WO1998004528A2 - 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 PDF

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Publication number
WO1998004528A2
WO1998004528A2 PCT/US1997/013248 US9713248W WO9804528A2 WO 1998004528 A2 WO1998004528 A2 WO 1998004528A2 US 9713248 W US9713248 W US 9713248W WO 9804528 A2 WO9804528 A2 WO 9804528A2
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WO
WIPO (PCT)
Prior art keywords
substituted
alkyl
phenyl
diisopropyl
carbon atoms
Prior art date
Application number
PCT/US1997/013248
Other languages
French (fr)
Other versions
WO1998004528A3 (en
Inventor
Gunter Schmidt
Rolf Angerbauer
Arndt Brandes
Matthias Muller-Gliemann
Hilmar Bischoff
Delf Schmidt
Stefan Wohlfeil
William R. Schoen
Gaetan H. Ladouceur
James H. Ii Cook
Timothy G. Lease
Donald J. Wolanin
Richard H. Kramss
Donald L. Hertzog
Martin H. Osterhout
Original Assignee
Bayer Corporation
Bayer Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to IL12825197A priority Critical patent/IL128251A0/en
Priority to BR9710637-2A priority patent/BR9710637A/en
Priority to EP97936259A priority patent/EP0934274A1/en
Priority to AU38971/97A priority patent/AU3897197A/en
Priority to JP50906898A priority patent/JP2001512416A/en
Priority to IL15560697A priority patent/IL155606A0/en
Priority to HU0100324A priority patent/HUP0100324A3/en
Priority to IL15560597A priority patent/IL155605A0/en
Application filed by Bayer Corporation, Bayer Aktiengesellschaft filed Critical Bayer Corporation
Priority to NZ333951A priority patent/NZ333951A/en
Priority to CA002262434A priority patent/CA2262434A1/en
Publication of WO1998004528A2 publication Critical patent/WO1998004528A2/en
Priority to NO19990399A priority patent/NO314143B1/en
Priority to BG103200A priority patent/BG103200A/en
Publication of WO1998004528A3 publication Critical patent/WO1998004528A3/en

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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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    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • This application relates to substituted biaryl compounds which inhibit cholesterol ester transfer proteins (CETPs), stimulate reverse cholesterol transport, and inhibit the action of glucagon.
  • CETPs cholesterol ester transfer proteins
  • 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-(poly substituted pyridyl) hept-6-enoates for the treatment of arteriosclerosis, Iipoproteinemia, and hyperlipoproteinemia are known from US 5 169 857.
  • 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 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 different strategies to address the different abnormalities in metabolism found in affected individuals.
  • a means of treating all forms of diabetes is to block the glucagon receptor with a suitable antagonist, 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: 1. Treatment of hyperglycemia associated with diabetes of any cause and associated with any other diseases or conditions. A glucagon receptor antagonist can be used either alone or in combination with any other therapies to treat hyperglycemia.
  • ITT impaired glucose tolerance
  • 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.
  • Glucagon receptor antagonists of the prior art 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.
  • Certain of the substituted pyridine compounds of the invention are highly effective inhibitors of cholesterol ester transfer proteins (CETP) and stimulate reverse cholesterol 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.
  • CETP cholesterol ester transfer proteins
  • glucagon 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 listed above.
  • the present invention concerns substituted biaryl compounds which fall 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 preferred and most preferred molecular constituents, procedures for making, examples of particular materials made, testing procedures, and results obtained.
  • the present invention concerns substituted pyridines of the general formula
  • 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
  • R1 and R 2 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,
  • 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,
  • R3 and R ⁇ are identical or different and have the meaning given above for Rl and R2,
  • R5 and R > are identical or different and have the meaning given above for Rl and R2,
  • 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
  • R ⁇ and R ⁇ 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 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 /
  • 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
  • RIO 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 /
  • Rl3 and R*4 are identical or different and have the meaning given above for R! and R 2 ,
  • R9 and RlO form a carbonyl group together with the carbon atom
  • the present invention also concerns substituted pyridines of general formula
  • 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 -NR 2 R 3 and/or - WR 4 ,
  • R2 and R 3 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
  • V stands for an oxygen or sulfur atom or for a group of the formula -NR ⁇ -,
  • 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, 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,
  • 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 RlO are identical or different and have the above-indicated meaning of R 2 and R 3 ,
  • 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,
  • 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 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 straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each,
  • This invention also relates to compounds having glucagon receptor antagonistic activity and the general formula (IC) shown below.
  • X represents N or CR ⁇ .
  • R° represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (Ci-Cl ⁇ )-alkyl, substituted (C ⁇ -C ⁇ o)-alkyl, (Ci-C6)-alkoxy, (C3-C7)- cycloalkyl, phenyl-(Ci-C3)-alkoxy, (C ⁇ -C6)-alkanoyloxy, (C ⁇ -C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5.
  • the substituents on the substituted phenyl or substituted alkyl R 8 groups are from 1 to 3 of, for example, hydroxy, fluoro, ( - C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(Ci-C3)-alkoxy, ( -C6)- alkanoyloxy, (Ci-C6)-alkoxy carbonyl, carboxy, formyl, or -NR4R5.
  • the groups R 4 and R ⁇ are independently hydrogen, (Cl-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)-alkyl, substituted phenyl-(C ⁇ -C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C ⁇ -C6)-alkyl, or substituted naphthyl-(C ⁇ -C6)- alkyl.
  • the substitutents on the substituted phenyl or substituted naphthyl R 4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)- alkyl, or (Cl-C4)-alkoxy groups.
  • R 4 and R ⁇ 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, NR ⁇ , O, or S(0)n in which n is 0, 1, or 2; and R6 is hydrogen, (Ci-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Ci-C6)-alkyl.
  • R* a and R 1 " are independently trifluoromethyl, (Cl-C ⁇ o)-alkyl, substituted (Ci-C ⁇ o)-alkyl, (C2-Cio)-alkenyl, substituted (C2-C ⁇ o)-alkenyl, (C2-Cio)-alkynyl, substituted (C2-Ci ⁇ )-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)- alkanoyl.
  • the substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R ⁇ a and R " groups are independently from 1 to 3 of, for example, -OR 4 , -C(0)R 4 , -CO2R 4 , -C(0)NR R5, -NR R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (C ⁇ -C4)-alkyl, or (Ci-C4)-alkoxy groups.
  • R 2 is (C ⁇ -C 10 )-alkyl, substituted (C r C 10 )-alkyl, (C2-C 10 )-alkenyl, substituted (C2-C ⁇ ) )-alkenyl, ⁇ -C j g alkynyl, substituted ⁇ -C j nJ-alkynyl, (C3- C 6 )-cycloalkyl-(C 1 -C 6 )-alkyl, or substituted (C 3 -C 6 )-cycloalkyl-(C r C 6 )-alkyl.
  • the substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R 2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, l,3-dioxolan-2-yl, -C(0)NR R5, or -S(0) m R 7 wherein m is 0, 1, or 2.
  • the substituents on the substituted phenyl R 2 substituent group are from 1 to 3 of, for example, halogen, (C2-C4)-alkyl, or (C ⁇ -C4)-alkoxy.
  • R? is (C ⁇ -C6)-alkyl, phenyl, substituted phenyl, phenyl-(C ⁇ -C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Cl-C6)- alkyl, substituted pyridyl-(C -C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-
  • (Cl-C6)-alkyl or substituted naphthyl-(C ⁇ -C6)-alkyl.
  • the substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R 7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (Cl-C6)-alkyl, (Ci-C6)-alkoxy, nitro, cyano, or hydroxy.
  • R 2 and R " may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R 2 and Rib are attached.
  • R 3 is hydroxy, trifluoroacetyl, (C- C ⁇ -alkanoyl, substituted (C j -C ⁇ ⁇ alkyl, or substituted ⁇ -CgJ-alkenyl.
  • the substitutents on the substituted alkyl and substituted alkenyl R 3 groups are from 1 to 3 hydroxy or trifluoromethyl groups.
  • Ar is an optionally substituted aromatic or heteroaromatic ring.
  • Ar groups are: phenyls, naphthyls, 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, substituted (C-i-C ⁇ )- alkyl, (C -C 6 )-alkenyl, substituted (C 2 -C6)-alkenyl, (C -C 6 )-alkynyl, substituted
  • 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, -NR 4 R 5 , phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, C ⁇ -CA) alkyl, or (C1-C4) alkoxy groups.
  • 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 protein inhibitors.
  • 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 protein 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 of hyperlipoproteinemia, 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 pharmaceutical products for the treatment of hyperlipoproteinemia.
  • the invention also relates to a pharmaceutical 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.
  • substituted pyridines according to the invention can also occur in the form of the salts thereof.
  • salts with organic or inorganic bases or acids are mentioned here.
  • physiologically safe salts are preferred.
  • 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 acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, prop ionic 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.
  • 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, 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 behave like an image and mirror image (diastereomers).
  • the invention concerns both enantiomers or diastereomers or the mixtures thereof. These mixtures of enantiomers and diastereomers can be separated in the known manner into stereoisomerically homogeneous components.
  • 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, benzothiazolyl, benzo[b]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 preferred,
  • 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 -NRlR 2 ,
  • R! and R 2 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,
  • 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 -NR 3 R 4 , wherein
  • R 3 and R 4 are identical or different and have the meaning given above for R and R 2 ,
  • 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 -NR ⁇ R",
  • R5 and R6 are identical or different and have the meaning given above for R 1 and R 2 ,
  • T stands for a radical of the formula
  • R7 and 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, carboxy 1, 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,
  • 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 hhyvddrrooxxyv.
  • R9 denotes hydrogen
  • RlO 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 - NR 3R1 4 ,
  • Rl3 and R are identical or different and have the meaning given above for R! and R 2 ,
  • R 9 and Rl° form a carbonyl group together with the carbon atom
  • 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,
  • 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,
  • 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,
  • 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
  • R 7 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
  • RlO denotes hydrogen, fluorine, chlorine, bromine, azido, amino, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 3 carbon atoms,
  • R9 and RlO form a carbonyl group together with the carbon atom
  • A stands for phenyl, which is optionally substituted by fluorine, chlorine, or methyl.
  • Rl5 stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms
  • 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.
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimethyl ether
  • hydrocarbons such as benzene, toluene,
  • Suitable organometallic reagents are systems such as Mg/bromobenzene trifluoride and p-trifluoromethylphenyllithium. The Mg/bromobenzene trifluoride system is preferred.
  • 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 preferred.
  • ethers such as dioxane, tetrahydrofuran, or diethyl ether
  • hydrocarbons such as benzene, hexane, or toluene.
  • Toluene and tetrahydrofuran are preferred.
  • Suitable reductants are complex metal hydrides, such as lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutylaluminum hydride, dimethoxymethylaluminate sodium salt, or sodium- 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 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 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.
  • 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.
  • 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.
  • the reaction can also take place via hydrogenation.
  • 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.
  • 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
  • the customary strong basic compounds can be used as auxiliary agents.
  • organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium, or phenyllithium, or amides, such as lithium diisopropylamide, sodium amide, or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides, such as sodium hydride or potassium hydride.
  • organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium, or phenyllithium
  • amides such as lithium diisopropylamide, sodium amide, or potassium amide, or lithium hexamethylsilylamide
  • alkali hydrides such as sodium hydride or potassium hydride.
  • n-butyllithium, or sodium hydride are used.
  • the customary inorganic bases are suitable bases.
  • alkali hydroxides or alkaline earth hydroxides such as sodium hydroxide, potassium hydroxide, or barium hydroxide
  • alkali carbonates such as sodium carbonate, potassium carbonate, or sodium hydrogen carbonate.
  • 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.
  • the halogenation generally takes place in one of the above-mentioned chlorinated hydrocarbons, whereby methylene chloride is preferred.
  • Diethylamino sulfur trifluoride (DAST) or SOCI2, 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 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 preferred.
  • bases are generally suitable as bases, preferably 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, preferably at 25°C to 40°C.
  • 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).
  • R 6 and Rl? are identical or different and stand for straight-chain or branched alkyl with up to 4 carbon atoms, in inert solvents with oxidants,
  • 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 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.
  • PCC pyridinium chlorochromate
  • osmium tetroxide osmium tetroxide
  • manganese dioxide manganese dioxide.
  • DDQ 2,3-dichloro-5,6-dicyanobenzoquinone
  • 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.
  • reaction is generally 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 of 0.5 to 5 bar).
  • reduced pressure or high pressure e.g., within a range of 0.5 to 5 bar.
  • Rl8 and Rl9 have the meaning given above for Rl6 and R ? and are identical to or different from these,
  • A, E, Rl8, and R 9 have the above-mentioned meanings
  • R ⁇ stands for cycloalkyl with 3 to 8 carbon atoms, or stands for straight-chain or branched alkyl with up to 8 carbon atoms, and
  • Y stands for halogen, preferably for bromine or iodine
  • 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) ammonium nitrate in acetonitrile, the alkylation is carried out with dimethyl formamide 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.
  • R denotes a straight-chain or branched alkoxycarbonyl with up to 3 carbon atoms
  • 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 formulas (IA) and (la) 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.
  • CETP cholesterol ester transfer proteins
  • 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 can therefore 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.
  • 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.
  • CETP is obtained in partially purified form from human plasma by differential centrifugation and column chromatography and is used for testing.
  • 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 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).
  • 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.
  • 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 3 H-CE-HDL, which was adjusted to approx. 5x10 ⁇ cpm per ml and used for the test.
  • the reaction was ended by adding Streptavidin-SPA® beads (Amersham), and the transferred radioactivity was determined directly in the liquid scintillation counter.
  • 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 an IC50 value.
  • blood was drawn from the animals by puncture of the retroorbital venous plexus (approx. 250 ⁇ l). Coagulation was completed 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 diluted in a suitable manner with physiological saline solution.
  • test substance which was dissolved in DMSO and suspended in 0.5% methylcellulose, was administered orally to Syrian golden hamsters from the company's own breeding via a pharyngeal 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 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.
  • 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 parenterally, in particular, perlingually or intravenously.
  • solutions of the active compound can be employed using suitable liquid excipients.
  • the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.
  • the aqueous phase is separated off, washed two times with saline solution, dried over Na2S ⁇ 4, 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 in a high vacuum.
  • the ethanol solution is concentrated, and the residue together with the ethanediol mother liquor is extracted four times with 1.5 1 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 volume of approx. 2 1, allowed to stand overnight again, and drawn off by suction from the precipitated sediment.
  • Example III Analogously to Example III, 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 (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).
  • DAST diethylamino sulfur trifluoride
  • the compounds according to the invention can also occur in the form of the salts thereof.
  • salts with organic or inorganic bases or acids are mentioned here.
  • 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, 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 preferred.
  • Physiologically safe salts can also be metallic or ammonium salts of the compounds according to the invention that possess a free carboxyl group.
  • 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, 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 behave like an image and mirror image (diastereomers).
  • the invention concerns both enantiomers or diastereomers or the mixtures thereof. These mixtures of enantiomers and diastereomers can be separated in the known manner into stereoisomerically homogeneous components.
  • 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.
  • 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 preferred.
  • 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 -NR ⁇ R 3 and /or by a group of the formula -W-R ⁇ ,
  • R2 and R 3 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
  • R 4 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
  • V stands for an oxygen or sulfur atom or for a group of the formula -NR ⁇ , wherein
  • R5 denotes hydrogen or straight-chain or branched alkyl with up to 4 carbon atoms or phenyl
  • R! stands for cyclopropyl, cyclopentyl, or cyclohexyl
  • 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, al
  • R6, R7, and R ⁇ 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,
  • 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,
  • 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
  • V stands for an oxygen or sulfur atom or for a group of the formula -NR ⁇
  • R5 denotes hydrogen or straight-chain or branched alkyl with up to 3 carbon atoms
  • R stands for cyclopropyl, cyclopentyl, or cyclohexyl, or tetrahydropyrinidyl stands for 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, al
  • R6, R7, and R ⁇ 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,
  • 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,
  • 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.
  • RU stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms or for the group of the formula -CH2-0-Si(CH3)2C(CH3)3,
  • Z stands for halogen, preferably chlorine or bromine
  • Rl2 stands for straight-chain alkyl with up to 4 carbon atoms
  • 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, 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 also possible to use mixtures of the solvents. Dichloromethane, tetrahydrofuran, toluene, or dimethylformamide are particularly preferred.
  • inorganic or organic bases may be used. These preferably include alkali hydroxides 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(Cj-C6)amines) such as triethylamine, or heterocyclic compounds such as l,4-diazabicyclo[2.2.2]octane (DABCO), l,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
  • 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 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).
  • reaction is carried out in a temperature range of 0°C to 150°C, and preferably from +20°C to +110°C.
  • the reaction can be carried out at normal, increased, or reduced pressure (for example, 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
  • 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 nitromethan
  • Suitable organometallic reagents are Grignard systems such as Mg/bromobenzotrifluoride and p-trifluoromethylphenyl lithium.
  • the Mg/bromobenzotrifluoride system is preferred.
  • 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 preferred.
  • Suitable reductants are complex metal hydrides such as lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutyl aluminum hydride, dimethoxy methyl aluminate sodium salt, or sodium-bis(2-methoxyethoxy) dihydroaluminate (Red-Al). Diisobutyl aluminum hydride and dimethoxymethylaluminate sodium salt are preferred.
  • the reductant is generally added in the amount of 4 moles to 10 moles, and preferably 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.
  • 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.
  • the reduction is carried out using complex metal hydrides such as lithium borohydride, 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.
  • noble metal catalysts such as Pd/C, Pt/C, or Raney nickel
  • alcohols such as methanol, ethanol, or propanol
  • 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.
  • the customary inorganic bases are suitable bases. These preferably 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 sodium hydrogencarbonate. Sodium hydroxide or potassium hydroxide are particularly preferred.
  • Alcohols such as methanol, ethanol, propanol, or tert-butanol are also suitable solvents for the individual reaction steps. Tert butanol is preferred.
  • halogenations generally take place in one of the above-mentioned chlorinated hydrocarbons, with methylene chloride being preferred.
  • DAST Diethylamino sulfur trifluoride
  • SOC_2 SOC-2, 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.
  • 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, preferably 0.5 moles 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).
  • R! and Rl4 are identical or different and denote straight-chain or branched alkyl with up to 4 carbon atoms,
  • Suitable solvents for the oxidation 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, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is also 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.
  • PCC pyridinium chlorochromate
  • osmium tetroxide osmium tetroxide
  • manganese dioxide manganese dioxide.
  • DDQ 2,3-dichloro-5,6-dicyanobenzoquinone
  • 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.
  • 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 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 transfer proteins (CETP) and stimulate reverse cholesterol transport.
  • CETP cholesterol ester transfer proteins
  • 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 can therefore 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.
  • glucosidase and /or amylase inhibitors are, for example, acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688, testratin, pradimicin-Q, and salbostatin.
  • CETP CETP was obtained in partially purified form from human plasma by differential 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 HC1, pH 7.4, and then eluted with dist. water.
  • 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 linear gradient (0-1 M
  • the pooled CETP fractions were dialyzed against 10 mM Tris HC1, pH 7.4, and were then further purified by chromatography over a Mono Q® column (Pharmacia).
  • 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.
  • 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 H-CE-HDL, which was adjusted to approx. 5 x l ⁇ 6 cmp per ml and used for the test.
  • the reaction was ended by adding Streptavidin-SPA® beads (Amersham), and the transferred radioactivity was determined directly in the liquid scintillation counter.
  • 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 h after administration of the test substance blood was drawn from the animals by puncture of the retroorbital venous plexus (approx. 250 ⁇ l).
  • Coagulation was completed by incubating at 4°C overnight, and the blood was then centrifuged for 10 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 ⁇ l 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).
  • the triglyceride /cholesterol concentration contained in the samples was determined using a parallel-measured standard curve.
  • the determination 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.
  • test substance which was dissolved in DMSO and suspended in 0.5% methylcellulose, was administered orally to Syrian golden hamsters from the company's own breeding via a pharyngeal 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.
  • 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, 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 solvents.
  • Administration takes place in a customary manner, preferably orally or parenterally, in particular, perlingually or intravenously.
  • solutions of the active compound can be employed using suitable liquid excipients.
  • the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.
  • PE petroleum ether
  • EE ethyl acetate
  • 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 organic phase is washed once with a saturated NaCl solution, dried over Na2SC>4, and concentrated in a vacuum.
  • the residue is chromatographed over silica gel 60 with toluene / ethyl acetate (8:2).
  • 2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethylpyridine is dissolved in 220 g of analysis grade CH2CI2, 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 washed with cold NaHCC»3 solution, dried over Na2S ⁇ 4, concentrated, dried for 60 min. in a high vacuum, and then stored at -20°C.
  • 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 vacuum, and chromatographed over silica gel (mobile solvent ethyl acetate / petroleum ether 2:8).
  • CXL ⁇ i is desilylated in methanol in the presence of 3 N hydrochloric acid.
  • 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.
  • cycloalkyl means an alkyl group which is in the form of a ring and contains the designated number of carbon atoms. Examples include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
  • 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.
  • alkanoyl means groups of formula -C(0)-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include: acetyl, propionyl and butanoyl.
  • alkanoyloxy means groups of formula -OC(0)-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include -OC(0)CH3, -OC(0)C2H5, and -OC(0)C3H7-
  • alkoxycarbonyl means groups of formula -C(0)0-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include -C(0)OCH3, -C(0)OC2H5, and -C(0)OC3H7.
  • 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.
  • 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.
  • 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-C10H7.
  • 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.
  • 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.
  • 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.
  • halogen means the halogen atoms fluorine, chlorine, bromine and iodine.
  • 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 similar substituents can also be employed.
  • X preferably represents CR ⁇ .
  • R° is preferably hydrogen, halogen, trifluoromethyl or (Ci-
  • Cio alkyl.
  • R° is most preferably hydrogen.
  • R la and R lb preferably are independently trifluoromethyl, (C ⁇ -Cio)-alkyl, substituted (C -C ⁇ o)-alkyl, (C2-Cio)-alkenyl, substituted (C2-Cio)-alkenyl, (C3- C7)-cycloalkyl, or (C3-C7)-cycloalkenyl.
  • R a and ° most preferably are independently (C ⁇ -C6)-alkyl or (C2-C6)-alkenyl.
  • R 2 is preferably (C r C 10 )-alkyl, substituted (C r C 10 )-alkyl, (C 2 -C 10 )-alkenyl or substituted (C2-C ⁇ )-alkenyl.
  • the groups R 4 and R ⁇ are preferably independently hydrogen, (C1-C6) alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyI, phenyl, substituted phenyl, phenyl-(C ⁇ - C6)-alkyl, substituted phenyl-(C ⁇ -C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(C ⁇ -C6)-alkyl.
  • R 4 and R 5 are most preferably independently hydrogen, (C ⁇ -C6)-alkyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl (C ⁇ -C6)-alkyl or substituted phenyl (Ci-C6)-alkyl.
  • R 4 and R 5 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, 0, or S(0) n wherein n is 0, 1, or 2, and R6 is hydrogen, ( -C6) alkyl, phenyl, or phenyl (Ci-C ⁇ ) alkyl.
  • R? is preferably (Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)- alkyl, substituted phenyl-(Cl-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci- C6)-alkyl, or substituted pyridyl-(C ⁇ -C6)-alkyl.
  • R is most preferably (C ⁇ -C-6)- alkyl, phenyl, substituted phenyl, phenyl (Cl-C6)-alkyl or substituted phenyl (Cl- C6)-alkyl.
  • the substituents on the substituted 7 groups are preferably 1-3 of halogen, trifluoromethyl, or (C1-C6) alkyl.
  • this bridge preferably contains 3 or 4 carbon atoms.
  • R 3 is preferably (C ⁇ -Cg) alkanoyl, substituted (C j -C ⁇ J-alkyl, or substituted (C3-C )-alke yl, wherein the substitutents are preferably from 1 to 3 hydroxyl groups. Most preferably, R 3 is substituted alkenyl where the substitutents are from 1 to 2 hydroxyl groups.
  • R* a and R" 5 are independently trifluoromethyl, (Ci-C ⁇ o)-alkyl, substituted
  • (Cl-Cio)-alkyl (C2- o)-alkenyl, substituted (C2-C ⁇ o)-alkenyl, (C2-C ⁇ o)-alkynyl, substituted (C2-Cio)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (Ci-C ⁇ )- alkanoyl.
  • the substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R la and R lb groups are independently from 1 to 3 of, for example, -OR 4 , -C(0)R 4 , -CO2R 4 , -C(0)NR 4 R5, -NR 4 R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (Ci-C4)-alkyl, or
  • the groups R 4 and R ⁇ are independently hydrogen, (Cl-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C ⁇ -C6)-alkyl, substituted phenyl-(C ⁇ -C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Ci-C6)- alkyl.
  • R 4 and R ⁇ groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C2-C4)- alkyl, or (Ci-C4)-alkoxy groups.
  • R 4 and R ⁇ may be joined together to form -(CT_2)rA(CH2)s- wherein the subscripts r and s are independently 1 to 3 and A is CHR6, NR6, O, or S(0) n in which n is 0, 1, or 2; and R6 is hydrogen, (Cl-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(C ⁇ -C6)-alkyl.
  • R 2 is (C r C 10 )-alkyl, substituted (C r C 10 )-alkyl, (C 2 -C 10 )-alkenyl, substituted (C2-C ⁇ )-alkenyl, substituted (C2-C
  • substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R 2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, l,3-dioxolan-2-yl, -C(0)NR 4 R 5 , or -S(0) m R 7 wherein m is 0, 1, or 2.
  • the substituents on the substituted phenyl R 2 substituent group are from 1 to 3 of, for example, halogen, (C j -C ⁇ -alkyl, or (Cj-C4)-alkoxy.
  • R 7 is (C -C6)-alkyl, phenyl, substituted phenyl, phenyl-(C -C6)-alkyl, substituted phenyl-(C ⁇ -C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci-C6)- alkyl, substituted pyridyl-(C ⁇ -C6)-alkyl, naphthyl, substituted naphthyl, naphthyl- (C ⁇ -C6)-alkyl, or substituted naphthyl-(C ⁇ -C6)-alkyl.
  • substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R 7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (C ⁇ -C6)-alkyl, (C ⁇ -C6)-alkoxy, nitro, cyano, or hydroxy.
  • R 2 and R lb may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R 2 and V 3 are attached.
  • R3 is hydroxy, trifluoroacetyl, (C- C ⁇ J-alkanoyl, substituted (C- C ⁇ -alkyl, or substituted ⁇ -C ⁇ ⁇ 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.
  • 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, (C- C ⁇ -alkyl, substituted (C ⁇ -C ⁇ -a-kyl, (C2"C )-alkenyl, substituted (C2-
  • substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on Ar' are from 1 to 3 of, for example, halogen, hydroxy, -NR R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C ) alkyl, or ( -
  • heteroaromatic ring Ar' is preferably selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, rriazolyls, oxazolyls and thiazolyls, and the optional substitutents on Ar' are preferably independently from 1 to 3 of, for example, halogen, (C r C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C )-cycloalkyl, cyano, -OR 4 , or -OC(0)R 4 where R 4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (Ci-C ⁇ ) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C -C ) alkyl.
  • 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, (C j -CgJ-alkyl, ⁇ -C ⁇ -alkenyl,
  • R la and R ⁇ are independently trifluoromethyl, (C ⁇ -C ⁇ o)-alkyl, substituted
  • the substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R a and ⁇ " groups are independently from 1 to 3 of, for example, -OR 4 , -C(0)R 4 , -CO2R 4 , -C(0)NR R5, -NR R5, or phenyl which is optionally substituted with from 1 to 3 halogen, (Cl-C4)-alkyl, or (C ⁇ -C4)-alkoxy groups.
  • the groups R 4 and R ⁇ are independently hydrogen, (C ⁇ -C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C ⁇ -C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Ci-C6)-alkyl, or substituted naphthyl-(Ci-C6)- alkyl.
  • R 4 and groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)- alkyl, or (C ⁇ -C4)-alkoxy groups.
  • R 4 and R ⁇ 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(0)n in which n is 0, 1, or 2; and R6 is hydrogen, (Cl-C ⁇ )-alkyl, piperidin-1-yl, phenyl, or phenyl-(Ci-C6)-alkyl.
  • R 2 is (C r C 10 )-alkyl, substituted (C r C 10 )-alkyl, (C 2 -C 10 )-alkenyl, substituted (C 2 -C 10 )-alkenyl, (C 2 -C 10 )-alkynyl, substituted (C 2 -C 10 )-alkynyl, (C3-
  • substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R 2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, l,3-dioxolan-2-yl, -C(0)NR 4 R 5 , or -S(0) m R 7 wherein m is 0, 1, or 2.
  • the substituents on the substituted phenyl R 2 substituent group are from 1 to 3 of, for example, halogen, (C j -C )-alkyl, or (C ⁇ -C4)-alkoxy.
  • R 7 is (Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C ⁇ -C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci-C6)- alkyl, substituted pyridyl-(Cl-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl- (Ci-C6)-alkyl, or substituted naphthyl-(Ci-C6)-alkyl.
  • substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R 7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (Ci-C6)-alkyl, (Ci-C6)-alkoxy, nitro, cyano, or hydroxy.
  • R 2 and R lb may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R 2 and R lb are attached.
  • R3 is hydroxy, trifluoroacetyl, (C
  • the substitutents on the substituted alkyl and substituted alkenyl R 3 groups are from 1 to 3 hydroxy or trifluoromethyl groups.
  • Ar is an optionally substituted aromatic ring.
  • Ar 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, (C j -C ⁇ -alkyl, substituted (C ⁇ -Cg)- alkyl, (C2-C£)-alkenyl, substituted (C ⁇ -CgJ-alkenyl, (C2-Cg)-alkynyl, substituted
  • substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on Ar" are from 1 to 3 of, for example, halogen, hydroxy, -NR 4 R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C2-C4) alkyl, or (C1-C4) alkoxy groups.
  • aromatic ring Ar preferably is a phenyl ring wherein the optional substitutents are preferably independently from 1 to 3 of, for example, halogen, (C r C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR 4 or -OC(0)R 4 , where R 4 is hydrogen, (C1-C6) alkyl, phenyl ( -C ⁇ ) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C2-C4) alkyl.
  • R 4 is hydrogen, (C1-C6) alkyl, phenyl ( -C ⁇ ) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C2-C
  • the optional substitutents are from 1 to 3 of, for example, halogen, (C j -C ⁇ J-alkyl, (C2-C6)-alkenyl, -OR 4 or -OC(0)R 4 , where R 4 is hydrogen or (C1-C6) alkyl.
  • the heteroaryl-substituted benzenes included within formula (IC) have the formula IC
  • R° represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C ⁇ -Cio)-alkyl, substituted (C ⁇ -C ⁇ o)-alkyl, (Ci-C6)-alkoxy, (C3-C7)- cycloalkyl, phenyl-(C ⁇ -C3)-alkoxy, (C ⁇ -C6)-alkanoyloxy, (C ⁇ -C6)-alkoxy carbonyl, carboxy, formyl, or -NR R5.
  • the substituents on the substituted phenyl or substituted alkyl R° groups are from 1 to 3 of, for example, hydroxy, fluoro, (Ci- C ⁇ )-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(Ci-C3)-alkoxy, (C1-C6)- alkanoyloxy, (Cl-C6)-alkoxycarbonyl, carboxy, formyl, or -NR R5.
  • the groups R 4 and R ⁇ are independently hydrogen, (Ci-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cl-C6)- alkyl.
  • the substitutents on the substituted phenyl or substituted naphthyl R 4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C- [ -C ⁇ )- alkyl, or (C ⁇ -C.4)-alkoxy groups.
  • R 4 and R 5 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(0) n in which n is 0, 1, or 2; and R6 is hydrogen, (C -C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Ci-C6)-alkyl.
  • R* a and R"> are independently trifluoromethyl, (Ci-Cio)-alkyl, substituted (Cl-C ⁇ o)-alkyl, (C2-C ⁇ o)-alkenyl, substituted (C2-C ⁇ o)-alkenyl, (C2-Cio)-alkynyl, substituted (C2-Cl ⁇ )-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)- alkanoyl.
  • the substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R la and R" 3 groups are independently from 1 to 3 of, for example, -OR 4 , -C(0)R 4 , -CO2R 4 , -C(0)NR R5, -NR 4 R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (Cl-C4)-alkyl, or (Cl-C4)-alkoxy groups.
  • R 2 is (C r C 10 )-alkyl, substituted (C r C 10 )-alkyI, (C 2 -C 10 )-alkenyl, substituted (C 2 -C ⁇ )-alkenyl, (C2-C ⁇ g)-alkynyl, substituted (C2-C 10 )-alkynyl, (C 3 - C 6 )-cycloalkyl-(C 1 -C 6 )-alkyl, or substituted (C 3 -C 6 )-cycloalkyl-(C 1 -C 6 )-alkyl.
  • the substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R 2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, l,3-dioxolan-2-yl, -C(0)NR R 5 , or -S(0) m R 7 wherein m is 0, 1, or 2.
  • the substituents on the substituted phenyl R 2 substituent group are from 1 to 3 of, for example, halogen, (C
  • R 7 is (Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C ⁇ -C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci-C6)- alkyl, substituted pyridyl-(Ci-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-
  • (Ci-C6)-alkyl or substituted naphthyl-(Ci-C6)-alkyl.
  • the substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R 7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (C ⁇ -C6)-alkyl, (Ci-Co)-alkoxy, nitro, cyano, or hydroxy.
  • R 2 and R ⁇ may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R 2 and Rib are attached.
  • R3 is hydroxy, trifluoroacetyl, (C j -C ⁇ )-alkanoyl, substituted (C- C ⁇ -alkyl, or substituted (C3-C )-alkenyl.
  • the substitutents on the substituted alkyl and substituted alkenyl R ⁇ 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, (C j -C ⁇ -alkyl, substituted (C- Cg)-alkyl, ⁇ -C ⁇ -alkenyl, substituted (C2-
  • substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on Ar' are from 1 to 3 of, for example, halogen, hydroxy, -NR R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C- j -C4)-alkyl, or (Ci-
  • heteroaromatic ring Ar' is preferably selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and thiazolyls, and the optional substitutents on the group Ar' are preferably independently from 1 to 3 of, for example, halogen, (C j -C ⁇ ⁇ alkyl, ⁇ -C ⁇ -alkenyl,
  • R 4 is hydrogen, (C1-C6) alkyl, phenyl (Ci-C ⁇ ) 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 preferably independently from 1 to 3 of, for example, halogen, (C j -C ⁇ ) alkyl, (C -
  • aryl-substituted benzenes included within formula (IC) have the formula
  • R° represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (C ⁇ -C ⁇ o)-alkyl, substituted (C ⁇ -Cio)-alkyl, (C ⁇ -C6)-alkoxy, (C3-C7)- cycloalkyl, phenyl-(C ⁇ -C3)-alkoxy, (C ⁇ -C6)-alkanoyloxy, (C -C6)-alkoxycarbonyl, carboxy, formyl, or -NR R5.
  • the substituents on the substituted phenyl or substituted alkyl R° groups are from 1 to 3 of, for example, hydroxy, fluoro, (Ci- C ⁇ )-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(Ci-C3)-alkoxy, (Cl-C ⁇ )- alkanoyloxy, (C ⁇ -C6)-alkoxy carbonyl, carboxy, formyl, or -NR R5.
  • the groups R 4 and R 5 are independently hydrogen, (Ci-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C ⁇ -C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cl-C6)- alkyl.
  • substitutents on the substituted phenyl or substituted naphthyl R 4 and R5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C )- alkyl, or (Cl-C )-alkoxy groups.
  • R 4 and R 5 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(0) n in which n is 0, 1, or 2; and R6 is hydrogen, (C ⁇ -C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(C ⁇ -C6)-alkyl.
  • R ia and Rib are independently trifluoromethyl, (C ⁇ -C ⁇ o)-alkyl, substituted
  • the substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R a and R groups are independently from 1 to 3 of, for example, -OR 4 , -C(0)R 4 , -CO2R 4 , -C(0)NR R5, -NR 4 R 5 , or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (Cl-C4)-alkyl, or (C ⁇ -C.4)-alkoxy groups.
  • R 2 is (C r C 10 )-alkyl, substituted (C r C 10 )-alkyl, (C 2 -C 10 )-alkenyl, substituted (C2-C2 ⁇ )-alkenyl, (C2"
  • the substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R 2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, l,3-dioxolan-2-yl, -C(0)NR R 5 , or -S(0) m R 7 wherein m is 0, 1, or 2.
  • the substituents on the substituted phenyl R 2 substituent group are from 1 to 3 of, for example, halogen, (C
  • R 7 is (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C ⁇ -C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C ⁇ -C6)- alkyl, substituted pyridyl-(C -C6)-alkyl, naphthyl, substituted naphthyl, naphthyl- (C ⁇ -C6)-alkyl, or substituted naphthyl-(C ⁇ -C6)-alkyl.
  • substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R 7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (C ⁇ -C6)-alkyl, (C ⁇ -C6)-alkoxy, nitro, cyano, or hydroxy.
  • R 2 and Rl b 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 R 2 and R b are attached.
  • R3 is hydroxy, trifluoroacetyl, (C- C ⁇ -alkanoyl, substituted (C j -C ⁇ -alkyl, or substituted (C3-C£)-alkenyl.
  • the substitutents on the substituted alkyl and substituted alkenyl R ⁇ groups are from 1 to 3 hydroxy or trifluoromethyl groups.
  • Ar is an optionally substituted aromatic ring.
  • Ar 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, (C j -C ⁇ -alkyl, substituted (C j -C ⁇ )- alkyl, (C2-C 6 )-alkenyl, substituted (C ⁇ -C ⁇ -alkenyl, ⁇ -C ⁇ -alkynyl, substituted
  • Ar are from 1 to 3 of, for example, halogen, hydroxy, -NR R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C 1 -C 4 )-alkyl, or (C ⁇ -C4)-alkoxy groups.
  • the preferred and most preferred groups R a , Ri , R 2 , R3, and R8, as well as the additional groups R 4 , R ⁇ , R6, and R 7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.
  • aromatic ring Ar preferably is a phenyl ring wherein the optional substitutents are preferably from 1 to 3 of, for example, halogen, (C j -C ⁇ )- alkyl, (C 2 -C 6 )-alkenyl, (C2-C ⁇ )-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR 4 or -OC(0)R 4 , where R 4 is hydrogen, (Ci-C ⁇ ) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (Ci-C ⁇ ) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C2-C4) alkyl.
  • R 4 is hydrogen, (Ci-C ⁇ ) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (Ci-C ⁇ ) alkyl where the phenyl substitutents are from 1 to 3 of halogen
  • the substitutents are from 1 to 3 of, for example, halogen, (C r C 6 )-alkyl, (C 2 -C 6 )-alkenyl, -OR 4 or -OC(0)R 4 , where R 4 is hydrogen or ( -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 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 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.
  • Suitable amines for this purpose include ammonia, arylalkylamines such as dibenzylamine and N,N- dibenzylethylenediamine, lower alkylamines such as methylamine, f-butylamine, 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.
  • arylalkylamines such as dibenzylamine and N,N- dibenzylethylenediamine
  • lower alkylamines such as methylamine, f-butylamine
  • procaine lower alkylpiperidines such as N-ethylpiperidine
  • cycloalkylamines such as cyclohexylamine or dicyclohexylamine
  • the present invention also encompasses pharmaceutically acceptable "prodrugs" of the compounds of formula (IC) which form such derivatives.
  • pharmaceutically acceptable "prodrugs” of the compounds of formula (IC) which form such derivatives.
  • These 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 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.
  • 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.
  • compositions of the invention may also include one or more known antidiabetic agents in addition to a compound of structural formula (IC).
  • antidiabetic agents are: ⁇ -glucosidase inhibitors such as acarbose 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.
  • ⁇ -glucosidase inhibitors such as acarbose or
  • 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, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • 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, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents.
  • Tablets and pills can additionally be prepared with enteric coatings such as the OROS-CT/OsmetTM and PULSINCAPTM 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 diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending 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.
  • 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 adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • intramuscular, intraarticular or subcutaneous depot injection with or without encapsulation of the drug into degradable microspheres e.g., comprising poly(DL- lactide-co-glycolide) may be used to obtain prolonged sustained drug release.
  • an i.p. implanted reservoir and septum such as the Percuseal system available from Pharmacia. Improved convenience and patient compliance may also be achieved by the use of either injector pens (e.g. the NovoPen or Q-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 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, excipients such as cocoa butter or a suppository wax.
  • the compounds of this invention can be manufactured into the above listed formulations 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, fats, polyols such as polyethylene glycol, water, saccharose, alcohols, glycerin and the like.
  • the formulations may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions.
  • sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • Various preservatives, emulsifiers, dispersants, flavorants, wetting agents, 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 on the recipient and the condition being treated. The requisite amount may be determined 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 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 I and Type II) or of other conditions which are sometimes found in diabetic subjects.
  • 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 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.
  • these compounds 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 modulate hepatic glucose output.
  • compounds of the present invention may be useful for finding new glucagon antagonists.
  • a binding assay employing a radiolabeled derivative (such as 3 H) of a compound of formula (IC) would be useful in identifying new compounds that competitively bind to the glucagon receptor.
  • a radiolabeled derivative such as 3 H
  • Such an assay is useful in identifying structurally novel antagonists that may offer advantages in ease of chemical modification, selectivity and oral bioavailability.
  • 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 compounds of Formula (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.
  • the ketoester 1 (commercially available or prepared according to the procedure of Deslongchamps, Synth. Comm., 1976, 6, 169) is treated with an 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 3, 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 be protected during the Hantzsch pyridine synthesis.
  • a description of suitable protecting groups may be found in: Protective Groups in Organic Synthesis, Second Edition, T.
  • 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 (CH2CI2), or with eerie ammonium nitrate (CAN) in a mixture of solvents such as aqueous acetone, affords the intermediate 6.
  • DDQ 2,3-dichloro-5,6-dicyanobenzoquinone
  • CH2CI2 methylene chloride
  • CAN eerie ammonium nitrate
  • Chemical reducing agents such as sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) in an inert solvent, such as tetrahydrofuran (THF) or diethyl ether (Et2 ⁇ ), can result in a monoreduction of the pyridinediester 6 to give the alcohol 9.
  • an inert solvent such as tetrahydrofuran (THF) or diethyl ether (Et2 ⁇
  • PCC pyridinium chlorochromate
  • a solvent such as CH2G2
  • the reagent 11a is 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 Reactions, 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 Et2 ⁇ , and hydrogen in the presence of a metal catalyst, such as palladium on carbon, in a polar solvent such as ethanol, to afford compounds of formula Ila.
  • a reducing agent such as lithium aluminum hydride (LAH)
  • LAH lithium aluminum hydride
  • Et2 ⁇ inert solvent
  • a metal catalyst such as palladium on carbon
  • a polar solvent such as ethanol
  • R 2 may contain substituents such as alcohol, acetate, ester, carboxylic acid, and amide.
  • Scheme 4 affords intermediates that can be converted to homologues of compounds of formula Ila, containing the -CH2-CH2- linkage between the pyridine nucleus and the hydroxy group (lib).
  • R ⁇ is 1-hydroxyethyl (Va), is outlined in Scheme 8.
  • Oxidants such as pyridinium chlorochromate (PCC), are used to convert compounds of formula II to the aldehyde 18.
  • PCC pyridinium chlorochromate
  • Treatment of 18 with an organometallic reagent such as methyl magnesium bromide or methyl lithium in an inert solvent such as THF or Et2 ⁇ affords racemic compounds of formula Va.
  • Chiral 1-hydroxyethyl aryl pyridine derivatives of formula Vb are obtained by resolution of the racemates Va by classical methods.
  • resolution can be achieved by formation of diastereomeric adducts of the racemic compounds with optically active reagents such as ⁇ -methoxy- ⁇ -(trifluoromethyl)phenylacetic acid (Dale, J.A.; Dull, D.L.; Mosher, H.S. /. Org. Chem. 1969, 34, 2543).
