenyl lithium. The Mg/bromobenzotrifluoride system is ~lefelled.
The reductions and derivatizations are carried out according to the above-mentioned methods.
In general, the reductions are carried out in ethers such as dioxane, tetrahydrofuran, or diethyl ether, or in hydrocarbons such as benzene, hexane, or toluene. Toluene and tetrahydrofuran are ~lefe.led.
Suitable reductants are complex metal hydrides such as lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutyl aluminum hydride, dimethoxymethyl aluminate sodium salt, or sodium-bis(2-methoxyethoxy) dihydroaluminate (Red-Al). Diisobutyl aluminum hydride and dimethoxymethylaluminate sodium salt are ~referred.
The reductant is generally added in the amount of 4 moles to 10 moles, and ~re~lably from 4 moles to 5 moles, relative to 1 mole of the compound to be reduced.
The reduction generally takes place within a temperature range of -78~C to +50~C, preferably from -78~C to 0~C, and particularly preferably at -78~C, depending on the choice of both the reductant and the solvent.
The reduction generally takes place at normal pressure, but it is also possible to work at increased or reduced pressure.
0 However, the reductions can also be carried out with reductants that are suitable for the reduction of ketones to hydroxy compounds. Particularly suitable in this regard is reduction using metal hydrides or complex metal hydrides in inert solvents, if appropriate, in the presence of a trialkyl borane. Preferably, the reduction is carried out using complex metal hydrides such as lithium borohydride, ~ 5 sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylborohydride, or lithium aluminum hydride. More preferably, the reaction is carried out using sodium borohydride in the presence of triethyl borane.
The hydrogenation takes place according to the customary methods using hydrogen in the presence of noble metal catalysts such as Pd/C, Pt/C, or Raney nickel in one of the above-mentioned solvents, preferably in alcohols such as methanol, ethanol, or propanol, within a temperature range of -20~C to +100~C, preferably from 0~C to 50~C, at normal pressure or elevated pressure.
As derivatizations, the following types of reactions are cited by way of examples: oxidations, reductions, hydrogenations, halogenation, Wittig/Grignard reactions, and amidation/sulfoamidation.
The customary strongly basic compounds can be used as bases for the individual steps. These preferably include organolithium compounds such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, or phenyl lithium, or amides such as lithium diisopropylamide, sodium amide, or potassium amide, or lithium hexamethylsilyl amide, or alkali hydrides such as sodium hydride or potassium hydride. n-butyl lithium or sodium hydride are particularly preferred.
Furthermore, the customary inorganic bases are suitable bases. These ~re~lably include alkali hydroxides or alkaline earth hydroxides such as sodium hydroxide, potassium hydroxide, or barium hydroxide, or alkali carbonates such as sodium carbonate, potassium carbonate, or sodiurn hydrogencarbonate. Sodium hydroxide or potassium hydroxide are particularly pre~el,ed.
Alcohols such as methanol, ethanol, propanol, or tert-butanol are also suitable solvents for the individual reaction steps. Tert butanol is ~re~lled.
It may possibly be necessary to carry out several reaction steps under a protective gas atmosphere.
WO 98/04528 PCT~US97113248 0 The halogenations generally take place in one of the above-mentioned chlorinated hydrocarbons, with methylene chloride being ~lef~lled.
Diethylamino sulfur trifluoride (DAST) or SOC12, for example, are suitable halogenation agents.
The halogenation generally takes place within a temperature range of -78~C
to +50~C, preferably from -78~C to 0~C, and particularly preferably at -78~C, depending on the choice of both the halogenation agent and the solvent.
The halogenation generally takes place at normal pressure, but it is also possible to work at increased or reduced pressure.
The customary reagents are suitable as Wittig reagents. 3-Trifluoro-methylbenzyltriphenylphosphonium bromide is preferred.
In general, one of the above-mentioned bases is suitable as a base, preferably Li-bis-(triethylbutyl)amide.
The base is used in an amount of 0.1 moles to 5 moles, ~refelably 0.5 moles 20 to 2 moles, in relation to 1 mole of the parent compound.
The reaction with Wittig reagents is generally carried out in a temperature range of 0~C to 150~C, preferably at 25~C to 40~C.
The Wittig reactions are generally carried out at normal pressure. However, it is also possible to carry out the process at reduced or high pressure (e.g., within a range of 0.5 to 5 bar).
The compounds of general formula (II) are known in part or new and can then be produced from the corresponding dihydropyridines of general formula (VII) Rl302C~Co2Rl4 L N T
.. ......... . . ...
WO g8/04528 PCTIUS97113248 0 in which A, L, and T have the above-indicated meaning, and R13 and R14 are identical or different and denote straight-chain or branched alkyl with up to 4 carbon atoms, through oxidation into the corresponding pyridines and finally depending 10 on the substituents a reduction according to conventional methods can be carried out.
Suitable solvents for the oxidation are ethers such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimethyl ether; or hydrocarbons such as benzene, 15 toluene, xylene, hexane, or cyclohexane, or petroleum fractions, or halocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene,or trichloroethylene, or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is also possible to use a mixture of said 20 solvents. Dichloromethane is preferred.
Suitable oxidants are, for example, 2,3-dichloro-5,6-dicyanobenzoquinone, pyridinium chlorochromate (PCC), osmium tetroxide, and manganese dioxide. For the above-mentioned step, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is 25 yrefe~,ed.
The oxidant is introduced in an amount of 1 mole to 10 moles, preferably 2 moles to 5 moles, relative to 1 mole of the compound of general formula (VII).
The oxidation generally takes place within a temperature range of -50~C to +100~C, preferably from 0~C to room temperature.
The oxidation generally takes place at normal pressure. However, it is also possible to carry out the oxidation at increased or reduced pressure.
The dihydropyridines of general formula (VII) are known per se or can be produced by customary methods.
WO 98/04~28 PCTrUS97/13248 The compounds of general formulas (III), (IV), and (VI) are known per se or can be produced by customary methods.
The compounds of general formula (V) are new or can be manufactured as 5 described above.
The 3-heteroalkyl-aryl-substituted pyridines according to the invention possess valuable pharmacological properties that are superior to those of the state of the art; in particular, they are highly effective inhibitors of cholesterol ester 10 transfer proteins (CETP) and stimulate reverse cholesterol transport. The active compounds according to the invention cause a reduction in LDL cholesterol levelsin the blood, while at the same time increasing HDL cholesterol levels. They cantherefore be used for the treatment of hyperlipoproteinemia or arteriosclerosis.
The invention additionally concerns the combination of compounds according to the invention with a glucosidase and/or amylase inhibitor for the treatment of f~mili~l hyperlipidemia, obesity (adiposis), and diabetes mellitus.Within the context of the invention, glucosidase and/or amylase inhibitors are, for example, acarbose, adiposine, voglibose, miglitol, emigl*ate, MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688, lesLl ali~, pradimicin-Q, and salbostatin.
The com~ination of acarbose, miglitol, emiglitate, or voglibose and one of the above-mentioned compounds of general formula (IB) according to the invention is preferred.
CETP Inhibition Test 1. Obtainin~ CETP
CETP was obtained in partially purified form from human plasma by di~ferenlial centrifugation and column chromatography and was used for testing. In so doing, human plasma was adjusted with NaBr to a density of 1.21 g/ml and was centrifuged for 18 h at 50,000 rpm at 4~C. The bottom fraction (d>1.21 g/ml) was applied to a Sephadex~) Phenyl-Sepharose 4B
(Pharmacia) column, washed with 0.15 m NaCl/0.001 m Tris HCI, pH 7.4, and then eluted with dist. water. The CETP-active fractions were pooled, dialyzed against 50 mM Na acetate, pH 4.5, and applied to a CM-Sepharose(~
Wo~ 1'?8 PCTrUS97/13248 0 (Pharmacia) column. They were then eluted with a linear gradient (0-1 MNaCl). The pooled CETP fractions were dialyzed against 10 mM Tris HCl, pH 7.4, and were then further purified by chromatography over a Mono Q(~) column (Pharmacia).
~ 5 2. Obtainin~radioactivel~-labeled HDL
50 ml of fresh human EDTA plasma was adjusted with NaBr to a density of 1.12 and centrifuged at 4~C for 18 h at 50,000 rpm in the Ty 65 rotor. The upper phase was used to obtain cold LDL. The lower phase was dialyzed against 3 x 4 l PDB buffer (10 mM Tris/HCl, pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN3). 20 ,ul of 3H cholesterol (Du Pont NET-725; 1 -~C/,ul dissolved in ethanol) was subsequently added per 10 m~ of dialysis residue volume and incubated for 72 h at 37~C under N2.
The sediment was then adjusted with NaBr to a density of 1.21 and centrifuged in the Ty 65 rotor for 18 h at 50,000 rpm at 20~C. The upper phase was obtained, and the lipoprotein fractions were purified by gradient centrifugation. In so doing, the isolated, tagged lipoprotein fraction was adjusted with NaBr to a density of 1.26. Every 4 ml of this solution was covered in centrifuge tubes (SW 40 rotor) with 4 ml of a solution with a density of 1.21 and 4.5 ml of a solution with a density of 1.063 (density solutions from PDB buffer and NaBr) and then centrifuged for 24 h at 38,000 rpm and 20~C in the SW 40 rotor. The intermediate layer between the density of 1.063 and 1.21 that contained the labeled HDL was dialyzed against 3 x 100 volumes of PDB buffer at 4~C.
The dialysis residue contained radioactively-labeled 3H-CE-HDL, which was adjusted to approx. 5 x 106 cmp per ml and used for the test.
3. Conductin~ the test In order to test the CETP activity, the transfer of 3H cholesterol ester from human HD lipo~roL~ s to biotinylated LD lipoproteins was measured.
The reaction was ended by adding Streptavidin-SPA(g) beads (Amersham), and the transferred radioactivity was determined directly in the liquid scintillation counter.
In the test batch, 10 ~l of HDL-3H cholesterol ester (~50,000 cpm) was incubated for 18 h at 37~C with 10 ~l of biotin-LDL (Amersham) in 50 mM
HEPES / 0.15 m NaCl / 0.1% bovine serum albumin / 0.05% NaN3, pH 7.4, with 10 ~l of CETP (1 mg/ml) and 3 ~l solution of the substance to be tested WO 98/0452B PCT~US97/13248 O (dissolved in 10% DMSO / 1% BSA). Then, 200 ~1 of the SPA-Streptavidinbead solution (Amersham TI~KQ 7005) was added, and the mixture was further incubated for 1 h under agitation and subsequently measured in the scintillation counter. Corresponding incubations with 10 ~l buffer, 10 ~LI
CETP at 4~C, and 10 ~ll CETP at 37~C served as controls.
The transferred activity in the control batches with CETP at 37~C was assessed as 100% transfer. The substance concentration in which this transfer was reduced by half was indicated as the ICso value.
Syrian golden hamsters from the company's own breeding were anesthetized after fasting for 24 h (0.88 mg/kg atropine, 0.80 mg/kg Ketavet(~ s.c., 30' later 50 mg/kg Nembutal i.p.). The jugular vein was then exposed and cannulated. The test substance was dissolved in a suitable solvent (as a rule, Adalat placebo solution: 60 g glycerin, 100 ml H2O, ad 100 ml PEG-400) and administeredto the animals via a PE catheter inserted into the jugular vein. The control animals received the same volume of solvent without any test substance. The vein was then ligated and the wound closed up. At different intervals--up to 24 h after administration of the test substance blood was drawn from the animals by puncture of the retroorbital venous plexus (approx. 250 ~ll). Coagulation was completed by incubating at 4~C overnight, and the blood was then centrifuged for10 minutes at 6,000 g. The cholesterol and triglyceride content in the serum obtained in this manner was determined using modified commercially-available enzyme tests (cholesterol enzymatic 14366 Merck, triglyceride 14364 Merck). The serum was diluted in a suitable manner with physiological saline solution. 100 ~l serum dilution was mixed with 100 ,ul of test substance in 96-well plates and incubated for 10 minutes at room temperature. The optical density was then determined with an automatic plate reader at a wavelength of 492 nm (SLT-Spectra). Ihe triglyceride/cholesterol concentration contained in the samples was determined using a parallel-measured standard curve.
The deterrnination of the HDL cholesterol content was carried out after precipitation of the lipoproteins containing Apo B by means of a reagent mixture(Sigma 352-4 HDL cholesterol reagent) according to the manufacturer's instructions.
In attempting to determine oral efficacy, the test substance, which was dissolved in DMSO and suspended in 0.5% methylcellulose, was administered orallyto Syrian golden hamsters from the company's own breeding via a pharyngeal WO 38~ 1528 PCT/US97113248 0 tube. The control animals received identical volumes of solvent without any test substance. Feed was then withheld from the animals, and blood was drawn at different intervals--up to 24 h after administration of the substance--via puncture of the retroorbital venous plexus. Further processing was carried out as described above.
The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions, and solutions, using inert, nontoxic, pharmaceutically-suitable excipients or solvents. In this connection, the 10 therapeutically-active compound should be present in each case in a concentration of about 0.5% to 90% by weight, i.e., in amounts that are sufficient to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active 15 compounds using solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, with it being possible, for example, in the case of the use of water as a diluent, to use organic solvents, if appropriate, as auxiliary soIvents.
Administration takes place in a customary manner, preferably orally or 20 parenterally, in particular, perlingually or intravenously.
In the case of parenteral use, solutions of the active compound can be employed using suitable liquid excipients.
In general, it has proved to be advantageous in intravenous administration to administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight, to obtain effective results, and in oral administration, the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.
In spite of this, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of administration route, individual response to the medication, the type of formulation thereof, and the time or interval at which administration takes place. Thus in some cases, it may be sufficient to manage with less than the minimum amount previously mentioned, whereas in other cases, the upper limit mentioned must be exceeded. If larger amounts are administered, it may be advisable to divide these into several individual doses over the day.
W 098/04528 PCTrUS9711324 I. Mobile solvents for thin-layer chromatog~ hy A1 = PE98:EE2 A2 = PE95: EE5 A3 = PE9 :EE1 A4 = PE85:EE15 As = PE8 :EE2 A6 = PE75:EE25 A7 = PE7 :EE3 A8 = PE 65: EE35 Ag = PE 6: EE 4 A1o = PE55:EE45 A11 = PE1 :EE1 A12 = Toluene/ethyl acetate 1/1 A13 = Toluene/ethyl acetate 8/2 A14 = Acetonitrile/water 9/1 PE = petroleum ether; EE = ethyl acetate 20 Example I
1,4-Dihydro-2-cyclopentyl-6-ethyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylic acid-3-methylester-5-ethylester ¢~
H3COOC~ COOC2Hs Il 11 ~N--/
\ I H
6.2 g ~50 mmol~ of 4-fluoroben~aldehyde, 8.5 g (50 mmol) of 3-amino-cyclopenlyl~rop-2-ene-carboxylic methylester, and 7.2 g (50 mmol) of 4-methylacetoacetic ethylester are heated for 18 hours to 130~C while stirring.
30 After cooling to room temperature, chromatography is carried out over silica gel W0~8~'~tCt~ PCTAUS97/13248 0 (200 g of silica gel, 230-400 mesh; d 3.5 cm, mobile solvent ethyl acetate/petroleum etherl :9).
Yield: 2.8 g (14% of theory) Rf (ethyl acetate / petroleum ether 2: 8) = 0.31 ~xa,l,~lc II
2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylic acid-3-methylester- 5-ethylester H3COOC~ ~OC2Hs V
2.8 g (6.98 mmol) of 1,4-dihydro-2-cyclopentyl-6-ethyl-~(4-fluoro-phenyl)pyridine-3,5-dicarboxylic acid-3-methylester-5-ethylester is dissolved in 100 ml of absol. methylene chloride, and after addition of 1.6 g (6.98 mmol) of 2,3-dichloro-5,6-dicyano- p-benzoquinone (DDQ), the mixture is stirred for 1 hour at room temperature. After this, it is drawn off by suction over diatomaceous earth and concentrated in a vacuum. The residue is chromatographed over silica gel (100 g of silica gel, 230-400 mesh, d 3.5 cm, mobile solvent ethyl acetate / petroleum ether 5:95).
Yield: 2.1 g (75.4% of theory) Rf (ethyl acetate / petroleum ether 1:9) = 0.56 H-NMR (CDCl3): ~ = 0.95 (t, 3H); 1.32 (t, 3H); 1.6 - 2.1 (m, 8H); 2.83 (q, 2H);
3.14 (m, lH); 3.53 (s, 3H); 4.02 (q, 2H); 7.0-7.3 (m, 4H) ppm.
Example III and Example IV
2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-3-hydroxymethylpyridine-5-carboxylic acid ethylester (Example III) and 2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-5-hydroxymethylpyridine-3-carboxylic acid methylester (Example IV) W 098/04528 PCT~US97113248 F F
~OC2Hs H CO~C,OH
(III) (IV) Under argon, 2.1 g (5.26 mmol) of 2-cyclopentyl-6-ethyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylic acid-3-methylester5-ethylester is dissolved in 50 ml of absol. toluene. 26.6 ml of diisobutyl aluminum hydride (1 M solution in toluene) is added dropwise to this solution at -60DC. After this, the mixture isstirred for 15 minutes at-60~C, and the reaction solution is then cooled at -30~C for 18 h. After heating to 0~C, 50 ml of water is added, and the resulting sediment is drawn off by suction and washed 4 times with 50 ml of ethyl acetate. The aqueousphase is washed with 100 ml of ethyl acetate, and the combined organic phases are shaken out with 150 ml of saturated sodium chloride solution, dried with sodium sulfate, and concentrated in a vacuum. The residue is chromatographed over silica gel (100 g of silica gel, 230-400 mesh, d 3.5 cm, mobile solvent ethyl acetate /petroleum ether 15:85).
Yield (Example III): 0.263 g (13.5% of theory) Rf (ethyl acetate / petroleum ether 2:8) = 0.42 H-NMR (CDCl3): ~ = 0.95 (t, 3H); 1.28 (t, 3H); 1.6-2.1 (m, 8H); 2.76 (q, 4H);
3.55 (m, lH); 3.97 (q, 4H); 4.48 (d, 2H); 7.0-7.3 (m, 4H) ppm.
Yield (Example IV): 0.907 g (48.3% of theory) Rf (ethyl acetate / petroleum ether 2:8) = 0.32 H-NMR (CDCl3): ~ = 1.32 (t, 3H); 1.6-2.1 (m, 8H); 2.97 (t, 3H); 3.06 (m, lH);
3.45 (s, 3H); 4.45 (d, 2H) ppm.
The compounds shown in Table I(B) are produced analogously to the instructions for Examples I-IV:
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WO 98/04528 PCTrUS97/13248 O Example CXXXIX
2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-3-(3-trifluoromethylbenzyloxy-methyl)-pyridine-5-carboxylic acid ethylester F
~, F3C~Cf ~~C2~5 186 mg (0.5 mmol) of 2-cyclopentyl-6-ethyl-4-(4-fluorophenyl)-3-hydroxy-methylpyridine-5-carboxylic acid ethylester dissolved in 5 ml of absol. dimethylformamide is added dropwise at 0~C while stirring to a suspension of 18 mg (0.5 mmol) of sodium hydride (80%) in 5 ml of dimethyl formamide and subsequently stirred for 30 minutes. After this, 143 mg (0.6 mmol) of trifluoromethylbenzylbromide dissolved in 3 ml of dimethyl formamide is added, and the mixture is stirred for 18 h at room temperature. After addition of 25 ml of water, the mixture is extracted twice with 50 ml of ethyl acetate each time, and the combined ethyl acetate phases are shaken out with 10 ml of saturated sodium chloride solution, dried with sodium sulfate, and concentrated in a vacuum. The residue is chromatographed over silica gel (100 g of silica gel, 230-400 mesh, diameter 3.5 cm, mobile solvent ethyl acetate / petroleum ether 1:9).
Yield: 0.246 g (93.1% of theory) Rf value (ethyl acetate / petroleum ether 1:9) = 0.35 H-NMR (CDCl3): ~ = 0.95 (t, 3H); 1.32 (t, 3H); 1.6-2.1 (m, 8H); 2.78 (q, 4H);
3.44 (m, lH); 3.95 (q, 4H); 4.28 (s, 2H); 4.42 (s, 2H); 7.0-7.6 (m, 8H) ppm.
W098/04528 PCTrUS97/13248 O Example CXL
2,6-Diisopropyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylic acid diethylester F
C2HsOOC~,COOC2Hs 3.8 g (16.4 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone is added to a solution of 6.6 g (16.4 mmol) of 1,4-dihydro-2,6-diisopropyl-4-(~fluorophenyl)pyridine-3,5-dicarboxylic acid diethylester in 200 ml of analysisgrade methylene chloride, and the mixture is then stirred for 1 h at room 10 temperature. After this, it is drawn off by suction over diatomaceous earth, and the methylene chloride phase is extracted 3 times with 100 ml of water each time anddried on magnesium sulfate. After concentrating in a vacuum, the residue is chromatographed on a column (100 g of silica gel, 70-230 mesh, diameter 3.5 cm, with ethyl acetate / petroleum ether 1:9).
Yield: 5.8 g (87.9% of theory) H-NMR (CDCl3): ~ = 0.98 (t, 6H); 1.41 (d, 12H); 31 (m, 2H); 4.11 (q, 4H);
7.04 (m, 2H); 7.25 (m, 2H) ppm.
Example CXLI
2,6-Diisopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-pyridine-3,5-carboxylic acid ethylester ¢~
HOH2C~ COOC2Hs ~~' N~
. , ~ . .
Under nitrogen, 21 ml (80.5 mmol) of a 3.5 molar solution of sodium bis(2-methoxyethoxy)dihydroaluminate in toluene is added to a solution of 9.2 g (23 mmol) of the compound from Example CXL in 100 ml of dried tetrahydrofuran at -10~C to -5~C, and the mixture is stirred for 5 h at room temperature. After cooling ~ 5 to O~C, 100 ml of water is carefully added dropwise, and extraction is carried out 3 times with 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated in a vacuum. The residue is chromatographed on a column (200 g of silica gel, 70-230 mesh, diameter 4.5 cm, with ethyl acetate / petroleum ether 3:7).
Yield: 7.2 g (87.2% of theory) H-NMR (CDCl3): ~ = 0.95 (t, 3H); 1.31 (m, 12H); 3.05 (m, lH); 3.48 (m, lH);
3.95 (q, 2H); 4.93 (d, 2H); 7.05-7.31 (m, 4H) ppm.
Iix~ ,le CXLII
5-(tert-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluoro-phenyl)-pyridine-3-carboxylic acid ethylester (H3C)3C--Si- O--H2C~COOC2Hs ~N~
2.1 g (13.8 mmol) of tert-Butyldimethylsilyl chloride, 1.8 g (27.5 mmol) of imidazole, and 0.05 g of 4-dimethyl-aminopyridine are added to a solution of 4.5 g (12.5 mmol) of the compound from Example CXLI in 50 ml of dimethyl formamide at room temperature. The mixture is stirred overnight at room temperature, 200 ml 25 of water is added, and the mixture is adjusted to a pH of 3 with 1 N hydrochloric acid. The mixture is extracted 3 times with 100 ml of ether each time, and the combined organic phases are washed once with saturated sodium chloride solution,dried over magnesium sulfate, and concentrated in a vacuum. The residue is chromatographed on a column (150 g of silica gel, 70-230 mesh, diameter 4 cm, with 30 ethyl acetate / petroleum ether 1:9).
WO 98104528 PCT~US97113248 0 Yield: 4.2 g (73.7% of theory) Rf = 0.75 (A3) Example CXLIII
3-(tert-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethylpyridine CH3 ¢~:1 (H3C)3C- Si- O--H2C~f OH
~ N \~
IJnder argon, 76.0 ml (0.266 mmol; 3.6 eq.) of a 3.5 molar solution of sodium bis(2methoxyethoxy)dihydroaluminate (Red-Al) in toluene is slowly added to a solution of 35.0 g (0.0738 mmol) of the compound from Example CXLII in 500 ml ofanalysis-grade THF at room temperature, and stirring is then carried out for 3 h.
The reaction solution is mixed under ice cooling with 50 ml of a 20% potassium sodium tartrate solution and extracted with 200 ml of ethyl acetate. The organicphase is washed once with a saturated NaCl solution, dried over Na2SO4, and concentrated in a vacuum. The residue is chromatographed over silica gel 60 withtoluene / ethyl acetate (8:2).
Yield: 30.2 g (94.7% of theory) Rf = 0.71 (toluene / ethyl acetate 8:2) l~xample CXLIV
3-(ter~-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-methylsulfonyloxymethylpyridine wogp/05e~ PCTrUS97/13248 o ¢~ O- Si H3C--I$--o--H2C~
~ O ~N'~/
16.94 g (39.24 mmol) of 3-(tert-butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethylpyridine is dissolved in 220 gof analysis grade CH2Cl2, cooled to -60~C, and mixed dropwise with 11.0 ml (78.48 mmol; 2 eq.) of triethylamine and 6.1 ml (78.48 mmol; 2 eq.) of methanesulfonyl chloride under nitrogen while stirring. Stirring is carried out for 1 h at -60~C to -20~C and for 30 minutes at 0~C. After this, the reaction solution is w~shed wi~cold NaHCO3 solution, dried over Na2SO4, concentrated, dried for 60 min. in a high vacuum, and then stored at -20~C.
Yield: 19.8 g (99% of theory) Rf = 0.77 (toluene / ethyl acetate 8:2) Example CXLV
3-(tert-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-(1-methylimidazole-2-thiomethyl)pyridine N~ S~
1.0 g (1.96 mmol) of 3-(tert-butyldimethylsilyloxymethyl)-2,~diisopropyl-4-(4-fluorophenyl)-5-methylsulfonyloxymethylpyridine is placed in 15 ml of analysis-grade DMF. 0.256 g (2.25 mmol; 1.15 eq.) of 2-mercapto-1-methylimidazole and 0.41 ml (2.35 mmol; 1.2 eq.) of N,N-diisopropylamine are added, and the .
0 mixture is stirred overnight at 60~C. After this, 80 ml of ethyl acetate is added, and the mixture is then successively washed with saturated NaHCO3 solution, 1 N
H2SO4, and saturated NaCl solution. The organic phase is dried over Na2SO4, filtered, and concentrated.
Yield: 0.93 g (89.8% of theory) Rf = 0.35 (toluene / ethyl acetate 8:2) Example CXLVI
3-(tert-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-10 (indolyl-5-aminomethyl)pyridine F
~, 2.0 g (3.92 mmol) of 3-(tert-butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-methylsulfonyloxymethylpyridine is reacted in 20 ml of analysis grade DMF under nitrogen with 0.674 g (5.1 mmol; 1.3 eq.) of 5-aminoindole and 0.82 ml (4.71 mmol) of N,N-diisopropylethylamine analogously to the instructionsof Example CXLII.
Yield: 2.05 g (95.8% of theory) Rf = 0.75 (toluene / ethyl acetate 8:2) Production Examples 25 Example 1 2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-5-hydroxymethyl-3-(3-tri-fluoromethylbenzyloxymethyl)pyridine WO ~81'~ PCTrUS97/13248 F
F3C~f ~,OH
A suspension of 30 mg (0.8 mmol) of lithium aluminum hydride in 10 ml of absol. tetrahydrofuran is heated under argon. After this, 212 mg (0.4 mmol) of 2-cyclopentyl-6-ethyl-4-(4-fluorophenyl)-3-(3trifluoromethylbenzyloxymethyl)-5 pyridine-5-carboxylic acid ethylester dissolved in 10 ml of absolute tetrahydrofuran is added. Next, the mixture is refluxed for 1 h. After cooling to room temperature, 10 ml of a 10% potassium hydroxide solution is added. The resulting sediment is drawn off by suction and boiled off several times with 10 ml of diethyl ether. The combined mother liquors are dried with sodium sulfate, concentrated in a vacu~
10 and chromatographed over silica gel (mobile solvent ethyl acetate / petroleum ether 2:8).
Yield: 149 mg (76.5% of theory) Rf value (ethyl acetate / petroleum ether 2:8) = 0.08 1~-NMR (CDCl3): ~ = 1.32 (t, 3H); 1.6-2.1 (m, 8H); 2.95 (q, 4H); 3.41 (m, lH);
4.16 (s, 2H); 4.38 (s, 2H); 7.0-7.6 (m, 8H) ppm.
Example 2 2,6-Diisopropyl-4-(4-fluorophenyl)-5-(1-methylimidazole-2-thiomethyl)-3-20 hydroxymethylpyridine F
N~ S~ OH
WO 98/04528 PCTlUS97tl3248 0 10 ml of 3 N hydrochloric acid is added to 0.5 g (0.947 mmol) of the compound from Example CXLII dissolved in 10 ml of methanol, and the mixture is stirred for 3 h at room temperature. The mixture is concentrated in a vacuum, covered with a layer of ethyl acetate, and adjusted to a pH of 8.0 with a saturated NaHCO3 solution, and the organic phase is separated off. The aqueous phase is again extracted with ethyl acetate, and the combined organic phases are washed with salt water, dried over Na2SO4, and concentrated.
Yield: 230 mg (58.7% of theory) Rf = 0.76 (toluene / ethyl acetate 1:1) WO 3n/~ PCT~US97/13248 0 The compounds listed in Tables l(B) through 5(B) are produced analogously to the procedures of Examples 1 and 2:
Table l(B):
R~ S~~ OH
--f N ~
Example No. Rl Rf (solvents) N
3 ~~ 0.56(A12) N-N
" ~~ 0.42 (A13) N~ 0.12 (A13) ~ CO2CH3 6 l~l~ 0.62 (A13) ~NH
N J' 0.42 (A14) wo 98/04528 ExampleNo. R1 Rf (solvents) 8 ¢~CO~ 0.54 (A13) 9 ~!~N 0.59 (A13) W~
N=\
~NH 0.23 tA12) ~N~
~I N
0.54 (A12) N J~
12 N~-- 0.5(A12) 13 F3C~J 0.68 (A13) ~W~
14 W~ J 0.71 (A13) o O Example 15 2,6-Diisopropyl-4-(4-fluorophenyl)-5-(indolyl-5-aminomethyl)-3-hydroxy-methylpyridine H 11 ¦
~H~,f OH
~N
Analogously to Example 2, 2.3 g (4.21 mmol) of ~he compound from Exampl~
CXLnI is desilylated in methanol in the presence of 3 N hydrochloric acid.
Yield: 720 mg (39.6% of theory) Rf = 0.48 (A13) The compounds listed in Table 2(B) are synthesized according to these instructions:
W 0~ ?8 PCTAUS97113248 0 Table 2(B):
¢~
R~ N ~~¢~ OH
~ N ~
ExampleNo. R1 Rf (solvents) 16 N 0.46 (A13) 17 Q/\ 0.33 (A13) ~ CH2 18 0.86 tA13) 19 F~J 0.48 (A13) J~--' 0.3~ (A13) MeO2C
21 ~CH3 0 39 (A13) W 098104~28 PCTtUS97tl3248 0 Table 3(B) Rl7 Il I
H~H
R~ E-O--~ OH
L N T
Ex. R17 Rl-E T L Rf (solvent) 22 F 4-F-C6H4 CH(CH3)2 CH(CH3)2 0.43 (A5) 23 F 4-CF3-C6H4 CH(CH3)2 CH(CH3)2 0.40 (A5) 24 F 3-CF3-C6H4 CH(CH3)2 CH(CH3)2 0.47 (A5) F 2-cF3-c6H4 CH(CH3)2 CH(CH3)2 0.41 (A5) 26 F 4-F-C6H4(CH2)2 CH(CH3)2 CH(CH3)2 0.17 (A3) 27 H 2-CF3-C6H4(CH2)2 CH(CH3)2 CH(CH3)2 0.38 (A5) 28 F 2-F-C6H4(CH2)2 CH(CH3)2 CH(CH3)2 0.16 (A3) 29 F 4-cF3-c6H4cHcH3 CH(CH3)2 CH(CH3)2 0.17 (A3) F 3-CF3-C6H4(CH2)2 CH(CH3)2 CH(CH3)2 0.49 (A5) 31 F 3-CF3-C6H4CHCH3 CH(CH3k CH(CH3)2 0 47 (A5) 32 F O NCH2CH2 CH(CH3)2 CH(CH3)2 0.20 ~ (A11) 33 F (4-py~dyl)CH2 CH(CH3)2 CH(CH3)2 0.16 (A9) Ex. R17 R1-E T L Rf ~solvent) 34 F (3-pyridyl)CH2 CH(CH3)2 CH(CH3)2 0.20 (Ag) F (2-pyridyl)CH2 CH(CH3)2 CH(CH3)2 0.38 (A9) 36 F 4-ph-c6H4 CH(CH3)2 CH(CH3)2 0.24 tA4) 37 F 3-Ph-C6H4 CH(CH3)2 CH(CH3)2 0.27 ~A4) 38 F 2-ph-c6H4 CH(CH3)2 CH(CH3)2 0.26 (A4) 39 F 4-F-C6H4(CH2)3 CH(CH3)2 CH(CH3)2 0.14 (A3) F ~ N- C6H4 CH(cH3)2 CH(CH3)2 0.13 N ~/ (A9) 41 F (1-naphthyl)CH2 CH(CH3)2 CH(cH3)2 0.14 (A3) 42 F 2-naphthyl(CH2)2 CH(CH3)2 CH(CH3)2 0.15 (A3) 43 F 1-naphthyl(CH2)2 CH(CH3)2 CH(CH3)2 0.15 (A3) 44 F C6H5 4-F-C6H4 CH(CH3)2 0-54 (A5) F 4-F-c6H4 4-F-c6H4 CH(CH3)2 0.42 (A5) 46 F 4-CF3-C6H4 4-F-c6H4 CH(CH3)2 0.40 (A5) 47 F 3-cF3-c6H4 4-F-C6H4 CH(CH3)2 0-45 (A5) 48 F 2-CF3-C6H4 4-F-c6H4 CH(CH3)2 0 33 (A5) 49 F 4-F-C6H4(CH2)2 4-F-c6H4 CH(CH3)2 0.15 (A3) H 2-CF3-C6H4(CH2)2 4-F-c6H4 CH(CH3)2 0.41 (A5) WO98/04528 PCT~S97/13248 Ex. R17 Rl-E T L Rf ~so1vent) 51 F 2-F-C6H4(CH2)2 ~F-c6H4 CH(CH3)2 0.14 (A3) 52 F 4-cF3-c6H4cHcH3 ~F-C6H4 CH(CH3)2 0.11 (A3) 53 F 3-CF3-C6H4(CH2)2 4-F-C6H4 CH(CH3)2 0 43 (A5) 54 F 3-cF3-c6H4cHcH3 4-F-c6H4 CH(CH3)2 0.42 (A5) F O NCH2CH2 ~F-c6H4 CH(CH3)2 0.48 \___/ (A9) 56 F (2-pyridyl)CH2 4-F-C6H4 CH(CH3)2 0.20 (A9) 57 F (3-pyridyl)CH2 4-F-C6H4 CH(CH3)2 0.19 (A9) 58 F 4-F-C6H4(CH2)3 ~F-C6H4 CH(CH3)2 0 33 (A5) 59 F (~pyridyl)CH2 4-F-C6H4 CH(CH3)2 0.25 (All) F 2-ph-c6H4 4-F-C6H4 CH(CH3)2 0.38 (A5) 61 F 3-Ph-C6H4 4-F-C6H4 CH(CH3)2 0.32 (A5) 62 F 4-Ph-C6H4 4-F-c6H4 CH(CH3)2 0 33 (A5) 63 F 2-naphthyl(CH2) 4-F-C6H4 CH(CH3)2 0 33 (A5) 64 F l-naphthyl(CH2) 4-F-c6H4 CH(CH3)2 0.32 (A5) F 2-naphthyl(CH2)2 4-F-C6H4 CH(CH3)2 0 34 (A5) 66 F l-naphthyl(CH2)2 4-F-c6H4 CH(CH3)2 0 34 (A3) 67 F 4-CF3O-C6H4CH2 4-F-c6H4 CH(CH3)2 0.31 (A5) Ex. R17 Rl-E T L Rf (solvent) 68 F 3-CF3O-C6H4CH2 4-F-c6H4 CH(CH3)20 34 (AS) 69 F 3-CF3-C6H4(CH2)34-F-C6H4 CH(CH3)20.16 (A4) 70 F 4-CF3O-C6H4CH2 4-F-C6H4 cyclo-C5H90.35 (A5) 71 F 3-CF30-C6H4CH2 4-F-C6H4 ~yclo-C5H90.33 (A5) 72 F 3-CF3-C6H4(CH2)34-F-C6H4 cyclo-CsHg0.28 (A4) 73 F 4-F-C6H4O(CH2)24-F-C6H4 cyclo-CsHg0.67 (A7) 74 F 3-cF3-c6H4 4-F-c6H4 cyclo-CsHg0.46 (A5) 75 F 4-CF3-C6H4 4-F-C6H4 cyclo-CsHg0.42 (A5) 76 F 3-CF3-C6H4(CH2)24-F-C6H4 cyclo-CsHg0.42 (A5) 77 F 3-CF3O-C6H4CH23-CF3-C6H4 cyclo-CsHg0.33 (A5) 78 F 3-CF3-C6H4CH2 4-F-C6H4 4-F-C6H4 0.20 (A7) o WO 98,~ ~'2x PCT/US97/13248 0 Table 4(B) R17 H~,H
Rl--E-O~[ 'OH
L N T
Ex. Rl-E T L Rf (solvent) 79 2-CN-C6H4CH2 CH(CH3)2 CH(CH3)2 0.16 (A3) 80 3-CN-C6H4CH2 CH(CH3)2 CH(CH3)2 0.10 (A3) 81 4~cN-c6H4cH2 CH(CH3)2 CH(CH3)2 0.10 (A3) 82 4-F-c6H4cH2 cyclo-C3H5 CH(CH3)2 0.46 (A5) 83 4-F-c6H4cH2 C2H5 CH(CH3)2 0.36 (A5) 84 C6H5CH2 C2H5 CH(CH3)2 0.36 (A5) 85 4-F-c6H4cH2 CH(CH3)2 pyrro~d~n-l-yl 0.10 (A3) 86 3-cF3-c6H4cH2 CH(CH3)2 cyclo-C6H11 0.15 (A3) 87 4-F-C6H4CH2 CH(CH3)2 cyclo-c6Hll 0.15 (A3) 88 4-F-c6H4cH2 CH(cH3)2 2-CH3-C6H4 0.12 (A3) 89 9-F-C6H4CH2 CH(CH3)2 4-Cl-C6H4 0.19 (A3) go 4-F-C6H4CH2 4-F- CH(CH3)2 0.11 C6H4(CH2)2 (A3) 91 3-cF3-c6H4cH2 4-F-c6H4 CF3 0.24 (A5) WOg8/04528 PCTrUS97/13248 Ex. Rl-E T L Rf ~so~vent) 92 ~F-C6H4CH2 4-F-c6H4 CF3 0.25 (A5 93 3-CF3-C6H4CH2 2,4-F2-C6H3 cyclo-CsHg 0.18 (A4) g4 ~CF3-C6H4CH2 2,4-F2-C6H3 cyclo-CsHg 0.22 (A4) o WO~8/~1C~8 PCTrUS97113248 ~ ~ o ~ o ¢ 3 ¢ o ¢ o ¢ o ¢
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W 098/04528 PCT~US97/13248 O Detailed .l~cription with l~fel~l,ce to co.,l~Gul,ds of ~eneral formula (IC) In the above structural formula (IC) the following terms have the indicated meanings:
The term alkyl means alkyl groups which are straight chain or branched and have the designated number of carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, and isohexyl.
The term cycloalkyl means an alkyl group which is in the form of a ring and contains the designated number of carbon atoms. Examples include the cyclo~r~yl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
The term alkoxy means a group in which the alkyl portion is straight or branched and has the designated number of carbon atoms. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, and isohexoxy.
The term alkanoyl means groups of formula -C(O)-alkyl in which the aL~cyl group has the designated number of carbon atoms. Examples include: acetyl, propionyl and butanoyl.
The term alkanoyloxy means groups of formula -OC(O)-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include -OC(O)CH3, -OC(O)C2H5, and -OC(O)C3H7.
The term alkoxycarbonyl means groups of formula -C(O)O-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include -C(O)OCH3, -C(O)OC2H5, and -C(O)OC3H7.
The term cycloalkyl-alkyl means groups in which an alkyl group bears a cycloalkyl substituent, and the cycloalkyl and alkyl portions each contain the designated number of carbon atoms. Examples include -C2H4-C5H9.
The term phenyl-alkyl means groups in which an alkyl group bears a phenyl substituent, and the alkyl portion contains the designated number of carbon atoms.
Examples include-C2H4-C6H5 The term naphthyl-alkyl means groups in which an alkyl group bears a naphthyl substituent, and the alkyl portion contains the designated number of carbon atoms. Examples include -c2H4-cloH7.
The term pyridyl-alkyl means groups in which an alkyl group bears a pyridyl substituent, and the alkyl portion contains the designated number of carbon atoms. Examples include -c2H4-pyridyl.
, , ~ ., ~
. ~
W O3~/01~8 PCT~US97113248 0 The term alkenyl means straight chain or branched groups having the designated number of carbon atoms and containing a carbon-carbon double bond.
Examples include: ethenyl, propen-1-yl, propen-2-yl and penten-1-yl.
The term alkynyl means straight chain or branched groups having the designated number of carbon atoms and containing a carbon-carbon triple bond.
Examples include ethynyl, propyn-1-yl and butyn-1-yl.
The term halogen means the halogen atoms fluorine, chlorine, bromine and iodine.
The term "substituted" is defined implicitly by the exemplary substituents disclosed for the various substituted groups in the above discussion of general formula (IC). These lists of exemplary substituents are not intended to be considered as limiting; those skilled in the art will recognize that other sirnilar substituents can also be employed.
Certain of the above defined terms may occur more than once in the formulae employed herein, and upon such occurrence each term shall be defined independently of the other.
Ple~l,~d and most preferred groups constituting the compounds of general formula (IC) are as follows:
X preferably represents CR8.
When X is CR8, R8 is ~e~ldbly hydrogen, halogen, trifluoromethyl or (C1-C1o) alkyl. R8 is most preferably hydrogen.
Rla and Rlb preferably are independently trifluoromethyl, (C1-C1o)-alkyl, substituted (Cl-Clo)-alkyl, (c2-clo)-alkenyl~ substituted (C2-C1o)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl. R1a and R1b most preferably are independently (Cl-C6)-alkyl or (C2-C6)-alkenyl.
R2 is preferably (C1-C1o)-alkyl, substituted (C1-C10)-alkyl, (C2-C1o)-alkenyl or substituted (C2-C1o)-alkenyl. The substituents on the substituted alkyl and substituted alkenyl R2 groups preferably are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(o)NR4R5, or -S(o)mR7 wherein m is 0,1, or 2. Mostprefeldbly, the substituents are halogen or -S(o)mR7 wherein m=0.
The groups R4 and R~ are preferably independently hydrogen, (C1-C6) alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl. R4 and R5 are most ~ 35 preferably independently hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl.
O When R4 and R5 are joined together to form -(CH2)rA(CH2)s~~ in this linkage it is preferable that the subscripts r and s are independently 1 to 3, and A is CHR6, NR6, O, or S(O)n wherein n is 0, 1, or 2, and R6 is hydrogen, (C1-C6) alkyl, phenyl, or phenyl (C1-C6) alkyl.
R7 is preferably (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, or substituted pyridyl-(C1-C6) alkyl. R7 is most preferably (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl. The substituents on the substituted R7 groups are preferably 1-3 of halogen, trifluoromethyl, or (C1-C6) alkyl.
When R2 and R1b are joined to form an alkylene bridge, this bridge preferably contains 3 or 4 carbon atoms.
R3 is preferably (C1-C6) alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl, wherein the substitutents are preferably from 1 to 3 hydroxyl groups. Most preferably, R3 is substituted (Cl-C6)-alkyl or substituted (C3-C6)-alkenyl where the substitutents are from 1 to 2 hydroxyl groups.
P.erer~llces for the aromatic and heteroaromatic groups Ar of structural formula (IC) are presented below. Compounds of general formula (IC) are further ifie~l into four subsets represented by structural formulae lA, lB, 1C, and lD, which relate respectively to 4-heteroaryl-substituted pyridines, 4-aryl-substituted pyridines, heteroaryl-substituted benzenes, and aryl-substituted benzenes.
The 4-heteroaryl pyridine compounds included within formula (IC) have the formula lA
Ar' R 1 a~ RR2 b lA
wherein R1a and R1b are independently trifluoromethyl, (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C2-C1o)-alkenyl, substituted (C2-C1o)-alkenyl, (C2-C1o)-alkynyl, substituted ~C2-C1Q)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R1a and R1b groups are independently from 1 to 3 of, for l28 ... . . . . . .. . .. . . ... .
W098/04528 PCTrUS97/13248 O example, -oR4, -C(o)R4, -co2R4l -C(o)NR4R5, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (cl-c4)-alkoxy groups.
The groups R4 and R5 are independently hydrogen, (cl-c6)-alkyl~ (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(cl-c6)-alkyl~ substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(cl-c6)-alkyl~ or substituted naphthyl-(C1-C6)-alkyl. The substitutents on the substituted phenyl or substituted naphthyl R4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
R4 and R5 may be joined together to form -(CH2)rA(CH2)S- wherein the subscripts r and s are independently 1 to 3 and A is CHR6, NR6, O, or S(O)n in which n is 0, 1, or 2; and R6 is hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cl-C6)-alkyl.
R2 is (C1-C1Q)-alkyl, substituted (Cl-C1o)-alkyl, (C2-C1o)-alkenyl, substituted (C2-Clo)-alkenyl, (C2-C1o)-alkynyl, substituted (C2-C1o)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl. The substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(o)NR4R5, or -S(o)mR7 wherein m is 0, 1, or 2. The substituents on the substituted phenyl R2 substituent group are from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy.
R7 is (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cl-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cl-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R7 groups are from 1 to 5 of, for example, halogn, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, cyano, or hydroxy.
R2 and R1b may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached.
R3 is hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl R3 groups from 1 to 3 hydroxy or trifluoromethyl groups.
Ar' is an optionally substituted heteroaromatic ring. Examples of possible Ar' groups are pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls. The .
. . _ , . ~
W 098104528 PCT~US97/13248 O optional subsliLul~llts on the group Ar' are independently 1 to 3 of, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -oR4, -C(o)R4, -oC(o)R4, -Co2R4, -NR4R5, -C(o)NR4R~, or -S(o)mR7. The substitutents on the substituted alkyl, substitutedalkenyl, and substituted alkynyl substituent groups on Ar' are from 1 to 3 of, for example, halogen, hydroxy, -NR4R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4) alkyl, or (C1-C4) alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
In formula lA, the preferred and most ~refelled groups R1a, R1b, R2, R3, as well as the additional groups R4, R5, R6, and R7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.
In formula lA, heteroaromatic ring Ar' is preferably selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and thiazolyls, and the optional substitutents on Ar' are pre~ldbly independently from 1 to 3 of, for example, halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -oR4, or -oC(o)R4 where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C1-C4) alkyl. Heteroaromatic ring Ar' is most preferably selected from the group consisting of pyridyls, furanyls and thiophenyls, and the optional substitutents thereon are most ~referably 2~ independently from 1 to 3 of, for example, halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -oR4, or -oC(o)R4 where R4 is hydrogen or (C1-C6) alkyl.
The ~aryl-substituted pyridines included within formula (IC) have the formula lB
Ar"
R1a~ ~ RR2b lB
wherein W O 98/04528 PCTrUS97/13248 0 R1a and R1b are independently trifluoromethyl, (C1-C1o)-alkyl, substituted (C1-C10)-alkyl, (C2-clO)-alkenyl~ substituted (C2-C1o)-alkenyl, (C2-C1o)-alkynyl, substituted (C2-Clo)-alkynyl~ (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R1a and R1b groups are independently from 1 to 3 of, for example, -oR4, -C(o)R4, -co2R4~ -C(o)NR4R5, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy ~ groups.
The groups R4 and R5 are independently hydrogen, (cl-c6)-alkyl~ (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl. The substitutents on the substituted phenyl or substituted naphthyl R4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
R4 and R5 may be joined together to form ~(CH2)rA(CH2)S- wherein the subscripts r and s are independently 1 to 3 and A is CHR6~ NR6~ O, or S(O)n in which n is 0, 1, or 2; and R6 is hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cl-C6)-alkyl.
R2 is (C1-C10)-alkyl, substituted (C1-C1o)-alkyl, (C2-C1o)-alkenyl, substituted (C2-C1o)-alkenyl, (C2-C1o)-alkynyl, substituted (C2-C1o)-alkynyl, (C3-C6)-cycloalkyl-(Cl-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl. The substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(o)NR~R5, or -S(o)mR7 wherein m is 0, 1, or 2. The substituents on the substituted phenyl R2 substituent group are from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy.
R7 is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C~-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy,nitro, cyano, or hydroxy.
R2 and R1b may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached.
WO 9~101C2% PCT/US97/13248 0 R3 is hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl R3 groups are ~rom 1 to 3 hydroxy or trifluoromethyl groups.Ar" is an optionally substituted aromatic ring. Examples of possible Ar"
groups are phenyls and naphthyls. The optional substitutents on the group Ar" are independently 1 to 3 of, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -oR4, -C(o)R4, -oC(o)R4, -Co2R4~ -NR4R5, -C(o)NR4R5, or -S(o)mR7. The substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on Ar" are from 1 to 3 of, for example, halogen, hydroxy, -NR4R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4) alkyl, or (Cl-C4) alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
In formula lB, the ~refe~l~d and most preferred groups R1a, R1b, R2, R3, as well as the additional groups R4, R5, R6, and R7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.
In formula lB, aromatic ring Ar" preferably is a phenyl ring wherein the optional substitutents are preferably independently from 1 to 3 of, for example,halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -oR4 or -~(o)R4, where R4 is hydrogen, (cl-c6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C1-C4) alkyl. Most preferably, the optional substitutents are from 1 to 3 of, for example, halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -oR4 or -oC(o)R4, where R4 is hydrogen or (C1-C6) alkyl.
WO ~ 1e~7~ PCT/US97/13248 O The heteroaryl-substituted benzenes ir~ ef~ within formula (IC) have the formula lC
Ar' Rla/~\ R1b lC
wherein R8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5. The substituents on the substituted phenyl or substituted alkyl R8 groups are from 1 to 3 of, for example, hydroxy, fluoro, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5.
The groups R4 and R5 are independently hydrogen, (Cl-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl. The substitutents on the substituted phenyl or substituted naphthyl R4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
R4 and R5 may be joined together to form -(CH2)rA(CH2)S- wherein the subscripts r and s are independently 1 to 3 and A is CHR6, NR6, O, or S(O)n ~n which n is 0, 1, or 2; and R6 is hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cl-C6)-alkyl.
R1a and R1b are independently trifluoromethyl, (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C2-Clo)-alkenyl~ substituted (C2-Clo)-alkenyl~ (C2-Clo)-alkynyl~
substituted (C2-C1o)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R1a and R1b groups are independently from 1 to 3 of, for example, -oR4, -C(o)R4, -Co2R4~ -C(o)NR4R5, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
R2 is (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C2-C1o)-alkenyl, substituted (C2-C1o)-alkenyl, (C2-C1o)-alkynyl, substituted (C2-C1o)-alkynyl, (C3-C6)-cycloalkyl-(Cl-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(Cl-C6)-alkyl. The WO 98104528 PCT~US97/13248 0 substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C~o)NR4R5, or -S(o)mR7 wherein m is 0, 1, or 2. The substituents on the substituted phenyl R2 substituent group are from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy.
R7 is (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy,nitro, cyano, or hydroxy.
R2 and R1b may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached.
R3 is hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl R3 groups are from 1 to 3 hydroxy or trifluoromethyl groups.Ar' is an optionally substituted heteroaromatic ring. Examples of possible Ar' groups are: pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls. The optional substitutents on the group Ar' are independently 1 to 3 of, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -oR4, -C(o)R4, -oC(o)R4, -Co2R4~ -NR4R5, -C(o)NR4R5, or -S(o)mR7 The substitutents on the substituted alkyl, substituted alkenyl, and substituted all~ynyl substituent groups on Ar' are from 1 to 3 of, for example, halogen, hydroxy, -NR4R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (Cl-C4)-alkyl, or (C1-C4)-alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
In formula lC, the pfere~led and most preferred groups Rla, Rlb, R2, R3, and R8, as well as the additional groups R4, R~, R6, and R7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.
In formula 1C, heteroaromatic ring Ar' is preferably selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and 1~4 ~ . . . .. . ... ~ . ~ ... .... .
WO 98/04528 PCTrUS97/13248 0 thiazolyls, and the optional substitutents on the group Ar' are preferably independently from 1 to 3 of, for example, halogen, (Cl-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -oR4, or -oC(o)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C1-C4) alkyl.
5 Heteroaromatic ring Ar' is most preferably selected from the group consisting of pyridyls, furanyls and thiophenyls, and the optional substitutents thereon are most preferably independently from 1 to 3 of, for example, halogen, (C1-C6) alkyl, (C2-C6) alkenyl, -oR4~ or -oC(o)R4, where R4 is hydrogen or (C1-C6) alkyl.
The aryl-substituted benzenes included within formula (IC) have the formula lD
Ar"
R1a ~ ~1b lD
wherein R8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5. The substituents on the substituted phenyl or substituted alkyl R8 groups are from 1 to 3 of, for example, hydroxy, fluoro, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(cl-c3)-alkoxy~ (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or-NR4R5.
The groups R4 and R5 are independently hydrogen, (cl-c6)-alkyl~ (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl. The substitutents on the substituted phenyl or substituted naphthyl R4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
R4 and R5 may be joined together to form -(CH2)rA(CH2)S- wherein the subscripts r and s are independently 1 to 3 and A is CHR6, NR6, O, or S(O)n in which n is 0, 1, or 2; and R6 is hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cl-C6)-alkyl .
W O 98104528 PCT~US97/13248 O Rla and Rlb are independently trifluoromethyl, (Cl-Clo)-alkyl, substituted (C1-C1o)-alkyl, (c2-clo)-alkenyl~ substituted (C2-Clo)-alkenyl~ (C2-C1o)-alkynyl, substituted (C2-Clo)-alkynyl~ (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R1a and R1b groups are independently from 1 to 3 of, for example, -oR4, -C(o)R4, -co2R4~ -C(o)NR4R~, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (cl-c4)-alkoxy groups.
R2 is (C1-C1o)-alkyl, substituted (C1-C1o)-alkyl, (C2-C10)-alkenyl, substituted (C2-C1o)-alkenyl, (C2-C1o)-alkynyl, substituted (C2-C1o)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl. The substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(o)NR4R5, or -S(o)mR7 wherein m is 0, 1, or 2. The substituents on the substituted phenyl R2 substituent group are from 1 to 3 of, for example, halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy.
R7 is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-~C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6) alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cl-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy,nitro, cyano, or hydroxy.
R2 and R1b may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms between the ring carbon atoms to which R2 and R1b are attached.
R3 is hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl. T~e substitutents on the substituted alkyl and substituted alkenyl R3 groups are from 1 to 3 hydroxy or trifluoromethyl groups.Ar" is an optionally substituted aromatic ring. Examples of possible Ar"
groups are phenyls and naphthyls. The optional substitutents on the group Ar areindependently 1 to 3 of, for example, halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6~-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -oR4, -C(o)R4, -oc(o)R4~-co2R4~ -NR4R5,-C(o)NR4R5, or -S(o)mR7. The substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on Ar are from 1 to 3 of, for example, halogen, hydroxy, -NR4R~, phenyl, or ,, W098104528 PCT~US97/13248 substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4)-alkyl, or (C1-C4)-alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
- 5 In formula lD, the preferred and most preferred groups R1a, R1b, R2, R3, and R8, as well as the additional groups R4, R5, R6, and R7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.
In formula lD, aromatic ring Ar" ~ref~Ldbly is a phenyl ring wherein the optional substitutents are preferably from 1 to 3 of, for example, halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (c2-c6)-alkynyL (C3-C7)-cycloalkyl, cyano, -oR4 or -oC(o)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C1-C4) alkyl. Most preferably, the substitutents are from 1 to 3 of, for example, halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -oR4 or -oC(o)R4, where R4 is hydrogen or (C1-C6) alkyl.
Basic compounds of the invention are generally isolated in the form of their pharmaceutically acceptable acid addition salts derived using inorganic or organic 20 acids. Examples of such materials are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, and malonic acids.Compounds of the invention which contain an acidic functionality such as a carboxyl group can be isolated in the form of pharmaceutically acceptable addition salts derived using inorganic or organic bases. The salt forming ion derived from 25 such bases can be a metal ion such as sodium, potassium, lithium, calcium, magnesium, etc., or an ion of an organic base, such as an ammonium or substituted ammonium ion derived from an amine. Examples of suitable amines for this purpose include ammonia, arylalkylamines such as dibenzylamine and N,N-dibenzylethylenediamine, lower alkylamines such as methylamine, ~-butylamine, 30 procaine, lower alkylpiperidines such as N-ethylpiperidine, cycloalkylamines such as cyclohexylamine or dicyclohexylamine, 1-adamantylamine, benzathine, or salts derived from amino acids such as arginine or lysine.
The present invention also encompasses pharmaceutically acceptable "prodrugs" of the compounds of formula (IC) which form such derivatives. These W O 93/OI¢~X PCT~US97/13248 0 are typically acylated derivatives of alcohol-containing compounds of the invention, though other types of prodrugs are known. Preparation of such derivatives is within the skill of the art.
The inhibitors of the present invention are contemplated for use in veterinary and human applications. For such applications, the active agent(s) are employed in pharmaceutical compositions which comprise the active ingredient(s) plus a pharmaceutically acceptable carrier which contains one or more diluents, fillers, binders, or other excipients, depending on the administration mode and dosage form contemplated. Examples of such agents include carriers such as sucrose, lactose, or starch; lubricating agents such as magnesium stearate;
adjuvants, such as wetting agents; excipients such as cocoa butter or suppository wax; emulsifying and suspending agents, and sweetening, flavoring and perfuming agents and buffering agents.
The pharmaceutical compositions of the invention may also include one or more known antidiabetic agents in addition to a compound of structural formula (IC). Examples of such antidiabetic agents are: a-glucosidase inhibitors such asacarbose or voglibose, insulin sensitizers such as bromocriptine, thiazolidinediones such as troglitazone, insulin secretagogues such as glimepride, sulfonylureas such as glyburide, GLP-1 and its derivatives such as insulinotropin, amylin and its derivatives such as AC-137, calcitonin, insulin and its derivatives such as HOE-901, biguanides such as metformin, aldose reductase inhibitors such as tolrestat, ~3 agonists such as BTA-243, and hypocholesterolemics such as lovastatin.
The method of treating glucagon-mediated conditions by administering a glucagon receptor antagonist of the present invention may be practiced in mammals, including humans, which exhibit such conditions. A typical application is treatment of diabetes.
The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection or implant), nasal, vaginal, rectal, sublin~ual, or topical routes of administration and can be formulated in dosage forms a~ro~riate for each route of administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, eg., lubricating agents such asmagnesium stearate. In the case of capsules, tablets and pills, the dosage forms 13~
W098/04S28 PCTrUS97113248 O may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings such as the ORO~CT/OsmetTM and PULSINCAP~M systems from ALZA and Scherer Drug Delivery Systems.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert 5 diluents commonly used in the art, such as water. Besides such inert diluents,compositions can also include adjuvants, such as wetting agents, emulsifying andsuspending agents, and sweetening, flavoring and perfuming agents.
Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
10 Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain ad~uvants such as preserving, wetting, emulsifying, and dispersing agents. Alternatively intramuscular, intraarticular or subcutaneous depot injection with or without 15 encapsulation of the drug into degradable microspheres e.g., comprising poly(DL-lactide-co-glycolide) may be used to obtain prolonged sustained drug release. For improved convenience of the dosage form it may be possible to use an i.p.
implanted reservoir and septum such as the Percuseal system available from Pharmacia. Improved convenience and patient compliance may also be achieved 20 by the use of either injector pens (e.g. the NovoPen or ~pen) or needle-free jet injectors (e.g. from Bioject, Mediject or Becton Dickinson). Prolonged zero-order or other precisely controlled release such as pulsatile release can also be achieved as needed using implantable pumps with delivery of the drug through a cannula into the synovial spaces. Examples include the subcutaneously implanted osmotic 25 pumps available from ALZA, such as the ALZET osmotic pump.
Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients30 such as cocoa butter or a suppository wax.
- The compounds of this invention can be manufactured into the above listed forrnulations by the addition of various therapeutically inert, inorganic or organic carriers well known to those skilled in the art. Examples of these include, but are not limited to, lactose, corn starch or derivatives thereof, talc, vegetable oils, waxes, 3~ fats, polyols such as polyethylene glycol, water, saccharose, alcohols, glycerin and the like. The formulations may be sterilized by, for example, filtration through a W 098J04~28 PCTfUS97tl3248 0 bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved insterile water, or some other sterile injectable medium immediately before use.
Various preservatives, emulsifiers, dispersants, flavorants, wetting agents, 5 antioxidants, sweeteners, colorants, stabilizers, salts, buffers and the like are also added, as required to assist in the stabilization of the formulation or to assist in increasing bioavailability of the active ingredient(s) or to yield a formulation of acceptable flavor or odor in the case of oral dosing.
The amount of the pharmaceutical composition to be employed will depend 10 on the recipient and the condition being treated. The requisite amount may bedetermined without undue experimentation by protocols known to those skilled in the art. Alternatively, the requisite amount may be calculated, based on a determination of the amount of target receptor which must be inhibited to treat the condition. An effective amount of active ingredient is generally in the range 0.0001 15 mg/kg to 100 mg/kg of body weight.
The treatment method of the invention is not limited to administration of the above-described pharmaceutical composition. Rather, this treatment regimen may be employed in combination with conventional treatments of diabetes (both Type I20 and Type II) or of other conditions which are sometimes found in diabetic subjects.
Thus, for example, treatment may be administered in conjunction with (a) diet restrictions and exercise; (b) insulin, or other drugs used to treat ketoacidosis; (c) any drug used for the treatment of hyperlipidemia, such as lovastatin, or cardiovascular disease, such as enalapril; (d) drugs used to treat diabetic 25 complications, such as epalrestat and (e) drugs that lower body weight, such as dexfenfluramine .
The glucagon receptor antagonists of the invention are useful not only for treatment of the pathophysiological conditions discussed above, but are also useful in other applications such as a diagnostic agent. For example, these compounds 30 can be administered to humans in vivo in the fasting state as a diagnostic tool to directly determine whether the glucagon receptor is functional. Serum samples taken before and after such administration can be assayed for glucose levels;
comparison of the amounts of blood glucose in each of these samples would be a means for directly determining the ability of the patient's glucagon receptor to O modulate hepatic glucose output. Alternatively, compounds of the present invention may be useful for finding new glucagon antagonists. For example, a binding assay employing a radiolabeled derivative (such as 3H) of a compound of formula (IC) would be useful in identifying new compounds that competitively bind to the glucagon receptor. Such an assay is useful in identifying structurally 5 novel antagonists that may offer advantages in ease of chemical modification, selectivity and oral bioavailability.
WO 98/04S28 PCTrUS97/13248 0 The compounds of the present invention may contain asymmetric centers on the molecule, depending upon the nature of the various substituents. Each such asymmetric center will produce two optical isomers. In certain instances, asymmetry may also be present due to restricted rotation about the central bond adjoining the two aromatic rings of the specified compounds. For example, for certain tompounds of Pormula (IC) wherein Ar is taken as substituted phenyl, there exist additional isomers due to restricted rotation about the central aryl-aryl bond, depending on the substitution pattern.
R~ b Rla~ R~b It is intended that all isomers, either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purifiedisomers or racemic mixtures thereof, be included within the ambit of the instantinvention. In the case of compounds of Formula (IC) wherein R3 is taken as 1-hydroxyethyl, it has been found that the isomer in which the hydroxy substituent is lS above the plane of the structure, as seen in Formula Ic, is more active and thus more preferred over the compound in which the hydroxy substituent is below the plane of the structure.
OH Ar H~ R1b WO~W'2~ PCT~US97/13248 0 Representative examples of the nomenclature employed herein are given below:
2,6-Dimethyl-3-hydroxymethyl-4-(3-bromophenyl)-5-isobutylpyridine ~,, Br HO
N
3,5-Di-t-butyl-2-(phenylthio)methyl-6- hydroxymethyl-3',5'-dichloro-1,1'-biphenyl HO~S J~3 The compounds of general formula (IC) of the present invention are prepared as indicated in the following reaction Schemes.
The phenylpyridine compounds of formula (IC) (X= N) are prepared from a common intermediate 6 using the well-known Hantzsch pyridine synthesis, as shown in Scheme 1 (Stout, D. M.; Myers, A. I. Chenl. Rev. 1982, 223).
W098/04~28 PCTrUS97/13248 R~b~CO2Et RlaJ~ AcO-NH4 /cyclohexanre 1a~CO2Et Ar-CHO
Ar Ar EtO2C~CO2Et DDQ / CH2C12 EtO2C~C02Et H R1a N R1b The ketoester 1, (commercially available or prepared according to the procedure of Deslongchamps, Syn~h. Comm., 1976, 6, 169) is treated with an S ammonium salt such as ammonium acetate, in an inert solvent such as cyclohexane capable of forming an azeotrope with water, to give the enamine 2. Compound 2 is then treated with the ketoester ~, which may or may not be identical to the ketoester 1, and an aromatic aldehyde, in a polar solvent such as ethanol, to produce the dihydropyridine 5. Certain substituents on aldehyde 4 may need to beprotected during the Hantzsch pyridine synthesis. A description of suitable protecting groups may be found in: Protective Groups in Or~anic S~nthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991. Oxidation of 5 is achieved by any of several known methods. For example, treatment of 5 with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in a solvent such as methylene chloride (CH2Cl2), or with ceric ammonium nitrate (CAN) in a mixture of solvents such as aqueous acetone, affords the intermediate 6. Separation of unwanted sideproducts and purification of intermediates is achieved by chromatography on silica gel, employing flash chromatography (Still, W.C.; Khan, M.; Mitra, A. J. Org. Chem., 1978, 43, 2923) An alternative Hantzsch pyridine synthesis of the intermediate 6, where R1a and R1b of formula (IC) are identical, can be accomplished following the procedure of Chucholowski (U.S. Patent 4,950,675), Scheme 2. By heating two equivalents ofketoester 1 with ammonium hydroxide and the aldehyde 4 in a polar solvent such as methanol, the dihydropyridine 5 is obtained directly. Compound 5 is oxidized to pyridine 6, according to the procedure described in Scheme 1.
.
WO 98/04528 PCTrUS97/13248 - Ar A
2 ~ Ar CHO ElO2C~C02Et DDQ/cHzcl2 EtO2C~CO2EI
R1aJ~ CO2Et NH40H/MeOH ~1a N R1a Rla~N R1a ~ In Scheme 3, another alternative Hantzsch pyridine synthesis of intermediate 6 is described. Ketoester 1 is condensed with aldehyde 4 by treatment with 5 catalysts such as acetic acid and piperidine without solvent to afford intermediate 7.
Treatment of 7 with ketoester 3 in the presence of a base such as sodium methoxyde, in a polar solvent such as methanol produces the diketone 8.
Cyclization of 8 is achieved by treatment with an ammonium salt such as ammonium acetate in a polar solvent such as acetic acid to afford the previously10 described dihydropyridine 5 (Scheme 1), which is oxidized to the pyridine 6 according to the procedure as indicated in Scheme 1.
o ArRl b J~ C02Et ArCHO I 3 Ar 0 4 ~CO2EtN OM EtO2C~J~C02Et R~ , C02Et o~ R1 a MeOH R 1 a ~lo 0~ Rl b Ar Ar NH40Ac EtO2C~CO2Et DDQ / CH2CI2 EtO2C~
AcOHR1a N Rlb R1a N R1b The synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl and R3 is hydroxymethyl (IIa) is described in Scheme 4.
W O~8J~'2X PCTrUS97/13248 Ar Ar EtO2C~CO2Et Red-AI I THF EtOzc~oH PCC / CH2C12 EtO2C~CHO R Ar 1) LAH ITHF
R1a N R1b THF F~1a NR1b 2) H2, Pd/C
Ar Ar HO ~ R2 HO ~ R2 R1a N R1b R1a N R1b Ila ~b Chemical reducing agents such as sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) in an inert solvent, such as tetrahydrofuran (THF) or diethyl ether 5 (Et2O), can result in a monoreduction of the pyridinediester 6 to give the alcohol 9.
Oxidants such as pyridinium chlorochromate (PCC), in a solvent such as CH2Cl2, convert compound 9 to the aldehyde 10. Wittig reaction with compound 10 and an ylide ~, in an inert solvent such as THF or Et20, affords olefin _ obtained usually, but not always, as a mixture of E and Z isomers . The reagent 11a is 10 prepared from an alkyl triphenyl phosphonium salt, wherein the alkyl group may contain a heteroatom, and a suitable base such as butyllithium or sodium amide, according to known methods (Maercker, A. in Organic l~eactions, Vol. 14, Ed.; Wiley, New York, 1965, Chapter 3). Olefin 12 is successively treated with a reducing agent such as lithium aluminum hydride (LAH), in an inert solvent such as THF or Et20,15 and hydrogen in the presence of a metal catalyst, such as p~ m~ on carbon, in a polar solvent such as ethanol, to afford compounds of formula IIa. ~ some of these compounds, R2 may contain substituents such as alcohol, acetate, ester, carboxylic acid, and amide. These products can be obtained directly by the procedures of Scheme 4, with or without the use of appropriate protecting groups, 20 or by additional steps familiar to those skilled in the art. For example, a primary alcohol can be converted to a carboxylic acid by standard methods of oxidation, WO ~X~ r~X PCTrUS97/13248 0 such as those described by Eisenbraun (Eisenbraun, E. J. Org. Syn. Coll., 1973, 5, 310).
If the Wittig reaction is performed with methoxymethyl triphenyl-phosphonium as ylide (~), followed by treatment with an acid such as hydrochloric acid, the homologous aldehyde 13 is obtained. This can undergo 5 another Wittig reaction to afford olefin 14, (Scheme 5). This known procedure (Wittg, G.; Walter, B.; Kruck, K.-H. Chem. Ber. 1962, 2514) allows one to synthesize extended alkyl chain (R2) analogs of formula IIa, which may not be directly prepared by usual Wittig reaction due to limited availability of the requisite alkyl triphenylphosphonium salt.
Oxidation of the compounds of formula IIa by the method described in Scheme 4 affords intermediates that can be converted to homologues of compounds of formula IIa, containing the -CH2-CH2- linkage between the pyridine nucleus and the hydroxy group (IIb).
Ar =~OMe Ar R
p1a N R1b 2) HCI R1a N Rlb Ar Ar EtO2C ,~ R2 R 1) LAH/THF HO T¦ r R1a~NJ'F~1b 2) H2, PdlC R1a~N ~'R1b 14 lIa Synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl 20 containing a heteroatom such as sulfur and R3 is hydroxymethyl (ma and IIIb), is outlined in Scheme 6. Alcohol 9 is converted to an alkyl halide 15 by treatrnent with a suitable reagent such as dibromotriphenylphosphorane in an inert solvent.
Treatment of 15 with a thiol and a base such as N-methyl morpholine in an inert solvent produces intermediate 16. The sulfur atom of compounds 16 can be 25 oxidized (n = 1 or 2) by any of several known methods. For example, it can be accomplished by treatment of 16 wherein n=0, with an oxidant such as m-chloroperbenzoic acid in a solvent such as CH2Cl2 Chemical reducing agents such WO 98~'~t-~X PCTrUS97/13248 O as lithium aluminum hydride (LAH) in an inert solvent such as tetrahydrofuran or diethyl ether, can reduce the ester 16 to a compound of formula IIIa. Intermediate _ can also react with alcohols following the methods outlined in Scheme 6, to afford compounds of formula IIIc.
Ar Ar EtO2C~OH Ph3P Br2EtO2C~Br R7SHICH2C12 R1a N R1b CH2C12 R1a N R1b N-Me-.,.o.~ " ,e Ar Ar Eto2c~s(o)n-R7 LAH / THF HO~S(o)n-R7 R1a N Rlb R1~ N R1b 16 IIIa Ar Ar HO--~S(O~n--R7 Ho~o~R4 R1a ~ N ~ R1b R1a N R1b Illb I~c The synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl containing a heteroatom such as nitrogen and R3 is hydroxymethyl (IVa), is 10 outlined in Scheme 7. Treatment of 15 with a primary or secondary amine in aninert solvent results in the intermediate 17. Chemical reducing agents such as lithium aluminum hydride in an inert solvent, such as tetrahydrofuran or diethylether, can reduce ester 17 to a compound of formula IVa. Reduction of aldehyde 13 by the method outlined in Scheme 4 affords an intermediate that can be converted15 to homologues of compounds of formula IIIa and IVa, containing the -CH2-CH2-linkage between the pyridine nucleus and the sulfur or nitrogen substituent (IIIb and IVb).
.... . .. .
WO 98/04528 PCTrUS97113248 Ar Ar ,R4 EtO2C~Br R4R5Ntl EtO2C~N~ LAH I THF
R1~ N R1 b CH2C12 R 1 a ~ll N~l R1 b R
R~R1b P' Ar N~
IVa IVb Synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl and R3 is 1-hydroxyethyl (Va), is outlined in Scheme 8. Oxidants such as pyridinium 5 chlorochromate (PCC), are used to convert compounds of formula II to the aldehyde 18. Treatment of 18 with an organometallic reagent such as methyl magnesium bromide or methyl li~ium in an inert solvent such as THF or Et20 affords racemic compounds of formula Va. Chiral 1-hydroxyethyl aryl pyridine derivatives of formula Vb are obtained by resolution of the racemates Va by 10 I~lA~sical methods. For example, resolution can be achieved by formation of diastereomeric adducts of the racemic compounds with optically active reagents such as a-methoxy-a-(trifluoromethyl)phenylacetic acid (Dale, J.A.; Dull, D.L.;
Mosher, H.S. J Org. Chem. 1969, 34, 2543). Alternatively, separation of enantiomers is achieved by HPLC on chiral solid phase. Determination of absolute 15 stereochemistry can be achieved in a number of ways familiar to those skilled in the art, including X-ray analysis of a suitable crystalline derivative, such as a Mosher ester.
Ar Ar HO~R PCC J CH2cl2OHC~R2 CH3Mg~r/THF
R1a N R1b R1a N R1b OH Ar CH3~ R2 Rta N R1b va W098/04528 PCTrUS97/13248 o An alternative synthesis of aryl pyridine derivatives of formula Vb is achieved by treating aldehyde 18 with the anion of methyl toluylsulfoxide 19 to give a diastereomeric mixture of alcohols 20 as shown in Scheme 9 (Blase, F. R.; Le H. Tet. Lett. 1995, 36, 4559). The diastereomers are separated by flash 5 chromatography and treated separately with Raney nickel and hydrogen in ethanol to provide pure enantiomers (>99% enantiomeric excess, e.e.) of the compounds offormula Vb. Alternatively, the chromatographic step is avoided by a two step sequence consisting of (1) oxidation of the mixture 20 with manganese dioxide in an inert solvent, followed by (2) reduction of the ketone with a chemical reductant10 such as LAH, to provide the enantiomerically pure alcohol 21. Treatment of 21 with Raney nickel and hydrogen in a polar solvent provides pure enantiomer (>99% e.e.) of the compounds of formula Vb.
o ~ ,~(S) CH2Li ~~R2 R1a N Rlb THF R1a N R1b 18 20 1 ) Ssparate r~u, ~
\~2) Hz Raney Ni 1) Mno2lcH2cl2 S OH Ar H2 OH Ar 2) LAH/THF, -78 ~s~f X Flaney Ni CH3 ~
R1a N Rlb R1a N Rlb 21 Vb A preferred alternative enantioselective synthesis of aryl pyridine derivatives of formula Vb is shown in Scheme 10. Treatment of the racemic mixture of compounds of formula Va with an oxidant such as pyridinium chlorochromate 20 (PCC), gives the ketone 22. Reduction of 22 with a complex of LAH and N-methylephedrine (Kawasaki, M.; Susuki, Y.; Terashima, S. Chem. Lett. 1984, 239) in an inert solvent, provides the alcohol of formula Vb with an enantiomeric excess of 95%.
WO 98104528 PCT~US97/13248 o SCHEME 10 ~ OH Ar O Ar CH3~R2 PCC/CH2C~> CH J~ ether, -7~ C
R1a N R1b R1a N R1b Va 22 OH Ar CH3~R1b Vb The synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl and R3 is 1,2-dihydroxyalkyl (VI), is described in Scheme 11. A methyl 5 triphenylphosphonium salt is treated with a suitable base such as butyllithiurn in an inert solvent and reacted with intermediate 18 to afford olefin 23. Treatment ofcompound 23 with a suitable oxidant such as osmium tetroxide in a polar solvent such as pyridine gives the compounds of formula VI.
Ar OHC~R2 Ph3P=CHR R ~R2 R1a N R1b T~IF R1a N R1b OsO4 R~
pyridine HO R1a N R1b VI
The synthesis of aryl pyridine derivatives of formula (IC) wherein R2 and Rlb are taken together to form an alkylene bridge and R3 is hydroxymethyl (VIIa), 15 is described in Scheme 12. The ketoester 1, is treated with an aromatic aldehyde and catalysts such acetic acid and piperidine, in ethanol, to afford the a"B-unsaturated ketoester 24. Treatment of 24 with the cyclic ketone 25 and a base such as lithium bis(trimethylsilyl)amide in an inert solvent such as THF affords an intermediate which is treated with ammonium acetate and copper acetate in acetic CA 02262434 l999-0l-28 W 098~04S28 PCTrUS97/13248 O acid to give the pyridine 26. ChPmie~l reducing agents reduce the ester 26 to analogs of formula VIIa. It may be appreciated that these analogs can be used asintermediates to generate new derivatives of formula (IC) wherein R2 and R1b aretaken together and R3 is 1-hydroxyethyl (VIIb) according to the procedures described in Scheme 8.
s Ar-CHO Ar 1) R
4 b co2Et~ R2 R1a Jl C02Et ~ ' ~
AcOH, piperidine 0~ ~ R1 a LiHMDStrtlF
~2) NH40Ac, AcOH
Ar 2 Ar EtO2~ ~ LAHlTHF HO~ R2 ) R1a N~R1b R1a N R1b 26 Vlla OH Ar ~, R2 ~
R1 a ~lN 1 R1 b ) Vllb The synthesis of the aryl pyridine derivative IIa wherein R1b is CH2OH is described in Scheme 13. Alcohol 27 (aryl pyridine IIa in which R1b is CH3) is treated with a trialkylsilyl chloride, such as tert-butyldiphenylsilyl chloride, and a base to yield silyl ether 28. Treatment of 28 with meta-chloroperbenzoic acid in an inert solvent, such as chloroform, provides the N-oxide 29. The N-oxide is treated 15 with acetic anhydride to afford pyridine acetate 30. Treatment of 30 with aqueous methanol in the presence of potassium carbonate, yields alcohol 31. The silyl ether is cleaved with tetrabutylammonium fluoride in THF to provide aryl pyridine derivative 32.
WO 98~O1'2~ PCTAUS97113248 Ar Ar HO~R2 TBDPsclr TBDPSO~R2 mCPBA
Il ,I Imidazole1~ ,J~
Rla ~N CH3 R la~ N CH
TBDPSO~ Ac20 TBDPSO~ ~O
O R1a OAc K2C 3 Ar Ar TBDPSO~R TBAFHO~R2 R1a N~ R1a N~
The synthesis of aryl pyridine derivatives Xa wherein R1b is -CH2NR4R5 is 5 described in Scheme 14. Oxidation of alcohol 31 as described in Scheme 4 yields aldehyde 33. Treatment of the aldehyde with an amine in the presence of a Lewis acid, such as zinc chloride, and a reducing agent, such as sodium cyanoborohydride, provides the amine 34. Deprotection of the alcohol as described in Scheme 13 affords aryl pyridine derivative Xa.
Ar Ar TBDPSO--~, PCC . TBDPSO~R2 HNR4PI5 R 1a N OH R1a CHO NaCNBH3 Ar Ar TBDPSO~R2 TBAF HO~R2 1a~N~NR4R5 1~J~N~NR4R5 34 Xa -An alternative synthesis of amine 34 is shown in Scheme 15. Treatment of pyridine N-oxide 29 with phosphorus oxychloride and a base, such as triethylamine, in CH2Cl2, yields chloromethylpyridine 35. The chloride is treated W 098/04528 PCTrUS97/13~48 O with an amine providing amine 34.
Ar Ar TBDPSO~R2 POC13 TBDPSO~R2 R1a N+ CH3 Et3N, CH2C12 R1a N CH2CI
Ar ~HNR4R5 TBDPSO~ R2 R1aJ~N--~,NR R
s The synthesis of aryl pyridine derivatives Xb wherein Rlb is -CH=CHR is described in Scheme 16. Alcohol 31 is converted to the corresponding bromide as described in Scheme 6. Treatment of 36 with sodium phosphite in benzene yields phosphonate 37. The phosphonate is treated with a base, such as sodium hydride, 10 and subsequently with an aldehyde affording olefin 38. Deprotection of the alcohol as described affords aryl pyridine Xb.
Ar Ar TBDPSO~;~ Br2PPh3 TBDPSO~ Napo~oEt)2 Ar Ar TBDPSO~ ,Ol 2~ RCHO ~ TBAF
R1a '(OEtk R1a N R
Ar HO~R2 R 1a--~N~R
Xb An alternative synthesis of olefin 38 is shown in Scheme 17. Aldehyde 33 is W 093/01C2~ PCT~US97/13248 0 treated with an ylide as described in Scheme 4 to yield olefin 38.
Ar Ar TBDPSO~ R2 R~= PPh3 TBDPSO~ R2 R1a~NJ'CHO RlaJ~N~J~R
s The synthesis of aryl pyridine derivative Xc wherein R1b is -CH2CH2R is described in Scheme 18. Hydrogenation of olefin Xb as described in Scheme 4 yields the alkane Xc R~ Pd/C ~--R
Xb Xc The synthesis of aryl pyridine derivative Xd wherein R1b is -CH(OH)R is described in Scheme 19. Treatment of aldehyde 33 with a Grignard reagent in an inert solvent, such as THF, yields alcohol 39. Deprotection of the alcohol as described affords aryl pyridine derivative Xd.
TBDPSO~R RMgBr TBDPSo~ TBAF
Ar HO~
OH
Xd The synthesis of aryl pyridine derivatives Xe wherein Rlb is -COR is CA 02262434 l999-0l-28 W 0~8/01't8 PCT~US97tl3248 O described in Scheme 20. Oxidation of alcohol 39 as described in Scheme 4 yields ketone 40. Deprotection of the alcohol as described affords the aryl pyridine derivative Xe.
s Ar Ar TBDPSO~ PCC TBDPSO~X~ TBAF
OH O
Ar HO~R2 Rla N~
Xe o The synthesis of aryl pyridine derivatives Xf wherein Rlb is -C(OH)RR' is described in Scheme 21. Grignard addition to ketone 40 as described in Scheme 1910 yields alcohol 41. Deprotection of the alcohol as described affords the aryl pyridine derivative Xf.
Ar Ar TBDPSO~ R'MgBr TBDPSO~ TBAF
Rl~ N"~R ~ R1a N~<
~ 110 R
Ar HO~R' HO R
Xf The synthesis of aryl pyridine derivatives Xg wherein R1b is -C(oR4)RR' is described in Scheme 22. Treatment of alcohol 41 with a base, such as sodium hydride, and an alkylating agent in THF, yields ether 42. Deprotection of the . . ~
W O 98/04S28 PCTrUS97/13248 0 alcohol as described affords the aryl pyridine derivative Xg.
Ar Ar ~ TBDPS0~ R4X TBDPS0~ TBAF
R1aNl><R NaH R1a N~<
Ar HO~R2 R~a NJ~<
Xg The biphenyl analogs described in formula (IC) (X = C-R8, wherein R8 is H), are prepared by the methods described by Fey, et al. US Patent 5,138,090. The key step of the synthesis is the coupling of an arylpalladium dimer with an aryl Grignard reagent (Scheme 23).
Ar RO~Pd 2) H+ ~CH0 15 A specific example of this method is shown in Scheme 24. Treatment of diol 43(prepared according to the procedure of Pey, et al. US Patent 5,138,090) with (2-methoxy)ethoxymethyl chloride and diisopropylethylamine in CH2C12 solvent gives MEM ether 44. Oxidation of the remaining alcohol of 44 as described in Scheme 4 provides aldehyde 45. Treatment of the aldehyde with aniline in the 20 presence of a catalytic amount of p-toluenesulfonic acid (pTSA) and molecularsieves in toluene solvent gives imine 46. The imine is converted to the pAllA~
dimer 47 upon treatment with palladium acetate in acetic acid solvent. Treatmentof 47 with triphenylphosphine, then with 4-fluorophenylmagnesium bromide WO ~8/01528 PCTIUS97/13248 O (prepared from 1-bromo-4-fluorobenzene and magnesium metal), and finally with aqueous hydrochloric acid in benzene solvent yields biphenyl 48. The aldehyde moiety of biphenyl 48 is converted to a pentyl group by the methods described inScheme 4. MEM ether 50 is treated with trimethylsilyl chloride and sodium iodidein acetonitrile solvent, and subsequently with sodium acetate in DM~ solvent to 5 provide acetate 51. Saponification of the acetate using potassium hydroxide inmethanol solvent provides alcohol 52. Hydroxymethyl biphenyl 52 is transformed to racemic hydroxyethyl biphenyl 54 as described in Scheme 8.
HO~f OH MEMCI MEMO~ PCC
~Pr2NEt MEMO~ PhNH2 ~ MEMO~ Pd(OAC)2 pTSA ~, HOAC
MEMO--Pd+NPh 1) F~MgBr ~1 2) H+ MEMO~O
F F
BuPPh3Br ~ H2 [~
~ ~ MEMO~H 11 . .
WO 9~ 2~ PCTAUS97tl3248 F F
1) TMSCVNal ¢~1 KOH ~ PCC
2)NaOAc o~,H~ HO~,H~
¢~ MeLi OH¢
o~H1 1 CH3~H
An alternative synthesis of biphenyls of formula (IC) is the coupling of a suitably functionalized benzene derivative 57 (where X can be trifluoro-5 methanesulfonate, methoxy, bromide, or iodide) with an arylmetal reagent ArMYn(where M may be B, Sn, or Mg, and Y is a ligand).
X Ar R3~ R2 ArMYn R3~,, R2 ll l M = B, Sn, Mg ll R1~--R1b R1a~~R1b X = OTf, OMe, Br, l An example of such a biaryl coupling is the Suzuki reaction (Miyaura, N., Yanagi, T., Suzuki, A. Synth Comm. 1981, 1~, 513-519; Oh-e, T., Miyaura, N., Suzuki, A. J. Org. Chem. 1993, 58, 2201-2208) in which a benzene derivative 58 (in which X
15 can be trifluoromethanesulfonate, bromide, or iodide) is coupled with an arylboronic acid (Scheme 26).
W 098/04528 PCTrUS97113248 o SCHEME 26 X Ar R3~, R2 ArB(OH)2 R3~ R2 Rla~R1b R1a~R1b X=OTf,Br,l The requisite arylboronic acid 60 may be prepared by sequential reaction of an aryl 5 halide 59 (X = Br or I) with magnesium metal, a boronic ester, and hydrochloric acid.
~ 3) HCI
A specific example of the use of the Suzuki reaction to synthesize a biphenyl analog is depicted in Scheme 28. Phenol 61 is treated sequentially with sodium hydride and allyl bromide in dimethylformamide solvent to afford allyl ether 62. Claisen 1~ rearrangement of the ether provides phenol 63. The phenol is treated with trifluoromethanesulfonic anhydride (triflic anhydride) and pyridine in CH2C12 solvent to give triflate 64. Treatment with 4-fluorophenylboronic acid, tetrakistriphenylphosphine palladium (0), potassium phosphate (tribasic), and potassium bromide in l,~dioxane solvent affords biphenyl 65. Catalytic 20 hydrogenation as described in Scheme 4, and reduction of the ketone with lithium aluminum hydride in THF solvent provides the desired biphenyl analog 67.
~ aH ,~
2~ 61 62 63 . ... .
O R1a OAc K2C 3 Ar Ar TBDPSO~R TBAFHO~R2 R1a N~ R1a N~
The synthesis of aryl pyridine derivatives Xa wherein R1b is -CH2NR4R5 is 5 described in Scheme 14. Oxidation of alcohol 31 as described in Scheme 4 yields aldehyde 33. Treatment of the aldehyde with an amine in the presence of a Lewis acid, such as zinc chloride, and a reducing agent, such as sodium cyanoborohydride, provides the amine 34. Deprotection of the alcohol as described in Scheme 13 affords aryl pyridine derivative Xa.