  • optically active reagents such as ⁇ -methoxy- ⁇ -(trifluoromethyl)phenylacetic acid (Dale, J.A.; Dull, D.L.; Mosher, H.S. /. Org. Chem. 1969, 34, 2543).
  • separation of enantiomers is achieved by HPLC on chiral solid phase. Determination of absolute 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.
  • 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 reductant 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.
  • biphenyl 48 Treatment of 47 with triphenylphosphine, then with 4-fluorophenylmagnesium bromide (prepared from l-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 in Scheme 4.
  • MEM ether 50 is treated with trimethylsilyl chloride and sodium iodide in acetonitrile solvent, and subsequently with sodium acetate in DMF solvent to provide acetate 5 Saponification of the acetate using potassium hydroxide in methanol solvent provides alcohol 52. Hydroxymethyl biphenyl 52 is transformed to racemic hydroxyethyl biphenyl 54 as described in Scheme 8.
  • biphenyls of formula (IC) is the coupling of a suitably functionalized benzene derivative 57 (where X can be trifluoromethanesulfonate, methoxy, bromide, or iodide) with an arylmetal reagent ArMY n
  • biaryl coupling is the Suzuki reaction (Miyaura, N., Yanagi, T., Suzuki, A. Synth. Comm. 1981, 11, 513-519; Oh-e, T., Miyaura, N., Suzuki, A. /. Org. Chem. 1993, 58, 2201-2208) in which a benzene derivative 58 (in which X can be trifluoromethanesulfonate, bromide, or iodide) is coupled with an arylboronic acid (Scheme 26).
  • biphenyls of type I uses a cycloaromatization of a ketodiester 68 with a diketone in the presence of a catalytic amount of sodium 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 the analog with the desired R ⁇ and R ⁇ groups.
  • the diester 70 can be further transformed by an alternative method shown in Scheme 31, to give the analogs with the desired R ⁇ and R 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 71 can be attached to a polymeric support such as Wang resin, by treatment with a 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 afford compound 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 resin, to afford the alcohol 75.

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

SUBSTITUTED PYRIDINES AND BIPHENYLS AS ANΗ-HYPERCHOLESTERINEMIC, ANTI-
HYPERLΓPOPROTEINEMIC AND ANTT-HYPERGLYCEMTC AGENTS
Field
This application relates to substituted biaryl compounds which inhibit cholesterol ester transfer proteins (CETPs), stimulate reverse cholesterol transport, and inhibit the action of glucagon.
Background
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-(poly substituted pyridyl) hept-6-enoates for the treatment of arteriosclerosis, Iipoproteinemia, 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 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 different strategies to address the different abnormalities in metabolism found in affected individuals.
In the diabetic state (all forms of Type I and Type II), 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, 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: 1. Treatment of hyperglycemia associated with diabetes of any cause and associated with any other diseases or conditions. A glucagon receptor antagonist can 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, hyper lipidemias and elevated hepatic glucose output 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 post receptor signal transduction. To treat diabetes associated with anti-insulin antibodies, drug induced diabetes, diabetes associated with endocrinopathies and diabetes 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. 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 protein 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 W09518153-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 Lett. 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 inhibitors of cholesterol ester transfer proteins (CETP) and stimulate reverse cholesterol 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 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 listed above.
Summary
The present invention concerns substituted biaryl compounds which fall 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 preferred and most preferred molecular constituents, procedures for making, examples of particular materials made, testing 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 substituent groups apply only to the particular subset of the compounds of the invention then under consideration. The same symbols may have different definitions in connection with the other subsets of compounds.
The present invention concerns substituted pyridines of the general formula
Figure imgf000006_0001
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
-NR^2,
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 R^ are identical or different and have the meaning given above for Rl and R2,
or
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 R > are identical or different and have the meaning given above for Rl 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
R* »10
R'- ____ or wherein
R^ and R^ 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 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 -NR^R^.
wherein RU and Rl2 are identical or different and have the meaning given above for Rl 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
RIO 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
Rl3 and R*4 are identical or different and have the meaning given above for R! and R2,
or
R9 and RlO form a carbonyl group together with the carbon atom,
and the salts thereof.
The present invention also concerns substituted pyridines of general formula
(IB)
Figure imgf000009_0001
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 -NR^-,
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, 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 -OR^, -SR-7, -SG^R^, 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 RlO 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 heterocyclic atoms 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 heterocycles 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.
This invention also relates to compounds having glucagon receptor antagonistic activity and the general formula (IC) shown below.
Figure imgf000012_0001
In general formula IC, the groups X, Rla, R">, R2, R3, and Ar have the following meanings:
X represents N or CR^.
R° represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (Ci-Clθ)-alkyl, substituted (Cι-Cιo)-alkyl, (Ci-C6)-alkoxy, (C3-C7)- cycloalkyl, phenyl-(Ci-C3)-alkoxy, (Cι-C6)-alkanoyloxy, (Cι-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, ( - C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(Ci-C3)-alkoxy, ( -C6)- alkanoyloxy, (Ci-C6)-alkoxy carbonyl, carboxy, formyl, or -NR4R5. The groups R4 and R^ are independently hydrogen, (Cl-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)-alkyl, substituted phenyl-(Cι-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cι-C6)-alkyl, or substituted naphthyl-(Cι-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 (Cl-C4)-alkoxy groups.
R4 and R^ 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, NRθ, O, or S(0)n in which n is 0, 1, or 2; and R6 is hydrogen, (Ci-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Ci-C6)-alkyl.
R*a and R1" are independently trifluoromethyl, (Cl-Cιo)-alkyl, substituted (Ci-Cιo)-alkyl, (C2-Cio)-alkenyl, substituted (C2-Cιo)-alkenyl, (C2-Cio)-alkynyl, substituted (C2-Ciθ)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)- alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R^a and R " groups are independently from 1 to 3 of, for example, -OR4, -C(0)R4, -CO2R4, -C(0)NR R5, -NR R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (Cι-C4)-alkyl, or (Ci-C4)-alkoxy groups.
R2 is (Cι-C10)-alkyl, substituted (CrC10)-alkyl, (C2-C10)-alkenyl, substituted (C2-Cκ))-alkenyl, ^-Cjg alkynyl, substituted ^-CjnJ-alkynyl, (C3- C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)-cycloalkyl-(CrC6)-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, l,3-dioxolan-2-yl, -C(0)NR R5, or -S(0)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, (C2-C4)-alkyl, or (Cι-C4)-alkoxy.
R? is (Cι-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cι-C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Cl-C6)- alkyl, substituted pyridyl-(C -C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-
(Cl-C6)-alkyl, or substituted naphthyl-(Cι-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, (Ci-C6)-alkoxy, nitro, cyano, or hydroxy.
R2 and R " may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and Rib are attached.
R3 is hydroxy, trifluoroacetyl, (C- C^-alkanoyl, substituted (Cj-Cβ^alkyl, or substituted ^-CgJ-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 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 the group Ar are independently 1 to 3 of, for example, halogen,
Figure imgf000013_0001
substituted (C-i-Cβ)- alkyl, (C -C6)-alkenyl, substituted (C2-C6)-alkenyl, (C -C6)-alkynyl, substituted
(C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(0)R4, -
OC(0)R4, -CQ2R4, -NR4R5, -C(0)NR4R5, or -S(0)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, C^-CA) 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 protein 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 of hyperlipoproteinemia, 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 pharmaceutical products for the treatment of hyperlipoproteinemia. The invention also relates to a pharmaceutical 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.
Detailed description with reference to compounds of general 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 preferred. 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 acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, prop ionic 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, 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 behave like an image and mirror image (diastereomers). The invention concerns both 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, benzothiazolyl, benzo[b]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 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, 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,
wherein
R! 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
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 R 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 -NR^R",
wherein
R5 and R6 are identical or different and have the meaning given above for R1 and R2,
and
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
R9 R10
R7 — X or wherein
R7 and 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, carboxy 1, 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
-NRllRl2,
wherein
U and R!2 are identical or different and have the meaning given above for R! 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 hhyvddrrooxxyv.
R9 denotes hydrogen,
and
RlO 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 - NR 3R14,
wherein
Rl3 and R are identical or different and have the meaning given above for R! and R2,
or
R9 and Rl° form a carbonyl group together with the carbon atom,
and the salts thereof. 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, 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
R9 R10
R7~X— or n8 ^- 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
RlO 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 RlO form a carbonyl group together with the carbon atom,
and the salts thereof. Compounds according to the invention of the general formula (IA) are most preferred, 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)
Figure imgf000021_0001
in which
A, E, L, and T have the above-mentioned meanings,
and
Rl5 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 of the general formula (III), direct reductions are carried out, optionally via several steps.
The compounds according to the invention can be explained, for example, by means of the following reaction diagram:
Figure imgf000022_0001
Figure imgf000023_0001
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 likewise possible to use mixtures of said solvents. Dichloromethane is preferred. Suitable organometallic reagents are systems such as Mg/bromobenzene trifluoride and p-trifluoromethylphenyllithium. The Mg/bromobenzene 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 are preferred.
Suitable reductants are complex metal hydrides, such as lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutylaluminum hydride, dimethoxymethylaluminate sodium salt, or sodium- 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 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 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 appropriate 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. The reaction can also take place via hydrogenation. 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 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 lithium 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, preferably, 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 preferably, 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 SOCI2, 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 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 preferred.
One of the above-mentioned bases are generally suitable as bases, preferably 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, preferably 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)
Figure imgf000026_0001
in which
A, E, and L' have the above-mentioned meanings,
R 6 and Rl? are identical or different and stand for straight-chain or branched alkyl with up to 4 carbon atoms, in inert solvents with oxidants,
and
selectively reducing the alkoxycarbonyl function (CO2R '7) to the hydroxy function 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 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.
l,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 possible to carry out the process at reduced pressure or high pressure (e.g., within a range of 0.5 to 5 bar). Compounds of the general formula (II) in the case wherein L is alkoxy /cyclooxy (__') are known and can be produced by first oxidizing compounds of the general formula (V)
Figure imgf000028_0001
in which
A and E have the above-mentioned meanings
and
Rl8 and Rl9 have the meaning given above for Rl6 and R ? and are identical to or different from these,
with ceric(IV) ammonium nitrate into compounds of the general formula (VI)
Figure imgf000028_0002
in which
A, E, Rl8, and R 9 have the above-mentioned meanings,
then, by reaction with alkylation agents of the general formula (VII)
R20_Y (VII)
in which
R υ stands for cycloalkyl with 3 to 8 carbon atoms, or stands for straight-chain or branched alkyl with up to 8 carbon atoms, 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 the general formula (VIII)
Figure imgf000029_0001
in which
A, E, Rl8, R!9, and R2^ have the above-mentioned meanings,
and finally, as described above, carrying out a selective reduction with diisobutylaluminum hydride of the alkoxycarbonyl group -CO2R 8 to the 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) ammonium nitrate in acetonitrile, the alkylation is carried out with dimethyl formamide 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)
Figure imgf000030_0001
in which
A, E, L, and T have the above-mentioned meanings
and
R denotes a straight-chain or branched alkoxycarbonyl with up to 3 carbon atoms,
first by reduction of the alkoxycarbonyl function, into compounds of the general formula (la)
Figure imgf000030_0002
in which
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 methods described above for the production of compounds of the general formula (II).
Compounds of the general formula (la) are also novel and can be produced as described above. Compounds of the general formulas (IA) and (la) according to the invention have an unforeseeable pharmacological spectrum of action.
Compounds of the general formulas (IA) and (la) 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 can therefore 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 (IA) 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. Obtaining CETP
CETP is obtained in partially purified form from human plasma by differential 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 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. Obtaining Radioactively Tagged 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 3x4 1 of PDB buffer (10 mM Tris/HCl, pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN3). 20 μl 3H cholesterol (Du Pont NET-725; 1 -μC/μl 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. 5x10^ cpm per ml and used for the test.
3. Conducting 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 scintillation counter.
In the test batch, 10 μl HDL-3H cholesterol ester (= 50,000 cpm) was incubated for 18 h at 37°C with 10 μl biotin-LDL (Amersham) in 50 mM HEPES /
0.15 m NaCl / 0.1% bovine serum albumin / 0.05% NaN3, pH 7.4, with 10 μl CETP
(1 mg/ml) and 3 μl solution of the substance to be tested (dissolved in 10% DMSO / 1% BSA). Then 200 μl 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 μl buffer, 10 μl CETP at 4°C, and 10 μl 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 an IC50 value.
CETP inhibitory activity of the following compounds:
Figure imgf000033_0001
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 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 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 puncture of the retroorbital venous plexus (approx. 250 μl). Coagulation was completed 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 diluted in a suitable manner with physiological saline solution.
100 μl serum dilution was mixed with 100 μl 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 nM (SLT-Spectra). The triglyceride /cholesterol concentration contained in the samples was determined using a parallel-measured standard curve. The determination 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 orally to Syrian golden hamsters from the company's own breeding via a pharyngeal 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 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 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 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 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. 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 behavior toward 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.
Starting Compounds
Example I
Diethyl 4-(4-fluorophenyl)-6-isopropyl-(lH)-pyrid-2-one-3,5-dicarboxylate
Figure imgf000035_0001
149 g (0.395 mmol) of diethyl 3,4-dihydro-4-(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 H2O, 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) Example II
Diethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxy-3,5-dicarboxylate
Figure imgf000036_0001
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 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
Figure imgf000036_0002
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 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 Na2Sθ4 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
Figure imgf000037_0001
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 HI in 400 ml CH2CI2 in the presence of neutral AI2O3 (10.07 g = 0.0988 mol), and the mixture is stirred for 1 h at room temperature. It is drawn off by suction over silica gel and subsequently washed with CH2CI2, 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) Example V
Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxy-3-[2-(benzoxazol-2-yl)-l-hydroxy- ethyl]-pyridine-5-carboxylate
Figure imgf000038_0001
400 mg (3 mmol) of 2-methylbenzoxazole dissolved in 5 g THF p.a. is cooled tinder 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 is 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 Na2Sθ4, 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 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)-6-isopropyl-2-methoxy-3-[2-(benzoxazol-2-yl)-ethenyl]- pyridine-5-carboxylate
Figure imgf000038_0002
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 is stirred 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 and toluene / 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 l,4-dihydro-2,6-diisopropyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylate
Figure imgf000039_0001
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 concentrated, and the residue together with the ethanediol mother liquor is extracted four times with 1.5 1 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 volume of approx. 2 1, allowed to stand overnight again, and drawn off by suction from the precipitated sediment.
Total yield: 556.9 g (69.1% of theory) H-NMR (CDC13): δ = 1.1 - 1.3 (m, 18H); 4.05 - 4.25 (m, 6H); 5.0 (s, 1H); 6.13
(s, 1H); 6.88 (m, 20H); 7.2 (m, 2H) ppm.
Example VIII
Diethyl 2,6-diisoproρyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate
Figure imgf000040_0001
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 1 of dichloromethane, and the mixture is stirred overnight at room temperature. The mixture is drawn off by suction over diatomaceous earth and subsequently washed well with dichloromethane. After concentration of the dichloromethane phase to a volume 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) H-NMR (CDCI3): δ = 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.
Example IX
Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-hydroxymethylpyridine-5-carboxylate
Figure imgf000041_0001
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 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. The residue is mixed with petroleum ether, drawn off by suction, and dried in a desiccator.
Yield: 69.1 g (64.2% of theory) H-NMR (CDCI3): δ = 0.95 (t, 3H); 1.31 (m, 12H); 3.05 (m, 1H); 3.48 (m, 1H);
3.95 (q, 2H); 4.93 (d, 2H); 7.05 - 7.31 (m, 4H) ppm.
Example X
Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-formyl-pyridine-5-carboxylate
Figure imgf000041_0002
14.18 g (0.139 mol) of neutral AI2O3 and 29.96 g (0.13 mol) of pyridinium chlorochromate (PCC) are added to a solution of 25.0 g (0.0695 mol) of the compound from Example IX in 500 ml CH2CI2 and the mixture is stirred for 1 h at room temperature. It is drawn off by suction over silica gel and subsequently washed with CH2CI2/ and the filtrate is concentrated in a vacuum, whereby the product precipitates out.
Yield: 20 g (80.48% of theory) iH-NMR (DMSO-d6): δ = 0.92 (t, 3H); 1.39 (dd, 6H); 3.02 - 3.13 (m, 1H); 3.75 -
3.86 (m, 1H); 3.95 - 4.05 (q, 2H); 7.32 (m, 4H); 9.8 (s, 1H) ppm.
Example XI
Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-[(4-fluorophenyl)hydroxymethyl]- pyridine-5-carboxylate
Figure imgf000042_0001
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 for another 2 h at -70°C. The reaction solution is mixed with 200 ml of cone. NH4CI solution, the cooling bath is removed, and the solution is adjusted with 1 molar HC1, pH = 6. After extraction with 400 ml of CH2CI2 and drying over Na2Sθ4, 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) Example XII
Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-[(4-fluorophenyl)-chloromethyl]- pyridine-5-carboxylate
Figure imgf000043_0001
907 mg (2 mmol) of the compound from Example XI is dissolved in 20 g of CH2CI2 p.a. and cooled under argon at -40°C, and 0.44 ml (6 mmol) SOCI2 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 NaHCθ3 solution. The organic phase is separated off, dried over Na2Sθ4, concentrated in a vacuum, and chromatographed on diatomaceous earth using toluene.
Yield: 899 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- one-3,5-dicarboxylate
Figure imgf000043_0002
30.69 g (115.3 mmol) of ethyl l-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 with water, dried over Na2Sθ4, 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-f luoropheny l)-6-p-fluoropheny l-( 1 H)-py rid-2-one-3,5- dicarboxylate
Figure imgf000044_0001
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)
Example XV
3-Ethyl 5-methyl 4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3,5- dicarboxylate
Figure imgf000045_0001
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- pyridine-5-carboxylate
Figure imgf000045_0002
Analogously to Example III, 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 (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)
Example XVII
Methyl 4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-formyl-pyridine-5- carboxylate
Figure imgf000046_0001
Following the instructions in Example IV, 1.636 g (3.72 mmol) of the compound from Example XVI in 150 ml of CH2CI2 is stirred with 0.759 g (7.44 mmol) of AI2O3 (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-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-[(naphthyI-2)- hydroxy-methyl]-pyridine-5-carboxylate
Figure imgf000047_0001
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
Figure imgf000047_0002
0.08 mmol (0.602 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 CH2CI2 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 / NaHCθ3 solution, and the organic layer is dried with Na2Sθ4 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
Figure imgf000048_0001
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 in 150 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) The compounds listed in Table 1(A) are produced in analogy to the instructions in Example I:
Table 1(A):
Figure imgf000049_0001
Figure imgf000049_0002
Example 5
4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-[(naphthyl-2)- fluoromethyl]-5-hydroxymethyl-pyridine
Figure imgf000050_0001
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 LΪA1H4 for 1 h under reflux. The compound is purified by 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
The compounds listed in Table 2(B) are produced in analogy to the instructions of Example 5:
Table 2(B):
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000052_0002
Example 14
2-Isopropyl-6-methoxy-4-(4-fluorophenyl)-5-[2-(benzoxazol-2-yl)ethyl]-3- hydroxymethylpyridine
Figure imgf000052_0001
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 obtained. Rf = 0.28 (toluene / ethyl acetate 9:1) Detailed description with reference to compounds of general 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, 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 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, 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 behave like an image and mirror image (diastereomers). The invention concerns both 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, 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 preferred.
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 -NR^R3 and /or by a group of the formula -W-R^,
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 -NR^, wherein
R5 denotes hydrogen or straight-chain or branched alkyl with up to 4 carbon atoms or phenyl,
R! 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 R^ 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.
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
E stands for a bond,
V stands for an oxygen or sulfur atom or for a group of the formula -NR^,
wherein
R5 denotes hydrogen or straight-chain or branched alkyl with up to 3 carbon atoms,
R stands for cyclopropyl, cyclopentyl, or cyclohexyl, or tetrahydropyrinidyl stands for 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 -OR^, -SR7, or -Sθ2R^,
wherein
R6, R7, and R^ 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. 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)
Figure imgf000058_0001
in which
A, D, L, and T have the indicated meaning,
and
RU stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms or for the group of the formula -CH2-0-Si(CH3)2C(CH3)3,
are reacted with compounds of general formula (UI)
Rl-E-Z (HI)
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
RH,
or
[B] compounds of general formula (II) are first converted by reactions with compounds of general formula (IV)
O R12— S- Cl (IV)
II
O
in which
Rl2 stands for straight-chain alkyl with up to 4 carbon atoms,
into compounds of general formula (V)
Figure imgf000059_0001
in which
A, D, L, T, RU, and R 2 have the indicated meaning, and these are then reacted with compounds of general formula (VI)
R -E-V-H (VI)
in which
R , E, and V have the indicated meaning,
and reductive separation is carried out, and optionally, the groups listed under substituents A, L, T, and R are introduced or varied according to customary methods.
The processes according to the invention can be explained, for example, by means of the following reaction diagrams:
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
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, 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 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 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(Cj-C6)amines) such as triethylamine, or heterocyclic compounds such as l,4-diazabicyclo[2.2.2]octane (DABCO), l,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 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 preferably from +20°C to +110°C.
The reaction can be carried out at normal, increased, or reduced pressure (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, Wittig/Grignard reactions, and amidation/sulfoamidation. 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 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 are preferred.
Suitable reductants are complex metal hydrides such as lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutyl aluminum hydride, dimethoxy methyl aluminate sodium salt, or sodium-bis(2-methoxyethoxy) dihydroaluminate (Red-Al). Diisobutyl aluminum hydride and dimethoxymethylaluminate sodium salt are preferred.
The reductant is generally added in the amount of 4 moles to 10 moles, and preferably 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. 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, 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 preferably 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 sodium hydrogencarbonate. Sodium hydroxide or potassium hydroxide are particularly preferred.
Alcohols such as methanol, ethanol, propanol, 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 halogenations generally take place in one of the above-mentioned chlorinated hydrocarbons, with methylene chloride being preferred.
Diethylamino sulfur trifluoride (DAST) or SOC_2, 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, preferably 0.5 moles 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)
Figure imgf000066_0001
in which
A, L, and T have the above-indicated meaning,
and
R! and Rl4 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 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, 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 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 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. 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 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 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 can therefore 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), tendamistate, AI-3688, testratin, pradimicin-Q, and salbostatin.
The combination 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. Obtaining CETP CETP was obtained in partially purified form from human plasma by differential 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 HC1, 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 linear gradient (0-1 M
NaCl). The pooled CETP fractions were dialyzed against 10 mM Tris HC1, pH 7.4, and were then further purified by chromatography over a Mono Q® column (Pharmacia).
2. Obtaining radioactivelv-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 1 PDB buffer (10 mM Tris/HCl, pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN3). 20 μl of 3H cholesterol (Du Pont NET-725; 1
-μC/μl 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 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 H-CE-HDL, which was adjusted to approx. 5 x lθ6 cmp per ml and used for the test.
3. Conducting 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 scintillation counter.
In the test batch, 10 μl of HDL-3H cholesterol ester (-50,000 cpm) was incubated for 18 h at 37°C with 10 μl 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 μl of CETP (1 mg/ml) and 3 μl solution of the substance to be tested (dissolved in 10% DMSO / 1% BSA). Then, 200 μl 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 μl buffer, 10 μl CETP at 4°C, and 10 μl 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 IC50 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 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 h after administration of the test substance blood was drawn from the animals by puncture of the retroorbital venous plexus (approx. 250 μl). Coagulation was completed by incubating at 4°C overnight, and the blood was then centrifuged for 10 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 μl serum dilution was mixed with 100 μl 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). The triglyceride /cholesterol concentration contained in the samples was determined using a parallel-measured standard curve.
The determination 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 orally to Syrian golden hamsters from the company's own breeding via a pharyngeal 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 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, 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 solvents.
Administration takes place in a customary manner, preferably orally or 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. I. Mobile solvents for thin-layer chromatography
Figure imgf000072_0002
PE = petroleum ether; EE = ethyl acetate
Example I
l,4-Dihydro-2-cyclopentyl-6-ethyl-4-(4-fluorophenyl)pyridine-3,5- dicarboxylic acid-3-methylester-5-ethylester
Figure imgf000072_0001
6.2 g (50 mmol) of 4-fluorobenzaldehyde, 8.5 g (50 mmol) of 3-amino- cyclopentylprop-2-ene-carboxylic methylester, and 7.2 g (50 mmol) of 4-methylacetoacetic ethylester are heated for 18 hours to 130°C while stirring. After cooling to room temperature, chromatography is carried out over silica gel (200 g of silica gel, 230-400 mesh; d 3.5 cm, mobile solvent ethyl acetate/petroleum ether 1 : 9).
Yield: 2.8 g (14% of theory)
Rf (ethyl acetate / petroleum ether 2 : 8) = 0.31
Example II
2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylic acid-3-methylester- 5-ethylester
Figure imgf000073_0001
2.8 g (6.98 mmol) of l,4-dihydro-2-cycloρentyl-6-ethyl-4-(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 iH-NMR (CDC13): δ = 0.95 (t, 3H); 1.32 (t, 3H); 1.6 - 2.1 (m, 8H); 2.83 (q, 2H); 3.14 (m, 1H); 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 HI) and
2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-5-hydroxymethylpyridine-3- carboxylic acid methylester (Example IV)
Figure imgf000074_0001
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 -60°C. After this, the mixture is stirred 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 aqueous phase 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 iH-NMR (CDCI3): δ = 0.95 (t, 3H); 1.28 (t, 3H); 1.6-2.1 (m, 8H); 2.76 (q, 4H);
3.55 (m, 1H); 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 (CDCI3): δ = 1.32 (t, 3H); 1.6-2.1 (m, 8H); 2.97 (t, 3H); 3.06 (m, 1H); 3.45 (s, 3H); 4.45 (d, 2H) ppm.
The compounds shown in Table 1(B) are produced analogously to the instructions for Examples I-IV: Table 1(B)
Figure imgf000075_0001
CO
Figure imgf000075_0002
Figure imgf000076_0001
«-sl
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000078_0002
-4
Figure imgf000079_0001
CD
Figure imgf000080_0001
10
Figure imgf000081_0001
00 o
Figure imgf000082_0001
oo
Figure imgf000083_0001
CO P
Figure imgf000084_0001
00 ω
Figure imgf000085_0001
00 *
Figure imgf000086_0001
00 in
Figure imgf000087_0001
α>
Figure imgf000088_0001
Example CXXXIX
2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-3-(3-trifluoromethylbenzyloxy- methyl)-pyridine-5-carboxylic acid ethylester
Figure imgf000089_0001
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. dimethyl formamide 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 iH-NMR (CDC13): δ = 0.95 (t, 3H); 1.32 (t, 3H); 1.6-2.1 (m, 8H); 2.78 (q, 4H);
3.44 (m, 1H); 3.95 (q, 4H); 4.28 (s, 2H); 4.42 (s, 2H); 7.0-7.6 (m, 8H) ppm. Example CXL
2,6-D_isopropyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylic acid diethylester
Figure imgf000090_0001
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 l,4-dihydro-2,6-diisopropyl-4- (4-fluorophenyl)pyridine-3,5-dicarboxylic acid diethylester in 200 ml of analysis grade methylene chloride, and the mixture is then stirred for 1 h at room 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 and dried 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) iH-NMR (CDC13): δ = 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.
Example CXLI
2,6-Diisopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-pyridine-3,5-carboxylic acid ethylester
Figure imgf000090_0002
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 to 0°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) iH-NMR (CDC13): δ = 0.95 (t, 3H); 1.31 (m, 12H); 3.05 (m, 1H); 3.48 (m, 1H);
3.95 (q, 2H); 4.93 (d, 2H); 7.05-7.31 (m, 4H) ppm.
Example CXLII
5-(£_τNButyldimethylsily_oxymethyl)-2,6-diisopropyl-4-(4-fluoro- phenyl)-pyridine-3-carboxylic acid ethylester
Figure imgf000091_0001
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 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 ethyl acetate / petroleum ether 1:9). Yield: 4.2 g (73.7% of theory)
Rf = 0.75 (A3)
Example CXLIII
3-(ferf-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5- hydroxymethylpyridine
Figure imgf000092_0001
Under 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 of analysis-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 organic phase is washed once with a saturated NaCl solution, dried over Na2SC>4, and concentrated in a vacuum. The residue is chromatographed over silica gel 60 with toluene / ethyl acetate (8:2).
Yield: 30.2 g (94.7% of theory) Rf = 0.71 (toluene / ethyl acetate 8:2)
Example CXLIV
3-(terNButyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fiuorophenyl)-5- methylsulfonyloxymethylpyridine
Figure imgf000093_0001
16.94 g (39.24 mmol) of 3-(tert-butyldimethylsilyloxymethyl)-
2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethylpyridine is dissolved in 220 g of analysis grade CH2CI2, 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 washed with cold NaHCC»3 solution, dried over Na2Sθ4, 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-(t_,rt-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-(l- methylimidazole-2-thiomethyl)pyridine
Figure imgf000093_0002
1.0 g (1.96 mmol) of 3-(tert-butyldimethylsilyloxymethyl)-2,6-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-l-methylimidazole and 0.41 ml (2.35 mmol; 1.2 eq.) of N,N-diisopropylamine are added, and the 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 NaHCθ3_ solution, 1 N
H2SO4, and saturated NaCl solution. The organic phase is dried over Na2SC>4, filtered, and concentrated.
Yield: 0.93 g (89.8% of theory)
Rf = 0.35 (toluene / ethyl acetate 8:2)
Example CXLVI
3-(t_τNButyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5- (indolyl-5-aminomethyl)pyridine
Figure imgf000094_0001
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 instructions of Example CXLII.
Yield: 2.05 g (95.8% of theory) Rf = 0.75 (toluene / ethyl acetate 8:2)
Production Examples
Example 1
2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-5-hydroxymethyl-3-(3-tri- fluoromethylbenzyloxymethyl)pyridine
Figure imgf000095_0001
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)- 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 vacuum, 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
!H-NMR (CDCI3): δ = 1.32 (t, 3H); 1.6-2.1 (m, 8H); 2.95 (q, 4H); 3.41 (m, 1H); 4.16 (s, 2H); 4.38 (s, 2H); 7.0-7.6 (m, 8H) ppm.
Example 2
2,6-Diisopropyl-4-(4-fluorophenyl)-5-(l-methylimidazole-2-thiomethyl)-3- hydroxymethylpyridine
Figure imgf000095_0002
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 NaHCθ3 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 Na2SC>4, and concentrated.
Yield: 230 mg (58.7% of theory)
Rf = 0.76 (toluene / ethyl acetate 1:1)
The compounds listed in Tables 1(B) through 5(B) are produced analogously to the procedures of Examples 1 and 2:
Table 1(B):
Figure imgf000097_0001
Figure imgf000097_0002
Figure imgf000098_0001
Example 15
2,6-Diisopropyl-4-(4-fluorophenyl)-5-(indolyl-5-aminomethyl)-3-hydroxy- methylpyridine
Figure imgf000099_0001
Analogously to Example 2, 2.3 g (4.21 mmol) of the compound from Examp
CXLπi 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:
Table 2(B):
Figure imgf000100_0001
Figure imgf000100_0002
Table 3(B)
Figure imgf000101_0001
Figure imgf000101_0002
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Table 4(B)
Figure imgf000105_0001
Figure imgf000105_0002
Figure imgf000106_0001
Table 5(B):
Figure imgf000107_0001
o
<J1
Figure imgf000107_0002
o
Figure imgf000108_0001
o
Figure imgf000109_0001
©
00
Figure imgf000110_0001
o
SO
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
!\>
Figure imgf000114_0001
00
Figure imgf000115_0001
Table 5(B): (Continued)
Figure imgf000116_0001
Table 5(B): (Continued)
n
Figure imgf000117_0001
σ.
Figure imgf000118_0001
Figure imgf000119_0001
00
Figure imgf000120_0001
Figure imgf000121_0001
<_-
Figure imgf000121_0002
o
Figure imgf000122_0001
no
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000124_0002
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
r en
Detailed description with reference to compounds of general 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 cyclopropyl, 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(0)-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include: acetyl, propionyl and butanoyl.
The term alkanoyloxy means groups of formula -OC(0)-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include -OC(0)CH3, -OC(0)C2H5, and -OC(0)C3H7-
The term alkoxycarbonyl means groups of formula -C(0)0-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include -C(0)OCH3, -C(0)OC2H5, and -C(0)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-C10H7.
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. 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 similar 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.
Preferred and most preferred groups constituting the compounds of general formula (IC) are as follows:
X preferably represents CR^. When X is CR^, R° is preferably hydrogen, halogen, trifluoromethyl or (Ci-
Cio) alkyl. R° is most preferably hydrogen.
Rla and Rlb preferably are independently trifluoromethyl, (Cι-Cio)-alkyl, substituted (C -Cιo)-alkyl, (C2-Cio)-alkenyl, substituted (C2-Cio)-alkenyl, (C3- C7)-cycloalkyl, or (C3-C7)-cycloalkenyl. R a and ° most preferably are independently (Cχ-C6)-alkyl or (C2-C6)-alkenyl.
R2 is preferably (CrC10)-alkyl, substituted (CrC10)-alkyl, (C2-C10)-alkenyl or substituted (C2-Cιø)-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(0)NR R5, or -S(0)mR7 wherein m is 0, 1, or 2. Most preferably, the substituents are halogen or -S(0)mR7 wherein m=0.
The groups R4 and R^ are preferably independently hydrogen, (C1-C6) alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyI, phenyl, substituted phenyl, phenyl-(Cι- C6)-alkyl, substituted phenyl-(Cι-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cι-C6)-alkyl. R4 and R5 are most preferably independently hydrogen, (Cι-C6)-alkyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl (Cχ-C6)-alkyl or substituted phenyl (Ci-C6)-alkyl. 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, 0, or S(0)n wherein n is 0, 1, or 2, and R6 is hydrogen, ( -C6) alkyl, phenyl, or phenyl (Ci-Cό) alkyl.
R? is preferably (Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)- alkyl, substituted phenyl-(Cl-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci- C6)-alkyl, or substituted pyridyl-(Cι-C6)-alkyl. R is most preferably (Cι-C-6)- alkyl, phenyl, substituted phenyl, phenyl (Cl-C6)-alkyl or substituted phenyl (Cl- C6)-alkyl. The substituents on the substituted 7 groups are preferably 1-3 of halogen, trifluoromethyl, or (C1-C6) alkyl. When R2 and R ° are joined to form an alkylene bridge, this bridge preferably contains 3 or 4 carbon atoms.
R3 is preferably (C^-Cg) alkanoyl, substituted (Cj-CβJ-alkyl, or substituted (C3-C )-alke yl, wherein the substitutents are preferably from 1 to 3 hydroxyl groups. Most preferably, R3 is substituted
Figure imgf000130_0001
alkenyl where the substitutents are from 1 to 2 hydroxyl groups.
Preferences for the aromatic and heteroaromatic groups Ar of structural formula (IC) are presented below. Compounds of general formula (IC) are further classified into four subsets represented by structural formulae IA, IB, IC, and ID, 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 IA
Figure imgf000130_0002
IA wherein
R*a and R"5 are independently trifluoromethyl, (Ci-Cχo)-alkyl, substituted
(Cl-Cio)-alkyl, (C2- o)-alkenyl, substituted (C2-Cιo)-alkenyl, (C2-Cιo)-alkynyl, substituted (C2-Cio)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (Ci-Cβ)- 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(0)R4, -CO2R4, -C(0)NR4R5, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (Ci-C4)-alkyl, or
(Cχ-C4)-alkoxy groups.
The groups R4 and R^ are independently hydrogen, (Cl-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cι-C6)-alkyl, substituted phenyl-(Cι-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Ci-C6)- alkyl. The substitutents on the substituted phenyl or substituted naphthyl R4 and Rβ groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C2-C4)- alkyl, or (Ci-C4)-alkoxy groups. R4 and R^ may be joined together to form -(CT_2)rA(CH2)s- wherein the subscripts r and s are independently 1 to 3 and A is CHR6, NR6, O, or S(0)n in which n is 0, 1, or 2; and R6 is hydrogen, (Cl-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cι-C6)-alkyl.
R2 is (CrC10)-alkyl, substituted (CrC10)-alkyl, (C2-C10)-alkenyl, substituted (C2-Cιø)-alkenyl,
Figure imgf000131_0001
substituted (C2-C|ø)-alkynyl, (C3-
C6)-cycloalkyl-(C -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, l,3-dioxolan-2-yl, -C(0)NR4R5, or -S(0)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, (Cj-C^-alkyl, or (Cj-C4)-alkoxy.
R7 is (C -C6)-alkyl, phenyl, substituted phenyl, phenyl-(C -C6)-alkyl, substituted phenyl-(Cι-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci-C6)- alkyl, substituted pyridyl-(Cι-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl- (Cι-C6)-alkyl, or substituted naphthyl-(Cι-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, (Cι-C6)-alkyl, (Cι-C6)-alkoxy, 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 V3 are attached.
R3 is hydroxy, trifluoroacetyl, (C- CβJ-alkanoyl, substituted (C- C^-alkyl, or substituted ^-Cβ^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 optional substitutents on the group Ar' are independently 1 to 3 of, for example, halogen, (C- C^-alkyl, substituted (C^-C^-a-kyl, (C2"C )-alkenyl, substituted (C2-
Cg)-alkenyl, (C2-C6)-alkynyl, substituted
Figure imgf000132_0001
(C3-C )-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(0)R4, -OC(0)R4, -CO2R4 -NR R5,
-C(0)NR4R5, or -S(0)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, -NR R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C ) alkyl, or ( -
C4) alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
In formula IA, the preferred and most preferred groups R^a, R^, R2, R3, as well as the additional groups R4, R^, R >, and R7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.
In formula IA, heteroaromatic ring Ar' is preferably selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, rriazolyls, oxazolyls and thiazolyls, and the optional substitutents on Ar' are preferably independently from 1 to 3 of, for example, halogen, (CrC6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C )-cycloalkyl, cyano, -OR4, or -OC(0)R4 where R4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (Ci-Cβ) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C -C ) alkyl. 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, (Cj-CgJ-alkyl, ^-C^-alkenyl,
-OR4, or -OC(0)R4 where R4 is hydrogen or ( -C6) alkyl.
The 4-aryl-substituted pyridines included within formula (IC) have the formula IB
Figure imgf000132_0002
wherein Rla and R^ are independently trifluoromethyl, (Cι-Cιo)-alkyl, substituted
(Cι-Cιo)-alkyl, (C2-Cio)-alkenyl, substituted (C2-Cio)-alkenyl, (C2-Cιo)-alkynyl, substituted (C2-Cio)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)- alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R a and }" groups are independently from 1 to 3 of, for example, -OR4, -C(0)R4, -CO2R4, -C(0)NR R5, -NR R5, or phenyl which is optionally substituted with from 1 to 3 halogen, (Cl-C4)-alkyl, or (Cι-C4)-alkoxy groups.
The groups R4 and R^ are independently hydrogen, (Cι-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Cι-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Ci-C6)-alkyl, or substituted naphthyl-(Ci-C6)- alkyl. The substitutents on the substituted phenyl or substituted naphthyl R4 and groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (C1-C4)- alkyl, or (Cι-C4)-alkoxy groups. R4 and R^ 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(0)n in which n is 0, 1, or 2; and R6 is hydrogen, (Cl-Cβ)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Ci-C6)-alkyl.
R2 is (CrC10)-alkyl, substituted (CrC10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-
C6)-cycloalkyl-(CrC6)-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, l,3-dioxolan-2-yl, -C(0)NR4R5, or -S(0)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, (Cj -C )-alkyl, or (Cι-C4)-alkoxy.
R7 is (Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cι-C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci-C6)- alkyl, substituted pyridyl-(Cl-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl- (Ci-C6)-alkyl, or substituted naphthyl-(Ci-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, (Ci-C6)-alkyl, (Ci-C6)-alkoxy, 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, (C|-Cg)-alkanoyl, substituted (Cj-C^-alkyl, or substituted (C -CgJ-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 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, (Cj-C^-alkyl, substituted (C^-Cg)- alkyl, (C2-C£)-alkenyl, substituted (C^-CgJ-alkenyl, (C2-Cg)-alkynyl, substituted
(C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(0)R4,
-OC(0)R4, -CO2R4, -NR4R5, -C(0)NR R5, or -S(0)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, (C2-C4) alkyl, or (C1-C4) alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
In formula IB, the preferred and most preferred groups Rla, R1^, 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 IB, aromatic ring Ar" preferably is a phenyl ring wherein the optional substitutents are preferably independently from 1 to 3 of, for example, halogen, (CrC6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4 or -OC(0)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl ( -Cβ) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C2-C4) alkyl. Most preferably, the optional substitutents are from 1 to 3 of, for example, halogen, (Cj-CβJ-alkyl, (C2-C6)-alkenyl, -OR4 or -OC(0)R4, where R4 is hydrogen or (C1-C6) alkyl.
The heteroaryl-substituted benzenes included within formula (IC) have the formula IC
Figure imgf000135_0001
IC wherein
R° represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (Cι-Cio)-alkyl, substituted (Cι-Cιo)-alkyl, (Ci-C6)-alkoxy, (C3-C7)- cycloalkyl, phenyl-(Cι-C3)-alkoxy, (Cι-C6)-alkanoyloxy, (Cι-C6)-alkoxy carbonyl, carboxy, formyl, or -NR R5. The substituents on the substituted phenyl or substituted alkyl R° groups are from 1 to 3 of, for example, hydroxy, fluoro, (Ci- Cό)-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(Ci-C3)-alkoxy, (C1-C6)- alkanoyloxy, (Cl-C6)-alkoxycarbonyl, carboxy, formyl, or -NR R5.
The groups R4 and R^ are independently hydrogen, (Ci-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cl-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, (C-[-C^)- alkyl, or (Cι-C.4)-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(0)n in which n is 0, 1, or 2; and R6 is hydrogen, (C -C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Ci-C6)-alkyl.
R*a and R"> are independently trifluoromethyl, (Ci-Cio)-alkyl, substituted (Cl-Cιo)-alkyl, (C2-Cιo)-alkenyl, substituted (C2-Cιo)-alkenyl, (C2-Cio)-alkynyl, substituted (C2-Clθ)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)- alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl Rla and R"3 groups are independently from 1 to 3 of, for example, -OR4, -C(0)R4, -CO2R4, -C(0)NR R5, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (Cl-C4)-alkyl, or (Cl-C4)-alkoxy groups. R2 is (CrC10)-alkyl, substituted (CrC10)-alkyI, (C2-C10)-alkenyl, substituted (C2-Cιø)-alkenyl, (C2-Cιg)-alkynyl, substituted (C2-C10)-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, l,3-dioxolan-2-yl, -C(0)NR R5, or -S(0)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, (C|-C4)-alkyl, or (Ci-C4)-alkoxy. R7 is (Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cι-C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci-C6)- alkyl, substituted pyridyl-(Ci-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-
(Ci-C6)-alkyl, or substituted naphthyl-(Ci-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, (Cι-C6)-alkyl, (Ci-Co)-alkoxy, nitro, cyano, or hydroxy.
R2 and R^ may be joined to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and Rib are attached.
R3 is hydroxy, trifluoroacetyl, (Cj-C^)-alkanoyl, substituted (C- C^-alkyl, or substituted (C3-C )-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl Rβ 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, (Cj-C^-alkyl, substituted (C- Cg)-alkyl, ^-C^-alkenyl, substituted (C2-
Cg)-alkenyl, (C2-C6)-alkynyl, substituted ^-C^-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(0)R4, -OC(0)R4, -CO2R4, -NR R5,
-C(0)NR4R5, or -S(0)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, -NR R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C-j-C4)-alkyl, or (Ci-
C4)-alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
In formula IC, the preferred and most preferred groups R a, R , R2, R , and Rβ, as well as the additional groups R4, R , Rβ, and R7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.