Ar Ar TBDPSO--~, PCC . TBDPSO~R2 HNR4PI5 R 1a N OH R1a CHO NaCNBH3 Ar Ar TBDPSO~R2 TBAF HO~R2 1a~N~NR4R5 1~J~N~NR4R5 34 Xa -An alternative synthesis of amine 34 is shown in Scheme 15. Treatment of pyridine N-oxide 29 with phosphorus oxychloride and a base, such as triethylamine, in CH2Cl2, yields chloromethylpyridine 35. The chloride is treated W 098/04528 PCTrUS97/13~48 O with an amine providing amine 34.
Ar Ar TBDPSO~R2 POC13 TBDPSO~R2 R1a N+ CH3 Et3N, CH2C12 R1a N CH2CI
Ar ~HNR4R5 TBDPSO~ R2 R1aJ~N--~,NR R
s The synthesis of aryl pyridine derivatives Xb wherein Rlb is -CH=CHR is described in Scheme 16. Alcohol 31 is converted to the corresponding bromide as described in Scheme 6. Treatment of 36 with sodium phosphite in benzene yields phosphonate 37. The phosphonate is treated with a base, such as sodium hydride, 10 and subsequently with an aldehyde affording olefin 38. Deprotection of the alcohol as described affords aryl pyridine Xb.
Ar Ar TBDPSO~;~ Br2PPh3 TBDPSO~ Napo~oEt)2 Ar Ar TBDPSO~ ,Ol 2~ RCHO ~ TBAF
R1a '(OEtk R1a N R
Ar HO~R2 R 1a--~N~R
Xb An alternative synthesis of olefin 38 is shown in Scheme 17. Aldehyde 33 is W 093/01C2~ PCT~US97/13248 0 treated with an ylide as described in Scheme 4 to yield olefin 38.
Ar Ar TBDPSO~ R2 R~= PPh3 TBDPSO~ R2 R1a~NJ'CHO RlaJ~N~J~R
s The synthesis of aryl pyridine derivative Xc wherein R1b is -CH2CH2R is described in Scheme 18. Hydrogenation of olefin Xb as described in Scheme 4 yields the alkane Xc R~ Pd/C ~--R
Xb Xc The synthesis of aryl pyridine derivative Xd wherein R1b is -CH(OH)R is described in Scheme 19. Treatment of aldehyde 33 with a Grignard reagent in an inert solvent, such as THF, yields alcohol 39. Deprotection of the alcohol as described affords aryl pyridine derivative Xd.
TBDPSO~R RMgBr TBDPSo~ TBAF
Ar HO~
OH
Xd The synthesis of aryl pyridine derivatives Xe wherein Rlb is -COR is CA 02262434 l999-0l-28 W 0~8/01't8 PCT~US97tl3248 O described in Scheme 20. Oxidation of alcohol 39 as described in Scheme 4 yields ketone 40. Deprotection of the alcohol as described affords the aryl pyridine derivative Xe.
s Ar Ar TBDPSO~ PCC TBDPSO~X~ TBAF
OH O
Ar HO~R2 Rla N~
Xe o The synthesis of aryl pyridine derivatives Xf wherein Rlb is -C(OH)RR' is described in Scheme 21. Grignard addition to ketone 40 as described in Scheme 1910 yields alcohol 41. Deprotection of the alcohol as described affords the aryl pyridine derivative Xf.
Ar Ar TBDPSO~ R'MgBr TBDPSO~ TBAF
Rl~ N"~R ~ R1a N~<
~ 110 R
Ar HO~R' HO R
Xf The synthesis of aryl pyridine derivatives Xg wherein R1b is -C(oR4)RR' is described in Scheme 22. Treatment of alcohol 41 with a base, such as sodium hydride, and an alkylating agent in THF, yields ether 42. Deprotection of the . . ~
W O 98/04S28 PCTrUS97/13248 0 alcohol as described affords the aryl pyridine derivative Xg.
Ar Ar ~ TBDPS0~ R4X TBDPS0~ TBAF
R1aNl><R NaH R1a N~<
Ar HO~R2 R~a NJ~<
Xg The biphenyl analogs described in formula (IC) (X = C-R8, wherein R8 is H), are prepared by the methods described by Fey, et al. US Patent 5,138,090. The key step of the synthesis is the coupling of an arylpalladium dimer with an aryl Grignard reagent (Scheme 23).
Ar RO~Pd 2) H+ ~CH0 15 A specific example of this method is shown in Scheme 24. Treatment of diol 43(prepared according to the procedure of Pey, et al. US Patent 5,138,090) with (2-methoxy)ethoxymethyl chloride and diisopropylethylamine in CH2C12 solvent gives MEM ether 44. Oxidation of the remaining alcohol of 44 as described in Scheme 4 provides aldehyde 45. Treatment of the aldehyde with aniline in the 20 presence of a catalytic amount of p-toluenesulfonic acid (pTSA) and molecularsieves in toluene solvent gives imine 46. The imine is converted to the pAllA~
dimer 47 upon treatment with palladium acetate in acetic acid solvent. Treatmentof 47 with triphenylphosphine, then with 4-fluorophenylmagnesium bromide WO ~8/01528 PCTIUS97/13248 O (prepared from 1-bromo-4-fluorobenzene and magnesium metal), and finally with aqueous hydrochloric acid in benzene solvent yields biphenyl 48. The aldehyde moiety of biphenyl 48 is converted to a pentyl group by the methods described inScheme 4. MEM ether 50 is treated with trimethylsilyl chloride and sodium iodidein acetonitrile solvent, and subsequently with sodium acetate in DM~ solvent to 5 provide acetate 51. Saponification of the acetate using potassium hydroxide inmethanol solvent provides alcohol 52. Hydroxymethyl biphenyl 52 is transformed to racemic hydroxyethyl biphenyl 54 as described in Scheme 8.
HO~f OH MEMCI MEMO~ PCC
~Pr2NEt MEMO~ PhNH2 ~ MEMO~ Pd(OAC)2 pTSA ~, HOAC
MEMO--Pd+NPh 1) F~MgBr ~1 2) H+ MEMO~O
F F
BuPPh3Br ~ H2 [~
~ ~ MEMO~H 11 . .
WO 9~ 2~ PCTAUS97tl3248 F F
1) TMSCVNal ¢~1 KOH ~ PCC
2)NaOAc o~,H~ HO~,H~
¢~ MeLi OH¢
o~H1 1 CH3~H
An alternative synthesis of biphenyls of formula (IC) is the coupling of a suitably functionalized benzene derivative 57 (where X can be trifluoro-5 methanesulfonate, methoxy, bromide, or iodide) with an arylmetal reagent ArMYn(where M may be B, Sn, or Mg, and Y is a ligand).
X Ar R3~ R2 ArMYn R3~,, R2 ll l M = B, Sn, Mg ll R1~--R1b R1a~~R1b X = OTf, OMe, Br, l An example of such a biaryl coupling is the Suzuki reaction (Miyaura, N., Yanagi, T., Suzuki, A. Synth Comm. 1981, 1~, 513-519; Oh-e, T., Miyaura, N., Suzuki, A. J. Org. Chem. 1993, 58, 2201-2208) in which a benzene derivative 58 (in which X
15 can be trifluoromethanesulfonate, bromide, or iodide) is coupled with an arylboronic acid (Scheme 26).
W 098/04528 PCTrUS97113248 o SCHEME 26 X Ar R3~, R2 ArB(OH)2 R3~ R2 Rla~R1b R1a~R1b X=OTf,Br,l The requisite arylboronic acid 60 may be prepared by sequential reaction of an aryl 5 halide 59 (X = Br or I) with magnesium metal, a boronic ester, and hydrochloric acid.
~ 3) HCI
A specific example of the use of the Suzuki reaction to synthesize a biphenyl analog is depicted in Scheme 28. Phenol 61 is treated sequentially with sodium hydride and allyl bromide in dimethylformamide solvent to afford allyl ether 62. Claisen 1~ rearrangement of the ether provides phenol 63. The phenol is treated with trifluoromethanesulfonic anhydride (triflic anhydride) and pyridine in CH2C12 solvent to give triflate 64. Treatment with 4-fluorophenylboronic acid, tetrakistriphenylphosphine palladium (0), potassium phosphate (tribasic), and potassium bromide in l,~dioxane solvent affords biphenyl 65. Catalytic 20 hydrogenation as described in Scheme 4, and reduction of the ketone with lithium aluminum hydride in THF solvent provides the desired biphenyl analog 67.
~ aH ,~
2~ 61 62 63 . ... .
Tf20 J~ F~B(OHk ¢~ H2 .
Pyr Pd(PPh)3 J~, Pd/C
~ F 65 O ¢~ LAH ~ OH¢~
b~ ~
An alternative synthesis of biphenyls of type I uses a cycloaromatization of a ketodiester 68 with a diketone in the presence of a catalytic amount of sodium 5 methoxide in methanol solvent to give a phenol 69. The phenol is then coupled with an arylboronic acid as described in Scheme 28 to afford biphenyl diester 70.
The diester is then transformed as described in Schemes 4, 8, and 10 to give theanalog with the desired R2 and R3 groups.
O O ~ OH O 1) Tf20/Pyr MeOJw~oMe R1aJ~Rlb MeO'D~OMe 2)pdr( (OH)2 68 R1a R1b K3PO4/KBr MeO~OMe R3~R2 R1a R1b ~ R1a R1b 15 An alternative method of transforming phenol 69 to biphenyl 70 is shown in Scheme 30. Treatment of the phenol with dimethylsulfate and a base such as potassium carbonate yields the methyl ether 71. The ether is treated with an aryl Grignard reagent to afford biphenyl 70.
o OH o O OMe O
Jl 1 1~Me2SO4 Jl 1 J~
MeO ~ K2CO3 ~ OMe R1a R1b R1a R1b O Ar O
ArMgBr MeO~OMe R1a R1b 5 The diester 70 can be further transformed by an alternative method shown in Scheme 31, to give the analogs with the desired R2 and R3 groups. Chemical reducing agents such as sodium bis-(2-methoxyethoxy)-aluminum hydride (Red-Al), can result in a mono reduction of the diester 70 to give the alcohol 72. Alcohol 72 can be attached to a polymeric support such as Wang resin, by treatment with a 10 base such as sodium hydride in DMF, to give the intermediate 73. The ester group of intermediate 73 can be transformed to an alkyl halide in a two step process; 73 is treated with a reducing agent such as LAH, then Phosphorous tribromide to affordcompound 74. The alkyl halide 74 is treated with an alkyl thiol and a base such as N-methyl morpholine, then by TFA to cleave the ether linkage with the polymeric 15 resin, to a~ford the alcohol 75.
MeO~ OMe Red-AllTHF MeO~ CI
R1a R1b R1a R1b ~ 72 O Ar Ar MeOJ~~O~~ 1') LAH /THF Br~f O~~
RlaJ~R1b ~0 2) PBr3 R1a~R1b o 73 z 74 Z
1) R7SH/CH2C12 R7 Ar N-Me-i,,G~ ' ,e 's~f OH Z= Polystyrene 2) TFAICH2C12 R1a R1b .. ....
W098/04528 PCTrUS97113248 o It will be appreciated that synthesis of some compounds of formula (IC) may require use of protecting groups at various stages of the procedures. These are removed in subsequent steps. For example, the removal of O-benzyl ether protecting groups is carried out by treatment with hydrogen in the presence of a5 metal catalyst, such as palladium on carbon, in a polar solvent such as ethanol. The removal of silyl ether protecting groups is carried out by treatment with fluoride salts, such as tetrabutylamonium fluoride in a solvent such as THP. Conditions required to remove other protecting groups which may be present can be found in:Protective Groups in Or~anic Synthesis, Second Edition, T. W. Greene, John Wiley10 and Sons, New York, 1991.
The order of carrying out the steps of the foregoing reaction schemes is not always significant, and it is within the skill of the art to vary the order of reactions to facilitate the reaction or to avoid unwanted reaction products.
The following examples are provided for the purpose of further illustration only and are not intended to limit the disclosed invention.
EXAh~LE 1 F
HO ~----~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine ~ 25 Step A: 3-Amino-4-methyl-2-pentenoic acid, ethyl ester To 100 g (0.63 mol) of ethyl isobutyryl acetate was added ammonium acetate ~ (68.2 g, 0.89 mol), cyclohexane (230 mL) and isopropanol (74 mL). The mixture was heated at reflux under argon atmosphere with a Dean-Stark trap. After 2 hours, asecond portion of ammonium acetate (14.6 g, 0.19 mol) was added to the reaction.30 The reaction was heated at reflux for 12 hours and then allowed to cool to room 0 temperature. A total of ~30 mL of water was collected in the Dean-Stark trap. An ice bath was used to cool the reaction to 10~C and then ammonium hydroxide (63 mL) was added dropwise. The organic layer was separated, dried with sodium sulfate, filtered, and concentrated to yield a yellow oil. The crude product (90.9 g, 0.58 mol, 92%) was taken directly to the next step without any further purification.
s Step B: Diethyl 1,4-dihydro-2,~diisopropyl-4-(4-fluorophenyl)-3,5-pyridinedicarboxylate To ethyl 3-amino-4-methylpent-2-enoate (Step A) (90 g, 57 mmol) was added ethyl isobutyryl acetate (9Og, 57 mmol) and 4-fluorobenzaldehyde (61.4 mL, 0.57 mmol). The mixture was heated under argon at 130~C for 26 hours (Precaution:
Check the reflux condenser after a few hours as excess ammonium acetate will clog the condenser). The reaction was allowed to cool to room temperature and left tocrystallize for 4 days. The solid was collected by filtration with vacuum (46.9 g, 116 mmol, 20%) and taken directly to the next step without further purification.
Step C: Diethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3,5-pyridinedicarboxylate To the intermediate obtained in Step B (33 g, 82 mmol) in dichloromethane (400 ml) was added 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 20.5 g, 90 mmol) under argon and the mixture was stirred for 2 hours. The stirring was stopped toallow the precipitate to settle. The precipitate was filtered, washed with dichloromethane (3 x 30 mL), and discarded. The filtrate was concentrated to afford a brown solid, which was subjected to flash chromatography (6/4 mixture of dichloromethane/hexanes) resulting in a pure white solid (25.8 g, 64.3 mmol, 78%).
lH NMR (300 MHz, CDCl3): ~ 7.28 (m, 2 H), 7.06 (m, 2 H), 4.03 (q, J = 7.0 Hz, 4 H), 3.11 (septet, J = 6.6 Hz, 2 H), 1.32 (d, J = 6.5 Hz, 12 H), 0.979 (t, J = 3.3 Hz, 6 H). FAB-MS: r~ te~ for (C23H2~NO4F) 401, found 402 (M+H). Anal. calc for C23H2gNO4F: C, 68.64; H, 7.24; N, 3.48; F, 4.72. Found: C, 69.12; H, 6.98; N, 3.42;
F, 4.96. mp 72-74~C. Rf=0.4 (10% ethyl acetate/hexane).
Step D: Ethyl 2,6-diisopropyl-4-(4-fluorophen~rl)-5-hydroxymethyl-3 pyridinecarboxylate To a solution of the intermediate obtained in Step C (23.4 g, 58.3 mmol) in anhydrous tetrahydrofuran (300 mL) stirred under argon at 0~C was added a 35 solution of 3.4M of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (Red-Al) (61 mL, 204 mmol, 65 wt% in toluene) via syringe over 20 min. The reaction mixture was allowed to stir at room temperature for 7 hr, then cooled WO 98/04528 PCTrUS97113248 0 again to 0~C and carefully quenched by the dropwise addition of water. The solution was decanted from the solid which forms and the solvent removed in vacuo. The residue was purified by flash chromatography (300 g silica) via step gradient. Elution with 5% diethyl ether/hexane afforded 6.6 g (16.4 mmol, 28%) of recovered starting material and elution with 40% diethyl ether(Et2O) /hexane ~ 5 yielded the desired product as a yellow waxy solid (14 g, 39 mmol, 67%). lH NMR
(300 MHz, CDCl3): ~ 7.27 (m, 2 H), 7.10 (m, 2 H), 4.46 (d, J = 5.2 Hz, 2 H), 3.98 (q, J
= 7 Hz, 2 H), 3.48 (sept, J = 6.6 Hz, 1 H), 3.05 (sept, J = 6.6 Hz, 1 H), 1.32 (t, J = 6.6 Hz, 12 H), 0.97 (t, J = 7 Hz, 3 H). FAB-MS: calculated for (C21H26FNO3) 359, found 360 (M+H). Rf = 0.2 (20% ethyl acetate/hexane).
Step E: 5-Carboethox~l-2,6-diisopropyl-4-(4-fluorophenyl)-3-p~ridinecarboxaldehyde To a solution of the intermediate obtained in Step D (13 g, 36 mmol) in dichloromethane (1 L) was added Brockman I neutral alumina (7.4 g, 72 mmol).
The suspension was stirred at room temperature and treated with pyridinium chlorochromate (PCC) (16 g, 72 mmol) in three portions. The suspension was stirred at room temperature for 1 hr, then poured into 1:1 diethyl ether/hex (1 L), filtered through a pad of silica, the pad washed with diethyl ether (500 mL) and the combined eluent concentrated to afford a viscous oil which slowly solidified (12.8 g, 35.9 mmol, 99%): Rf = 0.31 (10% ethyl acetate/hexane). lH NMR (300 MHz, CDCl3): ~ 9.85 (s, 1 H), 7.27 (m, 2 H), 7.13 (m, 2 H), 4.04 (q, J = 7 Hz, 2 H), 3.88 (sept, J = 6.6 Hz, 1 H), 3.12 (sept, ~ = 6.6 Hz, 1 H), 1.33 (t, J = 6.6 Hz, 12 H), 1.00 (t, J =
7 Hz, 3 H). EI-MS calcd for (C21H24FNO3) 357, found 358 (M+H). Anal. Calcd for C21H24FNO3: C, 70.57; H, 6.77; N, 3.92. Found: C, 70.62; H, 6.78; N, 3.84.
Step F: Ethyl 2,~diisopropyl-4-(4-fluorophenyl)-5-(1-pentenyl)-3-pyridinecarboxylate Butyltriphenylphosphonium bromide (2.7 g, 6.76 mmol) was suspended in anhydrous THF (75 mL) under argon and stirred at -78~C. A 1.6 M solution of n-butyllithium in hexanes (4.2 mL, 6.76 mmol) was added dropwise. The reaction mixture was allowed to come to 0~C and was stirred at that temperature for 1.5 hr.
The resulting brightly colored solution was cooled again to -78~C and treated dropwise with a solution of the intermediate obtained in Step E (2 g, 5.60 mmol) in THF (20 mL). The reaction mixture was allowed to stir at 0~C for 1 hr, then quenched by the addition of water (5 mL). The THF was removed in V~C~lo, the residue partitioned between ethyl ether (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over MgSO4 and concentrated. Flash W O 98/04528 PCT~US97tl3248 0 chromatography through silica (5% diethyl ether/hexane) affords a viscous oil (2 g, 5 mmol, 90%) (E,Z mixture). 1H NMR (300 MHz, CDCl3): ~ 7.14 (m, 2 H), 7.02 (m, 2 h), 6.10 (dt, J = 1.8, 11.4 Hz, 0.4 H), 6.04 (dt, J = 1.5, 16.2 Hz, 0.6 H), 5.48 (dt, J = 7, 11.4 Hz, 0.4 H), ~.33 (dt, J = 7, 16.2 Hz, 0.6 H), 4.00 (q, J = 7 Hz, 0.8 H), 3.98 (q, J = 7 Hz, 1.2 H), 3.39 (sept, J = 6.6 Hz, 0.6 H), 3.27 (sept, J = 6.6 Hz, 0.4 H), 3.06 (m, 1 H), 1.95 (dq, J - 1.5, 7 Hz, 1 H), 1.26 (m, 13 H), 1.19 (m, 2 H), 0.97 (t, J = 7 HZ, 3 H), 0.77 (t, J = 7 Hz, 1.2 H), 0.76 (t, J = 7 Hz, 1.8 H). EI-MS calculated for (C25H32FNO2) 397, found 397 (M+). Rf = 0.5 (10% ethyl acetate/hexane).
Step G: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-( pentenyl)pyridine The intermediate obtained in Step F (2 g, 5.03 mmol) was dissolved in anhydrous THF (100 ml ) under argon and treated dropwise at room temperature with lithium aluminum hydride (1.0 M in THF, 10 mL, 10 mmol). The reaction mixture was stirred at reflux for 1 hr, cooled to room temperature and quenched by the addition of 0.38 mL H2O, 0.38 mL 20% aqueous NaOH and 1.1 mL H20.
The resulting suspension was filtered through a cake of Celite and the filtrate concentrated and purified by chromatography through silica (5% ethyl acetate/hexane) to afford the product as a white foam (1.42 g, 4.0 mmol, 80%). Rf =
0.2 (10% ethyl acetate/hexane).
Step H: 2,6-Diisopropyl-3-h~droxvmethyl-4-(4-fluorophenyl)-5 pentylpyridine The intermediate obtained in Step G was dissolved in absolute ethanol (50 mL) under argon, treated with 10% palladium on carbon (140 mg, 0.1 eq), then 25 stirred under a hydrogen atmosphere for 2 hr. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the product dried in vacuo to afford the title compound as a white solid (1.4 g, 3.9 mmol, 98%). lH NMR (300 MHz, CDCl3): ~ 7.15 (m, 4 H), 4.33 (d, J = 4.4 Hz, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 1.27 (m, 2 H), 1.13 (m, 5 H), 0.79 (t, J = 6.6 Hz, 3 H). FAB-MS: calculated for (C23H32FNO) 357, found 358(M+H). Anal. calcd for C23H32FNO: C, 77.27; H, 9.02; N, 3.92. Found: C, 77.46;
H, 8.95; N, 3.78. Rf=0.3 (20% ethyl acetatethexane). mp 100-101~C.
CA 02262434 l999-0l-28 WO 98/01~2~ PCT~US97/13248 .' ~0~
N
2,6-Dimethyl-3-hydroxymethYl~-Phenvl-5-(2-methyl-l-propenyl)-pyridirle The title compound was prepared from ethyl acetoacetate, benzaldehyde and isopropyl triphenylphosphonium iodide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDCl3): ~ 7.34 (m, 3 H), 7.10 (m, 2 H), 5.70 (s, 1 H), 4.42 (s, 2 H), 2.69 (s, 3 H), 2.43 (s, 3 H), 1.60 (s, 3 H), 1.35 (s, 3 H).
EI-MS calculated for (clgH2lNo) 267, found 267 (M+). mp 48-50~C. Rf = 0.3 (90%
ethyl acetate/hexane).
HO ~--N
2,6-Dimethyl-3-hydroxymethyl-4-phenyl-5-(1-penten~l)pyridine The title compound was prepared from ethyl acetoacetate, benzaldehyde and butyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 3:1 trans:cis isomers; gummy oil. lH NMR (300 MHz, CDCl3): ~ 7.37 (m, 3 H), 7.12 (m, 2 H), 5.94 (m, 1 H), 5.40 (m, 1 H), 4.41 (bs, 2 H), 2.71 & 2.68 (2s, 3 H), 2.57 & 2.46 (2s, 3 H), 1.91 & 1.69 (2q, J = 7 Hz, 2 H), 1.52 (bs, 1 H), 1.19 (m, 2 H), 0.77 (m, 3 H). E~-MS:
calculated for (C1gH23NO) 281, found 281. Rf = 0.4 (90% ethyl acetate/hexane).
W O 98/04528 PCT~US97113248 ~10 2,6-Dimeth~1-3-hydroxymethyl-4-phen~ 5-pent~lpyridine The title compound was prepared from 2,6-dimethyl-3-hydroxymethyl-4-phenyl-5-(1-pentenyl)pyridine (Example 3) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): ~ 7.42 (m, 3 H), 7.15 (m, 2 H), 4.33(s, 2 H), 2.65 (s, 3 H), 2.56 (s, 3 H), 2.27 (m, 2 H), 1.29 (m, 2 H), 1.11 (m, 4 H), 0.76 (t, J
= 7 Hz, 3 H). EI-MS: calculated for (C1gH2sNO) 283, found 283 (M+). Anal.
calculated for C1gH25NO: C, 80.52; H, 8.89; N, 4.94. Found: C, 80.39; H, 8.85; N, 4.85. mp 99-100~C. Rf = 0.3 (90% ethyl acetate/hexane).
[3 HO~
N
2,6-Dieth~1-3-hydroxymethyl-4-phenyl-5-(2-methyl-1-propenyl)p~,rridine The titlecompound was prepared from ethyl propionylacetate, benzaldehyde and isopropyl triphenylphosphonium iodide according to the procedures described in Example 1, Steps A-G. 1H NMR (300 MHz, CDCl3): ~ 7.34 (m, 3 H), 7.11 (m, 2 H), 5.76 (s, 1 H), 4.44(d,J=5.5Hz,2H), 3.01 (q, J = 7.4 Hz, 2 H), 2.75 (q, J = 7.4 Hz, 2 H), 1.58 (s, 3 H), 1.35 (m, 7 H), 1.21 (t, J = 7.4 Hz, 3 H). FAB-MS: calclllAted for (C20H2sNo) 295, found 296 (M+H). Anal. Calcd for C20H2sNo: C, 81.31; H, 8.53; N, 4.74. Found:
C, 81.03; H, 8.55; N, 4.65. mp 103-104~C. Rf = 0.4 (50% ethyl acetate/hexane).
CA 02262434 l999-0l-28 W098/04S28 PCTrUS97/13248 HO~--/
N
2,6-Diethvl-3-hydroxymethyl-4-phen~11-5-(l-pentenyl)p~,rridine The title compound was prepared from ethyl propionylacetate, benzaldehyde and butyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 6:4 trans:cis isomers. lH NMR (300 MHz, CDCl3): ~ 7.36 (m, 3 H), 7.14 (m, 2 H), 6.00 (m, 1 H), 5.37 (m, 1 H), 4.42 (m, 2 H), 2.90 (m, 4 H), 1.89 & 1.67 (2q, J =
7 Hz, 2 H), 1.25 (m, 9 H), 0.76 (m, 3 H). FAB-MS: calculated for (C21H27NO) 309,found 310 (M+H); Anal. Calcd for C21H27NO: C, 81.51; H, 8.79; N, 4.53. Found:
C, 81.95; H, 8.90; N, 4.45. mp 74-76~C. Rf = 0.5 (50% ethyl acetate/hexane) HO~----N
2,6-Diethyl-3-h~droxymethyl-4-phenyl-5-pentylpyAdine The title compound was prepared from 2,6-diethyl-3-hydroxymethyl-4-20 phenyl-5-(1-pentenyl)pyridine (Example 6) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): ~ 7.42 (m, 3 H), 7.18 (m, 2 H), 4.34(d, J = 6 Hz, 2 H), 2.96 (q, J = 7.7 Hz, 2 H), 2.84 (q, J = 7.7 Hz, 2 H), 2.28 (m, 2 H), 1.34 (m, 9 H), 1.09 (m, 4 H), 0.76 (t, J - 7 Hz, 3 H). FAB-MS: calculated for (C21H2gNO) 311, found 312 (M+H). mp 76-77~C. Rf = 0.5 (50% ethyl acetate/hexane).
WO 98~ 8 PCT/US97/13248 HO~
N
2,6-Diethyl-3-hvdroxymethyl-4-phenyl-~ ethenyl)pyridine The title compound was prepared from ethyl propionylacetate, benzaldehyde and methyl triphenylphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps A-G. 1H NMR (300 MHz, CDCl3): ~ 7.40 (m, 3 H), 7.20 (m, 2 H), 6.36 (dd, J - 11, 18 Hz, 1 H), 5.22 (dd, J
=11,2Hz,1H),5.00(dd,J=18,2Hz, lH),4.41 (d,J=6Hz,2H),2.96(m,4H), 1.35 (m, 7 H). FAB-MS: calculated for (C1gH21NO) 267, found 268 (M~H). Anal.
Calcd for C1gH21NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.65; H, 8.06; N, 5.09.
mp 84-85~C. Rf = 0.4 (50% ethyl acetate/hexane).
E~CAMPLE 9 HO~
N
2,5,6-Triethyl-3-hvdrox~methyl-4-phenylpyridine The title compound was prepared from 2,6-diethyl-3-hydroxymethyl-4-phenyl-5-(1-ethenyl)pyridine (Example 8) according to the procedure described inExample 1, Step H. 1H NMR t300 MHz, CDC13): ~ 7.44 (m, 3 H), 7.18 (m, 2 H), 4.33 (d,J=6Hz,2H),2.97(q,J=8Hz,2H),2.86(q,J=8Hz, 2H),2.36(q,~=8Hz,2 H), 1.34 (m, 7 H), 0.93 (t, J = 8 Hz, 3 H). FAB-MS: calculated for (C1gH23NO) 269, found 270 (M+H). Anal. Calcd for C1gH23NO: C, 80.26; H, 8.61; N, 5.20. Found:
C, 79.70; H, 8.54; N, 5.08. mp 100nC. R~ = 0.4 (50~/O ethyl acetate/hexane).
W 098/045t8 PCTAUS97113248 o EXAMPLE 10 HO ~"--"
~N~
2,6-Diisopropvl-3-h~droxYmethyl-4-phenyl-5-(l-pentenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, benzaldehyde and butyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDCl3): ~ 7.35 (m, 3 H), 7.14 (m, 2 H), 5.99 (m, 1 H), 5.35 (m, 1 H), 4.41 (m, 2 H), 3.36 (m, 2 H), 1.89 & 1.70 (2q, J = 7 Hz, 2 H), 1.24 (m, 15 H), 0.80 & 0.72 (2t, J = 7 Hz, 3 H). FAB-MS:
calculated for (C23H31NO) 337, found 338 (M+H). Anal. Calcd for C23H31NO: C, 81.85; H, 9.26; N, 4.15. Found: C, 81.88; H, 9.22; N, 3.93. mp 67-73~C. Rf = 0.1 (10%
ethyl acetate/hexane).
~0~
\~ N~
2,6-Diisoprop~ 3-hydroxvmethyl-4-phenyl-5-(2-methyl-l-propenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, benzaldehyde and isopropyl triphenylphosphonium iodide according to the procedures described in Example 1, Steps A-G. 1H NMR (300 MHz, CDCl3): ~ 7.32 ~ (m, 3 H), 7.11 (m, 2 H), 5.75 (s, 1 H), 4.43 (bs, 2 H), 3.46 (sept, J = 6.6 Hz, 1 H), 3.18 (sept, J = 6.6 Hz, 1 H), 1.57 (s, 3 H), 1.31 (m, 15 H). FAB-MS: calculated for (C22H2gNO) 323, found 324 (M+H). Anal. Calcd for C22H2gNO: C, 81.69; H, 9.04;
N, 4.33. Found: C, 81.59; H, 8.94; N, 4.29. mp 93-95~C. Rf = 0.1 (10% ethyl acetate/hexane).
WO 98/04528 PCTfiUS97/13248 HO
~N~/
2,6-Diisopropyl-3-h~rdroxymethyl-4-phen~ 5-(1-propenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, benzaldehyde and ethyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. lH NMR (300 MHz, CDCl3): ~ 7.4 (m, 3 H), 7.2 (m,2H),6.0(m, 1 H), 5.5 & 5.4 (2m, 1 H), 4.4 (m, 2 H), 3.4 & 3.2 (2m, 2 H), 1.6 (m, 2 H), 1.4 (m, 7 H), 1.3 (m, 7 H). PAB-MS: calculated for (C21H27NO) 309,found 310 (M~H~. Anal. Calcd for C21H27NO: C, 81.53; H, 9.98; N, 3.96. Found:
C, 79.06; H, 9.65; N, 3.61. Rf = 0.4 (20% ethyl acetate/hexane).
HO~
--f ' N~/
2,6-Diisopropyl-3-hydrox~methyl-4-phen~l-5-(l-butenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, 20 benzaldehyde and propyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. 1H NMR (300 MHz, CDCl3): ~ 7.4 (m, 3 H),7.2(m,2H),6.0(m,1H),5.4(m,1H),4.4(m,2H),3.3(m,3H),1.9 &1.7(2m,2 H), 1.3 (m, 12 H), 0.7 (m, 3 H). FAB-MS: calculated for (C22H2gNO) 323, found 324 25 (M+H). Rf = 0.4 (20% ethyl acetate/hexane).
WO 9~ t~2~ PCT/US97113248 HO
~N~/
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-pentylpyridine The title compound was prepared from 2,6-diisoproyl-3-hydroxymethyl-4-S phenyl-5-(1-pentenyl)pyridine (Example 10) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCI3) ~ 7.41 (m, 3 H), 7.18 (m, 2 H), 4.33 (s, 2 H), 3.42 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.32 (m, 13 H), 1.11 (m, 5 H), 0.76 (t, J = 7 Hz, 3 H). FAB(HR)-MS calcd for C23H33NO 339.2640; found 340.2640 (M+H). mp 81-82~C. Rf = 0.1 (10% ethyl 1 0 acetate/hexane).
HO ~ \
~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-(1-hexenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, benzaldehyde and pentyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. 1H NMR (300 MHz, CDCl3): ~ 7.35 (m, 3 H), 7.14 (m, 2 H), 5.99 (m, 1 H), 5.35 (m, 1 H), 4.40 (m, 2 H), 3.36 (m, 2 H), 1.92 &
1.70 (2m, 2 H), 1.20 (m, 17 H), 0.80 (m, 3 H). FAB-MS: calculated for (C24H33NO)~ 351, found 352 (M+H). Anal. Calcd for C24H33NO: C, 82.00; H, 9.46; N, 3.98.
Found: C, 81.58; H, 9.50; N, 4.62. Rf = 0.1 (10% ethyl acetate/hexane);
WO~8/017~ PCTrUS97113248 [~1 HO ~j~
\~ N~/
2,6-Diisopropyl-3-h~rdrox~meth~1-4-phenyl-5-hexylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-5 phenyl-5-(1-hexenyl)pyridine (Example 15) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDC13): ~ 7.40 (m, 3 H), 7.18 (m, 2 H), 4.33(d, J = 5 Hz, 2 H), 3.42 (septet, J = 7 Hz, 1 H), 3.23 (septet, J = 7 Hz, 1 H), 2.26 (m, 2 H), 1.31 (m, 13 H), 1.12 (m, 8 H), 0.80 (t, J = 7 Hz, 3 H). FAB-MS: calculated for (C24H3sNO) 353, found 354 (M+H). Anal. Calcd for C24H3sNO: C, 81.53; H, 9.98;
N, 3.96. Found:C, 79.06; H, 9.65; N, 3.61. mp 71-72~C. Rf = 0.1 (10% ethyl acetate/hexane).
[~
HO ~' ~f N'~/
2,6-Diisoprop~1-3-hydroxymeth~,r1-4-phenyl-5-propylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-phenyl-5-(1-propenyl)pyridine (~xample 12) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): ~ 7.41 (m, 3 H), 7.17 (m, 2 H), 4.33 (s, 2 H), 3.42 (sept, J - 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.25 (m, 2 H), 1.33(d,J=6.6Hz,6H),1.30(d,J=6.6Hz,6H),1.27(m,2H),1.20(m,1H),0.74(t,J
= 7 Hz, 3 H). FAB-MS: calculated for (C21H2gNO) 311, found 312 (M+H). Anal.
Calcd for C21H2gNO: C, 80.~8; H, 9.38; N, 4.50. Found: C, 80.72; H, 9.47; N, 4.38.
mp 89-90~C. Rf = 0.4 (20% ethyl acetate/hexane).
W O 98104528 PCTrUS97/13248 o EXAMPLE 18 HO~
~f N~
2,6-Diisopropyl-3-hvdroxymethyl-4-Phenyl-5-butylpyridine S The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-phenyl-5-(1-butenyl)pyridine (Example 13) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3): ~ 7.41 (m, 3 H), 7.17 (m, 2 H), 4.33 (s, 2 H), 3.42 (sept, J = 6.6 Hz, 1 H), 3.24 (sept, J = 6.6 Hz, 1 H), 2.28 (m, 2 H), 1.33 (d, J-6.6Hz,6H),1.31 (d,J=6.6Hz,6H),1.28(m,2H),1.14(m,3H),0.71 (t,J=7Hz, 3 H). FAB-MS: calculated for (C22H31NO) 325, found 326 (M+H). Anal. Calcd for C22H31NO: C, 81.18; H, 9.60; N, 4.30. Pound: C, 81.28; H, 9.87; N, 4.07. mp 83-84~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO ~~~
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-~4-fluorophenvl)-5-(1-hexenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, 20 4-fluorobenzaldehyde and pentyl triphenylphosphonium bromide according to theprocedures described in Example 1, Steps A-G. The product was obtained as a mixture 6:4 trans:cis isomers; gumn~y oil. lH NMR (300 MHz, CDCl3): ~ 7.10 (m, 4H), 5.98 (m, 1 H), 5.42 (dt, J = 7, 11.4 Hz, 0.4 H), 5.29 (dt, J = 7, 16.2 Hz, 0.6 H), 4.40 (d, J = 5.5 Hz, 2 H), 3.44 (m, 1 H), 3.36 (sept, J = 6.6 Hz, 0.6 H), 3.24 (sept, J = 6.6 Hz, 0.4 H), 1.94 (m, 1 H), 1.36 (m, 6 H), 1.23 (m, 8 H), 1.12 (m, 4 H), 0.82 (m, 3 H). FAB-W098104528 PCTrUS97tl3248 0 MS: calculated for (C24H32FNO) 369, found 370 (M+H). Rf = 0.4 (20% ethyl acetate/hexane).
E~CAMPLE 20 F
HO
~'N ~/
2,6-Diisopropyl-3-hvdroxYmethYl~-(4-fluorophenyl~-5-(l -butenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, ~fluorobenzaldehyde and propyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. lH NMR (300 MHz, CDC13): ~ 7.10 (m, 4 H), 5.97 (m, 1 H), 5.39 (dt, J = 7, 11.4 Hz, 0.5 H), 5.32 (dt, J = 7, 16.2 Hz, 0.5 H), 4.41 (d, J = 5.5 Hz, 2 H), 3.45 (m, 1 H), 3.36 (sept, J = 6 6 Hz, 0.5 H), 3.24 (sept, J = 6.6 Hz, 0.5H),1.95(m,1H),1.70(m,1H),1.35(d,J=6.6Hz,3H), 1.34 (d,J= 6.6Hz,3H), 1.25 (m, 7 H), 0.79 (t, J = 7.5 Hz, 1.5 H), 0.78 (t, J = 7.5 ~Iz, 1.5 H). FAB-MS: calculated for (C22H2gFNO) 341, found 342 (M+H). Rf - 0.4 (20% ethyl acetate/hexane).
HO~
~N~/
2,6-Diisopropyl-3-hydroxymethyl-~t4-fluorophenvl)-5-(l-propenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate~
4-fluorobenzaldehyde and ethyl triphenylphosphonium ~romide according to the procedures described in Example 1, Steps A-G. The product was obtained as a W O~8/01~ PCTrUS97/13248 0 mixture 1:1 trans:cis isomers. 1H NMR (300 MHz, CDCl3): ~ 7.11 (m, 4 H), 6.04 (d, J = 11.7 Hz, 0.5 H), 5.96 (d, J = 16.1 Hz, 0.5 H), 5.53 (m, 0.5 H), 5.33 (m, 0.5 H), 4.41 (m, 3 H), 3.42 (m, 1.5 H), 3.20 (sept, J = 6.6 Hz, 0.5 H), 1.61 (d, J = 6 Hz, 2 H), 1.3 (m, 13 H). FAB-MS: calculated for (C21H26FNO) 327, found 328 (M+H). Anal. Calcd forC21H26FNO: C,77.03;H,8.00;N,4.28. Found: C,77.15;H,8.07;N,4.11. mp 46-47~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO
\~ N
2,6-Diisopropyl-3-h~rdroxymethyl-4-(4-fluorophen~ll)-5-ethen~rlpyridine The title compound was prepared from ethyl isobutyrylacet~te, 4-fluorobenzaldehyde and methyl triphenylphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDCl3): ~ 7.12 (m, 4 H), 6.35 (dd, J = 11.5, 18 Hz, 1 H), 5.24 (dd, J = 1.5, 11.4 Hz, 1 H), 4.97 (dd, J = 1.5, 18 Hz, 1 H), 4.41 (d, J = 5.5 Hz, 2 H), 3.44 (sept, J = 6.6 Hz, 2 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.28 (d, J = 6.6 Hz, 6 H), 1.25 (m, 1 H). FAB-MS-calculated for (C20H24FNo) 313, found 314 (M+H). Anal. Calcd for C20H24FNo:
C, 76.65; H, 7.72; N, 4.47. Found: C, 76.87; H, 7.79; N, 4.33. mp 119-120~C. Rf = 0.4 20 (20% ethyl acetate/hexane).
h HO ~--/--~N~
WO 98/04~28 PCT~US97113248 o 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-hexylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-hexenyl)pyridine (Example 19) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): ~ 7.14 (m, 4 H), 4.33 5(s, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 1.26 (m, 1 H), 1.14 (m, 7 H), 0.82 (t, J = 7 Hz, 3 H). FAB-MS: calculated for (C24H34FNO) 371, found 372 (M+H). mp 93-95~C. Rf = 0.4 (20% ethyl acetate/hexane).
HO ~--' ~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-butylpyridine 15The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-butenyl)pyridine (Example 20) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDC13): ~ 7.15 (m, 4 H), 4.33 (d, J = 5.2 Hz, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.27 (m, 2 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 1.27 (m, 1 H), 1.16 (m, 3 H), 0.73 20(t, J = 7 Hz, 3 H). FAB-MS: calculated for (C22H30FNo) 343, found 344 (M+H).
Anal. Calcd for C22H30FNo: C, 76.93; H, 8.80; N, 4.08. Found: C, 76.93; H, 8.70;N, 3.96. mp 45-50~C. Rf = 0.4 (20% ethyl acetate/hexane).
o E~CAMPLE 25 HO ~--' ~f N~/
2,6-Diisopropyl-3-h~drox~methyl-4-(4-fluorophenyl)-5-prop~lpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-propenyl)pyridine (Example 21) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDC13): ~ 7.15 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.25 (m, 2 H), 1.33 (d, J=6.6Hz,6H),1.30(d,J=6.6Hz,6H),1.27(m,1H),l.l9(m,lH),0.76(t,J=7Hz, 3 H). FAB-MS: calculated for (C21H2gFNO) 329, found 330 (M+H). Anal. Calcd for C21H2gFNO: C, 76.56; H, 8.57; N, 4.25. Found: C, 76.55; H, 8.48; N, 4.11. mp 49-54 ~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO ~~
~N~/
2,6-Diisoprop~1-3-hydroxymethyl-4-(4-fluorophenyl)-5-eth~lpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-20 (4-fluorophenyl)-5-ethenylpyridine (Example 22) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3): ~ 7.15 (m, 4 H), 4.33 (d, J = 3.6 Hz, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.26 (sept, J = 6.6 Hz, 1 H), 2.34 (q, J =
7.35Hz,2H),1.33(d,J=6.6Hz,6H),1.31(d,J=6.6Hz,6H),l.l9(m,lH),0.93(t,J
= 7.35 Hz, 3 H). FAB-MS: calculated for (C20H26FNo) 315, found 316 (M+H). Anal.
W 098/04528 PCTrUS97113248 0 Calcd for C20H26FNo: C, 76.16; H, 8.31; N, 4.44. Found: C, 75.74; H, 8.50; N, 4.27.
mp 126-129~C. Rf - 0.4 (20% ethyl acetate/hexane).
EXA~LE 27 HO r (Z)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-methyl-1 -butenyl)p~ridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and isobutyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDCl3): ~
7.07 (m, 4 H), 5.92 (d, J = 10.7 Hz, 1 H), 5.20 (dd, J = 10.7, 11.4 Hz, 1 H), 4.42 (bs, 2 H), 3.45 (sept, J = 6.6 Hz, 1 H), 3.30 (sept, J = 6.6 Hz, 1 H), 2.06 (m, 1 H), 1.35 (d, J =
6.6 Hz, 6 H), 1.31 (m, 1 H), 1.24 (m, 5 H), 0.69 (bs, 6 H). FAB-MS: calculated for (C23H30FNO) 355, found 356 (M+H). Anal. Calcd for C23H30FNO: C, 77.71; H, 8.51; N, 3.94. Found: C, 77.94; H, 8.59; N, 3.79. mp 112~C. Rf = 0.3 (20% ethyl acetate/hexane).
F
HO
2,6-Diisopropvl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-meth penten~,rl)pyridine WO 98t04~28 PCTIUS97/13248 O The title compound was prepared from ethyl isobutyrylacetate, ~fluorobenzaldehyde and isoamyl triphenylphosphonium bromide according to ~e procedures described in Example 1, Steps A-G. The product is obtained as a 6:4 mixture of trans:cis isomers. lH NMR (300 MHz, CDCl3): ~ 7.11 (m, 4 H), 6.04 (dt, - J=1.5,11Hz,0.4H),5.96(dt,J=1.5,16Hz,0.6H),5.47(dt,J=7,11 Hz,0.4H),5.32 (dt, J = 7, 16 Hz, 0.6 H), 4.41 (m, 2 H), 3.44 (m, 0.8 H), 3.38 (sept, J = 6.6 Hz, 0.6 H), 3.24 (sept, J = 6.6 Hz, 0.6 H), 1.84 (m, 1 H), 1.45 (m, 1 H), 1.35 (m, 6 H), 1.24 (m, 7 H), 0.79 (d, J = 6.6 Hz, 2.4 H), 0.73 (d, J = 6.6 Hz, 3.6 H). FAB-MS: calculated for(C24H32FNO) 369, found 370 (M+H). Anal. Calcd for C24H32FNO: C, 78.01; H, 8.73; N, 3.79. Found: C, 78.14; H, 8.62; N, 3.50. mp 48-50~C. Rf = 0.3 (20% ethyl 10 acetate/hexane).
HO
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-methylbut~l)pvridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-methyl-1-butenyl)pyridine (Example 27) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3): ~ 7.14 (m, 20 4 H) 4.33 (d, J = 5.5 Hz, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.22 (sept, J = 6.6 Hz, 1 H), 2.27 (m, 2 H), 1.35 (m, 1 H), 1.33 (d, J = 7 Hz, 6 H), 1.30 (d, J = 7 Hz, 6 H), 1.17 (m, 3 H), 0.70 (d, J = 6.6 Hz, 6 H). FAB-MS: calculated for (C23H32FNO) 357, found 358(M+H). Anal. Calcd for C23H32FNO: C, 77.27; H, 9.02; N, 3.92. Found: C, 77.34;
H, 9.15; N, 3.69. mp 43-45~C. Rf = 0.2 (20% ethyl acetate/hexane).
W 098~'~?~ PCTAUS97/13248 HO~
~ N ~/
2,6-Diisopropvl-3-hydroxymethyl-~(4-fluorophenyl)-5-(4-methylpentyl~pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-methyl-1-pentenyl)pyridine (Example 28) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDC~3): ~ 7.14 (m, 4 H), 4.33 (d, J = 5 Hz, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.22 (sept, J = 6.6 Hz, 1 H), 2.23(m,2H),1.38(m,1H),1.33(d,J=6.6Hz,6H),1.30(d,J=6.6Hz,6H),1.27(m, 1 H), 1.17 (m, 1 H), 1.00 (m, 3 H), 0.76 (d, J = 6.6 Hz, 6 H). FAB-MS: calculated for (C24H34FNO) 371, found 372 (M+H). Anal. Calcd for C24H34FNO: C, 77.59; H, 9.22; N, 3.77. Found: C, 77.63; H, 9.39; N, 3.58. mp 101-103~C. Rf = 0.3 (20% ethyl acetate/hexane) .
HO~
\f N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(cyclopentyl-20 idenemethylene)pyridine The title compound was prepared from ethyl isobutyr~ylacetate, 4-fluorobenzaldehyde and cyclopentyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDC13):
7.13 (m, 2 H), 7.07 (m, 2 H), 5.88 (s, 1 H), 4.43 (d, J = 5.5 Hz, 2 H), 3.44 (sept, J = 6.6 1~2 W 098/01'~ PCTrUS97/13248 0 Hz, 1 H), 3.21 (sept, J = 6.6 Hz, 1 H), 2.11 (m, 2 H), 1.75 (m, 2 H), 1.47 (m, 4 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.29 (m, 1 H), 1.21 (d, J = 6.6 Hz, 6 H). FAB-MS: calculated for (C24H30FNO) 367, found 368 (M+H). Anal. Calcd for C24H30FNO: C, 78.44; H, 8.23; N, 3.81. Found: C, 78.46; H, 8.18; N, 3.63. mp 97-98~C. Rf = 0.3 (20% ethyl acetate/hexane).
- S
E)(AMPLE 32 HO ~--/
~N~
1 0 2,6-Diisoprop~1-3-hydrox~methyl-4-(4-fluorophenyl)-5-(l-heptenyl)-pyridineThe title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and n-hexyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. 1H NMR ~300 MHz, CDCl3): ~ 7.11 (m, 4 H), 5.99 (m, 1 H), 5.42 (dt, J = 7, 11 Hz, 0.5 H), 5.30 (dt, J = 7, 16 Hz, 0.5 H), 4.41 (d, J
= 5.5 Hz, 2 H), 3.45 (m, 1 H), 3.37 (sept, J = 6.6 Hz, 0.5 H), 3.24 (sept, J = 6.6 Hz, 0.5 H), 1.94 (m, 1 H), 1.35 (m, 6 H), 1.29 (m, 1 H), 1.26 (d, J = 6.6 Hz, 3 H), 1.22 ~m, 6 H), 1.15 (m, 4 H), 0.86 (m, 3 H). FAB-MS: calculated for (C25H34FNO) 383, found 384 (M+H). Anal. CalcdforC25H34FNO: C, 78.29; H, 8.93; N, 3.65. Found: C, 78.37;
H, 8.88; N, 3.57. Rf = 0.4 (20% ethyl acetate/hexane).
tlO ~ ~
W 098104S28 PCTrUS97113248 o 2,6-Diisopropyl-3-hvdroxymeth~l-4-(4-fluorophenyl)-5-(l-octenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and n-heptyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a S mixture 1:1 trans:cis isomers; gummy oil. lH NMR (300 MHz, CDCl3): ~ 7.11 (m, 4 H), 5.98 (m, 1 H), 5.42 (dt, J - 7, 11 Hz, 0.5 H), 5.30 (dt, J = 7, 16 Hz, 0.5 H), 4.41 (d, J
= 5.5 Hz, 2 H), 3.44 (m, 1 H), 3.37 (sept, J = 6.6 Hz, 0.5 H), 3.24 (sept, J = 6.6 Hz, 0.5 H), 1.94 (m, 1 H), 1.35 (m, 6 H), 1.30 (m, 1 H), 1.26 (d, J = 6.6 Hz, 6 H), 1.22 (m, 4 H), 1.16 (m, 5 H), 0.87 (m, 3 H). FAB-MS: calculated for (C26H36FNO) 397, found 398 (M+H). Anal. Calcd for C26H36FNo: C, 78.55; H, 9.13; N, 3.52. Found: C, 78.63;
H, 9.16; N, 3.48. Rf = 0.4 (20% ethyl acetate/hexane) HO--~N~/
2,6-Diisoprop~1-3-hydrox~nethyl-4-(4-fluorophenyl)-5-~2(E)-phen ethenyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and benzyl triphenylphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps A-G. 1H NMR (300 MHz, CDCl3): ~ 7.21 (m, 9 H), 6.70 (d, J = 16.5 Hz, 1 H), 6.26 (d, J = 16.5 Hz, 1 H), 4.45 (d, J = 5.5 Hz, 2 H), 3.48 (sept, J = 6.6 Hz, 2 H), 1.37 (d, J = 6.6 Hz, 6 H), 1.31 (d, J
= 6.6 Hz, 6 H), 1.29 (m, 1 H). FAB-MS: calculated for (C26H2gFNO) 389, found 390(M+H). ~nal. Calcd for C26H2gFNO: C, 80.17; H, 7.25; N, 3.60. Found: C, 79.89;
H, 7.28; N, 3.49. mp 107-110~C. Rf = 0.3 (20% ethyl acetate/hexane).
W O 98/~'-2% PCT~US97/13248 o EXAMPLE 35 HO ~----' ~N~/
2,6-Diisopropyl-3-hYdrox~nethyl-4-(4-fluorophenyl)-s-heptylpyridine S The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-heptenyl)pyridine (Example 32) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3): ~ 7.13 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.22 (sept, J = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J=6.6Hz,6H),1.30(d,J=6.6Hz,6H),1.22(m,3H),1.11 (m,8H),0.85(t,J=7Hz, 3 H). FAB-MS: calculated for (C25H36FNO) 385, found 386 (M+H). Anal. Calcd for C2sH36FNO: C, 77.88; H, 9.41; N, 3.63. Found: C, 77.86; H, 9.66; N, 3.59. mp 73-75~C. Rf = 0.3 (20% ethyl acetate/hexane).
F
HO
~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-octvlpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-octenyl)pyridine (Example 33) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3): ~ 7.14 (m, 4 H), 4.33 (d, l = 5.5 Hz, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 1.25 (m, 3 H), 1.15 (m, 10 H), 0.87 (t, J = 7 Hz, 3 H). FAB-MS: calculated for (C26H3gFNO) 399, found 400 (M+H).
W 09$/04528 PCTrUS97113248 0 Anal. Calcd for C26H3gFNO: C, 78.15; H, 9.59; N, 3.51. Found: C, 78.27; H, 9.81;
N, 3.43. Gummy oil; Rf = 0.3 (20% ethyl acetate/hexane).
HO ~/
~f N~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(2-phenylethyl)pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[2(E)-phenylethenyl]pyridine (Example 34) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDC13): ~ 7.19 (m, 7 H), 6.86 (m, 2 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.44 (sept, J = 6.6 Hz, 1 H), 3.35 (sept, J =
6.6 Hz, 1 H), 2.58 (m, 4 H), 1.35 (d, J - 6.6 Hz, 6 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.19 (t, J
= 5.5 Hz, 1 H). FAB-MS: calculated for (C26H30FNo) 391, found 392 (M+H). Anal.
Calcd for C26H30FNO: C, 79.76; H, 7.72; N, 3.58. Found: C, 79.57; H, 7.61; N, 3.44.
mp 158-159~C. Rf = 0.3 (20% ethyl acetate/hexane).
HO~ ~ 3 N
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophen~l)-5-(4-phenyl-l -20 butenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and 3-phenylpropyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 5:1 trans:cis isomers; gummy oil. lH NMR (300 MHz, W 098/04S28 PCTrUS97/13248 0 CDCl3): ~ 7.26 (m, 2 H), 7.19 (m, 1 H), 7.09 (m, 6 H), 6.05 (d, J = 11 Hz, 0.2 H), 5.98 (d, J = 16 Hz, 0.8 H), 5.47 (dt, J = 7, 11 Hz, 0.2 H), 5.33 (dt, J = 7, 16 Hz, 0.8 H),, 4.40 (d, J = 5 Hz, 2 H), 3.43 (m, 1 H), 3.26 (sept, J = 6.6 Hz, 1 H), 2.51 (m, 2 H), 2.29 (m, 1.6 H), 2.05 (m, 0.4 H), 1.34 (m, 6 H), 1.25 (m, 1 H), 1.22 (d, J = 6.6 Hz, 6 H). FAB~
calculated for (C2gH32FNO) 417, found 418 (M+H). Anal. Calcd for C2gH32FNO:
- 5 C, 80.54; H, 7.72; N, 3.35. Found: C, 80.56; H, 7.56; N, 3.32. Rf = 0.3 (20% ethyl acetate/hexane) HO~ }
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-phenylbutyl)pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-phenyl-1-butenyl)pyridine (Example 38) according to the procedure described in Example 1, Step H. Gummy oil; lH NMR (300 MHz, CDCl3): ~ 7.24 (m, 3 H), 7.08 (m, 6 H), 4.31 (d, J = 5.5 Hz, 2 H), 3.40 (sept, J = 6.6 Hz, 1 H), 3.17 (sept, J = 6.6 Hz, 1 H), 2.46 (t, J = 7.5 Hz, 2 H), 2.29 (m, 2 H), 1.47 (m, 2 H), 1.32 (d, J = 6.6 Hz, 6 H), 1.30 (m, 2 H), 1.27 (d, J = 6.6 Hz, 6 H), 1.15 (t, J = 5.5 Hz, 1 H). FAB-MS: calculated for (C2gH34FNO) 419, found 420 (M+H). Anal. Calcd for C2gH34FNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.06; H, 7.94; N, 3.28. Rf = 0.3 (20% ethyl acetate/hexane).
HO ~
0 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~2(E)-(2-meth phenyl)ethenyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and 2-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDC13): ~ 7.22 (m, 3 H), 7.10 (m, 5 H), 6.62 (d, J = 17 Hz, 1 H), 6.45 (d, J = 17 Hz, 1 H), 4.45 (d, J = 5.5 Hz, 2 H), 3.48 (m, 2 H), 2.12 (s, 3 H), 1.37 (d, J = 6.6 Hz, 6 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.31 (m, 1 H). FAB-MS: calculated for (C27H30FNO) 403, found 404 (M+H). Anal. Calcd for C27H30FNo: C, 80.36; H, 7.49; N, 3.47. Found:
C, 80.23; H, 7.23; N, 3.44. mp 108-111~C. Rf = 0.3 (20% ethyl acetate/hexane).
HO ~' ~N~
2,6-Diisoprop~1-3-hydroxymethyl-4-(4-fluorophenyl)-5-~2(E)-(3-methyl-phenyl)ethenyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and 3-methylbenzyl triphenylphosphonium chloride according to the procedures described in Example 1, Steps A-G. lH NMR (300 20 MHz, CDCl3): ~ 7.18 (m, 3 H), 7.11 (m, 2 H), 7.00 (m, 3 H), 6.68 (d, J = 17 Hz, 1 H), 6.23 (d, J = 17 Hz, 1 H), 4.44 (d, J = 5.5 Hz, 2 H), 3.47 (m, 2 H), 2.32 (s, 3 H), 1.37 (d, J
= 6.6 Hz, 6 H), 1.31 (d, J = 6.6 Hz, 6 H), 1.28 (m, 1 H). FAB-MS: calculated for(C27H30FNO) 403, found 404 (M+H). Anal. Calcd for C27H30FNO: C, 80.36; H, 7.49; N, 3.47. Found: C, 80.38; H, 7.45; N, 3.45. mp 97-99~C. Rf = 0.3 (20% ethyl 25 acetate/hexane).
O E~CAMPLE 42 [~ ~
HO~
~N~
2,6-Diisopropyl-3-hydroxymethYl-4-(4-fluorophenyl)-5-~2(E)-(4-methyl-phenyl)ethenyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and 4-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDCl3): ~ 7.18 (m, 2 H), 7.08 (m, 6 H), 6.63 (d, J = 17 Hz, 1 H), 6.23 (d, J = 17 Hz, 1 H), 4.43 (d, J = 5 Hz, 2 H), 3.47 (sept, J = 6.6 Hz, 2 H), 2.31 (s, 3 H), 1.36 (d, J =
6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 1.26 (m, 1 H). FAB-MS: calculated for (C27H30FNO) 403, found 404 (M+H). Anal. Calcd for C27H30FNO: C, ~0.36; H, 7.49, N, 3.47. Found: C, 79.93; H, 7.34; N, 3.47. mp 131-133~C. Rf = 0.3 (20% ethyl acetate/hexane).
HO ~/~~
~' ~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~2-(2-methyl-phenyl)ethyllpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[2(E)-(2-methylphenyl)ethenyl]pyridine (Example 40) accordingto the procedure described in Example 1, Step H. lH NMR (300 MHz, CDC13):
WO 98/04528 PCT/US97tl3248 0 7.16 (m, 4 H), 7.06 (m, 3 H), 6.81 (m, 1 H), 4.35 (d, J = 4 Hz, 2 H), 3.42 (sept, J = 6.6 Hz, 2 H), 2.57 (m, 4 H), 1.97 (s, 3 H), 1.36 (d, J = 6.6 Hz, 6 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.19 (m, 1 H). FAB-MS: calculated for (C27H32FNO) 405, found 406 (M+H). Anal.
Calcd for C27H32FNo: C, 79.96; H, 7.95; N, 3.45. Found: C, 80.08; H, 8.05; N, 3.46.
mp 125-126~C. Rf = 0.3 (20% ethyl acetate/hexane).
EXA~EE 44 ItO~
~N~/
2,6-Diisoprop~ 3-hydroxymethyl-4-(4-fluorophenyl)-5-~2-(3-meth phen~ ethyllpyridine The title compound was prepared 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[2(E)-(3-methylphenyl)ethenyl}pyridine (Example 41) according tothe procedure described in Example 1, Step H. lH NMR (300 M~Iz, CDCl3): ~ 7.18 (d, J = 7 Hz, 4 H), 7.10 (m, 1 H), 6.97 (m, 1 H), 6.65 (m, 2 H), 4.36 (s, 2 H), 3.44 (sept, J
= 6.6 Hz, 1 H), 3.35 (d, J = 6.6 Hz, 1 H), 2.57 (m, 4 H), 2.28 (s, 3 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.20 (m, 1 H). FAB-MS: calculated for (C27H32FNO) 405, found 406 (M+H). Anal. Calcd for C27H32FNO: C, 79.96; H, 7.95; N, 3.45.
Found: C, 79.30; H, 8.10; N, 3.36. mp 148-150~C. ~f = 0.3 (20% ethyl 20 acetate/hexane).
HO ~--~N~
o 2,6-Diisoprop~l-3-hydroxymethyl-4-(4-fluorophen~rl)-5-~2-(4-meth phenyl)ethyllpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[2(E)-(4-methylphenyl)ethenyllpyridine (Example 42) accordingS to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3):
7.17(m,4H),7.02(d,J=7.7Hz,2H),6.75(d,J=7.7Hz,2H),4.36(d,J=4Hz,2H), 3.43 (sept, J = 6.6 Hz, 1 H), 3.34 (sept, J = 6.6 Hz, 1 H), 2.55 (m, 4 H), 2.29 (s, 3 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.20 (m, 1 H). FAB-MS: calculated for tC27H32FNO)405, found 406 (M+H). Anal. Calcd for C27H32FNO: C, 79.96;
H, 7.95; N, 3.45. Found: C, 79.40; H, 7.84; N, 3.44. mp 121-123~C. Rf = 0.3 (20%
ethyl acetate/hexane).
¢~
HO~ ~--'rO>
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~3-(1,3-dioxolan-2-yl)propyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and 12-(1,3-dioxolan-2-yl)ethyl]triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. 1H NMR
(300 MHz, CDCl3): ~ 7.16 (m, 4 H), 4.63 (t, J = 4 Hz, 1 H), 4.33 (d, J = 5 Hz, 2 H), 3.88 (m, 2 H), 3.77 (m, 2 H), 3.41 (bm, 1 H), 3.24 (bm, 1 H), 2.34 (m, 2 H), 1.47 (m, 4 H), 1.32 (m, 12 H), 1.18 (m, 1 H). FAB-MS: calculated for (C24H32FNO3) 401, found 402 (M+H). mp 90-91~C. Rf = 0.2 (20% ethyl acetate/hexane).
W 098/04528 PCTrUS97113248 HO~S J~3 2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-~(phenylthio)-methyllpyridine Step A: Methyl 2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-3-pvridinecarboxylate Prepared from methyl isobutyrylacetate, 4-fluorobenzaldehyde and ammonium acetate by the procedures described in Example 1, Steps A-D.
Step B: Methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-bromomethyl-3 pyridinecarboxylate A solution of the intermediate obtained in Step A (20 g, 57.9 mmol) in acetonitrile (500 mL) was stirred at 0~C and treated with dibromo-triphenylphosphorane (36.7 g, 86.9 mmol) in portions. The suspension was then allowed to warm to room temperature and stirred for 2 hr. The solvent was removed in vacuo and the residue partitioned between diethyl ether (400 mL) and water (350 mL). The ether layer was washed with brine (150 mL), dried (MgSO4) and concentrated. Purification by chromatography through si~ica (5% diethyl ether/hexane) gave a white solid (20.6 g, 50.5 mmol, 87%). lH NMR (300 MHz, CDCl3): ~ 7.31 (m, 2 H), 7.12 (m, 2 H), 4.29 (s, 2 H), 3.49 (s, 3H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.06 (sept, J = 6.6 Hz, 1 H), 1.33 (m, 12 H). mp 109-111~C. Rf = 0.6 (50%
CH2Cl2/hexane).
Step C: 2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5 ~(,phenylthio)methyllPyridine A solution of the intermediate obtained in Step B (200 mg, 0.47 mmol) in anhydrous THF (5 mL), stirred under argon, was treated with benzenethiol (73 uL, WO ~&'G l'2~ PCT/US97113248 0 0.71 mmol) and N-methylmorpholine (0.26 mL, 2.4 mmol). The reaction mixture was stirred at reflux for 14 hr, allowed to cool to room temperature and treatedwith lithium aluminum hydride (1.9 mL, 1.9 mmol, 1.0M in THF). The reaction mixture was heated at reflux for 1 hr then allowed to cool to room temperature.
The mixture was quenched by the successive addition of water (80 uL), 20% NaOH
- 5 (80 uL) and water (240 uL). The resulting suspension was filtered through a cake of celite and concentrated. Purification by flash silica gel chromatography (5% ethyl acetate/hexane) afforded a white solid (160 mg, 0.39 mmol, 83%). lH NMR (300 MHz, CDCl3): ~ 7.23 (m, 5 H), 7.11 (m, 4 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.81 (s, 2 H), 3.45 (sept, J = 6.6 Hz, 1 H), 3.43 (sept, J = 6.6 Hz, 1 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.21 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C25H2gFNOS) 409, found 410 (M+H). Anal. Calcd for C25H2gFNos: C, 73.32; H, 6.89; N, 3.42; S, 7.83.
Found: C, 73.24; H, 6.90; N, 3.35; S, 8.01. mp 119-121~C. Rf = 0.3 (20% ethyl acetate/hexane) .
HO~,S ~ CF3 2,6-Diisoprop~1-3-hydroxymethyl-4-(4-fluorophenyl)-5-~((3-trifluoro-methyl)phenyl)thiolmethylpyridine The title compound was prepared from 3-trifluoromethyl-thiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13):
~ 7.34 (m, 2 H), 7.24 (m, 4 H), 7.10 (m, 2 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.85 (s, 2 H), 3.45 (sept, J = 6.6 Hz, 1 H), 3.38 (sept, J = 6.6 Hz, 1 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.23 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C26H27F4NOS) 477, found 478 (M~H). Anal. Calcd for C26H27F4NOS: C, 65.39; H, 5.70; N, 2.93; S, 6.71. Found: C, 65.39; H, 5.76; N, 2.88; S, 6.62. mp 110-111~C. Rf = 0.3 (20% ethyl acetate/hexane).
.
W O 98/04528 PCT~US97/13248 o EXAMPLE 49 F
HO~,S
N
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(4-fluoro-phenyl)thiolmethylpyridine The title compound was prepared from 4-fluorothiophenol according to the procedures described in Example 47. 1H NMR (300 MHz, CDCl3): ~ 7.24 (m, 2 H), 7.12 (m, 4 H), 6.93 (m, 2 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.76 (s, 2 H), 3.44 (sept, J = 6.6 Hz, 1 H), 3.40 (sept, J = 6.6 Hz, 1 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.22 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C2sH27F2NOS) 427, found 42~ (M+H).
Anal. Calcd for C2sH27F2NOS: C, 70.23; H, 6.37; N, 3.28; S, 7.50. Found: C, 70.22;
H, 6.41; N, 3.22; S, 7.39. mp 119-121~C. Rf = 0.3 (20% ethyl acetate/hexane).
F
HO~,S J~' 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl~-5-~((4-methyl) phenyl)thiolmethylpyridine The title compound was prepared from p-thiocresol according to the procedures described in Example 47. 1H NMR (300 MHz, CDCl3): ~ 7.27 (m, 2 H), 7.13 (m, 2 H), 7.03 (m, 4 H), 4.35 (d, ~ = 5.5 Hz, 2 H), 3.77 (s, 2 H), 3.44 (m, 2 H), 2.31 (s,3H),1.34(d,J=6.6Hz,6H),1.33(d,J=6.6Hz,6H),1.22(t,J-5.5Hz,1H).
FAB-MS calcd for (C26H30FNOS) 423, foLmd 424 (M+H). Anal. Calcd for W 098/045~8 PCTrUS97113248 O C26H30FNOS: C, 73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 74.00; H, 7.15; N, 3.36;
S, 7.32. mp 90-91~C. Rf = 0.3 (20% ethyl acetatethexane).
HO~,S ~3 2,6-Diisopropyl-3-hydroxymethY1-4-(4-fluorophenyl)-5-(l-naphthylthio) methylpyridine The title compound was prepared from l-naphthalenethiol according to the procedures described in Example 47. lH NMR (300 MHz, CDCl3): ~ 8.01 (d, J = 8.5 Hz,lH),7.82(d,J=8.5Hz,lH),7.74(d,J=8Hz,lH),7.46(m,3H),7.34(m,1H), 7.20 (m, 2 H), 7.06 (m, 2 H), 4.34 (d, J = 5.5 Hz, 2 H), 3.82 (s, 2 H), 3.51 (sept, J = 6.6 Hz,lH),3.45(sept,J=6.6Hz,lH),1.36(d,J=6.6Hz,6H),1.35(d,J=6.6Hz,6H), 1.19 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C2gH30FNOS) 459, found 460 (M+H).
Anal. Calcd for C29H30FNos: C, 75.78; H, 6.58; N, 3.05; S, 6.98. Found: C, 75.36;
H, 6.52; N, 2.91; S, 6.74. mp 77-79~C. Rf = 0.4 (20% ethyl acetate/hexane).
HO~S
2,6-Diiso~n3~yl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(2-naphth thio)methylpyridine -WO 3~ 1'28 PCTIUS97/13248 O The title compound was prepared from 2-naphthalenethiol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): ~ 7.77 (d, J = 9 Hz, 1 H), 7.68 (d, J = 9 Hz, 2 H), 7.52 (d, J = 1.5 Hz, 1 H), 7.45 (m, 2 H), 7.25 (m, 2 H), 7.17 (dd, J = 1.8, 8.5 Hz, 1 H), 7.07 (m, 2 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.91 (s, 2 H), 3.45 (sept,J=6.6Hz,2H),1.35(d,J=6.6Hz,6H),1.34(d,J=6.6Hz,6H),1.21 (t,J=5.5 Hz, 1 H). FAB-MS calcd for (C2gH30FNOS) 459, found 460 (M+H). Anal. Calcd for C2gH30FNOS: C, 75.78; H, 6.58; N, 3.05; S, 6.98. Found: C, 75.55; H, 6.60; N, 2.95;
S, 6.91. mp 127-129~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO~ ~ ,S ~ F
2,6-Diisopropyl-3-hydrox~rmethyl-4-(4-fluorophenyl)-5- ~(2,3,5,6-tetra-fluorophenyl)thiolmethylp-,rridine The title compound was prepared from pentafluorothiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDCl3): ~ 7.27 (m, 2 H), 7.11 (m, 2 H), 6.99 (m, 1 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.84 (s, 2 H), 3.44 (sept, J =
6.6Hz, 1 H),3.43 (sept,J= 6.6Hz, 1 H), 1.34 (d,J= 6.6Hz, 6H), 1.33 (d,J= 6.6 Hz, 6 H), 1.23 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C25H24FsNOS) 481, found 482 (M+H). Anal. Calcd for C25H24F5NOS: C, 62.36; H, 5.02; N, 2.91; S, 6.66; F, 19.73.
Found: C, 62.40; H, 4.96; N, 2.82; S, 6.74; F, 19.49. mp 109-110~C. Rf = 0.4 (20%
e~yl acetate/hexane).
HO--~S~OCH3 'f N~/
WO 98/04~28 PCT/US97/13248 0 2,6-Diisopropyl-3-hydroxvmethyl~-(4-fluorophen~,rl)-5-~(3-methoxy-phenyl)thiolmeth~lp~ridine The title compound was prepared from 3-methoxybenzenethiol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): d 7.24 (m, 2 H), 7.13 (m, 3 H), 6.72 (m, 2 H), 6.62 (m, 1 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.81 (s, 2 H), ~ 5 3.75 (s, 3 H), 3.44 (sept, J = 6.6 Hz, 1 H), 3.42 (sept, J = 6.6 Hz, 1 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.23 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for(C26H30FNo2s) 339, found 440 (M+H). Anal. Calcd for C26H30FNo2s: C, 71.04;
H, 6.88; N, 3.19; S, 7.29. Found: C, 70.94; H, 6.77; N, 2.96; S, 7.41. mp 93-94~C. Rf =
0.4 (20% ethyl acetate/hexane).
~OH
HO ~S
\~'N~/
2,6-Diiso~ro~1-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(4-hydroxy-phenyl)thiolmethylpyridine The title compound was prepared from 4-hydroxythiophenol according to the procedures described in Example 47. lH NMR (300 MHz, 5:1 CDC13/CD30D):
~ 7.15 (m, 2 H), 7.06 (m, 2 H), 6.97 (d, J = 8.5 Hz, 2 H), 6.64 (d, J = 8.5 Hz, 2 H), 4.27 (s,2H),3.66(s,2H),3.40(m,2H), 1.29(d,J=6.6Hz,6H), 1.28 (d,J = 6.6 Hz, 6 H).
FAB-MS calcd for (C2sH2gFNO2S) 425, found 426 (M+H). Anal. Calcd for C2sH2gFNO2S: C, 70.56; H, 6.63; N, 3.29; S, 7.53. Found: C, 70.29; H, 6.34; N, 3.12;
S, 7.44. mp 178-179~C. Rf = 0.3 (30% ethyl acetate/hexane).
~ 25 WO 98/04528 PCTrUS97/13248 o EXAMPLE 56 HO~--'S~
\~N~/
2,6-Diisopropyl-3-h~drox~methyl-4-(4-fluorophenyl)-5-~(4-methoxy-S phenyl)~iolmethylpyridine The title compound was prepared from 4-methoxybenzenethiol according to the procedures described in Example 47. lH NMR (300 MHz, CDCl3): ~ 7.23 (m, 2 H), 7.12 (m, 4 H), 6.77 (d, J = 9 Hz, 2 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.79 (s, 3 H), 3.73 (s,2H),3.44(sept,J=6.6Hz,2H),1.34(d,J=6.6Hz,6H), 1.33 (d,J=6.6Hz,6H), 1.21 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C26H30FNO2S) 339, found 440 (M+H).
Anal. Calcd for C26H30FNO2S: C, 71.04; H, 6.88; N, 3.19; S, 7.29. Found: C, 70.96;
H, 6.90; N, 3.15; S, 7.35. mp 92-93~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO~S ~\
2,6-Diisoprop~1-3-h~droxymethyl-4-(4-fluorophenyl)-5-~(3-methyl-phenyl)thiolmethylpyridine The title compound was prepared from m-thiocresol according to the procedures described in Example 47. 1H NMR (300 MHz, CDCl3): ~ 7.25 (m, 2 H), 7.11 (m, 3 H), 7.00 (m, 1 H), 6.94 (m, 2 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.81 (s, 2 H), 3.45 (sept, J = 6.6 Hz, 1 H), 3.43 (sept, J = 6.6 Hz, 1 H), 2.28 (s, 3 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.22 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for wo ~a,~ ~s~X PCT~US97/13248 0 (C26H30FNos) 423, found 424 (M+H). Anal. Calcd for C26H30FNOS: C, 73.72; H,7.14; N, 3.31; S, 7.57. Found: C, 73.76; H, 7.09; N, 3.27; S, 7.42. mp 92-93~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO~,S
2,6-Diisopropvl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(2-methy phenyl)thiolmethylpyridine 1 0 The title compound was prepared from o-thiocresol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): ~ 7.25 (m, 2 H), 7.11 ~m, 6 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.74 (s, 2 H), 3.45 (sept, J = 6.6 Hz, 2 H), 2.26 (s, 3 H), 1.35 (d, J = 6.6 Hz, 12 H), 1.21 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C26H30FNos) 423, found 424 (M+H). Anal. Calcd for C26H30FNOS: C, 73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 73.54; H, 7.09; N, 3.06; S, 7.37. mp 140-141~C. Rf =
0.4 (20% ethyl acetate/hexane).
HO--~SJ~F
- --'N'~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(3-fluor phenyl)thiolmethylpyridine WO ~8J'~ PCT/US97/13248 O The title compound was prepared from 3-fluorothiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): ~ 7.27 (m, 3 H), 7.11 (m, 2 H), 6.87 (m, 2 H), 6.78 (m, 1 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.82 (s, 2 H), 3.45 (sept, J = 6.6 Hz, 1 H), 3.38 (sept, J = 6.6 Hz, 1 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.33 (d, J -6.6 Hz, 6 H), 1.23 (t, J = 5.5 Hz, 1 H). FA~MS calcd for (C2sH27F2NOS) 427, found 428 (M+H). Anal. Calcd for C25H27F2NOS: C, 70.23; H, 6.37; N, 3.28; S, 7.50.
Found: C, 70.22; H, 6.31; N, 3.20; S, 7.41. mp 99-100~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO~,S ~
2,6-Diisoprop~1-3-h~droxymethyl-4-(4-fluorophen~,r1)-5-~(2-methoxy-phenyl)thiolmeth~lpyridine The title compound was prepared from 2-methoxythiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): ~ 7.22 (m, 3 H), 7.07 (m, 3 H), 6.83 (m, 2 H), 4.34 ~d, J = 5.~ Hz, 2 H), 3.78 (s, 3 H), 3.75 (s, 2 H), 3.49 (sept, J = 6.6 Hz, 1 H), 3.43 (sept, J = 6.6 Hz, 1 H), 1.34 (d, ~ = 6.6 Hz, 12 H), 1.19 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C26H30FNO2S) 339, found 440 (M+H). Anal.Calcd for C26H3oFNo2s: C, 71.04; H, 6.88; N, 3.19; S, 7.29. Found: C, 70.93; H, 6.67; N, 3.12; S, 7.48. mp 129-131~C. Rf = 0.4 (20% ethyl acetate/hexane).
E~CAMPLE 61 F
HO'--~--'S
\~N ~/
WO 98/01r~X PCT~US97113248 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(3,5-dimethyl-phenyl)thiolmethylpyridine The title compound was prepared from 3,5-dimethylthiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): â 7.24 (m, 2 H), 7.11 (m, 2 H), 6.80 (s, 1 H), 6.69 (s, 2 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.79 (s, 2 H), 3.44 (sept, J = 6.6 Hz, 1 H), 3.42 (sept, J = 6.6 Hz, 1 H), 2.23 (s, 6 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.21 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for(C27H32FNOS) 437, found 438 (M+H). Anal. Calcd for C27H32FNOS: C, 74.11; H, 7.37; N, 3.20; S, 7.33. Found: C, 74.18; H, 7.22; N, 3.13; S, 6.86. mp 109-110~C. Rf =
0.5 (20% ethyl acetate/hexane).
HO~,S ~~
2,6-Diisopropyl-3-hydroxvmethyl-4-(4-fluorophenyl)-5-~(4-ethyl-phenyl)thiolmethylpyridine The title compound was prepared from 4-ethylthiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDCl3): ~ 7.24 (m, 2 H), 7.05 (m, 6 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.77 (s, 2 H), 3.43 (m, 2 H), 2.60 (q, J = 7.7 Hz, 2 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.32 (d, J = 6.6 Hz, 6 H), 1.21 (m, 4 H). FAB-MS calcd for (C27H32FNOS) 437, found 438 (M+H). Anal. Calcd for C27H32FNOS: C, 74.11;
H, 7.37; N, 3.20; S, 7.33. Found: C, 74.07; H, 7.23; N, 3.09; S, 7.23. mp 102-103~C. Rf = 0.5 (20% ethyl acetate/hexane).
WO 98/04528 PCTrUS97J13248 HO ~,SJ~
2,6-Diisopropvl-3-hydroxymeth~1-4-(4-fluorophenyl)-5-~(4-isopropyl-phenyl)thiolmethylpyridine The title compound was prepared from 4-isopropylthiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): ~ 7.25 (m, 2 H), 7.06 (m, 6 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.79 (s, 2 H), 3.43 (m, 2 H), 2.86 (sept, J = 7 Hz,lH),1.34(d,J=6.6Hz,6H),1.32(d,J=6.6Hz,6H),1.22(d,J=7Hz,6H), 1.20 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C2gH34FNOS) 451, found 452 (M+H). Anal.
Calcd for C2gH34FNOS: C, 74.46; H, 7.59; N, 3.10; S, 7.10. Found: C, 74.51; H, 7.48;
N, 3.04; S, 6.85. mp 108-109~C. Rf = 0.5 (20% ethyl acetate/hexane).
F
Ho~S (3 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-benzylthio-methylpyridine The title compound was prepared from benzyl mercaptan according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): ~ 7.23 (m, 5 H), 7.08 (m, 4 H), 4.31 (d, J = 5.5 Hz, 2 H), 3.55 (s, 2 H), 3.40 (sept, J = 6.6 Hz, 1 H), 3.24 (s, 2 H), 3.19 (sept, J = 6.6 Hz, 1 H), 1.31 (d, J = 6.6 Hz, 6 H), 1.24 (d, J = 6.6 Hz, 6 H), 1.17 (t, J - 5.5 Hz, 1 H). FAB-MS calcd for (C26H30FNOS) 423, found 424 (M+H).
Anal. Calcd for C26H30FNOS: C, 73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 73.58;
0 H, 7.25; N, 3.05; S, 7.45. mp 150-151~C. Rf = 0.5 (20% ethyl acetate/hexane).
~ HO~,S
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(pheneth thiomethyllpyridine The title compound was prepared from phenethyl mercaptan according to the procedures described in Example 47. 1H NMR (300 MHz, CDC13): ~ 7.28 (m, 5 H), 7.11 (m, 4 H), 4.34 (d, J = 5.5 Hz, 2 H), 3.39 (m, 4 H), 2.70 (m, 2 H), 2.61 (m, 2 H), 1.33(d,J=6.6Hz,6H),1.32(d,J=6.6Hz,6H),1.20(t,J=5.5Hz,1H). FAB-MS
calcd for (C27H32FNOS) 437, found 438 (M+H). Anal. Calcd for C27H32FNOS: C, 74.11; H, 7.37; N, 3.20; S, 7.33. Found: C, 73.99; H, 7.46; N, 2.96; S, 7.23. Gummy oil.
Rf = 0.5 (20% ethyl acetate/hexane).
HO--~S~/
~' ~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(propylthio)-methylpyridine ~ The title compound was prepared from propyl mercaptan according to the procedures described in Example 47. ~H NMR (300 MHz, CDC13): ~ 7.30 (m, 2 H), WO~8101'?~ PCT~US97/13248 0 7.14(m,2H),4.34(d,J=5.5Hz,2H),3.41(m,2H),3.37(m,2H),2.31(t,J=7.0Hz, 2 H), 1.31 (m, 15 H), 0.89 (t, J = 7.4 Hz, 3 H). FAB-MS calcd for (C22H30NFos) 375, found 376 (M+H); Anal. Calcd for C22H30NoFs: C, 70.36; H, 8.05; N, 3.73; F, 5.06;
S, 8.54. Found: C, 70.32; H, 7.97; N, 3.58; F, 4.76; S, 8.49. mp 98~C (dec.). Rf = 0.3 (10% ethyl acetate/hexane).
I
HO~f S
~N~/
2,6-Diisopropyl-3-hydroxymethvl-4-(4-fluorophenyl)-5-(methylthio)-methylpyridine The title compound was prepared from methyl mercaptan according to the procedures described in Example 47. 1H NMR (300 MHz, CDCl3): ~ 7.30 (m, 2 H), 7.16 (m, 2 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.43 (m, 2 H), 3.38 (m, 2 H), 1.95 (s, 3 H), 1.30 (m, 12 H). FAB-MS calcd for (c2oH26NFos) 347, found 348 (M+H). Anal. Calcd for C~oH26NOFS: C, 69.13; H, 7.54; N, 4.03; F, 5.47. Found: C, 69.29; H, 7.54; N, 3.91; F, 5.45. mp 49~C (dec.). Rf = 0.2 (10% ethyl acetate/hexane).
F
HO ~~~ S
\f N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(4-nitrophenyl)-thio7methylpyridine WO ~8~ 't~ PCTIUS97113248 0 Step A: 2,6-Diisopropyl-3-hydroxymeth~l-4-(4-fluorophenyl)-5-~(t-butyldimethylsilox~,r)methyllpyridine A solution of 3 g (8.3 mmol) of methyl 2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-3-pyridinecarboxylate (Example 47, Step A) in anhydrous DMF (75 mL), was treated at room temperature with imidazole (1.3 g, 19 mmol), 4-~ 5 dimethylaminopyridine (50 mg, 0.4 mmol) and t-butyldimethylsilyl chloride (1.4 g, 9.3 mmol). The reaction mixture was allowed to stir at room temperature for 48 hr.
The solution was (~ te~1 with diethyl ether (200 mL) and washed with water (2 x ~ 100 mL), lN HCl (100 mL), sat. NaHCO3 (50 mL) and brine (100 mL), dried(MgSO4) and concentrated to 4 g as an oil: Rf = 0.4 (10% ethyl acetate/hexane).
This intermediate (4 g) was dissolved in anhydrous THF (100 mL), stirred under argon and treated with lithium aluminum hydride (17 mL, 17 mmol, 1.0M in THF). The reaction mixture was stirred at reflux for 1 hr, then allowed to cool to room temperature. The reaction was quenched by the successive dropwise addition of water (0.6 mL), 20% NaOH (0.6 mL) and water (1.9 mL). The resulting suspension was filtered through a cake of celite and concentrated. Purification by flash silica gel chromatography (5% ethyl acetate/hexane) afforded a colorless resin (1.8 g, 4.2 mmol, 51%). 1H NMR (300 MHz, CDCl3) ~ 7.25 (m, 2 H), 7.12 (m, 2 H), 4.38 (d, J = 5 Hz, 2 H), 4.28 (s, 2 H), 3.44 (sept, J = 6.6 Hz, 1 H), 3.39 (sept, J = 6.6 Hz, 1 H), 1.33 (t, J = 6.6 Hz, 12 H), 1.24 (t, J = 5.5 Hz, 1 H), 0.84 (s, 9 H), -0.08 (s, 6 H).
FAB-MS calcd for (C2sH3gFNSiO2) 431, found 432 (M+H). Anal. Calcd for C2sH3gFNSiO2: C, 69.56; H, 8.87; N, 3.24. Found: C, 69.70; H, 8.82; N, 3.12. Rf =
0.2 (10% ethyl acetate/hexane).
Step B: 2,6-Diisopropyl-3-bromomethyl-4-(4-fluorophenyl)-5 ~(t-butyldimethylsilox~)methyllpvridine The intermediate obtained in Step A (1.7 g, 3.9 mmol) was dissolved in acetonitrile (50 mL) at 0~C and treated with dibromotriphenylphosphorane (2.6 g,6.2 mmol) in portions. The suspension was then allowed to warm to room temperature and stirred for 2 hr. The solvent was removed in v~cuo and the residue partitioned between diethyl ether (150 mL) and water (100 mL). The etherlayer was washed with brine (50 mL), dried (MgSO4) and concentrated.
Purification by chromatography through silica (5% diethyl ether/hexane) affordeda viscous oil (1.4 g, 2.8 mmol, 72%) which slowly solidified on standing: 1H NMR- (300 MHz, CDCl3): ~ 7.28 (m, 2 H), 7.13 (m, 2 H), 4.23 (m, 4 H), 3.37 (m, 2 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 0.83 (s, 9 H), -0.09 (s, 6 H). FAB-MS
calcd for (C27H37BrFSiNO) 493, found 494 (M+H). mp 72-73~C. Rf = 0.5 (10% ethyl acetate/hexane).
WO 98/04S28 PCTrUS97/13248 o Step C: 2,~Diisopropyl-3-hydroxymethyl-4-(4-f~uorophenyl)-5-~(4-nitrophenyl)thiolmethylpyridine The intermediate obtained in Step B (200 mg, 0.40 mmol) was dissolved in anhydrous THF (5 mL), stirred under argon at room temperature and treated with ~mtrothiophenol (118 mg, 0.6 mmol, 80% tech. grade) and N-methylmorpholine (0.2 mL, 1.8 mmol). The reaction mixture was allowed to stir at reflux for 18 hr, then cooled to room temperature. The mixture was treated with tetrabutylammonium fluoride (0.8 mL, 0.8 mmol, 1.0M in THP) and allowed to sti at room temperature for 24 hr. The solvent was removed in vacuo, the residue dissolved in ethyl acetate (100 mL), washed with lN HCl (50 mL), sat. NaHCO3 (50mL) and brine (50 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient 5-10% ethyl acetate/hexane) afforded the title compound as a lightly colored solid (130 mg, 0.28 mmol, 70%).lH NMR (300 MHz, CDCl3~: ~ 8.08 (d, J = 8.5 Hz, 2 H), 7.27 (m, 2 H), 7.13 (m, 4 H), 1 5 4.37 (d, J = 5.5 Hz, 2 H), 3.91 (s, 2 H), 3.46 (sept, J = 6.6 Hz, 1 H), 3.33 (sept, J - 6.6 Hz,lH),1.35(d,J=6.6Hz,6H),1.34(d,J=6.6Hz,6H),1.27(t,J=5Hz, 1 H).