In formula IC, heteroaromatic ring Ar' is preferably selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and thiazolyls, and the optional substitutents on the group Ar' are preferably independently from 1 to 3 of, for example, halogen, (Cj-Cβ^alkyl, ^-C^-alkenyl,
(C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4, or -OC(0)R4, where R4 is hydrogen, (C1-C6) alkyl, phenyl (Ci-Cό) 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 preferably independently from 1 to 3 of, for example, halogen, (Cj-C^) alkyl, (C -
C6) alkenyl, -OR4' or -OC(0)R4, where R4 is hydrogen or (C1-C6) alkyl.
The aryl-substituted benzenes included within formula (IC) have the formula
ID
Figure imgf000137_0001
ID wherein
R° represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (Cι-Cιo)-alkyl, substituted (Cι-Cio)-alkyl, (Cι-C6)-alkoxy, (C3-C7)- cycloalkyl, phenyl-(Cι-C3)-alkoxy, (Cι-C6)-alkanoyloxy, (C -C6)-alkoxycarbonyl, carboxy, formyl, or -NR R5. The substituents on the substituted phenyl or substituted alkyl R° groups are from 1 to 3 of, for example, hydroxy, fluoro, (Ci- Cβ)-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(Ci-C3)-alkoxy, (Cl-Cβ)- alkanoyloxy, (Cι-C6)-alkoxy carbonyl, carboxy, formyl, or -NR R5.
The groups R4 and R5 are independently hydrogen, (Ci-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Cι-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cl-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-C )- alkyl, or (Cl-C )-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(0)n in which n is 0, 1, or 2; and R6 is hydrogen, (Cι-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cι-C6)-alkyl. Ria and Rib are independently trifluoromethyl, (Cι-Cιo)-alkyl, substituted
(Cι-Cιo)-alkyl, (C2-Cio)-alkenyl, substituted (C2-Cχo)-alkenyl, (C2-Cio)-alkynyl, substituted (C2-Cιo)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or ( -Co)- alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R a and R groups are independently from 1 to 3 of, for example, -OR4, -C(0)R4, -CO2R4, -C(0)NR R5, -NR4R5, or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (Cl-C4)-alkyl, or (Cι-C.4)-alkoxy groups.
R2 is (CrC10)-alkyl, substituted (CrC10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C2ø)-alkenyl, (C2" | )-alkynyl, substituted (C2-Cι )-alkynyl, (C3- C6)-cycloalkyl-(CrC6)-alkyl, or substituted (C3-C6)-cycloalkyl-(CrC6)-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, l,3-dioxolan-2-yl, -C(0)NR R5, or -S(0)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, (C|-C4)-alkyl, or (Cι-C4)-alkoxy.
R7 is (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cι-C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Cι-C6)- alkyl, substituted pyridyl-(C -C6)-alkyl, naphthyl, substituted naphthyl, naphthyl- (Cι-C6)-alkyl, or substituted naphthyl-(Cι-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, (Cι-C6)-alkyl, (Cι-C6)-alkoxy, 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 between the ring carbon atoms to which R2 and R b are attached.
R3 is hydroxy, trifluoroacetyl, (C- C^-alkanoyl, substituted (Cj-C^-alkyl, or substituted (C3-C£)-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl Rβ 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 are independently 1 to 3 of, for example, halogen, (Cj-C^-alkyl, substituted (Cj-C^)- alkyl, (C2-C6)-alkenyl, substituted (C^-C^-alkenyl, ^-C^-alkynyl, substituted
(C2-C6)-alkynyl, (C3-C7)-cycloaIkyl, cyano, nitro, trifluoromethyl, -OR4, -C(0)R4,
-OC(0)R4, -CO2R4, -NR R5, -C(0)NR4R5, or -S(0)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, -NR R5, phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C1-C4)-alkyl, or (Cι-C4)-alkoxy groups.
Pharmaceutically acceptable salts of these materials are within the scope of the invention.
In formula ID, the preferred and most preferred groups R a, Ri , 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 ID, aromatic ring Ar" preferably is a phenyl ring wherein the optional substitutents are preferably from 1 to 3 of, for example, halogen, (Cj-C^)- alkyl, (C2-C6)-alkenyl, (C2-Cβ)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4 or -OC(0)R4, where R4 is hydrogen, (Ci-Cό) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (Ci-Cό) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C2-C4) alkyl. Most preferably, the substitutents are from 1 to 3 of, for example, halogen, (CrC6)-alkyl, (C2-C6)-alkenyl, -OR4 or -OC(0)R4, where R4 is hydrogen or ( -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 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 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, f-butylamine, 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 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: α-glucosidase inhibitors such as acarbose 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, β3 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, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate 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, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings such as the OROS-CT/Osmet™ and PULSINCAP™ 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 diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending 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. 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 adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Alternatively intramuscular, intraarticular or subcutaneous depot injection with or without 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 by the use of either injector pens (e.g. the NovoPen or Q-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 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, excipients such as cocoa butter or a suppository wax.
The compounds of this invention can be manufactured into the above listed formulations 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, fats, polyols such as polyethylene glycol, water, saccharose, alcohols, glycerin and the like. The formulations may be sterilized by, for example, filtration through a 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 in sterile water, or some other sterile injectable medium immediately before use. Various preservatives, emulsifiers, dispersants, flavorants, wetting agents, 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 on the recipient and the condition being treated. The requisite amount may be determined 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 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 I 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 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 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 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 novel antagonists that may offer advantages in ease of chemical modification, selectivity and oral bioavailability.
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 compounds of Formula (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.
It is intended that all isomers, either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the ambit of the instant invention. 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 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.
Figure imgf000144_0002
Ic Representative examples of the nomenclature employed herein are given below:
2,6-Dimethyl-3-hydroxymethyl-4-(3-bromophenyl)-5-isobutylpyridine
Figure imgf000145_0001
3,5-Di-f-butyl-2-(phenylthio)methyl-6- hydroxymethyl-3',5'-dichloro-l, -biphenyl
Figure imgf000145_0002
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. Chem. Rev. 1982, 223).
SCHEME 1
Figure imgf000146_0001
2 4
Figure imgf000146_0002
The ketoester 1, (commercially available or prepared according to the procedure of Deslongchamps, Synth. Comm., 1976, 6, 169) is treated with an 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 3, 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 be protected during the Hantzsch pyridine synthesis. A description of suitable protecting groups may be found in: Protective Groups in Organic Synthesis, 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 (CH2CI2), or with eerie ammonium nitrate (CAN) in a mixture of solvents such as aqueous acetone, affords the intermediate 6. Separation of unwanted side products and purification of intermediates is achieved by chromatography on silica gel, employing flash chromatography (Still, W.C.; Khan, M.; Mitra, A. /. Org. Chem., 1978, 43, 2923) An alternative Hantzsch pyridine synthesis of the intermediate 6, where R a and R b 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 of ketoester 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. SCHEME 2
Et
Figure imgf000147_0001
In Scheme 3, another alternative Hantzsch pyridine synthesis of intermediate 6 is described. Ketoester 1 is condensed with aldehyde 4 by treatment with 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 previously described dihydropyridine 5 (Scheme 1), which is oxidized to the pyridine 6 according to the procedure as indicated in Scheme 1.
SCHEME 3
Figure imgf000147_0002
5 g
The synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl and Rβ is hydroxymethyl (Ila) is described in Scheme 4. SCHEME 4
PCC / CH2CI2
Figure imgf000148_0001
1)LAH/ THF
Figure imgf000148_0002
2) H2 , Pd/C lΩ 1Z
Figure imgf000148_0003
Ha lib
Chemical reducing agents such as sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) in an inert solvent, such as tetrahydrofuran (THF) or diethyl ether (Et2θ), 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 CH2G2, convert compound 9 to the aldehyde 10. Wittig reaction with compound K) and an ylide 11a, in an inert solvent such as THF or E.2O, affords olefin 12 obtained usually, but not always, as a mixture of E and Z isomers . The reagent 11a is 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 Reactions, 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 Et2θ, and hydrogen in the presence of a metal catalyst, such as palladium on carbon, in a polar solvent such as ethanol, to afford compounds of formula Ila. In 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, 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, 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 (lib), followed by treatment with an acid such as hydrochloric acid, the homologous aldehyde 13 is obtained. This can undergo 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 Ila, 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 Ha by the method described in
Scheme 4 affords intermediates that can be converted to homologues of compounds of formula Ila, containing the -CH2-CH2- linkage between the pyridine nucleus and the hydroxy group (lib).
SCHEME 5
Figure imgf000149_0001
Ifi 13
Figure imgf000149_0002
4 Ha
Synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl containing a heteroatom such as sulfur and Rβ is hydroxymethyl (Ilia and Illb), is outlined in Scheme 6. Alcohol 9 is converted to an alkyl halide 15 by treatment 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 oxidized (n = 1 or 2) by any of several known methods. For example, it can be accomplished by treatment of lj3 wherein n=0, with an oxidant such as m- chloroperbenzoic acid in a solvent such as CH2CI2. Chemical reducing agents such 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 Ma. Intermediate 15 can also react with alcohols following the methods outlined in Scheme 6, to afford compounds of formula IIIc.
SCHEME 6
Figure imgf000150_0001
2 15
Ar Ar
-tq,CγV-.s(0)n_R7 LAH /THF HO- S( ],-
,1a A '
-^ ^ plt , ,11aa A- ,1b l≤ Ilia
Figure imgf000150_0002
Hlb IHc
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 outlined in Scheme 7. Treatment of 15 with a primary or secondary amine in an inert solvent results in the intermediate 17- Chemical reducing agents such as lithium aluminum hydride in an inert solvent, such as tetrahydrofuran or diethyl ether, 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 converted to homologues of compounds of formula Ilia and IVa, containing the -CH2-CH2- linkage between the pyridine nucleus and the sulfur or nitrogen substituent (Illb and IVb). SCHEME 7
Figure imgf000151_0001
15 11
Figure imgf000151_0002
IVa IVb
Synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl and
Rβ is 1-hydroxyethyl (Va), is outlined in Scheme 8. Oxidants such as pyridinium 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 lithium in an inert solvent such as THF or Et2θ affords racemic compounds of formula Va. Chiral 1-hydroxyethyl aryl pyridine derivatives of formula Vb are obtained by resolution of the racemates Va by classical methods. For example, resolution can be achieved by formation of diastereomeric adducts of the racemic compounds with optically active reagents such as α-methoxy-α-(trifluoromethyl)phenylacetic acid (Dale, J.A.; Dull, D.L.; Mosher, H.S. /. Org. Chem. 1969, 34, 2543). Alternatively, separation of enantiomers is achieved by HPLC on chiral solid phase. Determination of absolute 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.
SCHEME 8
CH3MgBr THF
Figure imgf000151_0003
ii lδ
Figure imgf000151_0004
Va 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 chromatography and treated separately with Raney nickel and hydrogen in ethanol to provide pure enantiomers (>99% enantiomeric excess, e.e.) of the compounds of formula 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 reductant 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.
SCHEME 9
Figure imgf000152_0001
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 (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%. SCHEME 10
?H Ar O Ar
Me-ephedrine-LAH
CH ^^ CH3-VTR2 - ether, -78-C
Rla ^ _1L N ^ R1b R1a ^N<^R 1
Va 2Z
OH Ar
CH3"
R1aAϊVNARlb
R1
Vb
The synthesis of aryl pyridine derivatives of formula (IC) wherein R2 is alkyl and Rβ is 1,2-dihydroxyalkyl (VI), is described in Scheme 11. A methyl tiiphenylphosphonium salt is treated with a suitable base such as butyllithium in an inert solvent and reacted with intermediate 18 to afford olefin 23. Treatment of compound 23 with a suitable oxidant such as osmium tetroxide in a polar solvent such as pyridine gives the compounds of formula VI.
Figure imgf000153_0001
The synthesis of aryl pyridine derivatives of formula (IC) wherein R2 and Rib are taken together to form an alkylene bridge and Rβ is hydroxymethyl (Vila), 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 α,β- 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 acid to give the pyridine 26. Chemical reducing agents reduce the ester 26 to analogs of formula Vila. It may be appreciated that these analogs can be used as intermediates to generate new derivatives of formula (IC) wherein R2 and Ri are taken together and Rβ is 1-hydroxyethyl (Vllb) according to the procedures described in Scheme 8.
Figure imgf000154_0001
The synthesis of the aryl pyridine derivative Ila wherein Rib is CH2 H is described in Scheme 13. Alcohol 27 (aryl pyridine Ila in which Rib is CH3) is treated with a trialkylsilyl chloride, such as tørt-butyldiphenylsilyl chloride, and a base to yield silyl ether 28. Treatment of 28 with metø-chloroperbenzoic acid in an inert solvent, such as chloroform, provides the N-oxide 29. The N-oxide is treated 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. SCHEME 13
mCPBA
Figure imgf000155_0001
21 28
Figure imgf000155_0002
21 22
The synthesis of aryl pyridine derivatives Xa wherein R b is -CH2NR4R5 is 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.
SCHEME 14
Figure imgf000155_0003
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 CH2CI2, yields chloromethylpyridine 35. The chloride is treated with an amine providing amine 34.
SCHEME 15
Figure imgf000156_0001
34
The synthesis of aryl pyridine derivatives Xb wherein R b 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, and subsequently with an aldehyde affording olefin 38. Deprotection of the alcohol as described affords aryl pyridine Xb.
SCHEME 16
Figure imgf000156_0002
Xb
An alternative synthesis of olefin 38 is shown in Scheme 17. Aldehyde 33 is treated with an ylide as described in Scheme 4 to yield olefin 38.
SCHEME 17
Figure imgf000157_0001
The synthesis of aryl pyridine derivative Xc wherein R is -CH2CH2R is described in Scheme 18. Hydrogenation of olefin Xb as described in Scheme 4 yields the alkane Xc.
SCHEME 18
Figure imgf000157_0002
Figure imgf000157_0004
The synthesis of aryl pyridine derivative Xd wherein Rib 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.
Figure imgf000157_0005
Figure imgf000157_0003
Xd
The synthesis of aryl pyridine derivatives Xe wherein R b is -COR is 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.
SCHEME 20
Figure imgf000158_0001
The synthesis of aryl pyridine derivatives Xf wherein Ri is -C(OH)RR' is described in Scheme 21. Grignard addition to ketone 40 as described in Scheme 19 yields alcohol 41. Deprotection of the alcohol as described affords the aryl pyridine derivative Xf.
SCHEME 21
Figure imgf000158_0002
The synthesis of aryl pyridine derivatives Xg wherein Rib 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 alcohol as described affords the aryl pyridine derivative Xg.
SCHEME 22
Figure imgf000159_0001
The biphenyl analogs described in formula (IC) (X = C-R^, wherein R$ 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).
SCHEME 23
Figure imgf000159_0002
55
A specific example of this method is shown in Scheme 24. Treatment of diol 43 (prepared according to the procedure of Fey, et al. US Patent 5,138,090) with (2- methoxy)ethoxymethyl chloride and diisopropylethylamine in CH2CI2 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 presence of a catalytic amount of p-toluenesulfonic acid (pTSA) and molecular sieves in toluene solvent gives imine 46. The imine is converted to the palladium dimer 47 upon treatment with palladium acetate in acetic acid solvent. Treatment of 47 with triphenylphosphine, then with 4-fluorophenylmagnesium bromide (prepared from l-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 in Scheme 4. MEM ether 50 is treated with trimethylsilyl chloride and sodium iodide in acetonitrile solvent, and subsequently with sodium acetate in DMF solvent to provide acetate 5 Saponification of the acetate using potassium hydroxide in methanol solvent provides alcohol 52. Hydroxymethyl biphenyl 52 is transformed to racemic hydroxyethyl biphenyl 54 as described in Scheme 8.
SCHEME 24
1
Figure imgf000160_0001
42 5Q
Figure imgf000161_0001
51 52
An alternative synthesis of biphenyls of formula (IC) is the coupling of a suitably functionalized benzene derivative 57 (where X can be trifluoromethanesulfonate, methoxy, bromide, or iodide) with an arylmetal reagent ArMYn
(where M may be B, Sn, or Mg, and Y is a ligand).
SCHEME 25
Figure imgf000161_0002
5Z X = OTf, OMe, Br, I
An example of such a biaryl coupling is the Suzuki reaction (Miyaura, N., Yanagi, T., Suzuki, A. Synth. Comm. 1981, 11, 513-519; Oh-e, T., Miyaura, N., Suzuki, A. /. Org. Chem. 1993, 58, 2201-2208) in which a benzene derivative 58 (in which X can be trifluoromethanesulfonate, bromide, or iodide) is coupled with an arylboronic acid (Scheme 26).
Figure imgf000162_0002
The requisite arylboronic acid 60 may be prepared by sequential reaction of an aryl halide 59 (X = Br or I) with magnesium metal, a boronic ester, and hydrochloric acid.
SCHEME 27
X = Br- ' 2) B(OR)3 ArB^H)2
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 rearrangement of the ether provides phenol 63. The phenol is treated with trifluoromethanesulfonic anhydride (triflic anhydride) and pyridine in CH2CI2 solvent to give triflate 64. Treatment with 4-fluorophenylboronic acid, tetrakistriphenylphosphine palladium (0), potassium phosphate (tribasic), and potassium bromide in 1,4-dioxane solvent affords biphenyl 65. Catalytic hydrogenation as described in Scheme 4, and reduction of the ketone with lithium aluminum hydride in THF solvent provides the desired biphenyl analog & -
SCHEME 28
Figure imgf000162_0001
SI 62 S2
Figure imgf000163_0001
£_5 67
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 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 the analog with the desired R^ and Rβ groups.
SCHEME 29
Figure imgf000163_0002
ZΩ
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. SCHEME 30
Figure imgf000164_0001
ZQ
The diester 70 can be further transformed by an alternative method shown in Scheme 31, to give the analogs with the desired R^ and R 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 71 can be attached to a polymeric support such as Wang resin, by treatment with a 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 afford compound 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 resin, to afford the alcohol 75.
SCHEME 31
Figure imgf000164_0002
Z = Polystyrene
Figure imgf000164_0003
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 a 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 THF. Conditions required to remove other protecting groups which may be present can be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley 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.
EXAMPLE 1
Figure imgf000165_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentyIpyridine
Step A: 3-Amino-4-methyI-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, a second portion of ammonium acetate (14.6 g, 0.19 mol) was added to the reaction. The reaction was heated at reflux for 12 hours and then allowed to cool to room 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.
Step B: Diethyl l,4-dihydro-2,6-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 (90g, 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 to crystallize 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 to allow 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%). H NMR (300 MHz, CDCI3): δ 7.28 (m, 2 H), 7.06 (m, 2 H), 4.03 (q, / = 7.0 Hz, 4 H),
3.11 (septet, / = 6.6 Hz, 2 H), 1.32 (d, / = 6.5 Hz, 12 H), 0.979 (t, / = 3.3 Hz, 6 H). FAB- MS: calculated for (C23H28NO4F) 401, found 402 (M+H). Anal, calc for C23H28NO4F: 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-fluorophenyl)-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 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 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(Et2θ) /hexane yielded the desired product as a yellow waxy solid (14 g, 39 mmol, 67%). iH NMR (300 MHz, CDCI3): 5 7.27 (m, 2 H), 7.10 (m, 2 H), 4.46 (d, / = 5.2 Hz, 2 H), 3.98 (q, /
= 7 Hz, 2 H), 3.48 (sept, / = 6.6 Hz, 1 H), 3.05 (sept, / = 6.6 Hz, 1 H), 1.32 (t, / = 6.6 Hz, 12 H), 0.97 (t, / = 7 Hz, 3 H). FAB-MS: calculated for (C21H26FNO3) 359, found 360 (M+H). Rf = 0.2 (20% ethyl acetate/hexane).
Step E: 5-Carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3- pyridinecarboxaldehyde 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). iH NMR (300 MHz, CDCI3): δ 9.85 (s, 1 H), 7.27 (m, 2 H), 7.13 (m, 2 H), 4.04 (q, / = 7 Hz, 2 H), 3.88
(sept, / = 6.6 Hz, 1 H), 3.12 (sept, / = 6.6 Hz, 1 H), 1.33 (t, / = 6.6 Hz, 12 H), 1.00 (t, / = 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 2,6-diisopropyl-4-(4-fluorophenyl)-5-(l-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 vacuo, the residue partitioned between ethyl ether (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over MgSθ4 and concentrated. Flash chromatography through silica (5% diethyl ether/hexane) affords a viscous oil (2 g, 5 mmol, 90%) (E,Z mixture). iH NMR (300 MHz, CDCI3): δ 7.14 (m, 2 H), 7.02 (m,
2 h), 6.10 (dt, / = 1.8, 11.4 Hz, 0.4 H), 6.04 (dt, / = 1.5, 16.2 Hz, 0.6 H), 5.48 (dt, / = 7, 11.4 Hz, 0.4 H).5.33 (dt, / = 7, 16.2 Hz, 0.6 H), 4.00 (q, / = 7 Hz, 0.8 H), 3.98 (q, / = 7 Hz, 1.2 H), 3.39 (sept, / = 6.6 Hz, 0.6 H), 3.27 (sept, / = 6.6 Hz, 0.4 H), 3.06 (m, 1 H), 1.95 (dq, / = 1.5, 7 Hz, 1 H), 1.26 (m, 13 H), 1.19 (m, 2 H), 0.97 (t, / = 7 HZ, 3 H), 0.77 (t, / = 7 Hz, 1.2 H), 0.76 (t, / = 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-(l- 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 H2O.
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-hvdroxymethyl-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 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%). iH NMR (300 MHz, CDCI3): δ 7.15 (m, 4 H),
4.33 (d, / = 4.4 Hz, 2 H), 3.41 (sept, / = 6.6 Hz, 1 H), 3.23 (sept, / = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.30 (d, / = 6.6 Hz, 6 H), 1.27 (m, 2 H), 1.13 (m, 5 H), 0.79 (t, / = 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 acetate/hexane). mp 100-101°C. EXAMPLE 2
Figure imgf000169_0001
2,6-Dimethyl-3-hydroxymethyl-4-phenyl-5-(2-methyl-l-propenyl)-pyridine
The title compound was prepared from ethyl acetoacetate, benzaldehyde and isopropyl triphenylphosphonium iodide according to the procedures described in Example 1, Steps A-G. iH NMR (300 MHz, CDCI3): δ 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 (C18H21NO) 267, found 267 (M+). mp 48-50°C. Rf = 0.3 (90% ethyl acetate/hexane).
EXAMPLE 3
Figure imgf000169_0002
2,6-Dimethyl-3-hydroxymethyl-4-phenyl-5-(l-pentenyl)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 is isomers; gummy oil. H NMR (300 MHz, CDCI3): δ 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, / = 7 Hz, 2 H), 1.52 (bs, 1 H), 1.19 (m, 2 H), 0.77 (m, 3 H). EI-MS: calculated for (C19H23NO) 281, found 281. Rf = 0.4 (90% ethyl acetate/hexane). EXAMPLE 4
Figure imgf000170_0001
2,6-Dimethyl-3-hydroxymethyl-4-phenyl-5-pentylpyridine
The title compound was prepared from 2,6-dimethyl-3-hydroxymethyl-4- phenyl-5-(l-ρentenyl)pyridine (Example 3) according to the procedure described in Example 1, Step H. H NMR (300 MHz, CDCI3): δ 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, / = 7 Hz, 3 H). EI-MS: calculated for (C19H25NO) 283, found 283 (M+). Anal. calculated for Ci9H25NO: 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).
EXAMPLE 5
Figure imgf000170_0002
2,6-Diethyl-3-hydroxymethyl-4-phenyl-5-(2-methyl-l-propenyl)pyridine The title compound was prepared from ethyl propionylacetate, benzaldehyde and isopropyl triphenylphosphonium iodide according to the procedures described in Example 1,
Steps A-G. iH NMR (300 MHz, CDCI3): δ 7.34 (m, 3 H), 7.11 (m, 2 H), 5.76 (s, 1 H),
4.44 (d, / = 5.5 Hz, 2 H), 3.01 (q, / = 7.4 Hz, 2 H), 2.75 (q, / = 7.4 Hz, 2 H), 1.58 (s, 3 H), 1.35 (m, 7 H), 1.21 (t, / = 7.4 Hz, 3 H). FAB-MS: calculated for (C20H25NO) 295, found 296 (M+H). Anal. Calcd for C20H25NO: 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). EXAMPLE 6
Figure imgf000171_0001
2y6-Diethyl-3-hvdroxymethyl-4-phenyl-5-(l-pentenyl)pyridine
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 is isomers. iH NMR (300 MHz, CDCI3): δ 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, / = 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)
EXAMPLE 7
Figure imgf000171_0002
2,6-Diethyl-3-hvdroxymethyl-4-phenyl-5-pentylpyridine
The title compound was prepared from 2,6-diethyl-3-hydroxymethyl-4- phenyl-5-(l-pentenyl)pyridine (Example 6) according to the procedure described in Example 1, Step H. lH NMR (300 MHz, CDCI3): δ 7.42 (m, 3 H), 7.18 (m, 2 H), 4.34
(d, / = 6 Hz, 2 H), 2.96 (q, / = 7.7 Hz, 2 H), 2.84 (q, / = 7.7 Hz, 2 H), 2.28 (m, 2 H), 1.34 (m, 9 H), 1.09 (m, 4 H), 0.76 (t, / = 7 Hz, 3 H). FAB-MS: calculated for (C21H29NO) 311, found 312 (M+H). mp 7β-77°C. Rf = 0.5 (50% ethyl acetate/hexane). EXAMPLE 8
Figure imgf000172_0001
2,6-Diethyl-3-hydroxyτnethyl-4-phenyl-5-(l-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. iH NMR (300 MHz, CDCI3): δ 7.40 (m, 3 H), 7.20 (m, 2 H), 6.36 (dd, / = 11, 18 Hz, 1 H), 5.22 (dd, /
= 11, 2 Hz, 1 H), 5.00 (dd, / = 18, 2 Hz, 1 H), 4.41 (d, / = 6 Hz, 2 H), 2.96 (m, 4 H), 1.35 (m, 7 H). FAB-MS: calculated for (C18H21NO) 267, found 268 (M+H). Anal. Calcd for C18H21NO: 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).
EXAMPLE 9
Figure imgf000172_0002
2,5,6-Triethyl-3-hvdroxymethyl-4-phenylpyridine
The title compound was prepared from 2,6-diethyl-3-hydroxymethyl-4- phenyl-5-(l-ethenyl)pyridine (Example 8) according to the procedure described in
Example 1, Step H. iH NMR (300 MHz, CDCI3): δ 7.44 (m, 3 H), 7.18 (m, 2 H), 4.33
(d, / = 6 Hz, 2 H), 2.97 (q, / = 8 Hz, 2 H), 2.86 (q, / = 8 Hz, 2 H), 2.36 (q, / = 8 Hz, 2 H), 1.34 (m, 7 H), 0.93 (t, / = 8 Hz, 3 H). FAB-MS: calculated for (C18H23NO) 269, found 270 (M+H). Anal. Calcd for C18H23NO: C, 80.26; H, 8.61; N, 5.20. Found: C, 79.70; H, 8.54; N, 5.08. mp 100°C Rf = 0.4 (50% ethyl acetate/hexane). EXAMPLE 10
Figure imgf000173_0001
2,6-Diisopropyl-3-hydroxymethyl-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. !H NMR (300 MHz, CDCI3): δ 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, / = 7 Hz, 2 H), 1.24 (m, 15 H), 0.80 & 0.72 (2t, / = 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).
EXAMPLE 11
Figure imgf000173_0002
2,6-Diisopropyl-3-hydroxymethyl-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. H NMR (300 MHz, CDCI3): δ 7.32
(m, 3 H), 7.11 (m, 2 H), 5.75 (s, 1 H), 4.43 (bs, 2 H), 3.46 (sept, / = 6.6 Hz, 1 H), 3.18 (sept, / = 6.6 Hz, 1 H), 1.57 (s, 3 H), 1.31 (m, 15 H). FAB-MS: calculated for (C22H29NO) 323, found 324 (M+H). Anal. Calcd for C22H29NO: 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). EXAMPLE 12
Figure imgf000174_0001
2>6-Diisopropyl-3-hvdroxymethyl-4-phenyl-5-(l-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. iH NMR (300 MHz, CDCI3): δ 7.4 (m, 3
H), 7.2 (m, 2 H), 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). FAB-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).
EXAMPLE 13
Figure imgf000174_0002
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-(l-butenyl)pyridine
The title compound was prepared from ethyl isobutyrylacetate, 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 is isomers; gummy oil. iH NMR (300 MHz, CDCI3): δ 7.4 (m, 3
H), 7.2 (m, 2 H), 6.0 (m, 1 H), 5.4 (m, 1 H), 4.4 (m, 2 H), 3.3 (m, 3 H), 1.9 & 1.7 (2m, 2 H), 1.3 (m, 12 H), 0.7 (m, 3 H). FAB-MS: calculated for (C22H29NO) 323, found 324 (M+H). Rf = 0.4 (20% ethyl acetate/hexane). EXAMPLE 14
Figure imgf000175_0001
2,6-Diisopropyl-3-hydroxymethyl-4-phenyI-5-pentylpyridine
The title compound was prepared from 2,6-diisoproyl-3-hydroxymethyl-4- phenyl-5-(l-pentenyl)pyridine (Example 10) according to the procedure described in Example 1, Step H. l NMR (300 MHz, CDCI3) δ 7.41 (m, 3 H), 7.18 (m, 2 H),
4.33 (s, 2 H), 3.42 (sept, / = 6.6 Hz, 1 H), 3.23 (sept, / = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.32 (m, 13 H), 1.11 (m, 5 H), 0.76 (t, / = 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 acetate / hexane) .
EXAMPLE 15
Figure imgf000175_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-phenyl-5-(l-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. iH NMR (300 MHz, CDCI3): δ 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); EXAMPLE 16
Figure imgf000176_0001
2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-hexylpyrid_ne
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- phenyl-5-(l-hexenyl)pyridine (Example 15) according to the procedure described in Example 1, Step H. iH NMR (300 MHz, CDCI3): δ 7.40 (m, 3 H), 7.18 (m, 2 H), 4.33
(d, / = 5 Hz, 2 H), 3.42 (septet, / = 7 Hz, 1 H), 3.23 (septet, / = 7 Hz, 1 H), 2.26 (m, 2 H), 1.31 (m, 13 H), 1.12 (m, 8 H), 0.80 (t, / = 7 Hz, 3 H). FAB-MS: calculated for (C24H35NO) 353, found 354 (M+H). Anal. Calcd for C24H35NO: 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).
EXAMPLE 17
Figure imgf000176_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-phenyl-5-propylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- phenyl-5-(l-propenyl)pyridine (Example 12) according to the procedure described in Example 1, Step H. iH NMR (300 MHz, CDCI3): δ 7.41 (m, 3 H), 7.17 (m, 2 H),
4.33 (s, 2 H), 3.42 (sept, / = 6.6 Hz, 1 H), 3.23 (sept, / = 6.6 Hz, 1 H), 2.25 (m, 2 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.30 (d, / = 6.6 Hz, 6 H), 1.27 (m, 2 H), 1.20 (m, 1 H), 0.74 (t, / = 7 Hz, 3 H). FAB-MS: calculated for (C21H29NO) 311, found 312 (M+H). Anal. Calcd for C21H29NO: C, 80.98; 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). EXAMPLE 18
Figure imgf000177_0001
2>6-Diisopropyl-3-hvdroxymethyl-4-phenyl-5-butylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- phenyl-5-(l-butenyl)pyridine (Example 13) according to the procedure described in Example 1, Step H. iH NMR (300 MHz, CDCI3): δ 7.41 (m, 3 H), 7.17 (m, 2 H), 4.33
(s, 2 H), 3.42 (sept, / = 6.6 Hz, 1 H), 3.24 (sept, / = 6.6 Hz, 1 H), 2.28 (m, 2 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.31 (d, / = 6.6 Hz, 6 H), 1.28 (m, 2 H), 1.14 (m, 3 H), 0.71 (t, / = 7 Hz, 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. Found: C, 81.28; H, 9.87; N, 4.07. mp 83- 84°C. Rf = 0.4 (20% ethyl acetate/hexane).
EXAMPLE 19
Figure imgf000177_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(l-hexenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and pentyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 6:4 trans is isomers; gummy oil. iH NMR (300 MHz, CDCI3): δ 7.10 (m, 4
H), 5.98 (m, 1 H), 5.42 (dt, / = 7, 11.4 Hz, 0.4 H), 5.29 (dt, / = 7, 16.2 Hz, 0.6 H), 4.40 (d, / = 5.5 Hz, 2 H), 3.44 (m, 1 H), 3.36 (sept, / = 6.6 Hz, 0.6 H), 3.24 (sept, / = 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- MS: calculated for (C24H32FNO) 369, found 370 (M+H). Rf = 0.4 (20% ethyl acetate/hexane).
EXAMPLE 20
Figure imgf000178_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(l-butenyl)-pyridine
The title compound was prepared from ethyl isobutyrylacetate,
4-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. H NMR (300 MHz, CDCI3): δ 7.10 (m, 4
H), 5.97 (m, 1 H), 5.39 (dt, / = 7, 11.4 Hz, 0.5 H), 5.32 (dt, / = 7, 16.2 Hz, 0.5 H), 4.41 (d, / = 5.5 Hz, 2 H), 3.45 (m, 1 H), 3.36 (sept, / = 6.6 Hz, 0.5 H), 3.24 (sept, / = 6.6 Hz, 0.5 H), 1.95 (m, 1 H), 1.70 (m, 1 H), 1.35 (d, / = 6.6 Hz, 3 H), 1.34 (d, / = 6.6 Hz, 3 H), 1.25 (m, 7 H), 0.79 (t, / = 7.5 Hz, 1.5 H), 0.78 (t, / = 7.5 Hz, 1.5 H). FAB-MS: calculated for (C22H28FNO) 341, found 342 (M+H). Rf = 0.4 (20% ethyl acetate/hexane).
EXAMPLE 21
Figure imgf000178_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(l-propenyl)-pyridine
The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde 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 is isomers. iH NMR (300 MHz, CDCI3): δ 7.11 (m, 4 H), 6.04 (d, / = 11.7 Hz, 0.5 H), 5.96 (d, / = 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, / = 6.6 Hz, 0.5 H), 1.61 (d, / = 6 Hz, 2 H), 1.3 (m, 13 H). FAB-MS: calculated for (C21H26FNO) 327, found 328 (M+H). Anal. Calcd for C21H26FNO: 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).
EXAMPLE 22
Figure imgf000179_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-ethenyIpyridine
The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and methyl triphenylphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps A-G. iH NMR (300 MHz, CDCI3): δ 7.12 (m, 4 H), 6.35 (dd, / = 11.5, 18 Hz, 1 H), 5.24 (dd, / = 1.5, 11.4
Hz, 1 H), 4.97 (dd, / = 1.5, 18 Hz, 1 H), 4.41 (d, / = 5.5 Hz, 2 H), 3.44 (sept, / = 6.6 Hz,
2 H), 1.35 (d, / = 6.6 Hz, 6 H), 1.28 (d, / = 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% ethyl acetate/hexane).
EXAMPLE 23
Figure imgf000179_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-hexylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-fluorophenyl)-5-(l-hexenyl)pyridine (Example 19) according to the procedure described in Example 1, Step H. iH NMR (300 MHz, CDCI3): δ 7.14 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, / = 6.6 Hz, 1 H), 3.23 (sept, / = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.30 (d, / = 6.6 Hz, 6 H), 1.26 (m, 1 H), 1.14 (m, 7 H), 0.82 (t, / = 7 Hz, 3 H). FAB-MS: calculated for (C24H34FNO) 371, found 372 (M+H). mp 93-95βC. Rf
= 0.4 (20% ethyl acetate/hexane).
EXAMPLE 24
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-butylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-
(4-fluorophenyl)-5-(l-butenyl)pyridine (Example 20) according to the procedure described in Example 1, Step H. iH NMR (300 MHz, CDCI3): δ 7.15 (m, 4 H), 4.33
(d, / = 5.2 Hz, 2 H), 3.41 (sept, / = 6.6 Hz, 1 H), 3.23 (sept, / = 6.6 Hz, 1 H), 2.27 (m, 2 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.30 (d, / = 6.6 Hz, 6 H), 1.27 (m, 1 H), 1.16 (m, 3 H), 0.73 (t, / = 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).
EXAMPLE 25
Figure imgf000181_0001
2,6-Diisopropyl-3-hydroxymethv--4-(4-fluorophenyl)-5-propylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-fluorophenyl)-5-(l-propenyl)pyridine (Example 21) according to the procedure described in Example 1, Step H. iH NMR (300 MHz, CDCI3): δ 7.15 (m, 4 H), 4.33
(s, 2 H), 3.41 (sept, / = 6.6 Hz, 1 H), 3.23 (sept, / = 6.6 Hz, 1 H), 2.25 (m, 2 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.30 (d, / = 6.6 Hz, 6 H), 1.27 (m, 1 H), 1.19 (m, 1 H), 0.76 (t, / = 7 Hz, 3 H). FAB-MS: calculated for (C21H28FNO) 329, found 330 (M+H). Anal. Calcd for 21H28FNO: 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).
EXAMPLE 26
Figure imgf000181_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-ethylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-fluorophenyl)-5-ethenylpyridine (Example 22) according to the procedure described in Example 1, Step H. iH NMR (300 MHz, CDCI3): δ 7.15 (m, 4 H), 4.33
(d, / = 3.6 Hz, 2 H), 3.41 (sept, / = 6.6 Hz, 1 H), 3.26 (sept, / = 6.6 Hz, 1 H), 2.34 (q, / = 7.35 Hz, 2 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.31 (d, / = 6.6 Hz, 6 H), 1.19 (m, 1 H), 0.93 (t, / = 7.35 Hz, 3 H). FAB-MS: calculated for (C20H26FNO) 315, found 316 (M+H). Anal. 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).
EXAMPLE 27
Figure imgf000182_0001
(Z>2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(3-methyl-l- butenvDpyridine
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. iH NMR (300 MHz, CDCI3): δ
7.07 (m, 4 H), 5.92 (d, / = 10.7 Hz, 1 H), 5.20 (dd, / = 10.7, 11.4 Hz, 1 H), 4.42 (bs, 2 H), 3.45 (sept, / = 6.6 Hz, 1 H), 3.30 (sept, / = 6.6 Hz, 1 H), 2.06 (m, 1 H), 1.35 (d, / = 6.6 Hz, 6 H), 1.31 (m, 1 H), 1.24 ( , 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).
EXAMPLE 28
Figure imgf000182_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(4-methyl-l- pentenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate,
4-fluorobenzaldehyde and isoamyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product is obtained as a 6:4 mixture of trans is isomers. JH NMR (300 MHz, CDCI3): δ 7.11 (m, 4 H), 6.04 (dt,
/ = 1.5, 11 Hz, 0.4 H), 5.96 (dt, / = 1.5, 16 Hz, 0.6 H), 5.47 (dt, / = 7, 11 Hz, 0.4 H), 5.32 (dt, / = 7, 16 Hz, 0.6 H), 4.41 (m, 2 H), 3.44 (m, 0.8 H), 3.38 (sept, / = 6.6 Hz, 0.6 H), 3.24 (sept, / = 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, / = 6.6 Hz, 2.4 H), 0.73 (d, / = 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 acetate/hexane).
EXAMPLE 29
Figure imgf000183_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(3-methylbutyl)pyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-
(4-fluorophenyl)-5-(3-methyl-l-butenyl)pyridine (Example 27) according to the procedure described in Example 1, Step H. iH NMR (300 MHz, CDCI3): δ 7.14 (m,
4 H) 4.33 (d, / = 5.5 Hz, 2 H), 3.41 (sept, / = 6.6 Hz, 1 H), 3.22 (sept, / = 6.6 Hz, 1 H), 2.27 (m, 2 H), 1.35 (m, 1 H), 1.33 (d, / = 7 Hz, 6 H), 1.30 (d, / = 7 Hz, 6 H), 1.17 (m, 3 H), 0.70 (d, / = 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). EXAMPLE 30
Figure imgf000184_0001
2,6-DiisopropyI-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-methylpentyl)pyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-
(4-fluoroρhenyl)-5-(4-methyl-l-pentenyl)pyridine (Example 28) according to the procedure described in Example 1, Step H. iH NMR (300 MHz, CDCI3): δ 7.14 (m,
4 H), 4.33 (d, / = 5 Hz, 2 H), 3.41 (sept, / = 6.6 Hz, 1 H), 3.22 (sept, / = 6.6 Hz, 1 H), 2.23 (m, 2 H), 1.38 (m, 1 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.30 (d, / = 6.6 Hz, 6 H), 1.27 (m, 1 H), 1.17 (m, 1 H), 1.00 (m, 3 H), 0.76 (d, / = 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).
EXAMPLE 31
Figure imgf000184_0002
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(cvclopentyl- idenemethylene)pyridine
The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and cyclopentyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. H NMR (300 MHz, CDCI3): δ 7.13 (m, 2 H), 7.07 (m, 2 H), 5.88 (s, 1 H), 4.43 (d, / = 5.5 Hz, 2 H), 3.44 (sept, / = 6.6 Hz, 1 H), 3.21 (sept, / = 6.6 Hz, 1 H), 2.11 (m, 2 H), 1.75 (m, 2 H), 1.47 (m, 4 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.29 (m, 1 H), 1.21 (d, / = 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).
EXAMPLE 32
Figure imgf000185_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(l-heptenyl)-pyridine
The 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. iH NMR (300 MHz, CDCI3): δ 7.11 (m, 4 H), 5.99 (m, 1 H), 5.42 (dt, / = 7, 11 Hz, 0.5 H), 5.30 (dt, / = 7, 16 Hz, 0.5 H), 4.41 (d, / = 5.5 Hz, 2 H), 3.45 (m, 1 H), 3.37 (sept, / = 6.6 Hz, 0.5 H), 3.24 (sept, / = 6.6 Hz, 0.5
H), 1.94 (m, 1 H), 1.35 (m, 6 H), 1.29 (m, 1 H), 1.26 (d, / = 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. Calcd for C25H34FNO: 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).
EXAMPLE 33
Figure imgf000185_0002
2,6-Diisopropyl-3-hvdroxymethyl-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 mixture 1:1 trans is isomers; gummy oil. XH NMR (300 MHz, CDCI3): δ 7.11 (m, 4
H), 5.98 (m, 1 H), 5.42 (dt, / = 7, 11 Hz, 0.5 H), 5.30 (dt, / = 7, 16 Hz, 0.5 H), 4.41 (d, / = 5.5 Hz, 2 H), 3.44 (m, 1 H), 3.37 (sept, / = 6.6 Hz, 0.5 H), 3.24 (sept, / = 6.6 Hz, 0.5 H), 1.94 (m, 1 H), 1.35 (m, 6 H), 1.30 (m, 1 H), 1.26 (d, / = 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)
EXAMPLE 34
Figure imgf000186_0001
26-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[2(E)-phenyl- 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. iH NMR (300
MHz, CDCI3): δ 7.21 (m, 9 H), 6.70 (d, / = 16.5 Hz, 1 H), 6.26 (d, / = 16.5 Hz, 1 H),
4.45 (d, / = 5.5 Hz, 2 H), 3.48 (sept, / = 6.6 Hz, 2 H), 1.37 (d, / = 6.6 Hz, 6 H), 1.31 (d, / = 6.6 Hz, 6 H), 1.29 (m, 1 H). FAB-MS: calculated for (C26H28FNO) 389, found 390 (M+H). Anal. Calcd for C26H28FNO: 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). EXAMPLE 35
Figure imgf000187_0001
2,6-Diisoρropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-heptylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-fluorophenyl)-5-(l-heptenyl)pyridine (Example 32) according to the procedure described in Example 1, Step H. iH NMR (300 MHz, CDCI3): δ 7.13 (m, 4 H), 4.33
(s, 2 H), 3.41 (sept, / = 6.6 Hz, 1 H), 3.22 (sept, / = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.30 (d, / = 6.6 Hz, 6 H), 1.22 (m, 3 H), 1.11 (m, 8 H), 0.85 (t, / = 7 Hz, 3 H). FAB-MS: calculated for (C25H36FNO) 385, found 386 (M+H). Anal. Calcd for 25H36F O: 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).