PAB-MS calcd for (C2~H27FSN203) 454, found 455 (M+H). mp 178-180~C. Rf = 0.3 (20% ethyl acetate/hexane).
HO ~N O
~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(morpholino-methyl)pyridine Step A: Methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(morpholino)methyl-3-pyridinecarboxylate A solution of methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-bromomethyl-3-pyridinecarboxylate (Example 47, Step B) (500 mg, 1.22 mmol) in CH2Cl2 (20 mL) O was treated with morpholine (0.14 mL, 1.61 mmol) under argon. The reaction wasstirred at room temperature for 48 hours. It was then diluted with CH2Cl2 (70 mL), washed with saturated NaHCO3 (2 x 40 mL), water (1 x 40 mL), and brine (1 x40 mL). The organic layer was dried with MgSO4, filtered, and concentrated to afford a white solid (4g5 mg, 1.2 mmol, 98%). lH NMR (300 MHz, CDCl3): ~ 7.16 S (m, 2 H), 7.07 (m, 2 H), 3.54 (t, J = 4.4 Hz, 4 H), 3.49 (m, 4 H), 3.27 (s, 2 H), 2.98 (septet, J = 6.6 Hz, 1 H), 2.19 (t, J = 4.8 Hz, 4 H), 1.30 (m, 12 H). FAB-MS calcd for (C24H31N2F03) 414, found 415 (M+H); Anal. Calcd for C24H31N203F: C, 69.54;
H, 7.54; N, 6.76; F, 4.58. Found: C, 69.55; H, 7.43; N, 6.50; F, 4.45. mp 132-134~C. Rf = 0.2 (20% diethyl ether/hexane).
Step B: 2,6-Diisopropyl-3-hydroxymethvl-4-(4-fluorophenyl)-5 (morpholinometh~l)pyridine The intermediate obtained in Step A (375 mg, 0.905 mmol) was dissolved in dry THF (50 mL), treated dropwise with lithium aluminum hydride (lM/THF, 1.81 mL) and the reaction stirred at reflux for 24 hours. The reaction was quenched by the successive dropwise addition of water (0.lml), NaOH 20% (0.lml), and water again (0.3ml). Concentration in vacuo afforded a white residue which was partitioned between CH2C12 and water. The organic layer was dried wi~ MgSO4, filtered, and concentrated to afford an oil. The product was passed through a pad of silica (40% diethyl ether/hexanes) yielding an oil which slowly solidified to give the title compound as a white solid (295 mg, 0.76 mmol, 84%). lH NMR ~300 MHz, CDCl3): ~ 7.14 (m, 4 H), 4.35 (d, 2 H), 3.53 (t, J = 4.8 Hz, 4 H), 3.45 (m, 2 H), 3.18 (s, 2 H), 2.18 (t, J = 4.5 Hz, 4 H), 1.26 (m, 13 H); FAB-MS calcd for (C23H31N2FO2) 386, found 387 (M+H). Anal. Calcd for C23H31N2O2F: C, 71.47; H, 8.08; N, 7.25; F, 4.92 25Found: C, 71.55; H, 8.16; N, 7.05; F, 4.70. mp 93.5-95.5~C. Rç = 0.4 (40% diethyl ether/hexane).
HO~,N~
W O 98/04528 PCT~US97113248 o 2,6-Diisopropyl-3-hydroxymethyl-4-~4-fluorophenyl)-5-(piperidinomethyl)pyridine The title compound was prepared from piperidine according to the procedures described in Example 69. 1H NMR (300 MHz, CDC13): ~ 7.05 (m, 4 H), 4.27 (d, J = 5.5 Hz, 2 H), 3.38 (m, 2 H), 3.01 (s, 2 H), 2.02 (m, 4 H), 1.22 (m, 24 H).
FAB-MS calcd for (C24H33N2FO) 384, found 385 (M+H). Anal. Calcd for C24H33N2OF: C, 74.96; H, 8.65; N, 7.28; F, 4.94. Found: C, 75.13; H, 8.48; N, 6.92;
F, 4.77. Gummy oil. Rf = 0.5 (40% diethyl ether/hexane).
F
HO ~ ~N~
\~ N ~/
2,6-Diisopropyl-3-h~,rdroxvmethyl-4-(4-fluorophenyl)-5-(pyrrolidino-methyl)pyridine The title compound was prepared from pyrrolidine according to the procedures described in Example 69. lH NMl~ (300 MHz, CDC13): ~ 7.13 (m, 4 H), 4.34 (d, J = 4.8 Hz, 2 H), 3.52 (septet, J = 6.6 Hz, 1 H), 3.42 (septet, J = 6.6 Hz, 1 H), 3.28 (s, 2 H), 2.22 (t, J = 6.3 Hz, 4 H), 1.60 (t, J = 3.3 Hz, 5 H), 1.27 (m, 12 H).
FAB-MS calcd for (C23H31N2FO) 370, found 371 (M+H). Anal. Calcd for C23H31N2OF: C, 74.56; H, 8.43; N, 7.56; F, 5.13. Found: C, 74.67; H, 8.72; N, 7.35;
F, 5.01. mp 122-124~C. Rf = 0.3 (40% diethyl ether/hexane).
F
~1 HO~ ~N~
.. ... .. . . . .
WO 98/01'"~ PCTIUS97/13248 O
2,6-Diisoprop~ 3-hydroxymethyl-4-(4-fluorophenyl)-5-~4-phenylpiperidin yl)methyl~pyridine The title compound was prepared from ~phenylpiperidine according to the procedures described in Example 69. lH NMR (300 MHz, CDCl3): ~ 7.29 (m, 2 H), 7.15 (m, 7 H), 4.36 (d, J = 5.2 Hz, 2 H), 3.48 (m, 2 H), 3.19 (s, 2 H), 2.71 (d, J = 11.0 Hz, 2 H), 2.38 (m, 1 H), 1.86 (m, 2 H), 1.71 (m, 2 H), 1.58 (m, 2 H), 1.58 (m, 13 H). FAB-MS calcd for (C30H31N2FO) 460, found 461 (M+H). Anal. Calcd for C23H31N20P:
C, 78.22; H, 8.10; N, 6.08; F, 4.12. Found: C, 78.01; H, 8.21; N, 5.96; F, 4.41. mp 66-68~C. Rf = 0.5 (40% diethyl ether/hexane).
0~
MeO~~N~}
\~ N \/
Methyl-2,6-diisopropvl-4-(4-fluorophenyl)-5-(4-piperid~nopiperidin-1-yl)methyl-3-pyridinecarboxylate The title compound was prepared from 4-piperdinopiperidine according to the procedure described in Example 69 (Step A). 1H NMR (300 MHz, CDCl3):
7.16 (m, 2 H), 7.04 (m, 2 H), 3.51 (septet, J = 5.5 Hz, 1 H), 3.47 (s, 3 H), 3.20 (s, 2 H), 20 2.98 (septet, J = 6.6 Hz, 1 H), 2.65 (d, J = 11.0 Hz, 2 H), 2.44 (m, 4 H), 2.05 (m, 1 H), 1.62 (m, 10 H), 1.31 (m, 16 H). FA~MS calcd for (C30H42N3Fo2) 495, found 496 (M+H). Anal. Calcd for C30H42N3o2F: C, 72.69; H, 8.54; N, 8.48; F, 3.83. Found:
C, 72.43; H, 8.56; N, 8.37; F, 3.74. mp 59-61~C. Rf = 0.1 (70% diethyl ether/hexane +
1 drop MeOH).
WO g8/01-2~ PCTrUS97/13248 HO~N~ N~
2,6-Diisopropyl-3-hydrox~methyl-4-(4-fluorophenyl)-5-~(4-piperidinopiperidin-1-yl)meth~llpyridine The title compound was prepared from 4-piperidinopiperidine according to the procedures described in Example 69. lH NMR (300 MHz, CDC13): ~ 7.12 (m, 4 H), 4.34 (d, J = 3.7 Hz, 2 H), 3.45 (m, 2 H), 3.10 (m, 2 H), 2.63 (d, J = 11.0 Hz, 2 H), 2.44 (m, 4 H), 2.03 (m, 1 H), 1.44 (m, 29 H). FAB-MS calcd for (C29H42N3FO) 467,1 0 found 468 (M+H). Anal. Calcd for C2gH42N3OF: C, 74.48; H, 9.05; N, 8.98; F, 4.06.
Found: C, 74.93; H, 9.35; N, 8.39; F, 3.83. mp 143-145~C. Rf = 0.1 (~0% diethyl e~er/hexane + 2 drops of MeOH).
F
HO~ N 6 2,6-Diisopropyl-3-hydroxymethyl-4-~4-fluorophenyl)-5-~(4-phenylpiperazin yl)methyllpyridine The title compound was prepared from 4-phenylpiperazine according to the procedures described in Example 69. lH NMR (300 MHz, CDCl3): ~ 7.16 (m, 6 H), 6.85(m,3H),4.36(d,J=5.2Hz,2H),3.47(m,2H),3.24(s,2H),3.04(t,J=4.8Hz, 4 H), 2.35 (t, J = 4.8 Hz, 4 H), 1.29 (m, 13 H). FAB-MS calcd for (C29H36N3FO) 461, found 462 (M+H). Anal. Calcd for C2gH36N3OF: C, 75.46; H, 7.86; N, 9.10; F, 4.12.
WO ~ x PCTrUS97/13248 0 Found: C, 75.35; H, 7.82; N, 8.80; F, 3.99. mp 111-113~C. Rf - 0.5 (40% diethyl ether/hexane).
HO ''~ N~N
\~' N'~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(imidazol-l-yl) methylpyridine The title compound was prepared from irnidazole according to the procedures described in Example 69. 1H NMR (300 MHz, CDC13): ~ 7.01 (m, 6 H), 6.57 (s, 1 H), 4.84 (s, 2 H), 4.39 (s, 2H), 3.49 (septet, J = 6.6 Hz, 1 H), 3.23 (septet, J
= 6.6 Hz, 1 H), 1.70 (s, 1 H), 1.36 (d,J= 6.6 Hz, 6 H), 1.27 (d, J = 6.6 Hz, 6 H). FAB-MS calcd for (C22H26N3FO) 367, found 368 (M+H). Anal. Calcd for C22H26N3OF:
C, 71.91; H, 7.13; N, 11.43; F, 5.17. Found: C, 71.26; H, 7.24; N, 11.03; F, 5.35. mp 184-186~C. Rf = 0.1 (50% diethyl ether/hexane w/ 2 drops MeOH).
HO ''~ H
~f N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(cyclopr amino)methylpyridine The title compound was prepared from cyclopropylamine according to the WO 98/01r2~ PCTAUS97/13248 O procedures described in Example 69. lH NMR (300 M~z, CDCl3): ~ 7.04 (m, 4 H), 4.21 (s, 2 H), 3.35 (s, 2 H), 3.26 (septet, J = 6.6 Hz, 2 H), 1.78 (m, 1 H), 1.17 (m, 13 H), 0.153 (m, 2 H), -0.006 (m, 2 H). FAB-MS calcd for (C22H2gN2FO) 356, found 357 (M+H). Anal. Calcd for C22H29N2OF: C, 74.12; H, 8.20; N, 7.86; F, 5.33. Found:
C, 74.29; H, 8.62; N, 7.93; F, 4.90. mp 81-83~C. Rf = 0.3 (40% diethyl ether/hexane).
s HO--~--N '~
~N~H
2,6-Diisopropyl-3-hydroxyrnethyl-4-(4-fluorophenyl)-5-(cyclohexyl-amino)methylpyridine The title compound was prepared from cyclohexylamine according to the procedures described in Example 69. 1H NMR (300 MHz, CDCl3): ~ 7.25 (m, 2 H), 7.13 (m, 2 H), 4.34 (s, 2 H), 3.38 (m, 4 H), 2.16 (m, 1 H), 1.58 (m, 5 H), 1.23 (m, 16 H), 0.936 (m, 2 H). FAB-MS calcd for (C25H3sN2FO) 398, found 399 (M+H). Anal.
Calcd for C2sH3sN2OF: C, 74.12; H, 8.20; N, 7.86; F, 5.33. Found: C, 74.29; H, 8.62;
N, 7.93; F, 4.90. mp 131-133~C. Rf = 0.1 (40% diethyl ether/hexane).
F
HO ~''N
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(dimethylamino)-methylpvridine WO 98/04528 PCTfUS97/13248 O The title compound was prepared from dimethylamine hydrochloride according to the procedures described in Example 69. lH NMR (300 MHz, CDC13):
7.12 (m, 4 H), 4.25 (m, 2 H), 4.09 (m, 1 H), 3.68 (septet, J = 6.6 Hz, 1 H), 3.41 (septet, J = 6.6 Hz, 1 H), 2.18 (m, 1 H), 1.69 (d, J = 4.1 Hz, 1 H), 1.26 (m, 12 H), 0.947 (d, J = 6.3 Hz, 3 H), 0.555 (d, J = 7.0 Hz, 1 H). FAB-MS calcd for (c22H3oNFo2) 359, found 360 (M+H). Anal. Calcd for C22H30No2F: C, 73.51; H, 8.41; N, 3.90; F, 5.28.
Found: C, 73.69; H, 8.40; N, 3.82; F, 5.04. mp 77-7g~C. Rf = 0.2 (40% diethyl ether/hexane).
.
F
HO~N--'f N~/
2,6-Diisopropvl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(dibutylamino)-methylpyridine The title compound was prepared from dibutylamine according to the procedures described in Example 69. 1H NMR (300 MHz, CDCl3): ~ 7.11 (m, 4 H), 4.33 (d, J = 5.5 Hz, 2 H), 3.62 (septet, J = 6.6 Hz, 1 H), 3.62 (septet, J = 6.6 Hz, 1 H), 3.24 (s, 2 H), 2.12 (t, J = 7.0 Hz, 4 H), 1.55 (s, 1 H), 1.33 (t, J = 6.6 Hz, 6 H), 1.26 (t, J =
6.6 Hz, 6 H), 1.16 (m, 8 H), 0.796 (t, J = 6.6 Hz, 6 H). FAB-MS calcd for (C27H41N2FO) 428, found 429 (M+H). Anal. Calcd for C27H41N2OF: C, 75.66; H, 9.64; N, 6.54; F, 4.43. Found: C, 75.91; H, 9.83; N, 6.26; F, 4.33. Gummy oil. Rf = 0.6 (40% diethyl ether/hexane).
HO~
N '~/
W O 981'~'52~ PCTAUS97/13248 2,6-Diisopropyl-3-hydroxymethyl~-(4-fluorophenyl)-5-methylpyridine A solution of methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-bromomethyl-3-pyridinecarboxylate (Example 47, Step B) (300 mg, 0.7 mmol), in anhydrous THF
(10 mL) was stirred under argon at room temperature and treated dropwise with S lithium aluminum hydride (2.1 mL, 1.0 M in THF, 2.1 mmol). The reaction mixture was heated at reflux for 1 hr, then allowed to cool to room temperature. The reaction was quenched by the dropwise sequential addition at room temperature of water (80 uL), 20% NaOH (80 uL) and water (240 uL). The resulting suspension was filtered through a pad of celite and concentrated. Purification by 10 chromatography through silica (5% ethyl acetate/hexane) afforded the title compound as a white solid (182 mg, 0.6 mmol, 85%). lH NMR (300 MHz, CDCl3):
7.15 (d, J = 7 Hz, 4 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.42 (sept, J = 6.6 Hz, 1 H), 3.26 (sept, J = 6.6 Hz, 1 H), 1.94 (s, 3 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.29 (d, J = 6.6 Hz, 6 H), 1.19 (t, J = 5.5 Hz, 1 H); FAB-MS calcd for (ClgH24FNo) 301, found 302 (M+H).
Anal. Calcd for C1gH24FNO: C, 75.72; H, 8.03; N, 4.65. Found: C, 75.62; H, 8.02;
N, 4.57. mp 127-128~C. Rf = 0.3 (20% ethyl acetate/hexane).
~' HO
2,6-Diiso~l o~yl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-phenyl-2 propenyl)pyridine Step A: Methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate Methoxymethyl triphenylphosphonium chloride (1.15 g, 3.35 mmol) was suspended in 25 mL of dry, distilled THF under argon and stirred at -78~C.
Butyllithium (1.6 M/hexane, 1.2 eq., 2.1 mL) was added dropwise and then the reaction mixture was allowed to stir at 0~C for 1.0 hour. The solution was cooled W 098/04528 PCTrUS97/13248 0 again to -78~C, treated dropwise with a solution of 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) (1 g, 2.8 mmol) in 20 mL of dry THF, and then warmed to room temperature and stirred overnight.
The reaction was quenched 2 mL water and the THF was evaporated in vacuo.
Diethyl ether was added and washed with water (2 x 40 mL), brine (1 x 40 mL), and S dried with MgSO4. The residue was dissolved in THF (20 ml), treated with a solution of concentrated HCl and stirred at room temperature for lh. The reaction mixture was diluted with diethyl ether (150 ml) washed wi'th water (50 ml), brine ~ (50 ml), dried with MgSO4 and evaporated in vac~o. Flash chromatography (10%
ethyl acetate/hexane) afforded 335 mg (0.9 mmol, 32%) of product. 1H NMR (300 MHz, CDCl3): ~ 9.62 (s, 1 H), 7.09 (m, 4 H), 3.97 (q, J = 7 Hz, 2 H), 3.60 (s, 2 H), 3.06 (sept, J = 6.6 Hz, 1 H), 3.00 (sept, J = 6.6 Hz, 1 H), 1.32 (d, J = 6.6 Hz, 6 H), 1.27 (d, J =
6.6 Hz, 6 H), 0.97 (t, J = 7 Hz, 3 H). FAB-MS: calcd for (C22H26FNO3) 371, found372 (M+H). Anal. Calcd for C22H26FNO3: C, 71.14; H, 7.06; N, 3.77. Found: C, 70.91; H, 6.91; N, 3.63. mp 69-71~C. Rf = 0.3 (10% ethyl acetate/hexane).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-phenyl-2 propenyl)pyrid~ne The title compound was prepared from the intermediate obtained in Step A
and benzyl triphenylphosphonium ~romide/sodium amide according to the procedures described in Example 1, Steps F-G. The product was obtained as a 6:4 mixture of trans:cis isomers. 1H NMR (300 MHz, CDC13): ~ 7.19 (m, 8 H), 6.96 (m,1 H), 6.32 (d, J = 11 Hz, 0.4 H), 6.09 (dt, J = 5.5, 16 Hz, 0.6 H), 5.96 (d, J = 16 Hz, 0.6 H), 5.45 ~dt, J = 7, 11 Hz, 0.4 H), 4.37 (d, J = 5 Hz, 1.25 H), 4.33 (d, J = 5.5 Hz, 0.75 H), 3.41 (m, 1.6 H), 3.25 (m, 2 H), 3.08 (m, 0.4 H), 1.35 (m, 5 H), 1.30 (d, J = 6.6 Hz, 5 H), 1.21 (m, 3 H). FAB-MS: calcd for (C27H30FNo) 403, found 404 (M+H). Anal.
Calcd for C27H30FNO: C, 80.36; H, 7.49; N, 3.47. Found: C, 80.15; H, 7.44; N, 3.26.
mp 72-73~C. Rf = 0.3 (20% ethyl acetate/hexane).
F
HO~--2,6-Diisopropyl-3-hydrox~methyl-4-(4-fluorophenyl)-5-(3-phenyl-propyl)pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-phenyl-2-propenyl)pyridine (Example 82) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3): ~ 7.11 (m, 9 H), 4.31 (s, 2 H), 3.40 (sept, J = 6.6 Hz, 1 H), 3.12 (sept, J = 6.6 Hz, 1 H), 2.46 (t, J =
7.35 Hz, 2 H), 2.29 (m, 2 H), 1.62 (m, 2 H), 1.32 (d, J = 6.6 Hz, 6 H), 1.26 (d, J = 6.6 Hz, 6 H), 1.16 (bm, 1 H). FAB-MS: calcd for (C27H32FNO) 405, found 406 (M+H). mp 137-140~C. Rf = 0.3 (20% ethyl acetate/hexane).
F
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~3-(2-methyl-1 5 phenyl)propyllpyridine The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and 2-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. lH NMR (300 MHz, CDCl3): ~ 7.07 (m, 7 H), 6.90 (m, 1 H), 4.31 (s, 2 H), 3.39 (sept, J = 6.6 Hz, 1 H), 3.15 (sept, J = 6.6 Hz, 1 H), 2.43 (t, J = 7.5 Hz, 2 H), 2.34 (m, 2 H), 2.17 (s, 3 H), 1.56 (m, 2 H), 1.31 (d, J = 6.6 Hz, 6 H), 1.27 (d, J = 6.6 Hz, 6 H), 1.15 (m, 1 ~I). FAB-MS: calcd for (C2gH34FNO) 419, found 420 (M~H). Anal. Calcd for C2gH34FNO: C, 80.15; H, 8.17; N, 3.34. Found:
C, 80.12; H, 8.01; N, 3.25. mp 65-70~C. Rf = 0.4 (20% ethyl acetate/hexane).
W O~ PCTrUS97tl3248 o EXAMPLE 85 HO ~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~3-(3-methyl-S phenyl)propyllpyridine The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and 3-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. lH NMR (300 MH:z, CDCl3): ~ 7.09 (m, 5 H), 6.98 (m, 1 H), 6.78 (m, 2 H), 4.31 (s, 2 H), 3.39 (sept, J = 6.6 Hz, 1 H), 3.12 (sept, J =
6.6Hz,lH),2.42(t,J=7Hz,2H),2.30(s,3H),2.28(m,2H),1.58(m,2H),1.31(d,J
= 6.6 Hz, 6 H), 1.26 (d, J = 6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C2gH34FNO) 419, found 420 (M+H). Anal. Calcd for C2gH34FNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.23; H, 8.17; N, 3.23. mp 68-70~C. Rf = 0.4 (20% ethyl acetate/hexane).
HO~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~3-(4-meth phenyl)propyllpyridine The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and 4-methylbenzyl triphenylphosphonium bromide according to the procedures O described in Example 1, Steps F-H. lH NMR (300 MHz, CDCl3): ~ 7.08 (m, 4 H), 7.01 (d,J= 8Hz,2H),6.85(d,J=8Hz,2H),4.30(s,2H),3.39 (sept,J=6.6Hz, 1 H), 3.13 (sept, J = 6.6 Hz, 1 H), 2.41 (t, J = 7 Hz, 2 H), 2.31 (s, 3 H), 2.27 (m, 2 H), 1.58 (m, 2 H), 1.31 (d, J = 6.6 Hz, 6 H), 1.26 (d, J = 6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C2gH34FNO) 419, found 420 (M+H). Anal. Calcd for C2gH34FNO: C, 80.15;
H, 8.17; N, 3.34. Found: C, 80.33; H, 8.28; N, 3.22. mp 79-80~C. Rf = 0.4 (20% ethyl acetate/hexane) .
HO--\~ N '~/
2,6-Diisopropyl-3-hydroxymethvl-4-(4-fluorophenyl)-5-(2-propenyl)-pyrid~ne The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and methyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. lH NMR (300 MHz, CDCl3): ~ 7.13 (m, 4 H), 5.73 (m, 1 H), 4.81 (dd, J = 4.8, 1.8 Hz, 2 H), 4.35 (s, 2 H), 3.43 (septet, J = 6.6 Hz, 1 H), 3.21 (septet, J
= 6.6 Hz, 1 H), 3.07 (d, J = 1.8 Hz, 2 H), 1.24 (m, 13 H). FAB-MS: calcd for (C21H26FNO) 327, found 328 (M+H). Anal. Calcd for C21H26FNO: C, 74.17; H, 7.71; N, 4.12; F, 5.59 + 0.7 H2O. Found: C, 74.17; H, 7.57; N, 3.94; F, 5.26. mp 69-71~C. Rf = 0.35 (15% ethyl acetate/hexane).
~1 HO~-- OH
\~N~/
W O~ e2~ PCT~US97/13248 o 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-hydrox~-butyl)pyridine To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[3-(1,3-dioxolan-2-yl)propyl]pyridine (Example 46) (2 g, 5 mmol) in THF (50 mL) wasadded 2N aq. HCl (10 mL). The solution was allowed to stir for 17 hr at room S temperature. The THF was removed in vacuo and the residual suspension carefully neutralized to pH 7 with sat. aq. NaHCO3. The aqueous phase was extracted with diethyl ether (3 x 100 mL), the combined ether extract washed with brine (50 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient, 10%-20% ethyl acetate/hexane) afforded a white solid (1.5 g, 4.2mmol, 83%): 1H NMR (300 MHz, CDCl3): d 9.57 (s, 1 H), 7.16 (m, 4 H), 4.33 (d, J =
5Hz,2H),3.42(m,1H),3.24(m,1H),2.33(m,2H),2.27(dt,J=1.8,7.4Hz,2H), 1.61 (m, 2 H), 1.32 (m, 12 H), 1.20 (m, 1 H). FAB-MS: calcd for (C22H30FNO2) 359, found 340 (M+H). Rf = 0.3 (20% ethyl acetate/hexane).
This intermediate (200 mg, 0.56 mmol) was dissolved in absolute ethanol (5 mL) and treated at room temperature, with stirring, with sodium borohydride (32 mg, 0.85 mmol). After stirring for 1 hr, the reaction was quenched by the dropwise addition of 2N HCl (3 mL). The solution was stirred 5 min, then neutralized by the careful addition of sat. NaHCO3. The aqueous phase was extracted with diethyl ether (3 x 50 mL), the combined extracts dried (MgSO4) and concentrated.
Purification by chromatography through silica (20% ethyl acetate/hexane) afforded the title compound as a white solid (88 mg, 0.25 mmol, 44%): lH NMR (300 MHz, CDCl3): ~ 7.16 (m, 4 H), 4.33 (d, J = 5 Hz, 2 H), 3.46 (m, 2 H), 3.41 (m, 1 H), 2.23 (m, 1 H), 2.32 (m, 2 H), 1.40 (m, 4 H), 1.32 (m, 12 H), 1.19 (m, 1 H), 1.09 (m, 1 H). FAB-MS: calcd for (C22H30FNO2) 359, found 360 (M+H). Anal. Calcd for C22H30FNo2: C, 73.51; H, 8.41; N, 3.90. Found: C, 73.37; H, 8.41; N, 3.72. mp 135-137~C. Rf = 0.4 (50% ethyl acetate/hexane);
¢~
HO--Y~ N
\~lN ~/
WO ~8/01'~8 PCTIUS97113248 0 2,6-Diisopropvl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(3-dimethyl-amino)propyllpyridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and (2-dimethylaminoethyl)triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. lH NMR (300 MHz, CDC13): ~ 7.17 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.21 (sept, J = 6.6 Hz, 1 H), 2.32 (m,2 H), 2.16 (m, 2 H), 2.14 (s, 6 H), 1.49 (m, 2 H), 1.32 (m, 13 H). FAB-MS: calcd for (C23H33FN20) 372,found 373 (M+H). mp 50-51~C. Rf = 0.35 (20%
ethanol/CH2Cl2) ¢~
-HO r (cH2~7 --f 'N~/
2,6-Diisoprop-~1-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(3-dimeth~
1 5 amino)heptyllp~ridine Step A 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4 oxobutyl)pvridine To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-l3-(1,3-dioxolan-2-yl)propyl]pyridine (Example 46) (2 g, 5 mmol) in THF (50 mL) wasadded 2N aq. HCl (10 mL). The solution was allowed to stir for 17 hr at room temperature. The THF was removed in vacuo and the residual suspension carefully neutrali~ed to pH 7 with sat. NaHCO3. The aqueous phase was extracted with diethyl ether (3 x 100 mL), the combined ether extract washed with brine (50 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient, 10%-20% ethyl acetate/hexane) afforded a white solid (1.5 g, 4.2mmol, 83%). lH NMR (300 MHz, CDCl3): ~ 9.57 (s, 1 H), 7.16 (m, 4 H), 4.33 (d, J =
5 Hz, 2 H), 3.42 (m, 1 H), 3.24 (m, 1 H), 2.33 (m, 2 H), 2.27 (dt, J = 1.8, 7.4 Hz, 2 H), 1.61 (m, 2 H), 1.32 (m, 12 H), 1.20 (m, 1 H). FAB-MS: calcd for (c22H28FNo2) 357, found 358 (M+H). Rf - 0.3 (20% e~yl acetate/hexane).
....
o Step B: 2,6-Diisopropyl-3-hydrox~methyl-4-(4-fluorophenyl)-5-~(3-dimethylamino)heptyllpyridine The intermediate prepared in Step A was treated with (3-dimethylamino)propyl triphenylphosphonium bromide according to the 5 procedures described in Example 1, Steps F-H, to afford the title compound as a solid. 1H NMR (300 MHz, CDCl3): ~ 7.16 (m, 4 H), 4.32 (s, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.22 (sept, J = 6.6 Hz, 1 H), 2.28 (s, 6 H), 2.26 (m, 4 H), 1.43 (m, 2 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 1.27 (m, 3 H), 1.31 (m, 6 H). FAB-~:
calcd for (c27H4lFN2o) 428, found 429 (M+H). mp 85-87~C. Rf = 0.1 (20%
EtOH/CH2C12) HO ~ (CH2)8COOH
\~ N ~/
2,6-Diisopropyl-3-h~ldrox-lmethyl-4-(4-fluorophenyl)-5-(8-carboxyheptyl)pyridineThe title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-oxobutyl)pyridine (Example 90, Step A) and (4-carboxybutyl)triphenylphosphonium bromide according to the procedure described in Example 90, Step B. 1H NMR (300 MHz, CD30D): ~ 7.17 (m, 4 H), 4.23 (s, 2 H), 3.44 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.28 (m, 2 H), 2.14 (t, J
=7.5Hz,2H),1.54(m,2H),1.28(d,J=6.6Hz,6H),1.24(d,J=6.6Hz,6H),1.22 (m, 4 H), 1.17 (m, 2 H), 1.10 (m, 4 H). EI-MS: calcd for (C27H3gFNO3) 443, found443 (M+). mp 240~C (dec). Rf = 0.3 (50% ethyl acetate/hexane).
W098/04528 PCTrUS97113248 HO ~'CO2H
\~N~/
2,~-Diisopropyl-3-hvdroxvmethyl-4-(4-fluorophenyl)-5-(3-carboxy~ro~yl)pvridine To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[3-(1,3-dioxolan-2-yl)propyl3pyridine (Example 46) (2 g, 5 mmol) in THF (50 mL) wasadded 2N aq. HC1 (10 mL). The solution was allowed to stir for 17 hr at room temperature. The THF was removed in v~cuo and the residual suspension carefully neutralized to pH 7 with sat. NaHCO3. The aqueous phase was extracted with diethyl ether (3 x 100 mL), and the combined ether extract washed with brine (50mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient, 10%-20% ethyl acetate/hexane) afforded 1.5 g of the intermediate as a white solid: Rf = 0.3 (20% ethyl acetate/hexane).
280 mg of the intermediate was dissolved in dry pyridine (5 mL), stirred at room temperature under argon and treated with acetic anhydride (0.37 mL, 3.9 rnmol). The reaction mixture was allowed to stir at room temperature for 17 hr.
The pyridine was removed in vacuo, and the residue dissolved in diethyl ether (50 mL), washed with sat. CuSO4 (10 mL), water (20 mL), sat. NaHCO3 (20 mL) and brine (10 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (20% ethyl acetate/hexane) afforded 220 mg as a viscous yellow oil:
Rf = 0.6 (50% ethyl acetate/hexane).
200 mg of the oil was dissolved in acetone (5 mL), stirred at room temperature and treated with Jones reagent (2 mL, prepared from 67 g CrO3, 125 mL H2O and 58 mL con. H2SO4). The reaction mixture was stirred 0.5 hr, quenched by the addition of 2-propanol, filtered through a short pad of silica and concentrated. The residue was dissolved in MeOH (5 mL), treated with 20% NaOH
(2 mL) and stirred 14 hr at room temperature. After neutralizing to pH 7 with aq.
HCl, the solution was saturated with NaCl and extracted with CHC13 (3 x 20 mL).
The combined extract was dried (MgSO4) and concentrated. Purification by chromatography through silica (1:1 ethyl acetate/hexane) afforded the title . , . . _~ . . . . . .....
0 compound as a white foam (22 mg). 1H NMR (300 MHz, CD30D): ~ 7.18 (m, 4 H), - 4.24 (s, 2 H), 3.46 (sept, J = 6.6 Hz, 1 H), 3.33 (sept, J = 6.6 Hz, 1 H), 2.34 (m, 2 H), 1.99(t,J=7Hz,2H),1.60(m,2H),1.29(d,J=6.6Hz,6H),1.26(d,J=6.6Hz,6H).
FAB-MS: calcd for (C22H2gFNO3) 373, found 374 (M+H). mp 160~C. Rf = 0.3 (50%
ethyl acetate/hexane).
s E~CAMPLE 93 F
~ OH
HO ~~\
\~' N '~/
(+)-2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(1-h~droxy-ethyl)pyridine Step A: (+)-Ethyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(1-h~rdroxy-ethyl)-3- pyridinecarboxylate To 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridine-carboxaldehyde (Example 1, Step E) (1 g, 2.91 mmol) in THF (30 mL) was added methyllithium (1.4 M, 1.0 eq., 2.08 mL) dropwise at -78~C under argon. The reaction was stirred for 2 hours, then quenched with water and the THF
evaporated to afford a white solid. The product was partitioned between diethyl ether and water. The organic layer was then dried with MgSO4, filtered, and concentrated to afford a white solid. The product was passed through a plug of silica (10% ethyl acetate/hexane) to afford a white solid (857 mg, 2,4 mmol, 82%).
1H NMR (300 MHz, CDC13): ~ 7.14 (m, 4 H), 4.86 (dq, J = 3.7, J = 6.6 Hz, 1 H), 3.80 (septet, J = 6.6 Hz, 1 H), 3.47 (s, 3 H), 2.96 (septet, J = 6.6 Hz, 1 H), 1.65 (d, J = 3.7 Hz, ~ 25 1 H), 1.46 (d, J = 6.6 Hz, 3 H), 1.27 (m, 12 H). FAB-MS: calcd for (C21H26NFO3) 35g, found 360 (M+H). Anal. Calcd for C21H26NO3F: C, 69.54; H, 7.54; N, 6.76; F, 4.58.
~ Found: C, 69.55; H, 7.43; N, 6.50; F, 4.45. mp 169-171 C. Rf = 0.2 (10% ethyl acetate/hexane).
W098/04528 PCTrUS97113248 0 Step B: (+)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-( hydroxyethyl)pyridine The intermediate obtained in Step A (300 mg, 0.835 mmol) was dissolved in 40 mL of dry THF, for a dropwise addition of a solution of LAH (1 M/THF, 1.67 mL, 2 eq.). The reaction mixture was stirred at reflux for 24 hours then cooled to room temperature and quenched with water(70 ~L), 20% NaOH (70 ~lL), and water (140~LL). After filtration, the solvent was evaporated to afford a white residue. The product was subjected to flash chromatography (20% ethyl acetate/hexane) which afforded the title compound as a white solid (84 mg, 0.25 mmol, 30%). lH NMR
(300 MElz, CDCl3): ~ 7.15 (m, 4 H), 4.71 (dq, J = 3.7, J = 6.6 Hz, 1 H), 4.30 (m, 2 H), 3.79 (septet, J = 6.6 Hz, 1 H), 3.42 (septet, J = 6.6 Hz, 1 H), 1.62 (d, J = 3.68 Hz, 1 H), 1.58 (s, lH), 1.43 (d, J = 6.6 Hz, 3 H), 1.28 (m, 16 H). FAB-MS: calcd for (C20H26NFo2) 331, found 332 (M+H). Anal. Calcd for C20H26No2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 184-186~C. Rf = 0.2 (20% ethyl acetate/hexane).
~ OH
HO~' '1 ~f N~/
(+)-2,6-Diisopropyl-3-h~droxymethyl-4-(4-fluorophenyl)-5-(1-hydroxy-prop~,rl)pyridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and ethyl magnesium bromide, according to the procedures described in Example 93. lH NMR (300 2~ MHz, CDC13): ~ 7.15 (m, 4 H), 4.40 (dq, J = 3.7, J = 5.2 Hz, 1 H), 4.30 (d, J = 5.5 Hz, 2 H), 3.72 (septet, J = 6.6 Hz, 1 H), 3.42 (septet, J = 6.6 Hz, 1 H), 1.88 (m, 1 H), 1.63 (t, J = 5.5 Hz, lH), 1.27 (m, 14 H), 0.804 (t, J = 7.36 Hz, 3 H). FAB-MS: calcd for (C21H2gNFO2) 345, found 346 (M+H). Anal. Calcd for C21H2gNO2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 173-175~C. Rf = 0.2 (20% ethyl acetate/hexane);
. .
WO9~tO1~X PCTrUS97/13248 o OH
HO~
\~ N ~/
(+)-2,6-Diisopropyl-3-hydroxymethYI-4-(4-fluorophenyl)-5-(1-hydroxy-pentyl)pyridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and n-butyllithium, according to the procedures described in Example 93. lH NMR (300 MHz, CDCl3):
~ 7.16 (m, 4 H), 4.49 (m, 1 H), 4.31 (d, J = 5.5 Hz, 2 H), 3.74 (septet, J = 6.6 Hz, 1 H), 3.42 (septet, J = 6.6 Hz, 1 H), 1.88 (m, 1 H), 1.5B (d, J = 3.3 Hz, 1 H), 1.18 (m, 18 H), 0.821 (t, J = 4.1 Hz, 3 H). ~AB-MS: calcd for (C23H32NF02) 373, found 374 (M~H).Anal. Calcd for C23H32NO2F: C, 73.96; H, 8.64; N, 3.75; F, 5.09. Pound: C, 73.81;
H, 8.60; N, 3.58; F, 5.02. mp 166-168~C. Rf = 0.3 (20% ethyl acetate/hexane).
~ OH
HO~
(+)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(hydroxy-phenylmethyl)pyridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl~-(4-fluorophenyl~-3-pyridinecarboxaldehyde (Example 1, Step E) and phenyllithium, according to the procedures described in Example 93. lH NMR (300 MHz, CDCl3):
WO 98/04528 PCTrUS97/13248 0 ~ 7.23(m,7H),7.06(m,2H),5.71 (d,J=5.14Hz,1H),4.38(d,J=5.5 Hz, 2 H), 3.47 (septet, J = 6.6 Hz, 1 H), 3.12 (septet, J = 6.6 Hz, 1 H), 2.12 (d, J = 5.1 Hz, 1 H), 1.57 (s, lH), 1.29 (m, 10 H), 0.797 (d, J = 6.6 Hz, 3 H). FAB~ calcd for (c25H28NFo2) 393, found 394 (M+H). Anal. Calcd for C25H2gNO2F: C, 76.84; H, 8.69; N, 3.90.
Found: C, 76.67; H, 8.76; N, 3.77. mp 202-204~C. Rf = 0.2 (20% ethyl 5 acetate/hexane).
HO~
\~ N ~/
(+)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(l-h~rdrox~-2 methyl)propyllp~ridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and isopropyl 15 magnesium bromide, according to the procedures described in Example g3. lH
NMR (300 MHz, CDC13): ~ 7.14 (m, 4 H), 4.35 (d, 2 H), 3.53 (t, J = 4.8 Hz, 4 H), 3.4~
(m, 2 H), 3.18 (s, 2 H), 2.18 (t, J = 4.5 Hz, 4 H), 1.26 (m, 13 H). FAB-MS: calcd for (C23H31N2F02) 386, found 387 (M~H). Anal. Calcd for C23H31N202F: C, 76.84;
H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 139-140~C. Rf = 0.3 (20%20 ethyl acetate/hexane).
E~CAMPLE 98 HO~
\~' N '~/
W 098/04528 PCT~US97/13248 o 2,6-Diisopropyl-3-h~droxymethyl-4-(4-fluorophen~ 5-(1-methoxy-ethyl)pyridine Step A: Methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-methoxyethyl)-3-pyridinecarboxylate (_)-Ethyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(1-hydroxyethyl)-3-pyridinecarboxylate (Example 93, Step A) ( 487 mg, 1.36 mmol) was dissolved in 50 mL of dry THF, treated with NaH ( 0.20 g, 8.13 mmol) under argon, stirred for 15min. and treated with methyl iodide (0.34 mL, 5.24 mmol). The reaction mixture was stirred at reflux for 2 hours, then cooled to room temperature, quenched with water, and concentrated to afford a watery residue. The product was partitioned between diethyl ether and water, the organic layer was dried with MgSO4, filtered, and concentrated to afford a white solid. The product was passed through a pad of silica (5% ethyl acetate/hexane) to yield a white solid (495 mg, 1.33 mmol, 98%). 1H
NMR (300 MHz, CDCl3): ~ 7.13 (m, 4 H), 4.25 (q, J = 6.6 Hz, 1 H), 3.80 (septet, J =
6.6 Hz, 1 H), 3.48 (s, 3 H), 3.10 (s, 3 H), 2.97 (septet, J = 6.6 Hz, 1 H), 1.41 (d, J = 6.6 Hz, 3 H), 1.29 (m, 12 H). FAB-MS: calcd for (C22H31FNO3) 373, found 374 (M+H).
Anal. Calcd for C24H31N2O3F: C, 70.75; H, 7.56; N, 3.75; F, 5.09. Found: C, 70.70;
H, 7.63; N, 3.59; F, 4.77. mp 132-134~C. Rf = 0.5 (10% ethyl acetate/hexane).
Step B: (_)-2,6-Diisopropyl-3-hydrox~lmethyl-4-(4-fluorophen~ll)-5-( methoxyeth~l)pyridine The intermediate obtained in Step A (359 mg, 0.961 mmol) was dissolved in 40 mL of dry THF, for a dropwise addition of a solution of LAH (1 M/THF, 1.92 mL, 2 eq.). The reaction mixture was stirred at reflux for 24 hours then cooled to room temperature and quenched with water (80 ~L), 20% NaOH (80 ~lL), and water (160 ~L). After filtration, the solvent was evaporated to afford a residue which was filtered through to a pad of silica (10% ethyl acetate/hexane) to afford the title compound as a white solid (281 mg, 0.72 mmol, 85%). 1H NMR (300 MHz, CDCl3):
~ 7.13 (m, 4 H), 4.32 (dq, J = 5.2 J = 11.4 Hz, 1 H), 4.11 (q, J = 6.3 Hz, 1 H), 3.77 (septet, J = 6.6 Hz, 1 H), 3.42 (septet, J = 6.6 Hz, 1 H), 3.10 (s, 3 H), 1.2g (m, 16 H).
FAB-MS: calcd for (C21H2gFNO2) 345, found 346 (M+H). Anal. Calcd for C21H2gNO2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 151-~ 153~C. Rf = 0.4 (20% ethyl acetate/hexane).
W 098/04528 PCTrUS97/13248 ~1 OCH3 HO~
~ N~/
(+)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-methoxy-5 propyl)pyridine The title compound was prepared from (+)-2,~diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-hydroxypropyl)pyridine (Example 94) according to the procedures described in Example 98. lH NMR (300 MHz, CDC13):
~ 7.11 (m, 4 H), 4.32 (m, 2 H), 3.83 (m, 1 H), 3.74 (septet, J = 6.6 Hz, 1 H), 3.41 10(septet, J = 6.6 Hz, 1 H), 3.12 (s, 2 H), 1.88 (m, 1 H), 1.56 (m, 2 H), 1.27 (m, 12 H), 0.776 (t, J = 3.7 Hz, 3 H). FAB-MS: calcd for (C22H30NFo2) 359, found 360 (M+H).Anal. Calcd forC22H30No2F: C, 73.51;H,8.41; N, 3.90; F, 5.28. Pound: C, 73.55;
H, 8.54; N, 3.75; F, 5.06. mp 147-149~C. Rf = 0.5 (20% ethyl acetate/hexane).
~ OCH3 HO ~----/
~N~/
(+)-2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(1-methoxy-20 pentyl)pyrid~ne The title compound was prepared from (+)-2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-hydroxypentyl)pyridine (Example 95) according to the procedures described in Example 98. lH NMR (300 MHz, CDCl3):
7.10 (m, 4 H), 4.32 (m, 2 H), 3.92 (m, 1 H), 3.76 (septet, J = 7.0 Hz, 1 H), 3.42 , . .
W 0 98/01-~ PCTrUS97/13248 O (septet, J = 6.6 Hz, 1 H), 3.12 (s, 3 H), 1.87 (m, 1 H), 1.52 (m, 2 H), 1.19 (m, 16 H), 0.821 (t, J = 7.4 Hz, 3 H). FAB~ calcd for (C24H34NF02) 387, found 388 (M+H).
Anal. Calcd for C24H34NO2F: C, 74.38; H, 8.84; N, 3.61; F, 4.90. Found: C, 74.38;
H, 8.B2; N, 3.45; F, 4.90. mp 121-123~C. Rf = 0.5 (20% ethyl acetate/hexane).
OH ¢~1 ~, \~ N ~/
(+)-2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-propyl-pyridine Step A: (+)-2,6-Diisopropyl-4-(4-fluorophenyl)-5-propyl-3-pyridine-carboxaldehyde To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-propylpyridine (Example 25) (5.7 g, 17 mmol) in dichloromethane (250 mL) was added Brockman I, neutral alumina (3.5 g, 34 mmol). The suspension was stirred at room temperature and treated with pyridinium chlorochromate (PCC) (7.5 g, 34 mmol). Stirring was continued at room temperature for 1 hr. The suspension was poured into 10% ethyl acetate/hexane (500 mL), filtered through a pad of silica and concentrated in vacuo to afford (4.2 g/12.8 mmol, 74%) as a waxy solid. lH NMR
(CDCl3, 300 MHz): ~ 9.72 (s, 1 H), 7.15 (m, 4 H), 3.83 (sept, J = 6.6 Hz, 1 H), 3.28 (sept, J = 6.6 Hz, 1 H), 2.31 (m, 2 H), 1.30 (m, 14 H), 0.78 (t, J = 7.4 Hz, 3 H). FAB-MS: calcd for (C21H26FNO) 327, found 328 (M+H). mp 81-83~C. Rf = 0.6 (10%
ethyl acetate/hexane).
Step B: (+)-2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-propylpyridine The intermediate obtained in Step A (400 mg, 1.22 mmol) in THF (10 mL) at -78~C under argon atmosphere was added dropwise MeLi (1.4 M, 1.2 eq, 1.05 mL).
The reaction was stirred for 20 min, then another 0.5 eq. of MeLi was added, as starting material was still present. After 20 min., the reaction was quenched with O water (2 mL) and the THF is evaporated in vacuo to afford an oil. The product was partitioned between water and CH2Cl2 (50 mL) and the organic layer was dried with MgSO4, filtered, and concentrated to yield a gummy solid. Flash Chromatography using silica gel (60% CH2cl2/hexane) to afford an oil which slowly soli~lifie~l to give the title compound as a solid (0.387 g/1.13 mmol, 92%). lH
S NMR (300 MHz, CDCl3): ~ 7.10 (m, 4 H), 4.66 (dq, J = 3.3, 6.6 Hz, 1 H), 3.75 (septet, J
= 6.6 Hz, 1 H), 3.20 (septet, J = 6.6 Hz, 1 H), 2.17 (t, J = 1.5 Hz, 2 H), 1.58 ~d, J = 5.2 Hz, 1 H), 1.41 (d, J = 6.6 Hz, 3 H), 1.29 (m, 14 H), 0.74 (t, J = 7.4 Hz, 3 H). FAB~
calcd for (C22H30PNO) 343, found 344 (M+H). Anal. Calcd for C22H30FNO: C, 76.93; H, 8.80; N, 4.08; F, 5.53. Found: C, 76.98; H, 8.73; N, 3.93; F, 5.80. mp 124.5-126.5~C. Rf = 0.2 (60% CH2Cl2/hexane).
EXAl\~LE 102 F
OH~
\~' N
(+)-2,6-Diisopropyl-3-(1-hydroxyethyl)-~(4-fluorophen~1)-5-propyl-pyridine The enantiomeric mixture of (+)-2,6-diisoplopyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-pro~yl~yl;dine (Example 101) was separated by chiral HPLC with a Chiralpak AD column, isocratic elution (99% hexane/methyl t-butyl ether). The first enantiomer to elute was obtained in 99% ee, mp 103-104~C, [a]D +40.4~
~I '1 OH\~
~/
\~ N~/
W O 98/04528 PCTrUS97113248 o 2,6-Diisopropyl-3-(1 -hydroxyethyl)-~(4-fluorophenyl)-5-propyl-pyridine The enantiomeric mixture of (+)-2,6-diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-propyl-pyridine (Example 101) was separated by chiral HPLC with ~ a Chiralpak AD column, isocratic elution (99% hexane/methyl t-butyl ether). The second enantiomer to elute was obtained in 90% ee. mp 95-97~C.
.
OH¢~
\~ N~/
~_)-2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-butyl-pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(~fluorophenyl)-5-butylpyridine (Example 24) according to the procedures described in Example 101. lH NMR (300 MHz, CDCl3): ~ 7.1 (m, 4 H), 4.7 (dq, J = 3 Hz, 1 H), 3.7 (septet, J = 7 Hz, 1 H), 3.2 (septet, J = 7 Hz, 1 H), 2.2 (t, J = 1.5 Hz, 2 H), 1.6 (d, J = 5 Hz, 1 H), 1.4 (d, J = 7 Hz, 3 H), 1.3 (m, 16 H), 0.8 (t, J = 7 Hz, 3 H). FAB-MS: calcd for (C23H32FNO) 357, found 358 (M+H). mp 103-104~C. Rf = 0.2 (60%
CH2C12/hexane).
F
OH ¢~
\~ N '~/
.
2,~Diisopropvl-3-(l-hydroxyeth~l)-~(4-fluorophen~ 5-pentyl-pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-W 098t04528 PCT~US97113248 0 (4-fluorophenyl)-5-pel~lyl~yr.dine (Example 1) according to the procedures described in Example 101. lH NMR (300 MHz, CDCl3): ~ 7.10 (m, 4 H), 4.65 (dq, J =
2.8, 6.6 Hz, 1 H), 3.75 (septet, J = 6.6 Hz, 1 H), 3.20 (septet, J = 6.6 Hz, 1 H), 2.19 (t, J
=8.1Hz,2H),1.63(d,J=2.6Hz,1H), 1.40(d,J=7.0Hz,3H),1.31 (m, 14H), 1.11 (m, 4 H), 0.79 (t, J = 6.6 Hz, 3 H). FAB-MS: calcd for (C24H34FNO) 371, found 372 S (M+H). Anal. Calcd for C24H34FNO: C, 77.59; H, 9.22; N, 3.77; F, 5.11. Found: C, 77.59; H, 9.34; N, 3.75; F, 5.26. mp 99-101 C. Rf = 0.2 (70% CH2C12/hexane).
OH~
V
~N~/
2,6-Diisopropyl-3-(l-hydroxyethyl)~-(4-fluorophenyl)-5-pentylpyridine The enantiomeric mixture of (+)-2,~-diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-pentylpyridine (Example 105) was separated by chiral HPLC with a15 Chiralpak AD column, isocratic elution (99% hexane/methyl t-butyl ether). The first enantiomer to elute was obtained in 99% ee. mp 83~C.
OH ¢~
\rl NJ~/
2,6-Diisopropvl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-pentylpyridine The enantiomeric mixture of (+)-2,6-diisopropyl-~(1-hydroxyethyl)~-(4-fluorophenyl)-5-pentylpyridine (Example 105) was separated by chiral HPLC with a WO 9~t. q5~x O Chiralpak AD column, isocratic elution (99% hexanemethyl t-butyl ether). The second enantiomer to elute was obtained in 93% ee. mp 84-86~C.
- OH~
,~
\~'N~/
s (+)-2,6-Diisopropyl-3-(l-hydroxyeth~ 4-(4-fluorophen~1)-5-hex~lpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-hexylpyridine (Example 23) according to the procedures described in Example 101. lH NMR (300 MHz, CDCl3): 8 7.13 (m, 3 H), 7.04 (m, 1 H~, 4.65 (m, 1 H), 3.73 (sept, J = 6.6 Hz, 1 H), 3.19 (sept, J = 6.6 ~Iz, 1 H), 2.18 (m, 2 H), 1.39 (d, J - 6.6 Hz, 3 H), 1.30 (m, 13 H), 1.18 (m, 4 H), 1.09 (m, 4 H), 0.81 (t, J = 7 Hz, 3 H). FA~MS: calcd for (C2sH36FNO) 385, found 386 (M~H). Anal. Calcd for C2sH36FNO: C, 77.88; H, 9.41; N, 3.63. Found: C, 77.84; H, 9.49; N, 3.65. mp 96- 99~C. Rf = 0.3 (10% ethyl acetate/hexane).
,~
Il I
OH\~
\~ N ~/
20 2,6-Diisopropyl-3-(1-h~droxvethYl)~(~fluorophenyl)-5-hexylpyridine - The enantiomeric mixture of (+)-2,6-diisopropyl-3-(1-hydroxyethyl~-~(4-fluorophenyl)-5-hexylpyridine (Example 108) was separated by chiral HPLC with a Chiralpak AD colurnn, isocratic elution (99% hexane/methyl t-butyl ether). The first enantiomer to elute was obtained in 98% ee. mp 75-77~C.
WO 98/01~ PCTAUS97113248 OH~
\~ N '~/
5 2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophen~ 5-hexylpyridine The enantiomeric mixture of (+)-2,6-diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-hexylpyridine (Example 108) was separated by chiral HPLC with a Chiralpak AD colurnn, isocratic elution (99% hexane/methyl t-butyl ether). The second enantiomer to elute was obtained in 88% ee. mp 66-68~C.
O OH¢~
~,S~
2,6-Diiso~ro~1-3-~1-hydrox~-2-((S)-toluylsulfoxy)ethyll-4-(4-fluoro-phenyl)-5-pentylpyridine A solution of lithium diisopropylamide was prepared by the addition of n-butyllithiurn (3.5 mL, 2 eq., 1.6 M/hexane) to a solution of diisopropylamine (0.73 mL, 5.57 mmol) in anhydrous tetrahydrofuran (50 mL) at 0~C. To this was added a solution of (S)-(-)-methyl p-tolylsulfoxide (0.863 g, 5.60 mmol) in anhydrous tetrahydrofuran (10 mL) dropwise, with stirring. The mixture was stirred at 0~C
for 2 hr, then treated with a solution of 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) (1.0 g, 2.~0 mmol) in anhydrous tetrahydrofuran (20 mL) dropwise and with stirring. After stirring 15 min at 0 ~C, the reaction mixture was quenched by the addition of sat. NH4Cl (1 mL). The ., . ~ , . .... . . ..
WO9~10~'2X PCTrUS97113248 0 solvent was removed in v~cuo and the residue partitioned between CHC13 (150 mL) and water (50 mL). The organic phase was washed with sat. NaHCO3 (100 mL), water (100 mL) and brine (50 mL), dried over MgSO4 and concentrated. The crude product consisted of a 1.2:1 ratio of diastereomers. Flash chromatography (step gradient 5%-10%-20% ethyl acetate/hexane) afforded 740 mg (52%) of the first ~ 5 diastereomer to elute. 1H NMR (CDCl3, 500 MHz): ~ 7.4 (m, 4 H), 7.0 (m, 2 H), 6.7 (m,2H),5.1(m,1H),4.6(s,1H),3.8(m,2H),2.6(sept,J=6.6Hz,lH),2.5(s,3H), 2.3 (m, 1 H), 2.1 (m, 2 H), 1.4 (m, 18 H), 0.8 (m, 3 H). FAB-MS: calcd for (C31H40FNO2S) 509, found 510 (M+H). Anal. calcd for C31H40FNO2S: C, 73.05;
H, 7.91; N, 2.75; S, 6.29. Found: C, 72.88; H, 7.95; N, 2.50; S, 6.38. mp 170-171~C. Rf = 0.3 (20% ethyl acetate/hexane).
o O H~
~,S~
2,6-Diisopropyl-3-ll-hydroxy-2-(s)-toluylsulfoxyethyll-4-(4-fluoro-phenyl)-5 pentylpyridine From the flash chromatography described in Example 111, the second diastereomer to elute afforded 600 mg (42%) of the title compound. 1H NMR
(CDCl3, 500 MHz): ~ 7.4 (m, 2 H), 7.2 (m, 2 H), 7.0 (m, 3 H), 6.8 (m, 1 H), 4.8 (m, 1 H), 3.8 (m, 1 H), 3.7 (m, 1 H), 3.2 (sept, J = 6.6 Hz, 1 H), 3.1 (s, 1 H), 2.7 (m, 1 H), 2.4 (s, 3 H), 2.1 (m, 2 H), 1.3 (m, 18 H), 0.6 (m, 3 H). FAB-MS: calcd for (C3lH40FNo2s) 509, found 510 (M+H). Anal. calcd for C31H40FN02S: C, 73.05; H, 7.91; N, 2.75; S, 6.29. Found: C, 72.90; H, 7.95; N, 2.50; S, 6.54. mp 190~C. Rf = 0.1 (20% ethyl acetate/hexane).
~ 30 W O 98104528 PCT~US97/13248 HO~S
(+)-2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-phenylthi~
methylpyridine The title compound was prepared from 2,6-diisopropyl-3-(1-hydroxymethyl)-4-(4-fluorophenyl)-5-[(phenylthio)methyl]pyridine (Example 47) according to the procedures described in Example 101. lH NMR (300 MHz, CDCl3): ~ 7.19 (m, 4 H), 7.09 (m, 5 H), 4.67 (m, 1 H), 3.74 (m, 3 H), 3.38 (sept, J = 6.6 Hz, 1 H), 1.58 (d, J = 4 Hz, 1 H), 1.41 (d, J = 6.6 Hz, 3 H), 1.31 (m, 12 H). FAB-MS:
calcd for (C26H30FNos) 423, found 424 (M+H). Anal. Calcd for C26H30FNOS: C, 73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 73.52; H, 7.12; N, 3.20; S, 7.51. mp 125-128~C. Rf = 0.5 (20% ethyl acetate/hexane).
OH¢~
\~ N~/
(+)-2,6-Diisopropyl-3-(l-hydroxy-2-propenyl)-4-(4-fluorophenyl)-5-pentylpyridine Step A: 2,6-Diisopropyl-4-~4-fluorophenyl)-5-pentyl-3-pyridine-carboxaldehyde 2,6-Diisopropyl-3-hydroxymethyl-~(4-fluorophenyl)-5-pentylpyridine (Example 1) (2.30 g, 6.43 mmol) was dissolved in 175 mL of CH2Cl2 under argon WO g3~ 8 PCT/US97/13248 O atrnosphere and treated with 2 eq. of alumina (neutral, 1.31 g, 12.87 mmol) followed by 2 eq of pyridinium chlorochromate (PCC) (2.77 g, 12.87 mmol). The reaction was stirred at room temperature for 1.5 h. The suspension was added to 500 mL of 1:1 hexane/diethyl ether, then filtered through a pad of silica (300 g).
- The pad was washed with 100 mL diethyl ether and the filtrate was combined and ~ 5 concentrated tn vacuo to afford a solid. Flash chromatography (60:40, CH2C12/hexane) using silica afforded 1.84 g of an off-white solid (5.2 mmol, 80%).
1H NMR (300 MHz, CDCl3): ~ 9.74 (s, 1 H), 7.17 (m, 4 H), 3.85 (septet, J = 6.6 Hz, 1 H), 3.30 (septet, J = 6.6 Hz, 1 H), 2.34 (t, J = 5.2 Hz, 2 H), 1.30 (m, 14 H), 1.15 (m, 4 H), 0.80 (t, J = 6.6 Hz, 3 H). FAB-MS: calcd for (C23H30FNO) 355, found 356. Anal.
Calcd for C23H30FNO: C, 77.71; H, 8.51; N, 3.94; F, 5.34 Found: C, 77.91; H, 8.47;
N, 3.83; F, 5.42. mp 75.5-77.5 C. Rf = 0.4 (50% CH2Cl2/hexane).
Step B: (+)-2,6-Diisopropyl-3-(l-hydroxy-2-propen~rl)-4-(4-fluorophenyl)-5 pentylpyridine To a solution of the intermediate obtained in Step A (100 mg, 0.281 mmol) in THF (10 mL) at -78~C under argon was added vinyl magnesium bromide (1 M, 1.5 eq., 0.42 mL) dropwise. After 1 h., a saturated solution of NH4Cl (2 mL) was added and the aqueous phase was extracted with diethyl ether. A precipitate formed when the NH4CI was added and was filtered off. The ether layer was dried with MgSO4, filtered and concentrated to yield a gummy oil. Flash chromatography (60% CH2Cl2/hexane) afforded the title compound as a solid (38 mg, 0.1 mmol, 35%). 1H NMR (300 MHz, CDCl3): ~ 7.11 (m, 4 H), 6.06 (~, J = 17.4 Hz, J = 10.3Hz, J
= 4.0 Hz, 1 H), 5.08 (q, J = 1.5 Hz, 1 H), 5.00 (m, 2 H), 3.51 (septet, J = 6.6 Hz, 1 H), 3.21 (septet, J = 6.6 Hz, 1 H), 2.21 (t, J = 4.4 Hz, 2 H), 1.74 (d, J = 4.1 Hz, 1 H), 1.27 (m, 14 H), 1.11 (m, 4 H), 0.783 (t, J = 6.6 Hz, 3 H). FAB-MS: calcd for (C25H34FNO) 383, found 384 (M+H). Anal. Calcd for C2sH34NOF: C, 78.29; H, 8.93; N, 3.65; 3~, 4.95.
Found: C, 78.28; H, 8.97; N, 3.53; F, 5.04. mp 83-85~C. Rf = 0.2 (50%
CH2C12/hexane).
OH~
\~N'~/
W O 98/04528 PCTrUS97/13248 (+)-2,6-Diisopropyl-3-(1-hydroxypentyl)~-(4-fluorophenyl)-5-pentyl-pyridine l~e title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (Example 1) and butyllithium according to the procedures described in Example 114. lH NMR (300 MHz, CDCl3): ~ 6.95 (m, 4 H), 4.33 (m, 1 H), 3.59 (septet, J = 6.6 Hz, 1 H), 3.09 (septet, J = 6.6 Hz, 1 H), 2.08 (t, J =
5.2 Hz, 2 H), 1.75 (m, 2 H), 1.47 (m, 2 H), 1.04 (m, 22 H), 0.719 (t, J = 7.0 Hz, 3 H), 0.674 (t, J = 7.0 Hz, 3 H). FAB-MS: calcd for (C27H40FNo) 413, found 414 (M+H).
Anal. Calcd for C27H40FNO: C, 78.41; H, 9.75; N, 3.39; F, 4.59. Found: C, 77.84;H, 9.51; N, 3.27; F, 5.08. mp 66-68~C. Rf = 0.2 (50% CH2Cl2/hexane).
,~
OH ~' ~'b~~
\~N~/
(+)-2,6-Diisopropyl-3-(1-hydrox~-2-butenyl~-4-(4-fluorophenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (Example 1) and allylmagnesium bromide according to the procedures described in Example 114. lH NMR (300 MEIz, CDC13): ~ 7.09 (m, 4 H), 6.58 (m, 1 H), 5.06 (s, 1 H), 5.01 (m, 1 H), 4.47 (m, 1 H), 3.71 (septet, J = 6.6 Hz, 1 H), 3.20 (septet, J = 6.6 Hz, 1 H), 2.59 (m, 1 H), 2.35 (m, 1 H), 2.18 (t, J = 4.8 Hz, 2 H), 1.72 (d, J = 2.9 Hz, 1 H), 1.28 (m, 14 H), 1.11 (m, 4 H), 0.783 (t, J = 6.6 Hz, 3 H). FAB-MS: calcd for (C26H36FNO) 397, found 398 (M+H). Anal.
Calcd for C26H36FNO: C, 77.88; H, 9.41; N, 3.63; F, 4.93. Found: C, 78.10; H, 9.21;
N, 3.43; F, 4.89. mp 70-72DC. Rf = 0.2 (50% CH2Cl2/hexane).
W 098/01~X PCTrUS97113248 ~ ,J
OH 1' \~ N ~/
(+)-2,6-Diisopropyl-3-(1-hydroxy-2-propyl)-4-(4-fluorophenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (Example 1) and ethylmagnesium chloride according to the procedures described in Example 114. lH NMR (300 MHz, CDCl3): ~ 7.10 (m, 4 H), 4.35 (dq, J = 3.7, 8.8 Hz, 1 H), 3.68 (septet, J = 6.3 Hz, 1 H), 3.20 (septet, J = 6.6 Hz, 1 H), 2.18 (t, J = 5.2 Hz, 2 H), 1.86 (septet, J - 5.5 Hz, 1 H), 1.63 (m, 2 H), 1.28 (m, 14 H), 1.09 (m, 4 H), 0.789 (m, 6 H). FAB-MS: calcd for (C25H36FNO) 385, found 386 (M+H). Anal. Calcd for C2sH36FNO: C, 77.88; H, 9.41; N, 3.63; F, 4.93. Found: C, 77.44; H, 9.37; N, 3.35; F, 4.87. mp 77-79nC. Rf = 0.2 (50% CH2Cl2/hexanes).
F
HO~f--' \~'N ~/
(+)-2,6-Diisopropvl-3-(2,2,2-trifluoro-l-hydroxy)ethyl-4-(4-fluoro-phen~ 5 20 pentylpyridine A stirred solution of 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) (190 mg, 0.53 mmol) in anhydrous THF (5 mL), under argon at 22~C, was treated with trimethyl(trifluoromethyl)silane (5.3 mL, 2.65 mmol, 0.5M in THF) followed by tetrabutylammonium fluoride (100 W098J04528 PCTrUS97/13248 O uL, 1.0M in THF). After stirring at 22~C for 5 min, tetrabutylammonium fluoride (3 mL, 3 mmol, 1.0 M in THF) was added and the reaction mixture stirred for 17 hr.
The solvent was removed in vacuo, the residue dissolved in diethyl ether (50 mL), washed with lN HCl (50 mL), saturated NaHCO3 (~0 mL), water (50 mL), brine (20 mL), dried (MgSO4) and concentrated. Purification by flash silica gel chromatography (2% ethyl acetate/hexane) afforded 153 mg (68%) of the title compound as a white solid. 1H NMR (300 MHz, CDC13): ~ 7.11 (m, 4 H), 4.90 (bs, 1H), 3.64 (bs, 1 H), 3.21 (sept, J = 6.6 Hz, 1 H), 2.35 (m, 1 H), 2.15 (m, 2 H), 1.30 (d, J =
6.6 Hz, 6 H), 1.29 (d, J = 6.6 Hz, 6 H), 1.26 (m, 2 H), 1.10 (m, 4 H), 0.77 (t, J = 6.6 Hz, 3 H). FAB-MS: calcd for (C24H31F4NO) 425, found 426 (M+H). Anal. Calcd for C24H31F4NO: C, 67.75; H, 7.34; N, 3.29; F, 17.86. Found: C, 67.82; H, 7.13; N, 3.02;
F, 18.05. mp 88-89~C. Rf = 0.35 (10% ethyl acetate/hexane).
F
HO
\~ N~/
2,6-Diisopropvl-3-(2-hydroxyethyl)-4-(4-fluorophenvl)-5-pentylpyridine Step A: 2,6-Diisopropvl-3-(2-oxoethyl)-4-(4-fluorophenyl)-5-pentylpyridine A solution of (methoxymethyl)triphenylphosphonium chloride (350 mg, 0.985 mmol) in THF (30 mL) was treated with butyllithium (1.6 M, 1.2 eq., 0.74 mL) at -78~C. The reaction was stirred at 0~C for 1 h. and then ~; cooled to -78~C again.
2,6-Diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) (350 mg, 0.985 mol) in THF (5 mL) was added dropwise and the reaction mixture allowed to come to room temperature. After 24 h., the reaction was ~uenched with water and the THF evaporated in vacuo. The residue was partitioned between ether and water. The organic layer was dried with MgSO4, filtered, and concentrated to yield an oil. Flash chromatography (10%
CH2C12/hexanes) afforded an oil (172 mg~.
The oil (172 mg) was taken up in THF (15 mL) and treated with 4 mL conc.
WO~101S~X PCT~US97/13248 O HCl. The solution was stirred for 1.5 hours and then diluted with ether (150 mL).
The reaction was washed with NaHCO3 (2 x 50 mL) and dried with MgSO4.
Filtration and concentration yielded a solid (20 mg, 0.054 mmol, 6%). The product was taken directly to the next step without further purification.
~ 5 Step B: 2,6-Diisopropyl-3-(2-hydroxyeth~1)-4-(4-fluorophenyl)-5-pentylpyridine To the intermediate obtained in Step A (20 mg, 0.054 mmol) in dry THF (10 mL) was added dropwise LAH (2 eq., 1 M, 0.11 mL) under argon and the mixture was stirred at reflux for 1 h. The reaction was quenched with water (3.9 ~lL), 20%
NaOH (3.9 ~lL), and water (7.8 ~L) again. Concentration afforded a white solid.
The product was subjected to a pad of silica gel (CH2C12) to afford the title compound as a white solid (14 mg, 0.038mmol, 70%). lH NMR (300 MHz, CDC13):
~ 7.39(m,2H),7.12(m,2H),3.52(t,J=5.5Hz,2H),3.23(m,2H),2.60(t,J=2.9 Hz,2H),2.20(t,J=3.7Hz,2H),1.30(m,14H),1.11(m,4H),0.771 (t,J=6.3Hz,3 H). FAB-MS: calcd for (C24H34FNO) 371, found 372 (M~H). Anal. Calcd for C24H34FNO: C, 77.59; H, 9.22; N, 3.77. Found: C, 77.57; H, 9.44; N, 3.05. mp 81- 83~C. Rf = 0.6 (10% ether/hexane).
F
N
H~N~
2,6-Diisopropyl-3-methylaminometh~1-4-(4-fluorophenyl)-5-pentyl-pyridine Methylammonium chloride (37.99 mg, 0.563 mmol) was added to a stirred 25 solution of methylamine in methanol (2 M, 0.28 mL) under argon in an oven-dried round bottom flask equipped with a stir bar. Then sodium cyanoborohydride (4 eq., 10.60 mg, 0.169 mmol) was added and 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) (100 mg, 0.281 mmol) was added as a solution in methanol (2 mL). The reaction was refluxed for 18 hours and 30 then quenched with water. Concentration and addition of CH2Cl2 (25 mL) allowed W098/04528 PCT~US97113248 (~ washings with water (2 x 15 mL), brine (1 x 25 mL), following which the solution was dried with MgSO4, filtered, and concentrated to afford a clear oil. Flash chromatography using silica gel (40% ether/CH2Cl2) yielded the title compound asa white solid (21 mg, 0.057 mmol, 20%). lH NMR (300 MHz, CDCl3): ~ 7.13 (m, 4 H), 3.26 (m, 4 H), 2.24 (m, 5 H), 1.20 (m, 19 H), 0.783 (t, J = 6.6 Hz, 3 H). FAB~
calcd for (C24H3sFN2)370, found 371 (M+H). mp 77-79~C. Rf = 0.2 (20%
ether/CH2Cl2) H2N ~--/
\f N~/
2,6-Diisopropyl-3-aminomethyl-4-(4-fluorophenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-4-(4-ffuorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and NH40Ac, according to the procedures described in Example 120. 1H NMR (300 MHz, CDCl3): ~ 7.10 (m, 4 H), 2.61 (m, 4 H), 2.20 (t, J = 5.5 Hz, 2 H), 1.17 (m, 20 H), 0.776 (t, J = 6.6 Hz, 3 H).
FAB-MS: calcd for (C23H33PN2) 356, found 357 (M+H). Anal. Calcd for C23H33N2F: C, 77.48; H, 9.33; N, 7.86; F, 5.33. Found: C, 77.42; H, 9.12; N, 7.64; F, 5.51. mp 47-49~C. Rf = 0.6 (50% CH2Cl2/hexanes).
N
'f N~/
, . . .
W098/04528 PCT~US97113248 0 2,6-Diisopropyl-3-~dimethylamino)methyl~-(4-fluorophenyl)-5-pent~Tl-pyridine The title compound was prepared from 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and dimethylamine hydrochloride, according to the procedures described in Example 120. lH NMR
~ (300 MHz, CDCl3): ~ 7.09 (m, 4 H), 3.49 (septet, J = 6.6 Hz, 1 H), 3.21 (septet, J = 6.6 Hz, 1 H), 3.05 (s, 2 H), 2.22 (t, J = 5.2 Hz, 2 H), 1.99 (s, 6 H), 1.18 (m, 18 H), 0.790 (t, J
= 6.3 Hz, 3 H). FAB-MS: calcd for (C25H37FN2) 384, found 385 (M+H). Anal.
Calcd for C23H37FN2: C, 78.08; H, 9.70; N, 7.28; F, 4.94. Found: C, 77.95; H, 9.66;
~ N, 7.12; F, 5.25. mp 69-71~C. Rf = 0.4 (20% ether/CH2Cl2).
--N~ /
\~ N ~/
2,6-Diisopropvl-3-(ethylamino)methyl-4-(4-fluorophen~1)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and ethylamine, according to the procedures described in Example 120. 1H NMR (300 MHz, CDCl3): ~ 7.06 (m,4H),3.18(m,4H),2.32(q,J=7.4Hz,2H),2.15(t,J=5.2Hz,2H),1.13(m,18 H), 0.839 (t, J = 7.4 Hz, 3 H), 0.698 (t, ~ = 6.6 Hz, 3 H). FAB-MS: calcd for (C2sH37FN2) 384, found 385 (M+H). Anal. Calcd for C23H37FN2: C, 78.08; H, 9.70; N, 7.28; F, 4.94. Found: C, 77.85; H, 9.50; N, 6.99; F, 4.79. mp 48-50~C. Rf = 0.1 (20% ether/CH2CI2)-OH~
HO ~ ,~
\~N~/
W O 98104528 PCT~S97/13248 O (+)-2,6-Diisoprop~1-3-(1,2-dihydroxyeth~1)-4-(4-fluorophenyl)-S-pentyl-pyridine Step A: 2~6-Diisopropyl-3-ethenyl-4-(4-fluorophenyl)-5-pelllvlpyl;dine Methyl triphenylphosphonium bromide was suspended in 15 mL of dry THF under argon and stirred at -78~C. Butyllithium (1.6 M, 0.42 mL) was added S dropwise over 2 min. and then the reaction mixture was allowed to stir at 0~C for 1.5 hours. The solution was cooled again to -78~C, treated dropwise with a solution of 2,6-diisopropyl-4-(4-~uorophenyl)-5-pentyl-3-pyridinecarbox-aldehyde (Example114, Step A) in 5 mL of dry THF, and then stirred at 0~C for 2.5 hours. The reaction was quenched with water (10 mL) and the THF evaporated in vacuo. Diethyl ether was added and the mixture was washed with water (2 x 20 mL), brine (1 x 20 mL), and dried with MgSO4. Filtration, concentration and flash chromatography (30%
CH2C12/hexanes) yielded a solid (0.132 g, 0.37 mmol, 66%). lH NMR (300 MHz, CDC13) ~ 7.08 (m, J = 1.1 Hz, 4 H), 6.34, 6.28 (d, J = 11.4 Hz, J = 11.4 Hz, 1 H), 5.19 (d, J = 1.8 Hz, 1 H), 4.96 (d, J = 1.8 Hz, 1 H), 3.39 (septet, J = 6.6 Hz, 1 H), 3.24 (septet, J=6.6Hz,1H),2.30(t,J=5.2Hz,2H),1.20~m,J=2.2Hz,18H),0.979~t,J=6.0Hz, 3 H). FAB-MS: calcd for (C24H32FN) 353, found 354 (M~H). Anal. Calcd for C24H32FN: C, 81.54; H, 9.12; N, 3.96; F, 5.37. Found: C, 81.46; H, 9.06; N, 3.78; F, 5.59. mp 44-46~C. Rf = 0.7 (30% CH2cl2/hexanes).
Step B: (_)-2,6-Diisopropyl-3-(1,2-dihydroxyethyl)-4-(4-fluoro-phenyl)-5-pentylpyridine To an oven-dried round bottom flask equipped with a stir bar was added the intermediate obtamed in Step A (150 mg, 0.424 mmol), in pyridine (10 mL) under argon. The solution was stirred and OsO4 (0.129 g, 0.509 mmol) was added in one portion. The reaction turned black as stirring continued at room temperature.
After 3 hours, the pyridine was evaporated in vacuo and the residue was dissolved in CH2C12 (10 mL) and sat. NaHSO3 (10 mL). The resulting heterogenous solution was stirred very rapidly for 18 hours. The layers were separated and the aqueouslayer was extracted several times with CH2Cl2. The combined organic layers were dried (MgSO4), filtered, and concentrated to give a white solid. The product wassubjected to a pad of silica (65/35; CH2Cl2/ether) to yield a white solid (70 mg, 0.18 mmol, 43%). 1H NMR (300 MHz, CDCl3): ~ 7.08 (m, 4 H), 4.57 (d, J = 1.5 Hz, 1 H),3.85 (m, lH), 3.65 (septet, J = 6.6 Hz, 1 H), 3.50 (m, 1 H), 3.20 (septet, J = 6.6 Hz, 1 H), 2.19 (m, 2 H), 1.96 (m, 1 H), 1.24 (m, 14 H), 1.07 (m, 4 H), 0.780 (t, J = 6.6 Hz, 3 H). FAB-MS: calcd for (C24H34FNO) 387, found 388 (M+H). Anal. Calcd for C24H34FNO: C, 74.38; H, 8.84; N, 3.61; F, 4.90. Found: C, 74.60; H, 9.03; N, 3.83; F, 5.04. mp 175-177~C. Rf = 0.5 (65/35; CH2Cl2/ether~.
. . " ,, WO ~8~'~1'28 PCTrUS97/13248 o EXAMPLE 125 tlO~
~f N~
2,6-Diisoprop~1-3-h~droxymethYl-4-l (4-trifluoromethyl)phenvll-5-(pent-1-S enyl)p~ridine Step A: Diethyl 1,4-dihydr~2,6-diisopropyl-4-l(4-trifluoro-methyl)phenyllpyridine-3,5-dicarboxylate Following the procedure of Chucholowski (U.S. Patent 4,950,675), to a solution of 18.0 g (0.11 mol) of ethyl isobutyrylacetate and 9.g g (56.8 mmol) of 4-(trifluoromethyl)benzaldehyde in ethanol (25 mL) was added concentrated ammonium hydroxide (3.0 mL). This reaction mixture was heated at reflux for 12 hrs. After cooling to room temperature, the reaction mixture was concentrated under vacuum to yield a yellow oil. The crude product was taken directly to the next step without purification.
Step B: Diethyl 2,6-diisopropyl-4-~(4-trifluorometh~l)phenyll-pyridine-3,5-dicarboxylate Prepared from the intermediate obtained in Step A by the procedure described in Example 160, Step B. lH NMR (300 MHz, CDC13): ~ 0.92 (t, J=7.0 Hz, 6H), 1.33 (d, J=6.6 Hz, 12H), 3.14 (m, 4H), 4.0 (q, J=7.0 Hz, 4H), 7.42 (d, J=8.0 Hz, 2H). mp 100-101~C.
Step C: Ethyl 2,6-diisoProPY1-4-~(4-trifluoromethYl)phenTlll-5 hydroxymethylpyridine-3-carboxylate Prepared from the intermediate obtained in Step B by the procedure described in Example 1, Step D. 1H NMR (300 MHz, CDC13): ~ 0.91 (t, J=7.0 Hz, 3H), 1.32 (d, J=6.6 Hz, 6H), 1.35 (d, J=6.6 Hz, 6H), 3.08 (m, lH), 3.50 (m, lH), 3.96 (q, J=7.0 Hz, 2H), 4.43 (d, J=4.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H).
mp 102-103~C.
o Step D: 5-Ethoxycarbonyl-2,6-diisoprop-~1-4-~(4-trifluoromethyl)-phen~rllpyridine-3-carboxaldeh~de To a solution of the intermediate obtained in Step C (1.9 g, 4.6 mmol) in dichloromethane (50 mL) was added Celite (2.0 g). The suspension was stirred at room temperature and treated with pyridinium chlorochromate (PCC) (2.0 g, 9.3 mmol) in three portions. The suspension was stirred at room temperature for 1 hr, then poured into 1:1 diethyl ether/hexane (250 mL), filtered through a pad of silica, the pad washed with diethyl ether (250 mL) and the combined eluent concentrated to afford 1.7 g (93%) of the product as a viscous oil which slowly solidified. 1H
NMR (300 MHz, CDCl3): ~ 0.94 (t, J=7.0 Hz, 3H), 1.33 (d, J=6.6 Hz, 6H), 1.34 (d,J=6.6 Hz, 6H), 3.14 (m, lH), 3.88 (m, lH), 4.0 (q, J=7.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 9.86 (s, lH). mp 105-106~C.
Step E: Ethyl 2,6-diisopropyl-4-~(4-trifluoromethyl)phenyll-5-(pent-1-l S enyl)p~ridine-3-carboxylate Prepared from the intermediate obtained in Step D by the procedure described in Example 1, Step D. lH NMR (300 MHz, CDC13): ~ 0.69 (t, J=7.0 H7, 3H), 0.90 (t, J=7.0 Hz, 3H), 1.09-1.34 (m, 14H), 1.92 (~, J=14.0, 7.0, 1.5 Hz, 2H), 3.07 (m, lH), 3.38 (m, lH), 3.96 (q, J=7.0 Hz, 2H), 5.29 (m, lH), 6.05 (m, lH), 7.31 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H). mp 70-72~C.
Step F: 2,6-Diisopropyl-3-hydroxYmethyl-4-~(4-trifluoromethyl)phen~ll-5 (pent-1 -enyl)pyridine The intermediate obtained in Step E (0.91 g, 2.04 mmol) was dissolved in 25 anhydrous THF (100 mL) under argon and treated dropwise at room temperature with lithium aluminum hydride (1.0 M in THF, 10 mL, 10 mmol). The reaction mixture was stirred at reflux for 1 hr, cooled to room temperature and quenched by the sequential addition of H20, 20% aqueous NaOH and H20. The resulting suspension was filtered through a cake of Celite and the filtrate concentrated and 30 purified by flash chromatography through silica (5% ethyl acetate/n-hexane) to afford 0.77 g (1.90 mmol, 93%) of the title compound as a white foam. lH NMR
(300 MHLz, CDCl3): ~ 0.68 (t, J=7.0 Hz, 3H), 1.05-1.40 (m, 14H), 1.90 (~, J=14. 7, 1.5 Hz, 2H), 3.34 (m, lH), 3.45 (m, lH), 4.37 (d, J=5.5 Hz, 2H), 5.26 (m, lH), 5.95 (m, lH), 7.30 (d, J=8.0 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H). Rf=0.36 (10% ethyl acetate/n-35 hexane). mp 77-78~C.
WO 9&'~ 8 PCTAJS97/13248 o EXAMPLE 126 ¢~
HO~
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-~(4-trifluoromethyl)phenyll-5-pentylpyridine S To 0.59 g (1.46 mmol) of the compound 2,6-diisopropyl-3-hydroxymethyl-4-[(4-trifluoromethyl)phenyl]-5-(pent-1-enyl)pyridine (Example 125) was dissolved in absolute ethanol (50 mL) and treated with 10% palladium on carbon (0.1 eq). The reaction flask was purged under aspirator vacuum and filled with hydrogen gas (3x). The reaction mixture was stirred under a hydrogen atmosphere for 6 hr.
After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed by concentration under vacuum and the crude product was purified by flash chromatography (10% ethyl acetate/n-hexane) to yield 0.58 g (1.41 mmol, 97%) of the title compound as a white solid. 1H
NMR (300 MHz, CDCl3): ~ 0.78 (t, J=7.0 Hz, 3H), 1.12 (m, 4H), 1.31 (m, 14H), 2.26 (m, 2H), 3.25 (m, lH), 3.42 (m, lH), 4.29 (s, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H). Rf=0.36 (10% ethyl acetate/n-hexane). mp 99-100~C.
¢~F
HO ~~
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(3-fluorophenyl)-5-(pent-l -enyl)-pyridine Step A: Ethyl 2,6-diisopropyl-4-(3-fluorophenyl)-5-(pent-1-enyl)-pyridine-3-carboxylate WO 98104S28 PCTrUS97113248 0 Prepared from 3-fluorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCl3): (reported as a mixture of olefin isomers): ~0.76 (m, 3H), 0.97 (t, J=7.0 Hz, 3H), 1.13-1.37 (m, 14H), 1.95 (m, 2H), 3.07 (m, lH), 3,21-3.45 (m, lH), 4.0 (m, 2H), 5.30-5.60 (m, lH), 6.06 (m, lH), 6.90-7.03 (m, 3H), 7.27 S (m, lH) Step B: 2,6-Diisopropyl-3-hydrox~rmethyl-4-(3-fluoroRhenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): ~ 0.78 (m, 3H), 1.13-1.37 (m, 14H), 1.93 (m, 2H), 3.41 (m, 2H), 4.40 (s, 2H), 5.28-5.45 (m, lH), 6.0 (m, lH), 6.87-7.07 (m, 3H), 7.34 (m, lH). Rf=0.36 (10% ethyl acetate/n-hexane). mp 117-118~C.
~F
HO ~~~"
~N~
2,6-Diisopropvl-3-hydrox-~methyl-4-(3-fluorophenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-fluorophenyl)-5-(pent-1-enyl)pyridine (Example 127) by the procedure described in Example 126. lH NMR (300 MHz, CDCl3): ~ 0.79 (t, J=7.0 Hz, 3H), 1.10-1.35 (m, 18H), 2.28 (m, 2H), 3.24 (m, lH), 3.42 (m, lH), 4.33 (s, 2H), 6.96 (m, 2H), 7.12 (m, lH), 7.40 (m, lH). mp 117-118~C. Rf=0.36 (10% ethyl acetate/n-hexane).
.
CA 02262434 l999-0l-28 WO~/01'~X PCTnUS97/13248 O EXA~LE 129 HO ~' ~N~/
2,6-Diisopropyl-3-h~,Tdroxymethyl-4-(4-methylphenyl)-5-(pent-1-enyl)-pyridine Step A: Ethyl 2,6-diisopropyl-4-(4-methylphenyl~-5-(pent-l-enyl)-pyridine-3 carboxylate Prepared from 4-methylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, 10 Steps A-E. lH NMR (300 MHz, CDCl3): ~ 0.75 (t, J=7.4 H7, 3H), 0.95 (t, J=7.4, 3 H), 1.20-1.40 (m, 14H), 1.95 (tdd, J=7.4, 7.4, 1.5 Hz, 2H), 2.35 ~s, 3H), 3.10 (m, lH), 3.40 (m, lH), 3.99 (q, J=7.4, 2H), 5.30-5.40 (m, lH), 6.05 (dt, J-16.2, 1.5 Hz, lH), 7.0-7.2 (m, 4H). mp 74-77~C.
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-(pent enyl)-p~ttridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): ~ 0.77 (t, J=7.0 Hz, 3 H), 1.1-1.3 (m, 15 H), 2.27 (m, 2 H), 2.42 (s, 3H), 3.4 (m, 2 H), 4.34 (d, J=6.0 Hz, 2 H), 5.30-5.40 (m, 1 H), 5.90 (d, J=16.0 Hz, 1 H), 7.0 (d, J=8.0 Hz, 2 H), 7.18 (d, J=8.0 Hz, 2 H). FAB-MS:
r~ t~l for C24H33N0 352; found 352 (M+H, 100%). Rf=0.38 (10% ethyl acetate/n-hexane). mp 72-75~C.
CA 02262434 l999-0l-28 WO~8~ Q PCTrUS97/13248 HO~
~N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-~pentylpyridine The title S compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-(pent-1-enyl)pyridine (Example 129) by the procedure described in Example 126. lH NMR (300 MHz, CDC13): ~ 0.77 (t, J=7.0 Hz, 3 H), 1.10-1.40 (m, 19 H), 2.27 (m, 2 H), 2.42 (s, 3 H), 3.22 (m, 1 H), 3.41 (m, 1 H), 4.34 (d, J=6.0 Hz, 2 H), 7.10 (d, J=8.0 Hz, 2 H), 7.20 (d, J=8.0 Hz, 2 H). FAB-MS: calculated for C24H3sNO
354; found 354 (M+H, 100%). Rf=0.38 (10% ethyl acetate/n-hexane). mp 92-94~C
E~CAMPLE 131 HO~
~N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-ethylphenyl)-5-(pent-1-enyl)-pyridine Step A: Ethyl 2,6-diisopropy~-4-(4-ethylphenyl)-5-(pent-1-enyl)-pyridine-3-carboxylate Prepared from 4-ethylbenzaldehyde, ethyl isobutyrylacetate and 20 concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCl3): ~ 0.78 (t, J=7.4 Hz, 3H), 0.90 (t, J=7.4 Hz,3H), 1.10-1.40 (m, 17H), 1.94 ~tdd, J=7.0, 7.0, 1.5 Hz, 2H), 2.64 (q, ~=7.7 Hz, 2H), 3.0 (m, lH), 3.40 (m, lH), 3.96 (q, J=7.4 Hz, 2H), 5.35 (m, lH), 6.08 (dt, J=16.2, 1.5 Hz, lH), 7.10 (m, 4H). mp 67-68~C.
2~0 , . . .. ... .. , . . ., . .. ~". ~ ....
WO 98/04528 PCTrUS97J13248 0 Step B: 2,6-Diisoprop~l-3-hydroxymethyl-4-(4-ethylphenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) ~ (reported as a mixture of olefin isomers): ~ 0.73 (t, J= 7.0 Hz, 3H), 1.10-1.40 (m, ~ 5 18H), 1.91 (tdd, J=7.0, 7.0, 1.0, 2H), 2.68 (q, J=7.4 Hz, 2H), 3.3-3.5 (m, 2H), 4.41 (d, J=
5.5 Hz, 2H), 5.20-5.40 (m, lH), 6.0 (dt, J=16.0, 1.0 Hz, lH), 7.0 (d, J=8.5 Hz, 2H), 7.23 (d, J= 8.5 Hz, 2H). FAB-MS: calculated for C2sH3sNO 366; found 366 (M+H, 100%).
~ Rf=0.31 (10% ethyl acetate/n-hexane).
HO ~--' --f N~
2,6-Diisopropyl-3-h~droxymethyl-4-(4-eth~lphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-15 (4-ethylphenyl)-5-(pent-1-enyl)pyridine (Example 131) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): ~ 0.77 (t, J=7.0 Hz, 3H), 1.0-1.40 (m, 22H), 2.28 (m, 2H), 2.73 (q, J= 7.5 Hz, 2H), 3.35 (m, lH), 3.45 (m, lH), 4.35 (s, 2H), 7.10 (d, J=8.0 Hz, 2H), 7.18-7.34 (d, J=8.0 Hz, 2H). FAB-MS: calculated for C2sH37NO 368; found 368 (M+H, 100%). Rf=0.31 (10% ethyl acetate/n-hexane).
20 mp 87-88~C.
H3C ~ CH3 ' - HO ~/--'' ~N~
W O 98~ PCT~US97113248 2,6-Diisopropyl-3-hydroxymethvl-4-(4-isopropylphenyl)-5-(pent-l-enyl)pyridine Step A: Ethyl 2,6-diisopropyl-4-(4-isopropylphenyl)-5-(pent-l-enyl)pyridine-3 carboxylate Prepared from 4-isopropylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDC13): ~ 0.70 (t, J-7.7 Hz, 3H), 0.84 (t, J=7.4, 3H), 1.10-1.40 (m, 20H), 1.95 (tdd, J=7.0, 7.0, 1.5 Hz, 2H), 2.80-3.10 ~m, 2H), 3.40 (m, lH), 3.94 (q, J=7.4 Hz, 2H), 5.30 (m, lH), 6.10 (dt, J=15.8, 1.5 Hz, lH), 7.0-7.20 (m, 4H).
mp 41-45~C.
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-isopropylphenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCI3) (reported as a mixture of olefins): ~ 0.68 (t, J=7.4 Hz, 3 H), 1.0-1.4 (m, 21 H), 1.90 (tdd, J=7.0, 7.0, 1.5 Hz, 2 H), 2.9 (m, lH), 3.3-3.5 (m, 2 H), 4.43 (d, J=6.0 Hz, 2 H), 5.20-5.35 (m, 1 H), 6.0 (dt, J= 16.0, 1.5 Hz, 1 H), 7.0 (d, J=8.0 Hz, 2 H), 7.25 (d, J=8.0 Hz, 2 H). FAB-MS: calculated for C26H37NO 380; found 380 (M+H, 100%). Rf-0.40 20 (10% ethyl acetate/n-hexane).
H3C C~3 HO
~N~
2,6-Diisopropyl-3-hydroxymethyl-~(4-isopropylphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-isopropylphenyl)-5-(pent-1-enyl)pyridine (Example 133) by the procedure described in Example 126. lH NMR (300 MHz, CDC13): ~ 0.74 (t, J= 7.0 Hz, 3 H), 1.0-1.40 (m, 25 H), 2.25 (m, 2 H), 2.95 (m, 1 H), 3.25 (m, 1 H), 3.40 (m, 1 H), 4.35 (d, ... ..... .. ..
W0~8~'~t-28 PCTrUS97/13248 O J=6.0 Hz, 2 H), 7.1, (d, J=8.5 Hz, 2 H), 7.25 (d, J= 8.5 Hz, 2 H). FAB~ rAlc~ te~1 for C26H3gNO 382; found 382 (M+H, 100%). Rf=0.40 (10% ethyl acetate/n-hexane).
mp 42-44~C.
~ EXAMPLE 135 ~ 5 HO~
\f N~
2,6-Diisopropyl-3-hydroxymethyl-4-~4-(phenyl)phenyll-5-(pent-1-enyl)pyridine Step A: Ethyl 2,6-diisopropyl-4-~4-(phenyl)phenyll-5-(pent-l-enyl)pyridine-3 carboxylate Prepared from 4-phenylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCl3): ~ 0.73 (t, J=7.4 Hz, 3H), 0.93 (t, ~=7.0 Hz,lS 3H), 1.10-1.40 (m, 14H), 1.97 (tdd, J=7.0, 7.0, 1.1 Hz, 2H), 3.10 (m, lH), 3.45 (m, lH), 4.0 (q, J=7.4 Hz, 2 H), 5.40 (m, lH), 6.10 (dt, J=16.2, 1.1 Hz, lH), 7.20-7.70 (m, 9H).
mp 104-106~C.
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-~4-(phenyl)phenyll-5-~pent-1-en~l)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): ~ 0.70 (t, J= 7.0 Hz, 3H), 1.10-1.40 (m, 15H), 1.90 (tdd, J=7.0, 7.0, 1.5, 2H), 3.30-3.50 (m, 2H), 4.40 (d, J=6.0 Hz, 2H), 5.35 (m, lH), 6.05 (dt, J=16.0, 1.5 Hz, lH), 7.20-7.24 (m, 2H), 7.35-7.70 (m, 7H). FAB-MS:
te~1 for C29H35N0 414; found 414 (M+H, 100 ~/O). Rf=0.15 (6% ethyl acetate/n-hexane). mp50-52~C.
W098/04528 PCTrUS97/13248 HO ~~
~N~
2,6-Diisopropyl-3-hydroxymeth~1-4-~4-(phenyl)phenyll-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-[4-S (phenyl)phenyl]-5-(pent-1-enyl)pyridine (Example 135) by the procedure described in Example 126. 1H NMR (300 MHz, CDC13): ~ 0.76 (t, J=7.0 Hz, 3H), 1.0-1.40 (m, 19H), 2.31 (m, 2H), 3.25 (m, lH), 3.44 (m, lH), 4.40 (d, J=5.9 Hz, 2H), 7.22-7.70 (m, 9H). FAB-MS: ~Alc~ ted for C2gH37NO 416; found 416 (M+H, 100 %). Rf=0.34 (10% ethyl acetate/n-hexane). mp 56-58~C.
[~F
HO ~~/
~N~
1 5 2,6-Diisopropvl-3-hydroxymethyl-4-(2-fluorophenyl)-5-(pent-l-enyl)-pyridine Step A: Ethyl 2,6-diisopropvl-4-(2-fluorophenyl)-5-(pent-l-enyl)-pyridine-3 carboxylate Prepared from 2-fluorobenzaldehyde, ethyl isobutyrylacetate and 20 concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1H NMR ~300 MHz, CDC13): (reported as a mixture of olefin isomers):
~ 0.70 (m, 3H), 0.92 (t, J= 7.0 Hz, 3H), 1.05-1.40 (m, 14H), 1.90 (m, 2H), 3.10 (m, lH), 3.35 (m, lH), 3.97 (m, 2H), 5.29-5.50 (m, lH), 6.16 (m, lH), 7.08-7.32 (m, 4H).
. .
W098/04~28 PCTrUS97/13248 Step B: 2,6-Diisopropyl-3-hydroxvmethyl-4-(2-fluorophenyl)-s-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) S (reported as a mixture of olefin isomers): ~ 0.69-0.82 (m, 3H), 1.09-1.40 (m, 14H), 1.90 (m, 2H), 3.20-3.45 (m, 2H), 4.40 (m, 2H), 5.25-5.45 (m, lH), 6.08 (m, lH), 7.08-7.41 (m, 5H). Rf=0.24 (10% ethyl acetate/n-hexane).
.
~F
HO ~~' ~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(2-fluorophenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-1 S (2-fluorophenyl)-5-(pent-1-enyl)pyridine (Example 137) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): ~ 0.78 (t, J=7.0 Hz, 3H), 1.07-1.40 (m,18H), 2.29 (m, 2H), 3.26 (m, lH), 3.46 (m, lH), 4.34 (m, 2H), 7.20 (m, 3H), 7.42 (m, lH). Rf=0.24 (10% ethyl acetate/n-hexane).
E)CAMPLE 139 ~, CH3 HO ~~V~~/
N~
2,6-Diisopropyl-3-hydroxymethyl-4-(3-methylphenyl)-5-(pent-l-enyl)-pyridine Step A: Ethyl 2,6-diisoproPyl-4-(3-methylphenvl)-5-(pent-1-enyl)-pyridine-3 carboxylate WO 98~ PCT/US97113248 O Prepared from 3-methylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described m Example 125, Steps A-E. lH NMR (300 MHz, CDC13): ~ 0.74 (t, J=7.4 Hz, 3H), 0.92 (t, J=7.0 Hz,3H), 1.10-1.40 (m, 14H), 1.95 (tdd, J=7.0, 7.0, 1.5 Hz, 2H), 2.32 (s, 3H), 3.10 (m, lH), 3.40 (m, lH), 3.96 (q, J=7.4 Hz, 2H), 5.40 (m, lH), 6.05 (dt, J=16.2, 1.5 Hz, lH), 6.90-7.20 (m, 4H).
StepB: 2,6-Diisopropyl-3-hydroxymethyl-4-(3-meth~ phenyl)-5-(pent en~l)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefins): ~ 0.73 (t, J=7.0 Hz, 3 H), 1.10-1.40 (m, 15H), 1.90 (tdd, J_7.0, 7.0, 1.0, 2H), 2.36 (s, 3H), 3.30-3.50 (m, 2H), 4.40 (d, J= 4.0 Hz, 2H), 5.20-5.40 (m, lH), 5.95 (dt, J=16.0, 1.0 Hz, lH), 6.90 (m, 2H), 7.10-7.30 (m, 2H). FAB-MS:
calculated for C24~33No 352; found 3~2 (M+H, 100%). Rf=0.34 (10% ethyl acetate/n-hexane). mp 94-97~C.
~ C ~3 HO ~--/
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(3-methylphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-methylphenyl)-5 (pent-1-enyl)pyridine (Example 139) by the procedure described in Example 126. lH NMR (300 MHz, CDC13): ~ 0.77 (t, J=7.0 Hz, 3 H), 1.0-1.40 (m, 19H), 2.25 (m, 2H~, 2.39 (s, 3H), 3.23 (m, lH), 3.44 (m, lH), 4.34 (s, 2H), 6.97 (m, 2H), 7.18-7.34 (m, 2H). FAB-MS: calculated for C24H3sNO 354; found 354 (M+H, 100 %). Rf=0.34 (10% ethyl acetate/n-hexane). mp 88-90~C.
~ CH3 HO ~~~
\~N~/
2,6-Diisoprop~1-3-hydroxymethyl-4-(2-methylphenyl)-5-(pent-1-enyl)-pyridine Step A: Ethyl 2,6-diisopropyl-4-(2-methylphenyl)-5-(pent-1-enyl)-pyridine-3-carboxylate Prepared from 2-methylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1H NMR (300 MHz, CDCl3): ~ 0.70 (t, J=7.4 Hz, 3H), 0.88 (t, ~=7.0 Hz,3H), 1.0-1.40 (m, 14H), 1.90 (td, J=7.0, 7.0 Hz, 2H), 2.0 (s, 3H), 3.10 (m, lH), 3.40 (m, lH), 3.90 (m, 2H), 5.30-5.40 (m, lH), 6.0 (m, lH), 7.0-7.20 (m, 4H).
Step B: 2,6-Diisopropyl-3-hydrox~methyl~-(2-methylphenyl)-5-(pent-1-enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): ~ 0.70 (t, J= 7.5 Hz, 3H), 1.10-1.40 (m, 15H), 1.87 (tdd, J=7.5, 7.5, 1.5, 2H), 1.95 (s, 3H), 3.30-3.50 (m, 2H), 4.20 (m, lH), 4.45 (m, lH), 5.30 (m, lH), 5.93 (m, 2H), 6.90-7.30 (m, 4H). FAB-MS: calculated for C24H33NO 352; found 352 (M+H, 100%). Rf=0.32 (10% ethyl acetate/n-hexane).
mp 76-79~C.
~ CH3 HO ~' ~' W0~8/01~2~ PCTAUS97~13248 2,6-Diisopropvl-3-hydro%ymethYl-4-(2-methylphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-~2-methylphenyl)-5-(pent-1-enyl)pyridine (Example 141) by the procedure described in Example 126. lH NMR (300 MHz, CDCl3): ~ 0.76 (t, J=6.6 Hz, 3H), 1.0-S 1.40 (m, 19H), 1.97 (s, 3H), 2.0 (m, lH), 2.35 (m, lH), 3.22 (m, lH), 3.42 (m, lH), 4.16 (dd, J=12.0, 5.0 Hz, lH), 4.40 (dd, J=12.0, 5.0 Hz, lH), 7.0-7.10 (m, lH), 7.20-7.40 (m, 3H). FAB-MS: calculated for C24H3sNO 354; found 354 (M+H, 100%). Rf=0.32 (10% ethyl acetate/n-hexane). mp 81-83~C.
HO ~~'~' ~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-(pent-1-enyl)-pyridine Step A: Ethyl 2,6-diisopropyl-4-(4-chlorophenyl)-5-(pent-1-enyl)-pyridine-3-carboxylate Prepared from 4-chlorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers):
0.76 (m, 3H), 0.98 (m, 3H), 1.15-1.35 (m, 14H), 1.95 (m, 2H), 3.05 (m, lH), 3.39 (m, lH), 4.0 (M, 2H), 5.29-5.48 (m, lH), 6.03 (m, lH), 7.11 (m, 2H), 7.30 (m, 2H).
Step B: 2,6-Diisopropyl-3-hydrox~methyl-4-(4-chlorophenyl)-5-(pent-1-enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a 6:1 mixture of olefin isomers): ~ 0.73-0.83 (m, 3H), 1.10-1.40 (14H), 1.91 (m, 2H), 3.93 (m, 2H), 4.39 (d, ~=5.0 Hz, 2H), 5.25-5.45 (m, lH), 5.98 (m, lH), 7.11 (m, 2H), 7.35 (m, 2H). Rf=0.36 (10% ethyl acetate/n-hexane).
CA 02262434 l999-0l-28 W O~/01'?8 PCTrUS97tl3248 o EXAMPLE 144 Cl HO ~~~~
~N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-pentylpyridine S The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-(pent-1-enyl)pyridine (Example 143) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): ~ 0.79 (t, J=7.0 Hz, 3H), 1.08-1.38 (m,18H), 2.26 (m, 2H), 3.22 (m, lH), 3.40 (m, lH), 4.31 (d, J=5.0 Hz, lH), 7.13 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H). mp 83-85~C. Rf=0.36 (10% ethyl acetate/n-hexane).
E~CAMPLE 145 ~,CI
HO ~~~
\~ N~/
l S 2,6-Diisopropyl-3-hydroxymethyl-4-(3-chlorophenyl)-5-(pent-l -enyl)-pyridine Step A: Ethyl 2,6-diisopropyl~-(3-chlorophenyl)-5-(pent-1-enyl)-pyridine-3-carboxylate Prepared from 3-chlorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCl3): ~ 0.75 (t, J=7.4 Hz, 3H), 0.98 (t, J=7.0 Hz,3H), 1.20-1.40 (m, 14H), 1.96 (tdd, J=7.0, 7.0, 1.5 Hz, 2H), 3.05 (m, lH), 3.40 (m, lH), 4.0 (q, J=7.0 Hz, 2H), 5.45 (m, lH), 6.05 (dt, J=16.2, 1.5 Hz, lH), 7.0-7.30 (m, 4H).
WO 9~ 2X PCTrUS97113248 O Step B: 2,6-Diisopropyl-3-h~droxvmethyl-4-(3-chlorophen~1)-5-(pent-1-enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCI3) (reported as a mixture o~ olefin isomers): ~ 0.75 (t, J=7.5 Hz, 3H), 1.10-1.40 (m, 15H), 1.93 (tdd, J=7.0, 7.0, 1.0 Hz, 2H), 3.30-3.50 (m, 2H), 4.37 (d, J=12.0 Hz, lH), 4.43 (d, J=12.0 Hz, lH), 5.20-5.40 (m, lH), 5.9 (dt, J=16.0, 1.1 Hz, lH), 7.0-7.40 (m, 4H). FAB-MS: calculated for C23H30NOCl 372; found 372 (M+H, 100%). Rf=0.26 (10% ethyl acetate/n-hexane). mp 101-104~C.
~CI
HO
\~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(3-chlorophenyl)-5-pen~lpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-chlorophenyl)-5-(pent-1-enyl)pyridine (Example 145) by the procedure described in Example 126. lH NMR (300 MHz, CDCl3): ~ 0.80 (t, J=7.0 Hz, 3H), 1.0-1.40 (m, 19H), 2.26 (m, 2H), 3.23 (m, lH), 3.41 (m, lH), 4.34 (m, 2H), 7.05-7.45 (m, 4H). FAB-MS: calculated for C23H32NOC1 374; found 374 (M+H, 100%). Rf 0.26 (10% ethyl 20 acetate/n-hexane). mp 94-95~C.
Cl ~CI
HO~
~ N~/
W O9B104528 PCT~US97/13248 0 2,6-Diisopropyl-3-hydroxymethyl-4-(2,4-dichlorophen~l)-S-(pent-l-enyl)pyridine Step A: Ethyl 2,6-diisopropyl-4-(2,4-dichlorophenyl)-5-(pent-1-enyl)pyridine-3-carboxylate Prepared from 2,4-dichlorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCI3) (reported as a 1:1 mixture of olefin isomers): ~ 0.79 (m, 3H), 0.99 (m, 3H), 1.12-1.38 (m, 14H), 1.91 (m, 2H), 3.12 (m, lH), ~ 3.32 (m, lH), 4.0 (m, 2H), 5.20 -5.60 (m, lH), 6.09 (m, lH), 7.05-7.41 (m, 3H).
Step B: 2,6-Diisopropyl-3-hydroxvmethyl-4-(2,4-dichlorophenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a 1:1 mixture of olefins): ~ 0.75-0.87 (m, 3H), 1.13-1.37 (m, 14H), 1.65-2.0 (m, 2H), 3.20-3.51 (m, 2H), 4.30 (m, lH), 4.42 (m, lH), 5.31-5.50 (m, lH), 6.0 (m, lH), 7.05 (m, lH), 7.28 (m, lH), 7.47 (m, lH). Rf 0.38 (10% ethyl acetate/n-hexane~.
Cl ~CI
HO ~/'~~/
'f ' N '~/
2,6-Diisopro1?yl-3-hydroxymethyl-4-(2,4-dichlorophenyl)-5-p~llLyl~y~idirle The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(2,4-dichlorophenyl)-5-(pent-1-enyl)pyridine (Example 147) by the procedure described in Example 126. lH NMR (300 MHz, CDCl3): ~ 0.80 (t, J=7.0 Hz, 3H), 1.12-1.48 (m, 18H), 2.12 (m, lH), 2.35 (m, lH), 3.26 ~m, lH) 3.45 (m, lH), 4.31 (AB, J=12.0 Hz, 2H), 7.16 (d, J=8.0 Hz, lH), 7.36 (dd, J=8.0, 2.0 Hz, lH), 7.54 (d, J=2.0, lH).
Rf 0.38 (10% ethyl acetate/n-hexane).
WO 981'~1e~,% PCT~US97113248 o EXAMPLE 149 ~,CI
HO~--~N~/
2,6-Diisoprop~1-3-hydroxymethyl-4-t3/4-dichlorophenyl)-5-(pent-l-en~l)pyridine s Step A: Ethyl 2,6-diisopropyl-4-(3,4-dichlorophenyl)-5-(pent-l-enyl)pyridine-3-carboxylate Prepared from 3,4-dichlorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 160, Steps A-E. 1H NMR (300 MHz, CDCl3) (reported as a 6:1 mixture of olefin isomers). ~ 0.78 (m, 3H)J 1.04 (m, 3H), 1.16-1.35 (m, 14H), 1.98 (m, 2H), 3.04 (m, lH), 3.57 (m, lH), 5.31-5.58 (m, 1H), 6.02 (m, lH), 7.04 (m, lH), 7.28-7.42 (m, 2H).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a 6:1 mixture of olefin isomers): ~ 0.80 (m, 3H), 1.16-1.57 (m, 14H), 1.95 (m, 2H), 3.40 (m, 2H), 4.41 (m, 2H), 5.28-5.42 (m, lH), 6.0 (m, lH), 7.05 (s, lH), 7.30 (s, lH), 7.45 ~m, lH). mp 46-48~C. Rf=0.38 (10% ethyl acetate/n-hexane).
~F
HO~
~N~/
WO 9~ 8 PCT/US97/13248 0 2,6-Diisopropyl-3-hydroxymethyl-4-(2,4-difluorophenyl)-5-(pent-l-enyl)pyridine Step A: Ethyl 2,6-diisopropyl~(2,4-difluorophenyl)-5-(pent-l-enyl)pvridine 3-carboxylate Prepared from 2,4-difluorobenzaldehyde, ethyl isobutyrylacetate and ~ 5 concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1H NMR (300 MHz, CDCl3): ~ 0.75 (t, J=7.4 Hz, 3H), 1.0 (t, J=7.0 Hz, 3H), 1.10-1.40 (m, 14H), 1.93 (tdd, J=7.4, 7.4, 1.5 Hz, 2H), 3.10 (m, lH), 3.35 (m, lH), 4.0 (q, J=7.0 Hz, 2H), 5.30 (dt, J=15.0, 7.0 Hz, lH), 6.10 (m, lH), 6.80-7.20 (m, 3H).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(2~4-difluorophenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): ~ 0.75 (t, J=7.5 Hz, 3H), 1.10-1.40 (m, 15H), lS 1.92 (tdd, J=7.0, 7.0, 1.5, 2H), 3.30-3.60 (m, 2 H), 4.34 (dd, J=12.0, 6.0 Hz, lH), 4.43 (dd, J=12.0, 5.0 Hz, lH), 5.3 (m, lH), 6.05 (d, J=16.0, Hz, lH), 6.80-7.20 (m, 3H).
FAB-MS: cAl~ll~te~ for C23H29NOF2 374; found 374 (M+H, 100%). Rf 0.24 (10%
ethyl acetate/n-hexane). mp 59-62~C.
~,1 ~' F
HO
~N~
2,6-Diisopropyl-3-hydroxymethyl~(2~4-difluorophenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(2,4-difluorophenyl)-5-(pent-1-enyl)pyridine (Example 150) by ~e procedure described in Example 126. lH NMR (300 MHz, CDCl3): ~ 0.79 (t, J=7.0 Hz, 3H), 1.10-1.40 (m, 18H), 2.30 (m, 2 H), 3.20 (m, lH), 3.40 (m, lH), 4.30 (d, J=12.0 Hz, lH),4.36 (d, J=12.0 Hz, lH), 6.90-7.20 (m, 3H). FAB-MS: calculated for C23H31F2NO
376; found 376 (M+H, 100%). Rf 0.24 (10% ethyl acetate/n-hexane). mp 93-95~C.
W O 98/04528 PCT~US97J13248 oJ3 HO~
'T--N~
2,6-Diisopropyl-3-hydroxymethyl-4-(3-benzyloxyphenyl)-5-(pent-1-enyl)pyridine Step A: Ethyl 2,6-diisopropyl-4-(3-benzyloxyphenyl)-5-(pent-1-enyl)pyridine-3-carboxylate Prepared from 3-benzyloxybenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 160, Steps A-E. lH NMR (300 MHz, CDCl3): ~ 0.75 (t, ~=7.4 Hz, 3H), 0.93 (t, J= 7.2 Hz, 3H), 1.25 (m, 14H), 1.93 (tdd, J=7.4, 7.4, 1.1 Hz, 2H), 3.07 (m, lH), 3.40 (m, lH), 3.97 (m, 2H), 5.04 (bs, 2H), 5.35 (m, lH), 6.06 (dt, J=16.2, 1.5 Hz, lH), ~.79 (m, 2H), 6.89 (m, lH), 7.31 (m, 6H).
Step B: 2,6-Diisoprop~1-3-hydroxymethvl-4-(3-benzyloxyphenyl)-5-(pent-1-enyl)p~ridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): ~ 0.74 (t, J_7.4 Hz, 3H), 1.25 (m, 14H), 1.90 (m, 2H), 3.39 (m, 2H), 4.39 (d, J=6.0 Hz, 2H), 5.07 (s, 2H), 5.32 (m, lH), 5.97 (m, lH), 6.74 (m, 2H), 6.95 (m, lH), 7.35 (m, 7H). FAB-MS: tal~ll~tPtl for C30H37N02, 444;
found 444 (M+H, 100%). Elemental analysis: cal~llate~l for C30H37NO2: C 81.22; H8.41; N 3.16, found: C 80.51; H 8.41; N 3.36. Rf 0.5 (25% ethyl acetate/n-hexane).
~,OH
l~,J
HO ~--/
\~' N~
.. _ .. . . . . .. . .
2,6-Diisopropyl-3-hydroxymethyl-4-(3-hydroxyphenyl)-5-pentvlpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-benzyloxyphenyl)-5-(pent-l-enyl)pyridine (Example 152) by the procedure described ~n Example 126. lH NMR (300 MHz, CDCl3): ~ 0.78 (t, J_7.0 Hz, 3H), - 5 1.28 (m, 18H), 2.28 (m, 2H), 3.22 (m, lH), 3.39 (m, lH), 4.34 (m, 2H), 5.52 (s, lH), 6.63 (m, lH), 6.71 (d, J=8.0 Hz, lH), 6.81 (m, lH), 7.26 (m, lH). FAB-MS: calculated for C23H33N02 356; found 357 (M+H, 100%). Elemental analysis: c~ tec~ for ~ C23H33NO2: C 77.70; H 9.36; N 3.94, found: C 76.51; H 9.49; N 3.85. Rf 0.21 (10%
ethyl acetate/n-hexane). mp 121-122~C.
~ CF3 HO ~~~
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(3-trifluoromethyl)phenyl-5-(pent en.~l)pyridine Step A: Ethyl 2,6-diiso~>lo~yl-4-(3-trifluoromethyl)phenyl-5-(pent enyl)pyridine-3-carboxylate Prepared from 3-(trifluoromethyl)benzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCl3) (reported as a 6:1 mixture of olefin isomers): ~ 0.72 (m, 3H), 0.94 (m, 3H), 1.10-1.40 (m, 14H), 1.94 (m, 2H), 3.07 (m, lH), 3.41 (m, lH), 3.97 (m, 2H), 5.33 (m, lH), 6.05 (m, lH), 7.29-7.60 (m, 4H).
Step B: 2,6-Diisopropyl-3-h~droxymethyl-4-t3-trifluoromethyl)phenyl-5 (pent-1-enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) ~ 30 (reported as a 6:1 mixture of olefin isomers): ~ 0.67-0.87 (m, 3H), 1.08-1.38 (m, 14H), 1.90 (m, 2H), 3.20-3.50 (m, 2H), 4.39 (qd, J=12.0, 5.0 Hz, 2H), 5.24-5.50 (m, lH), 5.93-W 098104528 PCT~US97113248 0 6.02 (m, lH), 7.37-7.62 (m, 3H). mp 100-103~C. Rf 0.36 (10% ethyl acetate/n-hexane).
ç~CF3 HO ~~~' ~N~/
s 2,6-DiisopropYl-3-hydrox~methyl-4-(3-trifluoromethyl)phenyl-5-pent~lpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-trifluoromethyl)phenyl-5-(pent-1-enyl)pyridine (Example 154) by the proceduredescribed in Example 126. lH NMR (300 MHz, CDCl3): ~ 0.75 (t, J=6.5 Hz, 3H), 1.07-1.39 (m, 18H), 2.24 (m, 2H), 3.24 (m, lH), 3.42 (m, lH), 4.31 (qd, ~=12.0, 5.0 Hz, 2H), 7.42 (d, J=8.0 Hz, lH), 7.50 (s, lH), 7.57 (t, J=8.0 Hz, lH), 7.67 (d, J=8.0 Hz, lH).
mp 96-97~C. Rf 0.36 (10% ethyl acetate/n-hexane).
HO~
~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(2-eLhyl,yl~henyl)-5-(pent-1-enyl)-pyridine Step A: Diethyl 2,~diiso~ 1-4-(2-iodophenyl)pyridine-3,5-dicarbox~late Prepared from 2-iodobenzaldehyde, ethyl isobutyrylacetate and concel~lldL~d ammonium hydroxide by the procedures described in Example 125, Steps A-B. lH NMR (300 MHz, CDCl3): ~ 0.94 (t, J= 7.0 Hz, 6H), 1.30 (d, J= 6.6 ~Iz, 6H), 1.34 (d, J= 6.6 Hz, 6H), 3.19 (septet, J= 6.6 Hz, 2H), 4.0 (q, J= 7.0 Hz, 4H), 7.0-7.40 (m, 3H), 7.85 (m, lH).
.. . .. ~ .. , W O 98104528 PCT~US97113248 o Step B: Diethyl 2,6-diisopropyl-4-~(2-trimethylsilylethynyl)phenyllpyridine- 3,5-dicarboxylate A solution of 1.50 g (3 mmole) of the intermediate obtained in Step A in toluene was treated with 1.48 g (15 mmole) of trimethylsilyl acetylene, 87.1 g (0.86 S mol) of triethylamine, 0.1 g (0.15 mmol) of ~s(triphenylphosphine) pall~ m~(II) chloride, 0.2 g (0.8 mmole) of triphenyl phosphine and 0.2 g (1.17 mmole) of copper iodide. This reaction mixture was stirred at rt for lhr and heated at 90~C, in asealed reaction vessel, for 16 hrs. The reaction mixture was to cooled to temperature, filtered through Celite, and stripped to give a dark oil which uponpurification by flash silica gel chromatography to yield 1.22 g (2.5 mmole) of the product. 1H NMR (300 MHz, CDCI3): ~ 0.0 (s, 9H), 0.93 (t, J= 7.0, 6H), 1.32 (d, J=
6.6 Hz, 6H), 1.33 (d, J=6.6 Hz, 6H), 3.18 (septet, J= 6.6, 2H), 3.90 (q, J= 7.0 Hz, 4H), 7.20-7.50 (m, 4H).
Step C: Diethyl 2,6-diisopropyl-4-(2-ethynylphenyl)pyridine-3~5-dicarboxylate A solution of 5.68 g (11.9 mmole) of the intermediate obtained in Step B in 800 mL ethanol was treated with 2.8 g (20.3 mmole) of potassium carbonate and the reaction mixture was allowed to stir at room temperature for 16 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous solution of ammonium chloride, brine and separated. The organic layer was dried over ma~nesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography, eluting with 10 ethyl acetate/n-hexane, to give 3.95 g (9.6 mmole) of the product. lH NMR (300 MHz, CDCl3): ~ 0.90 (t, J= 7.0 Hz, 6H), 1.32 (m, 12H), 2.97 (s, lH), 3.21 (septet, J=6.6, 2H), 3.90 (q, J= 7.0, 4H), 7.2-7.6 (m, 4H).
Step D: Ethyl 2,6-diisopropvl-4-(2-ethynylphenyl)-5-(pent-1-enyl)-pyridine-3-carboxylate Prepared from the intermediate obtained in Step C by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDC13): ~ 0.68 (t, J=7.4 Hz, 3H), 0.88 (td, J=7.0, 2.4 Hz, 3H), 1.20-1.40 (m, 14H), 1.88 (tdd, J=7.0, 7.0, 1.1 Hz, - 2H), 2.92 (d, J= 2.4 Hz, lH), 3.0-3.40 (m, 2H), 3.90 (m, 2H), 5.28 (dt, J=~6.2, 7.0 Hz, lH), 6.15 (dt, J=16.2, 1.5 Hz, lH), 7.10-7.60 (m, 4H).
Step E: 2,6-Diisopropyl-3-hydroxymethyl-4-(2-ethynylphenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step D
WO ~8J~ 8 PCT/US97/13248 O by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3)(reported as a mixture of olefin isomers): ~ 0.81 (t, J= 7.4 Hz, 3H), 1.0-1.40 (m, 15H), 1.75 (m, 2H), 2.98 (d, J= 3.3 Hz, lH), 3.20-3.60 (m, 2H), 4.20-4.50 (m, 2H), 5.40 (m, lH), 6.0 (m, lH), 7.0-7.60 (m, 4H). Rf=0.23 (10% ethyl acetate/n-hexane).
HO ~/~' y~ N ~/
2,6-DiisopropyI-3-hydroxymethyl-4-(2-ethenylphenyl)-5-pentylpyridine 1 0 The title compound was prepared from ethyl 2,6-diisopropyl-3-hydroxymethyl-4-(2-ethynylphenyl)-5-(pent-1-enyl)pyridine-3-carboxylate by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDC13) (reported as a mixture of olefin isomers): ~ 0.60-0.90 (m, 3H), 1.0-1.40 (m, 15H), 1.60-1.90 (m, 2H), 3.20-3.50 (m, 2H), 4.20-4.40 (m, 2H), 5.14 (dt, J= 11.0, 1.0 Hz, lH), 5.40 (m, lH), 5.90 (m, lH), 6.30 (m, lH), 7.0-7.70 (m, 4H). FAB-MS: calculated for C2sH33NO
363.5; found 364 (M+H, 100%). Rf 0.28 (10% ethyl acetate/n-hexane).
~F
HO~
~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(3~4-difluorophenyl)-5-(pent-l-enyl)pyridine Step A: Ethyl 2,6-diisopropyl-~(3,4-difluorophenyl)-5-(pent-l-enyl)pyridine 3-carboxvlate 0 Prepared from 3,4-difluorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 1, Steps A-E. lH NMR (300 MHz, CDCl3) (reported as a 8:1 mixture of olefin isomers): ~ 0.78 (m, 3H), 1.03 (m, 3H), 1.18-1.33 (m, 14H), 1.97 (m, 2H), 3.04 (m, lH), 3.38 (m, lH), 4.04 (m, 2H), 5.30-5.45 (m, lH), 6.02 (m, lH), 6.89-7.17 (m, 3H).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(3,4-difluorophen~1)-5-(pent-1-enyl)pyridine The title compound was prepared ~rom the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDC13) (reported as a mixture of olefin isomers): ~ 0.75 (m, 3H), 1.05-1.38 (m, 14H), 1.90 (m, 2H), 3.35 (m, 2H), 4.35 (m, 2H), 5.25 (m, lH), 5.91 (m, lH), 6.80-7.20 (m, 4H). mp 105-106~C. Rf=0.30 (10% ethyl acetate/n-hexane).
~5 F
~F
HO ~~~' ~N~
2,6-Diiso~,ro,~ 1-3-h~droxymethyl-4-(3,4-difluorophenyl)-5-pentyl-pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3,4-difluorophenyl)-5-(pent-1-enyl)pyridine (Example 158) by the procedure described in Example 126. lH NMR (300 MHz, CDC13): ~ 0.81 (t, J=7.0 Hz, 3H), 1.12 (m, 4H), 1.30 (m, 14H), 2.27 (m, 2H), 3.24 (m, lH), 3.41 (m, lH), 4.32 (d, J=4.0 Hz, 2H), 6.95 (m, lH), 7.06 (m, lH), 7.25 (m, lH). mp 106-107~C. Rf 0.30 (10% ethyl acetate/n-hexane).
W O 98104528 PCTrUS97113248 o EXAMPLE 160 OCH2Ph HO ~--~N~
2r6-Diisopropyl-3-hydroxymeth~ 4-(4-benzyloxyphenyl)-5-(pent-l-enyl)pyridine Step A: Diethyl 1,4-dihydro-2,6-diisopropyl-4-(4-benzyloxyphenyl)-3,5-pvridinedicarboxylate To 4-benzyloxybenzaldehyde (24.3 g, 114 mmol) and ethyl isobutyryl acetate (37.8 g, 239 mmol) were added ethanol (50 mL), acetic acid (1 mL), and piperidine (1.7 mL). The mixture was stirred under an argon atmosphere at 25~C
for 12 hours . Freshly prepared sodium ethoxide in ethanol (15%, 15 mL) was thenadded and the reaction mixture was stirred at 25~C for 2 hours. To this mixture was added a solution of ammonium acetate (13.1 g, 171 mmol) in acetic acid (100 mL). The reaction was heated at reflux for 14 h and was then cooled to 25~C, during which time a white precipitate developed. To the mixture was added a 40%
(v/v) solution of 2-propanol in water. The mixture was stirred for 0.5 hours at 25~C and was then cooled to -20~C for 2 hours. The white solid was collected by filtration with vacuum and washed with a 50% (v/v) solution of isopropanol in water to provide the product (41.8 g, 85 mmol, 75%) as a pure white solid (mp 140-141~C). lH NMR (300 MHz, CDC13): ~ 1.14-1.29 (m, 18H), 4.10 (q, J = 6.9 Hz, 4H),4.19 (sept, J = 6.9 Hz, 2H), 4.95 (s, lH), 5.01 (s, 2H), 6.12 (s, lH), 6.82 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 7.27-7.45 (m, 5H).
Step B: Diethyl 2,6-diisopropyl-4-(4-benzyloxyphenyl)-3,5-pvridine-dicarboxylate To a solution of the intermediate obtained in Step A (39.72 g, 81 mmol) in acetone (400 mL) stirred under argon at 25~C was added an aqueous solution of ammonium cerium(IV) nitrate ("CAN") (lM, 162 mL). The mixture was stirred at 25~C for 0.5 hours and the acetone was then removed under reduced pressure.
The resultant mixture was diluted with dichloromethane (400 mL) and poured into WO ~810 I'2X PCT/US97/13248 0 water (100 mL). The organic layer was saved and the aqueous layer is extracted with dichloromethane (100 mL). The combined organic layer was washed with a saturated solution of sodium chloride (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the product as a white powder (39.51 g, 100%) (mp 87~C). 1H NMR (300 MHz, CDCl3): ~ 0.96 (t, J = 6.9 Hz, 6H), ~ 5 1.31 (d, J = 6.6 Hz, 12H), 3.10 (sept, J = 6.6 Hz, 2H), 4.01 (q, J = 7.5 Hz, 4H), 5.09 (s, 2H), 6.95 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 7.32-7.46 (m, 5H).
Step C: Ethyl 2,6-diisopropyl-4-(4-benzyloxyphenyl)-5-(pent-1-enyl)-3-pyridinecarboxylate Prepared from the intermediate obtained in Step B by the procedure described in Example 1, Steps D-F. lH NMR (300 MHz, CDC13): ~ 0.77 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 1.21-1.34 (m, 14H), 1.96 (q, J = 7.2 Hz, 2H), 3.05 (septet, J = 6.6 Hz, lH), 3.42 (septet, J = 6.6 Hz, lH), 3.94-4.03 (m, 2H), 5.06-5.12 (m, 2H), 5.32-5.42 (m, lH), 6.03-6.15 (m, lH), 6.94 (d, J = 9.0 Hz, 2H), 7.10 (d, J - 9.0 Hz, 2H), 7.34-7.47 (m, 5H).
Step D: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-benzyloxyphenyl)-5-(pent enyl)pyridine The intermediate obtained in Step C (6 g, 12.35 mmol) was dissolved in 20 anhydrous tetrahydrofuran ("THF") (130 mL) under argon and treated dropwise at room temperature with lithium aluminum hydride ("LAH")(1.0 M in THF, 24.7 mL, 24.7 mmol). The reaction mixture was stirred at reflux for 3 hr, cooled to room temperature and quenched by the addition of 0.9 mL H2O, 0.9 mL 20% aqueous NaOH, and 2.7 mL H2O. The resulting suspension was filtered through a cake of 25 Celite and the filtrate concentrated and purified by chromatography through silica (20% ethyl acetate/hexane) to afford 4.76 g of the title compound as a colorlesswax. lH NMR (300 MHz, CDCl3): ~ 0.73-0.83 (m, 3H), 1.37-1.70 (m, 14H), 1.56 (s, lH), 1.92 (dq, J = 0.90, 6.90 Hz, 2H), 3.41 (~, J = 6.60, 13.20, 24.60 Hz, 2H), 4.43 (d, J =
5.1 Hz, 2H), 5.10 (s, 2H), 5.27-5.37 (m, lH), 5.97 (d, J = 15.90 Hz, lH), 6.97-7.09 (m, 30 4H), 7.35-7.48 (m, 5H).
, WO98101'?X PCTAUS97113248 OH
~0~
~N~
2,6-Diisopropyl-3-hvdroxymethYl-4-(4-hydroxyphenyl)-5-pentylpyridine 2,6-Diisopropyl-3-hydroxymethyl-4-(4-benzyloxyphenyl)-5-(pent-1-enyl)pyridine (Example 160) (500 mg, 1.13 mmol) was dissolved in absolute ethanol (10 mL) under argon, treated with 10% palladium on carbon (15 mg), then stirred under a hydrogen atmosphere for 14 h. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the residue is purified by flash chromatography (5% methanol-methylene chloride) to yield 371 mg of the title compound as a waxy solid (mp 158.5 C). lH NMR (300 MHz, CDCl3): ~ 0.79 (t, J = 6.6 Hz, 3H), 1.06-1.36 (m, 21H), 2.24-2.31 (m, 2H), 3.22 (sept, J = 6.6 Hz, lH), 3.40 (sept, J = 6.6 Hz, lH), 4.36 (d, J =
5.4 Hz, 2H), 4.85 (s, lH), 6.89 (d, J = 8.4 Hz, lH), 7.05 (d, J = 8.7 Hz, lH).
~OCH2Ph HO ~ ~' ~ N ~/
2,6-Diisopropyl-3-hydroxymethyl-4-~2-benzyloxyphenyl)-5-(pent-l-enyl)pyridine The title compound was prepared as a waxy solid from 2-benzyl-oxybenzaldehyde by the procedures described in Example 160. 1H NMR (300 MHz, CDCl3): ~ 0.69-0.74 (m, 3H), 1.07-1.38 (m, 14H), 1.69-1.79 (m, lH) 1.84-1.99 (m, 2H), 3.26-3.54 (m, 2H) 4.28-4.46 (m, 2H), 4.90-5.09 (m, 2H), 5.26-5.47 (m, lH), 6.00 (dd, J = 15.9, 1.2 Hz, lH), 7.05-7.10 (m, 5H), 7.24-7.36 (m, 4H).
, . .. .
WO 98/04528 PCTrUS97113248 E~CAMPLE 163 ~ OH
HO ~--' ~N~
I
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(2-benzyloxyphenyl)-5-(pent-1-enyl)pyridine (Example 162) by the method ~let~
in Example 161. lH NMR (300 MHz, CDCl3): ~ 0.75-0.73 (m, 3H), 1.09-1.15 (m, 4H),1.30-1.37 (m, 14H), 1.70-1.73 (m, lH), 2.16-2.28 (m, lH), 2.32-2.42 (m, lH), 3.22-3.32 (m, lH), 3.39-3.51 (m, lH), 4.29-4.35 (m, lH), 4.48-4.54 (m, lH), 5.14 (br s, lH), 7.02-7.05 (m, 3H), 7.28-7.36 (m, lH). FAB-MS: calcd for (C23H33NO2) 355, found 356 (M+ 1). Anal. calc. for C23H33NO2: C, 77.70; H, 9.36; N, 3.94. Found: C, 77.63; H,9.12; N, 3.75. mp 125.5 C.
OH~OH
CH3 ~----~N~
2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(2-hvdroxyphenyl)-5-pentyl-pyridine - Step A: 2,6-Diisopropyl-(2-benzyloxyphenyl)-5-pentyl-3-pyridine-carboxaldehyde 2,6-Diisopropyl-3-hydroxymethyl-4-(2-benzyloxyphenyl)-5-(pent-1 -enyl)-pyridine (Example 162) (680 mg, 1.53 mmol) was dissolved in 15 mL of methylene chloride under an argon atrnosphere and treated with a mixture of Celite (661 mg) and pyridinium chlorochromate ("PCC") (661 mg, 2 eq). The reaction was stirred at O room temperature for 1.5 h. The suspension was filtered through a pad of silica and the pad was washed with 50 mL CH2C12 and the filtrate was combined and concentrated in vacuo to afford 572.4 mg of product (84%). lH NMR (300 MHz, CDCl3): ~ 0.70 (t, J = 7.2 Hz, 3H), 1.08-1.35 (m, 15H), 1.85-1.93 (m, lH), 3.26-3.45 (m, lH), 3.87-3.97 (m, lH), 4.97-5.06 (m, 2H), 5.27-5.50 (m, lH), 6.01-6.10 (m, lH), 6.94-7.34 (m, 9H), 9.82 (d, J = 3.6 Hz, lH).
Step B: 2,6-Diisopropyl-3-(l-hydroxyethyl)~-(2-ben2ylox~phenyl)-5-(pent enyl)pyridine Prepared as a separable mixture of two diastereomers from the intermediate 1 0 from Step A by the method ~t~ in Example 101, Step B. The two diastereomers were separated by flash chromatography on silica eluting with 10%
ethyl acetate-hexane.
Diastereomer 1: colorless oil, 1H NMR (300 MHz, CDC13): ~ 0.68-1.91 (m, 23H), 3.19-3.40 (m, lH), 3.77 (sept, J = 6.6 Hz, lH), 4.69-4.79 (m, lH), 4.94 (dd, J =
12.3, 3.9 Hz, lH), 5.05 (d, J = 12.3 Hz, lH), 5.20-5.43 (m, lH), 5.90-6.05 (m, lH), 6.94-7.~ (m, 9H). FAB-MS: calcd for (C31H3gNO2) 457, found 458 (M + 1).
Diastereomer 2: colorless oil, lH NMR (300 MHz, CDCl3): ~ 0.69 (t, J = 7.2 Hz, 3H), 1.05-1.40 (m, 17H), 1.67-1.73 (m, lH), 1.80-1.88 (m, 2H), 3.18-3.41 (m, lH), 3.68-3.80 (m, lH), 4.84-5.08 (m, 3H), 5.25-5.42 (m, lH), 5.86-6.08 (m, lH), 6.90-7.38 (m, 9H). FAB-MS: calcd for (C31H3gNO2) 457, found 458 (M + 1).
Step C: 2,6-Diisoprop~1l-3-(l-hydroxyeth~1)-4-(2-hydroxyphenyl)-5 p~l~lyl~y~;dine The diastereomeric mixture of intermediates from Step B (39 mg) was dissolved in absolute ethanol (1.5 mL) under argon, treated with 10% pa~ladium on carbon (4 mg), then stirred under a hydrogen atmosphere for 8 hr. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the product dried in vacuo to afford 32 mg of the title compound as a colorless solid. Preparative thin layer chromatography ("prep TLC") using a 20% ethyl acetate-hexane mixture as the eluent provided thetwo diastereomers.
Diastereomer 1 (D1) (11.2 mg): 1H NMR (300 MHz, CDCl3): ~ 0.68 (t, J =
7.30 Hz, 3H), 0.99-1.03 (m, 4H), 1.19-1.34 (m, 17H), 1.62 (d, ~ = 3.60 Hz, lH), 1.97-2.07 (m, lH), 2.16-2.26 (m, lH), 3.14 (septet, J = 7.30 Hz, lH), 3.67 (septet, J = 7.30 Hz, lH), 4.72 (br s, lH), 4.83 (dq, J = 4.20, 6.60 Hz, lH), 6.89-6.97 (m, 3H), 7.19-7.25 (m, lH). FAB-MS: calcd for (C24H3sNO2) 369, found 370 (M + 1).
~, .
WO 9XJ'~ 1528 PCT/US97tl3248 O Diastereomer 1 (D1) could be resolved into the constituent enantiomers as follows. A Waters Prep LC 2000 HPLC system was equipped with a chiral HPLC
column (BRB-9668A; 6 x 50 cm ID). The system was equilibrated with a mobile phase consisting of 2% (1% acetic acid, 99% ethanol) and 98% hexane at a flow rate - of 175 mL/min. The sample was dissolved in mobile phase (20 mg/mL) and 5 mL
aliquots were injected at 30 minute intervals. The effluent was monitored at 280nm and two fractions (corresponding to the enantiomers) were cc-llPcte-l at (15-17 m~n, 100% ee) and (19-26 min, >99% ee), respectively.
Diastereomer 2 (D2) (11.8 mg): 1H NMR (300 MHz, CDCl3): ~ 0.68 (t, J =
6.60 Hz, 3H), 0.99-1.03 (m, 4H), 1.16-1.32 (m, 17H), 1.86 (br s, lH), 2.00-2.10 (m, lH), 2.19-2.29 (m, lH), 3.14 (septet, J = 6.60 Hz, lH), 3.67 (septet, J = 6.60 Hz, lH), 4.57 (q, J = 6.60 Hz, lH), 4.76 (br s, lH), 6.84-6.93 (m, 3H), 7.19-7.24 (m, lH). FAB-MS: calcd for (C24H35N02) 369, found 370 (M+1).
OH~OH
CH
~N~
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-~ro,uyl~yridine Step A: Diethyl-2,6-diisopropyl4-(2-benzyloxyphenyl)-3,5-pyridine-dicarboxylate Prepared from 2-benzyloxybenzaldehyde by the methods detailed in Example 160, Steps A-B. 1H NMR (300 MHz, CDCl3): ~ 0.87 (t, J = 6.9 Hz, 6H), 1.32 (d, J = 6.6 Hz, 6H), 1.33 (d, J = 6.6 Hz, 6H), 3.19 (sept, J = 6.6 Hz, 2H), 3.97 (q, J = 7.2 Hz, 4H), 5.01 (s, 2H), 6.88 (d, J = 8.1 Hz, lH), 6.94 (dt, J = 7.2, 0.6 Hz, lH), 7.16 (dd, J
= 7.8, 1.8 Hz, lH), 7.14-7.30 (m, 6H).
Step B: 5-Ethoxycarbonyl-2,6-diisopropyl-4-~2-benzyloxyphenyl)-3-pyridinecarboxaldehyde - 30 Prep~red from the intermediate from Step A by the methods ~1et~ile~ in Example 1, Steps D-E. lH NMR (300 MHz, CDCl3): ~ 0.91 (t, J = 6.6 Hz, 3H), 1.30-W 098104528 PCTrUS97/13248 0 1.39 (m, 12H), 3.18 (septet, J = 6.0 Hz, lH), 3.91-4.03 (m, 3H), 5.04 (dd, J = 6.6, 12.6 Hz, 2H), 6.96-7.05 (m, 2H), 7.17-7.28 (m, 6H), 7.34-7.40 (m, lH).
Step C: 2,6-Diisopropyl-4-(2-benzvloxyphenvl)-3~thoxycarbonyl-5-(pr enyl)pyridine S Ethyltriphenylphosphonium bromide (4.01 g, 10.8 mmol) was suspended inanhydrous THF (130 mL) under argon and stirred at -78~C. A 1.6 M solution of n-butyllithium in hexanes (6.75 mL, 10.8 mmol) was added dropwise. The reaction mixture was allowed to come to 0~C and stirred at that temperature for 1 hr. Theresulting brightly colored solution was cooled again to -78~C and treated dropwise with a solution of the intermediate obtained in Step B (4.0 g, 9.0 mmol) in THF (20 mL). The reaction mixture was allowed to stir at 25~C for 3 hrs, then quenched by the addition of water (5 mL). The THF was removed in vacuo, the residue partitioned between ethyl ether (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over MgS04 and concentrated. Flash chromatography through silica (5% ethyl acetate/hex) afforded 4.1 g of the product (E, Z mixture) as a viscous oil. 1H NMR (300 MHz, CDCl3): ~ 0.86-0.92 (m, 3H), 1.40-1.21 (m,15H), 3.06-3.28 (m, 2H), 3.91-4.01 (m, 2H), 5.00 (br s, 2H), 5.29-5.56 (m, lH), 6.10-6.19 (m, lH), 6.89-6.97 (m, 2H), 7.08-7.12 (m, lH), 7.15-7.19 (m, 2H), 7.22-7.29 (m, 4H).
Step D: 2,6-Diisopropvl-3-hydroxymethyl-4-(2-benzyloxyphenyl)-5-tpr enyl)pyridine Prepared from the intermediate from Step C by the method detailed in Example 160, Step D. lH NMR (300 MHz, CDCl3): ~ 1.21-1.60 (m, 15H), 1.90-1.95 (m, lH), 3.18-3.53 (m,2H), 4.26-4.58 (M, 2H), 4.87-4.94 (m, lH), 5.06 (d, J = 12.3 Hz, lH), 5.27-5.57 (m, lH), 5.95-6.05 (m, lH), 7.00-7.06 (m, 5H), 7.22-7.37 (m, 4H).
Step E: 2,6-Diiso~o~yl-3-(1-hydrox~eth~ 4-(2-hydroxyphen~,rl)-5-propylpyridine The intermediate from Step D was converted into the title compound by the methods detailed in Example 164, Steps A-C. The diastereomers were separated by radial band chromatography using a gradient eluent of 100% hexane to 5% ethyl acetate-hexane.
Diastereomer 1 (D1): lH NMR (300 MHz, CDCl3): ~ 0.66 (t, J = 7.50 Hz, 3H), 1.15-1.34 (m, 15H), 1.59 (br s, lH), 1.96-2.06 (m, lH), 2.15-2.25 (m, lH), 3.15 (sept, J =
6.60 Hz, lH), 3.56 (sept, J = 6.60 Hz, lH), 4.70 (br s, lH), 4.81-4.87 (m, lH), 6.90-6.97 (m, 3H), 7.19-7.26 (m, lH). FAB-MS: calcd for (C22H31NO2) 34~, found 342 (M+1).
WO 981'~ ''it~ PCT/US97/13248 0 Diastereomer 1 (D1) was resolved into its constituent enantiomers as follows. A Waters Prep LC 2000 HPLC system was equipped with a chiral HPLC
column (BRB-9466AD; 6 x 50 cm ID). The system was equilibrated with a mobile phase consisting of 25% hexane and 75% of a mixture of (15% THF in heptane) at 150 mL/min. The sample was dissolved in mobile phase (10 mg/mL) and 5 mL
~ 5 aliquots were injected at 35 min intervals. The effluent was monitored at 280 nm.
Peaks overlapped and were thus shaved. Mixed fractions were then evaporated and rein~ected. The collected enantiomers were assayed off line on an analytical- column (BRB-9705A) at 1.5 mL/min with a mobile phase of 1% (1% acetic acid in ethanol) and 99% hexane. The low Rt enantiomer from the preparative column was the high Rt enantiomer on the analytical column with Rt = 8.80 min; 98.8% ee.
The high Rt enantiomer from the preparative column was the low Rt enantiomer on the analytical column with Rt = 3.71 min; 81% ee.
Diastereomer 2 (D2): 1H NMR (300 MHz, CDCl3): ~ 0.72 (t, J = 7.50 Hz, 3H), 1.22-1.36 (m, 15H), 2.03-2.15 (m, lH), 2.23-2.33 (m, lH), 2.56 (d, J = 3.0 Hz, lH), 3.21 lS (septet, J = 6.60 Hz, lH), 3.73 (septet, J = 6.60 Hz, lH), 4.56-4.63 (dq, J = 3.0, 6.0 Hz, lH), 5.66 (br s, lH), 6.88-6.99 (m, 3H), 7.25-7.28 (m, lH). FAB-MS: calcd for (C22H31NO2) 341, found 342 (M+1).
E~CAMPLE 166 F
~OH
HO ~~
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-~(4-fluoro-2-hydroxy)phenyll-5-pent~lpyridine 25 Step A: 2-Benzyloxy-4-fluorobromobenzene To a solution containing 2-bromo-5-fluorophenol (50 g, 0.26 mol) in 500 mL
acetone was added potassium carbonate (54.2 g, 0.39 mmol) and benzyl bromide (34.3 mL, 0.288 mol). The reaction was heated at reflux under an argon atmosphere for 2 h and then allowed to cool to 25 C. The acetone was removed under reduced 30 pressure and the residue was taken up in ether (400 mL). The organic layer was W098/04528 PCT~US97/13248 0 washed with water (5 x 100 mL) and brine (1 x 100 mL) and then dried (MgSO4).
The solution was then concentrated under reduced pressure and subjected to flashchromatography using hexane as the eluent. In this manner, 2-benzyloxy-4-fluorobenzene was obtained as a white solid. lH NMR (300 MHz, CDCl3): ~ 5.14 (s, 2H), 6.57-6.63 (m, lH), 6.69 (dd, J = 2.7, 10.2 Hz, lH), 7.32-7.52 (m, 6H).
s Step B: 2-Benzyloxy-4-fluorobenzaldehyde To a slurry of magnesium (9.52 g, 0.39 mol) in THF (25 mL) in a 1 L round bottom flask fitted with a condenser was added the intermediate obtained in Step A
(1 g). A vigorous reflux commenced at once. To this refluxing mixture was added a solution of the intermediate from Step A (109 g) at a rate which maintained reflux.
After completion of addition the reaction was allowed to proceed until it cooled to 25 C and was then heated at reflux for 1 h. The reaction was allowed to cool to 25 C and DMF (48 mL) was then added portionwise. The reaction was allowed to cool to 25 C and was then filtered through a plug of Celite. The THF was removed1 5 under reduced pressure and the residue was dissolved in ethyl acetate (500 mL) and washed sequentially with water (100 mL), 10% HCl (100 mL), saturated sodium bicarbonate solution (100 mL), and brine (100 mL). The organic layer was dried (Na2S04) and concentrated under reduced pressure. The resultant residue was purified by flash chromatography (10% ethyl acetate-hexane) to provide 77.3 g of2-benzyloxy-4-fluorobenzaldehyde. lH NMR (300 MHz, CDCl3): ~ 5.16 (s, 2H), 6.70-6.76 (m, 2H), 7.34-7.44 (m, 5H), 7.87-7.92 (m, lH), 10.43 (s, lH). FAB-MS: calcd for (C14H11O2F) 230; found 231 (M+1).
Step C: 2,6-Diisopropyl-3-hydroxymethyl-4-~(2-benzyloxy-4-fluoro)phenyll-5-(pent-l-enyl)pyridine Prepeared from the intermediate obtained in Step B by the methods described in Example 160, Steps A-D. lH NMR (300 MHz, CDCl3): ~ 0.73 (t, J = 7.4 Hz, 3H), 1.09-1.36 (m, 14H), 1.63-1.73 (m, 2H), 1.89 (q, J = 6.9 Hz, lH), 3.25 (septet, J
= 6.6 Hz, lH), 3.46 (d septet, J = 2.7, 6.6 Hz, lH), 4.29-4.42 (m, 2H), 4.89-5.06 (m, 2H), 5.24-5.47 (m, lH), 5.95-6.00 (m, lH), 6.70-6.79 (m, 3H), 7.00-7.07 (m, 5H). FAB-MS:
calcd for (C30H36No2F) 461, found 462.
Step D: 2,6-Diisopropyl-3-(hydroxymethyl)-4-~(4-fluoro-2-hYdroxY)Phenyll-5-p~ yll~ylidine The title compound was prepared as a racemate from the intermediate obtained in Step C by the method ~l~tAile~l in ExAmple 161. lH NMR (300 MHz, , ~ . . ......
W 098/04528 PCTrUS97113248 O CDCl3): ~ 0.78 (t, J = 6.6 H~, 3H), 1.09-1.35 (m, 18H), 1.65 (t, J = 5.0 Hz, lH), 2.13-2.23 (m, lH), 2.28-2.38 (m, lH), 3.24 (sept, J = 6.6 Hz, lH), 3.39 (sept, J = 6.6 Hz, lH), 4.29 (dd, J = 11.1, 5.0 Hz, lH), 4.52 (dd, J = 11.1, 5.1 Hz, lH), 5.45 (bs, lH), 6.71-6.78 (m, 2H), 6.95-7.00 (m, lH). FAB-MS: calcd for (C23H32NO2F) 373, found 374 (M +
1). Rf =0.15 (20%ether-hexanes). mp 152 C.
OH~ OH
CH3 ~/~
~N ~/
2,6-Diisopropvl-3-(l-hydroxyethYl)-4-~(4-fluoro-2-hYdroxY)phenyll-5 pentylpyridine The title compound was prepared as two separable diastereomers from 2,6-diisopropyl-3-hydroxymethyl-4-[(2-benzyloxy-4-fluoro)phenyl]-5-(pent-1-enyl)pyridine (Example 166, Step C) by the methods detailed in Example 164, Steps A-C. The diastereomers were separated by radial band chromatography using a gradient eluent of 100% hexane to 20% ether-hexane.
Diastereomer 1 (D1): 1H NMR (300 MHz, CDCl3): ~ 0.80 (t, J = 6.6 Hz, 3H), 1.10-1.42 (m, 21H), 1.64 (d, ~ = 3.6 Hz, lH), 2.03-2.13 (m, lH), 2.21-2.31 (m, lH), 3.15-3.26 (septet, lH), 3.54-3.65 (septet, lH), 4.89-4.98 (m, lH), 4.99 (br s, lH), 6.69-6.75 (m, 2H), 6.94-6.99 (~, J = 2.7, 6.5, 6.5 Hz, lH). FAB-MS: calcd for (C24H34NO2F) 387, found 388 (M + 1). Rf = 0.41 (40% ether-hexanes). mp 124-126 C.
Diastereomer 1 (D1) was resolved into its constituent enantiomers as follows. A Waters Prep LC 2000 HPLC system was equipped with a chiral HPLC
column (BRB-9668A; 6 x 50 cm ID). The system was equilibrated with a mobile phase consisting of 2% (1% acetic acid, 99% ethanol) and 98% hexane at a flow rate of 175 mL/min. The sample was dissolved in mobile phase (50 mg/mL) and 5 mL
aliquots were injected at 30 min intervals. The effluent was monitored at 280 nmand two fractions (corresponding to the two enantiomers) were collected at (13-18 min,100% ee) and (18.5-27 min, >99%ee), respectively.
W O 98/04528 PCTrUS97113248 O Diastereomer 2 (D2): lH NMR (300 MHz, CDC13): ~ 0.78 (t, J = 6.5 Hz, 3H), 1.06-1.40 (m, 21H), 1.75 (d, J = 3.6 Hz, lH), 2.06-2.16 (m, lH), 2.26-2.37 (m, lH), 3.21 (septet, J = 6.6 Hz, lH), 3.74 (septet, J = 6.6, lH), 4.59-4.67 m, lH), 4.83 (br s, lH), 6.68-6.75 (m, 2H), 6.86-6.91 (~, J = 3.0, 6.6, 6.6 Hz, lH); FAB-MS: calcd for (C24H34NO2F) 387, found 388 (M + 1). Rf = 0.24 (40% ether-hexanes). mp 157-159~C.
HO ~--' \f~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methoxyphenyl)-5-(pent-l-enyl)pyridine The title compound was prepared from 4-methoxybenzaldehyde by the methods detailed in Example 125. lH NMR (300 MHz, CDCl3): ~ 0.76 and 0.81 (t, J
= 7.2 Hz, 3H), 1.12-1.39 (m, 14H), 1.60-1.80 (bs, lH), 1.86-1.97 (m, 2H), 3.33-3.50 (m, 2H), 3.85 (s, 3H), 4.43 (m, 2H), 5.27-5.48 (m, lH), 5.93-6.05 (m, lH), 6.92 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H). FAB-MS: calcd for (C24H33NO2) 367, found 368 (M+1).
HO ~~ ~~"
~ N~/
2,6-Diisopropyl-3-hydroxymethyl~-(4-methoxyphenyl)-5-pentyl-pyridine W O 98/04528 PCT~US97~13248 0 The title compound was prepared as a white solid from 2,~diisopropyl-3-hydroxymethyl-4-(4-methoxyphenyl)-5-(pent-1-enyl)pyridine (Example 168) by the methods detailed in Example 126. lH NMR (300 MHz, CDC13): ~ 0.80 (t, J = 6.6 Hz,3H), 1.08-1.19 (m, 4H), 1.24-1.38 (m, 15H), 2.27-2.33 (m, 2H), 3.24 (sept, J = 6.6 Hz, lH), 3.42 (sept, J = 6.6 Hz, lH), 3.87 (s, 3H), 4.35 (d, J = 5.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 8.7Hz, 2H). FAB-MS: calcd for (C24H3sNO2) 369, found 370 (M + 1). mp 47-49~C.
~,OCH3 HO ~~"
\~ N~
2,6-Diisopropyl-3-hydroxymethyl-4-(3-methoxyphenyl)-5-(pent-l-enyl)pyridine The title compound was prepared from 3-methoxybenzaldehyde by the methods detailed in Example 125. 1H NMR (300 MHz, CDCl3): ~ 0.78 (t, J = 7.5 Hz, 3H), 1.17-1.41 (m, 14H), 1.65 (s, lH), 1.97 (~, J = 14.0, 7.2, 1.5 Hz, 2H), 3.39-3.55 (m, 2H), 3.81 (s, 3H), 4.45 (s, 2H), 5.35-5.50 (m, lH), 6.01-6.09 (m, lH), 6.73-6.77 (m, 2H), 6.89 (~, J = 8.1, 2.1, 0.9 Hz, lH), 7.30 (t, J = 8.0 Hz, lH). FAB-MS: calcd for (C24H33NO2) 367, found 368 (M + 1). mp 71-75 C.
~,OCH3 HO ~~ ~~~
\~ N ~/
~ 2,6-Diisoprop~1-3-hydroxymethyl-4-(3-methoxyphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-WO ~8101~28 PCTrUS97113248 0 (3-methoxyphenyl)-5-(pent-1-enyl)pyridine (Example 170) by the methods detailed in Example 126. lH NMR (300 MlIz, CDC13): ~ 0.79 (t, J = 6.6 Hz, 3H), 1.09-1.33 (m, 7H), 1.30 (d, J = 6.6 Hz, 6H), 1.33 (d, J = 6.6 Hz, 6H), 2.25-2.31 (m, 2H), 3.23 (sept, J =
6.6 Hz, lH), 3.42 (sept, J = 6.6 Hz, lH), 3.82 (s, 3H), 4.35 (d, J = 6.0 Hz, 2H), 6.73 (dd, J = 2.4, 1.5 Hz, lH), 6.76 (dt, J = 7.5, 1.4 Hz), 6.93 (~, J = 8.4, 3.6, 1.2 Hz, lH), 7.34 (t, J
= 8.1 Hz, lH). FAB-MS: calcd for (C24H3sNO2) 369, found 370 (M + 1). mp 65-66 .
~ OCH3 HO ~~/
~N~/
2,6-Diisopropyl-3-hydroxymeth~1-4-(2-methoxyphenyl)-5-(pent-1-enyl)pyridine The title compound was prepared from 2-methoxybenzaldehyde by the methods detailed in Example 125. ~H NMR (300 MHz, CDCl3): ~ 0.82 and 0.72 (t, J
= 7 Hz, 3H), 1.05-1.47 (m, 15H), 1.80-2.00 (m, lH), 2.05 (~s, lH), 3.21-3.60 (m, 2H), 3.75 and 3.76 (s, 3H), 4.27 (d, J = 11.4 Hz, lH), 4.43 (d, J = 11.4 Hz, lH), 5.25-5.44 (m, lH), 6.01-6.07 (m, lH), 6.93-7.03 (m, 3H), 7.29-7.37 (m, lH).
~ OCH3 HO~
\~ N
2,6-Diisopropyl-3-hydroxymethyl-4-(2-methox-lphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(2-methoxyphenyl)-5-(pent-1-enyl)pyridine (Example 172) by the methods detailed in Example 126. lH NMR (300 MHz, CDC13): ~ 0.77 (t, J - 6.6 Hz, 3H), 1.06-1.11 (m, 4H), 1.22-1.38 (m, 14H), 1.87 (dd, J = 9.3, 3.3 Hz, lH), 2.14 -2.40 (m, 2H), 3.25 (sept, J
2~2 0 = 6.6 Hz, lH), 3.46 (sept, J = 6.6 Hz, lH), 3.76 (s, 3H), 4.19 (dd, J = 11.7, 3.0 Hz, lH), 4.39 (dd, J = 11.7, 9.0 Hz), 7.00-7.08 (m, 3H), 7.35-7.42 (m, lH).
HO ~/
~N~/
s 2,6-Diisopropyl-3-hydroxymethyl-4-~4-(methylthio)phenyll-5-(pent-l -enyl~pyridine The title compound was prepared as a thick colorless oil from 4-(methylthio)benzaldehyde by the methods detailed in Example 125. lH NMR (300 MHz, CDCl3): ~ 0.66 and 0.72 (t, J = 7.5 Hz, 3H), 1.05-1.32 (m, 14H), 1.51-1.70 (bs, lH), 1.80-1.89 (m, 2H), 2.43 (s, 3H), 3.12-3.41 (m, 2H), 4.32 (bs, 2H), 5.17-5.40 (m, lH), 5.85-5.97 (m, lH), 6.99 (d, J = 8.1 Hz), 7.18 (d, J = 8.1 Hz, 2H).
~Ol)CH3 HO~
\f N~/
2,6-Diisopropyl-3-hydrox~meth~1-4-~4-(methylsulfinyl)phenyll-5-(pent-1-enyl)p~,rridine 2,6-Diisopropyl-3-hydroxymethyl-4-[4-(methylthio)phenyl]-5-(pent-1-enyl)pyridine (100 mg, 0.261 mmol) (Example 174) was dissolved in methylene chloride (1.5 mL) and stirred at 0 C under an argon atmosphere. To this mixture was added a solution containing 3-chloroperoxybenzoic acid ("mCPBA") (85%, 53 mg, 0.261 mmol) in methylene chloride (1 mL). The mixture was stirred for 1.5 h at O C and ~ quenched with the addition of a saturated aqueous solution of NaHSO3 WO g8/04528 PCTrUS97/13248 0 (3 mL). The reaction mixture was further diluted through the addition of water (5 mL) and then extracted with methylene chloride (3 x 10 mL). The combined organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to S yield the title compound (52 mg, 50%) as a white solid, mp 133-135 C. ~H NMR
(300 MHz, CDCl3): ~ 0.77 and 0.69 (t, J = 7.5 Hz, 3H), 1.08-1.36 (m, 14H), 1.70-1.92 (m, 3H), 2.75 and 2.76 (s, 3H), 3.19-3.51 (m, 2H), 4.32-4.40 (m, 2H), 5.20-5.45 (m, lH), 5.93-6.00 (m, lH), 7.31-7.38 (m, 2H), 7.59-7.70 (m, 2H). Anal. calc. for C24H33NO2S:
C, 71.86; H, 8.29; N, 3.39; S, 7.73. Found: C, 72.14; H, 8.32; N, 3.51; S, 8.02.
so2CH3 HO~
~ N~/
2,6-Diisopropyl-3-h~droxymethyl-4-l4-~methylsulfonyl)phenyll-5-(pent-l -en~,rl)p~,rridine 2,6-Diisopropyl-3-hydroxymethyl-4-[4-(methylsulfinyl)phenyl]-5-(pent-1 -enyl)pyridine (100 mg, 0.261 mmol) (Example 174) was dissolved in methylene 20 chloride (1.5 mL) and stirred at 0 C under an argon atmosphere. To this mixture was added a solution containing 3-chloroperoxybenzoic acid ("mCPBA") (85%, 53 mg, 0.261 mmol) in methylene chloride (1 mL). The mixture was stirred for 1.5 h at 0 C and quenched with the addition of a saturated aqueous solution of NaHSO3 (3 mL). The reaction mixture was further diluted through the addition of water (5 25 mL) and is then extracted with methylene chloride (3 x 10 mL). The combined organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to yield the title compound (31.1 mg, 29%). 1H NMR (300 MHz, CDCl3): ~ 0.69 and 0.79 (t, J = 7.2 Hz, 3H), 1.08-1.37 (m, 14H), 1.45 (t, J = 4.2 Hz, lH), 1.86-1.93 (m, 2H), W 098/04~28 PCTAUS97/1~248 0 3.10 and 3.11 (s, 3H), 3.25-3.50 (m, 2H), 4.34-4.36 (m, 2H), 5.20-5.50 (m, lH), 5.93-6.00 (m, lH), 7.41 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H). Anal. calc. for - C24H33NO3S: C, 69.28; H, 7.91; N, 3.18; S, 7.50. Found: C, 69.36; H, 8.00; N, 3.37; S, 7.71.
S
F
~,CH20H
HO~
\~N~
2,6-Diisopropyl-3-hydroxymethYl-4- 1 (4-fluoro-3-hydroxymethyl)phenyll-5-pentylpyridine Step A: 2,6-Diisopropyl-3-~(t-butyldimethylsiloxy)methyll-4-(4-fluorophenyl) 5-pentylpyridine To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (3.14 g, 8.78 mmol) (Example 1, Step H) in methylene chloride (45mL) were added imidazole (0.9 g, 13.17 mmol, 1.5 eq) and f-butyl-dimethylsilyl chloride (2.0 g, 13.17 mmol, 1.5 eq). A white precipitate began to form immediately. The mixture was stirred for 14 h at 25~C and was then diluted with methylene chloride (100 mL) and washed sequentially with 10% hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), and brine (20 mL). The organic layer was concentrated under reduced pressure and the resultant residue was recryst~lli7e~1 from methanol to provide the product (3.27 g, 79%) as a white fluffy crystalline solid. lH NMR (300 MHz, CDCl3): S -0.10 (s, 6H), 0.79 (t, J = 6.9 Hz, 3H), 0.83 (s, 9H), 1.07-1.20 (m, 4H), 1.29-1.32 (m, 14H), 2.23-2.30 (m, 2H), 3.21 (sept, J = 6.6 Hz, lH), 3.35 (sept, J = 6.6 Hz, lH), 4.24 (s, 2H), 7.05-7.18 (m, 4H).
Anal. calc. for C2gH46NOFSi: C, 73.83; H, 9.83; N, 2.97. Found: C, 73.82; H, 9.95; N, 2.86.
Step B: 2,6-Diiso~lo~yl-3-~(t-bu'n~ldimethylsiloxy)methyll-4-~(4-fluoro-3-hydroxymethyl)phenyll-5-p~lllyl~ylidine To a solution of the intermediate from Step A (5.4 g, 11.4 mmol) in THF (80 W 098/04528 PCTrUS97113248 0 mL) was added sec-butyllithium (1.3 M, 26.4 mL, 3 eq) at -78~C under an argon atmosphere. ~he yellow solution was stirred for 1 h at -78~C and ~uenched through the ~ ition of of water (50 mL). The mixture was allowed to warm to 25~C and extracted with ethyl acetate (3 x 50 mL) and the organic layer was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the crude intermediate. (6.41 g).
This intermediate (3.2 g) was dissolved in THF (50 mL) and stirred at 0~C as lithium aluminum hydride ("LAH") (lM in THF, 25.7 mL, 25.7 mmol) was added to it. The resultant mixture was stirred at 0~C for 1.5 h and quenched through the sequential addition of water (1 mL), lN aqueous sodium hydroxide (1 mL), and water (3 mL). The resultant mixture was filtered and the precipitate rinsed withether (100 mL). The combined organic layer was washed with water (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was subjected to flash chromatography using a 10% ether-hexanemixture as the eluent. In this manner, 1.1 g of the product was obtained. lH NMR(300 MHz, CDCl3): ~ -0.09 (s, 6H), 0.83 (s, 9H), 1.07-1.20 (m, 4H), 1.29-1.33 (m, 17H), 1.96-2.02 (m, lH), 2.22-2.31 (m, 2H), 3.23 (sept, J = 6.6 Hz, lH), 3.36 (sept, J = 6.6 Hz, lH), 4.22-4.32 (m, 2H), 4.70-4.90 (m, 2H), 7.09-7.12 (m, 2H), 7.23-7.28 (m, lH).
Step C: 2,6-Diisopropyl-3-h~droxymethyl-4-~(4-~uoro-3-hydroxy-methyl)phenyll-5-pentylpyridine To a solution of the intermediate from Step B (123 mg, 0.245 mmol) in THF
(3 mL) was added tetrabutylammonim fluoride (lM in THF, 0.7 mL, 0.7 mmol) at 25~C under an argon atmosphere. The mixture was stirred for 14 h at 25~C and then diluted with water (5 mL) and extracted with methylene chloride (3 x 5 mL).The combined organic layer was washed with brine (5 mL), dried (Na2S04) and concentrated under reduced pressure. The resultant residue was purified by flashchromatography using a 40% ethyl acetate-hexane mixture as the eluent. In this manner, the title compound (79 mg, 83%) was produced as a colorless oil. lH NMR
(300 MHz, CDCl3): ~ 0.78 (t, J = 6.6 Hz, 3H), 1.10-1.17 (m, 4H), 1.24-1.35 (m, 14H), Z.10-2.40 (m, 2H), 2.73 (bs, lH), 3.22 (sept J = 6.6 Hz, lH), 3.34 (sept, J = 6.6 Hz, lH), 3.85 (bs, lH), 4.06 (d,J = 11.4 Hz, lH), 4.35 (d, J = 11.4 Hz, lH), 4.4~ (d, J = 14.1 Hz, lH), 4.73 (d, J = 14.1 Hz, lH), 7.00-7.06 (m, 2H), 7.25 (d, J = 7.2 Hz, lH).
WO 98/04528 PCT~US97113248 ,J~CO2CH3 HO~
~N~
2,6-Diisopropyl-3-hYdroxymethYl-4-l (4-fluoro-3-methoxycarbonyl~-phenyll-5-5 pentylpyridine ~A: 2,6-Diisopropyl-3-~(t-butyldimethylsiloxy)methyll-4-~(4-fluoro-3-formyl)phenyll -5-pentylpyridine To a solution of 2,6-diisopropyl-3-[(t-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-hydroxymethyl)phenyl]-5-pentylpyridine (Example 177, Step B) (1.09 g, 2.18 mmol) in methylene chloride (100 mL) was added a mixture of PCC (0.94 g, 4.35 mmol, 2 eq) and Celite (0.94 g). The resultant mixture was stirred for 2 h at 25 C and then filtered through a pad of silica gel. The silica gel pad was rinsed with a 10% ethyl acetate-hexane mixture (200 mL) and the combined organic layer was 15 concentrated to afford the crude product (0.78 g) as a white waxy solid.
Step B: 2,6-Diisopropyl-3-~(t-butyldimethylsiloxy)methyll-4-~(4-fluoro-3 methoxycarbonyl)phenyll -5-pentylpyridine To a solution of the intermediate from Step A (82 mg, 0.164 mmol) in 20 methanol (3 mL) were added potassium cyanide (53 mg, 0.82 mmol) and activatedmanganese dioxide (71 mg, 5 eq). The mixture was stirred at 25~C for 14 h and then filtered through a pad of Celite. The Celite pad was rinsed with ethyl acetate (25 mL) and the combined organic layer was washed with ~rine (5 mL), dried (Na2S04), and concentrated under reduced pressure. The resultant residue was 25 purified by flash chromatography to provide the intermediate (70 mg). 1H NMR
(300 MHz, CDCl3): ~ -0.13 (s, 6H), 0.75 (t, J = 6.6 Hz, 3H), 1.06-1.40 (m, 27H), 2.20-2.35 (m, 2H), 3.20 (sept, J = 6.6 Hz, lH), 3.32 (sept, J = 6.6 Hz, lH), 4.15 (d, J = 10.8 Hz, lH), 4.25 (d, J = 10.8 Hz, lH), 7.15-7.25 (m, lH), 7.40-7.50 (m, lH), 7.69 (dd, J =
~ 6.6, 2.4 Hz, lH), 10.41 (s, lH). FAB-MS: calcd ~or (C30H46NO2FSi) 499, found 500 30 (M+1).
W 098/0-'2X PCTAUS97113248 $tep C: 2,6-Diisopropyl-3-hvdrox~nethv1-4-~(4-fluoro-3-methoxy-carbonyl)phenyll -5-pentylpyridine The title compound was prepared from the intermediate obtained in Step B
by the method detailed in Example 177, Step C. 1H NMR (300 MHz, CDCl3): ~ 0.78 (t, J = 6.6 Hz, 3H), 1.08-1.16 (m, 4H), 1.23-1.34 (m, 15H), 2.20-2.30 (m, 2H), 3.22 (sept, J = 6.6 Hz, lH), 3.40 (sept, J = 6.6 Hz, lH), 3.93 (s, 3H), 4.25-4.39 (m, 2H), 7.12 (dd, J =
10.3, 8.5 Hz, lH), 7.28 (~, J = 8.5, 4.8, 2.2 Hz, lH), 7.69 (dd, J = 6.6, 2.2 Hz, lH).
F
HO ~--' \~ N '~/
2,6-Diisopropyl-3-hydrox~nethyl-4-~(4-fluoro-3-pentyl)phenyll-5-pentylpyridine Step A: 2,6-Diisopropyl-3-~(t-butvldimeth~lsiloxy)methyll4-~(4-fluoro-3 (pent-l-enyl))phenyll-5-pentylpyridine To a solution of 2,6-diiso~lo~yl-3-[(t-butyldimethylsiloxy)methyl~-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (Example 178, Step A) (200 mg, 0.40 mmol) in THF (10 mL) was added a butyltriphenylphosphonium bromide/sodium amide mixture (Fluka, 0.55 g, 3 eq) under an argon atmosphere. The reaction was stirred at 25 C for 1.5 h and ~s quenched by dropwise addition of water (3 mL) and further diluted with brine (5 mL). The mixture was extracted with ethyl acetate (2 x 20 mL) and the combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. I~e resultant residue was subjected to flash chromatography to yield the intermediate (205 mg). 1H NMR (300 MHz, CDCl3):
~-0.13 (s, 6H), 0.75-1.47 (m, 35H), 2.~3-2.33 (m, 4H), 3.21 (septet, J = 6.6 Hz, lH), 3.34 (septet, J = 6.6 Hz, lH), 2.7 (d, J = 2.7 Hz, 2H), 5.75-6.31 (m, lH), 6.41-6.59 (m, lH), 6.98-7.09 (m, 3H). FAB-MS: calcd for (C34Hs4NOFSi) 539, found 540 (M + 1).
.. . ... .
W 098101-2X PCT~US97113248 O Step B: 2,6-Diisopropyl-3-~(t-butyldimethylsiloxy)methyll-4-~(4-fluoro-3-pentyl)phenyll -5-pentylpyridine The intermediate from Step A (200 mg) was dissolved in ethanol (10 mL) and the mixture purged with argon. A quantity of 10% Pd-C (20 mg) was then added and the mixture was purged with hydrogen and stirred under a hydrogen ~ 5 atmosphere at 25 C for 16 h. The mixture was then filtered through a pad of silica and the silica pad ~; rinsed with ethanol (25 mL). The organic layer was concentrated under reduced pressure and the resultant residue was subjected to flash chromatography using hexane as the eluent to afford the intermediate (150 mg, 75%). 1H NMR (300 MHz, CDCl3): ~ -0.11 (s, 6H), 0.76-1.65 (m, 39H), 2.17-2.33 (m, 2H), 2.51-2.78 (m, 2H), 3.21 tseptet~ ~ = 6.6 Hz, lH), 3.35 (septet, J = 6.6 Hz, lH), 4.42 (dd, J = 10.2, 16.2, 2H), 6.92-7.05 (m, 3H). FAB-MS: calcd for (C34H56NOFSi) 541, found 542 (M+1).
Step C: 2,6-Diisopropyl-3-hvdroxymethyl-4-l(4-fluoro-3-Pentyl)-phenyll-5 1 5 pentylpyridine The title compound was prepared as a colorless oil from the intermediate from Step B by the method detailed in Example 177, Step C. lH NMR (300 MHz, CDCl3): ~ 0.77 (t, J = 6.9 Hz, 3H), 0.88 (t, J = 6.9 Hz, 3H), 1.08-1.34 (m, 24H), 1.57-1.65 (m, 1H), 2.22-2.29 (m, 2H), 2.57-2.75 (m, 2H), 3.21 (sept, J = 6.6 Hz, lH), 3.40 (sept, J = 6.6 Hz, lH), 4.33 (dd, J = 5.6, 1.4 Hz, 2H), 6.93-7.09 (m, 3H). FAB-MS: calcd for (C2gH42NOF) 427, found 428 (M + 1). Rf = 0.42 (20% ether-hexanes).
HO ~ ~~
~N ~/
2,6-Diisopropyl-3-hydroxymethyl-4-~(4-fluoro-3-ethyl)phenyll-5-pentylpyridine The title compound was prepared as a white wax from 2,6-diisopropyl-3-l(t-butyldimethylsiloxy)methyl]-4-[(4-fluor~3-formyl)phenyl]-5-pentylpyridine (Example 178, Step A) (200 mg, 0.40 mmol) and an ethyltriphenylphosphonium W098/04528 PCTrUS97113248 0 bromide/sodium amide mixture (Fluka) by the methods det~ile~ in Example 179, Steps A-C. lH NMR (300 MHz, CDC13): ~ 0.77 (t, J = 6.9 Hz, 3H), 1.10-1.33 (m, 22H), 2.17-2.33 (m, 2H), 2.60-2.80 (m, 2H), 3.21 (sept, J = 6.6 Hz, lH), 3.40 (sept, J =
6.6 Hz, lH), 4.34 (dd, J = 5.7, 1.8 Hz, 2H), 6.94-7.09 (m, 3H). FAB-MS: calcd for (C2sH36NOF) 385, found 386 (M+1). Rf = 0.38 (20% ether-hexanes).
F OH
HO
\~N~
10 2,6-Diisopropvl-3-hydroxymethYl-4-~4-fluoro-3-(a-hydroxy-4-fluoro-benzyl)l-5 pentylpyridine Step A: 2,6-Diisopropyl-3-(t-butyldimethylsilyloxymethyl)-4-~4-fluoro-3-( hydroxy-4-fluorobenzyl)phenyll -5-pentyl-pyridine To a solution of 2,6-diisopropyl-3-~(t-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (160 mg, 0.321 mmol) (Example 178, StepA) in THF (10 mL) was added 4-fluorophenyl magnesium bromide (1.0 M in THF, 0.4 mL, 2.5 eq) under an argon atmosphere at 25 C. The mixture was stirred for 30 min and then quenched by the dropwise addition of water (5 mL). The mixture was extracted with ether (2 x 10 mL) and the combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography using a 10% ether-hexane mixture as the eluent to provide 150 mg of the intermediate. lH NMR (300 MHz, CDCl3): ~ -0.19 (d, 6.3 Hz, 3H), -0.10 (d, J - 7.2 Hz, 3H), 0.71-1.30 (m, 30 H), 2.17-2.28 (m, 3H), 3.18 (septet, J = 6.6 Hz, lH), 3.25-3.40 (m, lH), 4.04-4.38 (m, 2H), 6.14 (dd, J = 4.4, 17.9 Hz, lH), 6.97-7.38 (m, 7H). FAB-MS: calcd for (C36Hs1NOF2Si) 595, found 596 (M + 1).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-~4-fluoro-3-(a-hydroxy-4-fluorobenzyl)phenyll-5-~elllyl~yridine W098/04528 PCTrUS97113248 O The title compound was prepared from the intermediate from Step A by themethod detailed in Example 177, Step C. lH NMR (300 MHz, CDCl3): ~ 0.72-1.45 (m, 22H), 2.13-2.36 (m, 2H), 2.65 (d, J = 4.2 Hz, lH), 3.21 (sept, J = 6.6 Hz, lH), 3.39 (sept, J = 6.6 Hz, lH), 4.21-4.39 (m, 2H), 6.14-6.17 (m, lH), 6.98-7.12 (m, 4H), 7.35-- 7.42 (m, 3H) FAB-MS: calcd for (C30H37NO2F2) 481, found 482 (M + 1) Rf = 0 21, 0.51 (50% ether-hexanes). mp 118-120 C.