EXAMPLE 36
Figure imgf000187_0002
2-6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-octylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-fluorophenyl)-5-(l-octenyl)pyridine (Example 33) according to the procedure described in Example 1, Step H. H NMR (300 MHz, CDCI3): δ 7.14 (m, 4 H), 4.33
(d, / = 5.5 Hz, 2 H), 3.41 (sept, / = 6.6 Hz, 1 H), 3.23 (sept, / = 6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.30 (d, / = 6.6 Hz, 6 H), 1.25 (m, 3 H), 1.15 (m, 10 H), 0.87 (t, / = 7 Hz, 3 H). FAB-MS: calculated for (C26H38FNO) 399, found 400 (M+H). Anal. Calcd for C26H38FNO: 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).
EXAMPLE 37
Figure imgf000188_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyI)-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. iH NMR (300 MHz, CDCI3): δ 7.19 (m,
7 H), 6.86 (m, 2 H), 4.36 (d, / = 5.5 Hz, 2 H), 3.44 (sept, / = 6.6 Hz, 1 H), 3.35 (sept, / = 6.6 Hz, 1 H), 2.58 (m, 4 H), 1.35 (d, / = 6.6 Hz, 6 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.19 (t, / = 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).
EXAMPLE 38
Figure imgf000188_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(4-phenyl-l- butenvDpyridine
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. H NMR (300 MHz, CDCI3): δ 7.26 (m, 2 H), 7.19 (m, 1 H), 7.09 (m, 6 H), 6.05 (d, / = 11 Hz, 0.2 H), 5.98 (d, / = 16 Hz, 0.8 H), 5.47 (dt, / = 7, 11 Hz, 0.2 H), 5.33 (dt, / = 7, 16 Hz, 0.8 H), , 4.40 (d, / = 5 Hz, 2 H), 3.43 (m, 1 H), 3.26 (sept, / = 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, / = 6.6 Hz, 6 H). FAB-MS: calculated for (C28H32FNO) 417, found 418 (M+H). Anal. Calcd for C28H32FNO: 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) .
EXAMPLE 39
Figure imgf000189_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(4-phenylbutyl)pyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-
(4-fluorophenyl)-5-(4-phenyl-l-butenyl)pyridine (Example 38) according to the procedure described in Example 1, Step H. Gummy oil; iH NMR (300 MHz,
CDCI3): δ 7.24 (m, 3 H), 7.08 (m, 6 H), 4.31 (d, / = 5.5 Hz, 2 H), 3.40 (sept, / = 6.6 Hz,
1 H), 3.17 (sept, / = 6.6 Hz, 1 H), 2.46 (t, / = 7.5 Hz, 2 H), 2.29 (m, 2 H), 1.47 (m, 2 H), 1.32 (d, / = 6.6 Hz, 6 H), 1.30 (m, 2 H), 1.27 (d, / = 6.6 Hz, 6 H), 1.15 (t, / = 5.5 Hz, 1 H). FAB-MS: calculated for (C28H34FNO) 419, found 420 (M+H). Anal. Calcd for C28H34FNO: 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).
EXAMPLE 40
Figure imgf000189_0002
2,6-Diisopropyl-3-hvdroxymethvI-4-(4-fluorophenyl)-5-[2(E)-(2-methyl- phenvDethenyllpyridine
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. H NMR (300 MHz, CDCI3): δ 7.22 (m, 3 H), 7.10 (m, 5 H), 6.62 (d, / = 17 Hz, 1 H), 6.45 (d, / = 17
Hz, 1 H), 4.45 (d, / = 5.5 Hz, 2 H), 3.48 (m, 2 H), 2.12 (s, 3 H), 1.37 (d, / = 6.6 Hz, 6 H), 1.33 (d, / = 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).
EXAMPLE 41
Figure imgf000190_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-[2(E)-(3-methyl- phenvDethenyllpyridine
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. iH NMR (300 MHz, CDCI3): δ 7.18 (m, 3 H), 7.11 (m, 2 H), 7.00 (m, 3 H), 6.68 (d, / = 17 Hz, 1 H),
6.23 (d, / = 17 Hz, 1 H), 4.44 (d, / = 5.5 Hz, 2 H), 3.47 (m, 2 H), 2.32 (s, 3 H), 1.37 (d, / = 6.6 Hz, 6 H), 1.31 (d, / = 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 acetate/hexane). EXAMPLE 42
Figure imgf000191_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-f2(E)-(4-methyl- phenyl)ethenyl]pyridine
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. iH NMR (300 MHz, CDCI3): δ 7.18 (m, 2 H), 7.08 (m, 6 H), 6.63 (d, J = 17 Hz, 1 H), 6.23 (d, / = 17
Hz, 1 H), 4.43 (d, / = 5 Hz, 2 H), 3.47 (sept, / = 6.6 Hz, 2 H), 2.31 (s, 3 H), 1.36 (d, / = 6.6 Hz, 6 H), 1.30 (d, / = 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, 80.36; 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).
EXAMPLE 43
Figure imgf000191_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-[2-(2-methyI- 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) according to the procedure described in Example 1, Step H. iH NMR (300 MHz, CDCI3): δ 7.16 (m, 4 H), 7.06 (m, 3 H), 6.81 (m, 1 H), 4.35 (d, / = 4 Hz, 2 H), 3.42 (sept, / = 6.6 Hz, 2 H), 2.57 (m, 4 H), 1.97 (s, 3 H), 1.36 (d, / = 6.6 Hz, 6 H), 1.35 (d, / = 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).
EXAMPLE 44
Figure imgf000192_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-f2-(3-methyl- phenyl)ethyl]pyridine
The title compound was prepared 2,6-diisopropyl-3-hydroxymethyl-4-(4- fluorophenyl)-5-[2(E)-(3-methylphenyl)ethenyl]pyridine (Example 41) according to the procedure described in Example 1, Step H. H NMR (300 MHz, CDCI3): δ 7.18 (d, / = 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, / = 6.6 Hz, 1 H), 3.35 (d, / = 6.6 Hz, 1 H), 2.57 (m, 4 H), 2.28 (s, 3 H), 1.35 (d, / = 6.6 Hz, 6 H), 1.34 (d, / = 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. Rf = 0.3 (20% ethyl acetate/hexane).
EXAMPLE 45
Figure imgf000192_0002
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenvI)-5-f2-(4-methyl- phenvDethyllpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-
(4-fluorophenyl)-5-[2(E)-(4-methylphenyl)ethenyl]pyridine (Example 42) according to the procedure described in Example 1, Step H. iH NMR (300 MHz, CDCI3): δ
7.17 (m, 4 H), 7.02 (d, / = 7.7 Hz, 2 H), 6.75 (d, / = 7.7 Hz, 2 H), 4.36 (d, / = 4 Hz, 2 H), 3.43 (sept, / = 6.6 Hz, 1 H), 3.34 (sept, / = 6.6 Hz, 1 H), 2.55 (m, 4 H), 2.29 (s, 3 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.33 (d, / = 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, 79.40; H, 7.84; N, 3.44. mp 121-123'C. Rf = 0.3 (20% ethyl acetate/hexane).
EXAMPLE 46
Figure imgf000193_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-[3-(l,3-dioxolan-2- vDpropyllpyridine
The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and [2-(l,3-dioxolan-2-yl)ethyl]triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. iH NMR
(300 MHz, CDCI3): δ 7.16 (m, 4 H), 4.63 (t, / = 4 Hz, 1 H), 4.33 (d, / = 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). EXAMPLE 47
Figure imgf000194_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[(phenylthio)- methyllpyridine
Step A: Methyl 2,6-diisopropyl-4-(4-fluoropheny l)-5-hydroxymethy 1-3- pyridinecarboxylate 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 (MgSθ4) and concentrated. Purification by chromatography through silica (5% diethyl ether/hexane) gave a white solid (20.6 g, 50.5 mmol, 87%). iH NMR (300 MHz, CDCI3): δ 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-hydroxymethyl-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, 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 treated with 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 (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%). iH NMR (300 MHz, CDC13): δ 7.23 (m, 5 H), 7.11 (m, 4 H), 4.36 (d, / = 5.5 Hz, 2 H), 3.81 (s, 2 H),
3.45 (sept, / = 6.6 Hz, 1 H), 3.43 (sept, / = 6.6 Hz, 1 H), 1.35 (d, / = 6.6 Hz, 6 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.21 (t, / = 5.5 Hz, 1 H). FAB-MS calcd for (C25H28FNOS) 409, found 410 (M+H). Anal. Calcd for C25H28FNOS: 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).
EXAMPLE 48
Figure imgf000195_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-f((3-trifluoro- methyDphenyDthiolmethylpyridine
The title compound was prepared from 3-trifluoromethyl-thiophenol according to the procedures described in Example 47. H NMR (300 MHz, CDCI3): δ 7.34 (m, 2 H), 7.24 (m, 4 H), 7.10 (m, 2 H), 4.36 (d, / = 5.5 Hz, 2 H), 3.85 (s, 2 H), 3.45 (sept, / = 6.6 Hz, 1 H), 3.38 (sept, / = 6.6 Hz, 1 H), 1.35 (d, / = 6.6 Hz, 6 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.23 (t, / = 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-llloC. Rf = 0.3 (20% ethyl acetate /hexane) .
Figure imgf000196_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-f(4-fluoro- phenyDthiolmethylpyridine
The title compound was prepared from 4-fluorothiophenol according to the procedures described in Example 47. iH NMR (300 MHz, CDCI3): δ 7.24 (m, 2 H),
7.12 (m, 4 H), 6.93 (m, 2 H), 4.35 (d, / = 5.5 Hz, 2 H), 3.76 (s, 2 H), 3.44 (sept, / = 6.6 Hz, 1 H), 3.40 (sept, / = 6.6 Hz, 1 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.22 (t, / = 5.5 Hz, 1 H). FAB-MS calcd for (C25H27F2NOS) 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, 6.41; N, 3.22; S, 7.39. mp 119-121°C. Rf = 0.3 (20% ethyl acetate/hexane).
EXAMPLE 50
Figure imgf000196_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5- ((4-methyl)- phenyPthiolmethylpyridine The title compound was prepared from p-thiocresol according to the procedures described in Example 47. iH NMR (300 MHz, CDCI3): δ 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, 3 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.22 (t, / = 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, 74.00; H, 7.15; N, 3.36; S, 7.32. mp 90-91 °C. Rf = 0.3 (20% ethyl acetate/hexane).
EXAMPLE 51
Figure imgf000197_0001
2,6-DiisopropyI-3-hydroxymethyl-4-(4-fluorophenyl)-5-(l-naphthylthio)- methylpyridine
The title compound was prepared from 1-naphthalenethiol according to the procedures described in Example 47. H NMR (300 MHz, CDCI3): δ 8.01 (d, / = 8.5
Hz, 1 H), 7.82 (d, / = 8.5 Hz, 1 H), 7.74 (d, / = 8 Hz, 1 H), 7.46 (m, 3 H), 7.34 (m, 1 H), 7.20 (m, 2 H), 7.06 (m, 2 H), 4.34 (d, / = 5.5 Hz, 2 H), 3.82 (s, 2 H), 3.51 (sept, / = 6.6 Hz, 1 H), 3.45 (sept, / = 6.6 Hz, 1 H), 1.36 (d, / = 6.6 Hz, 6 H), 1.35 (d, / = 6.6 Hz, 6 H), 1.19 (t, / = 5.5 Hz, 1 H). FAB-MS calcd for (C29H30FNOS) 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).
EXAMPLE 52
Figure imgf000197_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(2-naphthyl- thio)methylpyridine The title compound was prepared from 2-naphthalenethiol according to the procedures described in Example 47. iH NMR (300 MHz, CDCI3): δ 7.77 (d, / = 9
Hz, 1 H), 7.68 (d, / = 9 Hz, 2 H), 7.52 (d, / = 1.5 Hz, 1 H), 7.45 (m, 2 H), 7.25 (m, 2 H), 7.17 (dd, / = 1.8, 8.5 Hz, 1 H), 7.07 (m, 2 H), 4.35 (d, / = 5.5 Hz, 2 H), 3.91 (s, 2 H), 3.45 (sept, / = 6.6 Hz, 2 H), 1.35 (d, / = 6.6 Hz, 6 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.21 (t, / = 5.5 Hz, 1 H). FAB-MS calcd for (C29H30FNOS) 459, found 460 (M+H). Anal. Calcd for C29H30FNOS: 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).
EXAMPLE 53
Figure imgf000198_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[(2,3,5,6-tetra- fluorophenvOthiolmethylpyridine The title compound was prepared from pentafluorothiophenol according to the procedures described in Example 47. iH NMR (300 MHz, CDCI3): δ 7.27 (m, 2
H), 7.11 (m, 2 H), 6.99 (m, 1 H), 4.35 (d, / = 5.5 Hz, 2 H), 3.84 (s, 2 H), 3.44 (sept, / = 6.6 Hz, 1 H), 3.43 (sept, / = 6.6 Hz, 1 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.23 (t, / = 5.5 Hz, 1 H). FAB-MS calcd for (C25H24F5NOS) 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% ethyl acetate/hexane).
Figure imgf000198_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-[(3-methoxy- phenyl)thio]methylpyridine
The title compound was prepared from 3-methoxybenzenethiol according to the procedures described in Example 47. iH NMR (300 MHz, CDCI3): d 7.24 (m, 2
H), 7.13 (m, 3 H), 6.72 (m, 2 H), 6.62 (m, 1 H), 4.35 (d, / = 5.5 Hz, 2 H), 3.81 (s, 2 H), 3.75 (s, 3 H), 3.44 (sept, / = 6.6 Hz, 1 H), 3.42 (sept, / = 6.6 Hz, 1 H), 1.34 (d, / = 6.6
Hz, 6 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.23 (t, / = 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).
EXAMPLE 55
Figure imgf000199_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[(4-hvdroxy- phenyDthiolmethylpyridine
The title compound was prepared from 4-hydroxythiophenol according to the procedures described in Example 47. iH NMR (300 MHz, 5:1 CDCI3/CD3OD): δ 7.15 (m, 2 H), 7.06 (m, 2 H), 6.97 (d, / = 8.5 Hz, 2 H), 6.64 (d, / = 8.5 Hz, 2 H), 4.27 (s, 2 H), 3.66 (s, 2 H), 3.40 (m, 2 H), 1.29 (d, / = 6.6 Hz, 6 H), 1.28 (d, / = 6.6 Hz, 6 H). FAB-MS calcd for (C25H28FNO2S) 425, found 426 (M+H). Anal. Calcd for 25H28FNO2S: 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). EXAMPLE 56
Figure imgf000200_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-f(4-methoxy- phenvDthiolmethylpyridine
The title compound was prepared from 4-methoxybenzenethiol according to the procedures described in Example 47. H NMR (300 MHz, CDCI3): δ 7.23 (m, 2
H), 7.12 (m, 4 H), 6.77 (d, / = 9 Hz, 2 H), 4.35 (d, / = 5.5 Hz, 2 H), 3.79 (s, 3 H), 3.73 (s, 2 H), 3.44 (sept, / = 6.6 Hz, 2 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.21 (t, / = 5.5 Hz, 1 H). FAB-MS calcd for (C26H30F O2S) 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 92-93βC. Rf = 0.4 (20% ethyl acetate/hexane).
EXAMPLE 57
Figure imgf000200_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-[(3-methyl- phenvPthiolmethylpyridine The title compound was prepared from m-thiocresol according to the procedures described in Example 47. iH NMR (300 MHz, CDCI3): δ 7.25 (m, 2 H),
7.11 (m, 3 H), 7.00 (m, 1 H), 6.94 (m, 2 H), 4.36 (d, / = 5.5 Hz, 2 H), 3.81 (s, 2 H), 3.45 (sept, / = 6.6 Hz, 1 H), 3.43 (sept, / = 6.6 Hz, 1 H), 2.28 (s, 3 H), 1.35 (d, / = 6.6 Hz, 6 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.22 (t, / = 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, 73.76; H, 7.09; N, 3.27; S, 7.42. mp 92-93°C. Rf = 0.4 (20% ethyl acetate/hexane).
EXAMPLE 58
Figure imgf000201_0001
2,6-Diisoprop yl-3-hy droxymethyl-4-(4-fluorophenyl)-5- [ (2-methy 1- phenyl)thiolmethylpyridine The title compound was prepared from ø-thiocresol according to the procedures described in Example 47. iH NMR (300 MHz, CDCI3): δ 7.25 (m, 2 H),
7.11 (m, 6 H), 4.36 (d, / = 5.5 Hz, 2 H), 3.74 (s, 2 H), 3.45 (sept, / = 6.6 Hz, 2 H), 2.26 (s, 3 H), 1.35 (d, / = 6.6 Hz, 12 H), 1.21 (t, / = 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).
EXAMPLE 59
Figure imgf000201_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-[(3-fluoro- phenyDthiolmethylpyridine The title compound was prepared from 3-fluorothiophenol according to the procedures described in Example 47. iH NMR (300 MHz, CDCI3): δ 7.27 (m, 3 H),
7.11 (m, 2 H), 6.87 (m, 2 H), 6.78 (m, 1 H), 4.36 (d, / = 5.5 Hz, 2 H), 3.82 (s, 2 H), 3.45 (sept, / = 6.6 Hz, 1 H), 3.38 (sept, / = 6.6 Hz, 1 H), 1.35 (d, / = 6.6 Hz, 6 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.23 (t, / = 5.5 Hz, 1 H). FAB-MS calcd for (C25H27F2NOS) 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).
EXAMPLE 60
Figure imgf000202_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-f(2-methoxy- phen yl ) thiol methylpyridine The title compound was prepared from 2-methoxythiophenol according to the procedures described in Example 47. XH NMR (300 MHz, CDCI3): δ 7.22 (m, 3
H), 7.07 (m, 3 H), 6.83 (m, 2 H), 4.34 (d, / = 5.5 Hz, 2 H), 3.78 (s, 3 H), 3.75 (s, 2 H), 3.49 (sept, / = 6.6 Hz, 1 H), 3.43 (sept, / = 6.6 Hz, 1 H), 1.34 (d, / = 6.6 Hz, 12 H), 1.19 (t, / = 5.5 Hz, 1 H). FAB-MS calcd for (C26H30FNO2S) 339, found 440 (M+H). Anal. Calcd for C26H30 NO2S: 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).
Figure imgf000202_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-f(3,5-dimethyl- phenyl)thio1methylpyridine
The title compound was prepared from 3,5-dimethylthiophenol according to the procedures described in Example 47. iH NMR (300 MHz, CDCI3): δ 7.24 (m, 2
H), 7.11 (m, 2 H), 6.80 (s, 1 H), 6.69 (s, 2 H), 4.35 (d, / = 5.5 Hz, 2 H), 3.79 (s, 2 H), 3.44 (sept, / = 6.6 Hz, 1 H), 3.42 (sept, / = 6.6 Hz, 1 H), 2.23 (s, 6 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.21 (t, / = 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).
Figure imgf000203_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[(4-ethyl- phenyl)thiolmethylpyridine
The title compound was prepared from 4-ethylthiophenol according to the procedures described in Example 47. iH NMR (300 MHz, CDCI3): δ 7.24 (m, 2 H),
7.05 (m, 6 H), 4.35 (d, / = 5.5 Hz, 2 H), 3.77 (s, 2 H), 3.43 (m, 2 H), 2.60 (q, / = 7.7 Hz, 2 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.32 (d, / = 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). EXAMPLE 63
Figure imgf000204_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-.(4-isopropyl- phenyDthiolmethylpyridine
The title compound was prepared from 4-isopropylthiophenol according to the procedures described in Example 47. iH NMR (300 MHz, CDCI3): δ 7.25 (m, 2
H), 7.06 (m, 6 H), 4.35 (d, / = 5.5 Hz, 2 H), 3.79 (s, 2 H), 3.43 (m, 2 H), 2.86 (sept, / = 7 Hz, 1 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.32 (d, / = 6.6 Hz, 6 H), 1.22 (d, / = 7 Hz, 6 H), 1.20 (t, / = 5.5 Hz, 1 H). FAB-MS calcd for (C28H34FNOS) 451, found 452 (M+H). Anal. Calcd for C28H34FNOS: 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).
EXAMPLE 64
Figure imgf000204_0002
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. H NMR (300 MHz, CDCI3): δ 7.23 (m, 5 H),
7.08 (m, 4 H), 4.31 (d, / = 5.5 Hz, 2 H), 3.55 (s, 2 H), 3.40 (sept, / = 6.6 Hz, 1 H), 3.24 (s, 2 H), 3.19 (sept, / = 6.6 Hz, 1 H), 1.31 (d, / = 6.6 Hz, 6 H), 1.24 (d, / = 6.6 Hz, 6 H), 1.17 (t, / = 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; H, 7.25; N, 3.05; S, 7.45. mp 150-151°C. Rf = 0.5 (20% ethyl acetate/hexane).
EXAMPLE 65
Figure imgf000205_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-f(phenethyl)- thiomethyllpyridine
The title compound was prepared from phenethyl mercaptan according to the procedures described in Example 47. H NMR (300 MHz, CDCI3): δ 7.28 (m, 5
H), 7.11 (m, 4 H), 4.34 (d, / = 5.5 Hz, 2 H), 3.39 (m, 4 H), 2.70 (m, 2 H), 2.61 (m, 2 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.32 (d, / = 6.6 Hz, 6 H), 1.20 (t, / = 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, 73.99; H, 7.46; N, 2.96; S, 7.23. Gummy oil. Rf = 0.5 (20% ethyl acetate/hexane).
EXAMPLE 66
Figure imgf000205_0002
2,6-Diisopropyl-3-hvdroxymethyl-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, CDCI3): δ 7.30 (m, 2 H), 7.14 (m, 2 H), 4.34 (d, / = 5.5 Hz, 2 H), 3.41 (m, 2 H), 3.37 (m, 2 H), 2.31 (t, / = 7.0 Hz, 2 H), 1.31 (m, 15 H), 0.89 (t, / = 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).
EXAMPLE 67
Figure imgf000206_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyI)-5-(methylthio)- methylpyridine
The title compound was prepared from methyl mercaptan according to the procedures described in Example 47. JH NMR (300 MHz, CDCI3): δ 7.30 (m, 2 H),
7.16 (m, 2 H), 4.35 (d, / = 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 (C20H26NFOS) 347, found 348 (M+H). Anal. Calcd for C20H26NOFS: 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).
EXAMPLE 68
Figure imgf000206_0002
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-f(4-nitrophenyl)- thiolmethylpyridine Step A: 2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-
[(t-butyldimethylsiloxy)methyl]pyridine
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- dimethylaminopyridine (50 mg, 0.4 mmol) and f-butyldimethylsilyl chloride (1.4 g,
9.3 mmol). The reaction mixture was allowed to stir at room temperature for 48 hr.
The solution was diluted with diethyl ether (200 mL) and washed with water (2 x
100 mL), IN HC1 (100 mL), sat. NaHCθ3 (50 mL) and brine (100 mL), dried
(MgSθ4) 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%). iH NMR (300 MHz, CDCI3) δ 7.25 (m, 2 H), 7.12 (m, 2 H),
4.38 (d, / = 5 Hz, 2 H), 4.28 (s, 2 H), 3.44 (sept, / = 6.6 Hz, 1 H), 3.39 (sept, / = 6.6 Hz, 1 H), 1.33 (t, / = 6.6 Hz, 12 H), 1.24 (t, / = 5.5 Hz, 1 H), 0.84 (s, 9 H), -0.08 (s, 6 H). FAB-MS calcd for (C25H38FNSiθ2) 431, found 432 (M+H). Anal. Calcd for C25H38FNSiθ2: 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-Diisoproρyl-3-bromomethyl-4-(4-fluorophenyl)-5- [(f-butyldimethylsiloxy)methyl]pyridine
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 vacuo and the residue partitioned between diethyl ether (150 mL) and water (100 mL). The ether layer was washed with brine (50 mL), dried (MgSθ4) and concentrated.
Purification by chromatography through silica (5% diethyl ether/hexane) afforded a viscous oil (1.4 g, 2.8 mmol, 72%) which slowly solidified on standing: iH NMR (300 MHz, CDCI3): δ 7.28 (m, 2 H), 7.13 (m, 2 H), 4.23 (m, 4 H), 3.37 (m, 2 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.30 (d, / = 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). Step C: 2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-f(4- nitrophenyDthiolmethylpyridine 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 4-nitiothiophenol (118 mg, 0.6 mmol, 80% tech. grade) and ZV-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 THF) and allowed to stir at room temperature for 24 hr. The solvent was removed in vacuo, the residue dissolved in ethyl acetate (100 mL), washed with IN HCl (50 mL), sat. NaHCθ3 (50 mL) and brine (50 mL), dried (MgSθ4) 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%). iH NMR (300 MHz, CDCI3): δ 8.08 (d, / = 8.5 Hz, 2 H), 7.27 (m, 2 H), 7.13 (m, 4 H),
4.37 (d, / = 5.5 Hz, 2 H), 3.91 (s, 2 H), 3.46 (sept, / = 6.6 Hz, 1 H), 3.33 (sept, / = 6.6 Hz, 1 H), 1.35 (d, / = 6.6 Hz, 6 H), 1.34 (d, / = 6.6 Hz, 6 H), 1.27 (t, / = 5 Hz, 1 H). FAB-MS calcd for (C25H27FSN2O3) 454, found 455 (M+H). mp 178-180°C. Rf = 0.3
(20% ethyl acetate/hexane).
EXAMPLE 69
Figure imgf000208_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyI)-5-(morpholino- methyPpyridine
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 CH2CI2 (20 mL) was treated with morpholine (0.14 mL, 1.61 mmol) under argon. The reaction was stirred at room temperature for 48 hours. It was then diluted with CH2CI2 (70 mL), washed with saturated NaHCθ3 (2 x 40 mL), water (1 x 40 mL), and brine (1 x 40 mL). The organic layer was dried with MgSθ4, filtered, and concentrated to afford a white solid (495 mg, 1.2 mmol, 98%). iH NMR (300 MHz, CDCI3): δ 7.16 (m, 2 H), 7.07 (m, 2 H), 3.54 (t, / = 4.4 Hz, 4 H), 3.49 (m, 4 H), 3.27 (s, 2 H), 2.98 (septet, / = 6.6 Hz, 1 H), 2.19 (t, / = 4.8 Hz, 4 H), 1.30 (m, 12 H). FAB-MS calcd for (C24H31N2FO3) 414, found 415 (M+H); Anal. Calcd for C24H31N2O3F: 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-hvdroxymethyl-4-(4-fluorophenyl)-5-
(morpholinomethyl)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 (1M/THF, 1.81 mL) and the reaction stirred at reflux for 24 hours. The reaction was quenched by the successive dropwise addition of water (0.1ml), NaOH 20% (0.1ml), and water again (0.3ml). Concentration in vacuo afforded a white residue which was partitioned between CH2CI2 and water. The organic layer was dried with MgSθ4, 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%). iH NMR (300 MHz, CDCI3): δ 7.14 (m, 4 H), 4.35 (d, 2 H), 3.53 (t, / = 4.8 Hz, 4 H), 3.45 (m, 2 H), 3.18 (s, 2 H), 2.18 (t, / = 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 Found: C, 71.55; H, 8.16; N, 7.05; F, 4.70. mp 93.5-95.5°C. Rf = 0.4 (40% diethyl ether /hexane).
EXAMPLE 70
Figure imgf000209_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(piperidinomethyl)pyridine
The title compound was prepared from piperidine according to the procedures described in Example 69. JH NMR (300 MHz, CDCI3): δ 7.05 (m, 4
H), 4.27 (d, / = 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).
EXAMPLE 71
Figure imgf000210_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(pyrroIidino- methvDpyridine The title compound was prepared from pyrrolidine according to the procedures described in Example 69. iH NMR (300 MHz, CDCI3): δ 7.13 (m, 4
H), 4.34 (d, / = 4.8 Hz, 2 H), 3.52 (septet, / = 6.6 Hz, 1 H), 3.42 (septet, / = 6.6 Hz, 1 H), 3.28 (s, 2 H), 2.22 (t, / = 6.3 Hz, 4 H), 1.60 (t, / = 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).
EXAMPLE 72
Figure imgf000210_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-[4-phenylpiperidin-l- vDmethyllpyridine
The title compound was prepared from 4-phenylpiperidine according to the procedures described in Example 69. iH NMR (300 MHz, CDCI3): δ 7.29 (m, 2 H),
7.15 (m, 7 H), 4.36 (d, / = 5.2 Hz, 2 H), 3.48 (m, 2 H), 3.19 (s, 2 H), 2.71 (d, / = 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 C23H31N2OF:
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).
EXAMPLE 73
Figure imgf000211_0002
Figure imgf000211_0001
MethyI-2,6-diisopropyl-4-(4-fluorophenyl)-5-(4-piperidinopiρeridin-l-yl)methyl-3- pyridinecarboxylate
The title compound was prepared from 4-piperdinopiperidine according to the procedure described in Example 69 (Step A). iH NMR (300 MHz, CDCI3): δ
7.16 (m, 2 H), 7.04 (m, 2 H), 3.51 (septet, / = 5.5 Hz, 1 H), 3.47 (s, 3 H), 3.20 (s, 2 H), 2.98 (septet, / = 6.6 Hz, 1 H), 2.65 (d, / = 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). FAB-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). EXAMPLE 74
Figure imgf000212_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-f(4-piperid-nopiperidin-l- yPmethyπpyridine
The title compound was prepared from 4-piperidinopiperidine according to the procedures described in Example 69. XH NMR (300 MHz, CDCI3): δ 7.12 (m, 4
H), 4.34 (d, / = 3.7 Hz, 2 H), 3.45 (m, 2 H), 3.10 (m, 2 H), 2.63 (d, / = 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, found 468 (M+H). Anal. Calcd for C29H42N3OF: 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 (50% diethyl ether/hexane + 2 drops of MeOH).
EXAMPLE 75
Figure imgf000212_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-f(4-phenylpiperazin-l- yPmethyllpyridine The title compound was prepared from 4-phenylpiperazine according to the procedures described in Example 69. iH NMR (300 MHz, CDCI3): δ 7.16 (m, 6 H),
6.85 (m, 3 H), 4.36 (d, / = 5.2 Hz, 2 H), 3.47 (m, 2 H), 3.24 (s, 2 H), 3.04 (t, / = 4.8 Hz, 4 H), 2.35 (t, / = 4.8 Hz, 4 H), 1.29 (m, 13 H). FAB-MS calcd for (C29H36N3FO) 461, found 462 (M+H). Anal. Calcd for C29H36N3OF: C, 75.46; H, 7.86; N, 9.10; F, 4.12. Found: C, 75.35; H, 7.82; N, 8.80; F, 3.99. mp 111-113°C. Rf = 0.5 (40% diethyl ether /hexane).
EXAMPLE 76
Figure imgf000213_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(imidazol-l-yl)- methylpyridine
The title compound was prepared from imidazole according to the procedures described in Example 69. XH NMR (300 MHz, CDCI3): δ 7.01 (m, 6
H), 6.57 (s, 1 H), 4.84 (s, 2 H), 4.39 (s, 2H), 3.49 (septet, / = 6.6 Hz, 1 H), 3.23 (septet, /
= 6.6 Hz, 1 H), 1.70 (s, 1 H), 1.36 (d, / = 6.6 Hz, 6 H), 1.27 (d, / = 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).
EXAMPLE 77
Figure imgf000213_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(cyclopropyl- amino)methylpyridine
The title compound was prepared from cyclopropylamine according to the procedures described in Example 69. iH NMR (300 MHz, CDCI3): δ 7.04 (m, 4 H),
4.21 (s, 2 H), 3.35 (s, 2 H), 3.26 (septet, / = 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 (C22H29N2FO) 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).
EXAMPLE 78
Figure imgf000214_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(cyclohexyl- amino)methylpyridine
The title compound was prepared from cyclohexylamine according to the procedures described in Example 69. iH NMR (300 MHz, CDCI3): δ 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 (C25H35N2FO) 398, found 399 (M+H). Anal. Calcd for C25H35N2OF: 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).
EXAMPLE 79
Figure imgf000214_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(dimethylamino)- methylpyridine The title compound was prepared from dimethylamine hydrochloride according to the procedures described in Example 69. H NMR (300 MHz, CDCI3): δ 7.12 (m, 4 H), 4.25 (m, 2 H), 4.09 (m, 1 H), 3.68 (septet, / = 6.6 Hz, 1 H), 3.41
(septet, / = 6.6 Hz, 1 H), 2.18 (m, 1 H), 1.69 (d, / = 4.1 Hz, 1 H), 1.26 (m, 12 H), 0.947 (d, / = 6.3 Hz, 3 H), 0.555 (d, / = 7.0 Hz, 1 H). FAB-MS calcd for (C22H30 FO2) 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 77-79°C. Rf = 0.2 (40% diethyl ether /hexane).
EXAMPLE 80
Figure imgf000215_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(,dibutylamino)- methylpyridine The title compound was prepared from dibutylamine according to the procedures described in Example 69. XH NMR (300 MHz, CDCI3): δ 7.11 (m, 4 H),
4.33 (d, / = 5.5 Hz, 2 H), 3.62 (septet, / = 6.6 Hz, 1 H), 3.62 (septet, / = 6.6 Hz, 1 H), 3.24 (s, 2 H), 2.12 (t, / = 7.0 Hz, 4 H), 1.55 (s, 1 H), 1.33 (t, / = 6.6 Hz, 6 H), 1.26 (t, / = 6.6 Hz, 6 H), 1.16 (m, 8 H), 0.796 (t, / = 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).
Figure imgf000215_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(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 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 chromatography through silica (5% ethyl acetate/hexane) afforded the title compound as a white solid (182 mg, 0.6 mmol, 85%). JH NMR (300 MHz, CDCI3): δ 7.15 (d, / = 7 Hz, 4 H), 4.36 (d, / = 5.5 Hz, 2 H), 3.42 (sept, / = 6.6 Hz, 1 H), 3.26
(sept, / = 6.6 Hz, 1 H), 1.94 (s, 3 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.29 (d, / = 6.6 Hz, 6 H), 1.19 (t, / = 5.5 Hz, 1 H); FAB-MS calcd for (C19H24FNO) 301, found 302 (M+H). Anal. Calcd for C19H24FNO: 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).
EXAMPLE 82
Figure imgf000216_0001
2,6-Diisopropyl-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 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 dried with MgSθ4. 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 with water (50 ml), brine (50 ml), dried with MgSθ4 and evaporated in vacuo. Flash chromatography (10% ethyl acetate/hexane) afforded 335 mg (0.9 mmol, 32%) of product. iH NMR (300 MHz, CDCI3): δ 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, found 372 (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-hvdroxymethyl-4-(4-fluorophenyl)-5-(3-phenyl-2- propenyl)pyridine The title compound was prepared from the intermediate obtained in Step A and benzyl triphenylphosphonium bromide /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. αH NMR (300 MHz, CDCI3): δ 7.19 (m, 8 H), 6.96 (m,
1 H), 6.32 (d, / = 11 Hz, 0.4 H), 6.09 (dt, / = 5.5, 16 Hz, 0.6 H), 5.96 (d, / = 16 Hz, 0.6 H), 5.45 (dt, / = 7, 11 Hz, 0.4 H), 4.37 (d, / = 5 Hz, 1.25 H), 4.33 (d, / = 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, / = 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).
Figure imgf000217_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(3-ρhenyl-propyl)ρyridine
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. iH NMR (300 MHz, CDCI3): δ 7.11 (m,
9 H), 4.31 (s, 2 H), 3.40 (sept, / = 6.6 Hz, 1 H), 3.12 (sept, / = 6.6 Hz, 1 H), 2.46 (t, / = 7.35 Hz, 2 H), 2.29 (m, 2 H), 1.62 (m, 2 H), 1.32 (d, / = 6.6 Hz, 6 H), 1.26 (d, / = 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).
EXAMPLE 84
Figure imgf000218_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-f3-(2-methyl- phenyDpropyllpyridine
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. iH NMR (300 MHz, CDCI3): δ 7.07 (m, 7 H),
6.90 (m, 1 H), 4.31 (s, 2 H), 3.39 (sept, / = 6.6 Hz, 1 H), 3.15 (sept, / = 6.6 Hz, 1 H), 2.43 (t, / = 7.5 Hz, 2 H), 2.34 (m, 2 H), 2.17 (s, 3 H), 1.56 (m, 2 H), 1.31 (d, / = 6.6 Hz, 6 H), 1.27 (d, / = 6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C28H34FNO) 419, found 420 (M+H). Anal. Calcd for C28H34FNO: 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). EXAMPLE 85
Figure imgf000219_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-[3-(3-methyl- phenvDpropyllpyridine
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. H NMR (300 MHz, CDCI3): δ 7.09 (m, 5 H), 6.98 (m, 1 H), 6.78 (m, 2 H), 4.31 (s, 2 H), 3.39 (sept, / = 6.6 Hz, 1 H), 3.12 (sept, / = 6.6 Hz, 1 H), 2.42 (t, / = 7 Hz, 2 H), 2.30 (s, 3 H), 2.28 (m, 2 H), 1.58 (m, 2 H), 1.31 (d, / = 6.6 Hz, 6 H), 1.26 (d, / = 6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C28H34FNO) 419, found 420 (M+H). Anal. Calcd for C28H34FNO: 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) .
EXAMPLE 86
Figure imgf000219_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-f3-(4-methyl- 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 described in Example 1, Steps F-H. H NMR (300 MHz, CDCI3): δ 7.08 (m, 4 H), 7.01 (d, / = 8 Hz, 2 H), 6.85 (d, / = 8 Hz, 2 H), 4.30 (s, 2 H), 3.39 (sept, / = 6.6 Hz, 1 H), 3.13 (sept, / = 6.6 Hz, 1 H), 2.41 (t, / = 7 Hz, 2 H), 2.31 (s, 3 H), 2.27 (m, 2 H), 1.58 (m, 2 H), 1.31 (d, / = 6.6 Hz, 6 H), 1.26 (d, / = 6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C28H34FNO) 419, found 420 (M+H). Anal. Calcd for C28H34FNO: 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).
EXAMPLE 87
Figure imgf000220_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(2-propenyl)-pyridine
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. H NMR (300 MHz, CDCI3): δ 7.13 (m, 4 H), 5.73 (m, 1 H),
4.81 (dd, / = 4.8, 1.8 Hz, 2 H), 4.35 (s, 2 H), 3.43 (septet, / = 6.6 Hz, 1 H), 3.21 (septet, / = 6.6 Hz, 1 H), 3.07 (d, / = 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).
EXAMPLE 88
Figure imgf000220_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(4-hvdroxy-butyl)pyridine
To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[3- (l,3-dioxolan-2-yl)propyl]pyridine (Example 46) (2 g, 5 mmol) in THF (50 mL) was added 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 neutralized to pH 7 with sat. aq. NaHCθ3. The aqueous phase was extracted with diethyl ether (3 x 100 mL), the combined ether extract washed with brine (50 mL), dried (MgSθ4) and concentrated. Purification by chromatography through silica
(step gradient, 10%-20% ethyl acetate/hexane) afforded a white solid (1.5 g, 4.2 mmol, 83%): XH NMR (300 MHz, CDCI3): d 9.57 (s, 1 H), 7.16 (m, 4 H), 4.33 (d, / =
5 Hz, 2 H), 3.42 (m, 1 H), 3.24 (m, 1 H), 2.33 (m, 2 H), 2.27 (dt, / = 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 (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. NaHCθ3. The aqueous phase was extracted with diethyl ether (3 x 50 mL), the combined extracts dried (MgSθ4) 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%): iH NMR (300 MHz, CDCI3): δ 7.16 (m, 4 H), 4.33 (d, / = 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);
EXAMPLE 89
Figure imgf000221_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-f(3-dimethyl- amino)propynpyridine
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. iH NMR (300 MHz, CDCI3): δ 7.17 (m, 4 H),
4.33 (s, 2 H), 3.41 (sept, / = 6.6 Hz, 1 H), 3.21 (sept, / = 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 (C23H33FN2O) 372, found 373 (M+H). mp 50-51°C. Rf = 0.35 (20% ethanol/CH2Cl2). EXAMPLE 90
Figure imgf000222_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-f(3-dimethyl- amino)heptyl1pyridine
Step A: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyD-5-(4- oxobutyPpyridine
To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[3- (l,3-dioxolan-2-yl)propyl]pyridine (Example 46) (2 g, 5 mmol) in THF (50 mL) was added 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 neutralized to pH 7 with sat. NaHCθ3. The aqueous phase was extracted with diethyl ether (3 x 100 mL), the combined ether extract washed with brine (50 mL), dried (MgSθ4) and concentrated. Purification by chromatography through silica
(step gradient, 10%-20% ethyl acetate/hexane) afforded a white solid (1.5 g, 4.2 mmol, 83%). iH NMR (300 MHz, CDCI3): δ 9.57 (s, 1 H), 7.16 (m, 4 H), 4.33 (d, / =
5 Hz, 2 H), 3.42 (m, 1 H), 3.24 (m, 1 H), 2.33 (m, 2 H), 2.27 (dt, / = 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% ethyl acetate/hexane). Step B: 2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-f(3- dimethylamino)heptyllpyridine
The intermediate prepared in Step A was treated with (3- dimethylamino)propyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H, to afford the title compound as a solid. iH NMR (300 MHz, CDCI3): δ 7.16 (m, 4 H), 4.32 (s, 2 H), 3.41 (sept, / = 6.6
Hz, 1 H), 3.22 (sept, / = 6.6 Hz, 1 H), 2.28 (s, 6 H), 2.26 (m, 4 H), 1.43 (m, 2 H), 1.33 (d, / = 6.6 Hz, 6 H), 1.30 (d, / = 6.6 Hz, 6 H), 1.27 (m, 3 H), 1.31 (m, 6 H). FAB-MS: calcd for (C27H41FN2O) 428, found 429 (M+H). mp 85-87°C. Rf = 0.1 (20% EtOH/CH2Cl2).
EXAMPLE 91
Figure imgf000223_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(8-carboxyheptyl)pyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-fluorophenyl)-5-(4-oxobutyl)pyridine (Example 90, Step A) and (4- carboxybutyPtriphenylphosphonium bromide according to the procedure described in Example 90, Step B. iH NMR (300 MHz, CD3OD): δ 7.17 (m, 4 H), 4.23
(s, 2 H), 3.44 (sept, / = 6.6 Hz, 1 H), 3.23 (sept, / = 6.6 Hz, 1 H), 2.28 (m, 2 H), 2.14 (t, / = 7.5 Hz, 2 H), 1.54 (m, 2 H), 1.28 (d, / = 6.6 Hz, 6 H), 1.24 (d, / = 6.6 Hz, 6 H), 1.22 (m, 4 H), 1.17 (m, 2 H), 1.10 (m, 4 H). EI-MS: calcd for (C27H38FNO3) 443, found 443 (M+). mp 240°C (dec). Rf = 0.3 (50% ethyl acetate/hexane). EXAMPLE 92
Figure imgf000224_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenvP-5-(3-carboxypropyl)pyridine To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[3-
(l,3-dioxolan-2-yl)propyl]pyridine (Example 46) (2 g, 5 mmol) in THF (50 mL) was added 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 neutralized to pH 7 with sat. NaHCθ3. The aqueous phase was extracted with diethyl ether (3 x 100 mL), and the combined ether extract washed with brine (50 mL), dried (MgSθ4) 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 mmol). 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. CuSθ4 (10 mL), water (20 mL), sat. NaHCθ3 (20 mL) and brine (10 mL), dried (MgSθ4) 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 Crθ3, 125 mL H2θ 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 CHCI3 (3 x 20 mL).
The combined extract was dried (MgSθ4) and concentrated. Purification by chromatography through silica (1:1 ethyl acetate/hexane) afforded the title compound as a white foam (22 mg). H NMR (300 MHz, CD3OD): δ 7.18 (m, 4 H), 4.24 (s, 2 H), 3.46 (sept, / = 6.6 Hz, 1 H), 3.33 (sept, / = 6.6 Hz, 1 H), 2.34 (m, 2 H), 1.99 (t, / = 7 Hz, 2 H), 1.60 (m, 2 H), 1.29 (d, / = 6.6 Hz, 6 H), 1.26 (d, / = 6.6 Hz, 6 H). FAB-MS: calcd for (C22H28FNO3) 373, found 374 (M+H). mp 160°C. Rf = 0.3 (50% ethyl acetate/hexane).
EXAMPLE 93
Figure imgf000225_0001
(±)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(l-hydroxy- ethvPpyridine
Step A: (±)-Ethyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(l-hydroxy-ethyP-3- pyridinecarboxylate To 5-carboethoxy-2,6-diisopropyl-4-(4-fluoropheny l)-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 MgSθ4, 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%). H NMR (300 MHz, CDCI3): δ 7.14 (m, 4 H), 4.86 (dq, / = 3.7 , / = 6.6 Hz, 1 H), 3.80
(septet, / = 6.6 Hz, 1 H), 3.47 (s, 3 H), 2.96 (septet, / = 6.6 Hz, 1 H), 1.65 (d, / = 3.7 Hz, 1 H), 1.46 (d, / = 6.6 Hz, 3 H), 1.27 (m, 12 H). FAB-MS: calcd for (C21H26NFO3) 359, 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) . Step B: (±)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(l- hydroxyethyPpyridine 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 μL), 20% NaOH (70 μL), and water (140μL). 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%). iH NMR (300 MHz, CDCI3): δ 7.15 (m, 4 H), 4.71 (dq, / = 3.7 , / = 6.6 Hz, 1 H), 4.30 (m, 2 H),
3.79 (septet, / = 6.6 Hz, 1 H), 3.42 (septet, / = 6.6 Hz, 1 H), 1.62 (d, / = 3.68 Hz, 1 H), 1.58 (s, IH), 1.43 (d, / = 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).
EXAMPLE 94
Figure imgf000226_0001
(±)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(l-hydroxy- propyPpyridine
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. JH NMR (300 MHz, CDCI3): δ 7.15 (m, 4 H), 4.40 (dq, / = 3.7 , / = 5.2 Hz, 1 H), 4.30 (d, / = 5.5 Hz,
2 H), 3.72 (septet, / = 6.6 Hz, 1 H), 3.42 (septet, / = 6.6 Hz, 1 H), 1.88 (m, 1 H), 1.63 (t, / = 5.5 Hz, IH), 1.27 (m, 14 H), 0.804 (t, / = 7.36 Hz, 3 H). FAB-MS: calcd for (C21H28NFO2) 345, found 346 (M+H). Anal. Calcd for C21H28NO2F: 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); EXAMPLE 95
Figure imgf000227_0001
(±)-2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyP-5-(l-hydroxy- pentyppyridine
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. iH NMR (300 MHz, CDCI3): δ 7.16 (m, 4 H), 4.49 (m, 1 H), 4.31 (d, / = 5.5 Hz, 2 H), 3.74 (septet, / = 6.6 Hz, 1 H), 3.42 (septet, / = 6.6 Hz, 1 H), 1.88 (m, 1 H), 1.58 (d, / = 3.3 Hz, 1 H), 1.18 (m, 18 H), 0.821 (t, / = 4.1 Hz, 3 H). FAB-MS: calcd for (C23H32NFO2) 373, found 374 (M+H). Anal. Calcd for C23H32NO2F: C, 73.96; H, 8.64; N, 3.75; F, 5.09. Found: C, 73.81; H, 8.60; N, 3.58; F, 5.02. mp 166-168°C. Rf = 0.3 (20% ethyl acetate/hexane).
EXAMPLE 96
Figure imgf000227_0002
(±)-2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenvP-5-(hydroxy- phenylmethyPpyridine
The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4- fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and phenyllithium, according to the procedures described in Example 93. iH NMR (300 MHz, CDCI3): δ 7.23 (m, 7 H), 7.06 (m, 2 H), 5.71 (d, / = 5.14 Hz, 1 H), 4.38 (d, / = 5.5 Hz, 2 H), 3.47 (septet, / = 6.6 Hz, 1 H), 3.12 (septet, / = 6.6 Hz, 1 H), 2.12 (d, / = 5.1 Hz, 1 H), 1.57 (s, IH), 1.29 (m, 10 H), 0.797 (d, / = 6.6 Hz, 3 H). FAB-MS: calcd for (C25H28 FO2) 393, found 394 (M+H). Anal. Calcd for C25H28NO2F: 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 acetate/hexane).
EXAMPLE 97
Figure imgf000228_0001
(±)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-f(l-hydroxy-2- methyPpropyllpyridine
The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4- fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and isopropyl magnesium bromide, according to the procedures described in Example 93. iH NMR (300 MHz, CDCI3): δ 7.14 (m, 4 H), 4.35 (d, 2 H), 3.53 (t, / = 4.8 Hz, 4 H), 3.45
(m, 2 H), 3.18 (s, 2 H), 2.18 (t, / = 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, 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% ethyl acetate/hexane).
EXAMPLE 98
Figure imgf000228_0002
(±)-2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(l-methoxy- ethyPpyridine
Step A: Methyl-2,6-diisopropyl-4-(4-fluorophenyP-5-(2-methoxyethvP-3- pyridinecarboxylate
(±)-Ethyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(l-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 15 min. 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 MgSθ4, 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%). H NMR (300 MHz, CDCI3): δ 7.13 (m, 4 H), 4.25 (q, / = 6.6 Hz, 1 H), 3.80 (septet, / =
6.6 Hz, 1 H), 3.48 (s, 3 H), 3.10 (s, 3 H), 2.97 (septet, / = 6.6 Hz, 1 H), 1.41 (d, / = 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-Diisoprop yl-3-hydroxymethyl-4-(4-fluorophenyP-5-( 1 - methoxyethyPpyridine 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 μL), 20% NaOH (80 μL), and water (160 μL). 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%). H NMR (300 MHz, CDCI3): δ 7.13 (m, 4 H), 4.32 (dq, / = 5.2 / = 11.4 Hz, 1 H), 4.11 (q, / = 6.3 Hz, 1 H), 3.77
(septet, / = 6.6 Hz, 1 H), 3.42 (septet, / = 6.6 Hz, 1 H), 3.10 (s, 3 H), 1.29 (m, 16 H). FAB-MS: calcd for (C21H28FNO2) 345, found 346 (M+H). Anal. Calcd for C21H28NO2F: 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). EXAMPLE 99
Figure imgf000230_0001
(±)-2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(l-methoxy- propyPpyridine
The title compound was prepared from (±)-2,6-diisopropyl-3- hydroxymethyl-4-(4-fluorophenyl)-5-(l-hydroxypropyl)pyridine (Example 94) according to the procedures described in Example 98. iH NMR (300 MHz, CDCI3): δ 7.11 (m, 4 H), 4.32 (m, 2 H), 3.83 (m, 1 H), 3.74 (septet, / = 6.6 Hz, 1 H), 3.41
(septet, / = 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, / = 3.7 Hz, 3 H). FAB-MS: calcd for (C22H30NFO2) 359, found 360 (M+H). Anal. Calcd for C22H30NO2F: C, 73.51; H, 8.41; N, 3.90; F, 5.28. Found: C, 73.55; H, 8.54; N, 3.75; F, 5.06. mp 147-149°C. Rf = 0.5 (20% ethyl acetate/hexane).
EXAMPLE 100
Figure imgf000230_0002
(±)-2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-(l-methoxy- pentyPpyridine
The title compound was prepared from (+)-2,6-diisopropyl-3- hydroxymethyl-4-(4-fluoropheny l)-5-( l-hydroxypentyl)pyridine (Example 95) according to the procedures described in Example 98. JH NMR (300 MHz, CDCI3): δ 7.10 (m, 4 H), 4.32 (m, 2 H), 3.92 (m, 1 H), 3.76 (septet, / = 7.0 Hz, 1 H), 3.42 (septet, / = 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, / = 7.4 Hz, 3 H). FAB-MS: calcd for (C24H34NFO2) 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, 8.82; N, 3.45; F, 4.90. mp 121-123°C. Rf = 0.5 (20% ethyl acetate/hexane).
EXAMPLE 101
Figure imgf000231_0001
(±)-2,6-Diisopropyl-3-(l-hvdroxyethvP-4-(4-fluorophenvP-5-propyl-pyridine
Step A: (±)-2,6-Diisopropyl-4-(4-fIuorophenyl)-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. iH NMR (CDCI3, 300 MHz): δ 9.72 (s, 1 H), 7.15 (m, 4 H), 3.83 (sept, / = 6.6 Hz, 1 H), 3.28
(sept, / = 6.6 Hz, 1 H), 2.31 (m, 2 H), 1.30 (m, 14 H), 0.78 (t, / = 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-(l-hvdroxyethyl)-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 water (2 mL) and the THF is evaporated in vacuo to afford an oil. The product was partitioned between water and CH2CI2 (50 mL) and the organic layer was dried with MgSθ4, filtered, and concentrated to yield a gummy solid. Flash Chromatography using silica gel (60% CH2CI2/ hexane) to afford an oil which slowly solidified to give the title compound as a solid (0.387 g/1. 3 mmol, 92%). iH NMR (300 MHz, CDCI3): δ 7.10 (m, 4 H), 4.66 (dq, / = 3.3, 6.6 Hz, 1 H), 3.75 (septet, /
= 6.6 Hz, 1 H), 3.20 (septet, / = 6.6 Hz, 1 H), 2.17 (t, / = 1.5 Hz, 2 H), 1.58 (d, / = 5.2 Hz, 1 H), 1.41 (d, / = 6.6 Hz, 3 H), 1.29 (m, 14 H), 0.74 (t, / = 7.4 Hz, 3 H). FAB-MS: calcd for (C22H30F O) 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).
Figure imgf000232_0001
(+)-2,6-Diisopropyl-3-(l-hvdroxyethvP-4-(4-fluorophenvP-5-propyl-pyridine
The enantiomeric mixture of (±)-2,6-diisopropyl-3-(l-hydroxyethyl)-4-(4- fluorophenyl)-5-propylpyridine (Example 101) was separated by chiral HPLC with a Chiralpak AD column, isocratic elution (99% hexane/methyl .utyl ether). The first enantiomer to elute was obtained in 99% ee, mp 103-104°C, [a]D +40.4°.
Figure imgf000232_0002
2,6-Diisopropyl-3-(l-hvdroxyethvP-4-(4-fluorophenvP-5-propyl-pyridine
The enantiomeric mixture of (±)-2,6-diisopropyl-3-(l-hydroxyethyl)-4-(4- fluorophenyl)-5-propyl-pyridine (Example 101) was separated by chiral HPLC with a Chiralpak AD column, isocratic elution (99% hexane /methyl f-butyl ether). The second enantiomer to elute was obtained in 90% ee. mp 95-97°C.
EXAMPLE 104
Figure imgf000233_0001
(±)-2,6-Diisopropyl-3-(l-hvdroxyethvP-4-(4-fluorophenvP-5-butyl-pyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-fluorophenyl)-5-butylpyridine (Example 24) according to the procedures described in Example 101. H NMR (300 MHz, CDCI3): δ 7.1 (m, 4 H), 4.7 (dq, / = 3
Hz, 1 H), 3.7 (septet, / = 7 Hz, 1 H), 3.2 (septet, / = 7 Hz, 1 H), 2.2 (t, / = 1.5 Hz, 2 H), 1.6 (d, / = 5 Hz, 1 H), 1.4 (d, / = 7 Hz, 3 H), 1.3 (m, 16 H), 0.8 (t, / = 7 Hz, 3 H). FAB- MS: calcd for (C23H32FNO) 357, found 358 (M+H). mp 103-104 °C. Rf = 0.2 (60% CH2θ2/hexane).
EXAMPLE 105
Figure imgf000233_0002
(±)-2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenvP-5-pentyl-pyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-fluorophenyl)-5-pentylpyridine (Example 1) according to the procedures described in Example 101. iH NMR (300 MHz, CDCI3): δ 7.10 (m, 4 H), 4.65 (dq, / = 2.8, 6.6 Hz, 1 H), 3.75 (septet, / = 6.6 Hz, 1 H), 3.20 (septet, / = 6.6 Hz, 1 H), 2.19 (t, / = 8.1 Hz, 2 H), 1.63 (d, / = 2.6 Hz, 1 H), 1.40 (d, / = 7.0 Hz, 3 H), 1.31 (m, 14 H), 1.11 (m, 4 H), 0.79 (t, / = 6.6 Hz, 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; F, 5.11. Found: C, 77.59; H, 9.34; N, 3.75; F, 5.26. mp 99-101 °C Rf = 0.2 (70% CH2CI2/ hexane).
Figure imgf000234_0001
2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-pentylpyridine
The enantiomeric mixture of (±)-2,6-diisopropyl-3-(l-hydroxyethyl)-4-(4- fluorophenyl)-5-pentylpyridine (Example 105) was separated by chiral HPLC with a Chiralpak AD column, isocratic elution (99% hexane /methyl f-butyl ether). The first enantiomer to elute was obtained in 99% ee. mp 83°C.
EXAMPLE 107
Figure imgf000234_0002
2,6-Diisopropyl-3-(l-hydroxyethvP-4-(4-fluorophenyP-5-pentylpyridine
The enantiomeric mixture of (±)-2,6-diisopropyl-3-(l-hydroxyethyl)-4-(4- fluorophenyl)-5-pentylpyridine (Example 105) was separated by chiral HPLC with a Chiralpak AD column, isocratic elution (99% hexanemethyl f-butyl ether). The second enantiomer to elute was obtained in 93% ee. mp 84-86°C.
EXAMPLE 108
Figure imgf000235_0001
(±)-2,6-Diisopropyl-3-(l-hvdroxyethvP-4-(4-fluorophenyP-5-hexylpyridine
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. iH NMR (300 MHz, CDCI3): δ 7.13 (m, 3 H), 7.04 (m, 1
H), 4.65 (m, 1 H), 3.73 (sept, / = 6.6 Hz, 1 H), 3.19 (sept, / = 6.6 Hz, 1 H), 2.18 (m, 2 H), 1.39 (d, / = 6.6 Hz, 3 H), 1.30 (m, 13 H), 1.18 (m, 4 H), 1.09 (m, 4 H), 0.81 (t, / = 7 Hz, 3 H). FAB-MS: calcd for (C25H36FNO) 385, found 386 (M+H). Anal. Calcd for C25H36FNO: 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).
Figure imgf000235_0002
2,6-Diisopropyl-3-(l-hvdroxyethyl)-4-(4-fluorophenvP-5-hexylpyridine
The enantiomeric mixture of (±)-2,6-diisopropyl-3-(l-hydroxyethyl)-4-(4- fluorophenyl)-5-hexylpyridine (Example 108) was separated by chiral HPLC with a Chiralpak AD column, isocratic elution (99% hexane /methyl I -butyl ether). The first enantiomer to elute was obtained in 98% ee. mp 75-77°C. EXAMPLE 110
Figure imgf000236_0001
2,6-Diisopropyl-3-(l-hydroxyethyP-4-(4-fluorophenyP-5-hexylpyridine
The enantiomeric mixture of (±)-2,6-diisopropyl-3-(l-hydroxyethyl)-4-(4- fluorophenyl)-5-hexylpyridine (Example 108) was separated by chiral HPLC with a Chiralpak AD column, isocratic elution (99% hexane/methyl f-butyl ether). The second enantiomer to elute was obtained in 88% ee. mp 66-68 °C
EXAMPLE 111
Figure imgf000236_0002
2,6-DiisopropyI-3-[l-hvdroxy-2-((S)-toluylsulfoxy)ethyll-4-(4-fluoro-phenyl)-5- pentylpyridine
A solution of lithium diisopropylamide was prepared by the addition of n- butyllithium (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, 2.80 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. NH4CI (1 mL). The solvent was removed in vacuo and the residue partitioned between CHCI3 (150 mL) and water (50 mL). The organic phase was washed with sat. NaHCθ3 (100 mL), water (100 mL) and brine (50 mL), dried over MgSθ4 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 diastereomer to elute. iH NMR (CDCI3, 500 MHz): δ 7.4 (m, 4 H), 7.0 (m, 2 H), 6.7
(m, 2 H), 5.1 (m, 1 H), 4.6 (s, 1 H), 3.8 (m, 2 H), 2.6 (sept, / = 6.6 Hz, 1 H), 2.5 (s, 3 H), 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).
EXAMPLE 112
Figure imgf000237_0001
2,6-Diisopropyl-3-[l-hydroxy-2-(S)-toluylsulfoxyethyll-4-(4-fluoro-phenyP-5- pentylpyridine
From the flash chromatography described in Example 111, the second diastereomer to elute afforded 600 mg (42%) of the title compound. H NMR (CDCI3, 500 MHz): δ 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, / = 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 (C31H40FNO2S) 509, found 510 (M+H). Anal, calcd for C31H40FNO2S: C, 73.05; H, 7.91; N, 2.75; S, 6.29. Found: C, 72.90; H, 7.95; N, 2.50; S, 6.54. mp 190°C. Rf = 0.1 (20% ethyl acetate/hexane). EXAMPLE 113
Figure imgf000238_0001
(±)-2,6-Piisopropyl-3-(l-hydroxyethyP-4-(4-fluorophenyl)-5-phenylthio- methylpyridine
The title compound was prepared from 2,6-diisopropyl-3-(l- hydroxymethyl)-4-(4-fluorophenyl)-5-[(phenylthio)methyl]pyridine (Example 47) according to the procedures described in Example 101. H NMR (300 MHz, CDCI3): δ 7.19 (m, 4 H), 7.09 (m, 5 H), 4.67 (m, 1 H), 3.74 (m, 3 H), 3.38 (sept, / = 6.6
Hz, 1 H), 1.58 (d, / = 4 Hz, 1 H), 1.41 (d, / = 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).
EXAMPLE 114
Figure imgf000238_0002
(±)-2,6-Diisopropyl-3-(l-hydroxy-2-propenvP-4-(4-fluorophenyl)-5-pentylpyridine
Step A: 2,6-Diisopropyl-4-(4-fluorophenyP-5-pentyl-3-pyridine- carboxaldehyde 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (Example 1) (2.30 g, 6.43 mmol) was dissolved in 175 mL of CH2CI2 under argon atmosphere and treated with 2 eq. of alumina (neutial, 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 concentrated in vacuo to afford a solid. Flash chromatography (60:40, CH2CI2 /hexane) using silica afforded 1.84 g of an off-white solid (5.2 mmol, 80%). iH NMR (300 MHz, CDCI3): δ 9.74 (s, 1 H), 7.17 (m, 4 H), 3.85 (septet, / = 6.6 Hz, 1
H), 3.30 (septet, / = 6.6 Hz, 1 H), 2.34 (t, / = 5.2 Hz, 2 H), 1.30 (m, 14 H), 1.15 (m, 4 H), 0.80 (t, / = 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% CH2CI2/ hexane).
Step B: (±)-2,6-Diisopropyl-3-(l-hvdroxy-2-propenyl)-4-(4-fluorophenvP-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 NH4CI (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 MgSθ4, filtered and concentrated to yield a gummy oil. Flash chromatography (60% CH2C_2/hexane) afforded the title compound as a solid (38 mg, 0.1 mmol, 35%). iH NMR (300 MHz, CDCI3): δ 7.11 (m, 4 H), 6.06 (δ, / = 17.4 Hz, / = 10.3Hz, / = 4.0 Hz, 1 H), 5.08 (q, / = 1.5 Hz, 1 H), 5.00 (m, 2 H), 3.51 (septet, / = 6.6 Hz, 1 H), 3.21 (septet, / = 6.6 Hz, 1 H), 2.21 (t, / = 4.4 Hz, 2 H), 1.74 (d, / = 4.1 Hz, 1 H), 1.27 (m, 14 H), 1.11 (m, 4 H), 0.783 (t, / = 6.6 Hz, 3 H). FAB-MS: calcd for (C25H34FNO) 383, found 384 (M+H). Anal. Calcd for C25H34NOF: C, 78.29; H, 8.93; N, 3.65; F, 4.95. Found: C, 78.28; H, 8.97; N, 3.53; F, 5.04. mp 83-85 °C. Rf = 0.2 (50% CH2Cl2/hexane).
Figure imgf000239_0001
(±)-2,6-Diisopropyl-3-(l-hvdroxypentyP-4-(4-fluorophenyP-5-pentyl-pyridine
The 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. iH NMR (300 MHz, CDCI3): δ 6.95 (m, 4 H), 4.33 (m, 1 H), 3.59 (septet, / = 6.6 Hz, 1 H), 3.09 (septet, / = 6.6 Hz, 1 H), 2.08 (t, / = 5.2 Hz, 2 H), 1.75 (m, 2 H), 1.47 (m, 2 H), 1.04 (m, 22 H), 0.719 (t, / = 7.0 Hz, 3 H), 0.674 (t, / = 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% CH2CI2/ hexane).
EXAMPLE 116
Figure imgf000240_0001
(±)-2,6-Diisopropyl-3-(l-hydroxy-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. H NMR (300 MHz, CDCI3): δ 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, / = 6.6 Hz, 1 H), 3.20 (septet, / = 6.6 Hz, 1 H), 2.59 (m, 1 H), 2.35 ( , 1 H), 2.18 (t, / = 4.8 Hz, 2 H), 1.72 (d, / = 2.9 Hz, 1 H), 1.28 (m, 14 H), 1.11 (m, 4 H), 0.783 (t, / = 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 70-72°C. Rf = 0.2 (50% CH2CI2/ hexane). EXAMPLE 117
Figure imgf000241_0001
(±)-2,6-Diisopropyl-3-(l-hydroxy-2-propyl)-4-(4-fluorophenyP-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-fluoroρhenyl)-5-pentylpyridine (Example 1) and ethylmagnesium chloride according to the procedures described in Example 114. iH NMR (300 MHz, CDCI3): δ 7.10 (m, 4 H), 4.35 (dq, / = 3.7, 8.8 Hz, 1 H), 3.68 (septet, / = 6.3 Hz, 1 H),
3.20 (septet, / = 6.6 Hz, 1 H), 2.18 (t, / = 5.2 Hz, 2 H), 1.86 (septet, / = 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 C25H36FNO: 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 77-79°C. Rf = 0.2 (50% CH2Cl2/hexanes).
EXAMPLE 118
Figure imgf000241_0002
(±)-2,6-Diisopropyl-3-(2,2,2-trifluoro-l-hydroxy)ethyl-4-(4-fluoro-phenvP-5- 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 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 IN HCl (50 mL), saturated NaHCθ3 (50 mL), water (50 mL), brine (20 mL), dried (MgSθ4) and concentrated. Purification by flash silica gel chromatography (2% ethyl acetate/hexane) afforded 153 mg (68%) of the title compound as a white solid. iH NMR (300 MHz, CDCI3): δ 7.11 (m, 4 H), 4.90 (bs, 1
H), 3.64 (bs, 1 H), 3.21 (sept, / = 6.6 Hz, 1 H), 2.35 (m, 1 H), 2.15 (m, 2 H), 1.30 (d, / = 6.6 Hz, 6 H), 1.29 (d, / = 6.6 Hz, 6 H), 1.26 (m, 2 H), 1.10 (m, 4 H), 0.77 (t, / = 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).
EXAMPLE 119
Figure imgf000242_0001
2,6-Diisopropyl-3-(2-hvdroxyethyl)-4-(4-fluorophenyP-5-pentylpyridine
Step A: 2,6-Diisopropyl-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 is 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 quenched with water and the THF evaporated in vacuo. The residue was partitioned between ether and water. The organic layer was dried with MgSθ4, filtered, and concentrated to yield an oil. Flash chromatography (10% CH2CI2/ hexanes) afforded an oil (172 mg). The oil (172 mg) was taken up in THF (15 mL) and treated with 4 L cone. HCl. The solution was stirred for 1.5 hours and then diluted with ether (150 mL). The reaction was washed with NaHCθ3 (2 x 50 mL) and dried with MgSQj.
Filtration and concentration yielded a solid (20 mg, 0.054 mmol, 6%). The product was taken directly to the next step without further purification.
Step B: 2,6-Diisopropyl-3-(2-hvdroxyethyl)-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 μL), 20% NaOH (3.9 μL), and water (7.8 μL) again. Concentration afforded a white solid.
The product was subjected to a pad of silica gel (CH2CI2) to afford the title compound as a white solid (14 mg, 0.038mmol, 70%). iH NMR (300 MHz, CDCI3): δ 7.39 (m, 2 H), 7.12 (m, 2 H), 3.52 (t, / = 5.5 Hz, 2 H), 3.23 (m, 2 H), 2.60 (t, / = 2.9
Hz, 2 H), 2.20 (t, / = 3.7 Hz, 2 H), 1.30 (m, 14 H), 1.11 (m, 4 H), 0.771 (t, / = 6.3 Hz, 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- 83βC. Rf = 0.6 (10% ether/hexane).
EXAMPLE 120
Figure imgf000243_0001
2,6-Diisopropyl-3-methylaminomethyl-4-(4-fluorophenyP-5-pentyl-pyridine
Methylammonium chloride (37.99 mg, 0.563 mmol) was added to a stirred 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 then quenched with water. Concentration and addition of CH2CI2 (25 mL) allowed washings with water (2 x 15 mL), brine (1 x 25 mL), following which the solution was dried with MgSθ4, filtered, and concentrated to afford a clear oil. Flash chromatography using silica gel (40% ether/CH2θ2) yielded the title compound as a white solid (21 mg, 0.057 mmol, 20%). JH NMR (300 MHz, CDCI3): δ 7.13 (m, 4
H), 3.26 (m, 4 H), 2.24 (m, 5 H), 1.20 (m, 19 H), 0.783 (t, / = 6.6 Hz, 3 H). FAB-MS: calcd for (C24H35FN2) 370, found 371 (M+H). mp 77-79°C. Rf = 0.2 (20% ether/CH2Cl2).
EXAMPLE 121
Figure imgf000244_0001
2,6-Diisopropyl-3-aminomethyl-4-(4-fluorophenyl)-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-4-(4-fluorophenyl)-5- pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and NH4OAC, according to the procedures described in Example 120. !H NMR (300 MHz, CDCI3): δ 7.10 (m, 4
H), 2.61 (m, 4 H), 2.20 (t, / = 5.5 Hz, 2 H), 1.17 (m, 20 H), 0.776 (t, / = 6.6 Hz, 3 H). FAB-MS: calcd for (C23H33FN2) 356, found 357 (M+H). Anal. Calcd for 23H33N2F: 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% CH2CI2 /hexanes).
EXAMPLE 122
Figure imgf000244_0002
2,6-Diisopropyl-3-(dimethylamino)methyl-4-(4-fluorophenvP-5-pentyl-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. iH NMR (300 MHz, CDCI3): δ 7.09 (m, 4 H), 3.49 (septet, / = 6.6 Hz, 1 H), 3.21 (septet, / = 6.6 Hz, 1 H), 3.05 (s, 2 H), 2.22 (t, / = 5.2 Hz, 2 H), 1.99 (s, 6 H), 1.18 (m, 18 H), 0.790 (t, / = 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/CH2C_2).
Figure imgf000245_0001
2,6-Diisopropyl-3-(ethylamino)methyl-4-(4-fluorophenvP-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. iH NMR (300 MHz, CDCI3): δ 7.06
(m, 4 H), 3.18 (m, 4 H), 2.32 (q, / = 7.4 Hz, 2 H), 2.15 (t, / = 5.2 Hz, 2 H), 1.13 (m, 18 H), 0.839 (t, / = 7.4 Hz, 3 H), 0.698 (t, / = 6.6 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, 77.85; H, 9.50; N, 6.99; F, 4.79. mp 48-50°C. Rf = 0.1 (20% ether/CH2Cl2).
EXAMPLE 124
Figure imgf000245_0002
(±)-2,6-Diisopropyl-3-(l>2-dihydroxyethvP-4-(4-fluorophenyl)-5-pentyl-pyridine
Step A: 2,6-Diisopropyl-3-ethenyl-4-(4-fluoroρhenvP-5-pentylpyridine
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 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-fluorophenyl)-5-pentyl-3-pyridinecarbox-aldehyde (Example 114, 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 MgSθ4. Filtration, concentration and flash chromatography (30% CH2Cl2/hexanes) yielded a solid (0.132 g, 0.37 mmol, 66%). iH NMR (300 MHz, CDCI3) δ 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 = 6.6 Hz, 1 H), 2.30 (t, J = 5.2 Hz, 2 H), 1.20 (m, J = 2.2 Hz, 18 H), 0.979 (t, J = 6.0 Hz, 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% CH2CI2/ hexanes).
Step B: (±)-2,6-Diisopropyl-3-Q,2-dihvdroxyethyP-4-(4-fluoro-phenyl)-5- pentylpyridine To an oven-dried round bottom flask equipped with a stir bar was added the intermediate obtained in Step A (150 mg, 0.424 mmol), in pyridine (10 mL) under argon. The solution was stirred and Osθ4 (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 CH2CI2 (10 mL) and sat. NaHSθ3 (10 mL). The resulting heterogenous solution was stirred very rapidly for 18 hours. The layers were separated and the aqueous layer was extracted several times with CH2CI2. The combined organic layers were dried (MgSQj), filtered, and concentrated to give a white solid. The product was subjected to a pad of silica (65/35; CH2C_2/ether) to yield a white solid (70 mg, 0.18 mmol, 43%). iH NMR (300 MHz, CDCI3): δ 7.08 (m, 4 H), 4.57 (d, / = 1.5 Hz, 1 H), 3.85 (m, IH), 3.65 (septet, / = 6.6 Hz, 1 H), 3.50 (m, 1 H), 3.20 (septet, / = 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, / = 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; CH2CI2/ ether). EXAMPLE 125
Figure imgf000247_0001
2,6-Diisopropyl-3-hydroxymethyl-4-f(4-trifluoromethyl)phenyl]-5-(pent-l- envPpyridine
Step A: Diethyl 1 ,4-dihydro-2,6-diisoprop yl-4-f (4-trifluoro- methyl)phenyπpyridine-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 9.9 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-r(4-trifluoromethyl)phenyl]-pyridine-3 ,5- dicarboxylate
Prepared from the intermediate obtained in Step A by the procedure described in Example 160, Step B. iH NMR (300 MHz, CDCI3): δ 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-diisopropyl-4-f(4-trifluoromethyl)phenyll-5- hvdroxymethylpyridine-3-carboxylate
Prepared from the intermediate obtained in Step B by the procedure described in Example 1, Step D. H NMR (300 MHz, CDCI3): δ 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, IH), 3.50 (m, IH), 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. Step D: 5-Ethoxycarbonyl-2,6-diisopropyl-4-[(4-trifluoromethyl)- phenyllpyridine-3-carboxaldehyde
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. H NMR (300 MHz, CDCI3): δ 0.94 (t, J=7.0 Hz, 3H), 1.33 (d, J=6.6 Hz, 6H), 1.34 (d,
1=6.6 Hz, 6H), 3.14 (m, IH), 3.88 (m, IH), 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, IH). mp 105-106°C
Step E: Ethyl 2,6-diisopropyl-4-[(4-trifluoromethvPphenyl,-5-(pent-l- enyl)pyridine-3-carboxylate
Prepared from the intermediate obtained in Step D by the procedure described in Example 1, Step D. iH NMR (300 MHz, CDCI3): δ 0.69 (t, J=7.0 Hz, 3H), 0.90 (t, J=7.0 Hz, 3H), 1.09-1.34 (m, 14H), 1.92 (δ, J=14.0, 7.0, 1.5 Hz, 2H), 3.07 (m, IH), 3.38 (m, IH), 3.96 (q, J=7.0 Hz, 2H), 5.29 (m, IH), 6.05 (m, IH), 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)phenyl]-5-
(pent-l-enyppyridine
The intermediate obtained in Step E (0.91 g, 2.04 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 sequential addition of H2O, 20% aqueous NaOH and H2O. The resulting suspension was filtered through a cake of Celite and the filtrate concentrated and 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. iH NMR
(300 MHz, CDCI3): δ 0.68 (t, J=7.0 Hz, 3H), 1.05-1.40 (m, 14H), 1.90 (δ, J=14. 7, 1.5
Hz, 2H), 3.34 (m, IH), 3.45 (m, IH), 4.37 (d, J=5.5 Hz, 2H), 5.26 (m, IH), 5.95 (m, IH), 7.30 (d, T=8.0 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H). Rf=0.36 (10% ethyl acetate/n- hexane). mp 77-78 °C. EXAMPLE 126
Figure imgf000249_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-[(4-trifluoromethyPphenyl1-5-pentylpyridine To 0.59 g (1.46 mmol) of the compound 2,6-diisopropyl-3-hydroxymethyl-4-
[(4-trifluoromethyl)phenyl]-5-(pent-l-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. iH NMR (300 MHz, CDCI3): δ 0.78 (t, J=7.0 Hz, 3H), 1.12 (m, 4H), 1.31 (m, 14H), 2.26 (m, 2H), 3.25 (m, IH), 3.42 (m, IH), 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 99-100βC.
EXAMPLE 127
Figure imgf000249_0002
2,6-DiisopropyI-3-hydroxymethyl-4-(3-fluorophenvP-5-(pent-l-envP-pyridine
Step A: Ethyl 2,6-diisopropyl-4-(3-fluorophenvP-5-(pent-l-enyP-pyridine-3- carboxylate Prepared from 3-fluorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. iH NMR (300 MHz, CDCI3): (reported as a mixture of olefin isomers): δ
0.76 (m, 3H), 0.97 (t, 1=7.0 Hz, 3H), 1.13-1.37 (m, 14H), 1.95 (m, 2H), 3.07 (m, IH), 3,21-3.45 (m, IH), 4.0 (m, 2H), 5.30-5.60 (m, IH), 6.06 (m, IH), 6.90-7.03 (m, 3H), 7.27 (m, IH).
Step B: 2,6-Diisopropyl-3-hvdroxymethyl-4-(3-fluorophenvP-5-(pent-l- envppyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. H NMR (300 MHz, CDCI3) (reported as a mixture of olefin isomers): δ 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, IH), 6.0 (m, IH), 6.87-7.07 (m, 3H), 7.34 (m, IH). Rf=0.36 (10% ethyl acetate/n-hexane). mp 117-118°C.
EXAMPLE 128
Figure imgf000250_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(3-fluorophenyl)-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (3-fluorophenyl)-5-(pent-l-enyl)pyridine (Example 127) by the procedure described in Example 126. iH NMR (300 MHz, CDCI3): δ 0.79 (t, J=7.0 Hz, 3H), 1.10-1.35 (m,
18H), 2.28 (m, 2H), 3.24 (m, IH), 3.42 (m, IH), 4.33 (s, 2H), 6.96 (m, 2H), 7.12 (m, IH), 7.40 (m, IH). mp 117-118°C. Rf=0.36 (10% ethyl acetate/n-hexane). EXAMPLE 129
Figure imgf000251_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenyP-5-(pent-l-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, Steps A-E. iH NMR (300 MHz, CDCI3): δ 0.75 (t, J=7.4 Hz, 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, IH), 3.40 (m, IH), 3.99 (q, J=7.4, 2H), 5.30-5.40 (m, IH), 6.05 (dt, J=16.2, 1.5 Hz, IH), 7.0-7.2 (m, 4H). mp 74-77°C.
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-methylphenvP-5-(pent-l- enyP-pyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. iH NMR (300 MHz, CDCI3)
(reported as a mixture of olefin isomers): δ 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: calculated for C24H33NO 352; found 352 (M+H, 100%). Rf=0.38 (10% ethyl acetate/n-hexane). mp 72-75°C. EXAMPLE 130
Figure imgf000252_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-methylphenyl)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4- methylphenyl)-5-(pent-l-enyl)pyridine (Example 129) by the procedure described in Example 126. JH NMR (300 MHz, CDCI3): δ 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 C24H35NO 354; found 354 (M+H, 100%). Rf=0.38 (10% ethyl acetate/n-hexane). mp 92-94°C
Figure imgf000252_0002
2,6-Diisopropyl-3-hydroxymethyl-4-(4-ethylphenyl)-5-(pent-l-enyl)-pyridine
Step A: Ethyl 2,6-diisopropyl-4-(4-ethylphenyl)-5-(pent-l-enyl)-pyridine-3- carboxylate Prepared from 4-ethylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. iH NMR (300 MHz, CDCI3): δ 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, J=7.7 Hz, 2H), 3.0 (m, IH), 3.40 (m, IH), 3.96 (q, J=7.4 Hz, 2H), 5.35 (m, IH), 6.08 (dt, J=16.2, 1.5 Hz, IH), 7.10 (m, 4H). mp 67-68°C. Step B: 2,6-Diisopropyl-3-hvdroxymethyl-4-(4-ethylphenvP-5-(pent-l- enyPpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. JH NMR (300 MHz, CDCI3)
(reported as a mixture of olefin isomers): δ 0.73 (t, J= 7.0 Hz, 3H), 1.10-1.40 (m, 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, IH), 6.0 (dt, J=16.0, 1.0 Hz, IH), 7.0 (d, J=8.5 Hz, 2H), 7.23 (d, J= 8.5 Hz, 2H). FAB-MS: calculated for C25H35NO 366; found 366 (M+H, 100%). Rf=0.31 (10% ethyl acetate/n-hexane).
EXAMPLE 132
Figure imgf000253_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-ethyIphenyl)-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-ethylphenyl)-5-(pent-l-enyl)pyridine (Example 131) by the procedure described in Example 126. iH NMR (300 MHz, CDCI3): δ 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, IH), 3.45 (m, IH), 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 C25H37NO 368; found 368 (M+H, 100%). Rf=0.31 (10% ethyl acetate/n-hexane). mp 87-88°C.
Figure imgf000253_0002
2,6-DiisopropyI-3-hvdroxymethyl-4-(4-isopropylphenyP-5-(pent-l-envPpyridine
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. H NMR (300 MHz, CDCI3): δ 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, IH), 3.94 (q, J=7.4 Hz, 2H), 5.30 (m, IH), 6.10 (dt, J=15.8, 1.5 Hz, IH), 7.0-7.20 (m, 4H). mp 41-45°C.
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-isopropylphenvP-5-(pent-l- envPpyridine
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. iH NMR (300 MHz, CDCI3)
(reported as a mixture of olefins): δ 0.68 (t, 1=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, IH), 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 (10% ethyl acetate/n-hexane).
EXAMPLE 134
Figure imgf000254_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-isopropylphenyl)-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-isopropylphenyl)-5-(pent-l-enyl)pyridine (Example 133) by the procedure described in Example 126. iH NMR (300 MHz, CDCI3): δ 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, J=6.0 Hz, 2 H), 7.1, (d, J=8.5 Hz, 2 H), 7.25 (d, 1= 8.5 Hz, 2 H). FAB-MS: calculated for C26H39NO 382; found 382 (M+H, 100%). Rf=0.40 (10% ethyl acetate/n-hexane). mp 42-44°C.
EXAMPLE 135
Figure imgf000255_0001
2/6-Diisopropyl-3-hydroxymethyl-4-[4-(phenyl)phenyll-5-(pent-l-enyl)pyridine
Step A: Ethyl 2,6-diisopropyl-4-[4-(phenyPphenyl1-5-(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. iH NMR (300 MHz, CDCI3): δ 0.73 (t, J=7.4 Hz, 3H), 0.93 (t, J=7.0 Hz, 3H), 1.10-1.40 (m, 14H), 1.97 (tdd, J=7.0, 7.0, 1.1 Hz, 2H), 3.10 (m, IH), 3.45 (m, IH), 4.0 (q, J=7.4 Hz, 2 H), 5.40 (m, IH), 6.10 (dt, 1=16.2, 1.1 Hz, IH), 7.20-7.70 (m, 9H). mp 104-106°C.
Step B: 2,6-Diisopropyl-3-hvdroxymethyl-4-[4-(phenyl)phenyll-5-(pent-l- enyPpyridine
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. XH NMR (300 MHz, CDCI3)
(reported as a mixture of olefin isomers): δ 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, IH), 6.05 (dt, J=16.0, 1.5 Hz, IH), 7.20-7.24 (m, 2H), 7.35-7.70 (m, 7H). FAB-MS: calculated for C29H35NO 414; found 414 (M+H, 100 %). Rf=0.15 (6% ethyl acetate/n-hexane). mp 50-52°C. EXAMPLE 136
Figure imgf000256_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-[4-(phenvPphenvn-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-[4- (phenyl)phenyl]-5-(pent-l-enyl)pyridine (Example 135) by the procedure described in Example 126. H NMR (300 MHz, CDCI3): δ 0.76 (t, J=7.0 Hz, 3H), 1.0-1.40 (m,
19H), 2.31 (m, 2H), 3.25 (m, IH), 3.44 (m, IH), 4.40 (d, J=5.9 Hz, 2H), 7.22-7.70 (m, 9H). FAB-MS: calculated for C29H37NO 416; found 416 (M+H, 100 %). Rf=0.34
(10% ethyl acetate/n-hexane). mp 56-58°C.
EXAMPLE 137
Figure imgf000256_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(2-fluorophenyl)-5-(pent-l-envP-pyridine
Step A: Ethyl 2,6-diisopropyl-4-(2-fluorophenyP-5-(pent-l-enyl)-pyridine-3- carboxylate Prepared from 2-fluorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. iH NMR (300 MHz, CDCI3): (reported as a mixture of olefin isomers): δ 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, IH), 3.35 (m, IH), 3.97 (m, 2H), 5.29-5.50 (m, IH), 6.16 (m, IH), 7.08-7.32 (m, 4H). Step B: 2,6-Diisopropyl-3-hvdroxymethyl-4-(2-fluorophenyl)-5-(pent-l- enyppyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. H NMR (300 MHz, CDCI3) (reported as a mixture of olefin isomers): δ 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, IH), 6.08 (m, IH), 7.08- 7.41 (m, 5H). Rf=0.24 (10% ethyl acetate/n-hexane).
EXAMPLE 138
Figure imgf000257_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(2-fluorophenyl)-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (2-fluorophenyl)-5-(pent-l-enyl)pyridine (Example 137) by the procedure described in Example 126. *H NMR (300 MHz, CDCI3): δ 0.78 (t, J=7.0 Hz, 3H), 1.07-1.40 (m,
18H), 2.29 (m, 2H), 3.26 (m, IH), 3.46 (m, IH), 4.34 (m, 2H), 7.20 (m, 3H), 7.42 (m, IH). Rf=0.24 (10% ethyl acetate/n-hexane).
Figure imgf000257_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(3-methylphenvP-5-(pent-l-enyP-pyridine
Step A: Ethyl 2-6-diisopropyI-4-(3-methylphenvI)-5-(pent-l-enyl)-pyridine-3- carboxylate Prepared from 3-methylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. iH NMR (300 MHz, CDCI3): δ 0.74 (t, J=7.4 Hz, 3H), 0.92 (t, 1=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, IH), 3.40 (m, IH), 3.96 (q, J=7.4 Hz, 2H), 5.40 (m, IH), 6.05 (dt, J=16.2, 1.5 Hz, IH), 6.90- 7.20 (m, 4H).
Step B: 2,6-Diisopropyl-3-hvdroxymethyl-4-(3-methylphenyl)-5-(pent-l- enyPpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. iH NMR (300 MHz, CDCI3)
(reported as a mixture of olefins): δ 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, IH), 5.95 (dt, J=16.0, 1.0 Hz, IH), 6.90 (m, 2H), 7.10-7.30 (m, 2H). FAB-MS: calculated for C24H33NO 352; found 352 (M+H, 100%). Rf=0.34 (10% ethyl acetate/n-hexane). mp 94-97°C.