F OH
HO~
\~N
2,6-Diisopropyl-3-h~drox~methyl-4-~4-fluoro-3-(l-hydroxyethyl)phenyll-5 pentylpyridine The title compound was prepared as an oil from 2,6-diisopropyl-3-[(t-butyldimethylsiloxy)methyl3-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyrid~ne (Example 178, Step A) and methylmagnesium bromide ~y the methods detailed in Example 181, Steps A-B. lH NMR (300 MHz, CDCl3): ~ 0.76 (t, J = 6.0 Hz, 3H), 1.0g-1.53 (m, 21H), 1.84 (br s, lH), 2.18-2.27 (m, 2H), 2.87 ( br s, 1 H), 3.20 (septet, J =
6.6 Hz, lH), 3.37 (septet, J = 6.6 Hz, lH), 4.16 (d, J = 11.4 Hz, lH), 4.28-4.35 (m, lH), 5.16-5.19 (m, lH), 7.01-7.07 (m, 2H), 7.25-7.34 (m, lH). FAB-MS: calcd for (C25H36NO2F) 401, found 402 (M + 1). Rf = 0.32 and 0.20 (50% ether-hexanes).
¢ ~f H
HO ~j~
\~N~
W O98/015~8 PCTrUS97/13248 o 2,6-Diisopropyl-3-hydroxymethyl-~4-fluoro-3-((N-((pyridin-2-yl) methyl)amino)methyl)lphenyl-5-pentylpyridine Step A: 2,6-Diisopropvl-3-~(t-butyldimethylsiloxy)meth~ l-4-~4-fluoro-3-((N
~(pyridin-2-yl)methyl)amino)methyl)lphenyl-5-pentylpyridine To a solution of 2,6-diisopropyl-3-[(t-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (500 mg, 1 mmol) (Example 178, Step A) in methanol (10 mL) and ether (2 mL) was added 2-methylaminopyridine (0.42 mL, 4 mmol, 4 eq) under an argon atmosphere at 25 C. To this solution were added ZnC12 (68.1 mg, 0.5 eq) and sodium cyanoborohydride (62.8 mg, 1 eq) in methanol (6 mL). The reaction was allowed to stir for 20 h and was then quenched with theaddition of aqueous sodium hydroxide (O.lN, 7 mL). The methanol was removed under reduced pressure and the aqueous residue was extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried (Na2S04), and concentrated under reduced pressure. The resultant residue was subjected to flash chromatography using a 60% ether-hexane mixture as the eluent to provide the intermediate (260 mg, 44%). lH NMR (300 MHz, CDC13)~
0.12 (s, 6H), 0.72-0.81 (m, 12H), 1.80 (br s, lH), 1.07-1.15 (m, 4H), 1.27-1.31 (m, 14H), 2.23-2.29 (m, 2H), 3.20 (septet, J = 6.6Hz, lH), 3.34 (septet, J = 6.6 Hz, lH), 3.83-4.03 (m, 4H), 4.25 (dd, J = 10.5, 27.6 Hz, 2H), 7.06-7.33 (m, 5H), 7.64 (~, J = 1.8, 7.5, 7.5 Hz, lH), 8.54-8.56 (m, lH). FAB-MS: calcd for (C36Hs4N3OFSi) 591, found 592 (M + 1).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-l4-fluoro-3-((N-((pyridin-2 yl)methyl)amino)meth~l)lphenyl-5-pentylpyridine The title compound was prepared as a colorless oil from the intermediate obtained in Step A by the method detailed in Example 177, Step C. lH NMR (300 MHz, CDC13): ~ 0.75 (t, J = 6.9 Hz, 3H), 1.07-1.36 (m, 18H), 1.75 (bs, 2H), 2.19-2.36 (m, 2H), 3.20 (sept, J = 6.6 Hz, lH), 3.47 (sept, J = 6.6 Hz, lH), 3.74 (d, J = 14.1 Hz, lH), 3.79 (d, J = 13.5 Hz, lH), 3.89 (d, J = 13.5 Hz, lH), 4.07 (d, J = 14.1 Hz, lH), 4.20 (d, J = 11.4 Hz, lH), 4.41 (d, J = 11.4 Hz, lH), 7.02-7.25 (m, 4H), 7.38 (d, J = 7.8 Hz, lH), 7.66 (~, J = 7.5, 7.5, 1.8 Hz, lH), 8.47 (m, lH). FAB-MS: calcd for (C30H40N3OF) 477, found 478 (M ~ 1). Rf = 0.4 (ethyl acetate).
WO 38~'~.152~ PCT/US97/13248 o EXAMPLE 184 F
~N~
HO ~~
~N~/
2,6-Diisopropyl-3-hydrox~nethyl-4-~4-fluoro-3-(pyrrolidin-1 -yl)methyllphenyl-5-5 pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-[(t-butyl-dimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (Example 178, Step A) by the methods detailed in Example 183, Steps A-B. lH NMR (300 MHz, CDC13): ~ 0.77 (t, J = 6.6 Hz, 3H), 1 05-1.31 (m, 18 H), 1.75-1.85 (m, 5 H), 2.23-102.29 (m, 2H), 2.50-3.50 (m, 4H), 3.20 (sept, J = 6.6 Hz, lH), 3.41 (sept, J = 6.6 Hz, 1 H), 3.71 (d, J = 12.9 Hz, lH), 3.82 (d, J = 12.9 Hz, lH), 4.29 (dd, J = 11.7, 20.4 Hz, 2H), 7.03-7.13 (m, 2H), 7.26-7.30 (m, lH). FA~MS: calcd for (C2gH41N2OF) 440, found 441 (M +1). Rf = 0.2 (ethyl acetate).
15E~CAMPLE 185 ~~ N ~\
HO ~~"~~"
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-~4-Iquoro-3-(butylamino)methyllphenyl-5 20 pelL~yl~,yl;dine ~ The title compound was prepared from 2,~diisopropyl-3-[(t-butyl-dimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (Example 178, Step A) by the methods ~1et~ilP~ in Example 183, Steps A-B. lH NMR (300 MHz, CDCI3): ~ 0.79 (t, J = 6.8 Hz, 3 H), 0.91 (t, J = 7.4 Hz, 3 H), 1.10-1.61 (m, 24 H), WO 9~101~2~ PCT~US97/13248 0 2.25-2.31 (m, 2 H), 2.62 (t, J = 7.2 Hz, 2 H), 3.23 (sept, J = 6.6 Hz, 1 H), 3.42 (sept, J =
6.6 Hz, lH), 3.89 (s, 2H), 4.32 (dd, 11.7 Hz, 2H), 7.04-7.20 (m, 3 H). FA~MS: calcd for (C2gH43N2OF) 442, found 443 (M +1). Rf = 0.33 (ethyl acetate).
s ¢~N
HO ~----~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(pyridin-3-yl)-5-pentylpyridine The title compound was prepared as an oil from ethyl isobutyryl acetate, 10 ammonium acetate and pyridine-3-carboxaldehyde in 0.56% yield by the methods described in Example 125. FAB-MS: calculated for C22H32N20 340; found 341 (M+1). lH NMR (300 MHz, CD30D): ~ 0.77 (t, J = 6.5 Hz, 3H), 1.08-1.32 (m, 18H), 2.27-2.33 (m, 2H), 3.28 (septet, J = 6.6 Hz, lH), 3.48 (septet, J = 6.6 Hz, lH), 4.25 (s, 2H), 7.52-7.57 (m, lH), 7.73-7.76 (m, lH), 8.42-8.43 (m, 2H), 8.59 (dd, J = 5.1, 1.5 Hz, 1 5 lH). Anal. calc for C22H32N2O: C, 77.60; H, 9.47; N, 8.23. Found: C, 75.96; H, 9.32;
N, 7.88. Rf = 0.40 (diethyl ether).
HO ~' ~N~
2,6-Diisopropvl-3-hydroxymethyl-4-(3-furyl)-5-(pent-l-enyl)pyridine Substituting 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) for ceric ammonium nitrate (CAN) to oxidize the dihydropyridine intermediate to the phenyl pyridine, the title compound was prepared as a mixture of E and Z isomers25 (4.5:1, E:Z) from ethyl isobutyryl acetate, ammonium acetate and furan-3-carboxaldehyde in 10% yield by the methods described in Example 125. FAB-MS:
.
WO 98~'~1r~8 PCT~US97/13248 O calculated ~or C21H2gNO2 327; found 328 (M+l). lH NMR (300 MHz, CD30D):
0.84 (t, J = 7.4 Hz, 3H), 1.17-1.38 (m, 14H), 2.01-2.04 (m, 2H), 3.39 (septet, J = 6.6 Hz, lH), 3.47 (septet, J = 6.6 Hz, lH), 4.44 (s, 2H), 5.40-5.58 (m, 2H), 6.11-6.25 (m, lH), 6.38-6.40 (m, lH), 7.41-7.54 (m, 2H).
HO~
~N~
2,6-Diisopropyl-3-hydroxvmethyl-4-(3-furyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-furyl)-5-(pent-1-enyl)pyridine (Example 187) in 6% yield by the methods described in Example 125. FAB-MS: calculated for C21H31N02 329; found 330 (M~l). lH NMR (300 MHz, CD30D): ~ 0.83 (t, J = 6.8 Hz, 3H), 1.19-1.36 (m, l9H), 2.42-2.48 (m, 2H), 3.25 (septet, J = 6.6 Hz, lH), 3.45 (septet, J = 6.6 Hz, lH), 4.38 (s, 2H), 6.42 (m, lH), 7.45-7.46 (m, lH), 7.61-7.62 (t, J = 1.7 Hz, lH). Anal. calc for C21H31NO2: C, 76.55; H, 9.48; N, 4.25. Found: C, 76.41; H, 9.76; N, 4.24. Rf = 0.59 (20% EtOAc/hex). mp 98-100 C.
HO ~'/
~N~
2,~Diisopropyl-3-hydroxymeth~l~-(thiophen-3-yl)-5-(pent-l -enyl)-pyridine The title compound was prepared as a mixture of E and Z isomers (5.5:1, 25 E:Z) from ethyl isobutyrylacetate, ammonium acetate and thiophene-3-carboxaldehyde in 7% yield by the methods described in Example 125. FAB-MS:
WO 98/04~28 PCTIUS97113248 O r~ te~l for C21H2gNOS 343; found 344 (M+1). lH NMR (300 MHz, CDCl3):
0.78-0.84 (m, 3H), 1.22-1.37 (m, 15H), 1.96-2.00 (m, 2H), 3.37-3.50 (m, 2H), 4.47 (d, J =
5.7 Hz, 2H), 5.32-5.43 (m, lH), 6.02-6.12 (m, lH), 6.95-6.97 (m, lH), 7.12-7.13 (m, lH), 7.35-7.38 (m, lH). Anal. calc for C21H29NOS: C, 73.43; H, 8.52; N, 4.08; S, 9.32.
Found: C, 73.38; H, 8.75; N, 3.97; S, 9.03. Rf = 0.65 (20% EtOAc/hex). mp 85-87 C.
s HO ~~'~' 3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-fluor~l,l'-biphenyl Step A: 1-(2-Methoxyethox-~)methox~methyl-2,4-diisopropyl-5-hydroxymethylbenzene A mixture of 1,5-bis(hydroxymethyl)-2,4-diisopropylbenzene (0.947 g, 4.26 mmol) (prepared by the method of Fey, et ~I. U.S. Patent 5,138,090), methoxyethoxymethyl chloride (0.49 mL, 4.29 mmol), and diisopropylethylamine (1.1 mL, 6.31 mmol) in CH2C12 (9.6 mL) was stirred overnight. The mixture was diluted witl water (50 mL) and extracted with CH2C12 (3 x 50 mL). Silica gel chromatography (67:33 hexanes/ethyl acetate) provided a colorless oil (0.679 g, 51%). lH NMR (CDCl3, 300 MHz): ~ 7.31 (s, lH), 7.29 (s, lH), 4.83 (s, 2H), 4.72 (s, 2H), 4.66 (s, 2H), 3.76 (m, 2H), 3.60 (m, 2H), 3.43 (s, 3H), 3.26 (m, 2H), 1.27 (d, 7.0 Hz, 12H). EI-MS: c~ te~l for ClgH30O4 310; found 292 (M-H20, 24%), 221 (100%).
Step B: 3-(2-MethoxyethoxY)methox~methyl-4,6-diiso~ ,ylbenzaldehyde Prepared from the intermediate obtained in Step A by the procedure described in Example 1, Step E. 1H NMR (CDCl3, 300 MHz): ~ 10.29 (s, lH), 7.80 (s, lH), 7.39 (s, lH), 4.83 (s, 2H), 4.70 (s, 2H), 3.98 (sept, 6.8 Hz, lH), 3.76 (m, 2H), 3.59 (m, 2H), 3.42 (s, 3H), 3.26 (sept, 6.8 Hz, lH), 1.30 (d, 7.0 Hz, 6H), 1.28 (d, 7.0 Hz, 6H).
FAB-MS: calculated for C18H2804 308; found 309 (M~H).
W O~ 8 PCTrUS97/13248 o Step C: N-Phenyl 3-(2-methoxyethoxy)methoxymethyl-4,6-diiso-propylbenzimine A mixture of the intermediate from Step B (2.35 g, 7.62 mmol), aniline (700 mL, 7.68 mmol), p-toluenesulfonic acid (58.8 mg, 309 mmol), and molecular sieves~ 5 (20.7 g) in toluene was refluxed overnight. The mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (65 mL) and washed with saturated aqueous NaHCO3 solution (50 mL) and water (50 mL), dried (MgSO4), and concentrated to give an orange oil (2.78 g, 96%). The productwas used in the next step without purification. lH NMR (C6D6, 300 MHz): ~ 8.70 (s, lH), 8.48 (s, lH), 7.31 (s, lH), 7.17 (m, 4H), 7.00 (m, lH), 4.61 (s, 2H), 4.60 (s, 2H), 3.56 (m, 2H), 3.46 (sept, 6.8 Hz, lH), 3.29 (m, 2H), 3.20 (sept, 6.8 Hz, lH), 3.07 (s, 3H), 1.17 (d, 7.0 Hz, 6H), 1.12 (d, 7.0 Hz, 6H).
Step D: Bis~(2-N-phenylmethylimino)-3,5-diisopropyl-6-(2-1 5 methoxyethoxy)methoxymeth~lphenylldipalladium A mixture of the intermediate from Step C (2.78 g, 7.27 mmol) and Pd(OAc)2 (1.63 g, 7.26 mmol) in acetic acid (34 mL) was refluxed for 1 h. The mixture wascooled to rt, poured into water (135 mL), and filtered through a medium porosityfritted funnel. The filtrate was lyophilized. The residue was dissolved in ethylacetate (100 mL) and washed with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL), dried (MgSO4), and concentrated to give a brown solid. The solid was mixed with 50:50 petroleum ether/ethyl acetate (17 mL) and cooled irl the freezer. The resulting precipitate was collectetl and dried to give a brown solid (0.951 g, 27%). lH NMR (C6D6, 300 MHz): ~ 7.70 (s, lH), 7.65 (s, lH), 7.63 (s, lH), 7.11 (s, lH), 7.08 (s, lH), 6.99 (m, lH), 6.73 (s, lH), 5.33 (s, 2H), 5.08 (s, 2H), 4.19 (m, 2H), 3.35 (m, ZH), 3.04 (s, 3H), 2.68 (sept, 6.8 Hz, lH), 2.15 (sept, 6.8 Hz, lH), 1.01 (d, 7.0 Hz, 6H), 0.96 (d, 7.0 Hz, 6H). FAB~ calculated for C4gH64N2O6Pd2 976; found 488 (M/2).
Step E: 3,5-Diisopropyl-2-formyl-6-(2-methoxyethoxy)methoxymethyl-4'-fluoro-l,l '-biphenyl A mixture of 1,2-dibromoethane (80 mL) and magnesium turnings (0.349 g, 14.4 mmol) in diethyl ether (1 mL) was heated to reflux for several minutes. Themixture was diluted with diethyl ether and a solution of l-bromo-4-fluorobenzene(950 mL, 8.65 mmol) and 1,2-dibromoethane (160 mL) in diethyl ether (3 mL) was added over several minutes. The reflux was continued for 1 h then the mixture was cooled to room temperature. The supernatant liquid was added via cannula to a WO 9~ PCT/US97tl3248 0 solution of the intermediate obtained in Step D (0.951 g, 973 mmol) and triphenylphosphine (2.02 g, 7.71 mmol) in benzene (19 mL) and the mixture stirred overnight. Aqueous 6N HCl (6 mL) was added and the mixture stirred for 2 h. The mixture was filtered and the solids washed with diethyl ether (75 mL). The combined filtrates were washed with saturated aqueous sodium chloride solution (50 mL). Silica gel chromatography provided a colorless solid (0.413 g, 53%). 1HNMR (CDCl3, 300 MHz): ~ 9.70 (s, lH), 7.50 (s, lH), 7.26 (m, 2H), 7.11 (m, 2H), 4.59 (s, 2H), 4.30 (s, 2H), 3.89 (sept, 6.8 Hz, 2H), 3.55 (m, 2H), 3.44 (m, 2H), 3.37 (s, 3H), 1.33 (d, 6.6 Hz, 6H), 0.96 (d, 7.0 Hz, 6H). FAB~ Altlllate~ for C24H31F04 402;
found 403 (M+H).
Step F: 3,5-Diisopropyl-2-(2-methoxyethoxy)methoxymethyl-6-(pent-l-enyl) 4'-fluoro-1,1 '-biphenyl Prepared from the intermediate obtained in Step E by the procedure described in Example 1, Step F. The olefin was a mixture of cis and trans isomers in a ratio of 9:91. lH NMR (CDCl3, 300 MHz): ~ 7.32 (s, lH), 7.12 (m, 2H), 7.01 (m,2H), 5.95 (d, 16.2 Hz, lH), 5.23 (dt, 16.2 Hz, 7.0 Hz, lH), 457 (s, 2H), 4.29 (s, 2H), 3.53 (m, 2H), 3.43 (m, 2H), 3.37 (s, 3H), 3.31 (m, 2H), 1.89 (m, 2H), 1.32 (d, 6.6 Hz, 6H), 1.23 (d, 7.0 Hz, 6H), 1.2 (m, 2 H), 0.74 (t, 7.4 Hz, 3H). FAB-MS: calculated for C2gH3gFO3 442; found 442 (M+).
Step G: 3,5-Diisopropyl-2-(2-methoxyethoxy)methoxymethyl-6-pentyl-4 fluoro-~ biphenyl Prepared from the intermediate obtained in Step F by the procedure described in Example 1, Step H. lH NMR (CDCl3, 300 MHz): ~ 7.29 (s, lH), 7.19 (m, 2H), 7.07 (m, 2H), 4.52 (s, 2H), 4.21 (s, 2H), 3.51 (m, 2H), 3.41 (m, 2H), 3.37 (s, 3H), 3.27 (sept, 6.8 Hz, lH), 3.16 (sept, 6.8 Hz, lH), 2.27 (m, 2H), 1.30 (d, 7.0 Hz, 6H), 1.27 (m, 2H), 1.23 (d, 7.0 Hz, 6H), 1.10 (m, 4H), 0.77 (t, 6.8 Hz, 3H). FAB-MS:
calculated for C2gH41FO3 444; found 445 (M+H).
Step H: 3,5-Diisopropyl-2-aceloxyl~lethyl-~pentyl-4'-fluoro-1,1'-biphenyl Chlorotrimethylsilane (110 mL, 867 mmol) was added to a cooled (0~C) mixture of the intermediate from Step G (62.4 mg, 140 mmol) and NaI (132 mg, 880mmol) in CH3CN (1.4 mL). After 25 min. the mixture was filtered through silica gel (5:1 hexanes/ethyl acetate) and the filtrate conce~ ed. A mixture of the residue and sodium acetate (122 mg, 1.4g mmol) in dimethyl formamide (2.3 mL) was heated to 80~C overnight. The solvent was removed and the residue dissolved in water (15 mL) and extracted with CH2Cl2 (3 x 15 mL). Silica gel ._ ........ ..
WO 981'~ 8 PCTIUS97/13248 0 chromatography (95:5 hexane/ethyl acetate) provided a colorless oil (38.2 mg, 69%). 1H NMR (CDCl3, 300 MHz): ~ 7.31 (s, lH), 7.15 (m, 2H), 7.07 (m, 2H), 4.76 (s, 2H), 3.18 (sept, 6.8 Hz, lH), 3.12 (sept, 6.8 Hz), 2.28 (m, 2H), 1.97 (s, 3H), 1.29 (d, 6.6 Hz, 6H), 1.29 (m, 2H), 1.29 (d, 6.6 Hz, 6H), 1.14 - 1.07 (m, 4H), 0.78 (t, 6.8 Hz, 3H).
FAB-MS: calculated for C26H3sFO2 398; found 338 (M-AcOH).
Step I: 3,5-Diiso~ro~-fl-2-hvdroxymethyl-6-pentyl-4'-fluoro-1,1'-biphen~
A solution of the interrnediate obtained in Step H (11.2 mg, 28.1 mmol) and potassium hydroxide (109 mg, 1.65 mmol) in methanol (2 mL) was heated at ~0~C
for 3 h. The solvent was removed, and the residue dissolved in saturated aqueousammonium chloride (15 mL) and extracted with diethyl ether (3 x 15 mL). Silica gel chromatography (5:1 hexane/ethyl acetate) provided the title compound as a colorless crystalline solid (12.0 mg, 120%). lH NM3~ (CDCl3, 300 MHz): ~ 7.30 (s, lH), 7.19 (m, 2H), 7.11 (m, 2H), 4.32 (s, 2H), 3.37 (sept, 6.9 Hz, lH), 3.16 (sept, 6.9 Hz, lH), 2.26 (m, 2H), 1.31 (d, 6.6 Hz, 6H), 1.29 (m, 2H), 1.28 (d, 7.0 Hz, 6H), 1.17 -1.03 ~m, 4H), 0.77 (t, 6.8 Hz, 3H). FAB-MS: calculated for C24H33FO 356; found 356 (M+). Rf = 0.33 (83:17 hexanes/ethyl acetate). Anal. calculated for C24H33FO: C, 80.85; H, 9.33 Found: C, 80.63; H, 9.40. mp 98-99~C.
HO ~--3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1 '-biphenyl Step A: 3,5-Diisopropyl-2-formyl-6-pentvl-4'-fluoro-1,1'-biphenyl Prepared from 3,5-diis~ro~yl-2-hydroxymethyl-6-pentyl-4'-fluoro-1,1'-biphenyl (Example 190) by the procedure described in Example 1, Step E. lH NMR
(CDCl3, 300 MHz): ~ 9.70 (s, lH), 7.42 (s, lH), 7.23-7.10 (m, 4H), 3.88 (sept, 6.8 Hz, lH), 3.23 (sept, 6.8 Hz, lH), 2.34 (m, 2H), 1.31 (d, 6.6 Hz, 6H), 1.29 (d, 7.0 Hz, 6H), 1.28 (m, 2H), 1.14 (m, 4H), 0.79 (t, 6.6 Hz, 3H). FAB-MS: calculated for C24H31FO
354; found 355 (M+H).
CA 02t62434 1999-01-28 WO 98/04528 PCTrUS97/13248 o Step B: 3,5-Diisol~o~ 2-(1-hydrox~,rethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 101, Step B. lH NMR (CDCl3, 300 MHz):
7.32 (s, lH), 7.19-7.06 (m, 4H), 4.70 (dq, 7.0 Hz, 2.9 Hz, lH), 3.88 (sept, 6.8 Hz, lH), 3.13 (sept, 6.8 Hz, lH), 2.20 (m, 2H), 1.63 (d, 2.9 Hz, lH), 1.40 (d, 6.6 Hz, 3H), 1.30 (d, 7.0 Hz, 6H), 1.3 (m, 2H), 1.27 (d, 7.0 Hz, 6H), 1.08 (m, 4H), 0.78 (t, 6.8 Hz, 3H). FAB-MS: calculated for C2sH3sFO 370; found 370 (M+). Rf = 0.36 (83:17 hexanes/ethyl acetate). mp 126~C.
EXA~LE 192 ~10~- ~
3,5-Diiso~lu,uyl-2-(1-h-~droxyeth~trl)-6-pentyl-4'-fluoro-1,1'-biphenyl In a separate experiment, the title compound was prepared by the methods described in Example 191. lH NMR (300 MHz, CDC13): ~ 0.76 - 0.80 (m, 3H), 1.04 -1.31 (m, 19H), 1.40 (d, J = 6.6 Hz, 3H), 2.17 - 2.22 (m, 2H), 3.11 - 3.16 (m, lH), 3.$6 -3.90 (m, lH), 4.66 - 4.73 (m, lH), 7.06 - 7.22 (m, 4H), 7.32 (s, lH). 13C NMR (75 MHz, CDCI3) d 13.87, 22.01, 23.37, 24.22, 24.55, 24.61, 25.08, 28.66, 28.94, 29.91, 31.02, 32.22, 68.89, 114.65 - 115.15 (2d, 2C), 124.25, 130.33 - 131.28 (2d, 2C), 135.51, 136.96, 137.72, 139.00, 145.80 (2C), 161.67 (d, J = 245.7 Hz, lC). FAB-MS: calc~ te~
for C25H35OF 370; found 370 (M+). Anal. calc for C2sH3sOF: C, 81.03; H, 9.52.
Found: C, 81.05; H, 9.70. Rf = 0.37 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A =
0.05 % aqueous trifluoroacetic acid, B = CH3CN; ~inear gradient: 75% - 100 %B over 30 min; 254 nm, 1 mL/min): R.T. 20.0 min. (91.1 area %); (Daicel Chiralcel OD-H;isocratic 99:1 hexanes:methyl t-butyl ether; 254 nm, 1.5 mL/min); R.T. = 5.83 min (49.0 area %), 7.67 min.(51 area %). mp 124.0-125.0~C.
; . CA 02262434 1999-01-28 . . . . -~ , DEMANDES OU BREVErS VOLUMINEUX
LA PRÉSENTE PARTIE DE ~; I I t DEMANDE OU CE BREVET
COMPREND PLUS D'UN TOME.
CECI EST LE TOME /--DE_~ -NOTE: Pour les tomes add;tionels, veuil1ez cc~ntacter le Bureau canadien des brevets JUl\~lBO APPLICATIONSIPATENTS - .
THIS SECTION OF THE APPLICATIONIPATENT CONTAINS MORE
THAN ONE VOLUME
TtllS IS VOLUME J OF
NO~E: ~or additiona1 ~Jcltsmes-please cs~ntac~~the Canadian Patent C)ff~c~
. .
Pyr Pd(PPh)3 J~, Pd/C
~ F 65 O ¢~ LAH ~ OH¢~
b~ ~
An alternative synthesis of biphenyls of type I uses a cycloaromatization of a ketodiester 68 with a diketone in the presence of a catalytic amount of sodium 5 methoxide in methanol solvent to give a phenol 69. The phenol is then coupled with an arylboronic acid as described in Scheme 28 to afford biphenyl diester 70.
The diester is then transformed as described in Schemes 4, 8, and 10 to give theanalog with the desired R2 and R3 groups.
O O ~ OH O 1) Tf20/Pyr MeOJw~oMe R1aJ~Rlb MeO'D~OMe 2)pdr( (OH)2 68 R1a R1b K3PO4/KBr MeO~OMe R3~R2 R1a R1b ~ R1a R1b 15 An alternative method of transforming phenol 69 to biphenyl 70 is shown in Scheme 30. Treatment of the phenol with dimethylsulfate and a base such as potassium carbonate yields the methyl ether 71. The ether is treated with an aryl Grignard reagent to afford biphenyl 70.
o OH o O OMe O
Jl 1 1~Me2SO4 Jl 1 J~
MeO ~ K2CO3 ~ OMe R1a R1b R1a R1b O Ar O
ArMgBr MeO~OMe R1a R1b 5 The diester 70 can be further transformed by an alternative method shown in Scheme 31, to give the analogs with the desired R2 and R3 groups. Chemical reducing agents such as sodium bis-(2-methoxyethoxy)-aluminum hydride (Red-Al), can result in a mono reduction of the diester 70 to give the alcohol 72. Alcohol 72 can be attached to a polymeric support such as Wang resin, by treatment with a 10 base such as sodium hydride in DMF, to give the intermediate 73. The ester group of intermediate 73 can be transformed to an alkyl halide in a two step process; 73 is treated with a reducing agent such as LAH, then Phosphorous tribromide to affordcompound 74. The alkyl halide 74 is treated with an alkyl thiol and a base such as N-methyl morpholine, then by TFA to cleave the ether linkage with the polymeric 15 resin, to a~ford the alcohol 75.
MeO~ OMe Red-AllTHF MeO~ CI
R1a R1b R1a R1b ~ 72 O Ar Ar MeOJ~~O~~ 1') LAH /THF Br~f O~~
RlaJ~R1b ~0 2) PBr3 R1a~R1b o 73 z 74 Z
1) R7SH/CH2C12 R7 Ar N-Me-i,,G~ ' ,e 's~f OH Z= Polystyrene 2) TFAICH2C12 R1a R1b .. ....
W098/04528 PCTrUS97113248 o It will be appreciated that synthesis of some compounds of formula (IC) may require use of protecting groups at various stages of the procedures. These are removed in subsequent steps. For example, the removal of O-benzyl ether protecting groups is carried out by treatment with hydrogen in the presence of a5 metal catalyst, such as palladium on carbon, in a polar solvent such as ethanol. The removal of silyl ether protecting groups is carried out by treatment with fluoride salts, such as tetrabutylamonium fluoride in a solvent such as THP. Conditions required to remove other protecting groups which may be present can be found in:Protective Groups in Or~anic Synthesis, Second Edition, T. W. Greene, John Wiley10 and Sons, New York, 1991.
The order of carrying out the steps of the foregoing reaction schemes is not always significant, and it is within the skill of the art to vary the order of reactions to facilitate the reaction or to avoid unwanted reaction products.
The following examples are provided for the purpose of further illustration only and are not intended to limit the disclosed invention.
EXAh~LE 1 F
HO ~----~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine ~ 25 Step A: 3-Amino-4-methyl-2-pentenoic acid, ethyl ester To 100 g (0.63 mol) of ethyl isobutyryl acetate was added ammonium acetate ~ (68.2 g, 0.89 mol), cyclohexane (230 mL) and isopropanol (74 mL). The mixture was heated at reflux under argon atmosphere with a Dean-Stark trap. After 2 hours, asecond portion of ammonium acetate (14.6 g, 0.19 mol) was added to the reaction.30 The reaction was heated at reflux for 12 hours and then allowed to cool to room 0 temperature. A total of ~30 mL of water was collected in the Dean-Stark trap. An ice bath was used to cool the reaction to 10~C and then ammonium hydroxide (63 mL) was added dropwise. The organic layer was separated, dried with sodium sulfate, filtered, and concentrated to yield a yellow oil. The crude product (90.9 g, 0.58 mol, 92%) was taken directly to the next step without any further purification.
s Step B: Diethyl 1,4-dihydro-2,~diisopropyl-4-(4-fluorophenyl)-3,5-pyridinedicarboxylate To ethyl 3-amino-4-methylpent-2-enoate (Step A) (90 g, 57 mmol) was added ethyl isobutyryl acetate (9Og, 57 mmol) and 4-fluorobenzaldehyde (61.4 mL, 0.57 mmol). The mixture was heated under argon at 130~C for 26 hours (Precaution:
Check the reflux condenser after a few hours as excess ammonium acetate will clog the condenser). The reaction was allowed to cool to room temperature and left tocrystallize for 4 days. The solid was collected by filtration with vacuum (46.9 g, 116 mmol, 20%) and taken directly to the next step without further purification.
Step C: Diethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3,5-pyridinedicarboxylate To the intermediate obtained in Step B (33 g, 82 mmol) in dichloromethane (400 ml) was added 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 20.5 g, 90 mmol) under argon and the mixture was stirred for 2 hours. The stirring was stopped toallow the precipitate to settle. The precipitate was filtered, washed with dichloromethane (3 x 30 mL), and discarded. The filtrate was concentrated to afford a brown solid, which was subjected to flash chromatography (6/4 mixture of dichloromethane/hexanes) resulting in a pure white solid (25.8 g, 64.3 mmol, 78%).
lH NMR (300 MHz, CDCl3): ~ 7.28 (m, 2 H), 7.06 (m, 2 H), 4.03 (q, J = 7.0 Hz, 4 H), 3.11 (septet, J = 6.6 Hz, 2 H), 1.32 (d, J = 6.5 Hz, 12 H), 0.979 (t, J = 3.3 Hz, 6 H). FAB-MS: r~ te~ for (C23H2~NO4F) 401, found 402 (M+H). Anal. calc for C23H2gNO4F: C, 68.64; H, 7.24; N, 3.48; F, 4.72. Found: C, 69.12; H, 6.98; N, 3.42;
F, 4.96. mp 72-74~C. Rf=0.4 (10% ethyl acetate/hexane).
Step D: Ethyl 2,6-diisopropyl-4-(4-fluorophen~rl)-5-hydroxymethyl-3 pyridinecarboxylate To a solution of the intermediate obtained in Step C (23.4 g, 58.3 mmol) in anhydrous tetrahydrofuran (300 mL) stirred under argon at 0~C was added a 35 solution of 3.4M of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (Red-Al) (61 mL, 204 mmol, 65 wt% in toluene) via syringe over 20 min. The reaction mixture was allowed to stir at room temperature for 7 hr, then cooled WO 98/04528 PCTrUS97113248 0 again to 0~C and carefully quenched by the dropwise addition of water. The solution was decanted from the solid which forms and the solvent removed in vacuo. The residue was purified by flash chromatography (300 g silica) via step gradient. Elution with 5% diethyl ether/hexane afforded 6.6 g (16.4 mmol, 28%) of recovered starting material and elution with 40% diethyl ether(Et2O) /hexane ~ 5 yielded the desired product as a yellow waxy solid (14 g, 39 mmol, 67%). lH NMR
(300 MHz, CDCl3): ~ 7.27 (m, 2 H), 7.10 (m, 2 H), 4.46 (d, J = 5.2 Hz, 2 H), 3.98 (q, J
= 7 Hz, 2 H), 3.48 (sept, J = 6.6 Hz, 1 H), 3.05 (sept, J = 6.6 Hz, 1 H), 1.32 (t, J = 6.6 Hz, 12 H), 0.97 (t, J = 7 Hz, 3 H). FAB-MS: calculated for (C21H26FNO3) 359, found 360 (M+H). Rf = 0.2 (20% ethyl acetate/hexane).
Step E: 5-Carboethox~l-2,6-diisopropyl-4-(4-fluorophenyl)-3-p~ridinecarboxaldehyde To a solution of the intermediate obtained in Step D (13 g, 36 mmol) in dichloromethane (1 L) was added Brockman I neutral alumina (7.4 g, 72 mmol).
The suspension was stirred at room temperature and treated with pyridinium chlorochromate (PCC) (16 g, 72 mmol) in three portions. The suspension was stirred at room temperature for 1 hr, then poured into 1:1 diethyl ether/hex (1 L), filtered through a pad of silica, the pad washed with diethyl ether (500 mL) and the combined eluent concentrated to afford a viscous oil which slowly solidified (12.8 g, 35.9 mmol, 99%): Rf = 0.31 (10% ethyl acetate/hexane). lH NMR (300 MHz, CDCl3): ~ 9.85 (s, 1 H), 7.27 (m, 2 H), 7.13 (m, 2 H), 4.04 (q, J = 7 Hz, 2 H), 3.88 (sept, J = 6.6 Hz, 1 H), 3.12 (sept, ~ = 6.6 Hz, 1 H), 1.33 (t, J = 6.6 Hz, 12 H), 1.00 (t, J =
7 Hz, 3 H). EI-MS calcd for (C21H24FNO3) 357, found 358 (M+H). Anal. Calcd for C21H24FNO3: C, 70.57; H, 6.77; N, 3.92. Found: C, 70.62; H, 6.78; N, 3.84.
Step F: Ethyl 2,~diisopropyl-4-(4-fluorophenyl)-5-(1-pentenyl)-3-pyridinecarboxylate Butyltriphenylphosphonium bromide (2.7 g, 6.76 mmol) was suspended in anhydrous THF (75 mL) under argon and stirred at -78~C. A 1.6 M solution of n-butyllithium in hexanes (4.2 mL, 6.76 mmol) was added dropwise. The reaction mixture was allowed to come to 0~C and was stirred at that temperature for 1.5 hr.
The resulting brightly colored solution was cooled again to -78~C and treated dropwise with a solution of the intermediate obtained in Step E (2 g, 5.60 mmol) in THF (20 mL). The reaction mixture was allowed to stir at 0~C for 1 hr, then quenched by the addition of water (5 mL). The THF was removed in V~C~lo, the residue partitioned between ethyl ether (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over MgSO4 and concentrated. Flash W O 98/04528 PCT~US97tl3248 0 chromatography through silica (5% diethyl ether/hexane) affords a viscous oil (2 g, 5 mmol, 90%) (E,Z mixture). 1H NMR (300 MHz, CDCl3): ~ 7.14 (m, 2 H), 7.02 (m, 2 h), 6.10 (dt, J = 1.8, 11.4 Hz, 0.4 H), 6.04 (dt, J = 1.5, 16.2 Hz, 0.6 H), 5.48 (dt, J = 7, 11.4 Hz, 0.4 H), ~.33 (dt, J = 7, 16.2 Hz, 0.6 H), 4.00 (q, J = 7 Hz, 0.8 H), 3.98 (q, J = 7 Hz, 1.2 H), 3.39 (sept, J = 6.6 Hz, 0.6 H), 3.27 (sept, J = 6.6 Hz, 0.4 H), 3.06 (m, 1 H), 1.95 (dq, J - 1.5, 7 Hz, 1 H), 1.26 (m, 13 H), 1.19 (m, 2 H), 0.97 (t, J = 7 HZ, 3 H), 0.77 (t, J = 7 Hz, 1.2 H), 0.76 (t, J = 7 Hz, 1.8 H). EI-MS calculated for (C25H32FNO2) 397, found 397 (M+). Rf = 0.5 (10% ethyl acetate/hexane).
Step G: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-( pentenyl)pyridine The intermediate obtained in Step F (2 g, 5.03 mmol) was dissolved in anhydrous THF (100 ml ) under argon and treated dropwise at room temperature with lithium aluminum hydride (1.0 M in THF, 10 mL, 10 mmol). The reaction mixture was stirred at reflux for 1 hr, cooled to room temperature and quenched by the addition of 0.38 mL H2O, 0.38 mL 20% aqueous NaOH and 1.1 mL H20.
The resulting suspension was filtered through a cake of Celite and the filtrate concentrated and purified by chromatography through silica (5% ethyl acetate/hexane) to afford the product as a white foam (1.42 g, 4.0 mmol, 80%). Rf =
0.2 (10% ethyl acetate/hexane).
Step H: 2,6-Diisopropyl-3-h~droxvmethyl-4-(4-fluorophenyl)-5 pentylpyridine The intermediate obtained in Step G was dissolved in absolute ethanol (50 mL) under argon, treated with 10% palladium on carbon (140 mg, 0.1 eq), then 25 stirred under a hydrogen atmosphere for 2 hr. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the product dried in vacuo to afford the title compound as a white solid (1.4 g, 3.9 mmol, 98%). lH NMR (300 MHz, CDCl3): ~ 7.15 (m, 4 H), 4.33 (d, J = 4.4 Hz, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 1.27 (m, 2 H), 1.13 (m, 5 H), 0.79 (t, J = 6.6 Hz, 3 H). FAB-MS: calculated for (C23H32FNO) 357, found 358(M+H). Anal. calcd for C23H32FNO: C, 77.27; H, 9.02; N, 3.92. Found: C, 77.46;
H, 8.95; N, 3.78. Rf=0.3 (20% ethyl acetatethexane). mp 100-101~C.
CA 02262434 l999-0l-28 WO 98/01~2~ PCT~US97/13248 .' ~0~
N
2,6-Dimethyl-3-hydroxymethYl~-Phenvl-5-(2-methyl-l-propenyl)-pyridirle The title compound was prepared from ethyl acetoacetate, benzaldehyde and isopropyl triphenylphosphonium iodide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDCl3): ~ 7.34 (m, 3 H), 7.10 (m, 2 H), 5.70 (s, 1 H), 4.42 (s, 2 H), 2.69 (s, 3 H), 2.43 (s, 3 H), 1.60 (s, 3 H), 1.35 (s, 3 H).
EI-MS calculated for (clgH2lNo) 267, found 267 (M+). mp 48-50~C. Rf = 0.3 (90%
ethyl acetate/hexane).
HO ~--N
2,6-Dimethyl-3-hydroxymethyl-4-phenyl-5-(1-penten~l)pyridine The title compound was prepared from ethyl acetoacetate, benzaldehyde and butyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 3:1 trans:cis isomers; gummy oil. lH NMR (300 MHz, CDCl3): ~ 7.37 (m, 3 H), 7.12 (m, 2 H), 5.94 (m, 1 H), 5.40 (m, 1 H), 4.41 (bs, 2 H), 2.71 & 2.68 (2s, 3 H), 2.57 & 2.46 (2s, 3 H), 1.91 & 1.69 (2q, J = 7 Hz, 2 H), 1.52 (bs, 1 H), 1.19 (m, 2 H), 0.77 (m, 3 H). E~-MS:
calculated for (C1gH23NO) 281, found 281. Rf = 0.4 (90% ethyl acetate/hexane).
W O 98/04528 PCT~US97113248 ~10 2,6-Dimeth~1-3-hydroxymethyl-4-phen~ 5-pent~lpyridine The title compound was prepared from 2,6-dimethyl-3-hydroxymethyl-4-phenyl-5-(1-pentenyl)pyridine (Example 3) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): ~ 7.42 (m, 3 H), 7.15 (m, 2 H), 4.33(s, 2 H), 2.65 (s, 3 H), 2.56 (s, 3 H), 2.27 (m, 2 H), 1.29 (m, 2 H), 1.11 (m, 4 H), 0.76 (t, J
= 7 Hz, 3 H). EI-MS: calculated for (C1gH2sNO) 283, found 283 (M+). Anal.
calculated for C1gH25NO: C, 80.52; H, 8.89; N, 4.94. Found: C, 80.39; H, 8.85; N, 4.85. mp 99-100~C. Rf = 0.3 (90% ethyl acetate/hexane).
[3 HO~
N
2,6-Dieth~1-3-hydroxymethyl-4-phenyl-5-(2-methyl-1-propenyl)p~,rridine The titlecompound was prepared from ethyl propionylacetate, benzaldehyde and isopropyl triphenylphosphonium iodide according to the procedures described in Example 1, Steps A-G. 1H NMR (300 MHz, CDCl3): ~ 7.34 (m, 3 H), 7.11 (m, 2 H), 5.76 (s, 1 H), 4.44(d,J=5.5Hz,2H), 3.01 (q, J = 7.4 Hz, 2 H), 2.75 (q, J = 7.4 Hz, 2 H), 1.58 (s, 3 H), 1.35 (m, 7 H), 1.21 (t, J = 7.4 Hz, 3 H). FAB-MS: calclllAted for (C20H2sNo) 295, found 296 (M+H). Anal. Calcd for C20H2sNo: C, 81.31; H, 8.53; N, 4.74. Found:
C, 81.03; H, 8.55; N, 4.65. mp 103-104~C. Rf = 0.4 (50% ethyl acetate/hexane).
CA 02262434 l999-0l-28 W098/04S28 PCTrUS97/13248 HO~--/
N
2,6-Diethvl-3-hydroxymethyl-4-phen~11-5-(l-pentenyl)p~,rridine The title compound was prepared from ethyl propionylacetate, benzaldehyde and butyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 6:4 trans:cis isomers. lH NMR (300 MHz, CDCl3): ~ 7.36 (m, 3 H), 7.14 (m, 2 H), 6.00 (m, 1 H), 5.37 (m, 1 H), 4.42 (m, 2 H), 2.90 (m, 4 H), 1.89 & 1.67 (2q, J =
7 Hz, 2 H), 1.25 (m, 9 H), 0.76 (m, 3 H). FAB-MS: calculated for (C21H27NO) 309,found 310 (M+H); Anal. Calcd for C21H27NO: C, 81.51; H, 8.79; N, 4.53. Found:
C, 81.95; H, 8.90; N, 4.45. mp 74-76~C. Rf = 0.5 (50% ethyl acetate/hexane) HO~----N
2,6-Diethyl-3-h~droxymethyl-4-phenyl-5-pentylpyAdine The title compound was prepared from 2,6-diethyl-3-hydroxymethyl-4-20 phenyl-5-(1-pentenyl)pyridine (Example 6) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): ~ 7.42 (m, 3 H), 7.18 (m, 2 H), 4.34(d, J = 6 Hz, 2 H), 2.96 (q, J = 7.7 Hz, 2 H), 2.84 (q, J = 7.7 Hz, 2 H), 2.28 (m, 2 H), 1.34 (m, 9 H), 1.09 (m, 4 H), 0.76 (t, J - 7 Hz, 3 H). FAB-MS: calculated for (C21H2gNO) 311, found 312 (M+H). mp 76-77~C. Rf = 0.5 (50% ethyl acetate/hexane).
WO 98~ 8 PCT/US97/13248 HO~
N
2,6-Diethyl-3-hvdroxymethyl-4-phenyl-~ ethenyl)pyridine The title compound was prepared from ethyl propionylacetate, benzaldehyde and methyl triphenylphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps A-G. 1H NMR (300 MHz, CDCl3): ~ 7.40 (m, 3 H), 7.20 (m, 2 H), 6.36 (dd, J - 11, 18 Hz, 1 H), 5.22 (dd, J
=11,2Hz,1H),5.00(dd,J=18,2Hz, lH),4.41 (d,J=6Hz,2H),2.96(m,4H), 1.35 (m, 7 H). FAB-MS: calculated for (C1gH21NO) 267, found 268 (M~H). Anal.
Calcd for C1gH21NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.65; H, 8.06; N, 5.09.
mp 84-85~C. Rf = 0.4 (50% ethyl acetate/hexane).
E~CAMPLE 9 HO~
N
2,5,6-Triethyl-3-hvdrox~methyl-4-phenylpyridine The title compound was prepared from 2,6-diethyl-3-hydroxymethyl-4-phenyl-5-(1-ethenyl)pyridine (Example 8) according to the procedure described inExample 1, Step H. 1H NMR t300 MHz, CDC13): ~ 7.44 (m, 3 H), 7.18 (m, 2 H), 4.33 (d,J=6Hz,2H),2.97(q,J=8Hz,2H),2.86(q,J=8Hz, 2H),2.36(q,~=8Hz,2 H), 1.34 (m, 7 H), 0.93 (t, J = 8 Hz, 3 H). FAB-MS: calculated for (C1gH23NO) 269, found 270 (M+H). Anal. Calcd for C1gH23NO: C, 80.26; H, 8.61; N, 5.20. Found:
C, 79.70; H, 8.54; N, 5.08. mp 100nC. R~ = 0.4 (50~/O ethyl acetate/hexane).
W 098/045t8 PCTAUS97113248 o EXAMPLE 10 HO ~"--"
~N~
2,6-Diisopropvl-3-h~droxYmethyl-4-phenyl-5-(l-pentenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, benzaldehyde and butyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDCl3): ~ 7.35 (m, 3 H), 7.14 (m, 2 H), 5.99 (m, 1 H), 5.35 (m, 1 H), 4.41 (m, 2 H), 3.36 (m, 2 H), 1.89 & 1.70 (2q, J = 7 Hz, 2 H), 1.24 (m, 15 H), 0.80 & 0.72 (2t, J = 7 Hz, 3 H). FAB-MS:
calculated for (C23H31NO) 337, found 338 (M+H). Anal. Calcd for C23H31NO: C, 81.85; H, 9.26; N, 4.15. Found: C, 81.88; H, 9.22; N, 3.93. mp 67-73~C. Rf = 0.1 (10%
ethyl acetate/hexane).
~0~
\~ N~
2,6-Diisoprop~ 3-hydroxvmethyl-4-phenyl-5-(2-methyl-l-propenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, benzaldehyde and isopropyl triphenylphosphonium iodide according to the procedures described in Example 1, Steps A-G. 1H NMR (300 MHz, CDCl3): ~ 7.32 ~ (m, 3 H), 7.11 (m, 2 H), 5.75 (s, 1 H), 4.43 (bs, 2 H), 3.46 (sept, J = 6.6 Hz, 1 H), 3.18 (sept, J = 6.6 Hz, 1 H), 1.57 (s, 3 H), 1.31 (m, 15 H). FAB-MS: calculated for (C22H2gNO) 323, found 324 (M+H). Anal. Calcd for C22H2gNO: C, 81.69; H, 9.04;
N, 4.33. Found: C, 81.59; H, 8.94; N, 4.29. mp 93-95~C. Rf = 0.1 (10% ethyl acetate/hexane).
WO 98/04528 PCTfiUS97/13248 HO
~N~/
2,6-Diisopropyl-3-h~rdroxymethyl-4-phen~ 5-(1-propenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, benzaldehyde and ethyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. lH NMR (300 MHz, CDCl3): ~ 7.4 (m, 3 H), 7.2 (m,2H),6.0(m, 1 H), 5.5 & 5.4 (2m, 1 H), 4.4 (m, 2 H), 3.4 & 3.2 (2m, 2 H), 1.6 (m, 2 H), 1.4 (m, 7 H), 1.3 (m, 7 H). PAB-MS: calculated for (C21H27NO) 309,found 310 (M~H~. Anal. Calcd for C21H27NO: C, 81.53; H, 9.98; N, 3.96. Found:
C, 79.06; H, 9.65; N, 3.61. Rf = 0.4 (20% ethyl acetate/hexane).
HO~
--f ' N~/
2,6-Diisopropyl-3-hydrox~methyl-4-phen~l-5-(l-butenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, 20 benzaldehyde and propyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. 1H NMR (300 MHz, CDCl3): ~ 7.4 (m, 3 H),7.2(m,2H),6.0(m,1H),5.4(m,1H),4.4(m,2H),3.3(m,3H),1.9 &1.7(2m,2 H), 1.3 (m, 12 H), 0.7 (m, 3 H). FAB-MS: calculated for (C22H2gNO) 323, found 324 25 (M+H). Rf = 0.4 (20% ethyl acetate/hexane).
WO 9~ t~2~ PCT/US97113248 HO
~N~/
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-pentylpyridine The title compound was prepared from 2,6-diisoproyl-3-hydroxymethyl-4-S phenyl-5-(1-pentenyl)pyridine (Example 10) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCI3) ~ 7.41 (m, 3 H), 7.18 (m, 2 H), 4.33 (s, 2 H), 3.42 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.32 (m, 13 H), 1.11 (m, 5 H), 0.76 (t, J = 7 Hz, 3 H). FAB(HR)-MS calcd for C23H33NO 339.2640; found 340.2640 (M+H). mp 81-82~C. Rf = 0.1 (10% ethyl 1 0 acetate/hexane).
HO ~ \
~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-(1-hexenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, benzaldehyde and pentyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. 1H NMR (300 MHz, CDCl3): ~ 7.35 (m, 3 H), 7.14 (m, 2 H), 5.99 (m, 1 H), 5.35 (m, 1 H), 4.40 (m, 2 H), 3.36 (m, 2 H), 1.92 &
1.70 (2m, 2 H), 1.20 (m, 17 H), 0.80 (m, 3 H). FAB-MS: calculated for (C24H33NO)~ 351, found 352 (M+H). Anal. Calcd for C24H33NO: C, 82.00; H, 9.46; N, 3.98.
Found: C, 81.58; H, 9.50; N, 4.62. Rf = 0.1 (10% ethyl acetate/hexane);
WO~8/017~ PCTrUS97113248 [~1 HO ~j~
\~ N~/
2,6-Diisopropyl-3-h~rdrox~meth~1-4-phenyl-5-hexylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-5 phenyl-5-(1-hexenyl)pyridine (Example 15) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDC13): ~ 7.40 (m, 3 H), 7.18 (m, 2 H), 4.33(d, J = 5 Hz, 2 H), 3.42 (septet, J = 7 Hz, 1 H), 3.23 (septet, J = 7 Hz, 1 H), 2.26 (m, 2 H), 1.31 (m, 13 H), 1.12 (m, 8 H), 0.80 (t, J = 7 Hz, 3 H). FAB-MS: calculated for (C24H3sNO) 353, found 354 (M+H). Anal. Calcd for C24H3sNO: C, 81.53; H, 9.98;
N, 3.96. Found:C, 79.06; H, 9.65; N, 3.61. mp 71-72~C. Rf = 0.1 (10% ethyl acetate/hexane).
[~
HO ~' ~f N'~/
2,6-Diisoprop~1-3-hydroxymeth~,r1-4-phenyl-5-propylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-phenyl-5-(1-propenyl)pyridine (~xample 12) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): ~ 7.41 (m, 3 H), 7.17 (m, 2 H), 4.33 (s, 2 H), 3.42 (sept, J - 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.25 (m, 2 H), 1.33(d,J=6.6Hz,6H),1.30(d,J=6.6Hz,6H),1.27(m,2H),1.20(m,1H),0.74(t,J
= 7 Hz, 3 H). FAB-MS: calculated for (C21H2gNO) 311, found 312 (M+H). Anal.
Calcd for C21H2gNO: C, 80.~8; H, 9.38; N, 4.50. Found: C, 80.72; H, 9.47; N, 4.38.
mp 89-90~C. Rf = 0.4 (20% ethyl acetate/hexane).
W O 98104528 PCTrUS97/13248 o EXAMPLE 18 HO~
~f N~
2,6-Diisopropyl-3-hvdroxymethyl-4-Phenyl-5-butylpyridine S The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-phenyl-5-(1-butenyl)pyridine (Example 13) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3): ~ 7.41 (m, 3 H), 7.17 (m, 2 H), 4.33 (s, 2 H), 3.42 (sept, J = 6.6 Hz, 1 H), 3.24 (sept, J = 6.6 Hz, 1 H), 2.28 (m, 2 H), 1.33 (d, J-6.6Hz,6H),1.31 (d,J=6.6Hz,6H),1.28(m,2H),1.14(m,3H),0.71 (t,J=7Hz, 3 H). FAB-MS: calculated for (C22H31NO) 325, found 326 (M+H). Anal. Calcd for C22H31NO: C, 81.18; H, 9.60; N, 4.30. Pound: C, 81.28; H, 9.87; N, 4.07. mp 83-84~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO ~~~
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-~4-fluorophenvl)-5-(1-hexenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, 20 4-fluorobenzaldehyde and pentyl triphenylphosphonium bromide according to theprocedures described in Example 1, Steps A-G. The product was obtained as a mixture 6:4 trans:cis isomers; gumn~y oil. lH NMR (300 MHz, CDCl3): ~ 7.10 (m, 4H), 5.98 (m, 1 H), 5.42 (dt, J = 7, 11.4 Hz, 0.4 H), 5.29 (dt, J = 7, 16.2 Hz, 0.6 H), 4.40 (d, J = 5.5 Hz, 2 H), 3.44 (m, 1 H), 3.36 (sept, J = 6.6 Hz, 0.6 H), 3.24 (sept, J = 6.6 Hz, 0.4 H), 1.94 (m, 1 H), 1.36 (m, 6 H), 1.23 (m, 8 H), 1.12 (m, 4 H), 0.82 (m, 3 H). FAB-W098104528 PCTrUS97tl3248 0 MS: calculated for (C24H32FNO) 369, found 370 (M+H). Rf = 0.4 (20% ethyl acetate/hexane).
E~CAMPLE 20 F
HO
~'N ~/
2,6-Diisopropyl-3-hvdroxYmethYl~-(4-fluorophenyl~-5-(l -butenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, ~fluorobenzaldehyde and propyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. lH NMR (300 MHz, CDC13): ~ 7.10 (m, 4 H), 5.97 (m, 1 H), 5.39 (dt, J = 7, 11.4 Hz, 0.5 H), 5.32 (dt, J = 7, 16.2 Hz, 0.5 H), 4.41 (d, J = 5.5 Hz, 2 H), 3.45 (m, 1 H), 3.36 (sept, J = 6 6 Hz, 0.5 H), 3.24 (sept, J = 6.6 Hz, 0.5H),1.95(m,1H),1.70(m,1H),1.35(d,J=6.6Hz,3H), 1.34 (d,J= 6.6Hz,3H), 1.25 (m, 7 H), 0.79 (t, J = 7.5 Hz, 1.5 H), 0.78 (t, J = 7.5 ~Iz, 1.5 H). FAB-MS: calculated for (C22H2gFNO) 341, found 342 (M+H). Rf - 0.4 (20% ethyl acetate/hexane).
HO~
~N~/
2,6-Diisopropyl-3-hydroxymethyl-~t4-fluorophenvl)-5-(l-propenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate~
4-fluorobenzaldehyde and ethyl triphenylphosphonium ~romide according to the procedures described in Example 1, Steps A-G. The product was obtained as a W O~8/01~ PCTrUS97/13248 0 mixture 1:1 trans:cis isomers. 1H NMR (300 MHz, CDCl3): ~ 7.11 (m, 4 H), 6.04 (d, J = 11.7 Hz, 0.5 H), 5.96 (d, J = 16.1 Hz, 0.5 H), 5.53 (m, 0.5 H), 5.33 (m, 0.5 H), 4.41 (m, 3 H), 3.42 (m, 1.5 H), 3.20 (sept, J = 6.6 Hz, 0.5 H), 1.61 (d, J = 6 Hz, 2 H), 1.3 (m, 13 H). FAB-MS: calculated for (C21H26FNO) 327, found 328 (M+H). Anal. Calcd forC21H26FNO: C,77.03;H,8.00;N,4.28. Found: C,77.15;H,8.07;N,4.11. mp 46-47~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO
\~ N
2,6-Diisopropyl-3-h~rdroxymethyl-4-(4-fluorophen~ll)-5-ethen~rlpyridine The title compound was prepared from ethyl isobutyrylacet~te, 4-fluorobenzaldehyde and methyl triphenylphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDCl3): ~ 7.12 (m, 4 H), 6.35 (dd, J = 11.5, 18 Hz, 1 H), 5.24 (dd, J = 1.5, 11.4 Hz, 1 H), 4.97 (dd, J = 1.5, 18 Hz, 1 H), 4.41 (d, J = 5.5 Hz, 2 H), 3.44 (sept, J = 6.6 Hz, 2 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.28 (d, J = 6.6 Hz, 6 H), 1.25 (m, 1 H). FAB-MS-calculated for (C20H24FNo) 313, found 314 (M+H). Anal. Calcd for C20H24FNo:
C, 76.65; H, 7.72; N, 4.47. Found: C, 76.87; H, 7.79; N, 4.33. mp 119-120~C. Rf = 0.4 20 (20% ethyl acetate/hexane).
h HO ~--/--~N~
WO 98/04~28 PCT~US97113248 o 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-hexylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-hexenyl)pyridine (Example 19) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): ~ 7.14 (m, 4 H), 4.33 5(s, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 1.26 (m, 1 H), 1.14 (m, 7 H), 0.82 (t, J = 7 Hz, 3 H). FAB-MS: calculated for (C24H34FNO) 371, found 372 (M+H). mp 93-95~C. Rf = 0.4 (20% ethyl acetate/hexane).
HO ~--' ~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-butylpyridine 15The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-butenyl)pyridine (Example 20) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDC13): ~ 7.15 (m, 4 H), 4.33 (d, J = 5.2 Hz, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.27 (m, 2 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 1.27 (m, 1 H), 1.16 (m, 3 H), 0.73 20(t, J = 7 Hz, 3 H). FAB-MS: calculated for (C22H30FNo) 343, found 344 (M+H).
Anal. Calcd for C22H30FNo: C, 76.93; H, 8.80; N, 4.08. Found: C, 76.93; H, 8.70;N, 3.96. mp 45-50~C. Rf = 0.4 (20% ethyl acetate/hexane).
o E~CAMPLE 25 HO ~--' ~f N~/
2,6-Diisopropyl-3-h~drox~methyl-4-(4-fluorophenyl)-5-prop~lpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-propenyl)pyridine (Example 21) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDC13): ~ 7.15 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.25 (m, 2 H), 1.33 (d, J=6.6Hz,6H),1.30(d,J=6.6Hz,6H),1.27(m,1H),l.l9(m,lH),0.76(t,J=7Hz, 3 H). FAB-MS: calculated for (C21H2gFNO) 329, found 330 (M+H). Anal. Calcd for C21H2gFNO: C, 76.56; H, 8.57; N, 4.25. Found: C, 76.55; H, 8.48; N, 4.11. mp 49-54 ~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO ~~
~N~/
2,6-Diisoprop~1-3-hydroxymethyl-4-(4-fluorophenyl)-5-eth~lpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-20 (4-fluorophenyl)-5-ethenylpyridine (Example 22) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3): ~ 7.15 (m, 4 H), 4.33 (d, J = 3.6 Hz, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.26 (sept, J = 6.6 Hz, 1 H), 2.34 (q, J =
7.35Hz,2H),1.33(d,J=6.6Hz,6H),1.31(d,J=6.6Hz,6H),l.l9(m,lH),0.93(t,J
= 7.35 Hz, 3 H). FAB-MS: calculated for (C20H26FNo) 315, found 316 (M+H). Anal.
W 098/04528 PCTrUS97113248 0 Calcd for C20H26FNo: C, 76.16; H, 8.31; N, 4.44. Found: C, 75.74; H, 8.50; N, 4.27.
mp 126-129~C. Rf - 0.4 (20% ethyl acetate/hexane).
EXA~LE 27 HO r (Z)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-methyl-1 -butenyl)p~ridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and isobutyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDCl3): ~
7.07 (m, 4 H), 5.92 (d, J = 10.7 Hz, 1 H), 5.20 (dd, J = 10.7, 11.4 Hz, 1 H), 4.42 (bs, 2 H), 3.45 (sept, J = 6.6 Hz, 1 H), 3.30 (sept, J = 6.6 Hz, 1 H), 2.06 (m, 1 H), 1.35 (d, J =
6.6 Hz, 6 H), 1.31 (m, 1 H), 1.24 (m, 5 H), 0.69 (bs, 6 H). FAB-MS: calculated for (C23H30FNO) 355, found 356 (M+H). Anal. Calcd for C23H30FNO: C, 77.71; H, 8.51; N, 3.94. Found: C, 77.94; H, 8.59; N, 3.79. mp 112~C. Rf = 0.3 (20% ethyl acetate/hexane).
F
HO
2,6-Diisopropvl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-meth penten~,rl)pyridine WO 98t04~28 PCTIUS97/13248 O The title compound was prepared from ethyl isobutyrylacetate, ~fluorobenzaldehyde and isoamyl triphenylphosphonium bromide according to ~e procedures described in Example 1, Steps A-G. The product is obtained as a 6:4 mixture of trans:cis isomers. lH NMR (300 MHz, CDCl3): ~ 7.11 (m, 4 H), 6.04 (dt, - J=1.5,11Hz,0.4H),5.96(dt,J=1.5,16Hz,0.6H),5.47(dt,J=7,11 Hz,0.4H),5.32 (dt, J = 7, 16 Hz, 0.6 H), 4.41 (m, 2 H), 3.44 (m, 0.8 H), 3.38 (sept, J = 6.6 Hz, 0.6 H), 3.24 (sept, J = 6.6 Hz, 0.6 H), 1.84 (m, 1 H), 1.45 (m, 1 H), 1.35 (m, 6 H), 1.24 (m, 7 H), 0.79 (d, J = 6.6 Hz, 2.4 H), 0.73 (d, J = 6.6 Hz, 3.6 H). FAB-MS: calculated for(C24H32FNO) 369, found 370 (M+H). Anal. Calcd for C24H32FNO: C, 78.01; H, 8.73; N, 3.79. Found: C, 78.14; H, 8.62; N, 3.50. mp 48-50~C. Rf = 0.3 (20% ethyl 10 acetate/hexane).
HO
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-methylbut~l)pvridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-methyl-1-butenyl)pyridine (Example 27) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3): ~ 7.14 (m, 20 4 H) 4.33 (d, J = 5.5 Hz, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.22 (sept, J = 6.6 Hz, 1 H), 2.27 (m, 2 H), 1.35 (m, 1 H), 1.33 (d, J = 7 Hz, 6 H), 1.30 (d, J = 7 Hz, 6 H), 1.17 (m, 3 H), 0.70 (d, J = 6.6 Hz, 6 H). FAB-MS: calculated for (C23H32FNO) 357, found 358(M+H). Anal. Calcd for C23H32FNO: C, 77.27; H, 9.02; N, 3.92. Found: C, 77.34;
H, 9.15; N, 3.69. mp 43-45~C. Rf = 0.2 (20% ethyl acetate/hexane).
W 098~'~?~ PCTAUS97/13248 HO~
~ N ~/
2,6-Diisopropvl-3-hydroxymethyl-~(4-fluorophenyl)-5-(4-methylpentyl~pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-methyl-1-pentenyl)pyridine (Example 28) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDC~3): ~ 7.14 (m, 4 H), 4.33 (d, J = 5 Hz, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.22 (sept, J = 6.6 Hz, 1 H), 2.23(m,2H),1.38(m,1H),1.33(d,J=6.6Hz,6H),1.30(d,J=6.6Hz,6H),1.27(m, 1 H), 1.17 (m, 1 H), 1.00 (m, 3 H), 0.76 (d, J = 6.6 Hz, 6 H). FAB-MS: calculated for (C24H34FNO) 371, found 372 (M+H). Anal. Calcd for C24H34FNO: C, 77.59; H, 9.22; N, 3.77. Found: C, 77.63; H, 9.39; N, 3.58. mp 101-103~C. Rf = 0.3 (20% ethyl acetate/hexane) .
HO~
\f N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(cyclopentyl-20 idenemethylene)pyridine The title compound was prepared from ethyl isobutyr~ylacetate, 4-fluorobenzaldehyde and cyclopentyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDC13):
7.13 (m, 2 H), 7.07 (m, 2 H), 5.88 (s, 1 H), 4.43 (d, J = 5.5 Hz, 2 H), 3.44 (sept, J = 6.6 1~2 W 098/01'~ PCTrUS97/13248 0 Hz, 1 H), 3.21 (sept, J = 6.6 Hz, 1 H), 2.11 (m, 2 H), 1.75 (m, 2 H), 1.47 (m, 4 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.29 (m, 1 H), 1.21 (d, J = 6.6 Hz, 6 H). FAB-MS: calculated for (C24H30FNO) 367, found 368 (M+H). Anal. Calcd for C24H30FNO: C, 78.44; H, 8.23; N, 3.81. Found: C, 78.46; H, 8.18; N, 3.63. mp 97-98~C. Rf = 0.3 (20% ethyl acetate/hexane).
- S
E)(AMPLE 32 HO ~--/
~N~
1 0 2,6-Diisoprop~1-3-hydrox~methyl-4-(4-fluorophenyl)-5-(l-heptenyl)-pyridineThe title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and n-hexyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. 1H NMR ~300 MHz, CDCl3): ~ 7.11 (m, 4 H), 5.99 (m, 1 H), 5.42 (dt, J = 7, 11 Hz, 0.5 H), 5.30 (dt, J = 7, 16 Hz, 0.5 H), 4.41 (d, J
= 5.5 Hz, 2 H), 3.45 (m, 1 H), 3.37 (sept, J = 6.6 Hz, 0.5 H), 3.24 (sept, J = 6.6 Hz, 0.5 H), 1.94 (m, 1 H), 1.35 (m, 6 H), 1.29 (m, 1 H), 1.26 (d, J = 6.6 Hz, 3 H), 1.22 ~m, 6 H), 1.15 (m, 4 H), 0.86 (m, 3 H). FAB-MS: calculated for (C25H34FNO) 383, found 384 (M+H). Anal. CalcdforC25H34FNO: C, 78.29; H, 8.93; N, 3.65. Found: C, 78.37;
H, 8.88; N, 3.57. Rf = 0.4 (20% ethyl acetate/hexane).
tlO ~ ~
W 098104S28 PCTrUS97113248 o 2,6-Diisopropyl-3-hvdroxymeth~l-4-(4-fluorophenyl)-5-(l-octenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and n-heptyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a S mixture 1:1 trans:cis isomers; gummy oil. lH NMR (300 MHz, CDCl3): ~ 7.11 (m, 4 H), 5.98 (m, 1 H), 5.42 (dt, J - 7, 11 Hz, 0.5 H), 5.30 (dt, J = 7, 16 Hz, 0.5 H), 4.41 (d, J
= 5.5 Hz, 2 H), 3.44 (m, 1 H), 3.37 (sept, J = 6.6 Hz, 0.5 H), 3.24 (sept, J = 6.6 Hz, 0.5 H), 1.94 (m, 1 H), 1.35 (m, 6 H), 1.30 (m, 1 H), 1.26 (d, J = 6.6 Hz, 6 H), 1.22 (m, 4 H), 1.16 (m, 5 H), 0.87 (m, 3 H). FAB-MS: calculated for (C26H36FNO) 397, found 398 (M+H). Anal. Calcd for C26H36FNo: C, 78.55; H, 9.13; N, 3.52. Found: C, 78.63;
H, 9.16; N, 3.48. Rf = 0.4 (20% ethyl acetate/hexane) HO--~N~/
2,6-Diisoprop~1-3-hydrox~nethyl-4-(4-fluorophenyl)-5-~2(E)-phen ethenyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and benzyl triphenylphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps A-G. 1H NMR (300 MHz, CDCl3): ~ 7.21 (m, 9 H), 6.70 (d, J = 16.5 Hz, 1 H), 6.26 (d, J = 16.5 Hz, 1 H), 4.45 (d, J = 5.5 Hz, 2 H), 3.48 (sept, J = 6.6 Hz, 2 H), 1.37 (d, J = 6.6 Hz, 6 H), 1.31 (d, J
= 6.6 Hz, 6 H), 1.29 (m, 1 H). FAB-MS: calculated for (C26H2gFNO) 389, found 390(M+H). ~nal. Calcd for C26H2gFNO: C, 80.17; H, 7.25; N, 3.60. Found: C, 79.89;
H, 7.28; N, 3.49. mp 107-110~C. Rf = 0.3 (20% ethyl acetate/hexane).
W O 98/~'-2% PCT~US97/13248 o EXAMPLE 35 HO ~----' ~N~/
2,6-Diisopropyl-3-hYdrox~nethyl-4-(4-fluorophenyl)-s-heptylpyridine S The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-heptenyl)pyridine (Example 32) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3): ~ 7.13 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.22 (sept, J = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J=6.6Hz,6H),1.30(d,J=6.6Hz,6H),1.22(m,3H),1.11 (m,8H),0.85(t,J=7Hz, 3 H). FAB-MS: calculated for (C25H36FNO) 385, found 386 (M+H). Anal. Calcd for C2sH36FNO: C, 77.88; H, 9.41; N, 3.63. Found: C, 77.86; H, 9.66; N, 3.59. mp 73-75~C. Rf = 0.3 (20% ethyl acetate/hexane).
F
HO
~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-octvlpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-octenyl)pyridine (Example 33) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3): ~ 7.14 (m, 4 H), 4.33 (d, l = 5.5 Hz, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 1.25 (m, 3 H), 1.15 (m, 10 H), 0.87 (t, J = 7 Hz, 3 H). FAB-MS: calculated for (C26H3gFNO) 399, found 400 (M+H).
W 09$/04528 PCTrUS97113248 0 Anal. Calcd for C26H3gFNO: C, 78.15; H, 9.59; N, 3.51. Found: C, 78.27; H, 9.81;
N, 3.43. Gummy oil; Rf = 0.3 (20% ethyl acetate/hexane).
HO ~/
~f N~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(2-phenylethyl)pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[2(E)-phenylethenyl]pyridine (Example 34) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDC13): ~ 7.19 (m, 7 H), 6.86 (m, 2 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.44 (sept, J = 6.6 Hz, 1 H), 3.35 (sept, J =
6.6 Hz, 1 H), 2.58 (m, 4 H), 1.35 (d, J - 6.6 Hz, 6 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.19 (t, J
= 5.5 Hz, 1 H). FAB-MS: calculated for (C26H30FNo) 391, found 392 (M+H). Anal.
Calcd for C26H30FNO: C, 79.76; H, 7.72; N, 3.58. Found: C, 79.57; H, 7.61; N, 3.44.
mp 158-159~C. Rf = 0.3 (20% ethyl acetate/hexane).
HO~ ~ 3 N
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophen~l)-5-(4-phenyl-l -20 butenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and 3-phenylpropyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 5:1 trans:cis isomers; gummy oil. lH NMR (300 MHz, W 098/04S28 PCTrUS97/13248 0 CDCl3): ~ 7.26 (m, 2 H), 7.19 (m, 1 H), 7.09 (m, 6 H), 6.05 (d, J = 11 Hz, 0.2 H), 5.98 (d, J = 16 Hz, 0.8 H), 5.47 (dt, J = 7, 11 Hz, 0.2 H), 5.33 (dt, J = 7, 16 Hz, 0.8 H),, 4.40 (d, J = 5 Hz, 2 H), 3.43 (m, 1 H), 3.26 (sept, J = 6.6 Hz, 1 H), 2.51 (m, 2 H), 2.29 (m, 1.6 H), 2.05 (m, 0.4 H), 1.34 (m, 6 H), 1.25 (m, 1 H), 1.22 (d, J = 6.6 Hz, 6 H). FAB~
calculated for (C2gH32FNO) 417, found 418 (M+H). Anal. Calcd for C2gH32FNO:
- 5 C, 80.54; H, 7.72; N, 3.35. Found: C, 80.56; H, 7.56; N, 3.32. Rf = 0.3 (20% ethyl acetate/hexane) HO~ }
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-phenylbutyl)pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-phenyl-1-butenyl)pyridine (Example 38) according to the procedure described in Example 1, Step H. Gummy oil; lH NMR (300 MHz, CDCl3): ~ 7.24 (m, 3 H), 7.08 (m, 6 H), 4.31 (d, J = 5.5 Hz, 2 H), 3.40 (sept, J = 6.6 Hz, 1 H), 3.17 (sept, J = 6.6 Hz, 1 H), 2.46 (t, J = 7.5 Hz, 2 H), 2.29 (m, 2 H), 1.47 (m, 2 H), 1.32 (d, J = 6.6 Hz, 6 H), 1.30 (m, 2 H), 1.27 (d, J = 6.6 Hz, 6 H), 1.15 (t, J = 5.5 Hz, 1 H). FAB-MS: calculated for (C2gH34FNO) 419, found 420 (M+H). Anal. Calcd for C2gH34FNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.06; H, 7.94; N, 3.28. Rf = 0.3 (20% ethyl acetate/hexane).
HO ~
0 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~2(E)-(2-meth phenyl)ethenyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and 2-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDC13): ~ 7.22 (m, 3 H), 7.10 (m, 5 H), 6.62 (d, J = 17 Hz, 1 H), 6.45 (d, J = 17 Hz, 1 H), 4.45 (d, J = 5.5 Hz, 2 H), 3.48 (m, 2 H), 2.12 (s, 3 H), 1.37 (d, J = 6.6 Hz, 6 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.31 (m, 1 H). FAB-MS: calculated for (C27H30FNO) 403, found 404 (M+H). Anal. Calcd for C27H30FNo: C, 80.36; H, 7.49; N, 3.47. Found:
C, 80.23; H, 7.23; N, 3.44. mp 108-111~C. Rf = 0.3 (20% ethyl acetate/hexane).
HO ~' ~N~
2,6-Diisoprop~1-3-hydroxymethyl-4-(4-fluorophenyl)-5-~2(E)-(3-methyl-phenyl)ethenyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and 3-methylbenzyl triphenylphosphonium chloride according to the procedures described in Example 1, Steps A-G. lH NMR (300 20 MHz, CDCl3): ~ 7.18 (m, 3 H), 7.11 (m, 2 H), 7.00 (m, 3 H), 6.68 (d, J = 17 Hz, 1 H), 6.23 (d, J = 17 Hz, 1 H), 4.44 (d, J = 5.5 Hz, 2 H), 3.47 (m, 2 H), 2.32 (s, 3 H), 1.37 (d, J
= 6.6 Hz, 6 H), 1.31 (d, J = 6.6 Hz, 6 H), 1.28 (m, 1 H). FAB-MS: calculated for(C27H30FNO) 403, found 404 (M+H). Anal. Calcd for C27H30FNO: C, 80.36; H, 7.49; N, 3.47. Found: C, 80.38; H, 7.45; N, 3.45. mp 97-99~C. Rf = 0.3 (20% ethyl 25 acetate/hexane).
O E~CAMPLE 42 [~ ~
HO~
~N~
2,6-Diisopropyl-3-hydroxymethYl-4-(4-fluorophenyl)-5-~2(E)-(4-methyl-phenyl)ethenyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and 4-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. lH NMR (300 MHz, CDCl3): ~ 7.18 (m, 2 H), 7.08 (m, 6 H), 6.63 (d, J = 17 Hz, 1 H), 6.23 (d, J = 17 Hz, 1 H), 4.43 (d, J = 5 Hz, 2 H), 3.47 (sept, J = 6.6 Hz, 2 H), 2.31 (s, 3 H), 1.36 (d, J =
6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 1.26 (m, 1 H). FAB-MS: calculated for (C27H30FNO) 403, found 404 (M+H). Anal. Calcd for C27H30FNO: C, ~0.36; H, 7.49, N, 3.47. Found: C, 79.93; H, 7.34; N, 3.47. mp 131-133~C. Rf = 0.3 (20% ethyl acetate/hexane).
HO ~/~~
~' ~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~2-(2-methyl-phenyl)ethyllpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[2(E)-(2-methylphenyl)ethenyl]pyridine (Example 40) accordingto the procedure described in Example 1, Step H. lH NMR (300 MHz, CDC13):
WO 98/04528 PCT/US97tl3248 0 7.16 (m, 4 H), 7.06 (m, 3 H), 6.81 (m, 1 H), 4.35 (d, J = 4 Hz, 2 H), 3.42 (sept, J = 6.6 Hz, 2 H), 2.57 (m, 4 H), 1.97 (s, 3 H), 1.36 (d, J = 6.6 Hz, 6 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.19 (m, 1 H). FAB-MS: calculated for (C27H32FNO) 405, found 406 (M+H). Anal.
Calcd for C27H32FNo: C, 79.96; H, 7.95; N, 3.45. Found: C, 80.08; H, 8.05; N, 3.46.
mp 125-126~C. Rf = 0.3 (20% ethyl acetate/hexane).
EXA~EE 44 ItO~
~N~/
2,6-Diisoprop~ 3-hydroxymethyl-4-(4-fluorophenyl)-5-~2-(3-meth phen~ ethyllpyridine The title compound was prepared 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[2(E)-(3-methylphenyl)ethenyl}pyridine (Example 41) according tothe procedure described in Example 1, Step H. lH NMR (300 M~Iz, CDCl3): ~ 7.18 (d, J = 7 Hz, 4 H), 7.10 (m, 1 H), 6.97 (m, 1 H), 6.65 (m, 2 H), 4.36 (s, 2 H), 3.44 (sept, J
= 6.6 Hz, 1 H), 3.35 (d, J = 6.6 Hz, 1 H), 2.57 (m, 4 H), 2.28 (s, 3 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.20 (m, 1 H). FAB-MS: calculated for (C27H32FNO) 405, found 406 (M+H). Anal. Calcd for C27H32FNO: C, 79.96; H, 7.95; N, 3.45.
Found: C, 79.30; H, 8.10; N, 3.36. mp 148-150~C. ~f = 0.3 (20% ethyl 20 acetate/hexane).
HO ~--~N~
o 2,6-Diisoprop~l-3-hydroxymethyl-4-(4-fluorophen~rl)-5-~2-(4-meth phenyl)ethyllpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[2(E)-(4-methylphenyl)ethenyllpyridine (Example 42) accordingS to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3):
7.17(m,4H),7.02(d,J=7.7Hz,2H),6.75(d,J=7.7Hz,2H),4.36(d,J=4Hz,2H), 3.43 (sept, J = 6.6 Hz, 1 H), 3.34 (sept, J = 6.6 Hz, 1 H), 2.55 (m, 4 H), 2.29 (s, 3 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.20 (m, 1 H). FAB-MS: calculated for tC27H32FNO)405, found 406 (M+H). Anal. Calcd for C27H32FNO: C, 79.96;
H, 7.95; N, 3.45. Found: C, 79.40; H, 7.84; N, 3.44. mp 121-123~C. Rf = 0.3 (20%
ethyl acetate/hexane).
¢~
HO~ ~--'rO>
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~3-(1,3-dioxolan-2-yl)propyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and 12-(1,3-dioxolan-2-yl)ethyl]triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. 1H NMR
(300 MHz, CDCl3): ~ 7.16 (m, 4 H), 4.63 (t, J = 4 Hz, 1 H), 4.33 (d, J = 5 Hz, 2 H), 3.88 (m, 2 H), 3.77 (m, 2 H), 3.41 (bm, 1 H), 3.24 (bm, 1 H), 2.34 (m, 2 H), 1.47 (m, 4 H), 1.32 (m, 12 H), 1.18 (m, 1 H). FAB-MS: calculated for (C24H32FNO3) 401, found 402 (M+H). mp 90-91~C. Rf = 0.2 (20% ethyl acetate/hexane).
W 098/04528 PCTrUS97113248 HO~S J~3 2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-~(phenylthio)-methyllpyridine Step A: Methyl 2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-3-pvridinecarboxylate Prepared from methyl isobutyrylacetate, 4-fluorobenzaldehyde and ammonium acetate by the procedures described in Example 1, Steps A-D.
Step B: Methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-bromomethyl-3 pyridinecarboxylate A solution of the intermediate obtained in Step A (20 g, 57.9 mmol) in acetonitrile (500 mL) was stirred at 0~C and treated with dibromo-triphenylphosphorane (36.7 g, 86.9 mmol) in portions. The suspension was then allowed to warm to room temperature and stirred for 2 hr. The solvent was removed in vacuo and the residue partitioned between diethyl ether (400 mL) and water (350 mL). The ether layer was washed with brine (150 mL), dried (MgSO4) and concentrated. Purification by chromatography through si~ica (5% diethyl ether/hexane) gave a white solid (20.6 g, 50.5 mmol, 87%). lH NMR (300 MHz, CDCl3): ~ 7.31 (m, 2 H), 7.12 (m, 2 H), 4.29 (s, 2 H), 3.49 (s, 3H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.06 (sept, J = 6.6 Hz, 1 H), 1.33 (m, 12 H). mp 109-111~C. Rf = 0.6 (50%
CH2Cl2/hexane).
Step C: 2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5 ~(,phenylthio)methyllPyridine A solution of the intermediate obtained in Step B (200 mg, 0.47 mmol) in anhydrous THF (5 mL), stirred under argon, was treated with benzenethiol (73 uL, WO ~&'G l'2~ PCT/US97113248 0 0.71 mmol) and N-methylmorpholine (0.26 mL, 2.4 mmol). The reaction mixture was stirred at reflux for 14 hr, allowed to cool to room temperature and treatedwith lithium aluminum hydride (1.9 mL, 1.9 mmol, 1.0M in THF). The reaction mixture was heated at reflux for 1 hr then allowed to cool to room temperature.
The mixture was quenched by the successive addition of water (80 uL), 20% NaOH
- 5 (80 uL) and water (240 uL). The resulting suspension was filtered through a cake of celite and concentrated. Purification by flash silica gel chromatography (5% ethyl acetate/hexane) afforded a white solid (160 mg, 0.39 mmol, 83%). lH NMR (300 MHz, CDCl3): ~ 7.23 (m, 5 H), 7.11 (m, 4 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.81 (s, 2 H), 3.45 (sept, J = 6.6 Hz, 1 H), 3.43 (sept, J = 6.6 Hz, 1 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.21 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C25H2gFNOS) 409, found 410 (M+H). Anal. Calcd for C25H2gFNos: C, 73.32; H, 6.89; N, 3.42; S, 7.83.
Found: C, 73.24; H, 6.90; N, 3.35; S, 8.01. mp 119-121~C. Rf = 0.3 (20% ethyl acetate/hexane) .
HO~,S ~ CF3 2,6-Diisoprop~1-3-hydroxymethyl-4-(4-fluorophenyl)-5-~((3-trifluoro-methyl)phenyl)thiolmethylpyridine The title compound was prepared from 3-trifluoromethyl-thiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13):
~ 7.34 (m, 2 H), 7.24 (m, 4 H), 7.10 (m, 2 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.85 (s, 2 H), 3.45 (sept, J = 6.6 Hz, 1 H), 3.38 (sept, J = 6.6 Hz, 1 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.23 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C26H27F4NOS) 477, found 478 (M~H). Anal. Calcd for C26H27F4NOS: C, 65.39; H, 5.70; N, 2.93; S, 6.71. Found: C, 65.39; H, 5.76; N, 2.88; S, 6.62. mp 110-111~C. Rf = 0.3 (20% ethyl acetate/hexane).
.
W O 98/04528 PCT~US97/13248 o EXAMPLE 49 F
HO~,S
N
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(4-fluoro-phenyl)thiolmethylpyridine The title compound was prepared from 4-fluorothiophenol according to the procedures described in Example 47. 1H NMR (300 MHz, CDCl3): ~ 7.24 (m, 2 H), 7.12 (m, 4 H), 6.93 (m, 2 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.76 (s, 2 H), 3.44 (sept, J = 6.6 Hz, 1 H), 3.40 (sept, J = 6.6 Hz, 1 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.22 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C2sH27F2NOS) 427, found 42~ (M+H).
Anal. Calcd for C2sH27F2NOS: C, 70.23; H, 6.37; N, 3.28; S, 7.50. Found: C, 70.22;
H, 6.41; N, 3.22; S, 7.39. mp 119-121~C. Rf = 0.3 (20% ethyl acetate/hexane).
F
HO~,S J~' 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl~-5-~((4-methyl) phenyl)thiolmethylpyridine The title compound was prepared from p-thiocresol according to the procedures described in Example 47. 1H NMR (300 MHz, CDCl3): ~ 7.27 (m, 2 H), 7.13 (m, 2 H), 7.03 (m, 4 H), 4.35 (d, ~ = 5.5 Hz, 2 H), 3.77 (s, 2 H), 3.44 (m, 2 H), 2.31 (s,3H),1.34(d,J=6.6Hz,6H),1.33(d,J=6.6Hz,6H),1.22(t,J-5.5Hz,1H).
FAB-MS calcd for (C26H30FNOS) 423, foLmd 424 (M+H). Anal. Calcd for W 098/045~8 PCTrUS97113248 O C26H30FNOS: C, 73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 74.00; H, 7.15; N, 3.36;
S, 7.32. mp 90-91~C. Rf = 0.3 (20% ethyl acetatethexane).
HO~,S ~3 2,6-Diisopropyl-3-hydroxymethY1-4-(4-fluorophenyl)-5-(l-naphthylthio) methylpyridine The title compound was prepared from l-naphthalenethiol according to the procedures described in Example 47. lH NMR (300 MHz, CDCl3): ~ 8.01 (d, J = 8.5 Hz,lH),7.82(d,J=8.5Hz,lH),7.74(d,J=8Hz,lH),7.46(m,3H),7.34(m,1H), 7.20 (m, 2 H), 7.06 (m, 2 H), 4.34 (d, J = 5.5 Hz, 2 H), 3.82 (s, 2 H), 3.51 (sept, J = 6.6 Hz,lH),3.45(sept,J=6.6Hz,lH),1.36(d,J=6.6Hz,6H),1.35(d,J=6.6Hz,6H), 1.19 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C2gH30FNOS) 459, found 460 (M+H).
Anal. Calcd for C29H30FNos: C, 75.78; H, 6.58; N, 3.05; S, 6.98. Found: C, 75.36;
H, 6.52; N, 2.91; S, 6.74. mp 77-79~C. Rf = 0.4 (20% ethyl acetate/hexane).
HO~S
2,6-Diiso~n3~yl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(2-naphth thio)methylpyridine -WO 3~ 1'28 PCTIUS97/13248 O The title compound was prepared from 2-naphthalenethiol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): ~ 7.77 (d, J = 9 Hz, 1 H), 7.68 (d, J = 9 Hz, 2 H), 7.52 (d, J = 1.5 Hz, 1 H), 7.45 (m, 2 H), 7.25 (m, 2 H), 7.17 (dd, J = 1.8, 8.5 Hz, 1 H), 7.07 (m, 2 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.91 (s, 2 H), 3.45 (sept,J=6.6Hz,2H),1.35(d,J=6.6Hz,6H),1.34(d,J=6.6Hz,6H),1.21 (t,J=5.5 Hz, 1 H). FAB-MS calcd for (C2gH30FNOS) 459, found 460 (M+H). Anal. Calcd for C2gH30FNOS: C, 75.78; H, 6.58; N, 3.05; S, 6.98. Found: C, 75.55; H, 6.60; N, 2.95;
S, 6.91. mp 127-129~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO~ ~ ,S ~ F
2,6-Diisopropyl-3-hydrox~rmethyl-4-(4-fluorophenyl)-5- ~(2,3,5,6-tetra-fluorophenyl)thiolmethylp-,rridine The title compound was prepared from pentafluorothiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDCl3): ~ 7.27 (m, 2 H), 7.11 (m, 2 H), 6.99 (m, 1 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.84 (s, 2 H), 3.44 (sept, J =
6.6Hz, 1 H),3.43 (sept,J= 6.6Hz, 1 H), 1.34 (d,J= 6.6Hz, 6H), 1.33 (d,J= 6.6 Hz, 6 H), 1.23 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C25H24FsNOS) 481, found 482 (M+H). Anal. Calcd for C25H24F5NOS: C, 62.36; H, 5.02; N, 2.91; S, 6.66; F, 19.73.