EXAMPLE 140
Figure imgf000258_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(3-methylphenyl)-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (3-methylphenyl)-5-(pent-l-enyl)pyridine (Example 139) by the procedure described in Example 126. iH NMR (300 MHz, CDCI3): δ 0.77 (t, 7=7.0 Hz, 3 H), 1.0- 1.40 (m, 19H), 2.25 (m, 2H), 2.39 (s, 3H), 3.23 (m, IH), 3.44 (m, IH), 4.34 (s, 2H), 6.97 (m, 2H), 7.18-7.34 (m, 2H). FAB-MS: calculated for C24H35NO 354; found 354 (M+H, 100 %). Rf=0.34 (10% ethyl acetate/n-hexane). mp 88-90°C. EXAMPLE 141
Figure imgf000259_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(2-methylphenvP-5-(pent-l-enyP-pyridine
Step A: Ethyl 2,6-diisopropyl-4-(2-methylphenyl)-5-(pent-l-envP-pyridine-3- carboxylate Prepared from 2-methylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. iH NMR (300 MHz, CDCI3): δ 0.70 (t, J=7.4 Hz, 3H), 0.88 (t, 1=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, IH), 3.40 (m, IH), 3.90 (m, 2H), 5.30-5.40 (m, IH), 6.0 (m, IH), 7.0-7.20 (m, 4H).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(2-methylphenyl)-5-(pent-l- enyPpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. H NMR (300 MHz, CDCI3) (reported as a mixture of olefin isomers): δ 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, IH), 4.45 (m, IH), 5.30 (m, IH), 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.
EXAMPLE 142
Figure imgf000259_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(2-methylphenyP-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (2-methylphenyl)-5-(pent-l-enyl)pyridine (Example 141) by the procedure described in Example 126. iH NMR (300 MHz, CDCI3): δ 0.76 (t, J=6.6 Hz, 3H), 1.0-
1.40 (m, 19H), 1.97 (s, 3H), 2.0 (m, IH), 2.35 (m, IH), 3.22 (m, IH), 3.42 (m, IH), 4.16 (dd, J=12.0, 5.0 Hz, IH), 4.40 (dd, J=12.0, 5.0 Hz, IH), 7.0-7.10 (m, IH), 7.20-7.40 (m, 3H). FAB-MS: calculated for C24H35NO 354; found 354 (M+H, 100%). Rf=0.32
(10% ethyl acetate/n-hexane). mp 81-83°C.
EXAMPLE 143
Figure imgf000260_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-chlorophenvI)-5-(pent-l-envP-pyridine
Step A: Ethyl 2,6-diisopropyl-4-(4-chlorophenyl)-5-(pent-l-envP-pyridine-3- carboxylate Prepared from 4-chlorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. iH NMR (300 MHz, CDCI3) (reported as a mixture of olefin isomers): δ
0.76 (m, 3H), 0.98 (m, 3H), 1.15-1.35 (m, 14H), 1.95 (m, 2H), 3.05 (m, IH), 3.39 (m, IH), 4.0 (M, 2H), 5.29-5.48 (m, IH), 6.03 (m, IH), 7.11 (m, 2H), 7.30 (m, 2H).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-(pent-l- enyPpyridine
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. iH NMR (300 MHz, CDCI3)
(reported as a 6:1 mixture of olefin isomers): δ 0.73-0.83 (m, 3H), 1.10-1.40 (14H),
1.91 (m, 2H), 3.93 (m, 2H), 4.39 (d, J=5.0 Hz, 2H), 5.25-5.45 (m, IH), 5.98 (m, IH), 7.11 (m, 2H), 7.35 (m, 2H). Rf=0.36 (10% ethyl acetate/n-hexane). EXAMPLE 144
Figure imgf000261_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-chlorophenvP-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-chlorophenyl)-5-(pent-l-enyl)pyridine (Example 143) by the procedure described in Example 126. H NMR (300 MHz, CDCI3): δ 0.79 (t, J=7.0 Hz, 3H), 1.08-1.38 (m,
18H), 2.26 (m, 2H), 3.22 (m, IH), 3.40 (m, IH), 4.31 (d, J=5.0 Hz, IH), 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).
EXAMPLE 145
Figure imgf000261_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(3-chlorophenyl)-5-(pent-l-envI)-pyridine
Step A: Ethyl 2,6-diisopropyl-4-(3-chlorophenyP-5-(pent-l-enyl)-pyridine-3- carboxylate Prepared from 3-chlorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. iH NMR (300 MHz, CDCI3): δ 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, IH), 3.40 (m, IH), 4.0 (q, J=7.0 Hz, 2H), 5.45 (m, IH), 6.05 (dt, T=16.2, 1.5 Hz, IH), 7.0-7.30 (m, 4H). Step B: 2,6-Diisopropyl-3-hvdroxymethyl-4-(3-chlorophenyl)-5-(pent-l- enyPpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. H NMR (300 MHz, CDCI3)
(reported as a mixture of olefin isomers): δ 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, IH), 4.43 (d, J=12.0 Hz, IH), 5.20-5.40 (m, IH), 5.9 (dt, J=16.0, 1.1 Hz, IH), 7.0-7.40 (m, 4H). FAB- MS: calculated for C23H30NOCI 372; found 372 (M+H, 100%). Rf=0.26 (10% ethyl acetate/n-hexane). mp 101-104°C.
EXAMPLE 146
Figure imgf000262_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(3-chlorophenvD-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-
(3-chlorophenyl)-5-(pent-l-enyl)pyridine (Example 145) by the procedure described in Example 126. iH NMR (300 MHz, CDCI3): δ 0.80 (t, J=7.0 Hz, 3H), 1.0-1.40 (m,
19H), 2.26 (m, 2H), 3.23 (m, IH), 3.41 (m, IH), 4.34 (m, 2H), 7.05-7.45 (m, 4H). FAB- MS: calculated for C23H32NOCI 374; found 374 (M+H, 100%). Rf 0.26 (10% ethyl acetate/n-hexane). mp 94-95°C.
EXAMPLE 147
Figure imgf000262_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(2,4-dichlorophenyP-5-(pent-l-envPpyridine
Step A: Ethyl 2,6-diisopropyl-4-(2,4-dichlorophenyl)-5-(pent-l-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. H NMR (300 MHz, CDCI3) (reported as a 1:1 mixture of olefin isomers): δ 0.79 (m, 3H), 0.99 (m, 3H), 1.12-1.38 (m, 14H), 1.91 (m, 2H), 3.12 (m, IH), 3.32 (m, IH), 4.0 (m, 2H), 5.20 -5.60 (m, IH), 6.09 (m, IH), 7.05-7.41 (m, 3H).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(2,4-dichlorophenyP-5-(pent-l- enyPpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. iH NMR (300 MHz, CDCI3)
(reported as a 1:1 mixture of olefins): δ 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, IH), 4.42 (m, IH), 5.31-5.50 (m, IH), 6.0 (m, IH), 7.05 (m, IH), 7.28 (m, IH), 7.47 (m, IH). Rf 0.38 (10% ethyl acetate/n-hexane).
EXAMPLE 148
Figure imgf000263_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(2,4-dichlorophenyP-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-
(2,4-dichlorophenyl)-5-(pent-l-enyl)pyridine (Example 147) by the procedure described in Example 126. iH NMR (300 MHz, CDCI3): δ 0.80 (t, T=7.0 Hz, 3H),
1.12-1.48 (m, 18H), 2.12 (m, IH), 2.35 (m, IH), 3.26 (m, IH) 3.45 (m, IH), 4.31 (AB, J=12.0 Hz, 2H), 7.16 (d, J=8.0 Hz, IH), 7.36 (dd, J=8.0, 2.0 Hz, IH), 7.54 (d, J=2.0, IH). Rf 0.38 (10% ethyl acetate/n-hexane). EXAMPLE 149
2,6-Diisopropyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-5-(pent-l-envPpyridine
Step A: Ethyl 2,6-diisopropyl-4-(3,4-dichlorophenvP-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. iH NMR (300 MHz, CDCI3) (reported as a 6:1 mixture of olefin isomers): δ 0.78 (m, 3H), 1.04 (m, 3H), 1.16-1.35 (m, 14H), 1.98 (m, 2H), 3.04 (m, IH), 3.57 (m, IH), 5.31-5.58 (m, IH), 6.02 (m, IH), 7.04 (m, IH), 7.28-7.42 (m, 2H).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(3,4-dichlorophenvP-5-(pent-l- enyppyridine
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. iH NMR (300 MHz, CDCI3)
(reported as a 6:1 mixture of olefin isomers): δ 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, IH), 6.0 (m, IH), 7.05 (s, IH), 7.30 (s, IH), 7.45 (m, IH). mp 46-48°C Rf=0.38 (10% ethyl acetate/n-hexane).
Figure imgf000264_0002
2,6-Diisopropyl-3-hydroxymethyl-4-(2,4-difluorophenyP-5-(pent-l-enyl)pyridine
Step A: Ethyl 2,6-diisopropyl-4-(2,4-difluorophenvI)-5-(pent-l-enyl)pyridine-
3-carboxylate Prepared from 2,4-difluorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. iH NMR (300 MHz, CDCI3): δ 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, 1=7.4, 7.4, 1.5 Hz, 2H), 3.10 (m, IH), 3.35 (m, IH), 4.0 (q, J=7.0 Hz, 2H), 5.30 (dt, J=15.0, 7.0 Hz, IH), 6.10 (m, IH), 6.80-7.20 (m, 3H).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(2,4-difluorophenyl)-5-(pent-l- enyPpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. iH NMR (300 MHz, CDCI3)
(reported as a mixture of olefin isomers): δ 0.75 (t, [=7.5 Hz, 3H), 1.10-1.40 (m, 15H), 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, IH), 4.43
(dd, J=12.0, 5.0 Hz, IH), 5.3 (m, IH), 6.05 (d, J=16.0, Hz, IH), 6.80-7.20 (m, 3H).
FAB-MS: calculated for C23H29NOF2 374; found 374 (M+H, 100%). Rf 0.24 (10% ethyl acetate/n-hexane). mp 59-62"C.
EXAMPLE 151
Figure imgf000265_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(2,4-difluorophenvP-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-
(2,4-difluorophenyl)-5-(pent-l-enyl)pyridine (Example 150) by the procedure described in Example 126. H NMR (300 MHz, CDCI3): δ 0.79 (t, J=7.0 Hz, 3H),
1.10-1.40 (m, 18H), 2.30 (m, 2 H), 3.20 (m, IH), 3.40 (m, IH), 4.30 (d, J=12.0 Hz, 1H),4.36 (d, J=12.0 Hz, IH), 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. EXAMPLE 152
Figure imgf000266_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(3-benzyloxyphenvP-5-(pent-l-enyl)pyridine
Step A: Ethyl 2,6-diisopropyl-4-(3-benzyloxyphenvP-5-(pent-l-envDpyridine-
3-carboxylate Prepared from 3-benzyloxybenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 160, Steps A-E. iH NMR (300 MHz, CDCI3): δ 0.75 (t, J=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, IH), 3.40 (m, IH), 3.97 (m, 2H), 5.04 (bs, 2H), 5.35 (m, IH), 6.06 (dt, J=16.2, 1.5 Hz, IH), 6.79 (m, 2H), 6.89 (m, IH), 7.31 (m, 6H).
Step B: 2,6-Diisopropyl-3-hvdroxymethyl-4-(3-benzyloxyphenyP-5-(pent-l- enyPpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. iH NMR (300 MHz, CDCI3)
(reported as a mixture of olefin isomers): δ 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, IH), 5.97 (m, IH), 6.74 (m, 2H), 6.95 (m, IH), 7.35 (m, 7H). FAB-MS: calculated for C30H37NO2, 444; found 444 (M+H, 100%). Elemental analysis: calculated for C30H37NO2: C 81.22; H 8.41; N 3.16, found: C 80.51; H 8.41; N 3.36. Rf 0.5 (25% ethyl acetate/n-hexane).
Figure imgf000266_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(3-hydroxyρhenvP-5-pentylpyridine
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 in Example 126. XH NMR (300 MHz, CDCI3): δ 0.78 (t, J=7.0 Hz, 3H), 1.28 (m, 18H), 2.28 (m, 2H), 3.22 (m, IH), 3.39 (m, IH), 4.34 (m, 2H), 5.52 (s, IH), 6.63 (m, IH), 6.71 (d, J=8.0 Hz, IH), 6.81 (m, IH), 7.26 (m, IH). FAB-MS: calculated for C23H33NO2 356; found 357 (M+H, 100%). Elemental analysis: calculated 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.
EXAMPLE 154
Figure imgf000267_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(3-trifluoromethvPphenyl-5-(pent-l- enyPpyridine
Step A: Ethyl 2,6-diisopropyl-4-(3-trifluoromethyl)phenyI-5-(pent-l- enyPpyridine-3-carboxylate Prepared from 3-(trifluoromethyl)benzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. iH NMR (300 MHz, CDCI3) (reported as a 6:1 mixture of olefin isomers): δ 0.72 (m, 3H), 0.94 (m, 3H), 1.10-1.40 (m, 14H), 1.94 (m, 2H), 3.07 (m, IH), 3.41 (m, IH), 3.97 (m, 2H), 5.33 (m, IH), 6.05 (m, IH), 7.29-7.60 (m, 4H).
Step B: 2,6-Diisopropyl-3-hvdroxymethyl-4-(3-trifluoromethvPphenyl-5-
(pent-l-enyPpyridine
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. iH NMR (300 MHz, CDCI3) (reported as a 6:1 mixture of olefin isomers): δ 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, IH), 5.93- 6.02 (m, IH), 7.37-7.62 (m, 3H). mp 100-103°C. Rf 0.36 (10% ethyl acetate/n- hexane).
EXAMPLE 155
Figure imgf000268_0001
2f6-Diisopropyl-3-hydroxymethyl-4-(3-trifluoromethvPphenyl-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-
(3-trifluoromethyl)phenyl-5-(pent-l-enyl)pyridine (Example 154) by the procedure described in Example 126. iH NMR (300 MHz, CDCI3): δ 0.75 (t, J=6.5 Hz, 3H),
1.07-1.39 (m, 18H), 2.24 (m, 2H), 3.24 (m, IH), 3.42 (m, IH), 4.31 (qd, J=12.0, 5.0 Hz, 2H), 7.42 (d, J=8.0 Hz, IH), 7.50 (s, IH), 7.57 (t, J=8.0 Hz, IH), 7.67 (d, J=8.0 Hz, IH). mp 96-97°C. Rf 0.36 (10% ethyl acetate/n-hexane).
EXAMPLE 156
Figure imgf000268_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(2-ethvnylphenvP-5-(pent-l-envP-pyridine
Step A: Diethyl 2,6-diisopropyl-4-(2-iodophenvPpyridine-3,5-dicarboxylate
Prepared from 2-iodobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-B. iH NMR (300 MHz, CDCI3): δ 0.94 (t, J= 7.0 Hz, 6H), 1.30 (d, J= 6.6 Hz,
6H), 1.34 (d, J= 6.6 Hz, 6H), 3.19 (septet, T= 6.6 Hz, 2H), 4.0 (q, J= 7.0 Hz, 4H), 7.0- 7.40 (m, 3H), 7.85 (m, IH). Step B: Diethyl 2,6-diisopropyl-4-f(2-trimethylsilylethynyl)phenyl|pyridine-
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 mol) of triethylamine, 0.1 g (0.15 mmol) of _>zs(triphenylphosphine) palladium(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 a sealed reaction vessel, for 16 hrs. The reaction mixture was to cooled to temperature, filtered through Celite, and stripped to give a dark oil which upon purification by flash silica gel chromatography to yield 1.22 g (2.5 mmole) of the product. iH NMR (300 MHz, CDCI3): δ 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-ethvnylphenvPpyridine-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 magnesium 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. iH NMR (300 MHz, CDCI3): δ 0.90 (t, J= 7.0 Hz, 6H), 1.32 (m, 12H), 2.97 (s, IH), 3.21 (septet, 1=6.6, 2H), 3.90 (q, J= 7.0, 4H), 7.2-7.6 (m, 4H).
Step D: Ethyl 2,6-diisoproρyl-4-(2-ethynylphenyl)-5-(pent-l-envP-pyridine-3- carboxylate
Prepared from the intermediate obtained in Step C by the procedures described in Example 125, Steps A-E. iH NMR (300 MHz, CDCI3): δ 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, IH), 3.0-3.40 (m, 2H), 3.90 (m, 2H), 5.28 (dt, J=16.2, 7.0 Hz, IH), 6.15 (dt, J=16.2, 1.5 Hz, IH), 7.10-7.60 (m, 4H).
Step E: 2,6-Diisopropyl-3-hvdroxymethyl-4-(2-ethynylphenyl)-5-(pent-l- enyPpyridine The title compound was prepared from the intermediate obtained in Step D by the procedure described in Example 125, Step F. αH NMR (300 MHz, CDCI3)
(reported as a mixture of olefin isomers): δ 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, IH), 3.20-3.60 (m, 2H), 4.20-4.50 (m, 2H), 5.40 (m, IH), 6.0 (m, IH), 7.0-7.60 (m, 4H). Rf=0.23 (10% ethyl acetate/n-hexane).
EXAMPLE 157
Figure imgf000270_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(2-ethenylphenvP-5-pentylpyridine The title compound was prepared from ethyl 2,6-diisopropyl-3- hydroxymethyl-4-(2-ethynylphenyl)-5-(pent-l-enyl)pyridine-3-carboxylate by the procedure described in Example 125, Step F. iH NMR (300 MHz, CDCI3) (reported as a mixture of olefin isomers): δ 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, IH), 5.40 (m, IH), 5.90 (m, IH), 6.30 (m, IH), 7.0-7.70 (m, 4H). FAB-MS: calculated for C25H33NO 363.5; found 364 (M+H, 100%). Rf 0.28 (10% ethyl acetate/n-hexane).
Figure imgf000270_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(3,4-difluorophenyP-5-(pent-l-enyl)pyridine
Step A: Ethyl 2,6-diisopropyl-4-(3,4-difluorophenyP-5-(pent-l-enyl)pyridine-
3-carboxylate Prepared from 3,4-difluorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 1, Steps A-E. iH NMR (300 MHz, CDCI3) (reported as a 8:1 mixture of olefin isomers): δ 0.78 (m, 3H), 1.03 (m, 3H), 1.18-1.33 (m, 14H), 1.97 (m, 2H), 3.04 (m, IH), 3.38 (m, IH), 4.04 (m, 2H), 5.30-5.45 (m, IH), 6.02 (m, IH), 6.89-7.17 (m, 3H).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-(3,4-difluorophenyl)-5-(pent-l- envPpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. iH NMR (300 MHz, CDCI3)
(reported as a mixture of olefin isomers): δ 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, IH), 5.91 (m, IH), 6.80-7.20 (m, 4H). mp 105-106°C. Rf=0.30 (10% ethyl acetate/n-hexane).
EXAMPLE 159
Figure imgf000271_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(3,4-difluorophenyl)-5-pentyl-pyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (3,4-difluorophenyl)-5-(pent-l-enyl)pyridine (Example 158) by the procedure described in Example 126. iH NMR (300 MHz, CDCI3): δ 0.81 (t, J=7.0 Hz, 3H), 1.12
(m, 4H), 1.30 (m, 14H), 2.27 (m, 2H), 3.24 (m, IH), 3.41 (m, IH), 4.32 (d, J=4.0 Hz, 2H), 6.95 (m, IH), 7.06 (m, IH), 7.25 (m, IH). mp 106-107"C. Rf 0.30 (10% ethyl acetate/n-hexane). EXAMPLE 160
Figure imgf000272_0001
2<6-Diisopropyl-3-hydroxymethyl-4-(4-benzyloxyphenyl)-5-(pent-l-enyPpyridine
Step A: Diethyl 1 ,4-dihydro-2,6-diisopropyl-4-(4-benzyloxyphenyl)-3,5- pyridinedicarboxylate 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 then added 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). iH NMR (300 MHz, CDCI3): δ 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, IH), 5.01 (s, 2H), 6.12 (s, IH), 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-benzyloxyphenyP-3,5-pyridine- 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") (1M, 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 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). *H NMR (300 MHz, CDCI3): δ 0.96 (t, J = 6.9 Hz, 6H), 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-l-enyl)-3- pyridinecarboxylate Prepared from the intermediate obtained in Step B by the procedure described in Example 1, Steps D-F. iH NMR (300 MHz, CDCI3): δ 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, IH), 3.42 (septet, J = 6.6 Hz, IH), 3.94-4.03 (m, 2H), 5.06-5.12 (m, 2H), 5.32-5.42 (m, IH), 6.03-6.15 (m, IH), 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-hydroxymethy.-4-(4-benzyloxyphenyl)-5-(pent-l- enyPpyridine The intermediate obtained in Step C (6 g, 12.35 mmol) was dissolved in 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 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 colorless wax. 1H NMR (300 MHz, CDCI3): δ 0.73-0.83 (m, 3H), 1.37-1.70 (m, 14H), 1.56 (s,
IH), 1.92 (dq, J = 0.90, 6.90 Hz, 2H), 3.41 (δ, 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, IH), 5.97 (d, J = 15.90 Hz, IH), 6.97-7.09 (m, 4H), 7.35-7.48 (m, 5H). EXAMPLE 161
Figure imgf000274_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-hvdroxyphenyP-5-pentylpyridine
2,6-Diisopropyl-3-hydroxymethyl-4-(4-benzyloxyphenyl)-5-(pent-l- enyPpyridine (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). H NMR (300 MHz, CDCI3): δ 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, IH), 3.40 (sept, J = 6.6 Hz, IH), 4.36 (d, J = 5.4 Hz, 2H), 4.85 (s, IH), 6.89 (d, J = 8.4 Hz, IH), 7.05 (d, J = 8.7 Hz, IH).
EXAMPLE 162
Figure imgf000274_0002
2,6-Diisopropyl-3-hydroxymethyl-4-(2-ber_zyloxyphenyP-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. iH NMR (300 MHz, CDCI3): δ 0.69-0.74 (m, 3H), 1.07-1.38 (m, 14H), 1.69-1.79 (m, IH) 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, IH), 6.00 (dd, J = 15.9, 1.2 Hz, IH), 7.05-7.10 (m, 5H), 7.24-7.36 (m, 4H). EXAMPLE 163
Figure imgf000275_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(2-hydroxyphenyP-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (2-benzyloxyphenyl)-5-(pent-l-enyl)pyridine (Example 162) by the method detailed in Example 161. iH NMR (300 MHz, CDCI3): δ 0.75-0.73 (m, 3H), 1.09-1.15 (m, 4H),
1.30-1.37 (m, 14H), 1.70-1.73 (m, IH), 2.16-2.28 (m, IH), 2.32-2.42 (m, IH), 3.22-3.32 (m, IH), 3.39-3.51 (m, IH), 4.29-4.35 (m, IH), 4.48-4.54 (m, IH), 5.14 (br s, IH), 7.02- 7.05 (m, 3H), 7.28-7.36 (m, IH). 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.
EXAMPLE 164
Figure imgf000275_0002
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-l-enyl)- pyridine (Example 162) (680 mg, 1.53 mmol) was dissolved in 15 mL of methylene chloride under an argon atmosphere and treated with a mixture of Celite (661 mg) and pyridinium chlorochromate ("PCC") (661 mg, 2 eq). The reaction was stirred at room temperature for 1.5 h. The suspension was filtered through a pad of silica and the pad was washed with 50 mL CH2CI2 and the filtrate was combined and concentrated in vacuo to afford 572.4 mg of product (84%). iH NMR (300 MHz, CDCI3): δ 0.70 (t, J = 7.2 Hz, 3H), 1.08-1.35 (m, 15H), 1.85-1.93 (m, IH), 3.26-3.45 (m,
IH), 3.87-3.97 (m, IH), 4.97-5.06 (m, 2H), 5.27-5.50 (m, IH), 6.01-6.10 (m, IH), 6.94- 7.34 (m, 9H), 9.82 (d, J = 3.6 Hz, IH).
Step B: 2,6-Diisopropyl-3-(l-hydroxyethvP-4-(2-benzyloxyphenyP-5-(pent-l- enyPpyridine Prepared as a separable mixture of two diastereomers from the intermediate from Step A by the method detailed 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, iH NMR (300 MHz, CDCI3): δ 0.68-1.91 (m,
23H), 3.19-3.40 (m, IH), 3.77 (sept, J = 6.6 Hz, IH), 4.69-4.79 (m, IH), 4.94 (dd, J = 12.3, 3.9 Hz, IH), 5.05 (d, J = 12.3 Hz, IH), 5.20-5.43 (m, IH), 5.90-6.05 (m, IH), 6.94-
7.38 (m, 9H). FAB-MS: calcd for (C31H39NO2) 457, found 458 (M + 1).
Diastereomer 2: colorless oil, iH NMR (300 MHz, CDCI3): δ 0.69 (t, J = 7.2
Hz, 3H), 1.05-1.40 (m, 17H), 1.67-1.73 (m, IH), 1.80-1.88 (m, 2H), 3.18-3.41 (m, IH),
3.68-3.80 (m, IH), 4.84-5.08 (m, 3H), 5.25-5.42 (m, IH), 5.86-6.08 (m, IH), 6.90-7.38 (m, 9H). FAB-MS: calcd for (C31H39NO2) 457, found 458 (M + 1).
Step C: 2,6-Diisopropyl-3-(l-hvdroxyethyP-4-(2-hydroxyphenyl)-5- pentylpyridine The diastereomeric mixture of intermediates from Step B (39 mg) was dissolved in absolute ethanol (1.5 mL) under argon, treated with 10% palladium 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 the two diastereomers.
Diastereomer 1 (DI) (11.2 mg): H NMR (300 MHz, CDCI3): δ 0.68 (t, J = 7.30 Hz, 3H), 0.99-1.03 (m, 4H), 1.19-1.34 (m, 17H), 1.62 (d, J = 3.60 Hz, IH), 1.97- 2.07 (m, IH), 2.16-2.26 (m, IH), 3.14 (septet, J = 7.30 Hz, IH), 3.67 (septet, J = 7.30 Hz, IH), 4.72 (br s, IH), 4.83 (dq, J = 4.20, 6.60 Hz, IH), 6.89-6.97 (m, 3H), 7.19-7.25 (m, IH). FAB-MS: calcd for (C24H35NO2) 369, found 370 (M + 1). Diastereomer 1 (DI) 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 280 ran and two fractions (corresponding to the enantiomers) were collected at (15-17 min, 100% ee) and (19-26 min, >99% ee), respectively.
Diastereomer 2 (D2) (11.8 mg): iH NMR (300 MHz, CDCI3): δ 0.68 (t, J =
6.60 Hz, 3H), 0.99-1.03 (m, 4H), 1.16-1.32 (m, 17H), 1.86 (br s, IH), 2.00-2.10 (m, IH), 2.19-2.29 (m, IH), 3.14 (septet, J = 6.60 Hz, IH), 3.67 (septet, J = 6.60 Hz, IH), 4.57 (q, J = 6.60 Hz, IH), 4.76 (br s, IH), 6.84-6.93 (m, 3H), 7.19-7.24 (m, IH). FAB-MS: calcd for (C24H35NO2) 369, found 370 (M+l).
EXAMPLE 165
Figure imgf000277_0001
2,6-Diisopropyl-3-(l-hvdroxyethvP-4-(2-hvdroxyphenyP-5-propylpyridine
Step A: Diethyl-2,6-diisopropyl-4-(2-benzyloxyphenyl)-3,5-pyridine- dicarboxylate Prepared from 2-benzyloxybenzaldehyde by the methods detailed in Example 160, Steps A-B. iH NMR (300 MHz, CDCI3): δ 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, IH), 6.94 (dt, J = 7.2, 0.6 Hz, IH), 7.16 (dd, J = 7.8, 1.8 Hz, IH), 7.14-7.30 (m, 6H).
Step B: 5-EthoxycarbonyI-2,6-diisopropyl-4-(2-benzyloxyphenyl)-3- pyridinecarboxaldehyde Prepared from the intermediate from Step A by the methods detailed in
Example 1, Steps D-E. αH NMR (300 MHz, CDCI3): δ 0.91 (t, J = 6.6 Hz, 3H), 1.30- 1.39 (m, 12H), 3.18 (septet, J = 6.0 Hz, IH), 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, IH).
Step C: 2,6-Diisopropyl-4-(2-benzyloxyphenyP-3-ethoxycarbonyl-5-(prop-l- enyPpyridine Ethyltriphenylphosphonium bromide (4.01 g, 10.8 mmol) was suspended in anhydrous 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. The resulting 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 MgSθ4 and concentrated. Flash chromatography through silica (5% ethyl acetate/hex) afforded 4.1 g of the product (E, Z mixture) as a viscous oil. iH NMR (300 MHz, CDCI3): δ 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, IH), 6.10-6.19 (m, IH), 6.89-6.97 (m, 2H), 7.08-7.12 (m, IH), 7.15-7.19 (m, 2H), 7.22- 7.29 (m, 4H).
Step D: 2,6-Diisopropyl-3-hydroxymethyl-4-(2-benzyloxyphenvP-5-(prop-l- enyppyridine Prepared from the intermediate from Step C by the method detailed in Example 160, Step D. H NMR (300 MHz, CDCI3): δ 1.21-1.60 (m, 15H), 1.90-1.95 (m, IH), 3.18-3.53 (m,2H), 4.26-4.58 (M, 2H), 4.87-4.94 (m, IH), 5.06 (d, J = 12.3 Hz, IH), 5.27-5.57 (m, IH), 5.95-6.05 (m, IH), 7.00-7.06 (m, 5H), 7.22-7.37 (m, 4H).
Step E: 2,6-Diisopropyl-3-(l-hydroxyethvP-4-(2-hydroxyphenvP-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 (DI): JH NMR (300 MHz, CDCI3): δ 0.66 (t, J = 7.50 Hz, 3H), 1.15-1.34 (m, 15H), 1.59 (br s, IH), 1.96-2.06 (m, IH), 2.15-2.25 (m, IH), 3.15 (sept, j = 6.60 Hz, IH), 3.56 (sept, J = 6.60 Hz, IH), 4.70 (br s, IH), 4.81-4.87 (m, IH), 6.90-6.97 (m, 3H), 7.19-7.26 (m, IH). FAB-MS: calcd for (C22H31NO2) 341, found 342 (M+l). Diastereomer 1 (DI) 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 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 reinjected. 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 Rf enantiomer from the preparative column was the high Rf enantiomer on the analytical column with Rf = 8.80 min; 98.8% ee. The high Rf enantiomer from the preparative column was the low Rf enantiomer on the analytical column with Rf = 3.71 min; 81% ee.
Diastereomer 2 (D2): iH NMR (300 MHz, CDCI3): δ 0.72 (t, J = 7.50 Hz, 3H), 1.22-1.36 (m, 15H), 2.03-2.15 (m, IH), 2.23-2.33 (m, IH), 2.56 (d, J = 3.0 Hz, IH), 3.21 (septet, J = 6.60 Hz, IH), 3.73 (septet, J = 6.60 Hz, IH), 4.56-4.63 (dq, J = 3.0, 6.0 Hz, IH), 5.66 (br s, IH), 6.88-6.99 (m, 3H), 7.25-7.28 (m, IH). FAB-MS: calcd for (C22H31NO2) 341, found 342 (M+l).
Figure imgf000279_0001
2,6-Diisopropyl-3-hydroxymethyl-4-f(4-fluoro-2-hvdroxy)phenyll-5-pentylpyridine
Step A: 2-Benz yloxy-4-fluorob romobenzene
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 pressure and the residue was taken up in ether (400 mL). The organic layer was washed with water (5 x 100 mL) and brine (1 x 100 mL) and then dried (MgSθ4). The solution was then concentrated under reduced pressure and subjected to flash chromatography using hexane as the eluent. In this manner, 2-benzyloxy-4- fluorobenzene was obtained as a white solid. H NMR (300 MHz, CDCI3): δ 5.14 (s, 2H), 6.57-6.63 (m, IH), 6.69 (dd, J = 2.7, 10.2 Hz, IH), 7.32-7.52 (m, 6H).
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 removed 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 (Na2Sθ4) and concentrated under reduced pressure. The resultant residue was purified by flash chromatography (10% ethyl acetate-hexane) to provide 77.3 g of 2-benzyloxy-4-fluorobenzaldehyde. H NMR (300 MHz, CDCI3): δ 5.16 (s, 2H),
6.70-6.76 (m, 2H), 7.34-7.44 (m, 5H), 7.87-7.92 (m, IH), 10.43 (s, IH). FAB-MS: calcd for (C14H11O2F) 230; found 231 (M+l).
Step C: 2,6-Diisopropyl-3-hydroxymethyl-4-f(2-benzyloxy-4-fluoro)phenyl]- 5-(pent-l-enyl)pyridine
Prepeared from the intermediate obtained in Step B by the methods described in Example 160, Steps A-D. iH NMR (300 MHz, CDCI3): δ 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, IH), 3.25 (septet, J = 6.6 Hz, IH), 3.46 (d septet, J = 2.7, 6.6 Hz, IH), 4.29-4.42 (m, 2H), 4.89-5.06 (m, 2H), 5.24-5.47 (m, IH), 5.95-6.00 (m, IH), 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-f(4-fluoro-2-hydroxy)phenyl1-5- pentylpyridine The title compound was prepared as a racemate from the intermediate obtained in Step C by the method detailed in Example 161. iH NMR (300 MHz, CDCI3): δ 0.78 (t, J = 6.6 Hz, 3H), 1.09-1.35 (m, 18H), 1.65 (t, J = 5.0 Hz, IH), 2.13- 2.23 (m, IH), 2.28-2.38 (m, IH), 3.24 (sept, J = 6.6 Hz, IH), 3.39 (sept, J = 6.6 Hz, IH), 4.29 (dd, J = 11.1, 5.0 Hz, IH), 4.52 (dd, J = 11.1, 5.1 Hz, IH), 5.45 (bs, IH), 6.71-6.78 (m, 2H), 6.95-7.00 (m, IH). FAB-MS: calcd for (C23H32NO2F) 373, found 374 (M + 1). Rf = 0.15 (20% ether-hexanes). mp 152°C.
EXAMPLE 167
Figure imgf000281_0001
2,6-Diisopropyl-3-(l-hydroxyethvP-4-[(4-fluoro-2-hydroxy)phenvn-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-l- 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 (DI): iH NMR (300 MHz, CDCI3): δ 0.80 (t, J = 6.6 Hz, 3H),
1.10-1.42 (m, 21H), 1.64 (d, J = 3.6 Hz, IH), 2.03-2.13 (m, IH), 2.21-2.31 (m, IH), 3.15- 3.26 (septet, IH), 3.54-3.65 (septet, IH), 4.89-4.98 (m, IH), 4.99 (br s, IH), 6.69-6.75 (m, 2H), 6.94-6.99 (δ, J = 2.7, 6.5, 6.5 Hz, IH). FAB-MS: calcd for (C24H34NO2F) 387, found 388 (M + 1). Rf = 0.41 (40% ether-hexanes). mp 124-126°C.
Diastereomer 1 (DI) 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 nm and two fractions (corresponding to the two enantiomers) were collected at (13-18 min,100% ee) and (18.5-27 min, >99%ee), respectively. Diastereomer 2 (D2): XH NMR (300 MHz, CDC1 ): δ 0.78 (t, J = 6.5 Hz, 3H),
1.06-1.40 (m, 21H), 1.75 (d, J = 3.6 Hz, IH), 2.06-2.16 (m, IH), 2.26-2.37 (m, IH), 3.21 (septet, ] = 6.6 Hz, IH), 3.74 (septet, J = 6.6, IH), 4.59-4.67 m, IH), 4.83 (br s, IH), 6.68-6.75 (m, 2H), 6.86-6.91 (δ, J = 3.0, 6.6, 6.6 Hz, IH); FAB-MS: calcd for (C24H34NO2F) 387, found 388 (M + 1). Rf = 0.24 (40% ether-hexanes). mp 157- 159°C.
EXAMPLE 168
Figure imgf000282_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methoxyphenyl)-5-(pent-l-envPpyridine
The title compound was prepared from 4-methoxybenzaldehyde by the methods detailed in Example 125. H NMR (300 MHz, CDCI3): δ 0.76 and 0.81 (t, J
= 7.2 Hz, 3H), 1.12-1.39 (m, 14H), 1.60-1.80 (bs, IH), 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, IH), 5.93-6.05 (m, IH), 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+l).
EXAMPLE 169
Figure imgf000282_0002
2,6-Diisopropyl-3-hydroxymethyl-4-(4-methoxyphenyl)-5-pentyl-pyridine The title compound was prepared as a white solid from 2,6-diisopropyl-3- hydroxymethyl-4-(4-methoxyphenyl)-5-(pent-l-enyl)pyridine (Example 168) by the methods detailed in Example 126. JH NMR (300 MHz, CDCI3): δ 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,
IH), 3.42 (sept, J = 6.6 Hz, IH), 3.87 (s, 3H), 4.35 (d, J = 5.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 8.7 Hz, 2H). FAB-MS: calcd for (C24H35NO2) 369, found 370
(M + 1). mp 47-49°C.
EXAMPLE 170
Figure imgf000283_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(3-methoxyphenyl)-5-(pent-l-enyl)pyridine
The title compound was prepared from 3-methoxybenzaldehyde by the methods detailed in Example 125. iH NMR (300 MHz, CDCI3): δ 0.78 (t, J = 7.5 Hz, 3H), 1.17-1.41 (m, 14H), 1.65 (s, IH), 1.97 (δ, 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, IH), 6.01-6.09 (m, IH), 6.73-6.77 (m, 2H), 6.89 (δ, J = 8.1, 2.1, 0.9 Hz, IH), 7.30 (t, J = 8.0 Hz, IH). FAB-MS: calcd for (C24H33NO2) 367, found 368 (M + 1). mp 71-75°C.
EXAMPLE 171
Figure imgf000283_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(3-methoxyphenyl)-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (3-methoxyphenyl)-5-(pent-l-enyl)pyridine (Example 170) by the methods detailed in Example 126. iH NMR (300 MHz, CDCI3): δ 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, IH), 3.42 (sept, J = 6.6 Hz, IH), 3.82 (s, 3H), 4.35 (d, J = 6.0 Hz, 2H), 6.73 (dd, J = 2.4, 1.5 Hz, IH), 6.76 (dt, J = 7.5, 1.4 Hz), 6.93 (δ, J = 8.4, 3.6, 1.2 Hz, IH), 7.34 (t, J = 8.1 Hz, IH). FAB-MS: calcd for (C24H35NO2) 369, found 370 (M + 1). mp 65-66°.
EXAMPLE 172
Figure imgf000284_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(2-methoxyphenvP-5-(pent-l-envPpyridine
The title compound was prepared from 2-methoxybenzaldehyde by the methods detailed in Example 125. iH NMR (300 MHz, CDCI3): δ 0.82 and 0.72 (t, J
= 7 Hz, 3H), 1.05-1.47 (m, 15H), 1.80-2.00 (m, IH), 2.05 (bs, IH), 3.21-3.60 (m, 2H), 3.75 and 3.76 (s, 3H), 4.27 (d, J = 11.4 Hz, IH), 4.43 (d, J = 11.4 Hz, IH), 5.25-5.44 (m, IH), 6.01-6.07 (m, IH), 6.93-7.03 (m, 3H), 7.29-7.37 (m, IH).
EXAMPLE 173
Figure imgf000284_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(2-methoxyphenvP-5-pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-
(2-methoxyphenyl)-5-(pent-l-enyl)pyridine (Example 172) by the methods detailed in Example 126. iH NMR (300 MHz, CDCI3): δ 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, IH), 2.14 -2.40 (m, 2H), 3.25 (sept, J = 6.6 Hz, IH), 3.46 (sept, J = 6.6 Hz, IH), 3.76 (s, 3H), 4.19 (dd, J = 11.7, 3.0 Hz, IH), 4.39 (dd, J = 11.7, 9.0 Hz), 7.00-7.08 (m, 3H), 7.35-7.42 (m, IH).
EXAMPLE 174
Figure imgf000285_0001
2,6-Diisoproρyl-3-hydroxymethyl-4-[4-(methylthio)phenyl1-5-(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. iH NMR (300
MHz, CDC_3): δ 0.66 and 0.72 (t, J = 7.5 Hz, 3H), 1.05-1.32 (m, 14H), 1.51-1.70 (bs,
IH), 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, IH), 5.85-5.97 (m, IH), 6.99 (d, J = 8.1 Hz), 7.18 (d, J = 8.1 Hz, 2H).
EXAMPLE 175
Figure imgf000285_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-[4-(methylsulfinyl)phenyl1-5-(pent-l- envPpyridine
2,6-Diisopropyl-3-hydroxymethyl-4-[4-(methylthio)phenyl]-5-(pent-l- enyPpyridine (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 0°C and is quenched with the addition of a saturated aqueous solution of NaHSθ3 (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 (Na2Sθ4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to yield the title compound (52 mg, 50%) as a white solid, mp 133-135°C. H NMR
(300 MHz, CDCI3): δ 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, IH), 5.93-6.00 (m, IH), 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.
EXAMPLE 176
Figure imgf000286_0001
2,6-Diisopropyl-3-hydroxymethyl-4-[4-(methylsulfonyl)phenyll-5-(pent-l- enyPpyridine
2,6-Diisopropyl-3-hydroxymethyl-4-[4-(methylsulfinyl)phenyl]-5-(pent-l- 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 0 C and quenched with the addition of a saturated aqueous solution of NaHSθ3 (3 mL). The reaction mixture was further diluted through the addition of water (5 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 (Na2Sθ4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to yield the title compound (31.1 mg, 29%). iH NMR (300 MHz, CDCI3): δ 0.69 and 0.79 (t, J = 7.2 Hz, 3H), 1.08-1.37 (m, 14H), 1.45 (t, J = 4.2 Hz, IH), 1.86-1.93 (m, 2H), 3.10 and 3.11 (s, 3H), 3.25-3.50 (m, 2H), 4.34-4.36 (m, 2H), 5.20-5.50 (m, IH), 5.93- 6.00 (m, IH), 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.
EXAMPLE 177
Figure imgf000287_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-[(4-fluoro-3-hydroxymethyPphenyl1-5- pentylpyridine
Step A: 2<6-Diisopropyl-3-[(^-butyldimethylsiloxy)methyl1-4-(4-fluorophenvP-
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 (45 mL) 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 recrystallized from methanol to provide the product (3.27 g, 79%) as a white fluffy crystalline solid. iH NMR (300 MHz, CDCI3): δ -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, IH), 3.35 (sept, J = 6.6 Hz, IH), 4.24 (s, 2H), 7.05-7.18 (m, 4H). Anal. calc. for C29H46NOFS1: C, 73.83; H, 9.83; N, 2.97. Found: C, 73.82; H, 9.95; N,
2.86.
Step B: 2,6-Diisopropyl-3-f(f-butyldimethylsiloxy)methyll-4-[(4-fluoro-3- hydroxymethyPphenyll-5-pentylpyridine To a solution of the intermediate from Step A (5.4 g, 11.4 mmol) in THF (80 mL) was added sec-butyllithium (1.3 M, 26.4 mL, 3 eq) at -78°C under an argon atmosphere. The yellow solution was stirred for 1 h at -78°C and quenched through the addition 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 (Na2Sθ4), 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") (1M 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), IN aqueous sodium hydroxide (1 mL), and water (3 mL). The resultant mixture was filtered and the precipitate rinsed with ether (100 mL). The combined organic layer was washed with water (25 mL) and brine (25 mL), dried (Na2Sθ4), and concentrated under reduced pressure. The resultant residue was subjected to flash chromatography using a 10% ether-hexane mixture as the eluent. In this manner, 1.1 g of the product was obtained. iH NMR (300 MHz, CDCI3): δ -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, IH), 2.22-2.31 (m, 2H), 3.23 (sept, J = 6.6 Hz, IH), 3.36 (sept, J = 6.6 Hz, IH), 4.22-4.32 (m, 2H), 4.70-4.90 (m, 2H), 7.09-7.12 (m, 2H), 7.23-7.28 (m, IH).