Found: C, 62.40; H, 4.96; N, 2.82; S, 6.74; F, 19.49. mp 109-110~C. Rf = 0.4 (20%
e~yl acetate/hexane).
HO--~S~OCH3 'f N~/
WO 98/04~28 PCT/US97/13248 0 2,6-Diisopropyl-3-hydroxvmethyl~-(4-fluorophen~,rl)-5-~(3-methoxy-phenyl)thiolmeth~lp~ridine The title compound was prepared from 3-methoxybenzenethiol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): d 7.24 (m, 2 H), 7.13 (m, 3 H), 6.72 (m, 2 H), 6.62 (m, 1 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.81 (s, 2 H), ~ 5 3.75 (s, 3 H), 3.44 (sept, J = 6.6 Hz, 1 H), 3.42 (sept, J = 6.6 Hz, 1 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.23 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for(C26H30FNo2s) 339, found 440 (M+H). Anal. Calcd for C26H30FNo2s: C, 71.04;
H, 6.88; N, 3.19; S, 7.29. Found: C, 70.94; H, 6.77; N, 2.96; S, 7.41. mp 93-94~C. Rf =
0.4 (20% ethyl acetate/hexane).
~OH
HO ~S
\~'N~/
2,6-Diiso~ro~1-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(4-hydroxy-phenyl)thiolmethylpyridine The title compound was prepared from 4-hydroxythiophenol according to the procedures described in Example 47. lH NMR (300 MHz, 5:1 CDC13/CD30D):
~ 7.15 (m, 2 H), 7.06 (m, 2 H), 6.97 (d, J = 8.5 Hz, 2 H), 6.64 (d, J = 8.5 Hz, 2 H), 4.27 (s,2H),3.66(s,2H),3.40(m,2H), 1.29(d,J=6.6Hz,6H), 1.28 (d,J = 6.6 Hz, 6 H).
FAB-MS calcd for (C2sH2gFNO2S) 425, found 426 (M+H). Anal. Calcd for C2sH2gFNO2S: C, 70.56; H, 6.63; N, 3.29; S, 7.53. Found: C, 70.29; H, 6.34; N, 3.12;
S, 7.44. mp 178-179~C. Rf = 0.3 (30% ethyl acetate/hexane).
~ 25 WO 98/04528 PCTrUS97/13248 o EXAMPLE 56 HO~--'S~
\~N~/
2,6-Diisopropyl-3-h~drox~methyl-4-(4-fluorophenyl)-5-~(4-methoxy-S phenyl)~iolmethylpyridine The title compound was prepared from 4-methoxybenzenethiol according to the procedures described in Example 47. lH NMR (300 MHz, CDCl3): ~ 7.23 (m, 2 H), 7.12 (m, 4 H), 6.77 (d, J = 9 Hz, 2 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.79 (s, 3 H), 3.73 (s,2H),3.44(sept,J=6.6Hz,2H),1.34(d,J=6.6Hz,6H), 1.33 (d,J=6.6Hz,6H), 1.21 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C26H30FNO2S) 339, found 440 (M+H).
Anal. Calcd for C26H30FNO2S: C, 71.04; H, 6.88; N, 3.19; S, 7.29. Found: C, 70.96;
H, 6.90; N, 3.15; S, 7.35. mp 92-93~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO~S ~\
2,6-Diisoprop~1-3-h~droxymethyl-4-(4-fluorophenyl)-5-~(3-methyl-phenyl)thiolmethylpyridine The title compound was prepared from m-thiocresol according to the procedures described in Example 47. 1H NMR (300 MHz, CDCl3): ~ 7.25 (m, 2 H), 7.11 (m, 3 H), 7.00 (m, 1 H), 6.94 (m, 2 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.81 (s, 2 H), 3.45 (sept, J = 6.6 Hz, 1 H), 3.43 (sept, J = 6.6 Hz, 1 H), 2.28 (s, 3 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.22 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for wo ~a,~ ~s~X PCT~US97/13248 0 (C26H30FNos) 423, found 424 (M+H). Anal. Calcd for C26H30FNOS: C, 73.72; H,7.14; N, 3.31; S, 7.57. Found: C, 73.76; H, 7.09; N, 3.27; S, 7.42. mp 92-93~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO~,S
2,6-Diisopropvl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(2-methy phenyl)thiolmethylpyridine 1 0 The title compound was prepared from o-thiocresol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): ~ 7.25 (m, 2 H), 7.11 ~m, 6 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.74 (s, 2 H), 3.45 (sept, J = 6.6 Hz, 2 H), 2.26 (s, 3 H), 1.35 (d, J = 6.6 Hz, 12 H), 1.21 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C26H30FNos) 423, found 424 (M+H). Anal. Calcd for C26H30FNOS: C, 73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 73.54; H, 7.09; N, 3.06; S, 7.37. mp 140-141~C. Rf =
0.4 (20% ethyl acetate/hexane).
HO--~SJ~F
- --'N'~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(3-fluor phenyl)thiolmethylpyridine WO ~8J'~ PCT/US97/13248 O The title compound was prepared from 3-fluorothiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): ~ 7.27 (m, 3 H), 7.11 (m, 2 H), 6.87 (m, 2 H), 6.78 (m, 1 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.82 (s, 2 H), 3.45 (sept, J = 6.6 Hz, 1 H), 3.38 (sept, J = 6.6 Hz, 1 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.33 (d, J -6.6 Hz, 6 H), 1.23 (t, J = 5.5 Hz, 1 H). FA~MS calcd for (C2sH27F2NOS) 427, found 428 (M+H). Anal. Calcd for C25H27F2NOS: C, 70.23; H, 6.37; N, 3.28; S, 7.50.
Found: C, 70.22; H, 6.31; N, 3.20; S, 7.41. mp 99-100~C. Rf = 0.4 (20% ethyl acetate/hexane).
F
HO~,S ~
2,6-Diisoprop~1-3-h~droxymethyl-4-(4-fluorophen~,r1)-5-~(2-methoxy-phenyl)thiolmeth~lpyridine The title compound was prepared from 2-methoxythiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): ~ 7.22 (m, 3 H), 7.07 (m, 3 H), 6.83 (m, 2 H), 4.34 ~d, J = 5.~ Hz, 2 H), 3.78 (s, 3 H), 3.75 (s, 2 H), 3.49 (sept, J = 6.6 Hz, 1 H), 3.43 (sept, J = 6.6 Hz, 1 H), 1.34 (d, ~ = 6.6 Hz, 12 H), 1.19 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C26H30FNO2S) 339, found 440 (M+H). Anal.Calcd for C26H3oFNo2s: C, 71.04; H, 6.88; N, 3.19; S, 7.29. Found: C, 70.93; H, 6.67; N, 3.12; S, 7.48. mp 129-131~C. Rf = 0.4 (20% ethyl acetate/hexane).
E~CAMPLE 61 F
HO'--~--'S
\~N ~/
WO 98/01r~X PCT~US97113248 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(3,5-dimethyl-phenyl)thiolmethylpyridine The title compound was prepared from 3,5-dimethylthiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): â 7.24 (m, 2 H), 7.11 (m, 2 H), 6.80 (s, 1 H), 6.69 (s, 2 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.79 (s, 2 H), 3.44 (sept, J = 6.6 Hz, 1 H), 3.42 (sept, J = 6.6 Hz, 1 H), 2.23 (s, 6 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.21 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for(C27H32FNOS) 437, found 438 (M+H). Anal. Calcd for C27H32FNOS: C, 74.11; H, 7.37; N, 3.20; S, 7.33. Found: C, 74.18; H, 7.22; N, 3.13; S, 6.86. mp 109-110~C. Rf =
0.5 (20% ethyl acetate/hexane).
HO~,S ~~
2,6-Diisopropyl-3-hydroxvmethyl-4-(4-fluorophenyl)-5-~(4-ethyl-phenyl)thiolmethylpyridine The title compound was prepared from 4-ethylthiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDCl3): ~ 7.24 (m, 2 H), 7.05 (m, 6 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.77 (s, 2 H), 3.43 (m, 2 H), 2.60 (q, J = 7.7 Hz, 2 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.32 (d, J = 6.6 Hz, 6 H), 1.21 (m, 4 H). FAB-MS calcd for (C27H32FNOS) 437, found 438 (M+H). Anal. Calcd for C27H32FNOS: C, 74.11;
H, 7.37; N, 3.20; S, 7.33. Found: C, 74.07; H, 7.23; N, 3.09; S, 7.23. mp 102-103~C. Rf = 0.5 (20% ethyl acetate/hexane).
WO 98/04528 PCTrUS97J13248 HO ~,SJ~
2,6-Diisopropvl-3-hydroxymeth~1-4-(4-fluorophenyl)-5-~(4-isopropyl-phenyl)thiolmethylpyridine The title compound was prepared from 4-isopropylthiophenol according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): ~ 7.25 (m, 2 H), 7.06 (m, 6 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.79 (s, 2 H), 3.43 (m, 2 H), 2.86 (sept, J = 7 Hz,lH),1.34(d,J=6.6Hz,6H),1.32(d,J=6.6Hz,6H),1.22(d,J=7Hz,6H), 1.20 (t, J = 5.5 Hz, 1 H). FAB-MS calcd for (C2gH34FNOS) 451, found 452 (M+H). Anal.
Calcd for C2gH34FNOS: C, 74.46; H, 7.59; N, 3.10; S, 7.10. Found: C, 74.51; H, 7.48;
N, 3.04; S, 6.85. mp 108-109~C. Rf = 0.5 (20% ethyl acetate/hexane).
F
Ho~S (3 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-benzylthio-methylpyridine The title compound was prepared from benzyl mercaptan according to the procedures described in Example 47. lH NMR (300 MHz, CDC13): ~ 7.23 (m, 5 H), 7.08 (m, 4 H), 4.31 (d, J = 5.5 Hz, 2 H), 3.55 (s, 2 H), 3.40 (sept, J = 6.6 Hz, 1 H), 3.24 (s, 2 H), 3.19 (sept, J = 6.6 Hz, 1 H), 1.31 (d, J = 6.6 Hz, 6 H), 1.24 (d, J = 6.6 Hz, 6 H), 1.17 (t, J - 5.5 Hz, 1 H). FAB-MS calcd for (C26H30FNOS) 423, found 424 (M+H).
Anal. Calcd for C26H30FNOS: C, 73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 73.58;
0 H, 7.25; N, 3.05; S, 7.45. mp 150-151~C. Rf = 0.5 (20% ethyl acetate/hexane).
~ HO~,S
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(pheneth thiomethyllpyridine The title compound was prepared from phenethyl mercaptan according to the procedures described in Example 47. 1H NMR (300 MHz, CDC13): ~ 7.28 (m, 5 H), 7.11 (m, 4 H), 4.34 (d, J = 5.5 Hz, 2 H), 3.39 (m, 4 H), 2.70 (m, 2 H), 2.61 (m, 2 H), 1.33(d,J=6.6Hz,6H),1.32(d,J=6.6Hz,6H),1.20(t,J=5.5Hz,1H). FAB-MS
calcd for (C27H32FNOS) 437, found 438 (M+H). Anal. Calcd for C27H32FNOS: C, 74.11; H, 7.37; N, 3.20; S, 7.33. Found: C, 73.99; H, 7.46; N, 2.96; S, 7.23. Gummy oil.
Rf = 0.5 (20% ethyl acetate/hexane).
HO--~S~/
~' ~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(propylthio)-methylpyridine ~ The title compound was prepared from propyl mercaptan according to the procedures described in Example 47. ~H NMR (300 MHz, CDC13): ~ 7.30 (m, 2 H), WO~8101'?~ PCT~US97/13248 0 7.14(m,2H),4.34(d,J=5.5Hz,2H),3.41(m,2H),3.37(m,2H),2.31(t,J=7.0Hz, 2 H), 1.31 (m, 15 H), 0.89 (t, J = 7.4 Hz, 3 H). FAB-MS calcd for (C22H30NFos) 375, found 376 (M+H); Anal. Calcd for C22H30NoFs: C, 70.36; H, 8.05; N, 3.73; F, 5.06;
S, 8.54. Found: C, 70.32; H, 7.97; N, 3.58; F, 4.76; S, 8.49. mp 98~C (dec.). Rf = 0.3 (10% ethyl acetate/hexane).
I
HO~f S
~N~/
2,6-Diisopropyl-3-hydroxymethvl-4-(4-fluorophenyl)-5-(methylthio)-methylpyridine The title compound was prepared from methyl mercaptan according to the procedures described in Example 47. 1H NMR (300 MHz, CDCl3): ~ 7.30 (m, 2 H), 7.16 (m, 2 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.43 (m, 2 H), 3.38 (m, 2 H), 1.95 (s, 3 H), 1.30 (m, 12 H). FAB-MS calcd for (c2oH26NFos) 347, found 348 (M+H). Anal. Calcd for C~oH26NOFS: C, 69.13; H, 7.54; N, 4.03; F, 5.47. Found: C, 69.29; H, 7.54; N, 3.91; F, 5.45. mp 49~C (dec.). Rf = 0.2 (10% ethyl acetate/hexane).
F
HO ~~~ S
\f N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(4-nitrophenyl)-thio7methylpyridine WO ~8~ 't~ PCTIUS97113248 0 Step A: 2,6-Diisopropyl-3-hydroxymeth~l-4-(4-fluorophenyl)-5-~(t-butyldimethylsilox~,r)methyllpyridine A solution of 3 g (8.3 mmol) of methyl 2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-3-pyridinecarboxylate (Example 47, Step A) in anhydrous DMF (75 mL), was treated at room temperature with imidazole (1.3 g, 19 mmol), 4-~ 5 dimethylaminopyridine (50 mg, 0.4 mmol) and t-butyldimethylsilyl chloride (1.4 g, 9.3 mmol). The reaction mixture was allowed to stir at room temperature for 48 hr.
The solution was (~ te~1 with diethyl ether (200 mL) and washed with water (2 x ~ 100 mL), lN HCl (100 mL), sat. NaHCO3 (50 mL) and brine (100 mL), dried(MgSO4) and concentrated to 4 g as an oil: Rf = 0.4 (10% ethyl acetate/hexane).
This intermediate (4 g) was dissolved in anhydrous THF (100 mL), stirred under argon and treated with lithium aluminum hydride (17 mL, 17 mmol, 1.0M in THF). The reaction mixture was stirred at reflux for 1 hr, then allowed to cool to room temperature. The reaction was quenched by the successive dropwise addition of water (0.6 mL), 20% NaOH (0.6 mL) and water (1.9 mL). The resulting suspension was filtered through a cake of celite and concentrated. Purification by flash silica gel chromatography (5% ethyl acetate/hexane) afforded a colorless resin (1.8 g, 4.2 mmol, 51%). 1H NMR (300 MHz, CDCl3) ~ 7.25 (m, 2 H), 7.12 (m, 2 H), 4.38 (d, J = 5 Hz, 2 H), 4.28 (s, 2 H), 3.44 (sept, J = 6.6 Hz, 1 H), 3.39 (sept, J = 6.6 Hz, 1 H), 1.33 (t, J = 6.6 Hz, 12 H), 1.24 (t, J = 5.5 Hz, 1 H), 0.84 (s, 9 H), -0.08 (s, 6 H).
FAB-MS calcd for (C2sH3gFNSiO2) 431, found 432 (M+H). Anal. Calcd for C2sH3gFNSiO2: C, 69.56; H, 8.87; N, 3.24. Found: C, 69.70; H, 8.82; N, 3.12. Rf =
0.2 (10% ethyl acetate/hexane).
Step B: 2,6-Diisopropyl-3-bromomethyl-4-(4-fluorophenyl)-5 ~(t-butyldimethylsilox~)methyllpvridine The intermediate obtained in Step A (1.7 g, 3.9 mmol) was dissolved in acetonitrile (50 mL) at 0~C and treated with dibromotriphenylphosphorane (2.6 g,6.2 mmol) in portions. The suspension was then allowed to warm to room temperature and stirred for 2 hr. The solvent was removed in v~cuo and the residue partitioned between diethyl ether (150 mL) and water (100 mL). The etherlayer was washed with brine (50 mL), dried (MgSO4) and concentrated.
Purification by chromatography through silica (5% diethyl ether/hexane) affordeda viscous oil (1.4 g, 2.8 mmol, 72%) which slowly solidified on standing: 1H NMR- (300 MHz, CDCl3): ~ 7.28 (m, 2 H), 7.13 (m, 2 H), 4.23 (m, 4 H), 3.37 (m, 2 H), 1.34 (d, J = 6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 0.83 (s, 9 H), -0.09 (s, 6 H). FAB-MS
calcd for (C27H37BrFSiNO) 493, found 494 (M+H). mp 72-73~C. Rf = 0.5 (10% ethyl acetate/hexane).
WO 98/04S28 PCTrUS97/13248 o Step C: 2,~Diisopropyl-3-hydroxymethyl-4-(4-f~uorophenyl)-5-~(4-nitrophenyl)thiolmethylpyridine The intermediate obtained in Step B (200 mg, 0.40 mmol) was dissolved in anhydrous THF (5 mL), stirred under argon at room temperature and treated with ~mtrothiophenol (118 mg, 0.6 mmol, 80% tech. grade) and N-methylmorpholine (0.2 mL, 1.8 mmol). The reaction mixture was allowed to stir at reflux for 18 hr, then cooled to room temperature. The mixture was treated with tetrabutylammonium fluoride (0.8 mL, 0.8 mmol, 1.0M in THP) and allowed to sti at room temperature for 24 hr. The solvent was removed in vacuo, the residue dissolved in ethyl acetate (100 mL), washed with lN HCl (50 mL), sat. NaHCO3 (50mL) and brine (50 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient 5-10% ethyl acetate/hexane) afforded the title compound as a lightly colored solid (130 mg, 0.28 mmol, 70%).lH NMR (300 MHz, CDCl3~: ~ 8.08 (d, J = 8.5 Hz, 2 H), 7.27 (m, 2 H), 7.13 (m, 4 H), 1 5 4.37 (d, J = 5.5 Hz, 2 H), 3.91 (s, 2 H), 3.46 (sept, J = 6.6 Hz, 1 H), 3.33 (sept, J - 6.6 Hz,lH),1.35(d,J=6.6Hz,6H),1.34(d,J=6.6Hz,6H),1.27(t,J=5Hz, 1 H).
PAB-MS calcd for (C2~H27FSN203) 454, found 455 (M+H). mp 178-180~C. Rf = 0.3 (20% ethyl acetate/hexane).
HO ~N O
~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(morpholino-methyl)pyridine Step A: Methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(morpholino)methyl-3-pyridinecarboxylate A solution of methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-bromomethyl-3-pyridinecarboxylate (Example 47, Step B) (500 mg, 1.22 mmol) in CH2Cl2 (20 mL) O was treated with morpholine (0.14 mL, 1.61 mmol) under argon. The reaction wasstirred at room temperature for 48 hours. It was then diluted with CH2Cl2 (70 mL), washed with saturated NaHCO3 (2 x 40 mL), water (1 x 40 mL), and brine (1 x40 mL). The organic layer was dried with MgSO4, filtered, and concentrated to afford a white solid (4g5 mg, 1.2 mmol, 98%). lH NMR (300 MHz, CDCl3): ~ 7.16 S (m, 2 H), 7.07 (m, 2 H), 3.54 (t, J = 4.4 Hz, 4 H), 3.49 (m, 4 H), 3.27 (s, 2 H), 2.98 (septet, J = 6.6 Hz, 1 H), 2.19 (t, J = 4.8 Hz, 4 H), 1.30 (m, 12 H). FAB-MS calcd for (C24H31N2F03) 414, found 415 (M+H); Anal. Calcd for C24H31N203F: C, 69.54;
H, 7.54; N, 6.76; F, 4.58. Found: C, 69.55; H, 7.43; N, 6.50; F, 4.45. mp 132-134~C. Rf = 0.2 (20% diethyl ether/hexane).
Step B: 2,6-Diisopropyl-3-hydroxymethvl-4-(4-fluorophenyl)-5 (morpholinometh~l)pyridine The intermediate obtained in Step A (375 mg, 0.905 mmol) was dissolved in dry THF (50 mL), treated dropwise with lithium aluminum hydride (lM/THF, 1.81 mL) and the reaction stirred at reflux for 24 hours. The reaction was quenched by the successive dropwise addition of water (0.lml), NaOH 20% (0.lml), and water again (0.3ml). Concentration in vacuo afforded a white residue which was partitioned between CH2C12 and water. The organic layer was dried wi~ MgSO4, filtered, and concentrated to afford an oil. The product was passed through a pad of silica (40% diethyl ether/hexanes) yielding an oil which slowly solidified to give the title compound as a white solid (295 mg, 0.76 mmol, 84%). lH NMR ~300 MHz, CDCl3): ~ 7.14 (m, 4 H), 4.35 (d, 2 H), 3.53 (t, J = 4.8 Hz, 4 H), 3.45 (m, 2 H), 3.18 (s, 2 H), 2.18 (t, J = 4.5 Hz, 4 H), 1.26 (m, 13 H); FAB-MS calcd for (C23H31N2FO2) 386, found 387 (M+H). Anal. Calcd for C23H31N2O2F: C, 71.47; H, 8.08; N, 7.25; F, 4.92 25Found: C, 71.55; H, 8.16; N, 7.05; F, 4.70. mp 93.5-95.5~C. Rç = 0.4 (40% diethyl ether/hexane).
HO~,N~
W O 98/04528 PCT~US97113248 o 2,6-Diisopropyl-3-hydroxymethyl-4-~4-fluorophenyl)-5-(piperidinomethyl)pyridine The title compound was prepared from piperidine according to the procedures described in Example 69. 1H NMR (300 MHz, CDC13): ~ 7.05 (m, 4 H), 4.27 (d, J = 5.5 Hz, 2 H), 3.38 (m, 2 H), 3.01 (s, 2 H), 2.02 (m, 4 H), 1.22 (m, 24 H).
FAB-MS calcd for (C24H33N2FO) 384, found 385 (M+H). Anal. Calcd for C24H33N2OF: C, 74.96; H, 8.65; N, 7.28; F, 4.94. Found: C, 75.13; H, 8.48; N, 6.92;
F, 4.77. Gummy oil. Rf = 0.5 (40% diethyl ether/hexane).
F
HO ~ ~N~
\~ N ~/
2,6-Diisopropyl-3-h~,rdroxvmethyl-4-(4-fluorophenyl)-5-(pyrrolidino-methyl)pyridine The title compound was prepared from pyrrolidine according to the procedures described in Example 69. lH NMl~ (300 MHz, CDC13): ~ 7.13 (m, 4 H), 4.34 (d, J = 4.8 Hz, 2 H), 3.52 (septet, J = 6.6 Hz, 1 H), 3.42 (septet, J = 6.6 Hz, 1 H), 3.28 (s, 2 H), 2.22 (t, J = 6.3 Hz, 4 H), 1.60 (t, J = 3.3 Hz, 5 H), 1.27 (m, 12 H).
FAB-MS calcd for (C23H31N2FO) 370, found 371 (M+H). Anal. Calcd for C23H31N2OF: C, 74.56; H, 8.43; N, 7.56; F, 5.13. Found: C, 74.67; H, 8.72; N, 7.35;
F, 5.01. mp 122-124~C. Rf = 0.3 (40% diethyl ether/hexane).
F
~1 HO~ ~N~
.. ... .. . . . .
WO 98/01'"~ PCTIUS97/13248 O
2,6-Diisoprop~ 3-hydroxymethyl-4-(4-fluorophenyl)-5-~4-phenylpiperidin yl)methyl~pyridine The title compound was prepared from ~phenylpiperidine according to the procedures described in Example 69. lH NMR (300 MHz, CDCl3): ~ 7.29 (m, 2 H), 7.15 (m, 7 H), 4.36 (d, J = 5.2 Hz, 2 H), 3.48 (m, 2 H), 3.19 (s, 2 H), 2.71 (d, J = 11.0 Hz, 2 H), 2.38 (m, 1 H), 1.86 (m, 2 H), 1.71 (m, 2 H), 1.58 (m, 2 H), 1.58 (m, 13 H). FAB-MS calcd for (C30H31N2FO) 460, found 461 (M+H). Anal. Calcd for C23H31N20P:
C, 78.22; H, 8.10; N, 6.08; F, 4.12. Found: C, 78.01; H, 8.21; N, 5.96; F, 4.41. mp 66-68~C. Rf = 0.5 (40% diethyl ether/hexane).
0~
MeO~~N~}
\~ N \/
Methyl-2,6-diisopropvl-4-(4-fluorophenyl)-5-(4-piperid~nopiperidin-1-yl)methyl-3-pyridinecarboxylate The title compound was prepared from 4-piperdinopiperidine according to the procedure described in Example 69 (Step A). 1H NMR (300 MHz, CDCl3):
7.16 (m, 2 H), 7.04 (m, 2 H), 3.51 (septet, J = 5.5 Hz, 1 H), 3.47 (s, 3 H), 3.20 (s, 2 H), 20 2.98 (septet, J = 6.6 Hz, 1 H), 2.65 (d, J = 11.0 Hz, 2 H), 2.44 (m, 4 H), 2.05 (m, 1 H), 1.62 (m, 10 H), 1.31 (m, 16 H). FA~MS calcd for (C30H42N3Fo2) 495, found 496 (M+H). Anal. Calcd for C30H42N3o2F: C, 72.69; H, 8.54; N, 8.48; F, 3.83. Found:
C, 72.43; H, 8.56; N, 8.37; F, 3.74. mp 59-61~C. Rf = 0.1 (70% diethyl ether/hexane +
1 drop MeOH).
WO g8/01-2~ PCTrUS97/13248 HO~N~ N~
2,6-Diisopropyl-3-hydrox~methyl-4-(4-fluorophenyl)-5-~(4-piperidinopiperidin-1-yl)meth~llpyridine The title compound was prepared from 4-piperidinopiperidine according to the procedures described in Example 69. lH NMR (300 MHz, CDC13): ~ 7.12 (m, 4 H), 4.34 (d, J = 3.7 Hz, 2 H), 3.45 (m, 2 H), 3.10 (m, 2 H), 2.63 (d, J = 11.0 Hz, 2 H), 2.44 (m, 4 H), 2.03 (m, 1 H), 1.44 (m, 29 H). FAB-MS calcd for (C29H42N3FO) 467,1 0 found 468 (M+H). Anal. Calcd for C2gH42N3OF: C, 74.48; H, 9.05; N, 8.98; F, 4.06.
Found: C, 74.93; H, 9.35; N, 8.39; F, 3.83. mp 143-145~C. Rf = 0.1 (~0% diethyl e~er/hexane + 2 drops of MeOH).
F
HO~ N 6 2,6-Diisopropyl-3-hydroxymethyl-4-~4-fluorophenyl)-5-~(4-phenylpiperazin yl)methyllpyridine The title compound was prepared from 4-phenylpiperazine according to the procedures described in Example 69. lH NMR (300 MHz, CDCl3): ~ 7.16 (m, 6 H), 6.85(m,3H),4.36(d,J=5.2Hz,2H),3.47(m,2H),3.24(s,2H),3.04(t,J=4.8Hz, 4 H), 2.35 (t, J = 4.8 Hz, 4 H), 1.29 (m, 13 H). FAB-MS calcd for (C29H36N3FO) 461, found 462 (M+H). Anal. Calcd for C2gH36N3OF: C, 75.46; H, 7.86; N, 9.10; F, 4.12.
WO ~ x PCTrUS97/13248 0 Found: C, 75.35; H, 7.82; N, 8.80; F, 3.99. mp 111-113~C. Rf - 0.5 (40% diethyl ether/hexane).
HO ''~ N~N
\~' N'~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(imidazol-l-yl) methylpyridine The title compound was prepared from irnidazole according to the procedures described in Example 69. 1H NMR (300 MHz, CDC13): ~ 7.01 (m, 6 H), 6.57 (s, 1 H), 4.84 (s, 2 H), 4.39 (s, 2H), 3.49 (septet, J = 6.6 Hz, 1 H), 3.23 (septet, J
= 6.6 Hz, 1 H), 1.70 (s, 1 H), 1.36 (d,J= 6.6 Hz, 6 H), 1.27 (d, J = 6.6 Hz, 6 H). FAB-MS calcd for (C22H26N3FO) 367, found 368 (M+H). Anal. Calcd for C22H26N3OF:
C, 71.91; H, 7.13; N, 11.43; F, 5.17. Found: C, 71.26; H, 7.24; N, 11.03; F, 5.35. mp 184-186~C. Rf = 0.1 (50% diethyl ether/hexane w/ 2 drops MeOH).
HO ''~ H
~f N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(cyclopr amino)methylpyridine The title compound was prepared from cyclopropylamine according to the WO 98/01r2~ PCTAUS97/13248 O procedures described in Example 69. lH NMR (300 M~z, CDCl3): ~ 7.04 (m, 4 H), 4.21 (s, 2 H), 3.35 (s, 2 H), 3.26 (septet, J = 6.6 Hz, 2 H), 1.78 (m, 1 H), 1.17 (m, 13 H), 0.153 (m, 2 H), -0.006 (m, 2 H). FAB-MS calcd for (C22H2gN2FO) 356, found 357 (M+H). Anal. Calcd for C22H29N2OF: C, 74.12; H, 8.20; N, 7.86; F, 5.33. Found:
C, 74.29; H, 8.62; N, 7.93; F, 4.90. mp 81-83~C. Rf = 0.3 (40% diethyl ether/hexane).
s HO--~--N '~
~N~H
2,6-Diisopropyl-3-hydroxyrnethyl-4-(4-fluorophenyl)-5-(cyclohexyl-amino)methylpyridine The title compound was prepared from cyclohexylamine according to the procedures described in Example 69. 1H NMR (300 MHz, CDCl3): ~ 7.25 (m, 2 H), 7.13 (m, 2 H), 4.34 (s, 2 H), 3.38 (m, 4 H), 2.16 (m, 1 H), 1.58 (m, 5 H), 1.23 (m, 16 H), 0.936 (m, 2 H). FAB-MS calcd for (C25H3sN2FO) 398, found 399 (M+H). Anal.
Calcd for C2sH3sN2OF: C, 74.12; H, 8.20; N, 7.86; F, 5.33. Found: C, 74.29; H, 8.62;
N, 7.93; F, 4.90. mp 131-133~C. Rf = 0.1 (40% diethyl ether/hexane).
F
HO ~''N
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(dimethylamino)-methylpvridine WO 98/04528 PCTfUS97/13248 O The title compound was prepared from dimethylamine hydrochloride according to the procedures described in Example 69. lH NMR (300 MHz, CDC13):
7.12 (m, 4 H), 4.25 (m, 2 H), 4.09 (m, 1 H), 3.68 (septet, J = 6.6 Hz, 1 H), 3.41 (septet, J = 6.6 Hz, 1 H), 2.18 (m, 1 H), 1.69 (d, J = 4.1 Hz, 1 H), 1.26 (m, 12 H), 0.947 (d, J = 6.3 Hz, 3 H), 0.555 (d, J = 7.0 Hz, 1 H). FAB-MS calcd for (c22H3oNFo2) 359, found 360 (M+H). Anal. Calcd for C22H30No2F: C, 73.51; H, 8.41; N, 3.90; F, 5.28.
Found: C, 73.69; H, 8.40; N, 3.82; F, 5.04. mp 77-7g~C. Rf = 0.2 (40% diethyl ether/hexane).
.
F
HO~N--'f N~/
2,6-Diisopropvl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(dibutylamino)-methylpyridine The title compound was prepared from dibutylamine according to the procedures described in Example 69. 1H NMR (300 MHz, CDCl3): ~ 7.11 (m, 4 H), 4.33 (d, J = 5.5 Hz, 2 H), 3.62 (septet, J = 6.6 Hz, 1 H), 3.62 (septet, J = 6.6 Hz, 1 H), 3.24 (s, 2 H), 2.12 (t, J = 7.0 Hz, 4 H), 1.55 (s, 1 H), 1.33 (t, J = 6.6 Hz, 6 H), 1.26 (t, J =
6.6 Hz, 6 H), 1.16 (m, 8 H), 0.796 (t, J = 6.6 Hz, 6 H). FAB-MS calcd for (C27H41N2FO) 428, found 429 (M+H). Anal. Calcd for C27H41N2OF: C, 75.66; H, 9.64; N, 6.54; F, 4.43. Found: C, 75.91; H, 9.83; N, 6.26; F, 4.33. Gummy oil. Rf = 0.6 (40% diethyl ether/hexane).
HO~
N '~/
W O 981'~'52~ PCTAUS97/13248 2,6-Diisopropyl-3-hydroxymethyl~-(4-fluorophenyl)-5-methylpyridine A solution of methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-bromomethyl-3-pyridinecarboxylate (Example 47, Step B) (300 mg, 0.7 mmol), in anhydrous THF
(10 mL) was stirred under argon at room temperature and treated dropwise with S lithium aluminum hydride (2.1 mL, 1.0 M in THF, 2.1 mmol). The reaction mixture was heated at reflux for 1 hr, then allowed to cool to room temperature. The reaction was quenched by the dropwise sequential addition at room temperature of water (80 uL), 20% NaOH (80 uL) and water (240 uL). The resulting suspension was filtered through a pad of celite and concentrated. Purification by 10 chromatography through silica (5% ethyl acetate/hexane) afforded the title compound as a white solid (182 mg, 0.6 mmol, 85%). lH NMR (300 MHz, CDCl3):
7.15 (d, J = 7 Hz, 4 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.42 (sept, J = 6.6 Hz, 1 H), 3.26 (sept, J = 6.6 Hz, 1 H), 1.94 (s, 3 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.29 (d, J = 6.6 Hz, 6 H), 1.19 (t, J = 5.5 Hz, 1 H); FAB-MS calcd for (ClgH24FNo) 301, found 302 (M+H).
Anal. Calcd for C1gH24FNO: C, 75.72; H, 8.03; N, 4.65. Found: C, 75.62; H, 8.02;
N, 4.57. mp 127-128~C. Rf = 0.3 (20% ethyl acetate/hexane).
~' HO
2,6-Diiso~l o~yl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-phenyl-2 propenyl)pyridine Step A: Methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate Methoxymethyl triphenylphosphonium chloride (1.15 g, 3.35 mmol) was suspended in 25 mL of dry, distilled THF under argon and stirred at -78~C.
Butyllithium (1.6 M/hexane, 1.2 eq., 2.1 mL) was added dropwise and then the reaction mixture was allowed to stir at 0~C for 1.0 hour. The solution was cooled W 098/04528 PCTrUS97/13248 0 again to -78~C, treated dropwise with a solution of 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) (1 g, 2.8 mmol) in 20 mL of dry THF, and then warmed to room temperature and stirred overnight.
The reaction was quenched 2 mL water and the THF was evaporated in vacuo.
Diethyl ether was added and washed with water (2 x 40 mL), brine (1 x 40 mL), and S dried with MgSO4. The residue was dissolved in THF (20 ml), treated with a solution of concentrated HCl and stirred at room temperature for lh. The reaction mixture was diluted with diethyl ether (150 ml) washed wi'th water (50 ml), brine ~ (50 ml), dried with MgSO4 and evaporated in vac~o. Flash chromatography (10%
ethyl acetate/hexane) afforded 335 mg (0.9 mmol, 32%) of product. 1H NMR (300 MHz, CDCl3): ~ 9.62 (s, 1 H), 7.09 (m, 4 H), 3.97 (q, J = 7 Hz, 2 H), 3.60 (s, 2 H), 3.06 (sept, J = 6.6 Hz, 1 H), 3.00 (sept, J = 6.6 Hz, 1 H), 1.32 (d, J = 6.6 Hz, 6 H), 1.27 (d, J =
6.6 Hz, 6 H), 0.97 (t, J = 7 Hz, 3 H). FAB-MS: calcd for (C22H26FNO3) 371, found372 (M+H). Anal. Calcd for C22H26FNO3: C, 71.14; H, 7.06; N, 3.77. Found: C, 70.91; H, 6.91; N, 3.63. mp 69-71~C. Rf = 0.3 (10% ethyl acetate/hexane).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-phenyl-2 propenyl)pyrid~ne The title compound was prepared from the intermediate obtained in Step A
and benzyl triphenylphosphonium ~romide/sodium amide according to the procedures described in Example 1, Steps F-G. The product was obtained as a 6:4 mixture of trans:cis isomers. 1H NMR (300 MHz, CDC13): ~ 7.19 (m, 8 H), 6.96 (m,1 H), 6.32 (d, J = 11 Hz, 0.4 H), 6.09 (dt, J = 5.5, 16 Hz, 0.6 H), 5.96 (d, J = 16 Hz, 0.6 H), 5.45 ~dt, J = 7, 11 Hz, 0.4 H), 4.37 (d, J = 5 Hz, 1.25 H), 4.33 (d, J = 5.5 Hz, 0.75 H), 3.41 (m, 1.6 H), 3.25 (m, 2 H), 3.08 (m, 0.4 H), 1.35 (m, 5 H), 1.30 (d, J = 6.6 Hz, 5 H), 1.21 (m, 3 H). FAB-MS: calcd for (C27H30FNo) 403, found 404 (M+H). Anal.
Calcd for C27H30FNO: C, 80.36; H, 7.49; N, 3.47. Found: C, 80.15; H, 7.44; N, 3.26.
mp 72-73~C. Rf = 0.3 (20% ethyl acetate/hexane).
F
HO~--2,6-Diisopropyl-3-hydrox~methyl-4-(4-fluorophenyl)-5-(3-phenyl-propyl)pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-phenyl-2-propenyl)pyridine (Example 82) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCl3): ~ 7.11 (m, 9 H), 4.31 (s, 2 H), 3.40 (sept, J = 6.6 Hz, 1 H), 3.12 (sept, J = 6.6 Hz, 1 H), 2.46 (t, J =
7.35 Hz, 2 H), 2.29 (m, 2 H), 1.62 (m, 2 H), 1.32 (d, J = 6.6 Hz, 6 H), 1.26 (d, J = 6.6 Hz, 6 H), 1.16 (bm, 1 H). FAB-MS: calcd for (C27H32FNO) 405, found 406 (M+H). mp 137-140~C. Rf = 0.3 (20% ethyl acetate/hexane).
F
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~3-(2-methyl-1 5 phenyl)propyllpyridine The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and 2-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. lH NMR (300 MHz, CDCl3): ~ 7.07 (m, 7 H), 6.90 (m, 1 H), 4.31 (s, 2 H), 3.39 (sept, J = 6.6 Hz, 1 H), 3.15 (sept, J = 6.6 Hz, 1 H), 2.43 (t, J = 7.5 Hz, 2 H), 2.34 (m, 2 H), 2.17 (s, 3 H), 1.56 (m, 2 H), 1.31 (d, J = 6.6 Hz, 6 H), 1.27 (d, J = 6.6 Hz, 6 H), 1.15 (m, 1 ~I). FAB-MS: calcd for (C2gH34FNO) 419, found 420 (M~H). Anal. Calcd for C2gH34FNO: C, 80.15; H, 8.17; N, 3.34. Found:
C, 80.12; H, 8.01; N, 3.25. mp 65-70~C. Rf = 0.4 (20% ethyl acetate/hexane).
W O~ PCTrUS97tl3248 o EXAMPLE 85 HO ~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~3-(3-methyl-S phenyl)propyllpyridine The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and 3-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. lH NMR (300 MH:z, CDCl3): ~ 7.09 (m, 5 H), 6.98 (m, 1 H), 6.78 (m, 2 H), 4.31 (s, 2 H), 3.39 (sept, J = 6.6 Hz, 1 H), 3.12 (sept, J =
6.6Hz,lH),2.42(t,J=7Hz,2H),2.30(s,3H),2.28(m,2H),1.58(m,2H),1.31(d,J
= 6.6 Hz, 6 H), 1.26 (d, J = 6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C2gH34FNO) 419, found 420 (M+H). Anal. Calcd for C2gH34FNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.23; H, 8.17; N, 3.23. mp 68-70~C. Rf = 0.4 (20% ethyl acetate/hexane).
HO~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~3-(4-meth phenyl)propyllpyridine The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and 4-methylbenzyl triphenylphosphonium bromide according to the procedures O described in Example 1, Steps F-H. lH NMR (300 MHz, CDCl3): ~ 7.08 (m, 4 H), 7.01 (d,J= 8Hz,2H),6.85(d,J=8Hz,2H),4.30(s,2H),3.39 (sept,J=6.6Hz, 1 H), 3.13 (sept, J = 6.6 Hz, 1 H), 2.41 (t, J = 7 Hz, 2 H), 2.31 (s, 3 H), 2.27 (m, 2 H), 1.58 (m, 2 H), 1.31 (d, J = 6.6 Hz, 6 H), 1.26 (d, J = 6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C2gH34FNO) 419, found 420 (M+H). Anal. Calcd for C2gH34FNO: C, 80.15;
H, 8.17; N, 3.34. Found: C, 80.33; H, 8.28; N, 3.22. mp 79-80~C. Rf = 0.4 (20% ethyl acetate/hexane) .
HO--\~ N '~/
2,6-Diisopropyl-3-hydroxymethvl-4-(4-fluorophenyl)-5-(2-propenyl)-pyrid~ne The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and methyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. lH NMR (300 MHz, CDCl3): ~ 7.13 (m, 4 H), 5.73 (m, 1 H), 4.81 (dd, J = 4.8, 1.8 Hz, 2 H), 4.35 (s, 2 H), 3.43 (septet, J = 6.6 Hz, 1 H), 3.21 (septet, J
= 6.6 Hz, 1 H), 3.07 (d, J = 1.8 Hz, 2 H), 1.24 (m, 13 H). FAB-MS: calcd for (C21H26FNO) 327, found 328 (M+H). Anal. Calcd for C21H26FNO: C, 74.17; H, 7.71; N, 4.12; F, 5.59 + 0.7 H2O. Found: C, 74.17; H, 7.57; N, 3.94; F, 5.26. mp 69-71~C. Rf = 0.35 (15% ethyl acetate/hexane).
~1 HO~-- OH
\~N~/
W O~ e2~ PCT~US97/13248 o 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-hydrox~-butyl)pyridine To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[3-(1,3-dioxolan-2-yl)propyl]pyridine (Example 46) (2 g, 5 mmol) in THF (50 mL) wasadded 2N aq. HCl (10 mL). The solution was allowed to stir for 17 hr at room S temperature. The THF was removed in vacuo and the residual suspension carefully neutralized to pH 7 with sat. aq. NaHCO3. The aqueous phase was extracted with diethyl ether (3 x 100 mL), the combined ether extract washed with brine (50 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient, 10%-20% ethyl acetate/hexane) afforded a white solid (1.5 g, 4.2mmol, 83%): 1H NMR (300 MHz, CDCl3): d 9.57 (s, 1 H), 7.16 (m, 4 H), 4.33 (d, J =
5Hz,2H),3.42(m,1H),3.24(m,1H),2.33(m,2H),2.27(dt,J=1.8,7.4Hz,2H), 1.61 (m, 2 H), 1.32 (m, 12 H), 1.20 (m, 1 H). FAB-MS: calcd for (C22H30FNO2) 359, found 340 (M+H). Rf = 0.3 (20% ethyl acetate/hexane).
This intermediate (200 mg, 0.56 mmol) was dissolved in absolute ethanol (5 mL) and treated at room temperature, with stirring, with sodium borohydride (32 mg, 0.85 mmol). After stirring for 1 hr, the reaction was quenched by the dropwise addition of 2N HCl (3 mL). The solution was stirred 5 min, then neutralized by the careful addition of sat. NaHCO3. The aqueous phase was extracted with diethyl ether (3 x 50 mL), the combined extracts dried (MgSO4) and concentrated.
Purification by chromatography through silica (20% ethyl acetate/hexane) afforded the title compound as a white solid (88 mg, 0.25 mmol, 44%): lH NMR (300 MHz, CDCl3): ~ 7.16 (m, 4 H), 4.33 (d, J = 5 Hz, 2 H), 3.46 (m, 2 H), 3.41 (m, 1 H), 2.23 (m, 1 H), 2.32 (m, 2 H), 1.40 (m, 4 H), 1.32 (m, 12 H), 1.19 (m, 1 H), 1.09 (m, 1 H). FAB-MS: calcd for (C22H30FNO2) 359, found 360 (M+H). Anal. Calcd for C22H30FNo2: C, 73.51; H, 8.41; N, 3.90. Found: C, 73.37; H, 8.41; N, 3.72. mp 135-137~C. Rf = 0.4 (50% ethyl acetate/hexane);
¢~
HO--Y~ N
\~lN ~/
WO ~8/01'~8 PCTIUS97113248 0 2,6-Diisopropvl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(3-dimethyl-amino)propyllpyridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and (2-dimethylaminoethyl)triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. lH NMR (300 MHz, CDC13): ~ 7.17 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.21 (sept, J = 6.6 Hz, 1 H), 2.32 (m,2 H), 2.16 (m, 2 H), 2.14 (s, 6 H), 1.49 (m, 2 H), 1.32 (m, 13 H). FAB-MS: calcd for (C23H33FN20) 372,found 373 (M+H). mp 50-51~C. Rf = 0.35 (20%
ethanol/CH2Cl2) ¢~
-HO r (cH2~7 --f 'N~/
2,6-Diisoprop-~1-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(3-dimeth~
1 5 amino)heptyllp~ridine Step A 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4 oxobutyl)pvridine To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-l3-(1,3-dioxolan-2-yl)propyl]pyridine (Example 46) (2 g, 5 mmol) in THF (50 mL) wasadded 2N aq. HCl (10 mL). The solution was allowed to stir for 17 hr at room temperature. The THF was removed in vacuo and the residual suspension carefully neutrali~ed to pH 7 with sat. NaHCO3. The aqueous phase was extracted with diethyl ether (3 x 100 mL), the combined ether extract washed with brine (50 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient, 10%-20% ethyl acetate/hexane) afforded a white solid (1.5 g, 4.2mmol, 83%). lH NMR (300 MHz, CDCl3): ~ 9.57 (s, 1 H), 7.16 (m, 4 H), 4.33 (d, J =
5 Hz, 2 H), 3.42 (m, 1 H), 3.24 (m, 1 H), 2.33 (m, 2 H), 2.27 (dt, J = 1.8, 7.4 Hz, 2 H), 1.61 (m, 2 H), 1.32 (m, 12 H), 1.20 (m, 1 H). FAB-MS: calcd for (c22H28FNo2) 357, found 358 (M+H). Rf - 0.3 (20% e~yl acetate/hexane).
....
o Step B: 2,6-Diisopropyl-3-hydrox~methyl-4-(4-fluorophenyl)-5-~(3-dimethylamino)heptyllpyridine The intermediate prepared in Step A was treated with (3-dimethylamino)propyl triphenylphosphonium bromide according to the 5 procedures described in Example 1, Steps F-H, to afford the title compound as a solid. 1H NMR (300 MHz, CDCl3): ~ 7.16 (m, 4 H), 4.32 (s, 2 H), 3.41 (sept, J = 6.6 Hz, 1 H), 3.22 (sept, J = 6.6 Hz, 1 H), 2.28 (s, 6 H), 2.26 (m, 4 H), 1.43 (m, 2 H), 1.33 (d, J = 6.6 Hz, 6 H), 1.30 (d, J = 6.6 Hz, 6 H), 1.27 (m, 3 H), 1.31 (m, 6 H). FAB-~:
calcd for (c27H4lFN2o) 428, found 429 (M+H). mp 85-87~C. Rf = 0.1 (20%
EtOH/CH2C12) HO ~ (CH2)8COOH
\~ N ~/
2,6-Diisopropyl-3-h~ldrox-lmethyl-4-(4-fluorophenyl)-5-(8-carboxyheptyl)pyridineThe title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-oxobutyl)pyridine (Example 90, Step A) and (4-carboxybutyl)triphenylphosphonium bromide according to the procedure described in Example 90, Step B. 1H NMR (300 MHz, CD30D): ~ 7.17 (m, 4 H), 4.23 (s, 2 H), 3.44 (sept, J = 6.6 Hz, 1 H), 3.23 (sept, J = 6.6 Hz, 1 H), 2.28 (m, 2 H), 2.14 (t, J
=7.5Hz,2H),1.54(m,2H),1.28(d,J=6.6Hz,6H),1.24(d,J=6.6Hz,6H),1.22 (m, 4 H), 1.17 (m, 2 H), 1.10 (m, 4 H). EI-MS: calcd for (C27H3gFNO3) 443, found443 (M+). mp 240~C (dec). Rf = 0.3 (50% ethyl acetate/hexane).
W098/04528 PCTrUS97113248 HO ~'CO2H
\~N~/
2,~-Diisopropyl-3-hvdroxvmethyl-4-(4-fluorophenyl)-5-(3-carboxy~ro~yl)pvridine To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[3-(1,3-dioxolan-2-yl)propyl3pyridine (Example 46) (2 g, 5 mmol) in THF (50 mL) wasadded 2N aq. HC1 (10 mL). The solution was allowed to stir for 17 hr at room temperature. The THF was removed in v~cuo and the residual suspension carefully neutralized to pH 7 with sat. NaHCO3. The aqueous phase was extracted with diethyl ether (3 x 100 mL), and the combined ether extract washed with brine (50mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient, 10%-20% ethyl acetate/hexane) afforded 1.5 g of the intermediate as a white solid: Rf = 0.3 (20% ethyl acetate/hexane).
280 mg of the intermediate was dissolved in dry pyridine (5 mL), stirred at room temperature under argon and treated with acetic anhydride (0.37 mL, 3.9 rnmol). The reaction mixture was allowed to stir at room temperature for 17 hr.
The pyridine was removed in vacuo, and the residue dissolved in diethyl ether (50 mL), washed with sat. CuSO4 (10 mL), water (20 mL), sat. NaHCO3 (20 mL) and brine (10 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (20% ethyl acetate/hexane) afforded 220 mg as a viscous yellow oil:
Rf = 0.6 (50% ethyl acetate/hexane).
200 mg of the oil was dissolved in acetone (5 mL), stirred at room temperature and treated with Jones reagent (2 mL, prepared from 67 g CrO3, 125 mL H2O and 58 mL con. H2SO4). The reaction mixture was stirred 0.5 hr, quenched by the addition of 2-propanol, filtered through a short pad of silica and concentrated. The residue was dissolved in MeOH (5 mL), treated with 20% NaOH
(2 mL) and stirred 14 hr at room temperature. After neutralizing to pH 7 with aq.
HCl, the solution was saturated with NaCl and extracted with CHC13 (3 x 20 mL).
The combined extract was dried (MgSO4) and concentrated. Purification by chromatography through silica (1:1 ethyl acetate/hexane) afforded the title . , . . _~ . . . . . .....
0 compound as a white foam (22 mg). 1H NMR (300 MHz, CD30D): ~ 7.18 (m, 4 H), - 4.24 (s, 2 H), 3.46 (sept, J = 6.6 Hz, 1 H), 3.33 (sept, J = 6.6 Hz, 1 H), 2.34 (m, 2 H), 1.99(t,J=7Hz,2H),1.60(m,2H),1.29(d,J=6.6Hz,6H),1.26(d,J=6.6Hz,6H).
FAB-MS: calcd for (C22H2gFNO3) 373, found 374 (M+H). mp 160~C. Rf = 0.3 (50%
ethyl acetate/hexane).
s E~CAMPLE 93 F
~ OH
HO ~~\
\~' N '~/
(+)-2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(1-h~droxy-ethyl)pyridine Step A: (+)-Ethyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(1-h~rdroxy-ethyl)-3- pyridinecarboxylate To 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridine-carboxaldehyde (Example 1, Step E) (1 g, 2.91 mmol) in THF (30 mL) was added methyllithium (1.4 M, 1.0 eq., 2.08 mL) dropwise at -78~C under argon. The reaction was stirred for 2 hours, then quenched with water and the THF
evaporated to afford a white solid. The product was partitioned between diethyl ether and water. The organic layer was then dried with MgSO4, filtered, and concentrated to afford a white solid. The product was passed through a plug of silica (10% ethyl acetate/hexane) to afford a white solid (857 mg, 2,4 mmol, 82%).
1H NMR (300 MHz, CDC13): ~ 7.14 (m, 4 H), 4.86 (dq, J = 3.7, J = 6.6 Hz, 1 H), 3.80 (septet, J = 6.6 Hz, 1 H), 3.47 (s, 3 H), 2.96 (septet, J = 6.6 Hz, 1 H), 1.65 (d, J = 3.7 Hz, ~ 25 1 H), 1.46 (d, J = 6.6 Hz, 3 H), 1.27 (m, 12 H). FAB-MS: calcd for (C21H26NFO3) 35g, found 360 (M+H). Anal. Calcd for C21H26NO3F: C, 69.54; H, 7.54; N, 6.76; F, 4.58.
~ Found: C, 69.55; H, 7.43; N, 6.50; F, 4.45. mp 169-171 C. Rf = 0.2 (10% ethyl acetate/hexane).
W098/04528 PCTrUS97113248 0 Step B: (+)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-( hydroxyethyl)pyridine The intermediate obtained in Step A (300 mg, 0.835 mmol) was dissolved in 40 mL of dry THF, for a dropwise addition of a solution of LAH (1 M/THF, 1.67 mL, 2 eq.). The reaction mixture was stirred at reflux for 24 hours then cooled to room temperature and quenched with water(70 ~L), 20% NaOH (70 ~lL), and water (140~LL). After filtration, the solvent was evaporated to afford a white residue. The product was subjected to flash chromatography (20% ethyl acetate/hexane) which afforded the title compound as a white solid (84 mg, 0.25 mmol, 30%). lH NMR
(300 MElz, CDCl3): ~ 7.15 (m, 4 H), 4.71 (dq, J = 3.7, J = 6.6 Hz, 1 H), 4.30 (m, 2 H), 3.79 (septet, J = 6.6 Hz, 1 H), 3.42 (septet, J = 6.6 Hz, 1 H), 1.62 (d, J = 3.68 Hz, 1 H), 1.58 (s, lH), 1.43 (d, J = 6.6 Hz, 3 H), 1.28 (m, 16 H). FAB-MS: calcd for (C20H26NFo2) 331, found 332 (M+H). Anal. Calcd for C20H26No2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 184-186~C. Rf = 0.2 (20% ethyl acetate/hexane).
~ OH
HO~' '1 ~f N~/
(+)-2,6-Diisopropyl-3-h~droxymethyl-4-(4-fluorophenyl)-5-(1-hydroxy-prop~,rl)pyridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and ethyl magnesium bromide, according to the procedures described in Example 93. lH NMR (300 2~ MHz, CDC13): ~ 7.15 (m, 4 H), 4.40 (dq, J = 3.7, J = 5.2 Hz, 1 H), 4.30 (d, J = 5.5 Hz, 2 H), 3.72 (septet, J = 6.6 Hz, 1 H), 3.42 (septet, J = 6.6 Hz, 1 H), 1.88 (m, 1 H), 1.63 (t, J = 5.5 Hz, lH), 1.27 (m, 14 H), 0.804 (t, J = 7.36 Hz, 3 H). FAB-MS: calcd for (C21H2gNFO2) 345, found 346 (M+H). Anal. Calcd for C21H2gNO2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 173-175~C. Rf = 0.2 (20% ethyl acetate/hexane);
. .
WO9~tO1~X PCTrUS97/13248 o OH
HO~
\~ N ~/
(+)-2,6-Diisopropyl-3-hydroxymethYI-4-(4-fluorophenyl)-5-(1-hydroxy-pentyl)pyridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and n-butyllithium, according to the procedures described in Example 93. lH NMR (300 MHz, CDCl3):
~ 7.16 (m, 4 H), 4.49 (m, 1 H), 4.31 (d, J = 5.5 Hz, 2 H), 3.74 (septet, J = 6.6 Hz, 1 H), 3.42 (septet, J = 6.6 Hz, 1 H), 1.88 (m, 1 H), 1.5B (d, J = 3.3 Hz, 1 H), 1.18 (m, 18 H), 0.821 (t, J = 4.1 Hz, 3 H). ~AB-MS: calcd for (C23H32NF02) 373, found 374 (M~H).Anal. Calcd for C23H32NO2F: C, 73.96; H, 8.64; N, 3.75; F, 5.09. Pound: C, 73.81;
H, 8.60; N, 3.58; F, 5.02. mp 166-168~C. Rf = 0.3 (20% ethyl acetate/hexane).
~ OH
HO~
(+)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(hydroxy-phenylmethyl)pyridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl~-(4-fluorophenyl~-3-pyridinecarboxaldehyde (Example 1, Step E) and phenyllithium, according to the procedures described in Example 93. lH NMR (300 MHz, CDCl3):
WO 98/04528 PCTrUS97/13248 0 ~ 7.23(m,7H),7.06(m,2H),5.71 (d,J=5.14Hz,1H),4.38(d,J=5.5 Hz, 2 H), 3.47 (septet, J = 6.6 Hz, 1 H), 3.12 (septet, J = 6.6 Hz, 1 H), 2.12 (d, J = 5.1 Hz, 1 H), 1.57 (s, lH), 1.29 (m, 10 H), 0.797 (d, J = 6.6 Hz, 3 H). FAB~ calcd for (c25H28NFo2) 393, found 394 (M+H). Anal. Calcd for C25H2gNO2F: C, 76.84; H, 8.69; N, 3.90.
Found: C, 76.67; H, 8.76; N, 3.77. mp 202-204~C. Rf = 0.2 (20% ethyl 5 acetate/hexane).
HO~
\~ N ~/
(+)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-~(l-h~rdrox~-2 methyl)propyllp~ridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and isopropyl 15 magnesium bromide, according to the procedures described in Example g3. lH
NMR (300 MHz, CDC13): ~ 7.14 (m, 4 H), 4.35 (d, 2 H), 3.53 (t, J = 4.8 Hz, 4 H), 3.4~
(m, 2 H), 3.18 (s, 2 H), 2.18 (t, J = 4.5 Hz, 4 H), 1.26 (m, 13 H). FAB-MS: calcd for (C23H31N2F02) 386, found 387 (M~H). Anal. Calcd for C23H31N202F: C, 76.84;
H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 139-140~C. Rf = 0.3 (20%20 ethyl acetate/hexane).
E~CAMPLE 98 HO~
\~' N '~/
W 098/04528 PCT~US97/13248 o 2,6-Diisopropyl-3-h~droxymethyl-4-(4-fluorophen~ 5-(1-methoxy-ethyl)pyridine Step A: Methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-methoxyethyl)-3-pyridinecarboxylate (_)-Ethyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(1-hydroxyethyl)-3-pyridinecarboxylate (Example 93, Step A) ( 487 mg, 1.36 mmol) was dissolved in 50 mL of dry THF, treated with NaH ( 0.20 g, 8.13 mmol) under argon, stirred for 15min. and treated with methyl iodide (0.34 mL, 5.24 mmol). The reaction mixture was stirred at reflux for 2 hours, then cooled to room temperature, quenched with water, and concentrated to afford a watery residue. The product was partitioned between diethyl ether and water, the organic layer was dried with MgSO4, filtered, and concentrated to afford a white solid. The product was passed through a pad of silica (5% ethyl acetate/hexane) to yield a white solid (495 mg, 1.33 mmol, 98%). 1H
NMR (300 MHz, CDCl3): ~ 7.13 (m, 4 H), 4.25 (q, J = 6.6 Hz, 1 H), 3.80 (septet, J =
6.6 Hz, 1 H), 3.48 (s, 3 H), 3.10 (s, 3 H), 2.97 (septet, J = 6.6 Hz, 1 H), 1.41 (d, J = 6.6 Hz, 3 H), 1.29 (m, 12 H). FAB-MS: calcd for (C22H31FNO3) 373, found 374 (M+H).
Anal. Calcd for C24H31N2O3F: C, 70.75; H, 7.56; N, 3.75; F, 5.09. Found: C, 70.70;
H, 7.63; N, 3.59; F, 4.77. mp 132-134~C. Rf = 0.5 (10% ethyl acetate/hexane).
Step B: (_)-2,6-Diisopropyl-3-hydrox~lmethyl-4-(4-fluorophen~ll)-5-( methoxyeth~l)pyridine The intermediate obtained in Step A (359 mg, 0.961 mmol) was dissolved in 40 mL of dry THF, for a dropwise addition of a solution of LAH (1 M/THF, 1.92 mL, 2 eq.). The reaction mixture was stirred at reflux for 24 hours then cooled to room temperature and quenched with water (80 ~L), 20% NaOH (80 ~lL), and water (160 ~L). After filtration, the solvent was evaporated to afford a residue which was filtered through to a pad of silica (10% ethyl acetate/hexane) to afford the title compound as a white solid (281 mg, 0.72 mmol, 85%). 1H NMR (300 MHz, CDCl3):
~ 7.13 (m, 4 H), 4.32 (dq, J = 5.2 J = 11.4 Hz, 1 H), 4.11 (q, J = 6.3 Hz, 1 H), 3.77 (septet, J = 6.6 Hz, 1 H), 3.42 (septet, J = 6.6 Hz, 1 H), 3.10 (s, 3 H), 1.2g (m, 16 H).
FAB-MS: calcd for (C21H2gFNO2) 345, found 346 (M+H). Anal. Calcd for C21H2gNO2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 151-~ 153~C. Rf = 0.4 (20% ethyl acetate/hexane).
W 098/04528 PCTrUS97/13248 ~1 OCH3 HO~
~ N~/
(+)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-methoxy-5 propyl)pyridine The title compound was prepared from (+)-2,~diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-hydroxypropyl)pyridine (Example 94) according to the procedures described in Example 98. lH NMR (300 MHz, CDC13):
~ 7.11 (m, 4 H), 4.32 (m, 2 H), 3.83 (m, 1 H), 3.74 (septet, J = 6.6 Hz, 1 H), 3.41 10(septet, J = 6.6 Hz, 1 H), 3.12 (s, 2 H), 1.88 (m, 1 H), 1.56 (m, 2 H), 1.27 (m, 12 H), 0.776 (t, J = 3.7 Hz, 3 H). FAB-MS: calcd for (C22H30NFo2) 359, found 360 (M+H).Anal. Calcd forC22H30No2F: C, 73.51;H,8.41; N, 3.90; F, 5.28. Pound: C, 73.55;
H, 8.54; N, 3.75; F, 5.06. mp 147-149~C. Rf = 0.5 (20% ethyl acetate/hexane).
~ OCH3 HO ~----/
~N~/
(+)-2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(1-methoxy-20 pentyl)pyrid~ne The title compound was prepared from (+)-2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-hydroxypentyl)pyridine (Example 95) according to the procedures described in Example 98. lH NMR (300 MHz, CDCl3):
7.10 (m, 4 H), 4.32 (m, 2 H), 3.92 (m, 1 H), 3.76 (septet, J = 7.0 Hz, 1 H), 3.42 , . .
W 0 98/01-~ PCTrUS97/13248 O (septet, J = 6.6 Hz, 1 H), 3.12 (s, 3 H), 1.87 (m, 1 H), 1.52 (m, 2 H), 1.19 (m, 16 H), 0.821 (t, J = 7.4 Hz, 3 H). FAB~ calcd for (C24H34NF02) 387, found 388 (M+H).
Anal. Calcd for C24H34NO2F: C, 74.38; H, 8.84; N, 3.61; F, 4.90. Found: C, 74.38;
H, 8.B2; N, 3.45; F, 4.90. mp 121-123~C. Rf = 0.5 (20% ethyl acetate/hexane).
OH ¢~1 ~, \~ N ~/
(+)-2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-propyl-pyridine Step A: (+)-2,6-Diisopropyl-4-(4-fluorophenyl)-5-propyl-3-pyridine-carboxaldehyde To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-propylpyridine (Example 25) (5.7 g, 17 mmol) in dichloromethane (250 mL) was added Brockman I, neutral alumina (3.5 g, 34 mmol). The suspension was stirred at room temperature and treated with pyridinium chlorochromate (PCC) (7.5 g, 34 mmol). Stirring was continued at room temperature for 1 hr. The suspension was poured into 10% ethyl acetate/hexane (500 mL), filtered through a pad of silica and concentrated in vacuo to afford (4.2 g/12.8 mmol, 74%) as a waxy solid. lH NMR
(CDCl3, 300 MHz): ~ 9.72 (s, 1 H), 7.15 (m, 4 H), 3.83 (sept, J = 6.6 Hz, 1 H), 3.28 (sept, J = 6.6 Hz, 1 H), 2.31 (m, 2 H), 1.30 (m, 14 H), 0.78 (t, J = 7.4 Hz, 3 H). FAB-MS: calcd for (C21H26FNO) 327, found 328 (M+H). mp 81-83~C. Rf = 0.6 (10%
ethyl acetate/hexane).
Step B: (+)-2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-propylpyridine The intermediate obtained in Step A (400 mg, 1.22 mmol) in THF (10 mL) at -78~C under argon atmosphere was added dropwise MeLi (1.4 M, 1.2 eq, 1.05 mL).
The reaction was stirred for 20 min, then another 0.5 eq. of MeLi was added, as starting material was still present. After 20 min., the reaction was quenched with O water (2 mL) and the THF is evaporated in vacuo to afford an oil. The product was partitioned between water and CH2Cl2 (50 mL) and the organic layer was dried with MgSO4, filtered, and concentrated to yield a gummy solid. Flash Chromatography using silica gel (60% CH2cl2/hexane) to afford an oil which slowly soli~lifie~l to give the title compound as a solid (0.387 g/1.13 mmol, 92%). lH
S NMR (300 MHz, CDCl3): ~ 7.10 (m, 4 H), 4.66 (dq, J = 3.3, 6.6 Hz, 1 H), 3.75 (septet, J
= 6.6 Hz, 1 H), 3.20 (septet, J = 6.6 Hz, 1 H), 2.17 (t, J = 1.5 Hz, 2 H), 1.58 ~d, J = 5.2 Hz, 1 H), 1.41 (d, J = 6.6 Hz, 3 H), 1.29 (m, 14 H), 0.74 (t, J = 7.4 Hz, 3 H). FAB~
calcd for (C22H30PNO) 343, found 344 (M+H). Anal. Calcd for C22H30FNO: C, 76.93; H, 8.80; N, 4.08; F, 5.53. Found: C, 76.98; H, 8.73; N, 3.93; F, 5.80. mp 124.5-126.5~C. Rf = 0.2 (60% CH2Cl2/hexane).
EXAl\~LE 102 F
OH~
\~' N
(+)-2,6-Diisopropyl-3-(1-hydroxyethyl)-~(4-fluorophen~1)-5-propyl-pyridine The enantiomeric mixture of (+)-2,6-diisoplopyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-pro~yl~yl;dine (Example 101) was separated by chiral HPLC with a Chiralpak AD column, isocratic elution (99% hexane/methyl t-butyl ether). The first enantiomer to elute was obtained in 99% ee, mp 103-104~C, [a]D +40.4~
~I '1 OH\~
~/
\~ N~/
W O 98/04528 PCTrUS97113248 o 2,6-Diisopropyl-3-(1 -hydroxyethyl)-~(4-fluorophenyl)-5-propyl-pyridine The enantiomeric mixture of (+)-2,6-diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-propyl-pyridine (Example 101) was separated by chiral HPLC with ~ a Chiralpak AD column, isocratic elution (99% hexane/methyl t-butyl ether). The second enantiomer to elute was obtained in 90% ee. mp 95-97~C.
.
OH¢~
\~ N~/
~_)-2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-butyl-pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(~fluorophenyl)-5-butylpyridine (Example 24) according to the procedures described in Example 101. lH NMR (300 MHz, CDCl3): ~ 7.1 (m, 4 H), 4.7 (dq, J = 3 Hz, 1 H), 3.7 (septet, J = 7 Hz, 1 H), 3.2 (septet, J = 7 Hz, 1 H), 2.2 (t, J = 1.5 Hz, 2 H), 1.6 (d, J = 5 Hz, 1 H), 1.4 (d, J = 7 Hz, 3 H), 1.3 (m, 16 H), 0.8 (t, J = 7 Hz, 3 H). FAB-MS: calcd for (C23H32FNO) 357, found 358 (M+H). mp 103-104~C. Rf = 0.2 (60%
CH2C12/hexane).
F
OH ¢~
\~ N '~/
.
2,~Diisopropvl-3-(l-hydroxyeth~l)-~(4-fluorophen~ 5-pentyl-pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-W 098t04528 PCT~US97113248 0 (4-fluorophenyl)-5-pel~lyl~yr.dine (Example 1) according to the procedures described in Example 101. lH NMR (300 MHz, CDCl3): ~ 7.10 (m, 4 H), 4.65 (dq, J =
2.8, 6.6 Hz, 1 H), 3.75 (septet, J = 6.6 Hz, 1 H), 3.20 (septet, J = 6.6 Hz, 1 H), 2.19 (t, J
=8.1Hz,2H),1.63(d,J=2.6Hz,1H), 1.40(d,J=7.0Hz,3H),1.31 (m, 14H), 1.11 (m, 4 H), 0.79 (t, J = 6.6 Hz, 3 H). FAB-MS: calcd for (C24H34FNO) 371, found 372 S (M+H). Anal. Calcd for C24H34FNO: C, 77.59; H, 9.22; N, 3.77; F, 5.11. Found: C, 77.59; H, 9.34; N, 3.75; F, 5.26. mp 99-101 C. Rf = 0.2 (70% CH2C12/hexane).
OH~
V
~N~/
2,6-Diisopropyl-3-(l-hydroxyethyl)~-(4-fluorophenyl)-5-pentylpyridine The enantiomeric mixture of (+)-2,~-diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-pentylpyridine (Example 105) was separated by chiral HPLC with a15 Chiralpak AD column, isocratic elution (99% hexane/methyl t-butyl ether). The first enantiomer to elute was obtained in 99% ee. mp 83~C.
OH ¢~
\rl NJ~/
2,6-Diisopropvl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-pentylpyridine The enantiomeric mixture of (+)-2,6-diisopropyl-~(1-hydroxyethyl)~-(4-fluorophenyl)-5-pentylpyridine (Example 105) was separated by chiral HPLC with a WO 9~t. q5~x O Chiralpak AD column, isocratic elution (99% hexanemethyl t-butyl ether). The second enantiomer to elute was obtained in 93% ee. mp 84-86~C.
- OH~
,~
\~'N~/
s (+)-2,6-Diisopropyl-3-(l-hydroxyeth~ 4-(4-fluorophen~1)-5-hex~lpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-hexylpyridine (Example 23) according to the procedures described in Example 101. lH NMR (300 MHz, CDCl3): 8 7.13 (m, 3 H), 7.04 (m, 1 H~, 4.65 (m, 1 H), 3.73 (sept, J = 6.6 Hz, 1 H), 3.19 (sept, J = 6.6 ~Iz, 1 H), 2.18 (m, 2 H), 1.39 (d, J - 6.6 Hz, 3 H), 1.30 (m, 13 H), 1.18 (m, 4 H), 1.09 (m, 4 H), 0.81 (t, J = 7 Hz, 3 H). FA~MS: calcd for (C2sH36FNO) 385, found 386 (M~H). Anal. Calcd for C2sH36FNO: C, 77.88; H, 9.41; N, 3.63. Found: C, 77.84; H, 9.49; N, 3.65. mp 96- 99~C. Rf = 0.3 (10% ethyl acetate/hexane).
,~
Il I
OH\~
\~ N ~/
20 2,6-Diisopropyl-3-(1-h~droxvethYl)~(~fluorophenyl)-5-hexylpyridine - The enantiomeric mixture of (+)-2,6-diisopropyl-3-(1-hydroxyethyl~-~(4-fluorophenyl)-5-hexylpyridine (Example 108) was separated by chiral HPLC with a Chiralpak AD colurnn, isocratic elution (99% hexane/methyl t-butyl ether). The first enantiomer to elute was obtained in 98% ee. mp 75-77~C.
WO 98/01~ PCTAUS97113248 OH~
\~ N '~/
5 2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophen~ 5-hexylpyridine The enantiomeric mixture of (+)-2,6-diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-hexylpyridine (Example 108) was separated by chiral HPLC with a Chiralpak AD colurnn, isocratic elution (99% hexane/methyl t-butyl ether). The second enantiomer to elute was obtained in 88% ee. mp 66-68~C.
O OH¢~
~,S~
2,6-Diiso~ro~1-3-~1-hydrox~-2-((S)-toluylsulfoxy)ethyll-4-(4-fluoro-phenyl)-5-pentylpyridine A solution of lithium diisopropylamide was prepared by the addition of n-butyllithiurn (3.5 mL, 2 eq., 1.6 M/hexane) to a solution of diisopropylamine (0.73 mL, 5.57 mmol) in anhydrous tetrahydrofuran (50 mL) at 0~C. To this was added a solution of (S)-(-)-methyl p-tolylsulfoxide (0.863 g, 5.60 mmol) in anhydrous tetrahydrofuran (10 mL) dropwise, with stirring. The mixture was stirred at 0~C
for 2 hr, then treated with a solution of 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) (1.0 g, 2.~0 mmol) in anhydrous tetrahydrofuran (20 mL) dropwise and with stirring. After stirring 15 min at 0 ~C, the reaction mixture was quenched by the addition of sat. NH4Cl (1 mL). The ., . ~ , . .... . . ..
WO9~10~'2X PCTrUS97113248 0 solvent was removed in v~cuo and the residue partitioned between CHC13 (150 mL) and water (50 mL). The organic phase was washed with sat. NaHCO3 (100 mL), water (100 mL) and brine (50 mL), dried over MgSO4 and concentrated. The crude product consisted of a 1.2:1 ratio of diastereomers. Flash chromatography (step gradient 5%-10%-20% ethyl acetate/hexane) afforded 740 mg (52%) of the first ~ 5 diastereomer to elute. 1H NMR (CDCl3, 500 MHz): ~ 7.4 (m, 4 H), 7.0 (m, 2 H), 6.7 (m,2H),5.1(m,1H),4.6(s,1H),3.8(m,2H),2.6(sept,J=6.6Hz,lH),2.5(s,3H), 2.3 (m, 1 H), 2.1 (m, 2 H), 1.4 (m, 18 H), 0.8 (m, 3 H). FAB-MS: calcd for (C31H40FNO2S) 509, found 510 (M+H). Anal. calcd for C31H40FNO2S: C, 73.05;
H, 7.91; N, 2.75; S, 6.29. Found: C, 72.88; H, 7.95; N, 2.50; S, 6.38. mp 170-171~C. Rf = 0.3 (20% ethyl acetate/hexane).
o O H~
~,S~
2,6-Diisopropyl-3-ll-hydroxy-2-(s)-toluylsulfoxyethyll-4-(4-fluoro-phenyl)-5 pentylpyridine From the flash chromatography described in Example 111, the second diastereomer to elute afforded 600 mg (42%) of the title compound. 1H NMR
(CDCl3, 500 MHz): ~ 7.4 (m, 2 H), 7.2 (m, 2 H), 7.0 (m, 3 H), 6.8 (m, 1 H), 4.8 (m, 1 H), 3.8 (m, 1 H), 3.7 (m, 1 H), 3.2 (sept, J = 6.6 Hz, 1 H), 3.1 (s, 1 H), 2.7 (m, 1 H), 2.4 (s, 3 H), 2.1 (m, 2 H), 1.3 (m, 18 H), 0.6 (m, 3 H). FAB-MS: calcd for (C3lH40FNo2s) 509, found 510 (M+H). Anal. calcd for C31H40FN02S: C, 73.05; H, 7.91; N, 2.75; S, 6.29. Found: C, 72.90; H, 7.95; N, 2.50; S, 6.54. mp 190~C. Rf = 0.1 (20% ethyl acetate/hexane).
~ 30 W O 98104528 PCT~US97/13248 HO~S
(+)-2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-phenylthi~
methylpyridine The title compound was prepared from 2,6-diisopropyl-3-(1-hydroxymethyl)-4-(4-fluorophenyl)-5-[(phenylthio)methyl]pyridine (Example 47) according to the procedures described in Example 101. lH NMR (300 MHz, CDCl3): ~ 7.19 (m, 4 H), 7.09 (m, 5 H), 4.67 (m, 1 H), 3.74 (m, 3 H), 3.38 (sept, J = 6.6 Hz, 1 H), 1.58 (d, J = 4 Hz, 1 H), 1.41 (d, J = 6.6 Hz, 3 H), 1.31 (m, 12 H). FAB-MS:
calcd for (C26H30FNos) 423, found 424 (M+H). Anal. Calcd for C26H30FNOS: C, 73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 73.52; H, 7.12; N, 3.20; S, 7.51. mp 125-128~C. Rf = 0.5 (20% ethyl acetate/hexane).
OH¢~
\~ N~/
(+)-2,6-Diisopropyl-3-(l-hydroxy-2-propenyl)-4-(4-fluorophenyl)-5-pentylpyridine Step A: 2,6-Diisopropyl-4-~4-fluorophenyl)-5-pentyl-3-pyridine-carboxaldehyde 2,6-Diisopropyl-3-hydroxymethyl-~(4-fluorophenyl)-5-pentylpyridine (Example 1) (2.30 g, 6.43 mmol) was dissolved in 175 mL of CH2Cl2 under argon WO g3~ 8 PCT/US97/13248 O atrnosphere and treated with 2 eq. of alumina (neutral, 1.31 g, 12.87 mmol) followed by 2 eq of pyridinium chlorochromate (PCC) (2.77 g, 12.87 mmol). The reaction was stirred at room temperature for 1.5 h. The suspension was added to 500 mL of 1:1 hexane/diethyl ether, then filtered through a pad of silica (300 g).
- The pad was washed with 100 mL diethyl ether and the filtrate was combined and ~ 5 concentrated tn vacuo to afford a solid. Flash chromatography (60:40, CH2C12/hexane) using silica afforded 1.84 g of an off-white solid (5.2 mmol, 80%).
1H NMR (300 MHz, CDCl3): ~ 9.74 (s, 1 H), 7.17 (m, 4 H), 3.85 (septet, J = 6.6 Hz, 1 H), 3.30 (septet, J = 6.6 Hz, 1 H), 2.34 (t, J = 5.2 Hz, 2 H), 1.30 (m, 14 H), 1.15 (m, 4 H), 0.80 (t, J = 6.6 Hz, 3 H). FAB-MS: calcd for (C23H30FNO) 355, found 356. Anal.
Calcd for C23H30FNO: C, 77.71; H, 8.51; N, 3.94; F, 5.34 Found: C, 77.91; H, 8.47;
N, 3.83; F, 5.42. mp 75.5-77.5 C. Rf = 0.4 (50% CH2Cl2/hexane).
Step B: (+)-2,6-Diisopropyl-3-(l-hydroxy-2-propen~rl)-4-(4-fluorophenyl)-5 pentylpyridine To a solution of the intermediate obtained in Step A (100 mg, 0.281 mmol) in THF (10 mL) at -78~C under argon was added vinyl magnesium bromide (1 M, 1.5 eq., 0.42 mL) dropwise. After 1 h., a saturated solution of NH4Cl (2 mL) was added and the aqueous phase was extracted with diethyl ether. A precipitate formed when the NH4CI was added and was filtered off. The ether layer was dried with MgSO4, filtered and concentrated to yield a gummy oil. Flash chromatography (60% CH2Cl2/hexane) afforded the title compound as a solid (38 mg, 0.1 mmol, 35%). 1H NMR (300 MHz, CDCl3): ~ 7.11 (m, 4 H), 6.06 (~, J = 17.4 Hz, J = 10.3Hz, J
= 4.0 Hz, 1 H), 5.08 (q, J = 1.5 Hz, 1 H), 5.00 (m, 2 H), 3.51 (septet, J = 6.6 Hz, 1 H), 3.21 (septet, J = 6.6 Hz, 1 H), 2.21 (t, J = 4.4 Hz, 2 H), 1.74 (d, J = 4.1 Hz, 1 H), 1.27 (m, 14 H), 1.11 (m, 4 H), 0.783 (t, J = 6.6 Hz, 3 H). FAB-MS: calcd for (C25H34FNO) 383, found 384 (M+H). Anal. Calcd for C2sH34NOF: C, 78.29; H, 8.93; N, 3.65; 3~, 4.95.
Found: C, 78.28; H, 8.97; N, 3.53; F, 5.04. mp 83-85~C. Rf = 0.2 (50%
CH2C12/hexane).
OH~
\~N'~/
W O 98/04528 PCTrUS97/13248 (+)-2,6-Diisopropyl-3-(1-hydroxypentyl)~-(4-fluorophenyl)-5-pentyl-pyridine l~e title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (Example 1) and butyllithium according to the procedures described in Example 114. lH NMR (300 MHz, CDCl3): ~ 6.95 (m, 4 H), 4.33 (m, 1 H), 3.59 (septet, J = 6.6 Hz, 1 H), 3.09 (septet, J = 6.6 Hz, 1 H), 2.08 (t, J =
5.2 Hz, 2 H), 1.75 (m, 2 H), 1.47 (m, 2 H), 1.04 (m, 22 H), 0.719 (t, J = 7.0 Hz, 3 H), 0.674 (t, J = 7.0 Hz, 3 H). FAB-MS: calcd for (C27H40FNo) 413, found 414 (M+H).
Anal. Calcd for C27H40FNO: C, 78.41; H, 9.75; N, 3.39; F, 4.59. Found: C, 77.84;H, 9.51; N, 3.27; F, 5.08. mp 66-68~C. Rf = 0.2 (50% CH2Cl2/hexane).
,~
OH ~' ~'b~~
\~N~/
(+)-2,6-Diisopropyl-3-(1-hydrox~-2-butenyl~-4-(4-fluorophenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (Example 1) and allylmagnesium bromide according to the procedures described in Example 114. lH NMR (300 MEIz, CDC13): ~ 7.09 (m, 4 H), 6.58 (m, 1 H), 5.06 (s, 1 H), 5.01 (m, 1 H), 4.47 (m, 1 H), 3.71 (septet, J = 6.6 Hz, 1 H), 3.20 (septet, J = 6.6 Hz, 1 H), 2.59 (m, 1 H), 2.35 (m, 1 H), 2.18 (t, J = 4.8 Hz, 2 H), 1.72 (d, J = 2.9 Hz, 1 H), 1.28 (m, 14 H), 1.11 (m, 4 H), 0.783 (t, J = 6.6 Hz, 3 H). FAB-MS: calcd for (C26H36FNO) 397, found 398 (M+H). Anal.
Calcd for C26H36FNO: C, 77.88; H, 9.41; N, 3.63; F, 4.93. Found: C, 78.10; H, 9.21;
N, 3.43; F, 4.89. mp 70-72DC. Rf = 0.2 (50% CH2Cl2/hexane).
W 098/01~X PCTrUS97113248 ~ ,J
OH 1' \~ N ~/
(+)-2,6-Diisopropyl-3-(1-hydroxy-2-propyl)-4-(4-fluorophenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (Example 1) and ethylmagnesium chloride according to the procedures described in Example 114. lH NMR (300 MHz, CDCl3): ~ 7.10 (m, 4 H), 4.35 (dq, J = 3.7, 8.8 Hz, 1 H), 3.68 (septet, J = 6.3 Hz, 1 H), 3.20 (septet, J = 6.6 Hz, 1 H), 2.18 (t, J = 5.2 Hz, 2 H), 1.86 (septet, J - 5.5 Hz, 1 H), 1.63 (m, 2 H), 1.28 (m, 14 H), 1.09 (m, 4 H), 0.789 (m, 6 H). FAB-MS: calcd for (C25H36FNO) 385, found 386 (M+H). Anal. Calcd for C2sH36FNO: C, 77.88; H, 9.41; N, 3.63; F, 4.93. Found: C, 77.44; H, 9.37; N, 3.35; F, 4.87. mp 77-79nC. Rf = 0.2 (50% CH2Cl2/hexanes).
F
HO~f--' \~'N ~/
(+)-2,6-Diisopropvl-3-(2,2,2-trifluoro-l-hydroxy)ethyl-4-(4-fluoro-phen~ 5 20 pentylpyridine A stirred solution of 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) (190 mg, 0.53 mmol) in anhydrous THF (5 mL), under argon at 22~C, was treated with trimethyl(trifluoromethyl)silane (5.3 mL, 2.65 mmol, 0.5M in THF) followed by tetrabutylammonium fluoride (100 W098J04528 PCTrUS97/13248 O uL, 1.0M in THF). After stirring at 22~C for 5 min, tetrabutylammonium fluoride (3 mL, 3 mmol, 1.0 M in THF) was added and the reaction mixture stirred for 17 hr.
The solvent was removed in vacuo, the residue dissolved in diethyl ether (50 mL), washed with lN HCl (50 mL), saturated NaHCO3 (~0 mL), water (50 mL), brine (20 mL), dried (MgSO4) and concentrated. Purification by flash silica gel chromatography (2% ethyl acetate/hexane) afforded 153 mg (68%) of the title compound as a white solid. 1H NMR (300 MHz, CDC13): ~ 7.11 (m, 4 H), 4.90 (bs, 1H), 3.64 (bs, 1 H), 3.21 (sept, J = 6.6 Hz, 1 H), 2.35 (m, 1 H), 2.15 (m, 2 H), 1.30 (d, J =
6.6 Hz, 6 H), 1.29 (d, J = 6.6 Hz, 6 H), 1.26 (m, 2 H), 1.10 (m, 4 H), 0.77 (t, J = 6.6 Hz, 3 H). FAB-MS: calcd for (C24H31F4NO) 425, found 426 (M+H). Anal. Calcd for C24H31F4NO: C, 67.75; H, 7.34; N, 3.29; F, 17.86. Found: C, 67.82; H, 7.13; N, 3.02;
F, 18.05. mp 88-89~C. Rf = 0.35 (10% ethyl acetate/hexane).
F
HO
\~ N~/
2,6-Diisopropvl-3-(2-hydroxyethyl)-4-(4-fluorophenvl)-5-pentylpyridine Step A: 2,6-Diisopropvl-3-(2-oxoethyl)-4-(4-fluorophenyl)-5-pentylpyridine A solution of (methoxymethyl)triphenylphosphonium chloride (350 mg, 0.985 mmol) in THF (30 mL) was treated with butyllithium (1.6 M, 1.2 eq., 0.74 mL) at -78~C. The reaction was stirred at 0~C for 1 h. and then ~; cooled to -78~C again.
2,6-Diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) (350 mg, 0.985 mol) in THF (5 mL) was added dropwise and the reaction mixture allowed to come to room temperature. After 24 h., the reaction was ~uenched with water and the THF evaporated in vacuo. The residue was partitioned between ether and water. The organic layer was dried with MgSO4, filtered, and concentrated to yield an oil. Flash chromatography (10%
CH2C12/hexanes) afforded an oil (172 mg~.
The oil (172 mg) was taken up in THF (15 mL) and treated with 4 mL conc.
WO~101S~X PCT~US97/13248 O HCl. The solution was stirred for 1.5 hours and then diluted with ether (150 mL).
The reaction was washed with NaHCO3 (2 x 50 mL) and dried with MgSO4.
Filtration and concentration yielded a solid (20 mg, 0.054 mmol, 6%). The product was taken directly to the next step without further purification.
~ 5 Step B: 2,6-Diisopropyl-3-(2-hydroxyeth~1)-4-(4-fluorophenyl)-5-pentylpyridine To the intermediate obtained in Step A (20 mg, 0.054 mmol) in dry THF (10 mL) was added dropwise LAH (2 eq., 1 M, 0.11 mL) under argon and the mixture was stirred at reflux for 1 h. The reaction was quenched with water (3.9 ~lL), 20%
NaOH (3.9 ~lL), and water (7.8 ~L) again. Concentration afforded a white solid.
The product was subjected to a pad of silica gel (CH2C12) to afford the title compound as a white solid (14 mg, 0.038mmol, 70%). lH NMR (300 MHz, CDC13):
~ 7.39(m,2H),7.12(m,2H),3.52(t,J=5.5Hz,2H),3.23(m,2H),2.60(t,J=2.9 Hz,2H),2.20(t,J=3.7Hz,2H),1.30(m,14H),1.11(m,4H),0.771 (t,J=6.3Hz,3 H). FAB-MS: calcd for (C24H34FNO) 371, found 372 (M~H). Anal. Calcd for C24H34FNO: C, 77.59; H, 9.22; N, 3.77. Found: C, 77.57; H, 9.44; N, 3.05. mp 81- 83~C. Rf = 0.6 (10% ether/hexane).