Step C: 2,6-DiisopropyI-3-hydroxymethyl-4-[(4-fluoro-3-hydroxy- methyPphenyll-5-pentylpyridine
To a solution of the intermediate from Step B (123 mg, 0.245 mmol) in THF (3 mL) was added tetrabutylammonim fluoride (1M 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 is 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 (Na2Sθ4) and concentrated under reduced pressure. The resultant residue was purified by flash chromatography 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. H NMR (300 MHz, CDCl3): δ 0.78 (t, J = 6.6 Hz, 3H), 1.10-1.17 (m, 4H), 1.24-1.35 (m, 14H), 2.10-2.40 (m, 2H), 2.73 (bs, IH), 3.22 (sept J = 6.6 Hz, IH), 3.34 (sept, J = 6.6 Hz, IH), 3.85 (bs, 1H), 4.06 (d, J = 11.4 Hz, IH), 4.35 (d, J = 11.4 Hz, IH), 4.48 (d, J = 14.1 Hz, IH), 4.73 (d, J = 14.1 Hz, IH), 7.00-7.06 (m, 2H), 7.25 (d, J = 7.2 Hz, IH). EXAMPLE 178
Figure imgf000289_0001
2,6-Diisopropyl-3-hydroxymethyl-4-[(4-fluoro-3-methoxycarbonyl)-phenyl1-5- pentylpyridine
Step A: 2,6-Diisopropyl-3-f(^-butyldimethylsiloxy)methyll-4-[(4-fluoro-3- formyl)phenyll-5-pentylpyridine To a solution of 2,6-diisopropyl-3-[(f-butyldimethylsiloxy)methyl]-4-[(4- fluoro-3-hydroxymethyl)ρhenyl]-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 concentrated to afford the crude product (0.78 g) as a white waxy solid.
Step B: 2,6-Diisopropyl-3-[(f-butyldimethylsiloxy)methyll-4-[(4-fluoro-3- methoxycarbonyl)phenvπ-5-pentylpyridine
To a solution of the intermediate from Step A (82 mg, 0.164 mmol) in methanol (3 mL) were added potassium cyanide (53 mg, 0.82 mmol) and activated manganese dioxide (71 mg, 5 eq). The mixture was stirred at 25°C for 14 h and is 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 brine (5 mL), dried
(Na2Sθ4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to provide the intermediate (70 mg). H NMR (300 MHz, CDCI3): δ -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, IH), 3.32 (sept, J = 6.6 Hz, IH), 4.15 (d, J = 10.8 Hz, 1H), 4.25 (d, J = 10.8 Hz, IH), 7.15-7.25 (m, IH), 7.40-7.50 (m, IH), 7.69 (dd, J = 6.6, 2.4 Hz, IH), 10.41 (s, IH). FAB-MS: calcd for (C30H46NO2FSP 499, found 500 (M+l). Step C: 2,6-Diisopropyl-3-hvdroxymethyl-4-[(4-fluoro-3-methoxy- carbonvPphenvn-5-pentylpyridine The title compound was prepared from the intermediate obtained in Step B by the method detailed in Example 177, Step C. iH NMR (300 MHz, CDCI3): δ 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, IH), 3.40 (sept, J = 6.6 Hz, IH), 3.93 (s, 3H), 4.25-4.39 (m, 2H), 7.12 (dd, J = 10.3, 8.5 Hz, IH), 7.28 (δ, J = 8.5, 4.8, 2.2 Hz, IH), 7.69 (dd, J = 6.6, 2.2 Hz, IH).
EXAMPLE 179
Figure imgf000290_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-f(4-fluoro-3-pentyl)phenvn-5-pentylpyridine
Step A: 2,6-Diisopropyl-3-f(Nbutyldimethylsiloxy)methyl1-4-f(4-fluoro-3-
(pent-l-envD)phenyπ-5-pentylpyridine
To a solution of 2,6-diisopropyl-3-[(M-utyldimethylsiloxy)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 is 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 (Na2Sθ4) and concentrated under reduced pressure. The resultant residue was subjected to flash chromatography to yield the intermediate (205 mg). JH NMR (300 MHz, CDCI3): δ -0.13 (s, 6H), 0.75-1.47 (m, 35H), 2.13-2.33 (m, 4H), 3.21 (septet, J = 6.6 Hz, IH),
3.34 (septet, J = 6.6 Hz, IH), 2.7 (d, J = 2.7 Hz, 2H), 5.75-6.31 (m, IH), 6.41-6.59 (m, IH), 6.98-7.09 (m, 3H). FAB-MS: calcd for (C34H54NOFSP 539, found 540 (M + 1). Step B: 2,6-Diisopropy.-3-f(,-butyldimethylsiloxy)methyll-4-r(4-fluoro-3- pentyDphenyll-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 atmosphere at 25 C for 16 h. The mixture was then filtered through a pad of silica and the silica pad is 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%). iH NMR (300 MHz, CDCI3): δ -0.11 (s, 6H), 0.76-1.65 (m, 39H), 2.17-2.33 (m, 2H), 2.51-2.78 (m, 2H), 3.21 (septet, J = 6.6 Hz, IH), 3.35 (septet, J = 6.6 Hz, IH), 4.42 (dd, J = 10.2, 16.2, 2H), 6.92-7.05 (m, 3H). FAB-MS: calcd for (C34H56NOFS-)
541, found 542 (M+l).
Step C: 2,6-Diisopropyl-3-hydroxymethyl-4-f(4-fluoro-3-pentvD-phenyl1-5- 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. iH NMR (300 MHz, CDCI3): δ 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, IH), 2.22-2.29 (m, 2H), 2.57-2.75 (m, 2H), 3.21 (sept, J = 6.6 Hz, IH), 3.40 (sept, J = 6.6 Hz, IH), 4.33 (dd, J = 5.6, 1.4 Hz, 2H), 6.93-7.09 (m, 3H). FAB-MS: calcd for (C28H42NOF) 427, found 428 (M + 1). Rf = 0.42 (20% ether-hexanes).
EXAMPLE 180
Figure imgf000291_0001
2,6-Diisopropyl-3-hydroxymethyl-4-f(4-fluoro-3-ethvPphenyn-5-pentylpyridine
The title compound was prepared as a white wax from 2,6-diisopropyl-3-[(f- butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (Example 178, Step A) (200 mg, 0.40 mmol) and an ethyltriphenylphosphonium bromide /sodium amide mixture (Fluka) by the methods detailed in Example 179, Steps A-C. iH NMR (300 MHz, CDCI3): δ 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, IH), 3.40 (sept, J = 6.6 Hz, IH), 4.34 (dd, J = 5.7, 1.8 Hz, 2H), 6.94-7.09 (m, 3H). FAB-MS: calcd for (C25H36NOF) 385, found 386 (M+l). Rf = 0.38 (20% ether-hexanes).
EXAMPLE 181
Figure imgf000292_0001
2,6-Diisopropyl-3-hydroxymethyl-4-[4-fluoro-3-(α-hvdroxy-4-fluoro-benzyPl-5- pentylpyridine
Step A: 2,6-Diisopropyl-3-(f-butyldimethylsilyloxymethyP-4-[4-fluoro-3-(α- 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, Step A) 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 (Na2Sθ4), 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. iH NMR (300 MHz, CDCI3): δ -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, IH), 3.25-3.40 (m, IH), 4.04-4.38 (m, 2H), 6.14 (dd, J = 4.4, 17.9 Hz, IH), 6.97-7.38 (m, 7H). FAB-MS: calcd for (C36H51NOF2SP
595, found 596 (M + 1).
Step B: 2,6-Diisopropyl-3-hvdroxymethyl-4-[4-fluoro-3-( -hydroxy-4- fluorobenzyl)phenyll-5-pentylpyridine The title compound was prepared from the intermediate from Step A by the method detailed in Example 177, Step C. JH NMR (300 MHz, CDCI3): δ 0.72-1.45
(m, 22H), 2.13-2.36 (m, 2H), 2.65 (d, J = 4.2 Hz, IH), 3.21 (sept, J = 6.6 Hz, IH), 3.39 (sept, J = 6.6 Hz, IH), 4.21-4.39 (m, 2H), 6.14-6.17 (m, IH), 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.
EXAMPLE 182
Figure imgf000293_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-[4-fluoro-3-(l-hydroxyethyl)phenvn-5- pentylpyridine
The title compound was prepared as an oil from 2,6-diisopropyl-3-[(f- butyldimethylsiloxy)methyl]-4-[(4-fluoro-3-formyl)phenyl]-5-pentylpyridine (Example 178, Step A) and methylmagnesium bromide by the methods detailed in Example 181, Steps A-B. iH NMR (300 MHz, CDCI3): δ 0.76 (t, J = 6.0 Hz, 3H),
1.09-1.53 (m, 21H), 1.84 (br s, IH), 2.18-2.27 (m, 2H), 2.87 ( br s, 1 H), 3.20 (septet, J = 6.6 Hz, IH), 3.37 (septet, J = 6.6 Hz, IH), 4.16 (d, J = 11.4 Hz, IH), 4.28-4.35 (m, IH), 5.16-5.19 (m, IH), 7.01-7.07 (m, 2H), 7.25-7.34 (m, IH). FAB-MS: calcd for ( 25H36NO2F) 401, found 402 (M + 1). Rf = 0.32 and 0.20 (50% ether-hexanes).
EXAMPLE 183
Figure imgf000293_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-[4-fluoro-3-((N-((pyridin-2-vP- methyPamino)methvPlphenyl-5-pentylpyridine
Step A: 2,6-Diisopropyl-3-l(t-butyldimethylsiloxy)methyll-4-[4-fluoro-3-((N- ((pyridin-2-yl)methvPamino)methvP1phenyl-5-pentylpyrid-ne
To a solution of 2,6-diisopropyl-3-[(f-butyldimethylsiloxy)methyl]-4-[(4-
_luoro-3-formyl)phenyl]-5-pentylpyrid_ne (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 ZnC_2 (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 the addition of aqueous sodium hydroxide (0.1N, 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 (Na2Sθ4), 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%). H NMR (300 MHz, CDCI3): δ -
0.12 (s, 6H), 0.72-0.81 (m, 12H), 1.80 (br s, IH), 1.07-1.15 (m, 4H), 1.27-1.31 (m, 14H), 2.23-2.29 (m, 2H), 3.20 (septet, J = 6.6Hz, IH), 3.34 (septet, J = 6.6 Hz, IH), 3.83-4.03 (m, 4H), 4.25 (dd, J = 10.5, 27.6 Hz, 2H), 7.06-7.33 (m, 5H), 7.64 (δ, J = 1.8, 7.5, 7.5 Hz, IH), 8.54-8.56 (m, IH). FAB-MS: calcd for (C36H54N3OFSP 591, found 592 (M + 1).
Step B: 2,6-Diisopropyl-3-hydroxymethyl-4-f4-fluoro-3-((N-((pyridin-2- yPmethvPamino)methvPlphenyl-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. iH NMR (300 MHz, CDCI3): δ 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, IH), 3.47 (sept, J = 6.6 Hz, IH), 3.74 (d, J = 14.1 Hz, IH), 3.79 (d, J = 13.5 Hz, IH), 3.89 (d, J = 13.5 Hz, IH), 4.07 (d, J = 14.1 Hz, IH), 4.20 (d, J = 11.4 Hz, IH), 4.41 (d, J = 11.4 Hz, IH), 7.02-7.25 (m, 4H), 7.38 (d, J = 7.8 Hz, IH), 7.66 (δ, J = 7.5, 7.5, 1.8 Hz, IH), 8.47 (m, IH). FAB-MS: calcd for (C30H40N3OF) 477, found 478 (M + 1). Rf = 0.4 (ethyl acetate). EXAMPLE 184
Figure imgf000295_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-[4-fluoro-3-(pyrrolidin-l-vPmethvnphenyl-5- pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-[(£-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. iH NMR (300 MHz, CDCI3): δ 0.77 (t, J = 6.6 Hz, 3H), 1.05-1.31 (m, 18 H), 1.75-1.85 (m, 5 H), 2.23-
2.29 (m, 2H), 2.50-3.50 (m, 4H), 3.20 (sept, J = 6.6 Hz, IH), 3.41 (sept, J = 6.6 Hz, 1 H), 3.71 (d, J = 12.9 Hz, IH), 3.82 (d, J = 12.9 Hz, IH), 4.29 (dd, J = 11.7, 20.4 Hz, 2H), 7.03-7.13 (m, 2H), 7.26-7.30 (m, IH). FAB-MS: calcd for (C28H41N2OF) 440, found 441 (M +1). Rf = 0.2 (ethyl acetate).
EXAMPLE 185
Figure imgf000295_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-l4-fluoro-3-(butylamino)methyllphenyl-5- pentylpyridine
The title compound was prepared from 2,6-diisopropyl-3-[(f-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. iH NMR (300 MHz, CDCI3): δ 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), 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, IH), 3.89 (s, 2H), 4.32 (dd, 11.7 Hz, 2H), 7.04-7.20 (m, 3 H). FAB-MS: calcd for (C28H43N20F) 442, found 443 (M +1). Rf = 0.33 (ethyl acetate).
EXAMPLE 186
Figure imgf000296_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(pyridin-3-vP-5-pentylpyridine
The title compound was prepared as an oil from ethyl isobutyryl acetate, ammonium acetate and pyridine-3-carboxaldehyde in 0.56% yield by the methods described in Example 125. FAB-MS: calculated for C22H32N2O 340; found 341
(M+l). αH NMR (300 MHz, CD3OD): δ 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, IH), 3.48 (septet, J = 6.6 Hz, IH), 4.25 (s,
2H), 7.52-7.57 (m, IH), 7.73-7.76 (m, IH), 8.42-8.43 (m, 2H), 8.59 (dd, J = 5.1, 1.5 Hz, IH). 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).
EXAMPLE 187
Figure imgf000296_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(3-furvP-5-(pent-l-enyl)pyridine
Substituting 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) for ceπc ammonium nitrate (CAN) to oxidize the dihydropyridine intermediate to the phenyl pyridine, the title compound was prepared as a mixture of E and Z isomers (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: calculated for C21H29N02 327; found 328 (M+1). H NMR (300 MHz, CD3OD): δ
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, IH), 3.47 (septet, J = 6.6 Hz, IH), 4.44 (s, 2H), 5.40-5.58 (m, 2H), 6.11-6.25 (m, IH), 6.38-6.40 (m, IH), 7.41-7.54 (m, 2H).
EXAMPLE 188
Figure imgf000297_0001
2,6-Diisopropyl-3-hydroxymethyl-4-(3-furyP-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-
(3-furyl)-5-(pent-l-enyl)pyridine (Example 187) in 6% yield by the methods described in Example 125. FAB-MS: calculated for C2ιH 1Nθ2 329; found 330
(M+1). H NMR (300 MHz, CD3OD): δ 0.83 (t, J = 6.8 Hz, 3H), 1.19-1.36 (m, 19H),
2.42-2.48 (m, 2H), 3.25 (septet, J = 6.6 Hz, IH), 3.45 (septet, J = 6.6 Hz, H), 4.38 (s, 2H), 6.42 (m, IH), 7.45-7.46 (m, IH), 7.61-7.62 (t, J = 1.7 Hz, IH). 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.
EXAMPLE 189
Figure imgf000297_0002
2,6-Diisopropyl-3-hvdroxymethyl-4-(thiophen-3-vP-5-(pent-l-enyl)-pyridine
The title compound was prepared as a mixture of E and Z isomers (5.5:1, E:Z) from ethyl isobutyrylacetate, ammonium acetate and thiophene-3- carboxaldehyde in 7% yield by the methods described in Example 125. FAB-MS: calculated for C21H29NOS 343; found 344 (M+1). NMR (300 MHz, CDCI3): δ
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, IH), 6.02-6.12 (m, IH), 6.95-6.97 (m, IH), 7.12-7.13 (m, IH), 7.35-7.38 (m, IH). 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.
EXAMPLE 190
Figure imgf000298_0001
3,5-Diisopropyl-2-hvdroxymethyl-6-pentyl-4/-fluoro-l , 1 '-biphenyl
Step A: l-(2-Methoxyethoxy)methoxymethyl-2,4-diisopropyl-5- hydroxymethylbenzene
A mixture of l,5-bis(hydroxymethyl)-2,4-diisopropylbenzene (0.947 g, 4.26 mmol) (prepared by the method of Fey, et al. U.S. Patent 5,138,090), methoxyethoxymethyl chloride (0.49 mL, 4.29 mmol), and diisopropylethylamine
(1.1 mL, 6.31 mmol) in CH2CI2 (9.6 mL) was stirred overnight. The mixture was diluted with water (50 mL) and extracted with CH2CI2 (3 x 50 mL). Silica gel chromatography (67:33 hexanes /ethyl acetate) provided a colorless oil (0.679 g, 51%). H NMR (CDCI3, 300 MHz): δ 7.31 (s, IH), 7.29 (s, IH), 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: calculated for C18H30O4 310; found 292 (M-H2O, 24%), 221
(100%).
Step B: 3-(2-Methoxyethoxy)methoxymethyl-4,6-diisopropylbenzaldehyde
Prepared from the intermediate obtained in Step A by the procedure described in Example 1, Step E. H NMR (CDCI3, 300 MHz): δ 10.29 (s, IH), 7.80 (s, IH), 7.39 (s, IH), 4.83 (s, 2H), 4.70 (s, 2H), 3.98 (sept, 6.8 Hz, IH), 3.76 (m, 2H), 3.59 (m, 2H), 3.42 (s, 3H), 3.26 (sept, 6.8 Hz, IH), 1.30 (d, 7.0 Hz, 6H), 1.28 (d, 7.0 Hz, 6H). FAB-MS: calculated for C18H28O4308; found 309 (M+H). Step C: -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 (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 NaHCθ3 solution (50 mL) and water (50 mL), dried (MgSθ4), and concentrated to give an orange oil (2.78 g, 96%). The product was used in the next step without purification. 1H NMR (C6D6, 300 MHz): δ 8.70 (s, IH), 8.48 (s, IH), 7.31 (s, IH), 7.17 (m, 4H), 7.00 (m, IH), 4.61 (s, 2H), 4.60 (s, 2H), 3.56 (m, 2H), 3.46 (sept, 6.8 Hz, IH), 3.29 (m, 2H), 3.20 (sept, 6.8 Hz, IH), 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- methoxyethoxy)methoxymethylphenylldipalladium
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 was cooled to rt, poured into water (135 mL), and filtered through a medium porosity fritted funnel. The filtrate was lyophilized. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous NaHCθ3 (50 mL) and saturated aqueous NaCl (50 mL), dried (MgSθ4), and concentrated to give a brown solid. The solid was mixed with 50:50 petroleum ether/ethyl acetate (17 mL) and cooled in the freezer. The resulting precipitate was collected and dried to give a brown solid (0.951 g, 27%). αH NMR (C6D 300 MHz): δ 7.70 (s, IH), 7.65 (s, IH), 7.63 (s, IH), 7.11 (s, IH), 7.08 (s, IH), 6.99 (m, IH), 6.73 (s, IH), 5.33 (s, 2H), 5.08 (s, 2H), 4.19 (m, 2H), 3.35 (m, 2H), 3.04 (s, 3H), 2.68 (sept, 6.8 Hz, IH), 2.15 (sept, 6.8 Hz, IH), 1.01 (d, 7.0 Hz, 6H), 0.96 (d, 7.0 Hz, 6H). FAB-MS: calculated for C48H64N2θ6Pd2 976; found 488 (M/2).
Step E: 3,5-Diisopropyl-2-formyl-6-(2-methoxyethoxy)methoxymethyl-4'- fluoro-1 ,1 '-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. The mixture 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 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%). H NMR (CDCI3, 300 MHz): δ 9.70 (s, IH), 7.50 (s, IH), 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-MS: calculated for C24H31FO4 402; found 403 (M+H).
Step F: 3,5-Diisopropyl-2-(2-methoxyethoxy)methoxymethyl-6-(pent-l-enyl)-
4 -fluoro-l ,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. l NMR (CDCI3, 300 MHz): δ 7.32 (s, IH), 7.12 (m, 2H), 7.01 (m,
2H), 5.95 (d, 16.2 Hz, IH), 5.23 (dt, 16.2 Hz, 7.0 Hz, IH), 4.57 (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 C28H39FO3442; found 442 (M+).
Step G: 3,5-Diisopropyl-2-(2-methoxyethoxy)methoxymethyl-6-pentyl-4 - fluoro-1 ,1 '-biphenyl Prepared from the intermediate obtained in Step F by the procedure described in Example 1, Step H. NMR (CDCI3, 300 MHz): δ 7.29 (s, IH), 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, IH), 3.16 (sept, 6.8 Hz, IH), 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 C28H41FO3444; found 445 (M+H).
Step H: 3,5-Diisopropyl-2-acetoxymethyl-6-pentyl-4'-fluoro-l, -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 Nal (132 mg, 880 mmol) in CH3CN (1.4 mL). After 25 min. the mixture was filtered through silica gel (5:1 hexanes /ethyl acetate) and the filtrate concentrated. A mixture of the residue and sodium acetate (122 mg, 1.49 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 CH2CI2 (3 x 15 mL). Silica gel chromatography (95:5 hexane/ethyl acetate) provided a colorless oil (38.2 mg, 69%). iH NMR (CDCI3, 300 MHz): δ 7.31 (s, IH), 7.15 (m, 2H), 7.07 (m, 2H), 4.76 (s, 2H), 3.18 (sept, 6.8 Hz, IH), 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 C26H35FO2398; found 338 (M-AcOH).
Step I: 3 ,5-Diisopropy 1-2-hvdroxymethy l-6-pentyl-4'-fluoro- 1 , 1 '-biphenyl
A solution of the intermediate 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 50°C for 3 h. The solvent was removed, and the residue dissolved in saturated aqueous ammonium 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%). 1H NMR (CDCI3, 300 MHz): δ 7.30 (s,
IH), 7.19 (m, 2H), 7.11 (m, 2H), 4.32 (s, 2H), 3.37 (sept, 6.9 Hz, IH), 3.16 (sept, 6.9 Hz, IH), 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.
Figure imgf000301_0001
3,5-Diisopropyl-2-(l-hvdroxyethvP-6-pentyl-4,-fluoro-l, -biphenyl
Step A: 3,5-Diisopropyl-2-formyl-6-pentyl-4'-fluoro-l,l'-biphenyl Prepared from 3,5-diisopropyl-2-hydroxymethyl-6-pentyl-4'-fluoro-l,F- biphenyl (Example 190) by the procedure described in Example 1, Step E. iH NMR (CDCI3, 300 MHz): δ 9.70 (s, IH), 7.42 (s, IH), 7.23-7.10 (m, 4H), 3.88 (sept, 6.8 Hz,
IH), 3.23 (sept, 6.8 Hz, IH), 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). Step B: 3,5-Diisopropyl-2-(l-hydroxyethvP-6-pentyl-4'-fluoro-l, -biphenyl
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 101, Step B. NMR (CDCI3, 300 MHz): δ
7.32 (s, IH), 7.19-7.06 (m, 4H), 4.70 (dq, 7.0 Hz, 2.9 Hz, IH), 3.88 (sept, 6.8 Hz, IH), 3.13 (sept, 6.8 Hz, IH), 2.20 (m, 2H), 1.63 (d, 2.9 Hz, IH), 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 C25H35FO 370; found 370 (M+). Rf = 0.36 (83:17 hexanes/ethyl acetate), mp 126°C.
EXAMPLE 192
Figure imgf000302_0001
3,5-Diisopropyl-2-(l-hvdroxyethvP-6-pentyl-4'-fluoro-l,r-biphenyl
In a separate experiment, the title compound was prepared by the methods described in Example 191. H NMR (300 MHz, CDCI3): δ 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, IH), 3.86 - 3.90 (m, IH), 4.66 - 4.73 (m, IH), 7.06 - 7.22 (m, 4H), 7.32 (s, IH). 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, IC). FAB-MS: calculated for C25H35OF 370; found 370 (M+). Anal, calc for C25H35OF: 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; linear 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 f-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. EXAMPLE 193
Figure imgf000303_0001
(+)-3,5-Diisopropyl-2-(l-hydroxyethyP-6-pentyl-4'-fluoro-l, -biphenyl
Step A: 3,5-Diisopropyl-2-(l-hydroxyethyP-6-pentyl-4'-fluoro-l, -biphenyl, hemi-phthalate ester
A solution of 1.90 g (5.36 mmol) of 3,5-diisopropyl-2-formyl-6-pentyl-4'- fluoro-1,1 '-biphenyl (Example 191, Step A) in 36 mL of tetrahydrofuran at -78°C under an argon atmosphere was treated with a dropwise addition of 4.6 mL (6.43 mmol) of a 1.4 M solution of methyllithium in ether. The reaction mixture was allowed to warm to room temperature over one hour. 1.03 g (6.97 mmol) of phthalic anhydride was then added as a solid and stirring was continued for another hour. The reaction was quenched with 30 mL saturated aqueous ammonium chloride and extracted with 60 mL ethyl acetate. Separated organic phase was washed again with 30 mL saturated aqueous ammonium chloride.
Combined aqueous portions were extracted with several portions of 20 mL of ethyl acetate. Combined organic portions were dried (Na2Sθ4) and concentrated in vacuo. The crude mixture was purified by flash column chromatography on silica using hexanes: ethyl acetate:acetic acid (75:24:1) as eluent to provide 2.55 g (4.94 mmol, 97 %) of the product. FAB-MS: calculated for C33H39O4F 518; found 519
(M+H). iH NMR (300 MHz, CDCI3): δ 0.77 (t, J = 7.0 Hz, 3H), 1.03 - 1.30 (m, 18H),
1.53 (d, J = 7.0 Hz, 3H), 2.16 - 2.22 (m, 2H), 3.05 - 3.20 (m, IH), 3.53 - 3.65 (m, IH), 5.87 - 5.93 (m, IH), 7.05 - 7.37 (m, 4H), 7.54 - 8.06 (m, 5H). Rf = 0.47 (75:24:1 hexanes:ethyl acetate:acetic acid).
Step B: (+)-3,5-DiisopropyI-2-(l-hvdroxyethvP-6-ρentyl-4'-fluoro-l ,1 '- biphenyl A solution of 2.54 g (4.90 mmol) of the hemi-phthalate ester from Step A in 50 mL of hexane and 0.5 mL of methanol at reflux was treated with 0.63 mL (4.90 mmol) of (R)-(+)-a-methylbenzylamine. Reflux was continued until solids began to precipitate. At this point, the flask was removed from the hot plate and allowed to cool. Further cooling was achieved by placing the flask in a freezer (-25°C) overnight. Crystals were harvested via filtration and washed with hexane. The amine salt crystals were then suspended in hexane and methanol was added at reflux until the crystals dissolved. Reflux was continued until solids began to precipitate. At this point, the flask was removed from the hot plate and allowed to cool. Further cooling was not necessary and the salt crystals were harvested as above. The salts were crystallized a third time via the second method described, and the harvested crystals were placed in a vacuum oven overnight at 50°C to afford 0.57 g (0.89 mmol, 18 %) of crystalline amine salt. A solution of 0.57 g (0.89 mmol) of the amine salt in 5 mL dioxane was treated with a 20% solution (w/v) of NaOH/H2θ and was held at reflux for 3.5 hours. After cooling to room temperature, the reaction mixture was diluted with 20 mL of ethyl acetate. The separated aqueous phase was extracted with ethyl acetate (2 x 10 mL). Combined organic extracts were dried (Na2Sθ4) and concentrated in vacuo. The crude oil was purified by flash column chromatography on silica using hexanes:ethyl acetate (19:1) and the resulting material placed in a vacuum oven overnight (at 50°C) to afford 0.26 g (0.70 mmol, 79%) of the title compound as a white solid. αH NMR (300 MHz, CDCI3): δ 0.75 - 0.80 (m, 3H), 1.02 - 1.31 (m, 19H), 1.40 (d, J = 6.6 Hz, 3H),
2.17 - 2.22 (m, 2H), 3.08 - 3.18 (m, IH), 3.83 - 3.92 (m, IH), 4.66 - 4.73 (m, IH), 7.05 - 7.23 (m, 4H), 7.32 (s, IH). 13c NMR (75 MHz, CDCI3): δ 13.88, 22.02, 23.38, 24.23,
24.56, 24.63, 25.09, 28.68, 28.96, 29.92, 31.04, 32.23, 68.91, 114.66 - 115.16 (2d, 2C), 124.27, 130.34 - 131.30 (2d, 2C), 135.53, 136.98, 137.74, 139.02, 145.82 (2C), 161.68 (d, J = 245.4 Hz, IC). FAB-MS: calculated for C25H35OF 370; found 370 (M+). Anal, calc for C25H35OF: C, 81.03; H, 9.52. Found: C, 81.15; H, 9.68. Rf = 0.36 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A = 0.05 % aqueous trifluoroacetic acid, B = CH3CN; linear gradient: 75%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 20.0 min (93.9 area %), (Daicel Chiralcel OD-H; isocratic 99:1 hexanes:methyl f-butyl ether; 254 nm, 1.5 mL/min); R.T. 5.23 min.(98.0 area %), 8.37 min. (0.89 area %); 98.2 % e.e. [a]D = +26.9° (c = 0.00196 g/mL, CH2CI2). mp 95.0-96.0°C. EXAMPLE 194
Figure imgf000305_0001
3,5-Diisopropyl-2-hydroxymethyl-6-(pent-l-enyl)-4'-fluoro-l,l'-biphenyl
The title compound was prepared from the intermediate obtained in Example 190, Step F by the procedures described in Example 190, Steps H and I. The olefin was a mixture of cis and trans isomers in a ratio of 17:83. H NMR (CDCI3, 300 MHz): δ 7.33 (s, IH), 7.15-7.02 (m, 4H), 5.95 (d, 16.2 Hz, IH), 5.24 (dt,
16.2 Hz, 7.0 Hz, IH), 4.40 (s, 2H), 3.41 (sept, 6.8 Hz, IH), 3.30 (sept, 6.8 Hz, IH), 1.89 (dt, 7.2 Hz, 7.2 Hz, 2H), 1.33 (d, 6.6 Hz, 6H), 1.24 (d, 7.0 Hz, 6H), 1.2 (m, 2H), 0.74 (t, 7.4 Hz, 3H). FAB-MS: calculated for C24H31FO 354; found 354 (M+). Rf = 0.36 (83:17 hexanes/ethyl acetate). Anal, calculated for C24H31FO: C, 81.31; H, 8.81 Found: C, 81.04; H, 8.65. mp 85-95°C.
EXAMPLE 195
Figure imgf000305_0002
3,5-Dimethyl-2-(l-hvdroxyethyl)-6-propyl-4'-fluoro-l, -biphenyl
Step A: 2-Allyloxy-4,6-dimethylacetophenone
A solution of 2-hydroxy-4,6-dimethylacetophenone (4.99 g, 30.4 mmol) in dimethylformamide (31 mL) was added to a cooled (0°C) suspension of sodium hydride (0.772 g, 32.1 mmol) in dimethylformamide (8 mL). The mixture was warmed to room temperature for 2.5 h. The mixture was recooled to 0°C and allyl bromide (5.4 mL, 62.4 mmol) added. The mixture was warmed to room temperature and stirred 25 h. The mixture was diluted with saturated aqueous sodium chloride solution (150 mL) and extracted with diethyl ether (250 mL + 2 x 125 mL). The combined organic phase was washed with 1 N KOH (2 x 125 mL) and saturated aqueous sodium chloride solution. Silica gel chromatography provided a colorless oil (5.74 g, 92%). :H NMR (CDCI3, 300 MHz): δ 6.64 (s, IH), 6.56 (s, IH), 6.03 (ddt, 17.3 Hz, 10.7 Hz, 5.2 Hz, IH), 5.38 (d, 17.3 Hz, IH), 5.27 (d, 10.7 Hz, IH), 4.55 (d, 5.0 Hz, 2H), 2.51 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H).
Step B: 2-Hvdroxy-3-(prop-2-enyl)-4,6-dimethylacetophenone A solution of the intermediate obtained in Step A (6.30 g, 30.8 mmol) and
2,6-di-£-butyl-4-methylphenol (71.9 mg, 326 mmol) in xylenes was degassed by three freeze-pump-thaw cycles. The mixture was heated in an oil bath at 225°C for 8 h. The mixture was cooled to room temperature and concentrated in vacuo. Silica gel chromatography provided a yellow oil (5.47 g, 87%). 1H NMR (CDCI3, 300 MHz): δ 13.09 (s, IH), 6.56 (s, IH), 5.93 (m, IH), 4.95 (m, 2H), 3.42 (d, 6.0 Hz, 2H), 2.65 (s, 3H), 2.55 (s, 3H), 2.27 (s, 3H). El MS: 204 (M+, 70), 189 (100).
Step C: 2-Acetyl-3,5-dimethyl-6-(prop-2-envPphenyltriflate
A solution of tiiflic anhydride (1.10 mL, 6.54 mmol) in CH2CI2 (3.8 mL) was added to a cooled (-10°C) solution of pyridine (0.58 mL, 6.54 mmol) in CH2CI2 (9.6 mL). After 35 min. a solution of the intermediate obtained in Step B (0.271 g, 1.33 mmol) in CH2CI2 (6.4 mL) was added and the mixture allowed to warm to room temperature. After 5 h the mixture was poured into ice water and extracted with CH2CI2 (2 x 15 mL). Silica gel chromatography provided a yellow oil (0.426 g, 95%). αH NMR (CDCI3, 300 MHz): δ 7.09 (s, IH), 5.86 (m, IH), 5.09 (d, 10.3 Hz,
IH), 4.93 (d, 17.1 Hz, IH), 3.51 (d, 5.6 Hz, 2H), 2.52 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H).
Step D: 3)5-Dimethyl-2-acetyl-6-(prop-2-enyl)-4'-fluoro-l,r-biphenyl
A mixture of the intermediate obtained in Step C (3.25 g, 9.68 mmol), 4- fluorophenylboronic acid (2.06 g, 14.7 mmol), Pd(PPh3)4 (1.13 g, 976 mmol), K3PO4
(4.10 g, 19.3 mmol), and KBr (1.97 g, 16.6 mmol) in 1,4-dioxane (50 mL) was heated at 85°C for 16.5 h. The mixture was poured into saturated aqueous ammonium chloride (100 mL) and extracted with diethyl ether (100 mL + 2 x 75 mL). Silica gel chromatography (95:5 hexanes/ethyl acetate) provided a yellow oil (1.03 g, 38%). αH NMR (CDCI3, 300 MHz): δ 7.18 (m, 2H), 7.06 (m, 3H), 5.76 (m, IH), 4.97 (d, 10.2
Hz, IH), 4.72 (d, 17.0 Hz, IH), 3.15 (d, 5.5 Hz, 2H), 2.32 (s, 3H), 2.24 (s, 3H), 1.91 (s, 3H). Step E: 3,5-Dimethyl-2-acetyl-6-propyI-4'-fluoro-l ,1 '-biphenyl
Prepared from the intermediate obtained in Step D by the procedure described in Example 1, Step H. XH NMR (CDCI3, 300 MHz): δ 7.19 (m, 2H), 7.07
(m, 3H), 2.36 (m, 5H), 2.22 (s, 3H), 1.91 (s, 3H), 1.32 (m, 2H), 0.75 (t, 7.2 Hz, 3H). FAB-MS: calculated for C19H21FO 284; found 285 (M+H).
Step F: 3,5-Dimethyl-2-(l-hvdroxyethyl)-6-propyl-4'-fluoro-l, -biphenyl
A mixture of the intermediate obtained in Step E (21.0 mg, 73.8 mmol) and lithium aluminum hydride (31.0 mg, 0.818 mmol) in tetrahydrofuran (2 mL) was refluxed overnight. Aqueous hydrochloric acid (5%, 1 mL) was added and the mixture stirred lh. The mixture was diluted with 5% aqueous hydrochloric acid (25 mL) and extracted with diethyl ether (3 x 15 mL). Silica gel chromatography provided the title compound as a colorless crystalline solid (15.7 mg, 74%). H NMR (CDCI3, 300 MHz): δ 7.19-7.01 (m, 5H), 4.71 (dq, 6.7 Hz, 3.2 Hz, IH), 2.56 (s, 3H), 2.32 (s, 3H), 2.20 (m, 2H), 1.52 (d, 3.3 Hz, IH), 1.38 (d, 7.0 Hz, 3H), 1.28 (m, 2H), 0.73 (t, 7.2 Hz). EI-MS: calculated for C19H23FO 286; found 286 (M+, 29), 225 (100). R/ = 0.31 (83:17 hexanes/ethyl acetate). Anal, calculated for C19H23FO: C, 79.68; H, 8.10 found: C, 79.46; H, 7.95. mp 98-99°C.
EXAMPLE 196
Figure imgf000307_0001
3,5-Dimethyl-2-(l-hvdroxyethvP-6-(prop-2-envP-4'-fluoro-l,l'-biphenyl The title compound was prepared from the intermediate obtained in
Example 195, Step D by the procedure described in Example 195, Step F. 1H NMR (CDCI3, 300 MHz): δ 7.16-7.02 (m, 5H), 5.66 (m, IH), 4.90 (d, 10.2 Hz, IH), 4.75-4.62
(m, 2H), 2.99 (d, 5.5 Hz, 2H), 2.57 (s, 3H), 2.28 (s, 3H), 1.50 (d, 3.7 Hz, IH), 1.38 (d, 7.0 Hz, 3H). Rf = 0.27 (83:17 hexanes/ethyl acetate). Anal, calculated for C19H21FO: C, 80.25; H, 7.44 Found: C, 80.14; H, 7.36. mp 92°C. EXAMPLE 197
Figure imgf000308_0001
2-Isopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-pentyl-6-methyl-pyridine
Step A: 2-Isopropyl-3-carboethoxy-4-(4-fluorophenyl)-5-carbomethoxy-6- methy 1- 1 ,4-dihyd ropy ridine A mixture of methyl 3-aminocrotonate (13 g, 114 mmol) and 4-carboethoxy- 5-(4-fluorophenyl)-2-methylpent-4-en-2-one (30 g, 114 mmol) (prepared by the method of Angerbauer, et al. U.S. Patent 5,169,857) in absolute ethanol (300 mL) was refluxed overnight. The mixture was concentrated in vacuo and the crude product taken to the next step without purification.
Step B: 2-Isopropyl-3-carboethoxy-4-(4-fluorophenyP-5-(pent-l-enyl)-6- methylpyridine
Prepared from the intermediate obtained in Step A by the procedures described in Example 1, Steps C-F. The olefin was obtained as a mixture of cis and trans isomers in a ratio of 34:66. αH NMR (300 MHz, CDC13): δ 7.16 (m, 2H), 7.04
(m, 2H), 6.02 (m, 1 H), 5.46 (m, IH), 4.01 (m, 2H), 3.06 (m, IH), 2.61 (s, 3H, major isomer), 2.50 (s, 3H, minor isomer), 1.99 (m, IH), 1.67 (m, IH), 1.4 - 1.15 (m, 8H), 0.98 (m, 3H), 0.79 (m, 3H).
Step C: 2-Isopropyl-3-hvdroxymethyl-4-(4-fluorophenyP-5-(pent-l-enyl)-6- methylpyridine A mixture of 1.25 g (3.38 mmol) the intermediate obtained in Step B and lithium aluminum hydride (0.28 g, 6.8 mmol) in tetrahydrofuran (50 mL) was refluxed for 2.5 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate to provide a colorless crystalline solid (1.0 g, 90%). The olefin was obtained as a mixture of cis and trans isomers in a ratio of 19:81. 1H NMR (300 MHz, CDCI3): δ 7.10 (m, 4H), 5.88 (d, 16.2 Hz, 1 H), 5.39 (dt, 16.2 Hz, 7.0 Hz, IH), 4.39 (d, 5.5 Hz, 2H), 3.44 (sept, 7.0 Hz, IH), 2.57 (s, 3H, major isomer), 2.46 (s, 3H, minor isomer), 1.92 (m, 2H), 1.4 - 1.15 (m, 4H), 1.33 (d, 6.6 Hz, 6H), 0.75 (t, 7.4 Hz, 3H). FAB-MS: calculated for C21H26FNO 310; found 326 ((M-H)+). R/= 0.44 (80:20 hexanes/ethyl acetate). Anal, calculated for C21H26FNO: C, 77.03; H, 8.00; F, 5.80; N, 4.28. Found: C, 77.02; H, 8.14; F, 5.99; N, 4.22. mp 106-108°C.
Step D: 2-Isopropyl-3-hvdroxymethyl-4-(4-fluorophenyP-5-pentyl-6- methylpyridine
A mixture of the intermediate obtained in Step C (1.3 g) and 10% Pd/C (0.1 g) in absolute ethanol (50 mL) was stirred under an atmosphere of hydrogen overnight. The mixture was filtered through a pad of silica gel and the pad washed with ethyl acetate. Silica gel chromatography (80:20 hexanes/ethyl acetate) followed by recrystallization from ethyl acetate afforded the title compound as colorless crystals (650 mg, 50%). 2H NMR (300 MHz, CDCI3): δ 7.25 (s, 2H), 7.23 (s,
2H), 4.43 (d, 5.5 Hz, 2H), 3.53 (sept, 7.0 Hz, IH), 2.69 (s, 3H), 2.35 (m, 2H), 1.44 (d, 6.6 Hz, 6H), 1.4 (m, 2H), 1.2 (m, 4H), 0.88 (t, 6.6 Hz, 3H). FAB-MS: calculated for C21H28FNO 310; found 328 ((M-H)+). Rf = 0.43 (80:20 hexanes/ethyl acetate). Anal, calculated for C21H28FNO: C, 76.56; H, 8.57; F, 5.77; N, 4.25. Found: C, 76.71; H, 8.60; F, 6.04; N, 4.21. mp 83-85°C.
EXAMPLE 198
Figure imgf000309_0001
2-Isopropyl-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethyl-6-methylpyridine
Step A: 2-Isopropyl-3-carboethoxy-4-(4-fluorophenyl)-5-hydroxymethyl-6- methylpyridine Prepared from the intermediate obtained in Example 197, Step A by the procedures described in Example 1, Steps C and D. JH NMR (300 MHz, CDCI3): δ 7.25 (m, 2H), 7.09 (m, 2H), 4.44 (d, 5.1 Hz, 2H), 3.97 (q, 7.1 Hz, 2H), 3.04 (sept, 6.8 Hz, IH), 2.71 (s, 3H), 1.53 (t, 5.2 Hz, IH), 1.30 (d, 6.6 Hz, 6H), 0.96 (t, 7.2 Hz, 3H). EI-MS: calculated for 9H22FNO3 331; found 331.
Step B: 2-Isopropyl-3-carboethoxy-4-(4-fluorophenyP-5-(f-butyI- dimethylsiloxy)methyl-6-methylpyridine A solution of the intermediate obtained in Step A (3.41 g, 10.3 mmol) f-butyldimethylsilylchloride (1.86 g, 1.2 equiv), and imidazole (1.75 g, 2.5 equiv) in dimethylformamide (6 mL) was stirred overnight. The mixture was diluted with water and extracted with ethyl acetate. Silica gel chromatography (95:5 hexanes/ethyl acetate) provided a colorless solid (3.5 g, 76%). iH NMR (300 MHz, CD3OD): δ 7.30 (m, 2H), 7.20 (m, 2H), 4.49 (s, 2H), 4.03 (q, 7 Hz, 2H), 3.1 (sept, IH),
2.72 (s, 3H), 1.34 (d, 7.0 Hz, 6H), 1.01 (t, 7.0 Hz, 3H), 0.90 (s, 9H), 0.00 (s, 6H). FAB- MS: calculated for C25H36FNθ3Si 331; found 446 (M+H).
Step C: 2-Isopropyl-3-(pent-l-envD-4-(4-fluorophenvD-5-(f-butyI- dimethylsiloxy)methv--6-methylpyridine
Prepared from the intermediate obtained in Step B by the procedures described in Example 1, Steps D, E, and F. XH NMR (300 MHz, CD3OD): δ 7.2-7.0
(m, 4H), 5.99 (d, 16.2 Hz, IH), 5.28 (dt, 15.6 Hz, 7.2 Hz, IH), 4.30 (s, 2H), 3.38 (m, IH), 2.67 (m, 3H), 1.92 (m, 2H), 1.4-1.2 (m, 8H), 0.85 (s, 9H), 0.75 (t, 7.4 Hz, 3H), - 0.06 (s, 6H).