F
N
H~N~
2,6-Diisopropyl-3-methylaminometh~1-4-(4-fluorophenyl)-5-pentyl-pyridine Methylammonium chloride (37.99 mg, 0.563 mmol) was added to a stirred 25 solution of methylamine in methanol (2 M, 0.28 mL) under argon in an oven-dried round bottom flask equipped with a stir bar. Then sodium cyanoborohydride (4 eq., 10.60 mg, 0.169 mmol) was added and 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) (100 mg, 0.281 mmol) was added as a solution in methanol (2 mL). The reaction was refluxed for 18 hours and 30 then quenched with water. Concentration and addition of CH2Cl2 (25 mL) allowed W098/04528 PCT~US97113248 (~ washings with water (2 x 15 mL), brine (1 x 25 mL), following which the solution was dried with MgSO4, filtered, and concentrated to afford a clear oil. Flash chromatography using silica gel (40% ether/CH2Cl2) yielded the title compound asa white solid (21 mg, 0.057 mmol, 20%). lH NMR (300 MHz, CDCl3): ~ 7.13 (m, 4 H), 3.26 (m, 4 H), 2.24 (m, 5 H), 1.20 (m, 19 H), 0.783 (t, J = 6.6 Hz, 3 H). FAB~
calcd for (C24H3sFN2)370, found 371 (M+H). mp 77-79~C. Rf = 0.2 (20%
ether/CH2Cl2) H2N ~--/
\f N~/
2,6-Diisopropyl-3-aminomethyl-4-(4-fluorophenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-4-(4-ffuorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and NH40Ac, according to the procedures described in Example 120. 1H NMR (300 MHz, CDCl3): ~ 7.10 (m, 4 H), 2.61 (m, 4 H), 2.20 (t, J = 5.5 Hz, 2 H), 1.17 (m, 20 H), 0.776 (t, J = 6.6 Hz, 3 H).
FAB-MS: calcd for (C23H33PN2) 356, found 357 (M+H). Anal. Calcd for C23H33N2F: C, 77.48; H, 9.33; N, 7.86; F, 5.33. Found: C, 77.42; H, 9.12; N, 7.64; F, 5.51. mp 47-49~C. Rf = 0.6 (50% CH2Cl2/hexanes).
N
'f N~/
, . . .
W098/04528 PCT~US97113248 0 2,6-Diisopropyl-3-~dimethylamino)methyl~-(4-fluorophenyl)-5-pent~Tl-pyridine The title compound was prepared from 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and dimethylamine hydrochloride, according to the procedures described in Example 120. lH NMR
~ (300 MHz, CDCl3): ~ 7.09 (m, 4 H), 3.49 (septet, J = 6.6 Hz, 1 H), 3.21 (septet, J = 6.6 Hz, 1 H), 3.05 (s, 2 H), 2.22 (t, J = 5.2 Hz, 2 H), 1.99 (s, 6 H), 1.18 (m, 18 H), 0.790 (t, J
= 6.3 Hz, 3 H). FAB-MS: calcd for (C25H37FN2) 384, found 385 (M+H). Anal.
Calcd for C23H37FN2: C, 78.08; H, 9.70; N, 7.28; F, 4.94. Found: C, 77.95; H, 9.66;
~ N, 7.12; F, 5.25. mp 69-71~C. Rf = 0.4 (20% ether/CH2Cl2).
--N~ /
\~ N ~/
2,6-Diisopropvl-3-(ethylamino)methyl-4-(4-fluorophen~1)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and ethylamine, according to the procedures described in Example 120. 1H NMR (300 MHz, CDCl3): ~ 7.06 (m,4H),3.18(m,4H),2.32(q,J=7.4Hz,2H),2.15(t,J=5.2Hz,2H),1.13(m,18 H), 0.839 (t, J = 7.4 Hz, 3 H), 0.698 (t, ~ = 6.6 Hz, 3 H). FAB-MS: calcd for (C2sH37FN2) 384, found 385 (M+H). Anal. Calcd for C23H37FN2: C, 78.08; H, 9.70; N, 7.28; F, 4.94. Found: C, 77.85; H, 9.50; N, 6.99; F, 4.79. mp 48-50~C. Rf = 0.1 (20% ether/CH2CI2)-OH~
HO ~ ,~
\~N~/
W O 98104528 PCT~S97/13248 O (+)-2,6-Diisoprop~1-3-(1,2-dihydroxyeth~1)-4-(4-fluorophenyl)-S-pentyl-pyridine Step A: 2~6-Diisopropyl-3-ethenyl-4-(4-fluorophenyl)-5-pelllvlpyl;dine Methyl triphenylphosphonium bromide was suspended in 15 mL of dry THF under argon and stirred at -78~C. Butyllithium (1.6 M, 0.42 mL) was added S dropwise over 2 min. and then the reaction mixture was allowed to stir at 0~C for 1.5 hours. The solution was cooled again to -78~C, treated dropwise with a solution of 2,6-diisopropyl-4-(4-~uorophenyl)-5-pentyl-3-pyridinecarbox-aldehyde (Example114, Step A) in 5 mL of dry THF, and then stirred at 0~C for 2.5 hours. The reaction was quenched with water (10 mL) and the THF evaporated in vacuo. Diethyl ether was added and the mixture was washed with water (2 x 20 mL), brine (1 x 20 mL), and dried with MgSO4. Filtration, concentration and flash chromatography (30%
CH2C12/hexanes) yielded a solid (0.132 g, 0.37 mmol, 66%). lH NMR (300 MHz, CDC13) ~ 7.08 (m, J = 1.1 Hz, 4 H), 6.34, 6.28 (d, J = 11.4 Hz, J = 11.4 Hz, 1 H), 5.19 (d, J = 1.8 Hz, 1 H), 4.96 (d, J = 1.8 Hz, 1 H), 3.39 (septet, J = 6.6 Hz, 1 H), 3.24 (septet, J=6.6Hz,1H),2.30(t,J=5.2Hz,2H),1.20~m,J=2.2Hz,18H),0.979~t,J=6.0Hz, 3 H). FAB-MS: calcd for (C24H32FN) 353, found 354 (M~H). Anal. Calcd for C24H32FN: C, 81.54; H, 9.12; N, 3.96; F, 5.37. Found: C, 81.46; H, 9.06; N, 3.78; F, 5.59. mp 44-46~C. Rf = 0.7 (30% CH2cl2/hexanes).
Step B: (_)-2,6-Diisopropyl-3-(1,2-dihydroxyethyl)-4-(4-fluoro-phenyl)-5-pentylpyridine To an oven-dried round bottom flask equipped with a stir bar was added the intermediate obtamed in Step A (150 mg, 0.424 mmol), in pyridine (10 mL) under argon. The solution was stirred and OsO4 (0.129 g, 0.509 mmol) was added in one portion. The reaction turned black as stirring continued at room temperature.
After 3 hours, the pyridine was evaporated in vacuo and the residue was dissolved in CH2C12 (10 mL) and sat. NaHSO3 (10 mL). The resulting heterogenous solution was stirred very rapidly for 18 hours. The layers were separated and the aqueouslayer was extracted several times with CH2Cl2. The combined organic layers were dried (MgSO4), filtered, and concentrated to give a white solid. The product wassubjected to a pad of silica (65/35; CH2Cl2/ether) to yield a white solid (70 mg, 0.18 mmol, 43%). 1H NMR (300 MHz, CDCl3): ~ 7.08 (m, 4 H), 4.57 (d, J = 1.5 Hz, 1 H),3.85 (m, lH), 3.65 (septet, J = 6.6 Hz, 1 H), 3.50 (m, 1 H), 3.20 (septet, J = 6.6 Hz, 1 H), 2.19 (m, 2 H), 1.96 (m, 1 H), 1.24 (m, 14 H), 1.07 (m, 4 H), 0.780 (t, J = 6.6 Hz, 3 H). FAB-MS: calcd for (C24H34FNO) 387, found 388 (M+H). Anal. Calcd for C24H34FNO: C, 74.38; H, 8.84; N, 3.61; F, 4.90. Found: C, 74.60; H, 9.03; N, 3.83; F, 5.04. mp 175-177~C. Rf = 0.5 (65/35; CH2Cl2/ether~.
. . " ,, WO ~8~'~1'28 PCTrUS97/13248 o EXAMPLE 125 tlO~
~f N~
2,6-Diisoprop~1-3-h~droxymethYl-4-l (4-trifluoromethyl)phenvll-5-(pent-1-S enyl)p~ridine Step A: Diethyl 1,4-dihydr~2,6-diisopropyl-4-l(4-trifluoro-methyl)phenyllpyridine-3,5-dicarboxylate Following the procedure of Chucholowski (U.S. Patent 4,950,675), to a solution of 18.0 g (0.11 mol) of ethyl isobutyrylacetate and 9.g g (56.8 mmol) of 4-(trifluoromethyl)benzaldehyde in ethanol (25 mL) was added concentrated ammonium hydroxide (3.0 mL). This reaction mixture was heated at reflux for 12 hrs. After cooling to room temperature, the reaction mixture was concentrated under vacuum to yield a yellow oil. The crude product was taken directly to the next step without purification.
Step B: Diethyl 2,6-diisopropyl-4-~(4-trifluorometh~l)phenyll-pyridine-3,5-dicarboxylate Prepared from the intermediate obtained in Step A by the procedure described in Example 160, Step B. lH NMR (300 MHz, CDC13): ~ 0.92 (t, J=7.0 Hz, 6H), 1.33 (d, J=6.6 Hz, 12H), 3.14 (m, 4H), 4.0 (q, J=7.0 Hz, 4H), 7.42 (d, J=8.0 Hz, 2H). mp 100-101~C.
Step C: Ethyl 2,6-diisoProPY1-4-~(4-trifluoromethYl)phenTlll-5 hydroxymethylpyridine-3-carboxylate Prepared from the intermediate obtained in Step B by the procedure described in Example 1, Step D. 1H NMR (300 MHz, CDC13): ~ 0.91 (t, J=7.0 Hz, 3H), 1.32 (d, J=6.6 Hz, 6H), 1.35 (d, J=6.6 Hz, 6H), 3.08 (m, lH), 3.50 (m, lH), 3.96 (q, J=7.0 Hz, 2H), 4.43 (d, J=4.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H).
mp 102-103~C.
o Step D: 5-Ethoxycarbonyl-2,6-diisoprop-~1-4-~(4-trifluoromethyl)-phen~rllpyridine-3-carboxaldeh~de To a solution of the intermediate obtained in Step C (1.9 g, 4.6 mmol) in dichloromethane (50 mL) was added Celite (2.0 g). The suspension was stirred at room temperature and treated with pyridinium chlorochromate (PCC) (2.0 g, 9.3 mmol) in three portions. The suspension was stirred at room temperature for 1 hr, then poured into 1:1 diethyl ether/hexane (250 mL), filtered through a pad of silica, the pad washed with diethyl ether (250 mL) and the combined eluent concentrated to afford 1.7 g (93%) of the product as a viscous oil which slowly solidified. 1H
NMR (300 MHz, CDCl3): ~ 0.94 (t, J=7.0 Hz, 3H), 1.33 (d, J=6.6 Hz, 6H), 1.34 (d,J=6.6 Hz, 6H), 3.14 (m, lH), 3.88 (m, lH), 4.0 (q, J=7.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 9.86 (s, lH). mp 105-106~C.
Step E: Ethyl 2,6-diisopropyl-4-~(4-trifluoromethyl)phenyll-5-(pent-1-l S enyl)p~ridine-3-carboxylate Prepared from the intermediate obtained in Step D by the procedure described in Example 1, Step D. lH NMR (300 MHz, CDC13): ~ 0.69 (t, J=7.0 H7, 3H), 0.90 (t, J=7.0 Hz, 3H), 1.09-1.34 (m, 14H), 1.92 (~, J=14.0, 7.0, 1.5 Hz, 2H), 3.07 (m, lH), 3.38 (m, lH), 3.96 (q, J=7.0 Hz, 2H), 5.29 (m, lH), 6.05 (m, lH), 7.31 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H). mp 70-72~C.
Step F: 2,6-Diisopropyl-3-hydroxYmethyl-4-~(4-trifluoromethyl)phen~ll-5 (pent-1 -enyl)pyridine The intermediate obtained in Step E (0.91 g, 2.04 mmol) was dissolved in 25 anhydrous THF (100 mL) under argon and treated dropwise at room temperature with lithium aluminum hydride (1.0 M in THF, 10 mL, 10 mmol). The reaction mixture was stirred at reflux for 1 hr, cooled to room temperature and quenched by the sequential addition of H20, 20% aqueous NaOH and H20. The resulting suspension was filtered through a cake of Celite and the filtrate concentrated and 30 purified by flash chromatography through silica (5% ethyl acetate/n-hexane) to afford 0.77 g (1.90 mmol, 93%) of the title compound as a white foam. lH NMR
(300 MHLz, CDCl3): ~ 0.68 (t, J=7.0 Hz, 3H), 1.05-1.40 (m, 14H), 1.90 (~, J=14. 7, 1.5 Hz, 2H), 3.34 (m, lH), 3.45 (m, lH), 4.37 (d, J=5.5 Hz, 2H), 5.26 (m, lH), 5.95 (m, lH), 7.30 (d, J=8.0 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H). Rf=0.36 (10% ethyl acetate/n-35 hexane). mp 77-78~C.
WO 9&'~ 8 PCTAJS97/13248 o EXAMPLE 126 ¢~
HO~
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-~(4-trifluoromethyl)phenyll-5-pentylpyridine S To 0.59 g (1.46 mmol) of the compound 2,6-diisopropyl-3-hydroxymethyl-4-[(4-trifluoromethyl)phenyl]-5-(pent-1-enyl)pyridine (Example 125) was dissolved in absolute ethanol (50 mL) and treated with 10% palladium on carbon (0.1 eq). The reaction flask was purged under aspirator vacuum and filled with hydrogen gas (3x). The reaction mixture was stirred under a hydrogen atmosphere for 6 hr.
After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed by concentration under vacuum and the crude product was purified by flash chromatography (10% ethyl acetate/n-hexane) to yield 0.58 g (1.41 mmol, 97%) of the title compound as a white solid. 1H
NMR (300 MHz, CDCl3): ~ 0.78 (t, J=7.0 Hz, 3H), 1.12 (m, 4H), 1.31 (m, 14H), 2.26 (m, 2H), 3.25 (m, lH), 3.42 (m, lH), 4.29 (s, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H). Rf=0.36 (10% ethyl acetate/n-hexane). mp 99-100~C.
¢~F
HO ~~
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(3-fluorophenyl)-5-(pent-l -enyl)-pyridine Step A: Ethyl 2,6-diisopropyl-4-(3-fluorophenyl)-5-(pent-1-enyl)-pyridine-3-carboxylate WO 98104S28 PCTrUS97113248 0 Prepared from 3-fluorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCl3): (reported as a mixture of olefin isomers): ~0.76 (m, 3H), 0.97 (t, J=7.0 Hz, 3H), 1.13-1.37 (m, 14H), 1.95 (m, 2H), 3.07 (m, lH), 3,21-3.45 (m, lH), 4.0 (m, 2H), 5.30-5.60 (m, lH), 6.06 (m, lH), 6.90-7.03 (m, 3H), 7.27 S (m, lH) Step B: 2,6-Diisopropyl-3-hydrox~rmethyl-4-(3-fluoroRhenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): ~ 0.78 (m, 3H), 1.13-1.37 (m, 14H), 1.93 (m, 2H), 3.41 (m, 2H), 4.40 (s, 2H), 5.28-5.45 (m, lH), 6.0 (m, lH), 6.87-7.07 (m, 3H), 7.34 (m, lH). Rf=0.36 (10% ethyl acetate/n-hexane). mp 117-118~C.
~F
HO ~~~"
~N~
2,6-Diisopropvl-3-hydrox-~methyl-4-(3-fluorophenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-fluorophenyl)-5-(pent-1-enyl)pyridine (Example 127) by the procedure described in Example 126. lH NMR (300 MHz, CDCl3): ~ 0.79 (t, J=7.0 Hz, 3H), 1.10-1.35 (m, 18H), 2.28 (m, 2H), 3.24 (m, lH), 3.42 (m, lH), 4.33 (s, 2H), 6.96 (m, 2H), 7.12 (m, lH), 7.40 (m, lH). mp 117-118~C. Rf=0.36 (10% ethyl acetate/n-hexane).
.
CA 02262434 l999-0l-28 WO~/01'~X PCTnUS97/13248 O EXA~LE 129 HO ~' ~N~/
2,6-Diisopropyl-3-h~,Tdroxymethyl-4-(4-methylphenyl)-5-(pent-1-enyl)-pyridine Step A: Ethyl 2,6-diisopropyl-4-(4-methylphenyl~-5-(pent-l-enyl)-pyridine-3 carboxylate Prepared from 4-methylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, 10 Steps A-E. lH NMR (300 MHz, CDCl3): ~ 0.75 (t, J=7.4 H7, 3H), 0.95 (t, J=7.4, 3 H), 1.20-1.40 (m, 14H), 1.95 (tdd, J=7.4, 7.4, 1.5 Hz, 2H), 2.35 ~s, 3H), 3.10 (m, lH), 3.40 (m, lH), 3.99 (q, J=7.4, 2H), 5.30-5.40 (m, lH), 6.05 (dt, J-16.2, 1.5 Hz, lH), 7.0-7.2 (m, 4H). mp 74-77~C.
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-(pent enyl)-p~ttridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): ~ 0.77 (t, J=7.0 Hz, 3 H), 1.1-1.3 (m, 15 H), 2.27 (m, 2 H), 2.42 (s, 3H), 3.4 (m, 2 H), 4.34 (d, J=6.0 Hz, 2 H), 5.30-5.40 (m, 1 H), 5.90 (d, J=16.0 Hz, 1 H), 7.0 (d, J=8.0 Hz, 2 H), 7.18 (d, J=8.0 Hz, 2 H). FAB-MS:
r~ t~l for C24H33N0 352; found 352 (M+H, 100%). Rf=0.38 (10% ethyl acetate/n-hexane). mp 72-75~C.
CA 02262434 l999-0l-28 WO~8~ Q PCTrUS97/13248 HO~
~N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-~pentylpyridine The title S compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-(pent-1-enyl)pyridine (Example 129) by the procedure described in Example 126. lH NMR (300 MHz, CDC13): ~ 0.77 (t, J=7.0 Hz, 3 H), 1.10-1.40 (m, 19 H), 2.27 (m, 2 H), 2.42 (s, 3 H), 3.22 (m, 1 H), 3.41 (m, 1 H), 4.34 (d, J=6.0 Hz, 2 H), 7.10 (d, J=8.0 Hz, 2 H), 7.20 (d, J=8.0 Hz, 2 H). FAB-MS: calculated for C24H3sNO
354; found 354 (M+H, 100%). Rf=0.38 (10% ethyl acetate/n-hexane). mp 92-94~C
E~CAMPLE 131 HO~
~N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-ethylphenyl)-5-(pent-1-enyl)-pyridine Step A: Ethyl 2,6-diisopropy~-4-(4-ethylphenyl)-5-(pent-1-enyl)-pyridine-3-carboxylate Prepared from 4-ethylbenzaldehyde, ethyl isobutyrylacetate and 20 concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCl3): ~ 0.78 (t, J=7.4 Hz, 3H), 0.90 (t, J=7.4 Hz,3H), 1.10-1.40 (m, 17H), 1.94 ~tdd, J=7.0, 7.0, 1.5 Hz, 2H), 2.64 (q, ~=7.7 Hz, 2H), 3.0 (m, lH), 3.40 (m, lH), 3.96 (q, J=7.4 Hz, 2H), 5.35 (m, lH), 6.08 (dt, J=16.2, 1.5 Hz, lH), 7.10 (m, 4H). mp 67-68~C.
2~0 , . . .. ... .. , . . ., . .. ~". ~ ....
WO 98/04528 PCTrUS97J13248 0 Step B: 2,6-Diisoprop~l-3-hydroxymethyl-4-(4-ethylphenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) ~ (reported as a mixture of olefin isomers): ~ 0.73 (t, J= 7.0 Hz, 3H), 1.10-1.40 (m, ~ 5 18H), 1.91 (tdd, J=7.0, 7.0, 1.0, 2H), 2.68 (q, J=7.4 Hz, 2H), 3.3-3.5 (m, 2H), 4.41 (d, J=
5.5 Hz, 2H), 5.20-5.40 (m, lH), 6.0 (dt, J=16.0, 1.0 Hz, lH), 7.0 (d, J=8.5 Hz, 2H), 7.23 (d, J= 8.5 Hz, 2H). FAB-MS: calculated for C2sH3sNO 366; found 366 (M+H, 100%).
~ Rf=0.31 (10% ethyl acetate/n-hexane).
HO ~--' --f N~
2,6-Diisopropyl-3-h~droxymethyl-4-(4-eth~lphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-15 (4-ethylphenyl)-5-(pent-1-enyl)pyridine (Example 131) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): ~ 0.77 (t, J=7.0 Hz, 3H), 1.0-1.40 (m, 22H), 2.28 (m, 2H), 2.73 (q, J= 7.5 Hz, 2H), 3.35 (m, lH), 3.45 (m, lH), 4.35 (s, 2H), 7.10 (d, J=8.0 Hz, 2H), 7.18-7.34 (d, J=8.0 Hz, 2H). FAB-MS: calculated for C2sH37NO 368; found 368 (M+H, 100%). Rf=0.31 (10% ethyl acetate/n-hexane).
20 mp 87-88~C.
H3C ~ CH3 ' - HO ~/--'' ~N~
W O 98~ PCT~US97113248 2,6-Diisopropyl-3-hydroxymethvl-4-(4-isopropylphenyl)-5-(pent-l-enyl)pyridine Step A: Ethyl 2,6-diisopropyl-4-(4-isopropylphenyl)-5-(pent-l-enyl)pyridine-3 carboxylate Prepared from 4-isopropylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDC13): ~ 0.70 (t, J-7.7 Hz, 3H), 0.84 (t, J=7.4, 3H), 1.10-1.40 (m, 20H), 1.95 (tdd, J=7.0, 7.0, 1.5 Hz, 2H), 2.80-3.10 ~m, 2H), 3.40 (m, lH), 3.94 (q, J=7.4 Hz, 2H), 5.30 (m, lH), 6.10 (dt, J=15.8, 1.5 Hz, lH), 7.0-7.20 (m, 4H).
mp 41-45~C.
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-isopropylphenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCI3) (reported as a mixture of olefins): ~ 0.68 (t, J=7.4 Hz, 3 H), 1.0-1.4 (m, 21 H), 1.90 (tdd, J=7.0, 7.0, 1.5 Hz, 2 H), 2.9 (m, lH), 3.3-3.5 (m, 2 H), 4.43 (d, J=6.0 Hz, 2 H), 5.20-5.35 (m, 1 H), 6.0 (dt, J= 16.0, 1.5 Hz, 1 H), 7.0 (d, J=8.0 Hz, 2 H), 7.25 (d, J=8.0 Hz, 2 H). FAB-MS: calculated for C26H37NO 380; found 380 (M+H, 100%). Rf-0.40 20 (10% ethyl acetate/n-hexane).
H3C C~3 HO
~N~
2,6-Diisopropyl-3-hydroxymethyl-~(4-isopropylphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-isopropylphenyl)-5-(pent-1-enyl)pyridine (Example 133) by the procedure described in Example 126. lH NMR (300 MHz, CDC13): ~ 0.74 (t, J= 7.0 Hz, 3 H), 1.0-1.40 (m, 25 H), 2.25 (m, 2 H), 2.95 (m, 1 H), 3.25 (m, 1 H), 3.40 (m, 1 H), 4.35 (d, ... ..... .. ..
W0~8~'~t-28 PCTrUS97/13248 O J=6.0 Hz, 2 H), 7.1, (d, J=8.5 Hz, 2 H), 7.25 (d, J= 8.5 Hz, 2 H). FAB~ rAlc~ te~1 for C26H3gNO 382; found 382 (M+H, 100%). Rf=0.40 (10% ethyl acetate/n-hexane).
mp 42-44~C.
~ EXAMPLE 135 ~ 5 HO~
\f N~
2,6-Diisopropyl-3-hydroxymethyl-4-~4-(phenyl)phenyll-5-(pent-1-enyl)pyridine Step A: Ethyl 2,6-diisopropyl-4-~4-(phenyl)phenyll-5-(pent-l-enyl)pyridine-3 carboxylate Prepared from 4-phenylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCl3): ~ 0.73 (t, J=7.4 Hz, 3H), 0.93 (t, ~=7.0 Hz,lS 3H), 1.10-1.40 (m, 14H), 1.97 (tdd, J=7.0, 7.0, 1.1 Hz, 2H), 3.10 (m, lH), 3.45 (m, lH), 4.0 (q, J=7.4 Hz, 2 H), 5.40 (m, lH), 6.10 (dt, J=16.2, 1.1 Hz, lH), 7.20-7.70 (m, 9H).
mp 104-106~C.
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-~4-(phenyl)phenyll-5-~pent-1-en~l)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): ~ 0.70 (t, J= 7.0 Hz, 3H), 1.10-1.40 (m, 15H), 1.90 (tdd, J=7.0, 7.0, 1.5, 2H), 3.30-3.50 (m, 2H), 4.40 (d, J=6.0 Hz, 2H), 5.35 (m, lH), 6.05 (dt, J=16.0, 1.5 Hz, lH), 7.20-7.24 (m, 2H), 7.35-7.70 (m, 7H). FAB-MS:
te~1 for C29H35N0 414; found 414 (M+H, 100 ~/O). Rf=0.15 (6% ethyl acetate/n-hexane). mp50-52~C.
W098/04528 PCTrUS97/13248 HO ~~
~N~
2,6-Diisopropyl-3-hydroxymeth~1-4-~4-(phenyl)phenyll-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-[4-S (phenyl)phenyl]-5-(pent-1-enyl)pyridine (Example 135) by the procedure described in Example 126. 1H NMR (300 MHz, CDC13): ~ 0.76 (t, J=7.0 Hz, 3H), 1.0-1.40 (m, 19H), 2.31 (m, 2H), 3.25 (m, lH), 3.44 (m, lH), 4.40 (d, J=5.9 Hz, 2H), 7.22-7.70 (m, 9H). FAB-MS: ~Alc~ ted for C2gH37NO 416; found 416 (M+H, 100 %). Rf=0.34 (10% ethyl acetate/n-hexane). mp 56-58~C.
[~F
HO ~~/
~N~
1 5 2,6-Diisopropvl-3-hydroxymethyl-4-(2-fluorophenyl)-5-(pent-l-enyl)-pyridine Step A: Ethyl 2,6-diisopropvl-4-(2-fluorophenyl)-5-(pent-l-enyl)-pyridine-3 carboxylate Prepared from 2-fluorobenzaldehyde, ethyl isobutyrylacetate and 20 concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1H NMR ~300 MHz, CDC13): (reported as a mixture of olefin isomers):
~ 0.70 (m, 3H), 0.92 (t, J= 7.0 Hz, 3H), 1.05-1.40 (m, 14H), 1.90 (m, 2H), 3.10 (m, lH), 3.35 (m, lH), 3.97 (m, 2H), 5.29-5.50 (m, lH), 6.16 (m, lH), 7.08-7.32 (m, 4H).
. .
W098/04~28 PCTrUS97/13248 Step B: 2,6-Diisopropyl-3-hydroxvmethyl-4-(2-fluorophenyl)-s-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) S (reported as a mixture of olefin isomers): ~ 0.69-0.82 (m, 3H), 1.09-1.40 (m, 14H), 1.90 (m, 2H), 3.20-3.45 (m, 2H), 4.40 (m, 2H), 5.25-5.45 (m, lH), 6.08 (m, lH), 7.08-7.41 (m, 5H). Rf=0.24 (10% ethyl acetate/n-hexane).
.
~F
HO ~~' ~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(2-fluorophenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-1 S (2-fluorophenyl)-5-(pent-1-enyl)pyridine (Example 137) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): ~ 0.78 (t, J=7.0 Hz, 3H), 1.07-1.40 (m,18H), 2.29 (m, 2H), 3.26 (m, lH), 3.46 (m, lH), 4.34 (m, 2H), 7.20 (m, 3H), 7.42 (m, lH). Rf=0.24 (10% ethyl acetate/n-hexane).
E)CAMPLE 139 ~, CH3 HO ~~V~~/
N~
2,6-Diisopropyl-3-hydroxymethyl-4-(3-methylphenyl)-5-(pent-l-enyl)-pyridine Step A: Ethyl 2,6-diisoproPyl-4-(3-methylphenvl)-5-(pent-1-enyl)-pyridine-3 carboxylate WO 98~ PCT/US97113248 O Prepared from 3-methylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described m Example 125, Steps A-E. lH NMR (300 MHz, CDC13): ~ 0.74 (t, J=7.4 Hz, 3H), 0.92 (t, J=7.0 Hz,3H), 1.10-1.40 (m, 14H), 1.95 (tdd, J=7.0, 7.0, 1.5 Hz, 2H), 2.32 (s, 3H), 3.10 (m, lH), 3.40 (m, lH), 3.96 (q, J=7.4 Hz, 2H), 5.40 (m, lH), 6.05 (dt, J=16.2, 1.5 Hz, lH), 6.90-7.20 (m, 4H).
StepB: 2,6-Diisopropyl-3-hydroxymethyl-4-(3-meth~ phenyl)-5-(pent en~l)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefins): ~ 0.73 (t, J=7.0 Hz, 3 H), 1.10-1.40 (m, 15H), 1.90 (tdd, J_7.0, 7.0, 1.0, 2H), 2.36 (s, 3H), 3.30-3.50 (m, 2H), 4.40 (d, J= 4.0 Hz, 2H), 5.20-5.40 (m, lH), 5.95 (dt, J=16.0, 1.0 Hz, lH), 6.90 (m, 2H), 7.10-7.30 (m, 2H). FAB-MS:
calculated for C24~33No 352; found 3~2 (M+H, 100%). Rf=0.34 (10% ethyl acetate/n-hexane). mp 94-97~C.
~ C ~3 HO ~--/
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(3-methylphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-methylphenyl)-5 (pent-1-enyl)pyridine (Example 139) by the procedure described in Example 126. lH NMR (300 MHz, CDC13): ~ 0.77 (t, J=7.0 Hz, 3 H), 1.0-1.40 (m, 19H), 2.25 (m, 2H~, 2.39 (s, 3H), 3.23 (m, lH), 3.44 (m, lH), 4.34 (s, 2H), 6.97 (m, 2H), 7.18-7.34 (m, 2H). FAB-MS: calculated for C24H3sNO 354; found 354 (M+H, 100 %). Rf=0.34 (10% ethyl acetate/n-hexane). mp 88-90~C.
~ CH3 HO ~~~
\~N~/
2,6-Diisoprop~1-3-hydroxymethyl-4-(2-methylphenyl)-5-(pent-1-enyl)-pyridine Step A: Ethyl 2,6-diisopropyl-4-(2-methylphenyl)-5-(pent-1-enyl)-pyridine-3-carboxylate Prepared from 2-methylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1H NMR (300 MHz, CDCl3): ~ 0.70 (t, J=7.4 Hz, 3H), 0.88 (t, ~=7.0 Hz,3H), 1.0-1.40 (m, 14H), 1.90 (td, J=7.0, 7.0 Hz, 2H), 2.0 (s, 3H), 3.10 (m, lH), 3.40 (m, lH), 3.90 (m, 2H), 5.30-5.40 (m, lH), 6.0 (m, lH), 7.0-7.20 (m, 4H).
Step B: 2,6-Diisopropyl-3-hydrox~methyl~-(2-methylphenyl)-5-(pent-1-enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): ~ 0.70 (t, J= 7.5 Hz, 3H), 1.10-1.40 (m, 15H), 1.87 (tdd, J=7.5, 7.5, 1.5, 2H), 1.95 (s, 3H), 3.30-3.50 (m, 2H), 4.20 (m, lH), 4.45 (m, lH), 5.30 (m, lH), 5.93 (m, 2H), 6.90-7.30 (m, 4H). FAB-MS: calculated for C24H33NO 352; found 352 (M+H, 100%). Rf=0.32 (10% ethyl acetate/n-hexane).
mp 76-79~C.
~ CH3 HO ~' ~' W0~8/01~2~ PCTAUS97~13248 2,6-Diisopropvl-3-hydro%ymethYl-4-(2-methylphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-~2-methylphenyl)-5-(pent-1-enyl)pyridine (Example 141) by the procedure described in Example 126. lH NMR (300 MHz, CDCl3): ~ 0.76 (t, J=6.6 Hz, 3H), 1.0-S 1.40 (m, 19H), 1.97 (s, 3H), 2.0 (m, lH), 2.35 (m, lH), 3.22 (m, lH), 3.42 (m, lH), 4.16 (dd, J=12.0, 5.0 Hz, lH), 4.40 (dd, J=12.0, 5.0 Hz, lH), 7.0-7.10 (m, lH), 7.20-7.40 (m, 3H). FAB-MS: calculated for C24H3sNO 354; found 354 (M+H, 100%). Rf=0.32 (10% ethyl acetate/n-hexane). mp 81-83~C.
HO ~~'~' ~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-(pent-1-enyl)-pyridine Step A: Ethyl 2,6-diisopropyl-4-(4-chlorophenyl)-5-(pent-1-enyl)-pyridine-3-carboxylate Prepared from 4-chlorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers):
0.76 (m, 3H), 0.98 (m, 3H), 1.15-1.35 (m, 14H), 1.95 (m, 2H), 3.05 (m, lH), 3.39 (m, lH), 4.0 (M, 2H), 5.29-5.48 (m, lH), 6.03 (m, lH), 7.11 (m, 2H), 7.30 (m, 2H).
Step B: 2,6-Diisopropyl-3-hydrox~methyl-4-(4-chlorophenyl)-5-(pent-1-enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a 6:1 mixture of olefin isomers): ~ 0.73-0.83 (m, 3H), 1.10-1.40 (14H), 1.91 (m, 2H), 3.93 (m, 2H), 4.39 (d, ~=5.0 Hz, 2H), 5.25-5.45 (m, lH), 5.98 (m, lH), 7.11 (m, 2H), 7.35 (m, 2H). Rf=0.36 (10% ethyl acetate/n-hexane).
CA 02262434 l999-0l-28 W O~/01'?8 PCTrUS97tl3248 o EXAMPLE 144 Cl HO ~~~~
~N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-pentylpyridine S The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-(pent-1-enyl)pyridine (Example 143) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): ~ 0.79 (t, J=7.0 Hz, 3H), 1.08-1.38 (m,18H), 2.26 (m, 2H), 3.22 (m, lH), 3.40 (m, lH), 4.31 (d, J=5.0 Hz, lH), 7.13 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H). mp 83-85~C. Rf=0.36 (10% ethyl acetate/n-hexane).
E~CAMPLE 145 ~,CI
HO ~~~
\~ N~/
l S 2,6-Diisopropyl-3-hydroxymethyl-4-(3-chlorophenyl)-5-(pent-l -enyl)-pyridine Step A: Ethyl 2,6-diisopropyl~-(3-chlorophenyl)-5-(pent-1-enyl)-pyridine-3-carboxylate Prepared from 3-chlorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCl3): ~ 0.75 (t, J=7.4 Hz, 3H), 0.98 (t, J=7.0 Hz,3H), 1.20-1.40 (m, 14H), 1.96 (tdd, J=7.0, 7.0, 1.5 Hz, 2H), 3.05 (m, lH), 3.40 (m, lH), 4.0 (q, J=7.0 Hz, 2H), 5.45 (m, lH), 6.05 (dt, J=16.2, 1.5 Hz, lH), 7.0-7.30 (m, 4H).
WO 9~ 2X PCTrUS97113248 O Step B: 2,6-Diisopropyl-3-h~droxvmethyl-4-(3-chlorophen~1)-5-(pent-1-enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCI3) (reported as a mixture o~ olefin isomers): ~ 0.75 (t, J=7.5 Hz, 3H), 1.10-1.40 (m, 15H), 1.93 (tdd, J=7.0, 7.0, 1.0 Hz, 2H), 3.30-3.50 (m, 2H), 4.37 (d, J=12.0 Hz, lH), 4.43 (d, J=12.0 Hz, lH), 5.20-5.40 (m, lH), 5.9 (dt, J=16.0, 1.1 Hz, lH), 7.0-7.40 (m, 4H). FAB-MS: calculated for C23H30NOCl 372; found 372 (M+H, 100%). Rf=0.26 (10% ethyl acetate/n-hexane). mp 101-104~C.
~CI
HO
\~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(3-chlorophenyl)-5-pen~lpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-chlorophenyl)-5-(pent-1-enyl)pyridine (Example 145) by the procedure described in Example 126. lH NMR (300 MHz, CDCl3): ~ 0.80 (t, J=7.0 Hz, 3H), 1.0-1.40 (m, 19H), 2.26 (m, 2H), 3.23 (m, lH), 3.41 (m, lH), 4.34 (m, 2H), 7.05-7.45 (m, 4H). FAB-MS: calculated for C23H32NOC1 374; found 374 (M+H, 100%). Rf 0.26 (10% ethyl 20 acetate/n-hexane). mp 94-95~C.
Cl ~CI
HO~
~ N~/
W O9B104528 PCT~US97/13248 0 2,6-Diisopropyl-3-hydroxymethyl-4-(2,4-dichlorophen~l)-S-(pent-l-enyl)pyridine Step A: Ethyl 2,6-diisopropyl-4-(2,4-dichlorophenyl)-5-(pent-1-enyl)pyridine-3-carboxylate Prepared from 2,4-dichlorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCI3) (reported as a 1:1 mixture of olefin isomers): ~ 0.79 (m, 3H), 0.99 (m, 3H), 1.12-1.38 (m, 14H), 1.91 (m, 2H), 3.12 (m, lH), ~ 3.32 (m, lH), 4.0 (m, 2H), 5.20 -5.60 (m, lH), 6.09 (m, lH), 7.05-7.41 (m, 3H).
Step B: 2,6-Diisopropyl-3-hydroxvmethyl-4-(2,4-dichlorophenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a 1:1 mixture of olefins): ~ 0.75-0.87 (m, 3H), 1.13-1.37 (m, 14H), 1.65-2.0 (m, 2H), 3.20-3.51 (m, 2H), 4.30 (m, lH), 4.42 (m, lH), 5.31-5.50 (m, lH), 6.0 (m, lH), 7.05 (m, lH), 7.28 (m, lH), 7.47 (m, lH). Rf 0.38 (10% ethyl acetate/n-hexane~.
Cl ~CI
HO ~/'~~/
'f ' N '~/
2,6-Diisopro1?yl-3-hydroxymethyl-4-(2,4-dichlorophenyl)-5-p~llLyl~y~idirle The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(2,4-dichlorophenyl)-5-(pent-1-enyl)pyridine (Example 147) by the procedure described in Example 126. lH NMR (300 MHz, CDCl3): ~ 0.80 (t, J=7.0 Hz, 3H), 1.12-1.48 (m, 18H), 2.12 (m, lH), 2.35 (m, lH), 3.26 ~m, lH) 3.45 (m, lH), 4.31 (AB, J=12.0 Hz, 2H), 7.16 (d, J=8.0 Hz, lH), 7.36 (dd, J=8.0, 2.0 Hz, lH), 7.54 (d, J=2.0, lH).
Rf 0.38 (10% ethyl acetate/n-hexane).
WO 981'~1e~,% PCT~US97113248 o EXAMPLE 149 ~,CI
HO~--~N~/
2,6-Diisoprop~1-3-hydroxymethyl-4-t3/4-dichlorophenyl)-5-(pent-l-en~l)pyridine s Step A: Ethyl 2,6-diisopropyl-4-(3,4-dichlorophenyl)-5-(pent-l-enyl)pyridine-3-carboxylate Prepared from 3,4-dichlorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 160, Steps A-E. 1H NMR (300 MHz, CDCl3) (reported as a 6:1 mixture of olefin isomers). ~ 0.78 (m, 3H)J 1.04 (m, 3H), 1.16-1.35 (m, 14H), 1.98 (m, 2H), 3.04 (m, lH), 3.57 (m, lH), 5.31-5.58 (m, 1H), 6.02 (m, lH), 7.04 (m, lH), 7.28-7.42 (m, 2H).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a 6:1 mixture of olefin isomers): ~ 0.80 (m, 3H), 1.16-1.57 (m, 14H), 1.95 (m, 2H), 3.40 (m, 2H), 4.41 (m, 2H), 5.28-5.42 (m, lH), 6.0 (m, lH), 7.05 (s, lH), 7.30 (s, lH), 7.45 ~m, lH). mp 46-48~C. Rf=0.38 (10% ethyl acetate/n-hexane).
~F
HO~
~N~/
WO 9~ 8 PCT/US97/13248 0 2,6-Diisopropyl-3-hydroxymethyl-4-(2,4-difluorophenyl)-5-(pent-l-enyl)pyridine Step A: Ethyl 2,6-diisopropyl~(2,4-difluorophenyl)-5-(pent-l-enyl)pvridine 3-carboxylate Prepared from 2,4-difluorobenzaldehyde, ethyl isobutyrylacetate and ~ 5 concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1H NMR (300 MHz, CDCl3): ~ 0.75 (t, J=7.4 Hz, 3H), 1.0 (t, J=7.0 Hz, 3H), 1.10-1.40 (m, 14H), 1.93 (tdd, J=7.4, 7.4, 1.5 Hz, 2H), 3.10 (m, lH), 3.35 (m, lH), 4.0 (q, J=7.0 Hz, 2H), 5.30 (dt, J=15.0, 7.0 Hz, lH), 6.10 (m, lH), 6.80-7.20 (m, 3H).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(2~4-difluorophenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): ~ 0.75 (t, J=7.5 Hz, 3H), 1.10-1.40 (m, 15H), lS 1.92 (tdd, J=7.0, 7.0, 1.5, 2H), 3.30-3.60 (m, 2 H), 4.34 (dd, J=12.0, 6.0 Hz, lH), 4.43 (dd, J=12.0, 5.0 Hz, lH), 5.3 (m, lH), 6.05 (d, J=16.0, Hz, lH), 6.80-7.20 (m, 3H).
FAB-MS: cAl~ll~te~ for C23H29NOF2 374; found 374 (M+H, 100%). Rf 0.24 (10%
ethyl acetate/n-hexane). mp 59-62~C.
~,1 ~' F
HO
~N~
2,6-Diisopropyl-3-hydroxymethyl~(2~4-difluorophenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(2,4-difluorophenyl)-5-(pent-1-enyl)pyridine (Example 150) by ~e procedure described in Example 126. lH NMR (300 MHz, CDCl3): ~ 0.79 (t, J=7.0 Hz, 3H), 1.10-1.40 (m, 18H), 2.30 (m, 2 H), 3.20 (m, lH), 3.40 (m, lH), 4.30 (d, J=12.0 Hz, lH),4.36 (d, J=12.0 Hz, lH), 6.90-7.20 (m, 3H). FAB-MS: calculated for C23H31F2NO
376; found 376 (M+H, 100%). Rf 0.24 (10% ethyl acetate/n-hexane). mp 93-95~C.
W O 98/04528 PCT~US97J13248 oJ3 HO~
'T--N~
2,6-Diisopropyl-3-hydroxymethyl-4-(3-benzyloxyphenyl)-5-(pent-1-enyl)pyridine Step A: Ethyl 2,6-diisopropyl-4-(3-benzyloxyphenyl)-5-(pent-1-enyl)pyridine-3-carboxylate Prepared from 3-benzyloxybenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 160, Steps A-E. lH NMR (300 MHz, CDCl3): ~ 0.75 (t, ~=7.4 Hz, 3H), 0.93 (t, J= 7.2 Hz, 3H), 1.25 (m, 14H), 1.93 (tdd, J=7.4, 7.4, 1.1 Hz, 2H), 3.07 (m, lH), 3.40 (m, lH), 3.97 (m, 2H), 5.04 (bs, 2H), 5.35 (m, lH), 6.06 (dt, J=16.2, 1.5 Hz, lH), ~.79 (m, 2H), 6.89 (m, lH), 7.31 (m, 6H).
Step B: 2,6-Diisoprop~1-3-hydroxymethvl-4-(3-benzyloxyphenyl)-5-(pent-1-enyl)p~ridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): ~ 0.74 (t, J_7.4 Hz, 3H), 1.25 (m, 14H), 1.90 (m, 2H), 3.39 (m, 2H), 4.39 (d, J=6.0 Hz, 2H), 5.07 (s, 2H), 5.32 (m, lH), 5.97 (m, lH), 6.74 (m, 2H), 6.95 (m, lH), 7.35 (m, 7H). FAB-MS: tal~ll~tPtl for C30H37N02, 444;
found 444 (M+H, 100%). Elemental analysis: cal~llate~l for C30H37NO2: C 81.22; H8.41; N 3.16, found: C 80.51; H 8.41; N 3.36. Rf 0.5 (25% ethyl acetate/n-hexane).
~,OH
l~,J
HO ~--/
\~' N~
.. _ .. . . . . .. . .
2,6-Diisopropyl-3-hydroxymethyl-4-(3-hydroxyphenyl)-5-pentvlpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-benzyloxyphenyl)-5-(pent-l-enyl)pyridine (Example 152) by the procedure described ~n Example 126. lH NMR (300 MHz, CDCl3): ~ 0.78 (t, J_7.0 Hz, 3H), - 5 1.28 (m, 18H), 2.28 (m, 2H), 3.22 (m, lH), 3.39 (m, lH), 4.34 (m, 2H), 5.52 (s, lH), 6.63 (m, lH), 6.71 (d, J=8.0 Hz, lH), 6.81 (m, lH), 7.26 (m, lH). FAB-MS: calculated for C23H33N02 356; found 357 (M+H, 100%). Elemental analysis: c~ tec~ for ~ C23H33NO2: C 77.70; H 9.36; N 3.94, found: C 76.51; H 9.49; N 3.85. Rf 0.21 (10%
ethyl acetate/n-hexane). mp 121-122~C.
~ CF3 HO ~~~
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(3-trifluoromethyl)phenyl-5-(pent en.~l)pyridine Step A: Ethyl 2,6-diiso~>lo~yl-4-(3-trifluoromethyl)phenyl-5-(pent enyl)pyridine-3-carboxylate Prepared from 3-(trifluoromethyl)benzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDCl3) (reported as a 6:1 mixture of olefin isomers): ~ 0.72 (m, 3H), 0.94 (m, 3H), 1.10-1.40 (m, 14H), 1.94 (m, 2H), 3.07 (m, lH), 3.41 (m, lH), 3.97 (m, 2H), 5.33 (m, lH), 6.05 (m, lH), 7.29-7.60 (m, 4H).
Step B: 2,6-Diisopropyl-3-h~droxymethyl-4-t3-trifluoromethyl)phenyl-5 (pent-1-enyl)pyridine The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3) ~ 30 (reported as a 6:1 mixture of olefin isomers): ~ 0.67-0.87 (m, 3H), 1.08-1.38 (m, 14H), 1.90 (m, 2H), 3.20-3.50 (m, 2H), 4.39 (qd, J=12.0, 5.0 Hz, 2H), 5.24-5.50 (m, lH), 5.93-W 098104528 PCT~US97113248 0 6.02 (m, lH), 7.37-7.62 (m, 3H). mp 100-103~C. Rf 0.36 (10% ethyl acetate/n-hexane).
ç~CF3 HO ~~~' ~N~/
s 2,6-DiisopropYl-3-hydrox~methyl-4-(3-trifluoromethyl)phenyl-5-pent~lpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-trifluoromethyl)phenyl-5-(pent-1-enyl)pyridine (Example 154) by the proceduredescribed in Example 126. lH NMR (300 MHz, CDCl3): ~ 0.75 (t, J=6.5 Hz, 3H), 1.07-1.39 (m, 18H), 2.24 (m, 2H), 3.24 (m, lH), 3.42 (m, lH), 4.31 (qd, ~=12.0, 5.0 Hz, 2H), 7.42 (d, J=8.0 Hz, lH), 7.50 (s, lH), 7.57 (t, J=8.0 Hz, lH), 7.67 (d, J=8.0 Hz, lH).
mp 96-97~C. Rf 0.36 (10% ethyl acetate/n-hexane).
HO~
~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(2-eLhyl,yl~henyl)-5-(pent-1-enyl)-pyridine Step A: Diethyl 2,~diiso~ 1-4-(2-iodophenyl)pyridine-3,5-dicarbox~late Prepared from 2-iodobenzaldehyde, ethyl isobutyrylacetate and concel~lldL~d ammonium hydroxide by the procedures described in Example 125, Steps A-B. lH NMR (300 MHz, CDCl3): ~ 0.94 (t, J= 7.0 Hz, 6H), 1.30 (d, J= 6.6 ~Iz, 6H), 1.34 (d, J= 6.6 Hz, 6H), 3.19 (septet, J= 6.6 Hz, 2H), 4.0 (q, J= 7.0 Hz, 4H), 7.0-7.40 (m, 3H), 7.85 (m, lH).
.. . .. ~ .. , W O 98104528 PCT~US97113248 o Step B: Diethyl 2,6-diisopropyl-4-~(2-trimethylsilylethynyl)phenyllpyridine- 3,5-dicarboxylate A solution of 1.50 g (3 mmole) of the intermediate obtained in Step A in toluene was treated with 1.48 g (15 mmole) of trimethylsilyl acetylene, 87.1 g (0.86 S mol) of triethylamine, 0.1 g (0.15 mmol) of ~s(triphenylphosphine) pall~ m~(II) chloride, 0.2 g (0.8 mmole) of triphenyl phosphine and 0.2 g (1.17 mmole) of copper iodide. This reaction mixture was stirred at rt for lhr and heated at 90~C, in asealed reaction vessel, for 16 hrs. The reaction mixture was to cooled to temperature, filtered through Celite, and stripped to give a dark oil which uponpurification by flash silica gel chromatography to yield 1.22 g (2.5 mmole) of the product. 1H NMR (300 MHz, CDCI3): ~ 0.0 (s, 9H), 0.93 (t, J= 7.0, 6H), 1.32 (d, J=
6.6 Hz, 6H), 1.33 (d, J=6.6 Hz, 6H), 3.18 (septet, J= 6.6, 2H), 3.90 (q, J= 7.0 Hz, 4H), 7.20-7.50 (m, 4H).
Step C: Diethyl 2,6-diisopropyl-4-(2-ethynylphenyl)pyridine-3~5-dicarboxylate A solution of 5.68 g (11.9 mmole) of the intermediate obtained in Step B in 800 mL ethanol was treated with 2.8 g (20.3 mmole) of potassium carbonate and the reaction mixture was allowed to stir at room temperature for 16 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous solution of ammonium chloride, brine and separated. The organic layer was dried over ma~nesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography, eluting with 10 ethyl acetate/n-hexane, to give 3.95 g (9.6 mmole) of the product. lH NMR (300 MHz, CDCl3): ~ 0.90 (t, J= 7.0 Hz, 6H), 1.32 (m, 12H), 2.97 (s, lH), 3.21 (septet, J=6.6, 2H), 3.90 (q, J= 7.0, 4H), 7.2-7.6 (m, 4H).
Step D: Ethyl 2,6-diisopropvl-4-(2-ethynylphenyl)-5-(pent-1-enyl)-pyridine-3-carboxylate Prepared from the intermediate obtained in Step C by the procedures described in Example 125, Steps A-E. lH NMR (300 MHz, CDC13): ~ 0.68 (t, J=7.4 Hz, 3H), 0.88 (td, J=7.0, 2.4 Hz, 3H), 1.20-1.40 (m, 14H), 1.88 (tdd, J=7.0, 7.0, 1.1 Hz, - 2H), 2.92 (d, J= 2.4 Hz, lH), 3.0-3.40 (m, 2H), 3.90 (m, 2H), 5.28 (dt, J=~6.2, 7.0 Hz, lH), 6.15 (dt, J=16.2, 1.5 Hz, lH), 7.10-7.60 (m, 4H).
Step E: 2,6-Diisopropyl-3-hydroxymethyl-4-(2-ethynylphenyl)-5-(pent enyl)pyridine The title compound was prepared from the intermediate obtained in Step D
WO ~8J~ 8 PCT/US97/13248 O by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDCl3)(reported as a mixture of olefin isomers): ~ 0.81 (t, J= 7.4 Hz, 3H), 1.0-1.40 (m, 15H), 1.75 (m, 2H), 2.98 (d, J= 3.3 Hz, lH), 3.20-3.60 (m, 2H), 4.20-4.50 (m, 2H), 5.40 (m, lH), 6.0 (m, lH), 7.0-7.60 (m, 4H). Rf=0.23 (10% ethyl acetate/n-hexane).
HO ~/~' y~ N ~/
2,6-DiisopropyI-3-hydroxymethyl-4-(2-ethenylphenyl)-5-pentylpyridine 1 0 The title compound was prepared from ethyl 2,6-diisopropyl-3-hydroxymethyl-4-(2-ethynylphenyl)-5-(pent-1-enyl)pyridine-3-carboxylate by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDC13) (reported as a mixture of olefin isomers): ~ 0.60-0.90 (m, 3H), 1.0-1.40 (m, 15H), 1.60-1.90 (m, 2H), 3.20-3.50 (m, 2H), 4.20-4.40 (m, 2H), 5.14 (dt, J= 11.0, 1.0 Hz, lH), 5.40 (m, lH), 5.90 (m, lH), 6.30 (m, lH), 7.0-7.70 (m, 4H). FAB-MS: calculated for C2sH33NO
363.5; found 364 (M+H, 100%). Rf 0.28 (10% ethyl acetate/n-hexane).
~F
HO~
~ N~/
2,6-Diisopropyl-3-hydroxymethyl-4-(3~4-difluorophenyl)-5-(pent-l-enyl)pyridine Step A: Ethyl 2,6-diisopropyl-~(3,4-difluorophenyl)-5-(pent-l-enyl)pyridine 3-carboxvlate 0 Prepared from 3,4-difluorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 1, Steps A-E. lH NMR (300 MHz, CDCl3) (reported as a 8:1 mixture of olefin isomers): ~ 0.78 (m, 3H), 1.03 (m, 3H), 1.18-1.33 (m, 14H), 1.97 (m, 2H), 3.04 (m, lH), 3.38 (m, lH), 4.04 (m, 2H), 5.30-5.45 (m, lH), 6.02 (m, lH), 6.89-7.17 (m, 3H).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(3,4-difluorophen~1)-5-(pent-1-enyl)pyridine The title compound was prepared ~rom the intermediate obtained in Step A
by the procedure described in Example 125, Step F. lH NMR (300 MHz, CDC13) (reported as a mixture of olefin isomers): ~ 0.75 (m, 3H), 1.05-1.38 (m, 14H), 1.90 (m, 2H), 3.35 (m, 2H), 4.35 (m, 2H), 5.25 (m, lH), 5.91 (m, lH), 6.80-7.20 (m, 4H). mp 105-106~C. Rf=0.30 (10% ethyl acetate/n-hexane).
~5 F
~F
HO ~~~' ~N~
2,6-Diiso~,ro,~ 1-3-h~droxymethyl-4-(3,4-difluorophenyl)-5-pentyl-pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3,4-difluorophenyl)-5-(pent-1-enyl)pyridine (Example 158) by the procedure described in Example 126. lH NMR (300 MHz, CDC13): ~ 0.81 (t, J=7.0 Hz, 3H), 1.12 (m, 4H), 1.30 (m, 14H), 2.27 (m, 2H), 3.24 (m, lH), 3.41 (m, lH), 4.32 (d, J=4.0 Hz, 2H), 6.95 (m, lH), 7.06 (m, lH), 7.25 (m, lH). mp 106-107~C. Rf 0.30 (10% ethyl acetate/n-hexane).
W O 98104528 PCTrUS97113248 o EXAMPLE 160 OCH2Ph HO ~--~N~
2r6-Diisopropyl-3-hydroxymeth~ 4-(4-benzyloxyphenyl)-5-(pent-l-enyl)pyridine Step A: Diethyl 1,4-dihydro-2,6-diisopropyl-4-(4-benzyloxyphenyl)-3,5-pvridinedicarboxylate To 4-benzyloxybenzaldehyde (24.3 g, 114 mmol) and ethyl isobutyryl acetate (37.8 g, 239 mmol) were added ethanol (50 mL), acetic acid (1 mL), and piperidine (1.7 mL). The mixture was stirred under an argon atmosphere at 25~C
for 12 hours . Freshly prepared sodium ethoxide in ethanol (15%, 15 mL) was thenadded and the reaction mixture was stirred at 25~C for 2 hours. To this mixture was added a solution of ammonium acetate (13.1 g, 171 mmol) in acetic acid (100 mL). The reaction was heated at reflux for 14 h and was then cooled to 25~C, during which time a white precipitate developed. To the mixture was added a 40%
(v/v) solution of 2-propanol in water. The mixture was stirred for 0.5 hours at 25~C and was then cooled to -20~C for 2 hours. The white solid was collected by filtration with vacuum and washed with a 50% (v/v) solution of isopropanol in water to provide the product (41.8 g, 85 mmol, 75%) as a pure white solid (mp 140-141~C). lH NMR (300 MHz, CDC13): ~ 1.14-1.29 (m, 18H), 4.10 (q, J = 6.9 Hz, 4H),4.19 (sept, J = 6.9 Hz, 2H), 4.95 (s, lH), 5.01 (s, 2H), 6.12 (s, lH), 6.82 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 7.27-7.45 (m, 5H).
Step B: Diethyl 2,6-diisopropyl-4-(4-benzyloxyphenyl)-3,5-pvridine-dicarboxylate To a solution of the intermediate obtained in Step A (39.72 g, 81 mmol) in acetone (400 mL) stirred under argon at 25~C was added an aqueous solution of ammonium cerium(IV) nitrate ("CAN") (lM, 162 mL). The mixture was stirred at 25~C for 0.5 hours and the acetone was then removed under reduced pressure.
The resultant mixture was diluted with dichloromethane (400 mL) and poured into WO ~810 I'2X PCT/US97/13248 0 water (100 mL). The organic layer was saved and the aqueous layer is extracted with dichloromethane (100 mL). The combined organic layer was washed with a saturated solution of sodium chloride (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the product as a white powder (39.51 g, 100%) (mp 87~C). 1H NMR (300 MHz, CDCl3): ~ 0.96 (t, J = 6.9 Hz, 6H), ~ 5 1.31 (d, J = 6.6 Hz, 12H), 3.10 (sept, J = 6.6 Hz, 2H), 4.01 (q, J = 7.5 Hz, 4H), 5.09 (s, 2H), 6.95 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 7.32-7.46 (m, 5H).
Step C: Ethyl 2,6-diisopropyl-4-(4-benzyloxyphenyl)-5-(pent-1-enyl)-3-pyridinecarboxylate Prepared from the intermediate obtained in Step B by the procedure described in Example 1, Steps D-F. lH NMR (300 MHz, CDC13): ~ 0.77 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 1.21-1.34 (m, 14H), 1.96 (q, J = 7.2 Hz, 2H), 3.05 (septet, J = 6.6 Hz, lH), 3.42 (septet, J = 6.6 Hz, lH), 3.94-4.03 (m, 2H), 5.06-5.12 (m, 2H), 5.32-5.42 (m, lH), 6.03-6.15 (m, lH), 6.94 (d, J = 9.0 Hz, 2H), 7.10 (d, J - 9.0 Hz, 2H), 7.34-7.47 (m, 5H).
Step D: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-benzyloxyphenyl)-5-(pent enyl)pyridine The intermediate obtained in Step C (6 g, 12.35 mmol) was dissolved in 20 anhydrous tetrahydrofuran ("THF") (130 mL) under argon and treated dropwise at room temperature with lithium aluminum hydride ("LAH")(1.0 M in THF, 24.7 mL, 24.7 mmol). The reaction mixture was stirred at reflux for 3 hr, cooled to room temperature and quenched by the addition of 0.9 mL H2O, 0.9 mL 20% aqueous NaOH, and 2.7 mL H2O. The resulting suspension was filtered through a cake of 25 Celite and the filtrate concentrated and purified by chromatography through silica (20% ethyl acetate/hexane) to afford 4.76 g of the title compound as a colorlesswax. lH NMR (300 MHz, CDCl3): ~ 0.73-0.83 (m, 3H), 1.37-1.70 (m, 14H), 1.56 (s, lH), 1.92 (dq, J = 0.90, 6.90 Hz, 2H), 3.41 (~, J = 6.60, 13.20, 24.60 Hz, 2H), 4.43 (d, J =
5.1 Hz, 2H), 5.10 (s, 2H), 5.27-5.37 (m, lH), 5.97 (d, J = 15.90 Hz, lH), 6.97-7.09 (m, 30 4H), 7.35-7.48 (m, 5H).
, WO98101'?X PCTAUS97113248 OH
~0~
~N~
2,6-Diisopropyl-3-hvdroxymethYl-4-(4-hydroxyphenyl)-5-pentylpyridine 2,6-Diisopropyl-3-hydroxymethyl-4-(4-benzyloxyphenyl)-5-(pent-1-enyl)pyridine (Example 160) (500 mg, 1.13 mmol) was dissolved in absolute ethanol (10 mL) under argon, treated with 10% palladium on carbon (15 mg), then stirred under a hydrogen atmosphere for 14 h. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the residue is purified by flash chromatography (5% methanol-methylene chloride) to yield 371 mg of the title compound as a waxy solid (mp 158.5 C). lH NMR (300 MHz, CDCl3): ~ 0.79 (t, J = 6.6 Hz, 3H), 1.06-1.36 (m, 21H), 2.24-2.31 (m, 2H), 3.22 (sept, J = 6.6 Hz, lH), 3.40 (sept, J = 6.6 Hz, lH), 4.36 (d, J =
5.4 Hz, 2H), 4.85 (s, lH), 6.89 (d, J = 8.4 Hz, lH), 7.05 (d, J = 8.7 Hz, lH).
~OCH2Ph HO ~ ~' ~ N ~/
2,6-Diisopropyl-3-hydroxymethyl-4-~2-benzyloxyphenyl)-5-(pent-l-enyl)pyridine The title compound was prepared as a waxy solid from 2-benzyl-oxybenzaldehyde by the procedures described in Example 160. 1H NMR (300 MHz, CDCl3): ~ 0.69-0.74 (m, 3H), 1.07-1.38 (m, 14H), 1.69-1.79 (m, lH) 1.84-1.99 (m, 2H), 3.26-3.54 (m, 2H) 4.28-4.46 (m, 2H), 4.90-5.09 (m, 2H), 5.26-5.47 (m, lH), 6.00 (dd, J = 15.9, 1.2 Hz, lH), 7.05-7.10 (m, 5H), 7.24-7.36 (m, 4H).
, . .. .
WO 98/04528 PCTrUS97113248 E~CAMPLE 163 ~ OH
HO ~--' ~N~
I
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(2-benzyloxyphenyl)-5-(pent-1-enyl)pyridine (Example 162) by the method ~let~
in Example 161. lH NMR (300 MHz, CDCl3): ~ 0.75-0.73 (m, 3H), 1.09-1.15 (m, 4H),1.30-1.37 (m, 14H), 1.70-1.73 (m, lH), 2.16-2.28 (m, lH), 2.32-2.42 (m, lH), 3.22-3.32 (m, lH), 3.39-3.51 (m, lH), 4.29-4.35 (m, lH), 4.48-4.54 (m, lH), 5.14 (br s, lH), 7.02-7.05 (m, 3H), 7.28-7.36 (m, lH). FAB-MS: calcd for (C23H33NO2) 355, found 356 (M+ 1). Anal. calc. for C23H33NO2: C, 77.70; H, 9.36; N, 3.94. Found: C, 77.63; H,9.12; N, 3.75. mp 125.5 C.
OH~OH
CH3 ~----~N~
2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(2-hvdroxyphenyl)-5-pentyl-pyridine - Step A: 2,6-Diisopropyl-(2-benzyloxyphenyl)-5-pentyl-3-pyridine-carboxaldehyde 2,6-Diisopropyl-3-hydroxymethyl-4-(2-benzyloxyphenyl)-5-(pent-1 -enyl)-pyridine (Example 162) (680 mg, 1.53 mmol) was dissolved in 15 mL of methylene chloride under an argon atrnosphere and treated with a mixture of Celite (661 mg) and pyridinium chlorochromate ("PCC") (661 mg, 2 eq). The reaction was stirred at O room temperature for 1.5 h. The suspension was filtered through a pad of silica and the pad was washed with 50 mL CH2C12 and the filtrate was combined and concentrated in vacuo to afford 572.4 mg of product (84%). lH NMR (300 MHz, CDCl3): ~ 0.70 (t, J = 7.2 Hz, 3H), 1.08-1.35 (m, 15H), 1.85-1.93 (m, lH), 3.26-3.45 (m, lH), 3.87-3.97 (m, lH), 4.97-5.06 (m, 2H), 5.27-5.50 (m, lH), 6.01-6.10 (m, lH), 6.94-7.34 (m, 9H), 9.82 (d, J = 3.6 Hz, lH).
Step B: 2,6-Diisopropyl-3-(l-hydroxyethyl)~-(2-ben2ylox~phenyl)-5-(pent enyl)pyridine Prepared as a separable mixture of two diastereomers from the intermediate 1 0 from Step A by the method ~t~ in Example 101, Step B. The two diastereomers were separated by flash chromatography on silica eluting with 10%
ethyl acetate-hexane.
Diastereomer 1: colorless oil, 1H NMR (300 MHz, CDC13): ~ 0.68-1.91 (m, 23H), 3.19-3.40 (m, lH), 3.77 (sept, J = 6.6 Hz, lH), 4.69-4.79 (m, lH), 4.94 (dd, J =
12.3, 3.9 Hz, lH), 5.05 (d, J = 12.3 Hz, lH), 5.20-5.43 (m, lH), 5.90-6.05 (m, lH), 6.94-7.~ (m, 9H). FAB-MS: calcd for (C31H3gNO2) 457, found 458 (M + 1).
Diastereomer 2: colorless oil, lH NMR (300 MHz, CDCl3): ~ 0.69 (t, J = 7.2 Hz, 3H), 1.05-1.40 (m, 17H), 1.67-1.73 (m, lH), 1.80-1.88 (m, 2H), 3.18-3.41 (m, lH), 3.68-3.80 (m, lH), 4.84-5.08 (m, 3H), 5.25-5.42 (m, lH), 5.86-6.08 (m, lH), 6.90-7.38 (m, 9H). FAB-MS: calcd for (C31H3gNO2) 457, found 458 (M + 1).
Step C: 2,6-Diisoprop~1l-3-(l-hydroxyeth~1)-4-(2-hydroxyphenyl)-5 p~l~lyl~y~;dine The diastereomeric mixture of intermediates from Step B (39 mg) was dissolved in absolute ethanol (1.5 mL) under argon, treated with 10% pa~ladium on carbon (4 mg), then stirred under a hydrogen atmosphere for 8 hr. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the product dried in vacuo to afford 32 mg of the title compound as a colorless solid. Preparative thin layer chromatography ("prep TLC") using a 20% ethyl acetate-hexane mixture as the eluent provided thetwo diastereomers.
Diastereomer 1 (D1) (11.2 mg): 1H NMR (300 MHz, CDCl3): ~ 0.68 (t, J =
7.30 Hz, 3H), 0.99-1.03 (m, 4H), 1.19-1.34 (m, 17H), 1.62 (d, ~ = 3.60 Hz, lH), 1.97-2.07 (m, lH), 2.16-2.26 (m, lH), 3.14 (septet, J = 7.30 Hz, lH), 3.67 (septet, J = 7.30 Hz, lH), 4.72 (br s, lH), 4.83 (dq, J = 4.20, 6.60 Hz, lH), 6.89-6.97 (m, 3H), 7.19-7.25 (m, lH). FAB-MS: calcd for (C24H3sNO2) 369, found 370 (M + 1).
~, .
WO 9XJ'~ 1528 PCT/US97tl3248 O Diastereomer 1 (D1) could be resolved into the constituent enantiomers as follows. A Waters Prep LC 2000 HPLC system was equipped with a chiral HPLC
column (BRB-9668A; 6 x 50 cm ID). The system was equilibrated with a mobile phase consisting of 2% (1% acetic acid, 99% ethanol) and 98% hexane at a flow rate - of 175 mL/min. The sample was dissolved in mobile phase (20 mg/mL) and 5 mL
aliquots were injected at 30 minute intervals. The effluent was monitored at 280nm and two fractions (corresponding to the enantiomers) were cc-llPcte-l at (15-17 m~n, 100% ee) and (19-26 min, >99% ee), respectively.
Diastereomer 2 (D2) (11.8 mg): 1H NMR (300 MHz, CDCl3): ~ 0.68 (t, J =
6.60 Hz, 3H), 0.99-1.03 (m, 4H), 1.16-1.32 (m, 17H), 1.86 (br s, lH), 2.00-2.10 (m, lH), 2.19-2.29 (m, lH), 3.14 (septet, J = 6.60 Hz, lH), 3.67 (septet, J = 6.60 Hz, lH), 4.57 (q, J = 6.60 Hz, lH), 4.76 (br s, lH), 6.84-6.93 (m, 3H), 7.19-7.24 (m, lH). FAB-MS: calcd for (C24H35N02) 369, found 370 (M+1).
OH~OH
CH
~N~
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-~ro,uyl~yridine Step A: Diethyl-2,6-diisopropyl4-(2-benzyloxyphenyl)-3,5-pyridine-dicarboxylate Prepared from 2-benzyloxybenzaldehyde by the methods detailed in Example 160, Steps A-B. 1H NMR (300 MHz, CDCl3): ~ 0.87 (t, J = 6.9 Hz, 6H), 1.32 (d, J = 6.6 Hz, 6H), 1.33 (d, J = 6.6 Hz, 6H), 3.19 (sept, J = 6.6 Hz, 2H), 3.97 (q, J = 7.2 Hz, 4H), 5.01 (s, 2H), 6.88 (d, J = 8.1 Hz, lH), 6.94 (dt, J = 7.2, 0.6 Hz, lH), 7.16 (dd, J
= 7.8, 1.8 Hz, lH), 7.14-7.30 (m, 6H).
Step B: 5-Ethoxycarbonyl-2,6-diisopropyl-4-~2-benzyloxyphenyl)-3-pyridinecarboxaldehyde - 30 Prep~red from the intermediate from Step A by the methods ~1et~ile~ in Example 1, Steps D-E. lH NMR (300 MHz, CDCl3): ~ 0.91 (t, J = 6.6 Hz, 3H), 1.30-W 098104528 PCTrUS97/13248 0 1.39 (m, 12H), 3.18 (septet, J = 6.0 Hz, lH), 3.91-4.03 (m, 3H), 5.04 (dd, J = 6.6, 12.6 Hz, 2H), 6.96-7.05 (m, 2H), 7.17-7.28 (m, 6H), 7.34-7.40 (m, lH).
Step C: 2,6-Diisopropyl-4-(2-benzvloxyphenvl)-3~thoxycarbonyl-5-(pr enyl)pyridine S Ethyltriphenylphosphonium bromide (4.01 g, 10.8 mmol) was suspended inanhydrous THF (130 mL) under argon and stirred at -78~C. A 1.6 M solution of n-butyllithium in hexanes (6.75 mL, 10.8 mmol) was added dropwise. The reaction mixture was allowed to come to 0~C and stirred at that temperature for 1 hr. Theresulting brightly colored solution was cooled again to -78~C and treated dropwise with a solution of the intermediate obtained in Step B (4.0 g, 9.0 mmol) in THF (20 mL). The reaction mixture was allowed to stir at 25~C for 3 hrs, then quenched by the addition of water (5 mL). The THF was removed in vacuo, the residue partitioned between ethyl ether (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over MgS04 and concentrated. Flash chromatography through silica (5% ethyl acetate/hex) afforded 4.1 g of the product (E, Z mixture) as a viscous oil. 1H NMR (300 MHz, CDCl3): ~ 0.86-0.92 (m, 3H), 1.40-1.21 (m,15H), 3.06-3.28 (m, 2H), 3.91-4.01 (m, 2H), 5.00 (br s, 2H), 5.29-5.56 (m, lH), 6.10-6.19 (m, lH), 6.89-6.97 (m, 2H), 7.08-7.12 (m, lH), 7.15-7.19 (m, 2H), 7.22-7.29 (m, 4H).
Step D: 2,6-Diisopropvl-3-hydroxymethyl-4-(2-benzyloxyphenyl)-5-tpr enyl)pyridine Prepared from the intermediate from Step C by the method detailed in Example 160, Step D. lH NMR (300 MHz, CDCl3): ~ 1.21-1.60 (m, 15H), 1.90-1.95 (m, lH), 3.18-3.53 (m,2H), 4.26-4.58 (M, 2H), 4.87-4.94 (m, lH), 5.06 (d, J = 12.3 Hz, lH), 5.27-5.57 (m, lH), 5.95-6.05 (m, lH), 7.00-7.06 (m, 5H), 7.22-7.37 (m, 4H).
Step E: 2,6-Diiso~o~yl-3-(1-hydrox~eth~ 4-(2-hydroxyphen~,rl)-5-propylpyridine The intermediate from Step D was converted into the title compound by the methods detailed in Example 164, Steps A-C. The diastereomers were separated by radial band chromatography using a gradient eluent of 100% hexane to 5% ethyl acetate-hexane.
Diastereomer 1 (D1): lH NMR (300 MHz, CDCl3): ~ 0.66 (t, J = 7.50 Hz, 3H), 1.15-1.34 (m, 15H), 1.59 (br s, lH), 1.96-2.06 (m, lH), 2.15-2.25 (m, lH), 3.15 (sept, J =
6.60 Hz, lH), 3.56 (sept, J = 6.60 Hz, lH), 4.70 (br s, lH), 4.81-4.87 (m, lH), 6.90-6.97 (m, 3H), 7.19-7.26 (m, lH). FAB-MS: calcd for (C22H31NO2) 34~, found 342 (M+1).
WO 981'~ ''it~ PCT/US97/13248 0 Diastereomer 1 (D1) was resolved into its constituent enantiomers as follows. A Waters Prep LC 2000 HPLC system was equipped with a chiral HPLC
column (BRB-9466AD; 6 x 50 cm ID). The system was equilibrated with a mobile phase consisting of 25% hexane and 75% of a mixture of (15% THF in heptane) at 150 mL/min. The sample was dissolved in mobile phase (10 mg/mL) and 5 mL
~ 5 aliquots were injected at 35 min intervals. The effluent was monitored at 280 nm.
Peaks overlapped and were thus shaved. Mixed fractions were then evaporated and rein~ected. The collected enantiomers were assayed off line on an analytical- column (BRB-9705A) at 1.5 mL/min with a mobile phase of 1% (1% acetic acid in ethanol) and 99% hexane. The low Rt enantiomer from the preparative column was the high Rt enantiomer on the analytical column with Rt = 8.80 min; 98.8% ee.
The high Rt enantiomer from the preparative column was the low Rt enantiomer on the analytical column with Rt = 3.71 min; 81% ee.
Diastereomer 2 (D2): 1H NMR (300 MHz, CDCl3): ~ 0.72 (t, J = 7.50 Hz, 3H), 1.22-1.36 (m, 15H), 2.03-2.15 (m, lH), 2.23-2.33 (m, lH), 2.56 (d, J = 3.0 Hz, lH), 3.21 lS (septet, J = 6.60 Hz, lH), 3.73 (septet, J = 6.60 Hz, lH), 4.56-4.63 (dq, J = 3.0, 6.0 Hz, lH), 5.66 (br s, lH), 6.88-6.99 (m, 3H), 7.25-7.28 (m, lH). FAB-MS: calcd for (C22H31NO2) 341, found 342 (M+1).
E~CAMPLE 166 F
~OH
HO ~~
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-~(4-fluoro-2-hydroxy)phenyll-5-pent~lpyridine 25 Step A: 2-Benzyloxy-4-fluorobromobenzene To a solution containing 2-bromo-5-fluorophenol (50 g, 0.26 mol) in 500 mL
acetone was added potassium carbonate (54.2 g, 0.39 mmol) and benzyl bromide (34.3 mL, 0.288 mol). The reaction was heated at reflux under an argon atmosphere for 2 h and then allowed to cool to 25 C. The acetone was removed under reduced 30 pressure and the residue was taken up in ether (400 mL). The organic layer was W098/04528 PCT~US97/13248 0 washed with water (5 x 100 mL) and brine (1 x 100 mL) and then dried (MgSO4).
The solution was then concentrated under reduced pressure and subjected to flashchromatography using hexane as the eluent. In this manner, 2-benzyloxy-4-fluorobenzene was obtained as a white solid. lH NMR (300 MHz, CDCl3): ~ 5.14 (s, 2H), 6.57-6.63 (m, lH), 6.69 (dd, J = 2.7, 10.2 Hz, lH), 7.32-7.52 (m, 6H).
s Step B: 2-Benzyloxy-4-fluorobenzaldehyde To a slurry of magnesium (9.52 g, 0.39 mol) in THF (25 mL) in a 1 L round bottom flask fitted with a condenser was added the intermediate obtained in Step A
(1 g). A vigorous reflux commenced at once. To this refluxing mixture was added a solution of the intermediate from Step A (109 g) at a rate which maintained reflux.
After completion of addition the reaction was allowed to proceed until it cooled to 25 C and was then heated at reflux for 1 h. The reaction was allowed to cool to 25 C and DMF (48 mL) was then added portionwise. The reaction was allowed to cool to 25 C and was then filtered through a plug of Celite. The THF was removed1 5 under reduced pressure and the residue was dissolved in ethyl acetate (500 mL) and washed sequentially with water (100 mL), 10% HCl (100 mL), saturated sodium bicarbonate solution (100 mL), and brine (100 mL). The organic layer was dried (Na2S04) and concentrated under reduced pressure. The resultant residue was purified by flash chromatography (10% ethyl acetate-hexane) to provide 77.3 g of2-benzyloxy-4-fluorobenzaldehyde. lH NMR (300 MHz, CDCl3): ~ 5.16 (s, 2H), 6.70-6.76 (m, 2H), 7.34-7.44 (m, 5H), 7.87-7.92 (m, lH), 10.43 (s, lH). FAB-MS: calcd for (C14H11O2F) 230; found 231 (M+1).
Step C: 2,6-Diisopropyl-3-hydroxymethyl-4-~(2-benzyloxy-4-fluoro)phenyll-5-(pent-l-enyl)pyridine Prepeared from the intermediate obtained in Step B by the methods described in Example 160, Steps A-D. lH NMR (300 MHz, CDCl3): ~ 0.73 (t, J = 7.4 Hz, 3H), 1.09-1.36 (m, 14H), 1.63-1.73 (m, 2H), 1.89 (q, J = 6.9 Hz, lH), 3.25 (septet, J
= 6.6 Hz, lH), 3.46 (d septet, J = 2.7, 6.6 Hz, lH), 4.29-4.42 (m, 2H), 4.89-5.06 (m, 2H), 5.24-5.47 (m, lH), 5.95-6.00 (m, lH), 6.70-6.79 (m, 3H), 7.00-7.07 (m, 5H). FAB-MS:
calcd for (C30H36No2F) 461, found 462.
Step D: 2,6-Diisopropyl-3-(hydroxymethyl)-4-~(4-fluoro-2-hYdroxY)Phenyll-5-p~ yll~ylidine The title compound was prepared as a racemate from the intermediate obtained in Step C by the method ~l~tAile~l in ExAmple 161. lH NMR (300 MHz, , ~ . . ......
W 098/04528 PCTrUS97113248 O CDCl3): ~ 0.78 (t, J = 6.6 H~, 3H), 1.09-1.35 (m, 18H), 1.65 (t, J = 5.0 Hz, lH), 2.13-2.23 (m, lH), 2.28-2.38 (m, lH), 3.24 (sept, J = 6.6 Hz, lH), 3.39 (sept, J = 6.6 Hz, lH), 4.29 (dd, J = 11.1, 5.0 Hz, lH), 4.52 (dd, J = 11.1, 5.1 Hz, lH), 5.45 (bs, lH), 6.71-6.78 (m, 2H), 6.95-7.00 (m, lH). FAB-MS: calcd for (C23H32NO2F) 373, found 374 (M +
1). Rf =0.15 (20%ether-hexanes). mp 152 C.
OH~ OH
CH3 ~/~
~N ~/
2,6-Diisopropvl-3-(l-hydroxyethYl)-4-~(4-fluoro-2-hYdroxY)phenyll-5 pentylpyridine The title compound was prepared as two separable diastereomers from 2,6-diisopropyl-3-hydroxymethyl-4-[(2-benzyloxy-4-fluoro)phenyl]-5-(pent-1-enyl)pyridine (Example 166, Step C) by the methods detailed in Example 164, Steps A-C. The diastereomers were separated by radial band chromatography using a gradient eluent of 100% hexane to 20% ether-hexane.
Diastereomer 1 (D1): 1H NMR (300 MHz, CDCl3): ~ 0.80 (t, J = 6.6 Hz, 3H), 1.10-1.42 (m, 21H), 1.64 (d, ~ = 3.6 Hz, lH), 2.03-2.13 (m, lH), 2.21-2.31 (m, lH), 3.15-3.26 (septet, lH), 3.54-3.65 (septet, lH), 4.89-4.98 (m, lH), 4.99 (br s, lH), 6.69-6.75 (m, 2H), 6.94-6.99 (~, J = 2.7, 6.5, 6.5 Hz, lH). FAB-MS: calcd for (C24H34NO2F) 387, found 388 (M + 1). Rf = 0.41 (40% ether-hexanes). mp 124-126 C.
Diastereomer 1 (D1) was resolved into its constituent enantiomers as follows. A Waters Prep LC 2000 HPLC system was equipped with a chiral HPLC
column (BRB-9668A; 6 x 50 cm ID). The system was equilibrated with a mobile phase consisting of 2% (1% acetic acid, 99% ethanol) and 98% hexane at a flow rate of 175 mL/min. The sample was dissolved in mobile phase (50 mg/mL) and 5 mL
aliquots were injected at 30 min intervals. The effluent was monitored at 280 nmand two fractions (corresponding to the two enantiomers) were collected at (13-18 min,100% ee) and (18.5-27 min, >99%ee), respectively.
W O 98/04528 PCTrUS97113248 O Diastereomer 2 (D2): lH NMR (300 MHz, CDC13): ~ 0.78 (t, J = 6.5 Hz, 3H), 1.06-1.40 (m, 21H), 1.75 (d, J = 3.6 Hz, lH), 2.06-2.16 (m, lH), 2.26-2.37 (m, lH), 3.21 (septet, J = 6.6 Hz, lH), 3.74 (septet, J = 6.6, lH), 4.59-4.67 m, lH), 4.83 (br s, lH), 6.68-6.75 (m, 2H), 6.86-6.91 (~, J = 3.0, 6.6, 6.6 Hz, lH); FAB-MS: calcd for (C24H34NO2F) 387, found 388 (M + 1). Rf = 0.24 (40% ether-hexanes). mp 157-159~C.
HO ~--' \f~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methoxyphenyl)-5-(pent-l-enyl)pyridine The title compound was prepared from 4-methoxybenzaldehyde by the methods detailed in Example 125. lH NMR (300 MHz, CDCl3): ~ 0.76 and 0.81 (t, J
= 7.2 Hz, 3H), 1.12-1.39 (m, 14H), 1.60-1.80 (bs, lH), 1.86-1.97 (m, 2H), 3.33-3.50 (m, 2H), 3.85 (s, 3H), 4.43 (m, 2H), 5.27-5.48 (m, lH), 5.93-6.05 (m, lH), 6.92 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H). FAB-MS: calcd for (C24H33NO2) 367, found 368 (M+1).
HO ~~ ~~"
~ N~/
2,6-Diisopropyl-3-hydroxymethyl~-(4-methoxyphenyl)-5-pentyl-pyridine W O 98/04528 PCT~US97~13248 0 The title compound was prepared as a white solid from 2,~diisopropyl-3-hydroxymethyl-4-(4-methoxyphenyl)-5-(pent-1-enyl)pyridine (Example 168) by the methods detailed in Example 126. lH NMR (300 MHz, CDC13): ~ 0.80 (t, J = 6.6 Hz,3H), 1.08-1.19 (m, 4H), 1.24-1.38 (m, 15H), 2.27-2.33 (m, 2H), 3.24 (sept, J = 6.6 Hz, lH), 3.42 (sept, J = 6.6 Hz, lH), 3.87 (s, 3H), 4.35 (d, J = 5.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 8.7Hz, 2H). FAB-MS: calcd for (C24H3sNO2) 369, found 370 (M + 1). mp 47-49~C.
~,OCH3 HO ~~"
\~ N~
2,6-Diisopropyl-3-hydroxymethyl-4-(3-methoxyphenyl)-5-(pent-l-enyl)pyridine The title compound was prepared from 3-methoxybenzaldehyde by the methods detailed in Example 125. 1H NMR (300 MHz, CDCl3): ~ 0.78 (t, J = 7.5 Hz, 3H), 1.17-1.41 (m, 14H), 1.65 (s, lH), 1.97 (~, J = 14.0, 7.2, 1.5 Hz, 2H), 3.39-3.55 (m, 2H), 3.81 (s, 3H), 4.45 (s, 2H), 5.35-5.50 (m, lH), 6.01-6.09 (m, lH), 6.73-6.77 (m, 2H), 6.89 (~, J = 8.1, 2.1, 0.9 Hz, lH), 7.30 (t, J = 8.0 Hz, lH). FAB-MS: calcd for (C24H33NO2) 367, found 368 (M + 1). mp 71-75 C.
~,OCH3 HO ~~ ~~~
\~ N ~/
~ 2,6-Diisoprop~1-3-hydroxymethyl-4-(3-methoxyphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-WO ~8101~28 PCTrUS97113248 0 (3-methoxyphenyl)-5-(pent-1-enyl)pyridine (Example 170) by the methods detailed in Example 126. lH NMR (300 MlIz, CDC13): ~ 0.79 (t, J = 6.6 Hz, 3H), 1.09-1.33 (m, 7H), 1.30 (d, J = 6.6 Hz, 6H), 1.33 (d, J = 6.6 Hz, 6H), 2.25-2.31 (m, 2H), 3.23 (sept, J =
6.6 Hz, lH), 3.42 (sept, J = 6.6 Hz, lH), 3.82 (s, 3H), 4.35 (d, J = 6.0 Hz, 2H), 6.73 (dd, J = 2.4, 1.5 Hz, lH), 6.76 (dt, J = 7.5, 1.4 Hz), 6.93 (~, J = 8.4, 3.6, 1.2 Hz, lH), 7.34 (t, J
= 8.1 Hz, lH). FAB-MS: calcd for (C24H3sNO2) 369, found 370 (M + 1). mp 65-66 .
~ OCH3 HO ~~/
~N~/
2,6-Diisopropyl-3-hydroxymeth~1-4-(2-methoxyphenyl)-5-(pent-1-enyl)pyridine The title compound was prepared from 2-methoxybenzaldehyde by the methods detailed in Example 125. ~H NMR (300 MHz, CDCl3): ~ 0.82 and 0.72 (t, J
= 7 Hz, 3H), 1.05-1.47 (m, 15H), 1.80-2.00 (m, lH), 2.05 (~s, lH), 3.21-3.60 (m, 2H), 3.75 and 3.76 (s, 3H), 4.27 (d, J = 11.4 Hz, lH), 4.43 (d, J = 11.4 Hz, lH), 5.25-5.44 (m, lH), 6.01-6.07 (m, lH), 6.93-7.03 (m, 3H), 7.29-7.37 (m, lH).
~ OCH3 HO~
\~ N
2,6-Diisopropyl-3-hydroxymethyl-4-(2-methox-lphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(2-methoxyphenyl)-5-(pent-1-enyl)pyridine (Example 172) by the methods detailed in Example 126. lH NMR (300 MHz, CDC13): ~ 0.77 (t, J - 6.6 Hz, 3H), 1.06-1.11 (m, 4H), 1.22-1.38 (m, 14H), 1.87 (dd, J = 9.3, 3.3 Hz, lH), 2.14 -2.40 (m, 2H), 3.25 (sept, J
2~2 0 = 6.6 Hz, lH), 3.46 (sept, J = 6.6 Hz, lH), 3.76 (s, 3H), 4.19 (dd, J = 11.7, 3.0 Hz, lH), 4.39 (dd, J = 11.7, 9.0 Hz), 7.00-7.08 (m, 3H), 7.35-7.42 (m, lH).
HO ~/
~N~/
s 2,6-Diisopropyl-3-hydroxymethyl-4-~4-(methylthio)phenyll-5-(pent-l -enyl~pyridine The title compound was prepared as a thick colorless oil from 4-(methylthio)benzaldehyde by the methods detailed in Example 125. lH NMR (300 MHz, CDCl3): ~ 0.66 and 0.72 (t, J = 7.5 Hz, 3H), 1.05-1.32 (m, 14H), 1.51-1.70 (bs, lH), 1.80-1.89 (m, 2H), 2.43 (s, 3H), 3.12-3.41 (m, 2H), 4.32 (bs, 2H), 5.17-5.40 (m, lH), 5.85-5.97 (m, lH), 6.99 (d, J = 8.1 Hz), 7.18 (d, J = 8.1 Hz, 2H).
~Ol)CH3 HO~
\f N~/
2,6-Diisopropyl-3-hydrox~meth~1-4-~4-(methylsulfinyl)phenyll-5-(pent-1-enyl)p~,rridine 2,6-Diisopropyl-3-hydroxymethyl-4-[4-(methylthio)phenyl]-5-(pent-1-enyl)pyridine (100 mg, 0.261 mmol) (Example 174) was dissolved in methylene chloride (1.5 mL) and stirred at 0 C under an argon atmosphere. To this mixture was added a solution containing 3-chloroperoxybenzoic acid ("mCPBA") (85%, 53 mg, 0.261 mmol) in methylene chloride (1 mL). The mixture was stirred for 1.5 h at O C and ~ quenched with the addition of a saturated aqueous solution of NaHSO3 WO g8/04528 PCTrUS97/13248 0 (3 mL). The reaction mixture was further diluted through the addition of water (5 mL) and then extracted with methylene chloride (3 x 10 mL). The combined organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to S yield the title compound (52 mg, 50%) as a white solid, mp 133-135 C. ~H NMR
(300 MHz, CDCl3): ~ 0.77 and 0.69 (t, J = 7.5 Hz, 3H), 1.08-1.36 (m, 14H), 1.70-1.92 (m, 3H), 2.75 and 2.76 (s, 3H), 3.19-3.51 (m, 2H), 4.32-4.40 (m, 2H), 5.20-5.45 (m, lH), 5.93-6.00 (m, lH), 7.31-7.38 (m, 2H), 7.59-7.70 (m, 2H). Anal. calc. for C24H33NO2S:
C, 71.86; H, 8.29; N, 3.39; S, 7.73. Found: C, 72.14; H, 8.32; N, 3.51; S, 8.02.
so2CH3 HO~
~ N~/
2,6-Diisopropyl-3-h~droxymethyl-4-l4-~methylsulfonyl)phenyll-5-(pent-l -en~,rl)p~,rridine 2,6-Diisopropyl-3-hydroxymethyl-4-[4-(methylsulfinyl)phenyl]-5-(pent-1 -enyl)pyridine (100 mg, 0.261 mmol) (Example 174) was dissolved in methylene 20 chloride (1.5 mL) and stirred at 0 C under an argon atmosphere. To this mixture was added a solution containing 3-chloroperoxybenzoic acid ("mCPBA") (85%, 53 mg, 0.261 mmol) in methylene chloride (1 mL). The mixture was stirred for 1.5 h at 0 C and quenched with the addition of a saturated aqueous solution of NaHSO3 (3 mL). The reaction mixture was further diluted through the addition of water (5 25 mL) and is then extracted with methylene chloride (3 x 10 mL). The combined organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to yield the title compound (31.1 mg, 29%). 1H NMR (300 MHz, CDCl3): ~ 0.69 and 0.79 (t, J = 7.2 Hz, 3H), 1.08-1.37 (m, 14H), 1.45 (t, J = 4.2 Hz, lH), 1.86-1.93 (m, 2H), W 098/04~28 PCTAUS97/1~248 0 3.10 and 3.11 (s, 3H), 3.25-3.50 (m, 2H), 4.34-4.36 (m, 2H), 5.20-5.50 (m, lH), 5.93-6.00 (m, lH), 7.41 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H). Anal. calc. for - C24H33NO3S: C, 69.28; H, 7.91; N, 3.18; S, 7.50. Found: C, 69.36; H, 8.00; N, 3.37; S, 7.71.
S
F
~,CH20H
HO~
\~N~
2,6-Diisopropyl-3-hydroxymethYl-4- 1 (4-fluoro-3-hydroxymethyl)phenyll-5-pentylpyridine Step A: 2,6-Diisopropyl-3-~(t-butyldimethylsiloxy)methyll-4-(4-fluorophenyl) 5-pentylpyridine To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (3.14 g, 8.78 mmol) (Example 1, Step H) in methylene chloride (45mL) were added imidazole (0.9 g, 13.17 mmol, 1.5 eq) and f-butyl-dimethylsilyl chloride (2.0 g, 13.17 mmol, 1.5 eq). A white precipitate began to form immediately. The mixture was stirred for 14 h at 25~C and was then diluted with methylene chloride (100 mL) and washed sequentially with 10% hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), and brine (20 mL). The organic layer was concentrated under reduced pressure and the resultant residue was recryst~lli7e~1 from methanol to provide the product (3.27 g, 79%) as a white fluffy crystalline solid. lH NMR (300 MHz, CDCl3): S -0.10 (s, 6H), 0.79 (t, J = 6.9 Hz, 3H), 0.83 (s, 9H), 1.07-1.20 (m, 4H), 1.29-1.32 (m, 14H), 2.23-2.30 (m, 2H), 3.21 (sept, J = 6.6 Hz, lH), 3.35 (sept, J = 6.6 Hz, lH), 4.24 (s, 2H), 7.05-7.18 (m, 4H).
Anal. calc. for C2gH46NOFSi: C, 73.83; H, 9.83; N, 2.97. Found: C, 73.82; H, 9.95; N, 2.86.
Step B: 2,6-Diiso~lo~yl-3-~(t-bu'n~ldimethylsiloxy)methyll-4-~(4-fluoro-3-hydroxymethyl)phenyll-5-p~lllyl~ylidine To a solution of the intermediate from Step A (5.4 g, 11.4 mmol) in THF (80 W 098/04528 PCTrUS97113248 0 mL) was added sec-butyllithium (1.3 M, 26.4 mL, 3 eq) at -78~C under an argon atmosphere. ~he yellow solution was stirred for 1 h at -78~C and ~uenched through the ~ ition of of water (50 mL). The mixture was allowed to warm to 25~C and extracted with ethyl acetate (3 x 50 mL) and the organic layer was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the crude intermediate. (6.41 g).
This intermediate (3.2 g) was dissolved in THF (50 mL) and stirred at 0~C as lithium aluminum hydride ("LAH") (lM in THF, 25.7 mL, 25.7 mmol) was added to it. The resultant mixture was stirred at 0~C for 1.5 h and quenched through the sequential addition of water (1 mL), lN aqueous sodium hydroxide (1 mL), and water (3 mL). The resultant mixture was filtered and the precipitate rinsed withether (100 mL). The combined organic layer was washed with water (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was subjected to flash chromatography using a 10% ether-hexanemixture as the eluent. In this manner, 1.1 g of the product was obtained. lH NMR(300 MHz, CDCl3): ~ -0.09 (s, 6H), 0.83 (s, 9H), 1.07-1.20 (m, 4H), 1.29-1.33 (m, 17H), 1.96-2.02 (m, lH), 2.22-2.31 (m, 2H), 3.23 (sept, J = 6.6 Hz, lH), 3.36 (sept, J = 6.6 Hz, lH), 4.22-4.32 (m, 2H), 4.70-4.90 (m, 2H), 7.09-7.12 (m, 2H), 7.23-7.28 (m, lH).
Step C: 2,6-Diisopropyl-3-h~droxymethyl-4-~(4-~uoro-3-hydroxy-methyl)phenyll-5-pentylpyridine To a solution of the intermediate from Step B (123 mg, 0.245 mmol) in THF
(3 mL) was added tetrabutylammonim fluoride (lM in THF, 0.7 mL, 0.7 mmol) at 25~C under an argon atmosphere. The mixture was stirred for 14 h at 25~C and then diluted with water (5 mL) and extracted with methylene chloride (3 x 5 mL).The combined organic layer was washed with brine (5 mL), dried (Na2S04) and concentrated under reduced pressure. The resultant residue was purified by flashchromatography using a 40% ethyl acetate-hexane mixture as the eluent. In this manner, the title compound (79 mg, 83%) was produced as a colorless oil. lH NMR
(300 MHz, CDCl3): ~ 0.78 (t, J = 6.6 Hz, 3H), 1.10-1.17 (m, 4H), 1.24-1.35 (m, 14H), Z.10-2.40 (m, 2H), 2.73 (bs, lH), 3.22 (sept J = 6.6 Hz, lH), 3.34 (sept, J = 6.6 Hz, lH), 3.85 (bs, lH), 4.06 (d,J = 11.4 Hz, lH), 4.35 (d, J = 11.4 Hz, lH), 4.4~ (d, J = 14.1 Hz, lH), 4.73 (d, J = 14.1 Hz, lH), 7.00-7.06 (m, 2H), 7.25 (d, J = 7.2 Hz, lH).
WO 98/04528 PCT~US97113248 ,J~CO2CH3 HO~
~N~
2,6-Diisopropyl-3-hYdroxymethYl-4-l (4-fluoro-3-methoxycarbonyl~-phenyll-5-5 pentylpyridine ~A: 2,6-Diisopropyl-3-~(t-butyldimethylsiloxy)methyll-4-~(4-fluoro-3-formyl)phenyll -5-pentylpyridine To a solution of 2,6-diisopropyl-3-[(t-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-hydroxymethyl)phenyl]-5-pentylpyridine (Example 177, Step B) (1.09 g, 2.18 mmol) in methylene chloride (100 mL) was added a mixture of PCC (0.94 g, 4.35 mmol, 2 eq) and Celite (0.94 g). The resultant mixture was stirred for 2 h at 25 C and then filtered through a pad of silica gel. The silica gel pad was rinsed with a 10% ethyl acetate-hexane mixture (200 mL) and the combined organic layer was 15 concentrated to afford the crude product (0.78 g) as a white waxy solid.
Step B: 2,6-Diisopropyl-3-~(t-butyldimethylsiloxy)methyll-4-~(4-fluoro-3 methoxycarbonyl)phenyll -5-pentylpyridine To a solution of the intermediate from Step A (82 mg, 0.164 mmol) in 20 methanol (3 mL) were added potassium cyanide (53 mg, 0.82 mmol) and activatedmanganese dioxide (71 mg, 5 eq). The mixture was stirred at 25~C for 14 h and then filtered through a pad of Celite. The Celite pad was rinsed with ethyl acetate (25 mL) and the combined organic layer was washed with ~rine (5 mL), dried (Na2S04), and concentrated under reduced pressure. The resultant residue was 25 purified by flash chromatography to provide the intermediate (70 mg). 1H NMR
(300 MHz, CDCl3): ~ -0.13 (s, 6H), 0.75 (t, J = 6.6 Hz, 3H), 1.06-1.40 (m, 27H), 2.20-2.35 (m, 2H), 3.20 (sept, J = 6.6 Hz, lH), 3.32 (sept, J = 6.6 Hz, lH), 4.15 (d, J = 10.8 Hz, lH), 4.25 (d, J = 10.8 Hz, lH), 7.15-7.25 (m, lH), 7.40-7.50 (m, lH), 7.69 (dd, J =
~ 6.6, 2.4 Hz, lH), 10.41 (s, lH). FAB-MS: calcd ~or (C30H46NO2FSi) 499, found 500 30 (M+1).
W 098/0-'2X PCTAUS97113248 $tep C: 2,6-Diisopropyl-3-hvdrox~nethv1-4-~(4-fluoro-3-methoxy-carbonyl)phenyll -5-pentylpyridine The title compound was prepared from the intermediate obtained in Step B
by the method detailed in Example 177, Step C. 1H NMR (300 MHz, CDCl3): ~ 0.78 (t, J = 6.6 Hz, 3H), 1.08-1.16 (m, 4H), 1.23-1.34 (m, 15H), 2.20-2.30 (m, 2H), 3.22 (sept, J = 6.6 Hz, lH), 3.40 (sept, J = 6.6 Hz, lH), 3.93 (s, 3H), 4.25-4.39 (m, 2H), 7.12 (dd, J =
10.3, 8.5 Hz, lH), 7.28 (~, J = 8.5, 4.8, 2.2 Hz, lH), 7.69 (dd, J = 6.6, 2.2 Hz, lH).
F
HO ~--' \~ N '~/
2,6-Diisopropyl-3-hydrox~nethyl-4-~(4-fluoro-3-pentyl)phenyll-5-pentylpyridine Step A: 2,6-Diisopropyl-3-~(t-butvldimeth~lsiloxy)methyll4-~(4-fluoro-3 (pent-l-enyl))phenyll-5-pentylpyridine To a solution of 2,6-diiso~lo~yl-3-[(t-butyldimethylsiloxy)methyl~-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (Example 178, Step A) (200 mg, 0.40 mmol) in THF (10 mL) was added a butyltriphenylphosphonium bromide/sodium amide mixture (Fluka, 0.55 g, 3 eq) under an argon atmosphere. The reaction was stirred at 25 C for 1.5 h and ~s quenched by dropwise addition of water (3 mL) and further diluted with brine (5 mL). The mixture was extracted with ethyl acetate (2 x 20 mL) and the combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. I~e resultant residue was subjected to flash chromatography to yield the intermediate (205 mg). 1H NMR (300 MHz, CDCl3):
~-0.13 (s, 6H), 0.75-1.47 (m, 35H), 2.~3-2.33 (m, 4H), 3.21 (septet, J = 6.6 Hz, lH), 3.34 (septet, J = 6.6 Hz, lH), 2.7 (d, J = 2.7 Hz, 2H), 5.75-6.31 (m, lH), 6.41-6.59 (m, lH), 6.98-7.09 (m, 3H). FAB-MS: calcd for (C34Hs4NOFSi) 539, found 540 (M + 1).
.. . ... .
W 098101-2X PCT~US97113248 O Step B: 2,6-Diisopropyl-3-~(t-butyldimethylsiloxy)methyll-4-~(4-fluoro-3-pentyl)phenyll -5-pentylpyridine The intermediate from Step A (200 mg) was dissolved in ethanol (10 mL) and the mixture purged with argon. A quantity of 10% Pd-C (20 mg) was then added and the mixture was purged with hydrogen and stirred under a hydrogen ~ 5 atmosphere at 25 C for 16 h. The mixture was then filtered through a pad of silica and the silica pad ~; rinsed with ethanol (25 mL). The organic layer was concentrated under reduced pressure and the resultant residue was subjected to flash chromatography using hexane as the eluent to afford the intermediate (150 mg, 75%). 1H NMR (300 MHz, CDCl3): ~ -0.11 (s, 6H), 0.76-1.65 (m, 39H), 2.17-2.33 (m, 2H), 2.51-2.78 (m, 2H), 3.21 tseptet~ ~ = 6.6 Hz, lH), 3.35 (septet, J = 6.6 Hz, lH), 4.42 (dd, J = 10.2, 16.2, 2H), 6.92-7.05 (m, 3H). FAB-MS: calcd for (C34H56NOFSi) 541, found 542 (M+1).
Step C: 2,6-Diisopropyl-3-hvdroxymethyl-4-l(4-fluoro-3-Pentyl)-phenyll-5 1 5 pentylpyridine The title compound was prepared as a colorless oil from the intermediate from Step B by the method detailed in Example 177, Step C. lH NMR (300 MHz, CDCl3): ~ 0.77 (t, J = 6.9 Hz, 3H), 0.88 (t, J = 6.9 Hz, 3H), 1.08-1.34 (m, 24H), 1.57-1.65 (m, 1H), 2.22-2.29 (m, 2H), 2.57-2.75 (m, 2H), 3.21 (sept, J = 6.6 Hz, lH), 3.40 (sept, J = 6.6 Hz, lH), 4.33 (dd, J = 5.6, 1.4 Hz, 2H), 6.93-7.09 (m, 3H). FAB-MS: calcd for (C2gH42NOF) 427, found 428 (M + 1). Rf = 0.42 (20% ether-hexanes).
HO ~ ~~
~N ~/
2,6-Diisopropyl-3-hydroxymethyl-4-~(4-fluoro-3-ethyl)phenyll-5-pentylpyridine The title compound was prepared as a white wax from 2,6-diisopropyl-3-l(t-butyldimethylsiloxy)methyl]-4-[(4-fluor~3-formyl)phenyl]-5-pentylpyridine (Example 178, Step A) (200 mg, 0.40 mmol) and an ethyltriphenylphosphonium W098/04528 PCTrUS97113248 0 bromide/sodium amide mixture (Fluka) by the methods det~ile~ in Example 179, Steps A-C. lH NMR (300 MHz, CDC13): ~ 0.77 (t, J = 6.9 Hz, 3H), 1.10-1.33 (m, 22H), 2.17-2.33 (m, 2H), 2.60-2.80 (m, 2H), 3.21 (sept, J = 6.6 Hz, lH), 3.40 (sept, J =
6.6 Hz, lH), 4.34 (dd, J = 5.7, 1.8 Hz, 2H), 6.94-7.09 (m, 3H). FAB-MS: calcd for (C2sH36NOF) 385, found 386 (M+1). Rf = 0.38 (20% ether-hexanes).
F OH
HO
\~N~
10 2,6-Diisopropvl-3-hydroxymethYl-4-~4-fluoro-3-(a-hydroxy-4-fluoro-benzyl)l-5 pentylpyridine Step A: 2,6-Diisopropyl-3-(t-butyldimethylsilyloxymethyl)-4-~4-fluoro-3-( hydroxy-4-fluorobenzyl)phenyll -5-pentyl-pyridine To a solution of 2,6-diisopropyl-3-~(t-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (160 mg, 0.321 mmol) (Example 178, StepA) in THF (10 mL) was added 4-fluorophenyl magnesium bromide (1.0 M in THF, 0.4 mL, 2.5 eq) under an argon atmosphere at 25 C. The mixture was stirred for 30 min and then quenched by the dropwise addition of water (5 mL). The mixture was extracted with ether (2 x 10 mL) and the combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography using a 10% ether-hexane mixture as the eluent to provide 150 mg of the intermediate. lH NMR (300 MHz, CDCl3): ~ -0.19 (d, 6.3 Hz, 3H), -0.10 (d, J - 7.2 Hz, 3H), 0.71-1.30 (m, 30 H), 2.17-2.28 (m, 3H), 3.18 (septet, J = 6.6 Hz, lH), 3.25-3.40 (m, lH), 4.04-4.38 (m, 2H), 6.14 (dd, J = 4.4, 17.9 Hz, lH), 6.97-7.38 (m, 7H). FAB-MS: calcd for (C36Hs1NOF2Si) 595, found 596 (M + 1).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-~4-fluoro-3-(a-hydroxy-4-fluorobenzyl)phenyll-5-~elllyl~yridine W098/04528 PCTrUS97113248 O The title compound was prepared from the intermediate from Step A by themethod detailed in Example 177, Step C. lH NMR (300 MHz, CDCl3): ~ 0.72-1.45 (m, 22H), 2.13-2.36 (m, 2H), 2.65 (d, J = 4.2 Hz, lH), 3.21 (sept, J = 6.6 Hz, lH), 3.39 (sept, J = 6.6 Hz, lH), 4.21-4.39 (m, 2H), 6.14-6.17 (m, lH), 6.98-7.12 (m, 4H), 7.35-- 7.42 (m, 3H) FAB-MS: calcd for (C30H37NO2F2) 481, found 482 (M + 1) Rf = 0 21, 0.51 (50% ether-hexanes). mp 118-120 C.
F OH
HO~
\~N
2,6-Diisopropyl-3-h~drox~methyl-4-~4-fluoro-3-(l-hydroxyethyl)phenyll-5 pentylpyridine The title compound was prepared as an oil from 2,6-diisopropyl-3-[(t-butyldimethylsiloxy)methyl3-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyrid~ne (Example 178, Step A) and methylmagnesium bromide ~y the methods detailed in Example 181, Steps A-B. lH NMR (300 MHz, CDCl3): ~ 0.76 (t, J = 6.0 Hz, 3H), 1.0g-1.53 (m, 21H), 1.84 (br s, lH), 2.18-2.27 (m, 2H), 2.87 ( br s, 1 H), 3.20 (septet, J =
6.6 Hz, lH), 3.37 (septet, J = 6.6 Hz, lH), 4.16 (d, J = 11.4 Hz, lH), 4.28-4.35 (m, lH), 5.16-5.19 (m, lH), 7.01-7.07 (m, 2H), 7.25-7.34 (m, lH). FAB-MS: calcd for (C25H36NO2F) 401, found 402 (M + 1). Rf = 0.32 and 0.20 (50% ether-hexanes).
¢ ~f H
HO ~j~
\~N~
W O98/015~8 PCTrUS97/13248 o 2,6-Diisopropyl-3-hydroxymethyl-~4-fluoro-3-((N-((pyridin-2-yl) methyl)amino)methyl)lphenyl-5-pentylpyridine Step A: 2,6-Diisopropvl-3-~(t-butyldimethylsiloxy)meth~ l-4-~4-fluoro-3-((N
~(pyridin-2-yl)methyl)amino)methyl)lphenyl-5-pentylpyridine To a solution of 2,6-diisopropyl-3-[(t-butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (500 mg, 1 mmol) (Example 178, Step A) in methanol (10 mL) and ether (2 mL) was added 2-methylaminopyridine (0.42 mL, 4 mmol, 4 eq) under an argon atmosphere at 25 C. To this solution were added ZnC12 (68.1 mg, 0.5 eq) and sodium cyanoborohydride (62.8 mg, 1 eq) in methanol (6 mL). The reaction was allowed to stir for 20 h and was then quenched with theaddition of aqueous sodium hydroxide (O.lN, 7 mL). The methanol was removed under reduced pressure and the aqueous residue was extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried (Na2S04), and concentrated under reduced pressure. The resultant residue was subjected to flash chromatography using a 60% ether-hexane mixture as the eluent to provide the intermediate (260 mg, 44%). lH NMR (300 MHz, CDC13)~
0.12 (s, 6H), 0.72-0.81 (m, 12H), 1.80 (br s, lH), 1.07-1.15 (m, 4H), 1.27-1.31 (m, 14H), 2.23-2.29 (m, 2H), 3.20 (septet, J = 6.6Hz, lH), 3.34 (septet, J = 6.6 Hz, lH), 3.83-4.03 (m, 4H), 4.25 (dd, J = 10.5, 27.6 Hz, 2H), 7.06-7.33 (m, 5H), 7.64 (~, J = 1.8, 7.5, 7.5 Hz, lH), 8.54-8.56 (m, lH). FAB-MS: calcd for (C36Hs4N3OFSi) 591, found 592 (M + 1).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-l4-fluoro-3-((N-((pyridin-2 yl)methyl)amino)meth~l)lphenyl-5-pentylpyridine The title compound was prepared as a colorless oil from the intermediate obtained in Step A by the method detailed in Example 177, Step C. lH NMR (300 MHz, CDC13): ~ 0.75 (t, J = 6.9 Hz, 3H), 1.07-1.36 (m, 18H), 1.75 (bs, 2H), 2.19-2.36 (m, 2H), 3.20 (sept, J = 6.6 Hz, lH), 3.47 (sept, J = 6.6 Hz, lH), 3.74 (d, J = 14.1 Hz, lH), 3.79 (d, J = 13.5 Hz, lH), 3.89 (d, J = 13.5 Hz, lH), 4.07 (d, J = 14.1 Hz, lH), 4.20 (d, J = 11.4 Hz, lH), 4.41 (d, J = 11.4 Hz, lH), 7.02-7.25 (m, 4H), 7.38 (d, J = 7.8 Hz, lH), 7.66 (~, J = 7.5, 7.5, 1.8 Hz, lH), 8.47 (m, lH). FAB-MS: calcd for (C30H40N3OF) 477, found 478 (M ~ 1). Rf = 0.4 (ethyl acetate).
WO 38~'~.152~ PCT/US97/13248 o EXAMPLE 184 F
~N~
HO ~~
~N~/
2,6-Diisopropyl-3-hydrox~nethyl-4-~4-fluoro-3-(pyrrolidin-1 -yl)methyllphenyl-5-5 pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-[(t-butyl-dimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (Example 178, Step A) by the methods detailed in Example 183, Steps A-B. lH NMR (300 MHz, CDC13): ~ 0.77 (t, J = 6.6 Hz, 3H), 1 05-1.31 (m, 18 H), 1.75-1.85 (m, 5 H), 2.23-102.29 (m, 2H), 2.50-3.50 (m, 4H), 3.20 (sept, J = 6.6 Hz, lH), 3.41 (sept, J = 6.6 Hz, 1 H), 3.71 (d, J = 12.9 Hz, lH), 3.82 (d, J = 12.9 Hz, lH), 4.29 (dd, J = 11.7, 20.4 Hz, 2H), 7.03-7.13 (m, 2H), 7.26-7.30 (m, lH). FA~MS: calcd for (C2gH41N2OF) 440, found 441 (M +1). Rf = 0.2 (ethyl acetate).
15E~CAMPLE 185 ~~ N ~\
HO ~~"~~"
~N~
2,6-Diisopropyl-3-hydroxymethyl-4-~4-Iquoro-3-(butylamino)methyllphenyl-5 20 pelL~yl~,yl;dine ~ The title compound was prepared from 2,~diisopropyl-3-[(t-butyl-dimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (Example 178, Step A) by the methods ~1et~ilP~ in Example 183, Steps A-B. lH NMR (300 MHz, CDCI3): ~ 0.79 (t, J = 6.8 Hz, 3 H), 0.91 (t, J = 7.4 Hz, 3 H), 1.10-1.61 (m, 24 H), WO 9~101~2~ PCT~US97/13248 0 2.25-2.31 (m, 2 H), 2.62 (t, J = 7.2 Hz, 2 H), 3.23 (sept, J = 6.6 Hz, 1 H), 3.42 (sept, J =
6.6 Hz, lH), 3.89 (s, 2H), 4.32 (dd, 11.7 Hz, 2H), 7.04-7.20 (m, 3 H). FA~MS: calcd for (C2gH43N2OF) 442, found 443 (M +1). Rf = 0.33 (ethyl acetate).
s ¢~N
HO ~----~N~
2,6-Diisopropyl-3-hydroxymethyl-4-(pyridin-3-yl)-5-pentylpyridine The title compound was prepared as an oil from ethyl isobutyryl acetate, 10 ammonium acetate and pyridine-3-carboxaldehyde in 0.56% yield by the methods described in Example 125. FAB-MS: calculated for C22H32N20 340; found 341 (M+1). lH NMR (300 MHz, CD30D): ~ 0.77 (t, J = 6.5 Hz, 3H), 1.08-1.32 (m, 18H), 2.27-2.33 (m, 2H), 3.28 (septet, J = 6.6 Hz, lH), 3.48 (septet, J = 6.6 Hz, lH), 4.25 (s, 2H), 7.52-7.57 (m, lH), 7.73-7.76 (m, lH), 8.42-8.43 (m, 2H), 8.59 (dd, J = 5.1, 1.5 Hz, 1 5 lH). Anal. calc for C22H32N2O: C, 77.60; H, 9.47; N, 8.23. Found: C, 75.96; H, 9.32;
N, 7.88. Rf = 0.40 (diethyl ether).
HO ~' ~N~
2,6-Diisopropvl-3-hydroxymethyl-4-(3-furyl)-5-(pent-l-enyl)pyridine Substituting 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) for ceric ammonium nitrate (CAN) to oxidize the dihydropyridine intermediate to the phenyl pyridine, the title compound was prepared as a mixture of E and Z isomers25 (4.5:1, E:Z) from ethyl isobutyryl acetate, ammonium acetate and furan-3-carboxaldehyde in 10% yield by the methods described in Example 125. FAB-MS:
.
WO 98~'~1r~8 PCT~US97/13248 O calculated ~or C21H2gNO2 327; found 328 (M+l). lH NMR (300 MHz, CD30D):
0.84 (t, J = 7.4 Hz, 3H), 1.17-1.38 (m, 14H), 2.01-2.04 (m, 2H), 3.39 (septet, J = 6.6 Hz, lH), 3.47 (septet, J = 6.6 Hz, lH), 4.44 (s, 2H), 5.40-5.58 (m, 2H), 6.11-6.25 (m, lH), 6.38-6.40 (m, lH), 7.41-7.54 (m, 2H).
HO~
~N~
2,6-Diisopropyl-3-hydroxvmethyl-4-(3-furyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-furyl)-5-(pent-1-enyl)pyridine (Example 187) in 6% yield by the methods described in Example 125. FAB-MS: calculated for C21H31N02 329; found 330 (M~l). lH NMR (300 MHz, CD30D): ~ 0.83 (t, J = 6.8 Hz, 3H), 1.19-1.36 (m, l9H), 2.42-2.48 (m, 2H), 3.25 (septet, J = 6.6 Hz, lH), 3.45 (septet, J = 6.6 Hz, lH), 4.38 (s, 2H), 6.42 (m, lH), 7.45-7.46 (m, lH), 7.61-7.62 (t, J = 1.7 Hz, lH). Anal. calc for C21H31NO2: C, 76.55; H, 9.48; N, 4.25. Found: C, 76.41; H, 9.76; N, 4.24. Rf = 0.59 (20% EtOAc/hex). mp 98-100 C.
HO ~'/
~N~
2,~Diisopropyl-3-hydroxymeth~l~-(thiophen-3-yl)-5-(pent-l -enyl)-pyridine The title compound was prepared as a mixture of E and Z isomers (5.5:1, 25 E:Z) from ethyl isobutyrylacetate, ammonium acetate and thiophene-3-carboxaldehyde in 7% yield by the methods described in Example 125. FAB-MS:
WO 98/04~28 PCTIUS97113248 O r~ te~l for C21H2gNOS 343; found 344 (M+1). lH NMR (300 MHz, CDCl3):
0.78-0.84 (m, 3H), 1.22-1.37 (m, 15H), 1.96-2.00 (m, 2H), 3.37-3.50 (m, 2H), 4.47 (d, J =
5.7 Hz, 2H), 5.32-5.43 (m, lH), 6.02-6.12 (m, lH), 6.95-6.97 (m, lH), 7.12-7.13 (m, lH), 7.35-7.38 (m, lH). Anal. calc for C21H29NOS: C, 73.43; H, 8.52; N, 4.08; S, 9.32.
Found: C, 73.38; H, 8.75; N, 3.97; S, 9.03. Rf = 0.65 (20% EtOAc/hex). mp 85-87 C.
s HO ~~'~' 3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-fluor~l,l'-biphenyl Step A: 1-(2-Methoxyethox-~)methox~methyl-2,4-diisopropyl-5-hydroxymethylbenzene A mixture of 1,5-bis(hydroxymethyl)-2,4-diisopropylbenzene (0.947 g, 4.26 mmol) (prepared by the method of Fey, et ~I. U.S. Patent 5,138,090), methoxyethoxymethyl chloride (0.49 mL, 4.29 mmol), and diisopropylethylamine (1.1 mL, 6.31 mmol) in CH2C12 (9.6 mL) was stirred overnight. The mixture was diluted witl water (50 mL) and extracted with CH2C12 (3 x 50 mL). Silica gel chromatography (67:33 hexanes/ethyl acetate) provided a colorless oil (0.679 g, 51%). lH NMR (CDCl3, 300 MHz): ~ 7.31 (s, lH), 7.29 (s, lH), 4.83 (s, 2H), 4.72 (s, 2H), 4.66 (s, 2H), 3.76 (m, 2H), 3.60 (m, 2H), 3.43 (s, 3H), 3.26 (m, 2H), 1.27 (d, 7.0 Hz, 12H). EI-MS: c~ te~l for ClgH30O4 310; found 292 (M-H20, 24%), 221 (100%).
Step B: 3-(2-MethoxyethoxY)methox~methyl-4,6-diiso~ ,ylbenzaldehyde Prepared from the intermediate obtained in Step A by the procedure described in Example 1, Step E. 1H NMR (CDCl3, 300 MHz): ~ 10.29 (s, lH), 7.80 (s, lH), 7.39 (s, lH), 4.83 (s, 2H), 4.70 (s, 2H), 3.98 (sept, 6.8 Hz, lH), 3.76 (m, 2H), 3.59 (m, 2H), 3.42 (s, 3H), 3.26 (sept, 6.8 Hz, lH), 1.30 (d, 7.0 Hz, 6H), 1.28 (d, 7.0 Hz, 6H).
FAB-MS: calculated for C18H2804 308; found 309 (M~H).
W O~ 8 PCTrUS97/13248 o Step C: N-Phenyl 3-(2-methoxyethoxy)methoxymethyl-4,6-diiso-propylbenzimine A mixture of the intermediate from Step B (2.35 g, 7.62 mmol), aniline (700 mL, 7.68 mmol), p-toluenesulfonic acid (58.8 mg, 309 mmol), and molecular sieves~ 5 (20.7 g) in toluene was refluxed overnight. The mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (65 mL) and washed with saturated aqueous NaHCO3 solution (50 mL) and water (50 mL), dried (MgSO4), and concentrated to give an orange oil (2.78 g, 96%). The productwas used in the next step without purification. lH NMR (C6D6, 300 MHz): ~ 8.70 (s, lH), 8.48 (s, lH), 7.31 (s, lH), 7.17 (m, 4H), 7.00 (m, lH), 4.61 (s, 2H), 4.60 (s, 2H), 3.56 (m, 2H), 3.46 (sept, 6.8 Hz, lH), 3.29 (m, 2H), 3.20 (sept, 6.8 Hz, lH), 3.07 (s, 3H), 1.17 (d, 7.0 Hz, 6H), 1.12 (d, 7.0 Hz, 6H).
Step D: Bis~(2-N-phenylmethylimino)-3,5-diisopropyl-6-(2-1 5 methoxyethoxy)methoxymeth~lphenylldipalladium A mixture of the intermediate from Step C (2.78 g, 7.27 mmol) and Pd(OAc)2 (1.63 g, 7.26 mmol) in acetic acid (34 mL) was refluxed for 1 h. The mixture wascooled to rt, poured into water (135 mL), and filtered through a medium porosityfritted funnel. The filtrate was lyophilized. The residue was dissolved in ethylacetate (100 mL) and washed with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL), dried (MgSO4), and concentrated to give a brown solid. The solid was mixed with 50:50 petroleum ether/ethyl acetate (17 mL) and cooled irl the freezer. The resulting precipitate was collectetl and dried to give a brown solid (0.951 g, 27%). lH NMR (C6D6, 300 MHz): ~ 7.70 (s, lH), 7.65 (s, lH), 7.63 (s, lH), 7.11 (s, lH), 7.08 (s, lH), 6.99 (m, lH), 6.73 (s, lH), 5.33 (s, 2H), 5.08 (s, 2H), 4.19 (m, 2H), 3.35 (m, ZH), 3.04 (s, 3H), 2.68 (sept, 6.8 Hz, lH), 2.15 (sept, 6.8 Hz, lH), 1.01 (d, 7.0 Hz, 6H), 0.96 (d, 7.0 Hz, 6H). FAB~ calculated for C4gH64N2O6Pd2 976; found 488 (M/2).
Step E: 3,5-Diisopropyl-2-formyl-6-(2-methoxyethoxy)methoxymethyl-4'-fluoro-l,l '-biphenyl A mixture of 1,2-dibromoethane (80 mL) and magnesium turnings (0.349 g, 14.4 mmol) in diethyl ether (1 mL) was heated to reflux for several minutes. Themixture was diluted with diethyl ether and a solution of l-bromo-4-fluorobenzene(950 mL, 8.65 mmol) and 1,2-dibromoethane (160 mL) in diethyl ether (3 mL) was added over several minutes. The reflux was continued for 1 h then the mixture was cooled to room temperature. The supernatant liquid was added via cannula to a WO 9~ PCT/US97tl3248 0 solution of the intermediate obtained in Step D (0.951 g, 973 mmol) and triphenylphosphine (2.02 g, 7.71 mmol) in benzene (19 mL) and the mixture stirred overnight. Aqueous 6N HCl (6 mL) was added and the mixture stirred for 2 h. The mixture was filtered and the solids washed with diethyl ether (75 mL). The combined filtrates were washed with saturated aqueous sodium chloride solution (50 mL). Silica gel chromatography provided a colorless solid (0.413 g, 53%). 1HNMR (CDCl3, 300 MHz): ~ 9.70 (s, lH), 7.50 (s, lH), 7.26 (m, 2H), 7.11 (m, 2H), 4.59 (s, 2H), 4.30 (s, 2H), 3.89 (sept, 6.8 Hz, 2H), 3.55 (m, 2H), 3.44 (m, 2H), 3.37 (s, 3H), 1.33 (d, 6.6 Hz, 6H), 0.96 (d, 7.0 Hz, 6H). FAB~ Altlllate~ for C24H31F04 402;
found 403 (M+H).
Step F: 3,5-Diisopropyl-2-(2-methoxyethoxy)methoxymethyl-6-(pent-l-enyl) 4'-fluoro-1,1 '-biphenyl Prepared from the intermediate obtained in Step E by the procedure described in Example 1, Step F. The olefin was a mixture of cis and trans isomers in a ratio of 9:91. lH NMR (CDCl3, 300 MHz): ~ 7.32 (s, lH), 7.12 (m, 2H), 7.01 (m,2H), 5.95 (d, 16.2 Hz, lH), 5.23 (dt, 16.2 Hz, 7.0 Hz, lH), 457 (s, 2H), 4.29 (s, 2H), 3.53 (m, 2H), 3.43 (m, 2H), 3.37 (s, 3H), 3.31 (m, 2H), 1.89 (m, 2H), 1.32 (d, 6.6 Hz, 6H), 1.23 (d, 7.0 Hz, 6H), 1.2 (m, 2 H), 0.74 (t, 7.4 Hz, 3H). FAB-MS: calculated for C2gH3gFO3 442; found 442 (M+).
Step G: 3,5-Diisopropyl-2-(2-methoxyethoxy)methoxymethyl-6-pentyl-4 fluoro-~ biphenyl Prepared from the intermediate obtained in Step F by the procedure described in Example 1, Step H. lH NMR (CDCl3, 300 MHz): ~ 7.29 (s, lH), 7.19 (m, 2H), 7.07 (m, 2H), 4.52 (s, 2H), 4.21 (s, 2H), 3.51 (m, 2H), 3.41 (m, 2H), 3.37 (s, 3H), 3.27 (sept, 6.8 Hz, lH), 3.16 (sept, 6.8 Hz, lH), 2.27 (m, 2H), 1.30 (d, 7.0 Hz, 6H), 1.27 (m, 2H), 1.23 (d, 7.0 Hz, 6H), 1.10 (m, 4H), 0.77 (t, 6.8 Hz, 3H). FAB-MS:
calculated for C2gH41FO3 444; found 445 (M+H).
Step H: 3,5-Diisopropyl-2-aceloxyl~lethyl-~pentyl-4'-fluoro-1,1'-biphenyl Chlorotrimethylsilane (110 mL, 867 mmol) was added to a cooled (0~C) mixture of the intermediate from Step G (62.4 mg, 140 mmol) and NaI (132 mg, 880mmol) in CH3CN (1.4 mL). After 25 min. the mixture was filtered through silica gel (5:1 hexanes/ethyl acetate) and the filtrate conce~ ed. A mixture of the residue and sodium acetate (122 mg, 1.4g mmol) in dimethyl formamide (2.3 mL) was heated to 80~C overnight. The solvent was removed and the residue dissolved in water (15 mL) and extracted with CH2Cl2 (3 x 15 mL). Silica gel ._ ........ ..
WO 981'~ 8 PCTIUS97/13248 0 chromatography (95:5 hexane/ethyl acetate) provided a colorless oil (38.2 mg, 69%). 1H NMR (CDCl3, 300 MHz): ~ 7.31 (s, lH), 7.15 (m, 2H), 7.07 (m, 2H), 4.76 (s, 2H), 3.18 (sept, 6.8 Hz, lH), 3.12 (sept, 6.8 Hz), 2.28 (m, 2H), 1.97 (s, 3H), 1.29 (d, 6.6 Hz, 6H), 1.29 (m, 2H), 1.29 (d, 6.6 Hz, 6H), 1.14 - 1.07 (m, 4H), 0.78 (t, 6.8 Hz, 3H).
FAB-MS: calculated for C26H3sFO2 398; found 338 (M-AcOH).
Step I: 3,5-Diiso~ro~-fl-2-hvdroxymethyl-6-pentyl-4'-fluoro-1,1'-biphen~
A solution of the interrnediate obtained in Step H (11.2 mg, 28.1 mmol) and potassium hydroxide (109 mg, 1.65 mmol) in methanol (2 mL) was heated at ~0~C
for 3 h. The solvent was removed, and the residue dissolved in saturated aqueousammonium chloride (15 mL) and extracted with diethyl ether (3 x 15 mL). Silica gel chromatography (5:1 hexane/ethyl acetate) provided the title compound as a colorless crystalline solid (12.0 mg, 120%). lH NM3~ (CDCl3, 300 MHz): ~ 7.30 (s, lH), 7.19 (m, 2H), 7.11 (m, 2H), 4.32 (s, 2H), 3.37 (sept, 6.9 Hz, lH), 3.16 (sept, 6.9 Hz, lH), 2.26 (m, 2H), 1.31 (d, 6.6 Hz, 6H), 1.29 (m, 2H), 1.28 (d, 7.0 Hz, 6H), 1.17 -1.03 ~m, 4H), 0.77 (t, 6.8 Hz, 3H). FAB-MS: calculated for C24H33FO 356; found 356 (M+). Rf = 0.33 (83:17 hexanes/ethyl acetate). Anal. calculated for C24H33FO: C, 80.85; H, 9.33 Found: C, 80.63; H, 9.40. mp 98-99~C.
HO ~--3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1 '-biphenyl Step A: 3,5-Diisopropyl-2-formyl-6-pentvl-4'-fluoro-1,1'-biphenyl Prepared from 3,5-diis~ro~yl-2-hydroxymethyl-6-pentyl-4'-fluoro-1,1'-biphenyl (Example 190) by the procedure described in Example 1, Step E. lH NMR
(CDCl3, 300 MHz): ~ 9.70 (s, lH), 7.42 (s, lH), 7.23-7.10 (m, 4H), 3.88 (sept, 6.8 Hz, lH), 3.23 (sept, 6.8 Hz, lH), 2.34 (m, 2H), 1.31 (d, 6.6 Hz, 6H), 1.29 (d, 7.0 Hz, 6H), 1.28 (m, 2H), 1.14 (m, 4H), 0.79 (t, 6.6 Hz, 3H). FAB-MS: calculated for C24H31FO
354; found 355 (M+H).
CA 02t62434 1999-01-28 WO 98/04528 PCTrUS97/13248 o Step B: 3,5-Diisol~o~ 2-(1-hydrox~,rethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl The title compound was prepared from the intermediate obtained in Step A
by the procedure described in Example 101, Step B. lH NMR (CDCl3, 300 MHz):
7.32 (s, lH), 7.19-7.06 (m, 4H), 4.70 (dq, 7.0 Hz, 2.9 Hz, lH), 3.88 (sept, 6.8 Hz, lH), 3.13 (sept, 6.8 Hz, lH), 2.20 (m, 2H), 1.63 (d, 2.9 Hz, lH), 1.40 (d, 6.6 Hz, 3H), 1.30 (d, 7.0 Hz, 6H), 1.3 (m, 2H), 1.27 (d, 7.0 Hz, 6H), 1.08 (m, 4H), 0.78 (t, 6.8 Hz, 3H). FAB-MS: calculated for C2sH3sFO 370; found 370 (M+). Rf = 0.36 (83:17 hexanes/ethyl acetate). mp 126~C.
EXA~LE 192 ~10~- ~
3,5-Diiso~lu,uyl-2-(1-h-~droxyeth~trl)-6-pentyl-4'-fluoro-1,1'-biphenyl In a separate experiment, the title compound was prepared by the methods described in Example 191. lH NMR (300 MHz, CDC13): ~ 0.76 - 0.80 (m, 3H), 1.04 -1.31 (m, 19H), 1.40 (d, J = 6.6 Hz, 3H), 2.17 - 2.22 (m, 2H), 3.11 - 3.16 (m, lH), 3.$6 -3.90 (m, lH), 4.66 - 4.73 (m, lH), 7.06 - 7.22 (m, 4H), 7.32 (s, lH). 13C NMR (75 MHz, CDCI3) d 13.87, 22.01, 23.37, 24.22, 24.55, 24.61, 25.08, 28.66, 28.94, 29.91, 31.02, 32.22, 68.89, 114.65 - 115.15 (2d, 2C), 124.25, 130.33 - 131.28 (2d, 2C), 135.51, 136.96, 137.72, 139.00, 145.80 (2C), 161.67 (d, J = 245.7 Hz, lC). FAB-MS: calc~ te~
for C25H35OF 370; found 370 (M+). Anal. calc for C2sH3sOF: C, 81.03; H, 9.52.
Found: C, 81.05; H, 9.70. Rf = 0.37 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A =
0.05 % aqueous trifluoroacetic acid, B = CH3CN; ~inear gradient: 75% - 100 %B over 30 min; 254 nm, 1 mL/min): R.T. 20.0 min. (91.1 area %); (Daicel Chiralcel OD-H;isocratic 99:1 hexanes:methyl t-butyl ether; 254 nm, 1.5 mL/min); R.T. = 5.83 min (49.0 area %), 7.67 min.(51 area %). mp 124.0-125.0~C.
; . CA 02262434 1999-01-28 . . . . -~ , DEMANDES OU BREVErS VOLUMINEUX
LA PRÉSENTE PARTIE DE ~; I I t DEMANDE OU CE BREVET
COMPREND PLUS D'UN TOME.
CECI EST LE TOME /--DE_~ -NOTE: Pour les tomes add;tionels, veuil1ez cc~ntacter le Bureau canadien des brevets JUl\~lBO APPLICATIONSIPATENTS - .
THIS SECTION OF THE APPLICATIONIPATENT CONTAINS MORE
THAN ONE VOLUME
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NO~E: ~or additiona1 ~Jcltsmes-please cs~ntac~~the Canadian Patent C)ff~c~
. .
Claims (47)
1. Substituted pyridines of the general formula (IA), in which A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR1R2, wherein R1 and R2 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms, D stands for straight-chain or branched alkyl with up to 8 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 8 carbon atoms, which is optionally substituted by cycloalkyl with 3 to 8 carbon atoms, or stands for cycloalkyl with 3 to 8 carbon atoms, or E has the above-mentioned meaning and L in this case stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR3R4, wherein R3 and R4 are identical or different and have the meaning given above for R1 and R2, or E stands for straight-chain or branched alkyl with up to 8 carbon atoms, or stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR5R6, wherein R5 and R6 are identical or different and have the meaning given above for R1 and R2, and L in this case stands for straight-chain or branched alkoxy with up to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbon atoms, T stands for a radical of the formula R7~X~ or , wherein R7 and R8 are identical or different and denote cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms, or denote a 5- to 7-member aromatic, optionally benzo-condensed, heterocyclic compound with up to 3 heteroatoms from the series S, N and/or O, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by halogen, trifluoromethyl, or trifluoromethoxy, and/or the rings are substituted by a group of the formula -NR11R12, wherein R11 and R12 are identical or different and have the meaning given above for R1 and R2, X denotes a straight or branched alkyl chain or alkenyl chain with 2 to 10 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, R9 denotes hydrogen, and R10 denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 5 carbon atoms, or a radical of the formula -NR13R14, wherein R13 and R14 are identical or different and have the meaning given above for R1 and R2, or R9 and R10 form a carbonyl group together with the carbon atom, and the salts thereof.
2. Substituted pyridines of the formula according to claim 1, in which A stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR1R2, wherein R1 and R2 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 4 carbon atoms, D stands for straight-chain or branched alkyl with up to 6 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 6 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or E has the above-mentioned meaning and L in this case stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR3R4, wherein R3 and R4 are identical or different and have the meaning given above for R1 and R2, or E stands for straight-chain or branched alkyl with up to 5 carbon atoms, or stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR5R6, wherein R5 and R6 are identical or different and have the meaning given above for R1 and R2, and L in this case stands for straight-chain or branched alkoxy with up to 6 carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy, T stands for a radical of the formula R7~X~ or , wherein R7 and R8 are identical or different and denote cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, or denote naphthyl, phenyl, pyridyl, quinolyl, indolyl, benzothiazolyl, or benzoxazolyl, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, fluorine, chlorine, bromine, hydroxy, carboxyl, by straight-chain or branched alkyl, alkoxy, or alkoxycarbonyl with up to 5 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn by substituted by fluorine, chlorine, bromine, trifluoromethyl, or trifluoromethoxy, and/or the rings are optionally substituted by a group of the formula -NR11R12, wherein R11 and R12 are identical or different and have the meaning given above for R1 and R2, X denotes a straight or branched alkyl chain or alkenyl chain with 2 to 8 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, R9 denotes hydrogen, and R10 denotes hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 4 carbon atoms, or a radical of the formula -NR13R14, wherein R13 and R14 are identical or different and have the meaning given above for R1 and R2, or R9 and R10 form a carbonyl group together with the carbon atom, and the salts thereof.
3. Substituted pyridines of the formula according to claim 1, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, D stands for straight-chain or branched alkyl with up to 5 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 5 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or E has the above-mentioned meaning and L in this case stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, or E stands for straight-chain or branched alkyl with up to 4 carbon atoms, or stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, and L in this case stands for straight-chain or branched alkoxy with up to 5 carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy, T stands for a radical of the formula R7~X~ or , wherein R7 and R8 are identical or different and denote cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, or denote phenyl, pyridyl, quinolyl, indolyl, naphthyl, benzothiazolyl, or benzoxazolyl, which are optionally substituted up to 2 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, fluorine, chlorine, bromine, hydroxy, carboxyl, by straight-chain or branched alkyl, alkoxy, or alkoxycarbonyl with up to 4 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by fluorine, chlorine, bromine, trifluoromethyl, or trifluoromethoxy, X denotes a straight or branched alkyl chain with 2 to 6 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, R9 denotes hydrogen, and R10 denotes hydrogen, fluorine, chlorine, bromine, azido, amino, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 3 carbon atoms, or R9 and R10 form a carbonyl group together with the carbon atom, and the salts thereof.
4. Substituted pyridines of the formula according to claim 1, in which A stands for phenyl, which is optionally substituted by fluorine, chlorine, or methyl.
5. Substituted pyridines according to claims 1 through 4 for therapeutic use.
6. Process for the production of substituted pyridines according to claims 1 through 4, characterized by the fact that compounds of the general formula (II) or (III) in which A, E, L, and T have the above-mentioned meanings, and R15 stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms, are either first reacted, using the Grignard or Wittig reaction, in an inert solvent, with further derivatization optionally being carried out according to the customary methods, and then are reduced in inert solvents, or, in the case of compounds with the general formula (III), direct reductions are carried out, optionally via several steps.
7. Pharmaceutical product containing the substituted pyridines according to claims 1 through 4 and, if appropriate, a pharmacologically tolerable formulation adjuvant.
8. Pharmaceutical product according to claim 7 for the inhibition of cholesterol ester transfer proteins.
9. Use of the substituted pyridines according to claims 1 through 4 for the production of pharmaceutical products.
10. Use of substituted pyridines according to claims 1 through 4 for the production of cholesterol ester transfer protein inhibitors.
11. 3-heteroalkyl-aryl-substituted pyridines of general formula (IB) in which A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR2R3 and/or -WR4, wherein R2 and R3 are the same or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms, W denotes an oxygen or sulfur atom, R4 denotes aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, trifluoromethyl, trifluoromethoxy, hydroxy, or by straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each, D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 8 carbon atoms, or E stands for a bond, V stands for an oxygen or sulfur atom or for a group of the formula -NR5-, wherein R5 denotes hydrogen or straight-chain or branched alkyl with up to 6 carbon atoms or phenyl, R1 stands for cycloalkyl with 3 to 6 carbon atoms, or stands for aryl with 6 to 10 carbon atoms or for a 5- to 7-member, optionally benzo-condensed, saturated or unsaturated, mono-, bi-, or tricyclic heterocyclic compound with up to 4 heteroatoms from the series S, N, and/or O, in which the rings, also via the N function in the case of nitrogen-containing rings, are optionally substituted up to 3 times in an identical manner or differently by halogen, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, by aryl with 6 to 10 carbon atoms, or by an optionally benzo-condensed, aromatic 5- to 7-member heterocyclic compound with up to 3 heteroatoms from the series S, N, and/or O, and/or are substituted by a group of the formula -OR6, -SR7, -SO2R8, or -NR9R10, wherein R6, R7, and R8 are identical or different and denote aryl with 6 to 10 carbon atoms, which in turn is substituted up to 2 times in an identical manner or differently by phenyl or halogen or by straight-chain or branched alkyl with up to 4 carbon atoms, R9 and R10 are identical or different and have the above-indicated meaning of R2 and R3, L and T are identical or different and stand for trifluoromethyl or straight-chain or branched alkyl with up to 8 carbon atoms, which are optionally substituted by cycloalkyl with 3 to 7 carbon atoms, or by aryl with 6 to 10 carbon atoms, which in turn can be substituted up to 2 times in an identical manner or differently by halogen, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or L and/or T stand for cycloalkyl with 3 to 7 carbon atoms or stand for aryl with 6 to 10 carbon atoms or for a 5- to 7-member, saturated, partially unsaturated, or unsaturated heterocyclic compound with up to 3 heteroatoms from the series S, N and/or O, with binding in the case of a nitrogen atom also being possible via this atom, with the rings optionally being substituted up to 3 times in an identical manner or differently by halogen, nitro, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, and the salts thereof.
12. 3-heteroalkyl-aryl-substituted pyridines of the formula according to Claim 11, in which A stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR2R3 and/or by a group of the formula -W-R4, wherein R2 and R3 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 4 carbon atoms, W denotes an oxygen or sulfur atom, R4 denotes phenyl or benzyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, hydroxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 6 carbon atoms, or E stands for a bond, V stands for an oxygen or sulfur atom or for a group of the formula -NR5, wherein R5 denotes hydrogen or straight-chain or branched alkyl with up to 4 carbon atoms or phenyl, R1 stands for cyclopropyl, cyclopentyl, or cyclohexyl, or tetrahydropyrimidyl or stands for phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrizinyl, pyrrolidinyl, tetrahydropyrimidyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl, pyrazolopyrimidyl, or pyrine-yl, with the rings, also via the N function in the case of nitrogen-containing rings, being optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine,trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 4 carbon atoms each, triazolyl, tetrazolyl, benzoxathiazolyl, or phenyl, and/or by a group of the formula -OR6, -SR7, or -SO2R8, wherein R6, R7, and R8 are identical or different and denote phenyl, which in turn is substituted up to 2 times in an identical manner or differently by phenyl, fluorine, chlorine, or by straight-chain or branched alkyl with up to 4 carbon atoms, L and T are identical or different and stand for trifluoromethyl, pyrrolidinyl, or for straight-chain or branched alkyl with up to 7 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, naphthyl, or phenyl, which in turn can be substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or L and/or T stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or for naphthyl, phenyl, pyridyl, or furyl, which optionally can be substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, and the salts thereof.
13. 3-heteroalkyl-aryl-substituted pyridines of the formula according to Claim 11, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 4 carbon atoms each or by benzyloxy, which in turn can be substituted by fluorine or chlorine.
D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 3 carbon atoms, or E stands for a bond, V stands for an oxygen or sulfur atom or for a group of the formula -NR5, wherein R5 denotes hydrogen or straight-chain or branched alkyl with up to 3 carbon atoms, R1 stands for cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyrinidyl, phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, tetrahydropyrimidyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl, pyrazolopyrimidyl, or purine-yl, with the rings, also via the N-function in the case of nitrogen-containing rings, optionally being substituted up to 3 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 3 carbon atoms each, triazolyl, tetrazolyl, benzoxathiazolyl, or phenyl, and/or substituted by a group of the formula -OR6, -SR7, or -SO2R8, wherein R6, R7, and R8 are identical or different and denote phenyl, which in turn is substituted up to 2 times in an identical manner or differently by phenyl, fluorine, chlorine, or is substituted by straight-chain or branched alkyl with up to 3 carbon atoms, L and T are identical or different and stand for trifluoromethyl, pyrrolidinyl, or for straight-chain or branched alkyl with up to 6 carbon atoms, which are optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, which in turn may be substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 4 carbon atoms each, or L and/or T stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for naphthyl, phenyl, or furyl, which are optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 3 carbon atoms each, and the salts thereof.
D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 3 carbon atoms, or E stands for a bond, V stands for an oxygen or sulfur atom or for a group of the formula -NR5, wherein R5 denotes hydrogen or straight-chain or branched alkyl with up to 3 carbon atoms, R1 stands for cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyrinidyl, phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, tetrahydropyrimidyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl, pyrazolopyrimidyl, or purine-yl, with the rings, also via the N-function in the case of nitrogen-containing rings, optionally being substituted up to 3 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 3 carbon atoms each, triazolyl, tetrazolyl, benzoxathiazolyl, or phenyl, and/or substituted by a group of the formula -OR6, -SR7, or -SO2R8, wherein R6, R7, and R8 are identical or different and denote phenyl, which in turn is substituted up to 2 times in an identical manner or differently by phenyl, fluorine, chlorine, or is substituted by straight-chain or branched alkyl with up to 3 carbon atoms, L and T are identical or different and stand for trifluoromethyl, pyrrolidinyl, or for straight-chain or branched alkyl with up to 6 carbon atoms, which are optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, which in turn may be substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 4 carbon atoms each, or L and/or T stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for naphthyl, phenyl, or furyl, which are optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 3 carbon atoms each, and the salts thereof.
14. 3-heteroalkyl-aryl-substituted pyridines of the formula according to Claim 11, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, methoxy, methyl, or by fluorine- or chlorine-substituted benzyloxy.
15. 3-heteroalkyl-aryl-substituted pyridines according to Claims 11 through 14 for therapeutic treatment.
16. Process for the production of 3-heteroalkyl-aryl-substituted pyridines according to Claims 11 through 14, characterized in that [A] in the case of V = O
compounds of general formula (II) in which A, D, L, and T have the indicated meaning, and R11 stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms or for the group of the formula are reacted with compounds of general formula (III) R1-E-Z (III) in which R1 and E have the indicated meaning and Z stands for halogen, preferably chlorine or bromine, in inert solvents, optionally in the presence of bases and/or auxiliary agents, and reductive separation is then carried out, depending on the meaning of the group R11, [B] compounds of general formula (II) are next converted by reactions with compounds of general formula (IV) in which R12 stands for straight-chain alkyl with up to 4 carbon atoms, into compounds of general formula (V) in which A, D, L, T, R11, and R12 have the indicated meaning, and these are then reacted with compounds of general formula (VI) R1-E-V-H (VI) in which R1, E, and V have the indicated meaning, and reductive separation is carried out, and optionally, the groups listed under substituents A, L, T, and R1 are introduced or varied according to customary methods.
compounds of general formula (II) in which A, D, L, and T have the indicated meaning, and R11 stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms or for the group of the formula are reacted with compounds of general formula (III) R1-E-Z (III) in which R1 and E have the indicated meaning and Z stands for halogen, preferably chlorine or bromine, in inert solvents, optionally in the presence of bases and/or auxiliary agents, and reductive separation is then carried out, depending on the meaning of the group R11, [B] compounds of general formula (II) are next converted by reactions with compounds of general formula (IV) in which R12 stands for straight-chain alkyl with up to 4 carbon atoms, into compounds of general formula (V) in which A, D, L, T, R11, and R12 have the indicated meaning, and these are then reacted with compounds of general formula (VI) R1-E-V-H (VI) in which R1, E, and V have the indicated meaning, and reductive separation is carried out, and optionally, the groups listed under substituents A, L, T, and R1 are introduced or varied according to customary methods.
17. Pharmaceutical product containing 3-heteroalkyl-aryl-substituted pyridines according to Claims 11 through 14, as well as a pharmacologically safe formulation auxiliary.
18. Pharmaceutical product according to Claim 17 for the treatment of hyperlipoproteinemia.
19. Use of 3-heteroalkyl-aryl-substituted pyridines according to Claims 11 through 14 for the production of pharmaceutical products.
20. Use according to Claim 19 for the production of pharmaceutical products for the treatment of hyperlipoproteinemia.
21, A compound having glucagon receptor antagonistic activity and the structural formula 1A
wherein R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl; the substitutents on said substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups being independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(O)NR4R5, or -S(O)mR7 wherein m is 0, 1, or 2;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R4 and R5 optionally may be joined together to form (CH2)r A(CH2)s- wherein r and s are independently 1, 2, or 3; and wherein A represents O, S(O)n, CHR6, or NR6; wherein n is 0, 1, or 2; and R6 represents hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(C1-C6)-alkyl;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6) alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R3 groups being from 1 to 3 hydroxyl or trifluoromethyl groups; and Ar' represents an optionally mono-, di-, or tri-substituted heteroaromatic ring selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls, wherein the substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2; and pharmaceutically acceptable salts thereof.
wherein R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl; the substitutents on said substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups being independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(O)NR4R5, or -S(O)mR7 wherein m is 0, 1, or 2;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R4 and R5 optionally may be joined together to form (CH2)r A(CH2)s- wherein r and s are independently 1, 2, or 3; and wherein A represents O, S(O)n, CHR6, or NR6; wherein n is 0, 1, or 2; and R6 represents hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(C1-C6)-alkyl;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6) alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R3 groups being from 1 to 3 hydroxyl or trifluoromethyl groups; and Ar' represents an optionally mono-, di-, or tri-substituted heteroaromatic ring selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls, wherein the substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2; and pharmaceutically acceptable salts thereof.
22. A compound of claim 21, wherein in structural formula 1A, R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R6 represents hydrogen, (C1-C6)-alkyl, phenyl, or phenyl-(C1-C6)-alkyl;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, or substituted pyridyl-(C1-C6) alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents (C1-C6) alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl, wherein the substitutents are from 1 to 3 hydroxyl groups; and Ar' is selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and thiazolyls, and the optional substitutents on Ar' are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4, or -OC(O)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl.
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R6 represents hydrogen, (C1-C6)-alkyl, phenyl, or phenyl-(C1-C6)-alkyl;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, or substituted pyridyl-(C1-C6) alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents (C1-C6) alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl, wherein the substitutents are from 1 to 3 hydroxyl groups; and Ar' is selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and thiazolyls, and the optional substitutents on Ar' are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4, or -OC(O)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl.
23. A compound of claim 21, wherein in structural formula 1A, R1a and R1b independently represent (C1-C6)-alkyl or (C2-C6)-alkenyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10) alkyl, (C2-C10)-alkenyl, or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen or -S(O)m R7 wherein m=0, R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl;
R3 represents substituted (C1-C6)-alkyl or substituted (C3-C6)-alkenyl, wherein the substitutents are 1 or 2 hydroxyl groups; and Ar' is selected from the group consisting of pyridyls, furanyls and thiophenyls, and the optional substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -OR4, or -OC(O)R4, where R4 is hydrogen or (C1-C6) alkyl.
R2 represents (C1-C10)-alkyl, substituted (C1-C10) alkyl, (C2-C10)-alkenyl, or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen or -S(O)m R7 wherein m=0, R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl;
R3 represents substituted (C1-C6)-alkyl or substituted (C3-C6)-alkenyl, wherein the substitutents are 1 or 2 hydroxyl groups; and Ar' is selected from the group consisting of pyridyls, furanyls and thiophenyls, and the optional substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -OR4, or -OC(O)R4, where R4 is hydrogen or (C1-C6) alkyl.
24. A pharmaceutical composition for use in treating a glucagon-mediated condition, which comprises: a compound of claim 21, and a pharmaceutically acceptable carrier.
25. A method for treating a glucagon-mediated condition which comprises administering to a subject an effective amount of a compound of claim 21.
26. The method of claim 25, wherein the subject is human, the glucagon-mediated condition is diabetes, and the treatment results in lowering of blood glucose.
27. A compound having glucagon receptor antagonistic activity and the structural formula 1B
wherein R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl; the substitutents on said substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups being independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R4 and R5 optionally may be joined together to form -(CH2)r A(CH2)s- wherein r and s are independently 1, 2, or 3; and wherein A represents O, S(O)n, CHR6, or NR6; wherein n is 0, 1, or 2; and R6 represents hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(C1-C6)-alkyl;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6) alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R3 groups being from 1 to 3 hydroxyl or trifluoromethyl groups; and Ar" represents an optionally mono-, di-, or tri-substituted aromatic ring selected from the group consisting of phenyls and naphthyls, wherein the substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2; and pharmaceutically acceptable salts thereof.
wherein R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl; the substitutents on said substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups being independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R4 and R5 optionally may be joined together to form -(CH2)r A(CH2)s- wherein r and s are independently 1, 2, or 3; and wherein A represents O, S(O)n, CHR6, or NR6; wherein n is 0, 1, or 2; and R6 represents hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(C1-C6)-alkyl;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6) alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R3 groups being from 1 to 3 hydroxyl or trifluoromethyl groups; and Ar" represents an optionally mono-, di-, or tri-substituted aromatic ring selected from the group consisting of phenyls and naphthyls, wherein the substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2; and pharmaceutically acceptable salts thereof.
28. A compound of claim 27, wherein in structural formula 1B, R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R6 represents hydrogen, (C1-C6)-alkyl, phenyl, or phenyl-(C1-C6)-alkyl;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, or substituted pyridyl-(C1-C6) alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents (C1-C6) alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl, wherein the substitutents are from 1 to 3 hydroxyl groups; and Ar" represents a phenyl ring, and the optional substitutents on Ar" are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4, or -OC(O)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl.
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R6 represents hydrogen, (C1-C6)-alkyl, phenyl, or phenyl-(C1-C6)-alkyl;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, or substituted pyridyl-(C1-C6) alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents (C1-C6) alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl, wherein the substitutents are from 1 to 3 hydroxyl groups; and Ar" represents a phenyl ring, and the optional substitutents on Ar" are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4, or -OC(O)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl.
29. A compound of claim 27, wherein in structural formula 1B, R1a and R1b independently represent (C1-C6)-alkyl or (C2-C6) alkenyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10) alkyl, (C2-C10)-alkenyl, or substituted (C2-C10) alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen or -S(O)m R7 wherein m=0;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl;
R3 represents substituted (C1-C6)-alkyl or substituted (C3-C6)-alkenyl, wherein the substitutents are 1 or 2 hydroxyl groups; and Ar" represents a phenyl ring, and the optional substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -OR4, or -OC(O)R4, where R4 is hydrogen or (C1-C6) alkyl.
R2 represents (C1-C10)-alkyl, substituted (C1-C10) alkyl, (C2-C10)-alkenyl, or substituted (C2-C10) alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen or -S(O)m R7 wherein m=0;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl;
R3 represents substituted (C1-C6)-alkyl or substituted (C3-C6)-alkenyl, wherein the substitutents are 1 or 2 hydroxyl groups; and Ar" represents a phenyl ring, and the optional substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -OR4, or -OC(O)R4, where R4 is hydrogen or (C1-C6) alkyl.
30. A compound of claim 27, selected from the following group of compounds:
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-ethylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxy-4-fluorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-propylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-propylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-propylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-propylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-propylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxy-4-fluorophenyl)-5-propylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-butylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-butylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-butyl-pyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxy-4-fluorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-pentylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-pentyl-pyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-pentyl-pyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxy-4-fluorophenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-hexylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxy-4-fluorophenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-phenyl-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-fluorophenyl)-5-hydroxymethylpyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-chlorophenyl)-5-hydroxymethylpyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-methylphenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(2-hydroxyphenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(2-hydroxy-4-fluorophenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-phenyl-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-fluorophenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-chlorophenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-methylphenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(2-hydroxyphenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(2-hydroxy-4-fluorophenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-phenyl-5-ethylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-methylphenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-phenyl-5-propylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-propylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-propylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-methylphenyl)-5-propylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-propylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-propylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-phenyl-5-butylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-methylphenyl)-5-butylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-butylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-phenyl-5-pentylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-methylphenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-phenyl-5-hexylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-hexyl-pyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-methylphenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-phenyl-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-fluorophenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-chlorophenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-methylphenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(2-hydroxyphenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(2-hydroxy-4-fluorophenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-phenyl-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-fluorophenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-chlorophenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-methylphenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(2-hydroxyphenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-1((4-fluorophenyl)thio)methyl]-4-(2-hydroxy-4-fluorophenyl)-5-(1-hydroxyethyl)-pyridine.
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-ethylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxy-4-fluorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-propylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-propylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-propylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-propylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-propylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxy-4-fluorophenyl)-5-propylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-butylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-butylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-butyl-pyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxy-4-fluorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-pentylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-pentyl-pyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-pentyl-pyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxy-4-fluorophenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-hexylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-(2-hydroxy-4-fluorophenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-phenyl-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-fluorophenyl)-5-hydroxymethylpyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-chlorophenyl)-5-hydroxymethylpyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-methylphenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(2-hydroxyphenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(2-hydroxy-4-fluorophenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-phenyl-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-fluorophenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-chlorophenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-methylphenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(2-hydroxyphenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(2-hydroxy-4-fluorophenyl)-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-phenyl-5-ethylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-methylphenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-phenyl-5-propylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-propylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-propylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-methylphenyl)-5-propylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-propylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-propylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-phenyl-5-butylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-methylphenyl)-5-butylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-butylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-phenyl-5-pentylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-methylphenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-phenyl-5-hexylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluorophenyl)-5-hexyl-pyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-chlorophenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-methylphenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxyphenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-hexylpyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-phenyl-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-fluorophenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-chlorophenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-methylphenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(2-hydroxyphenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(2-hydroxy-4-fluorophenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-phenyl-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-fluorophenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-chlorophenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-methylphenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(2-hydroxyphenyl)-5-(1-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-1((4-fluorophenyl)thio)methyl]-4-(2-hydroxy-4-fluorophenyl)-5-(1-hydroxyethyl)-pyridine.
31. A pharmaceutical composition for use in treating a glucagon-mediated condition, which comprises: a compound of claim 27, and a pharmaceutically acceptable carrier.
32. A method for treating a glucagon-mediated condition which comprises administering to a subject an effective amount of a compound of claim 27.
33. The method of claim 32, wherein the subject is human, the glucagon-mediated condition is diabetes, and the treatment results in lowering of blood glucose.
34. A compound having glucagon receptor antagonistic activity and the structural formula 1C
wherein R8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R4 and R5 optionally may be joined together to form (CH2)r A(CH2)s- wherein r and s are independently 1, 2, or 3, and wherein A represents O, S(O)n, CHR6, or NR6; wherein n is 0, 1, or 2; and R6 represents hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(C1-C6)-alkyl;
R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl; the substitutents on said substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups being independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6) alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R3 groups being from 1 to 3 hydroxyl or trifluoromethyl groups;
Ar' represents an optionally mono-, di-, or tri-substituted heteroaromatic ring selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls, wherein the substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2 and pharmaceutically acceptable salts thereof.
wherein R8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R4 and R5 optionally may be joined together to form (CH2)r A(CH2)s- wherein r and s are independently 1, 2, or 3, and wherein A represents O, S(O)n, CHR6, or NR6; wherein n is 0, 1, or 2; and R6 represents hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(C1-C6)-alkyl;
R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl; the substitutents on said substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups being independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6) alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R3 groups being from 1 to 3 hydroxyl or trifluoromethyl groups;
Ar' represents an optionally mono-, di-, or tri-substituted heteroaromatic ring selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls, wherein the substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2 and pharmaceutically acceptable salts thereof.
35. A compound of claim 34, wherein in structural formula 1C, R8 represents hydrogen, halogen, trifluoromethyl or (C1-C10) alkyl;
R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R6 represents hydrogen, (C1-C6)-alkyl, phenyl, or phenyl-(C1-C6)-alkyl;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, or substituted pyridyl-(C1-C6) alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents (C1-C6) alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl, wherein the substitutents are from 1 to 3 hydroxyl groups; and Ar' is selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and thiazolyls, and the optional substitutents on Ar' are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4, or -OC(O)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl.
R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R6 represents hydrogen, (C1-C6)-alkyl, phenyl, or phenyl-(C1-C6)-alkyl;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, or substituted pyridyl-(C1-C6) alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents (C1-C6) alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl, wherein the substitutents are from 1 to 3 hydroxyl groups; and Ar' is selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and thiazolyls, and the optional substitutents on Ar' are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4, or -OC(O)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl.
36. A compound of claim 34, wherein in structural formula 1C, R8 represents hydrogen;
R1a and R1b independently represent (C1-C6)-alkyl or (C2-C6)-alkenyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10) alkyl, (C2-C10)-alkenyl, or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen or -S(O)m R7 wherein m=0, R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl;
R3 represents substituted (C1-C6)-alkyl or substituted (C3-C6)-alkenyl; where the substitutents are 1 or 2 hydroxyl groups; and Ar' is selected from the group consisting of pyridyls, furanyls and thiophenyls, and the optional substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -OR4, or -OC(O)R4, where R4 is hydrogen or (C1-C6) alkyl.
R1a and R1b independently represent (C1-C6)-alkyl or (C2-C6)-alkenyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10) alkyl, (C2-C10)-alkenyl, or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen or -S(O)m R7 wherein m=0, R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl;
R3 represents substituted (C1-C6)-alkyl or substituted (C3-C6)-alkenyl; where the substitutents are 1 or 2 hydroxyl groups; and Ar' is selected from the group consisting of pyridyls, furanyls and thiophenyls, and the optional substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -OR4, or -OC(O)R4, where R4 is hydrogen or (C1-C6) alkyl.
37. A pharmaceutical composition for use in treating a glucagon-mediated condition, which comprises: a compound of claim 34, and a pharmaceutically acceptable carrier.
38. A method for treating a glucagon-mediated condition which comprises administering to a subject an effective amount of a compound of claim 34.
39. The method of claim 38, wherein the subject is human, the glucagon-mediated condition is diabetes, and the treatment results in lowering of blood glucose.
40. A compound having glucagon receptor antagonistic activity and the structural formula 1D
wherein R8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R4 and R5 optionally may be joined together to form -(CH2)r A(CH2)s- wherein r and s are independently 1, 2, or 3, and wherein A represents O, S(O)n, CHR6, or NR6, wherein n is 0, 1, or 2; and R6 represents hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(C1-C6)-alkyl;
R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl; the substitutents on said substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups being independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6) alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R3 groups being from 1 to 3 hydroxyl or trifluoromethyl groups;
Ar" represents an optionally mono-, di-, or tri-substituted aromatic ring selected from the group consisting of phenyls and naphthyls, wherein the substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5, -C(O)NR4R5, or -S(O)mR7 wherein m is 0,1, or 2; and pharmaceutically acceptable salts thereof.
wherein R8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C1-C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl-(C1-C3)-alkoxy, (C1-C6)-alkanoyloxy, (C1-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R4 and R5 optionally may be joined together to form -(CH2)r A(CH2)s- wherein r and s are independently 1, 2, or 3, and wherein A represents O, S(O)n, CHR6, or NR6, wherein n is 0, 1, or 2; and R6 represents hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(C1-C6)-alkyl;
R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)-alkanoyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(C1-C6)-alkyl; the substitutents on said substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R2 groups being independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(O)NR4R5, or -S(O)m R7 wherein m is 0, 1, or 2;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, substituted pyridyl-(C1-C6) alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents hydroxy, trifluoroacetyl, (C1-C6)-alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R3 groups being from 1 to 3 hydroxyl or trifluoromethyl groups;
Ar" represents an optionally mono-, di-, or tri-substituted aromatic ring selected from the group consisting of phenyls and naphthyls, wherein the substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(O)R4, -OC(O)R4, -CO2R4, -NR4R5, -C(O)NR4R5, or -S(O)mR7 wherein m is 0,1, or 2; and pharmaceutically acceptable salts thereof.
41. A compound of claim 40, wherein in structural formula 1D, R8 represents hydrogen, halogen, trifluoromethyl or (C1-C10) alkyl;
R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(O)NR4R5, or -S(O)mR7 wherein m is 0,1,or 2;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R6 represents hydrogen, (C1-C6)-alkyl, phenyl, or phenyl-(C1-C6)-alkyl;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, or substituted pyridyl-(C1-C6) alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents (C1-C6) alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl, wherein the substitutents are from 1 to 3 hydroxyl groups; and Ar" represents a phenyl ring, and the optional substitutents on Ar" are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4, or -OC(O)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl.
R1a and R1b independently represent trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(O)NR4R5, or -S(O)mR7 wherein m is 0,1,or 2;
R4 and R5 independently represent hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl;
R6 represents hydrogen, (C1-C6)-alkyl, phenyl, or phenyl-(C1-C6)-alkyl;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C6)-alkyl, or substituted pyridyl-(C1-C6) alkyl;
R2 optionally may be joined to R1b to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R2 and R1b are attached;
R3 represents (C1-C6) alkanoyl, substituted (C1-C6)-alkyl, or substituted (C3-C6)-alkenyl, wherein the substitutents are from 1 to 3 hydroxyl groups; and Ar" represents a phenyl ring, and the optional substitutents on Ar" are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4, or -OC(O)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl.
42. A compound of claim 40, wherein in structural formula 1D, R8 represents hydrogen;
R1a and R1b independently represent (C1-C6)-alkyl or (C2-C6)-alkenyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10) alkyl, (C2-C10)-alkenyl, or substituted (C2-C10) alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen or -S(O)mR7 wherein m=0;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl;
R3 represents substituted (C1-C6)-alkyl or substituted (C3-C6)-alkenyl; where the substitutents are 1 or 2 hydroxyl groups; and Ar" represents a phenyl ring, and the optional substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -OR4, or -OC(O)R4, where R4 is hydrogen or (C1-C6) alkyl.
R1a and R1b independently represent (C1-C6)-alkyl or (C2-C6)-alkenyl;
R2 represents (C1-C10)-alkyl, substituted (C1-C10) alkyl, (C2-C10)-alkenyl, or substituted (C2-C10) alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen or -S(O)mR7 wherein m=0;
R7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl;
R3 represents substituted (C1-C6)-alkyl or substituted (C3-C6)-alkenyl; where the substitutents are 1 or 2 hydroxyl groups; and Ar" represents a phenyl ring, and the optional substitutents are independently from 1 to 3 of halogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, -OR4, or -OC(O)R4, where R4 is hydrogen or (C1-C6) alkyl.
43. A compound of claim 40, selected from the following group of compounds:
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-propyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-propyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-propyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-propyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-propyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-propyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-butyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-butyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-butyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-butyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-butyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-butyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-hexyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-hexyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-hexyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-hexyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-hexyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-hexyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(1-hydroxyethyl)-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(1-hydroxyethyl)-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(1-hydroxyethyl)-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(1-hydroxyethyl)-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(1-hydroxyethyl)-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(1-hydroxyethyl)-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(1-hydroxyethyl)-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(1-hydroxyethyl)-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(1-hydroxyethyl)-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(1-hydroxyethyl)-2'-hydroxy-4'-fluoro-1,1'-biphenyl.
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-propyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-propyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-propyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-propyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-propyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-propyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-butyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-butyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-butyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-butyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-butyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-butyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-pentyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-hexyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-hexyl-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-hexyl-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-hexyl-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-hexyl-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-(1-hydroxyethyl)-6-hexyl-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(1-hydroxyethyl)-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(1-hydroxyethyl)-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(1-hydroxyethyl)-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(1-hydroxyethyl)-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(1-hydroxyethyl)-2'-hydroxy-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(1-hydroxyethyl)-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(1-hydroxyethyl)-4'-fluoro-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(1-hydroxyethyl)-4'-chloro-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(1-hydroxyethyl)-4'-methyl-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(1-hydroxyethyl)-2'-hydroxy-1,1'-biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(1-hydroxyethyl)-2'-hydroxy-4'-fluoro-1,1'-biphenyl.
44. A pharmaceutical composition for use in treating a glucagon-mediated condition, which comprises: a compound of claim 40, and a pharmaceutically acceptable carrier.
45. A method for treating a glucagon-mediated condition which comprises administering to a subject an effective amount of a compound of claim 40.
46. The method of claim 45, wherein the subject is human, the glucagon-mediated condition is diabetes, and the treatment results in lowering of blood glucose.
47. A compound of claim 21, 27, 34, or 40 wherein the substituent shown as R3 is a hydroxyethyl group having the following stereochemistry
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US69011196A | 1996-07-31 | 1996-07-31 | |
US08/690,111 | 1996-07-31 | ||
PCT/US1997/013248 WO1998004528A2 (en) | 1996-07-31 | 1997-07-29 | Substituted pyridines and biphenyls as anti-hypercholesterinemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents |
Publications (1)
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CA2262434A1 true CA2262434A1 (en) | 1998-02-05 |
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Family Applications (1)
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CA002262434A Abandoned CA2262434A1 (en) | 1996-07-31 | 1997-07-29 | Substituted pyridines and biphenyls as anti-hypercholesterinemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents |
Country Status (24)
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US (1) | US6218431B1 (en) |
EP (1) | EP0934274A1 (en) |
JP (1) | JP2001512416A (en) |
KR (1) | KR20000029723A (en) |
CN (1) | CN1239474A (en) |
AR (2) | AR008789A1 (en) |
AU (1) | AU3897197A (en) |
BG (1) | BG103200A (en) |
BR (1) | BR9710637A (en) |
CA (1) | CA2262434A1 (en) |
CO (1) | CO4900061A1 (en) |
CZ (1) | CZ30899A3 (en) |
HR (1) | HRP970425A2 (en) |
HU (1) | HUP0100324A3 (en) |
ID (1) | ID19422A (en) |
IL (1) | IL128251A0 (en) |
NO (1) | NO314143B1 (en) |
NZ (1) | NZ333951A (en) |
PL (1) | PL333465A1 (en) |
RU (1) | RU2195443C2 (en) |
TR (3) | TR199902326T2 (en) |
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NO177005C (en) * | 1988-01-20 | 1995-07-05 | Bayer Ag | Analogous process for the preparation of substituted pyridines, as well as intermediates for use in the preparation |
NO890046L (en) * | 1988-01-20 | 1989-07-21 | Bayer Ag | DISUBSTITUTED PYRIDINES. |
NO890521L (en) | 1988-02-25 | 1989-08-28 | Bayer Ag | SUBSTITUTED PYRIMIDINES. |
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NO890988L (en) | 1988-03-24 | 1989-09-25 | Bayer Ag | DISUBSTITUTED PYROLES. |
EP0339342A1 (en) | 1988-04-23 | 1989-11-02 | Bayer Ag | N-substituted N-amino pyrroles |
EP0352575A3 (en) | 1988-07-28 | 1991-08-21 | Bayer Ag | Substituted annealed pyrroles |
US5032602A (en) | 1988-12-14 | 1991-07-16 | Bayer Aktiengesellschaft | Inhibiting HMG-CoA reductase with novel substituted 2-pyridones and pyrid-2-thiones |
US5164506A (en) | 1988-12-14 | 1992-11-17 | Bayer Aktiengesellschaft | Substituted 2-pyridones and pyrid-2-thiones compounds |
AU618158B2 (en) | 1989-01-07 | 1991-12-12 | Bayer Aktiengesellschaft | New substituted pyrido(2,3-d)pyrimidines |
DE3905908A1 (en) | 1989-02-25 | 1990-09-06 | Bayer Ag | Substituted quinolines, process for their preparation, and their use in medicaments |
DE3909378A1 (en) | 1989-03-22 | 1990-09-27 | Bayer Ag | SUBSTITUTED BIPHENYLE |
DE3911064A1 (en) | 1989-04-06 | 1990-10-11 | Bayer Ag | SUBSTITUTED 1,8-NAPHTHYRIDINE |
US5145959A (en) | 1989-07-18 | 1992-09-08 | Bayer Aktiengesellschaft | Substituted pyrido (2,3-d) pyrimidines as intermediates |
US5183897A (en) | 1989-08-03 | 1993-02-02 | Bayer Aktiengesellschaft | Certain intermediate imino-substituted pyridines |
US5072023A (en) | 1990-02-15 | 1991-12-10 | E. R. Squibb & Sons, Inc. | Process for preparing highly substituted phenyls |
NZ237097A (en) * | 1990-02-26 | 1993-12-23 | Squibb & Sons Inc | Pyridine derivatives substituted in the 3-position by a phosphinic moiety. |
DE4022414A1 (en) | 1990-07-13 | 1992-01-16 | Bayer Ag | SUBSTITUTED PYRROLO-PYRIDINE |
DE4023308A1 (en) | 1990-07-21 | 1992-01-23 | Bayer Ag | SUBSTITUTED PYRIDO OXAZINE |
DE4244029A1 (en) * | 1992-12-24 | 1994-06-30 | Bayer Ag | New substituted pyridines |
EP0742208A1 (en) * | 1995-05-05 | 1996-11-13 | Grelan Pharmaceutical Co., Ltd. | 2-Ureido-benzamide derivatives |
DE19610932A1 (en) * | 1996-03-20 | 1997-09-25 | Bayer Ag | 2-aryl substituted pyridines |
-
1997
- 1997-07-28 AR ARP970103411A patent/AR008789A1/en unknown
- 1997-07-29 HU HU0100324A patent/HUP0100324A3/en unknown
- 1997-07-29 CZ CZ99308A patent/CZ30899A3/en unknown
- 1997-07-29 HR HR08/690,111A patent/HRP970425A2/en not_active Application Discontinuation
- 1997-07-29 WO PCT/US1997/013248 patent/WO1998004528A2/en not_active Application Discontinuation
- 1997-07-29 EP EP97936259A patent/EP0934274A1/en not_active Withdrawn
- 1997-07-29 ZA ZA9706730A patent/ZA976730B/en unknown
- 1997-07-29 IL IL12825197A patent/IL128251A0/en unknown
- 1997-07-29 BR BR9710637-2A patent/BR9710637A/en not_active IP Right Cessation
- 1997-07-29 CA CA002262434A patent/CA2262434A1/en not_active Abandoned
- 1997-07-29 CO CO97043316A patent/CO4900061A1/en unknown
- 1997-07-29 RU RU99104527/04A patent/RU2195443C2/en not_active IP Right Cessation
- 1997-07-29 JP JP50906898A patent/JP2001512416A/en not_active Ceased
- 1997-07-29 CN CN97198258A patent/CN1239474A/en active Pending
- 1997-07-29 TR TR1999/02326T patent/TR199902326T2/en unknown
- 1997-07-29 TR TR1999/02325T patent/TR199902325T2/en unknown
- 1997-07-29 PL PL97333465A patent/PL333465A1/en unknown
- 1997-07-29 TW TW086110851A patent/TW520360B/en not_active IP Right Cessation
- 1997-07-29 KR KR1019997000826A patent/KR20000029723A/en not_active Application Discontinuation
- 1997-07-29 AU AU38971/97A patent/AU3897197A/en not_active Abandoned
- 1997-07-29 NZ NZ333951A patent/NZ333951A/en unknown
- 1997-07-29 TR TR1999/00163T patent/TR199900163T2/en unknown
- 1997-07-31 ID IDP972662A patent/ID19422A/en unknown
- 1997-07-31 US US08/904,119 patent/US6218431B1/en not_active Expired - Fee Related
-
1999
- 1999-01-28 NO NO19990399A patent/NO314143B1/en not_active IP Right Cessation
- 1999-02-23 BG BG103200A patent/BG103200A/en unknown
-
2002
- 2002-11-11 AR ARP020104321A patent/AR037300A2/en unknown
Also Published As
Publication number | Publication date |
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NO990399L (en) | 1999-03-29 |
NZ333951A (en) | 2000-09-29 |
TW520360B (en) | 2003-02-11 |
CN1239474A (en) | 1999-12-22 |
CZ30899A3 (en) | 1999-05-12 |
AU3897197A (en) | 1998-02-20 |
AR008789A1 (en) | 2000-02-23 |
NO314143B1 (en) | 2003-02-03 |
TR199902325T2 (en) | 2000-02-21 |
AR037300A2 (en) | 2004-11-03 |
PL333465A1 (en) | 1999-12-20 |
US6218431B1 (en) | 2001-04-17 |
BR9710637A (en) | 2000-10-31 |
RU2195443C2 (en) | 2002-12-27 |
TR199900163T2 (en) | 1999-04-21 |
HUP0100324A2 (en) | 2001-05-28 |
NO990399D0 (en) | 1999-01-28 |
EP0934274A1 (en) | 1999-08-11 |
ID19422A (en) | 1998-07-09 |
HRP970425A2 (en) | 1998-08-31 |
HUP0100324A3 (en) | 2001-06-28 |
WO1998004528A2 (en) | 1998-02-05 |
IL128251A0 (en) | 1999-11-30 |
ZA976730B (en) | 1999-07-29 |
KR20000029723A (en) | 2000-05-25 |
JP2001512416A (en) | 2001-08-21 |
CO4900061A1 (en) | 2000-03-27 |
TR199902326T2 (en) | 2000-05-22 |
BG103200A (en) | 1999-11-30 |
WO1998004528A3 (en) | 1999-11-11 |
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EEER | Examination request | ||
FZDE | Discontinued |