Step D: 2-Isopropyl-3-(pent-l-enyP-4-(4-fluorophenyP-5-hvdroxymethyl-6- methylpyridine
Tetrabutylammonium fluoride (1 mL of 1.0 M solution in tetrahydrofuran, 2.5 equiv) was added to a solution of the intermediate obtained in Step C (200 mg,
0.45 mmol) in tetrahydrofuran (10 mL). After 2 h the mixture was concentrated in vacuo. The residue was dissolved in water and extracted with ethyl acetate. Silica gel chromatography (80:20 hexanes/ethyl acetate) provided a colorless solid (120 mg, 81%). The olefin was obtained as a mixture of cis and trans isomers in a ratio of 8:92. αH NMR (300 MHz, CDCI3): δ 7.09 (m, 4H), 5.96 (d, 16.2 Hz, 1 H), 5.27 (dt,
16.2 Hz, IH), 4.38 (d, 5.5 Hz, 2H), 3.36 (sept, IH), 2.69 (s, 3H), 1.90 (m, 2H), 1.4 - 1.1 (m, 4H), 1.25 (d, 6.6 Hz, 6H), 0.73 (t, 7.4 Hz, 3H). FAB-MS: calculated for C21H26FNO 327; found 327 (M+). R/= 0.23 (80:20 hexanes/ethyl acetate). Anal, calculated for C21H26FNO: C, 77.03; H, 8.00; F, 5.80; N, 4.28. Found: C, 76.92; H, 8.07; F, 5.92; N, 4.15. mp 119-120°C. Step E: 2-Isopropyl-3-pentyl-4-(4-fluorophenyP-5-hydroxymethyl-6- methylpyridine The title compound was obtained as a colorless solid in 86% yield from the intermediate obtained in Step D by the procedure described in Example 1, Step H. iH NMR (300 MHz, CDC13): δ 7.2 (m, 4H), 4.29 (d, 5.5 Hz, 2H), 3.24 (sept, 6.6 Hz, IH), 2.65 (s, 3H), 2.26 (m, 2H), 1.29 (d, 6.6 Hz, 6H), 1.25 (m, 4H), 1.1 (m, 4H), 0.76 (t, 7.0 Hz, 3H). FAB-MS: calculated for C21H28FNO 329; found 328 ((M-H)+). Rf = 0.20 (80:20 hexanes/ethyl acetate). Anal, calculated for C21H28FNO: C, 76.56; H, 8.57; F, 5.77; N, 4.25. Found: C, 76.49; H, 8.55; F, 5.78; N, 4.21. mp 110-112°C.
EXAMPLE 199
Figure imgf000311_0001
2-Morphol_nomethyl-3-pentyl-4-(4-fluorophenvP-5-hydroxymethyl-6- isopropylpyridine
Step A: 2-Isopropyl-3-(--butyldiphenylsiloxy)methyl-4-(4-fluorophenyl)-5- pentyl-6-methylpyridine
A solution of the intermediate from Example 197, Step D (50 mg, 0.15 mmol), t-butyldiphenylsilylchloride (50 mg, 1.2 equiv), and imidazole (25 mg, 2.5 equiv) in dimethylformamide (0.5 mL) was stirred for 2 h. The mixture was diluted with water and extracted with ethyl acetate. Silica gel chromatography (95:5 hexanes/ethyl acetate) provided a colorless solid (64 mg, 75%). 1H NMR (300
MHz, CD3OD): δ 7.41 (m, 6H), 7.33 (m, 4H), 7.05 (m, 4H), 4.25 (s, 2H), 3.13 (sept, 6.8 Hz, IH), 2.57 (s, 3H), 2.23 (m, 2H), 1.3 (m, 2H), 1.17 (d, 6.6 Hz, 6H), 1.15 (m, 4H), 0.99 (s, 9H), 0.78 (t, 6.4 Hz, 3H).
Step B: 2-Isopropyl-3-(f-butyldiphenylsiloxy)methyl-4-(4-fluorophenyl)-5- pentyI-6-methylpyridine N-oxide A mixture of the intermediate from Step A (60 mg, 0.11 mmol) and 3- chloroperoxybenzoic acid (52 mg, 1.4 equiv) in chloroform (5 mL) was refluxed for 15 min. The mixture was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution (3 x 25 mL). The organic phase was filtered through a shoroom temperature pad of silica gel and concentrated to give a yellow solid (54 mg, 84%). XH NMR (300 MHz, CDC13): δ 7.31 (m, 6H), 7.24 (m, 4H), 6.96 (m, 4H), 4.13 (s, 2H), 3.16 (br s,lH), 2.47 (s,3H), 2.18 (m, 2H), 1.33 (d, 6.6 Hz, 6H), 1.25 (m, 2H), 1.05 (m, 4H), 0.93 (s, 9H), 0.70 (t, 6.4 Hz, 3H).
Step C: 2-Chloromethyl-3-pentyl-4-(4-fluorophenvP-5-(--butyl- diphenylsiloxy)methyl-6-isopropylpyridine Phosphorus oxychloride(9.5 g) and triethyl amine (8.6 mL) were added simultaneously to a refluxing solution of the intermediate obtained in Step B (15 g, 25.8 mmol) in CH2CI2 (30 mL). After 3 h , the mixture was diluted with CH2CI2
(100 mL) and washed with saturated aqueous sodium bicarbonate solution (3 x 100 mL). Silica gel chromatography (90:10 hexanes/ethyl acetate) provided a solid (9.4 g, 61%). iH NMR (300 MHz, CDCI3): δ 7.41 (m, 6H), 7.32 (m, 4H), 7.06 (m, 4H),
4.75 (s, 2H), 4.27 (s, 2H), 3.15 (sept, 6.8 Hz, IH), 2.39 (m, 2H), 1.35 (m, 2H), 1.18 (d, 6.6 Hz, 6H), 1.12 (m, 4H), 1.00(s, 9H), 0.79 (t, 6.6 Hz, 3H).
Step D: 2-MorpholinomethyI-3-pentyl-4-(4-fluorophenyl)-5- (f-butyldiphenylsiloxy)methyl-6-isopropylpyridine
A mixture of the intermediate prepared in Step C (0.5 g, 0.83 mmol), morpholine (0.108 g, 1.5 equiv), and 4-dimethylaminopyridine (0.172 g, 1.7 equiv) in CH2CI2 (15 mL) was refluxed for 2 h. The mixture was washed with saturated aqueous sodium chloride solution. Silica gel chromatography (90:10 hexanes/ethyl acetate) provided a yellow oil (170 mg, 30%). αH NMR (300 MHz, CDCI3): δ 7.41
(m, 6H), 7.34 (m, 4H), 7.05 (m, 4H), 4.26 (s, 2H), 3.71 (m, 4H), 3.67 (s, 2H), 3.13 (sept, 6.8 Hz, IH), 2.61 (m, 4H), 2.35 (m, 2H), 1.15 (d, 6.6 Hz, 6H), 1.1 (m, 4H), 0.99 (s, 9H), 0.9 (m, 2H), 0.78 (t, 7.0 Hz, 3H).
Step E: 2-Morpholinomethyl-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethyl-
6-isopropylpyridine The title compound was prepared from the intermediate obtained in Step D by the procedure described in Example 198, Step D. XH NMR (300 MHz, CDCI3): δ
7.17 (m, 4H), 4.36 (d, 5.1 Hz, 2H), 3.68 (m, 6H), 3.42 (sept, 6.6 Hz, IH), 2.59 (m, 4H), 2.39 (m, 2H), 1.32 (d, 6.6 Hz, 6H), 1.25 (m, 2H), 1.1 (m, 4H), 0.78 (t, 6.6 Hz, 3H).
FAB-MS: calculated for C25H35FN2O2 414; found 415 (M+H). Anal, calculated for C25H35FN2O2: C, 72.43; H, 8.51; F, 4.58; N, 6.76. Found: C, 72.49; H, 8.42; F, 4.71; N, 7.05.
EXAMPLE 200
Figure imgf000313_0001
2,5-Bis(hydroxymethyl)-3-pentyl-4-(4-fluorophenyl)-6-isopropylpyridine
Step A: 2-Acetoxymethyl-3-pentyl-4-(4-fluorophenvP-5-(f-butyl- diphenylsiloxy)methyl-6-isopropylpyridine
A mixture of the intermediate obtained in Example 199, Step B (4.8 g, 7.97 mmol) and acetic anhydride (20 mL) was heated to 100°C for 20 min. The mixture was poured onto ice and the aqueous phase extracted with ethyl acetate (3 x 30 mL). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution (3 x 50 mL), and saturated aqueous sodium chloride solution
(3 x 50 mL). Silica gel chromatography provided a yellow oil (4.4 g, 90%). 1H NMR (300 MHz, CDCI3): δ 7.40 (m, 6H), 7.31 (m, 4H), 7.06 (m, 4H), 5.29 (s, 2H), 4.26 (s,
2H), 3.14 (sept, 6.8 Hz, IH), 2.2 (m, 2H), 2.18 (s, 3H), 1.2 (m, 2H), 1.16 (d, 6.6 Hz,
6H), 1.05 (m, 4H), 0.99 (s, 9H), 0.77 (t, 6.8 Hz, 3H).
Step B: 2-HydroxymethyI-3-pentyl-4-(4-fluorophenyl)-5-(f-butyl- diphenylsiloxy)methyl-6-isopropylpyridine A mixture of the intermediate obtained in Step A (60 mg, 0.096 mmol) and potassium carbonate (5 equiv) in methanol (8 mL) and water (2 mL) was refluxed for 1.5 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. Concentration of the organic phase provided a colorless solid (60 mg, 100%) that was used in the next step without purification.
2H NMR (300 MHz, CDCI3): δ 7.4-7.2 (m, 10H), 7.11 (m, 4H), 4.90 (s, 2H), 4.39 (s,
2H), 3.34 (sept, 7.0 Hz, IH), 2.34 (m, 2H), 1.25 (d, 7.0 Hz, 6H), 1.2 (m, 2H), 1.04 (m, 4H), 0.90 (s, 9H), 0.68 (t, 7.0 Hz, 3H). Step C: 2,5-Bis(hydroxymethyl)-3-pentyl-4-(4-fluorophenyD-6- isopropylpyridine The title compound was prepared from the intermediate obtained in Step B by the procedure described in Example 198, Step D. 2H NMR (300 MHz, CD3OD): δ 7.21 (m, 4H), 4.70 (s, 2H), 4.30 (s, 2H), 3.54 (sept, 6.6 Hz, IH), 2.28 (m, 2H), 1.32 (d,
6.6 Hz, 6H), 1.25 (m, 2H), 1.1 (m, 4H), 0.75 (t, 6.8 Hz, 3H). FAB-MS: calculated for C21H28FNO2 345; found 346 (M+H). Anal, calculated for C21H28FNO2: C, 73.01;
H, 8.17; F, 5.50; N, 4.05. Found: C, 72.89; H, 8.25; F, 5.21; N, 4.41. mp 135-136°C.
EXAMPLE 201
Figure imgf000314_0001
2-Methoxymethyl-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethyl-6- isopropylpyridine
Step A: 2-MethoxymethyI-3-pentyl-4-(4-fluorophenvD-5-(f-butyl- diphenylsiloxy)methyl-6-isopropylpyridine
A mixture of the intermediate obtained in Example 200, Step B (0.1 g, 0.17 mmol), methyl iodide (0.013 mL, 1.2 equiv), and sodium hydride (8 mg of a 60% dispersion in mineral oil, 1.2 equiv) in tetrahydrofuran (1 mL) was heated at 40 °C for 3 h. The mixture was diluted with water and extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated aqueous sodium chloride solution (3 x 10 mL). Silica gel chromatography provided a colorless solid (40 mg, 40%). JH NMR (300 MHz, CDCI3): δ 7.41 (m, 6H), 7.32 (m, 4H), 7.06 (m,
4H), 4.62 (s, 2H), 4.27 (s, 2H), 3.48 (s, 3H), 3.15 (sept, 6.6 Hz, IH), 2.36 (m, 2H), 1.27 (m, 2H), 1.18 (d, 6.6 Hz, 6H), 1.12 (m, 2H), 1.00 (s, 9H), 0.87 (m, 2H), 0.78 (t, 6.6 Hz, 3H). Step B: 2-Methoxymethyl-3-pentyl-4-(4-fluorophenyP-5-hydroxymethyl-6- isopropylpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 198, Step D. αH NMR (300 MHz, CDCI3): δ
7.14 (m, 4H), 4.62 (s, 2H), 4.36 (d, 5.2 Hz, 2H), 3.46 (s, 3H), 3.44 (sept, 6.6 Hz, IH), 2.38 (m, 2H), 1.34 (d, 7.0 Hz, 6H), 1.23 (m, 2H), 1.12 (m, 4H), 0.77 (t, 6.8 Hz, 3H).
FAB-MS: calculated for C22H30FNO2 359; found 360 (M+H). Anal, calculated for 22H30FNO2: C, 73.51; H, 8.41; F, 5.28; N, 3.90. Found: C, 73.40; H, 8.47; F, 5.19;
N, 3.91.
Figure imgf000315_0001
2-Ethoxymethyl-3-pentyl-4-(4-fluorophenyP-5-hvdroxymethyl-6-isopropylpyridine
The title compound was prepared from the intermediate obtained in Example 200, Step B by the procedures described in Example 201, Step A, and
Example 198, Step D. 2H NMR (300 MHz, CDCI3): δ 7.18 (m, 4H), 4.68 (s, 2H), 4.35
(d, 4.4 Hz, 2H), 3.65 (q, 7.0 Hz, 2H), 3.44 (sept, 6.6 Hz, IH), 2.40 (m, 2H), 1.4 (m, 2H), 1.34 (d, 6.6 Hz, 6H), 1.26 (t, 7.0 Hz, 3H), 1.13 (m, 4H), 0.78 (t, 6.6 Hz, 3H). FAB-MS: calculated for C23H32FNO2 373; found 374 (M+H). Anal, calculated for C23H32FNO2: C, 73.96; H, 8.64; F, 5.09; N, 3.75. Found: C, 73.97; H, 8.83; F, 5.33; N, 3.52.
EXAMPLE 203
Figure imgf000315_0002
2-(Prop-2-enyloxy)methyl-3-pentyl-4-(4-fluorophenvP-5-hydroxymethyl-6- isopropylpyridine
The title compound was prepared from the intermediate obtained in
Example 200, Step B by the procedures described in Example 201, Step A, and Example 198, Step D. XH NMR (300 MHz, CDCI3): δ 7.15 (m, 4H), 5.97 (ddt, 17.1
Hz, 10.5 Hz, 6 Hz, 2H), 5.33 (d, 17.3 Hz, IH), 5.21 (d, 10.3 Hz, IH), 4.68 (s, 2H), 4.34 (s, 2H), 4.12 (d, 5.5 Hz, 2H), 3.44 (sept, 6.8 Hz, IH), 2.39 (m, 2H), 1.33 (d, 6.6 Hz, 6H), 1.29 (m, 2H), 1.10 (m, 4H), 0.77 (t, 6.8 Hz, 3H). FAB-MS: calculated for C24H32FNO2 385; found 386 (M+H). Anal, calculated for C24H32FNO2: C, 74.8; H, 8.37; F, 4.93; N, 3.63. Found: C, 75.2; H, 8.54; F, 4.90; N, 3.52.
EXAMPLE 204
Figure imgf000316_0001
2-Benxyloxymethyl-3-pentyl-4-(4-fluorophenvP-5-hvdroxymethyl-6- isopropylpyridine
The title compound was prepared from the intermediate obtained in
Example 200, Step B by the procedures described in Example 201, Step A, and Example 198, Step D. NMR (300 MHz, CDCI3): δ 7.43-7.30 (m, 5H), 7.17 (m,
4H), 4.73 (s, 2H), 4.66 (s, 2H), 4.36 (s, 2H), 3.46 (sept, 6.6 Hz, IH), 2.38 (m, 2H), 1.36 (d, 6.6 Hz, 6H), 1.25 (m, 2H), 1.05 (m, 4H), 0.75 (t, 6.6 Hz, 3H). FAB-MS: calculated for C24H32FNO2 435; found 436 (M+H). Anal, calculated for C28H34FNO2: C,
77.21; H, 7.87; F, 4.36; N, 3.22. Found: C, 77.26; H, 7.84; F, 4.42; N, 3.11. mp 110- 112°C. EXAMPLE 205
Figure imgf000317_0001
2-(l-Hydroxybut-3-envP-3-pentyl-4-(4-fluorophenyP-5-hydroxymethyl-6- isopropylpyridine
Step A: 2-Formyl-3-pentyl-4-(4-fluorophenyP-5-(f-butyldiphenyl- siloxy)methyl-6-isopropylpyridine Prepared from 2-hydroxymethyl-3-pentyl-4-(4-fluorophenyl)-5-
[(f-butyldiρhenylsiloxy)methyl]-6-isopropylpyridine (Example 200, Step B) by the procedure described in Example 1, Step E. JH NMR (300 MHz, CDCI3): δ 10.20 (s,
IH), 7.41 (m, 6H), 7.33 (m, 4H), 7.04 (m, 4H), 4.33 (s, 2H), 3.23 (sept, 6.6 Hz, IH), 2.66 (m, 2H), 1.3-1.1 (m, 6H), 1.22 (d, 6.6 Hz, 6H), 1.01 (s, 9H), 0.79 (t, 7.0 Hz, 3H). FAB-MS: calculated for C37H44FNθ2Si 581; found 582 (M+H).
Step B: 2-(l-Hvdroxybut-3-envD-3-pen-yl-4-(4-fluoroρhenvP-5-
(f-butyldiphenylsiloxy)methyl-6-isopropylpyridine
A mixture of the intermediate obtained in Step A (0.2 g, 0.34 mmol) and allylmagnesium bromide (1 mL of 1.0 M solution in tetrahydrofuran, 3 equiv) in tetrahydrofuran (10 mL) was refluxed for 1.5 h. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution. Silica gel chromatography (97:3 hexanes/ethyl acetate) provided a yellow oil (110 mg, 52%). XH NMR (300 MHz, CDCI3): δ 7.42
(m, 6H), 7.2 (m, 4H), 7.06 (m, 4H), 5.94 (m, IH), 5.14-5.08 (m, 2H), 4.99-4.90 (m, 2H), 4.28 (d, 2.2 Hz, 2H), 3.16 (sept, 6.8 Hz, IH), 2.55 (m, IH), 2.45-2.15 (m, 3H), 1.3 (m, 2H), 1.20 (d, 6.6 Hz, 3H), 1.15 (d, 6.6 Hz, 3H), 1.1 (m, 4H), 0.76 (t, 6.6 Hz, 3H).
Step C: 2-(l-Hvdroxybut-3-envD-3-pentyl-4-(4-fluorophenvP-5- hydroxymethyl-6-isopropylpyridine The title compound was prepared from the intermediate obtained in Step B by the procedure described in Example 198, Step D. H NMR (300 MHz, CDCI3): δ 7.16 (m, 4H), 5.94 (m, IH), 5.13 (d, 7.7 Hz, IH), 5.08 (s, IH), 4.92 (s, 2H), 4.38 (m, 2H), 3.47 (sept, 6.7 Hz, IH), 2.51 (m, IH), 2.4-2.1 (m, 3H), 1.35 (d, 6.6 Hz, 3H), 1.34 (d, 6.6 Hz, 3H), 1.29 (m, 2H), 1.10 (m, 4H), 0.77 (t, 6.6 Hz, 3H). FAB-MS: calculated for C24H32FNO2 385; found 386 (M+H). Rf = 0.15 (85:15 hexanes/ethyl acetate). Anal, calculated for C24H32FNO2: C, 74.77; H, 8.37; F, 4.93; N, 3.63. Found: C, 74.85; H, 8.53; F, 4.99; N, 3.50.
EXAMPLE 206
Figure imgf000318_0001
2-(l-Hvdroxyprop-2-enyl)-3-pentγl-4-(4-_luorophenvP-5-hvdroxymethyl-6- isopropylpyridine
Prepared from the intermediate in Example 205, Step A by the procedures described in Example 205, Step B, and Example 198, Step D. H NMR (300 MHz, CDCI3): δ 7.16 (m, 4H), 5.89 (δ, 17.0 Hz, 10.0 Hz, 7.1 Hz, IH), 5.66 (d, 5.5 Hz, IH), 5.37 (d, 16.9 Hz, IH), 5.26 (t, 5.7 Hz, IH), 5.20 (d, 9.9 Hz, IH), 4.38 (d, 4.8 Hz, 2H), 3.49 (sept, 6.7 Hz, IH), 2.33 (m, IH), 2.13 (m, 2H), 1.35 (d, 6.6 Hz, 3H), 1.34 (d, 6.6 Hz, 3H), 1.2 (m, 2H), 1.10 (m, 4H), 0.76 (t, 6.8 Hz, 3H). FAB-MS: calculated for C23H30FNO2 371; found 372 (M+H).
Figure imgf000318_0002
0.15 (85:15 hexanes/ethyl acetate). MP = 113-115°C. Anal, calculated for C23H30FNO2: C, 74.36; H, 8.14; F, 5.11; N, 3.77. Found: C, 74.16; H, 8.28; F, 5.11; N, 3.60.
Figure imgf000318_0003
2-(Hvdroxy-p-tolyPmethyl-3-pentyl-4-(4-fluorophenyl)-5-hvdroxymethyl-6- isopropylpyridine, hydrochloride
Prepared from the intermediate in Example 205, Step A by the procedures described in Example 205, Step B, and Example 198, Step D. XH NMR (CD3OD, 300 MHz): δ 7.28 (m, 6H), 7.21 (m, 2H), 6.90 (d, 7.7 Hz, IH), 6.43 (s, IH), 4.48 (d, 11.8 Hz, IH), 4.41 (d, 11.8 Hz, IH), 3.96 (sept, 6.8 Hz, IH), 2.46 (s, 3H), 2.19 (m, 2H), 1.61 (d, 7.0 Hz, 3H), 1.58 (d, 7.0 Hz, 3H), 1.0-0.6 (m, 5H), 0.57 (t, 7.0 Hz, 3H), 0.3 (m, IH). FAB-MS: calculated for C28H34FNO2 435; found 436 (M+H). Anal, calculated for C28H34FN02-HC1: C, 71.25; H, 7.47; Cl, 7.51; F, 4.02; N, 2.97. Found: C, 71.43; H, 7.49; Cl, 7.48; F, 4.10; N, 2.87. mp 178-180°C.
EXAMPLE 208
Figure imgf000319_0001
2-(a-Hydroxy)benzyl-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethyl-6- isopropylpyridine
Prepared from the intermediate in Example 205, Step A by the procedures described in Example 205, Step B, and Example 198, Step D. :H NMR (CDCI3, 300 MHz): δ 7.30 (m, 5H), 7.17 (m, 4H), 6.43 (d, 6.6 Hz, IH), 5.79 (d, 6.6 Hz, IH), 4.40 (m, 2H), 3.55 (sept, 6.6 Hz, IH), 2.21-2.09 (m, 2H), 1.45 (d, 6.6 Hz, 3H), 1.43 (d, 6.6 Hz, 3H), 1.32 ( , IH), 1.14-0.88 (m, 6H), 0.69 (t, 3H). FAB-MS: calculated for C27H32FNO2421; found 422 (M+H).
Figure imgf000319_0002
0.10 (85:15 hexanes/ethyl acetate). Anal, calculated for C27H32FNO2: C, 76.93; H, 7.65; F, 4.51; N, 3.32. Found: C, 76.70; H, 7.86; F, 4.45; N, 3.14. EXAMPLE 209
Figure imgf000320_0001
2-(4-Fluorophenyl)hvdroxymethyl-3-pentyl-4-(4-fluorophenvP-5-hydroxymethyl- 6-isopropylpyridine
Prepared from the intermediate in Example 205, Step A by the procedures described in Example 205, Step B, and Example 198, Step D. αH NMR (CDCI3, 300 MHz): δ 7.24 (m, 2H), 7.15 (m, 4H), 6.98 (m, 2H), 6.40 (d, 5.9 Hz, IH), 5.77 (d, 5.5 Hz, IH), 4.40 (m, 2H), 3.55 (sept, 6.6 Hz, IH), 2.13 (m, 2H), 1.43 (d, 6.3 Hz, 3H), 1.41 (d, 6.6 Hz, 3H), 1.08 (m, IH), 0.99 (m, 6H), 0.69 (t, 6.6 Hz, 3H). FAB-MS: calculated for C27H31F2NO2 439; found 440 (M+H). Rf = 0.15 (85:15 hexanes/ethyl acetate). Anal, calculated for C27H31F2NO2: C, 73.78; H, 7.11; F, 8.64; N, 3.19. Found: C, 73.49; H, 7.23; F, 8.45; N, 3.01.
EXAMPLE 210
Figure imgf000320_0002
2-(l-HvdroxyethvP-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethyl-6- isopropylpyridine
Step A: 2-(l-HydroxyethvP-3-pentyl-4-(4-fluorophenvD-5-(f-butyl- diphenvsiloxy)methyl-6-isopropylpyridine Prepared from the intermediate in Example 205, Step A by the procedure described in Example 205, Step B. JH NMR (300 MHz, CDCI3): δ 7.42 (m, 6H), 7.32
(m, 4H), 7.05 (m, 4H), 5.16 (d, 7.7 Hz, IH), 4.99 (m, IH), 4.28 (s, 2H), 3.16 (sept, 6.8 Hz, IH), 2.25 (m, 2H), 1.45 (d, 6.3 Hz, 2H), 1.19 (d, 6.6 Hz, 3H), 1.16 (d, 6.6 Hz, 3H), 1.10 (m, 6H), 0.76 (t, 6.8 Hz, 3H).
Step B: 2-(l-HvdroxyethvP-3-pentyl-4-(4-fluorophenvP-5-hvdroxymethyl-6- isopropylpyridine The title compound was prepared from the intermediate in Step A by the procedure described in Example 198, Step D. XH NMR (CDCI3, 300 MHz): δ 7.19- 7.15 (m, 4H), 5.12 (d, 7.0 H, IH), 4.99 (t, IH), 4.38 (d, 5.5 Hz, 2H), 3.48 (sept, 6.8 Hz, IH), 2.27 (m, 2H), 1.43 (d, 6.3 Hz, IH), 1.35 (d, 6.6 Hz, 6H), 1.30 (m 2H), 1.09 (m, 7H), 0.76 (t, 6.6 Hz, 3H). FAB-MS: calculated for C22H30FNO2 359; found 360 (M+H). Rf= 0.15 (85:15 hexanes/ethyl acetate). Anal, calculated for C22H30FNO2: C, 73.51; H, 8.41; F, 5.28; N, 3.90. Found: C, 73.24; H, 8.40; F, 5.41; N, 3.85. mp 125- 127°C.
EXAMPLE 211
Figure imgf000321_0001
2-(l-HvdroxybutvP-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethyl-6- isopropylpyridine
Prepared from the compound obtained in Example 205 by the procedure described in Example 1, Step H. 2H NMR (300 MHz, CDCI3): δ 7.17 (m, 4H), 4.92
(br s, 2H), 4.85 (br s, 2H), 4.37 (d, 5.2 Hz, 2H), 3.47 (sept, 6.6 Hz, IH), 2.29-2.23 (m, 2H), 1.62-1.53 (m, 5H), 1.35 (d, 6.6 Hz, 3H), 1.34 (d, 6.6 Hz, 3H), 1.3 (m, IH), 1.11 (m, 5H), 0.94 (t, 7.0 Hz, 3H), 0.77 (t, 6.4 Hz, 3H). FAB-MS: calculated for C24H34FNO2 387; found 388 (M+H). Anal, calculated for C24H34FNO2: C, 74.38; H, 8.84; F, 4.90; N, 3.61. Found: C, 74.11; H, 8.93; F, 4.96; N, 3.51. EXAMPLE 212
Figure imgf000322_0001
2-(l-HvdroxypropyP-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethyl-6- isopropylpyridine
The title compound was prepared from the intermediate obtained in
Example 206 by the procedure described in Example 1, Step H. H NMR (300 MHz, CDC13): δ 7.18 (m, 4H), 4.94 (br s, IH), 4.82 (br s, IH), 4.39 (d, 4.8 Hz, 2H), 3.48
(sept, 6.6 Hz, IH), 2.3-2.1 (m, 2H), 1.82 (m, IH), 1.36 (d, 5.5 Hz, 3H), 1.34 (d, 6.3 Hz, 3H), 1.11 (m, 8H), 1.02 (t, 7.4 Hz, 3H), 0.78 (t, 6.6 Hz, 3H). FAB-MS: calculated for C23H32FNO2373; found 374 (M+H).
Figure imgf000322_0002
0.15 (85:15 hexanes/ethyl acetate). Anal, calculated for C23H32FNO2: C, 73.96; H, 8.64; F, 5.09; N, 3.75. Found: C, 73.88; H, 8.57; F, 5.17; N, 3.53. mp 89-90°C.
EXAMPLE 213
Figure imgf000322_0003
2-N-(2-MethoxyρhenvP aminomethy l-3-pentyl-4- (4-fluoropheny P-5- hvdroxymethyl-6-isopropylpyridine
Step A: 2-N-(2-MethoxyphenyPaminomethyl-3-pentyl-4-(4-fluorophenvP-5-
(f-bu-yldiphenvsiloxy)methyl-6-isopropylpyridine A mixture of the intermediate from Example 205, Step A (60 mg, 0.10 mmol) and m-anisidine (50 mg, 4 equiv) in methanol (10 mL) was treated with a mixture of zinc chloride (7 mg, 0.5 equiv) and sodium cyanoborohydride (6 mg, 1 equiv) in methanol (15 mL). After stirring at room temperature overnight the mixture was quenched with water and extracted with ethyl actetate (3 x 15 mL). The combined organic phase was washed with saturated aqueous sodium chloride solution (3 x 15 mL). Silica gel chromatography provided a colorless solid (70 mg, 99%). iH NMR (300 MHz, CDC13): δ 7.43 (m, 6H), 7.32 (m, 4H), 7.16 (m, IH), 7.06 (m, 4H), 6.43 (m,
IH), 6.32 (m, 2H), 5.98 (br s, IH), 4.38 (s, 2H), 4.29 (s, 2H), 3.83 (s, 3H), 3.19 (sept, 6.6 Hz, IH), 2.28 (m, 2H), 1.25 (m, 2H), 1.22 (d, 6.6 Hz, 6H), 1.14 (m, 2H), 0.99 (s, 9H), 0.80 (t, 6.8 Hz, 3H).
Step B: 2-N-(2-MethoxyphenyPaminomethyl-3-pentyl-4-(4-fluorophenyl)-5- hydroxymethyl-ό-isopropylpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 198, Step D. XH NMR (300 MHz, CDCI3): δ
7.16 (m, 5H), 6.43 (m, IH), 6.32 (m, 2H), 4.40 (s, 2H), 4.39 (s, 2H), 3.83 (s, 3H), 3.50 (sept, 6.6 Hz, IH), 2.32 (m, 2H), 1.39 (d, 6.6 Hz, 6H), 1.31 (m, 2H), 1.16 (m, 4H), 0.80 (t, 6.4 Hz, 3H). FAB-MS: calculated for C28H35FN2O2450; found 451 (M+H). Anal, calculated for C28H35FN2O2: C, 74.64; H, 7.83; N, 6.22. Found: C, 74.44; H, 7.75; N, 6.03. mp 109-110°C.
EXAMPLE 214
Figure imgf000323_0001
2-Ethenyl-3-pentyl-4-(4-fluorophenyl)-5-hvdroxymethyl-6-isopropylpyridine
Step A: 2-Ethenyl-3-pentyl-4-(4-fluorophenyl)-5-(f-butyldiphenyl- siloxy)methyl-6-isopropylpyridine n-Butyl lithium (0.03 mL of 1.6 M solution in hexanes) was added to a cooled (0°C) solution of methyltriphenylphosphonium bromide (18 mg) in tetrahydrofuran (3 mL). After 2 h, a solution of 2-formyl-3-pentyl-4-(4- fluorophenyl)-5-(f-butyldiphenylsiloxy)methyl-6-isopropylpyridine (Example 205, Step A) in tetrahydrofuran (1 mL) was added and the mixture warmed to room temperature. After 30 min. the mixture was quenched with water and extracted with ethyl acetate. Silica gel chromatography (95:5 hexanes/ethyl acetate) afforded a colorless solid (20 mg). XH NMR (CDCI3, 300 MHz): δ 7.44-7.36 (m, 6H), 7.34-7.27 (m, 4H), 7.08-6.98 (m, 5H), 6.59 (dd, 16.7 Hz, 2.7 Hz, IH), 5.48 (dd, 10.5 Hz, 2.8 Hz, IH), 4.26 (s, 2H), 3.16 (sept, 6.6 Hz, IH), 2.29 (m, 2H), 1.4-1.2 (m, 2H), 1.19 (d, 6.6 Hz, 6H), 1.15 (m, 4H), 0.98 (s, 9H), 0.78 (t, 6.8 Hz, 3H).
Step B: 2-Ethenyl-3-pentyl-4-(4-fluoroρhenyl)-5-hydroxymethyl-6- isopropylpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 198, Step D. XH NMR (CDCI3, 300 MHz): δ 7.17 (s, 2H), 7.14 (s, 2H), 7.04 (dd, 16.7 Hz, 10.5 Hz, IH), 6.61 (dd, 16.7 Hz, 2.8 Hz, IH), 5.51 (dd, 10.5 Hz, 2.8 Hz, IH), 4.36 (s, 2H), 3.45 (sept, 6.7 Hz, IH), 2.32 (m, 2H), 1.37 (d, 6.6 Hz, 6H), 1.34 (m 2H), 1.15 (m, 4H), 0.80 (t, 6.6 Hz, 3H). FAB-MS: calculated for C22H28FNO 341; found 342 (M+H). Anal, calculated for C22H28FNO: C, 77.38; H, 8.27; N, 4.10. Found: C, 77.15; H, 7.98; N, 4.06.
EXAMPLE 215
Figure imgf000324_0001
2-(2-CarbomethoxyethenvD-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethyl-6- isopropylpyridine
Step A: 2-(2-CarbomethoxyethenvP-3-pentyl-4-(4-fluorophenyl)-5-
(t-butyldiphenylsiIoxy)methyl-6-isopropylpyridine A mixture of the intermediate obtained in Example 205, Step A (50 mg, 85 mmol) and methyl (triphenylphosphoranylidene)acetate (31 mg, 1.1 equiv) in toluene (5 mL) was heated to reflux for 5 h. The mixture was cooled to rt and concentrated in vacuo. Silica gel chromatography provided a yellow oil (60 mg). αH NMR (CDCI3, 300 MHz): δ 7.96 (d, 15.1 Hz, IH), 7.42 (m, 6H), 7.34-7.21 (m, 5H),
7.05 (s, 2H), 7.03 (s, 2H), 4.28 (s, 2H), 3.84 (s, 3H), 3.17 (sept, 6.8 Hz, IH), 2.38 (m, 2H), 1.31 (m, 2H), 1.19 (d, 6.6 Hz, 6H), 1.14 (m, 4H), 1.00 (s, 9H), 0.79 (t, 6.6 Hz, 3H).
Step B: 2-(2-Carbomethoxyethenyl)-3-pentyl-4-(4-fluorophenyl)-5- hvdroxymethyl-6-isopropylpyridine
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 198, Step D. XH NMR (CDCI3, 300 MHz): d
7.95 (d, 15.1 Hz, IH), 7.25 (d, 15.1 Hz, IH), 7.17 (s, 2H), 7.15 (s, 2H), 4.37 (d, 3.7 Hz,
2H), 3.84 (s, 3H), 3.45 (sept, 6.6 Hz, IH), 2.40 (m, 2H), 1.35 (d, 6.6 Hz, 6H), 1.3 (m,
4H), 1.14 (m, 4H), 1.00 (s, 9H), 0.79 (t, 6.6 Hz, 3H). EI-MS: calculated for
C24H30FNO3399; found 399 (M+). Anal, calculated for C24H30FNO3: C, 72.16; H, 7.57; N, 3.51. Found: C, 71.79; H, 7.50; N, 3.32. mp 82-83°C.
EXAMPLE 216
Figure imgf000325_0001
2-(l-MethoxyethyP-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethyl-6- isopropylpyridine
The title compound was prepared from the intermediate obtained in
Example 210, Step A by the procedures described in Example 201, Step A, and Example 198, Step D. 2H NMR (CDCI3, 300 MHz): δ 7.15 (m, 4H), 4.75 (q, 6.3 Hz,
IH), 4.35 (d, 3.7 Hz, 2H), 3.44 (sept, 6.4 Hz, IH), 3.31 (s, 3H), 2.4-2.2 (m, 2H), 1.58 (d, 6.3 Hz, 3H), 1.35 (d, 6.3 Hz, 3H), 1.34 (d, 6.6 Hz, 3H), 1.27 (m, 2H), 1.11 (m, 4H), 0.78 (t, 6.6 Hz, 3H). FAB-MS: calculated for C23H32FNO2 373; found 374 (M+H). Anal, calculated for C23H32FNO2: C, 73.96; H, 8.64; F, 5.09; N, 3.75. Found: C, 73.92; H, 8.75; F, 4.93; N, 3.60. EXAMPLE 217
Figure imgf000326_0001
2-(l-Ethoxyethyl)-3-pentyl-4-(4-fluorophenvP-5-hydroxymethyl-6- isopropylpyridine
The title compound was prepared from the intermediate obtained in
Example 210, Step A by the procedures described in Example 201, Step A, and Example 198, Step D. αH NMR (CDCI3, 300 MHz): δ 7.16 (m, 4H), 4.83 (q, 6.5 Hz,
1H), 4.34 (d, 4.4 Hz, 2H), 3.5-3.2 (m, 3H), 2.4-2.2 (m, 2H), 1.57 (d, 6.6 Hz, 3H), 1.34 (d, 6.6 Hz, 3H), 1.33 (d, 6.6 Hz, 3H), 1.27 (m 2H), 1.10 (m, 4H), 1.20 (t, 7.2 Hz, 3H), 0.77 (t, 6.8 Hz, 3H). FAB-MS: calculated for C24H34FNO2 387; found 388 (M+H). Anal, calculated for C24H34FNO2: C, 74.38; H, 8.84; F, 4.90; N, 3.61. Found: C, 74.67; H, 9.00; F, 5.14; N, 3.27.
EXAMPLE 218
Figure imgf000326_0002
2-Acetyl-3-pentyl-4-(4-fluorophenvP-5-hvdroxymethyl-6-isopropylpyridine
Step A: 2-Acetyl-3-pentyl-4-(4-fluorophenyl)-5-(f-butyldiphenylsiloxy)methyl-
6-isopropylpyridine A mixture of the intermediate obtained in Example 210, Step A (210 mg, 0.35 mmol), pyridinium chlorochromate (113 mg, 1.5 equiv), and Celite (110 mg) in CH2CI2 (13 mL) was stirred overnight. The mixture was filtered through a short pad of silica gel. Silica gel chromatography (95:5 hexanes/ethyl acetate) afforded a colorless solid (120 mg, 57%). :H NMR (CDCI3, 300 MHz): δ 7.41 (m, 6H), 7.34 (m, 4H), 7.06 (s, 2H), 7.03 (s, 2H), 4.29 (s, 2H), 3.18 (sept, 6.6 Hz, IH), 2.75 (s, 3H), 2.54 (m, 2H), 1.3 (m, 2H), 1.19 (d, 6.6 Hz, 6H), 1.15 (m, 4H), 1.00 (s, 9H), 0.77 (m, 3H).
Step B: 2-Acetyl-3-pentyl-4-(4-fluorophenvP-5-hydroxymethyl-6- isopropylpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 198, Step D. lU NMR (CDCI3, 300 MHz): δ
7.17 (s, 2H), 7.15 (s, 2H), 4.39 (d, 5.2 Hz, 2H), 3.48 (sept, 6.8 Hz, 3H), 2.74 (s, 3H), 2.55 (m, 2H), 1.35 (d, 6.6 Hz, 6H), 1.3 (m, 2H), 1.1 (m, 4H), 0.77 (t, 6.6 Hz, 3H). FAB-MS: calculated for C22H28FNO2 357; found 358 (M+H). Anal, calculated for C22H28FNO2: C, 73.92; H, 7.90; N, 3.92. Found: C, 73.89; H, 8.14; N, 3.88. mp 69- 70°C.
EXAMPLE 219
Figure imgf000327_0001
2-(l-Hydroxy-l-methylethyP-3-pentyl-4-(4-fluorophenyP-5-hydroxymethyl-6- isopropylpyridine
Step A: 2-(l-Hvdroxy-l-methylethyl)-3-pentyl-4-(4-fluorophenvP-5- (f-butyldiphenylsiloxy)methyl-6-isopropylpyridine
Prepared from the intermediate obtained in Example 218, Step A by the procedure described in Example 205, Step B. XH NMR (CDCI3, 300 MHz): δ 7.41
(m, 6H), 7.32 (m, 4H), 7.08 (m, 4H), 4.25 (s, 2H), 3.13 (sept, 6.8 Hz, IH), 2.44 (m, 2H), 1.62 (s, 6H), 1.2 (m, 2H), 1.17 (d, 6.6 Hz, 6H), 1.03 (m, 4H), 1.01 (s, 9H), 0.72 (t, 6.8 Hz, 3H). Step B: 2-(l-Hvdroxy-l-methylethvD-3-ρentyl-4-(4-fluorophenvD-5- hvdroxymethyl-6-isopropylpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 198, Step D. 2H NMR (CDCI3, 300 MHz): δ
7.19 (m, 4H), 4.36 (d, 5.5 Hz, 2H), 3.48 6(sept, 6.6 Hz, IH), 2.47 (m, 2H), 1.60 (s, 6H), 1.35 (d, 6.6 Hz, 6H), 1.25 (m, 2H), 1.05 (m, 4H), 0.72 (t, 6.6 Hz, 3H). FAB-MS: calculated for C23H32FNO2 373; found 374 (M+H). Anal, calculated for C23H32FNO2: C, 73.96; H, 8.63; F, 5.09; N, 3.75. Found: C, 73.88; H, 8.64; F, 4.81; N, 3.59. mp l80-182°C.
EXAMPLE 220
Figure imgf000328_0001
2-(l-Methoxy-l-methvPethyl-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethyl-6- isopropylpyridine
The title compound was prepared from the intermediate obtained in Example 219, Step A by the procedures described in Example 201, Step A, and Example 198, Step D. lH NMR (CDCI3, 300 MHz): δ 7.26-7.12 (m, 4H), 4.34 (d, 5.5 Hz, 2H), 3.40 (sept, 6.5 Hz, IH), 3.12 (s, 3H), 2.76 (m, 2H), 1.67 (s, 6H), 1.31 (d, 6.6 Hz, 6H), 1.3-0.9 (m, 6H), 0.72 (t, 6.8 Hz, 3H). FAB-MS: calculated for C24H34FNO2 387; found 388 (M+H). Anal, calculated for C24H34FNO2: C, 74.38; H, 8.84; N, 3.61. Found: C, 74.64; H, 8.97; N, 3.61. mp 57-59°C. EXAMPLE 221
Figure imgf000329_0001
2-(l-Ethoxy-l-methyPethyl-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethyl-6- isopropylpyridine
The title compound was prepared from the intermediate obtained in Example 219, Step A by the procedures described in Example 201, Step A, and Example 198, Step D. NMR (CDCI3, 300 MHz): δ 7.23-7.11 (m, 4H), 4.33 (d, 5.1 Hz, 2H), 3.39 (sept, 6.6 Hz, IH), 3.28 (q, 7.0 Hz, 2H), 2.80 (m, 2H), 1.67 (s, 6H), 1.30 (d, 6.6 Hz, 6H), 1.15 (t, 7.0 Hz, 3 H), 1.15-0.9 (m, 6H), 0.71 (t, 6.6 Hz, 3H). FAB-MS: calculated for C25H36FNO2 401; found 402 (M+H). Anal, calculated for C25H36FNO2: C, 74.78; H, 9.04; N, 3.49. Found: C, 74.89; H, 9.22; N, 3.24.
EXAMPLE 222
Figure imgf000329_0002
(+)-2,6-Diisopropyl-3-(l-hvdroxyethvP-4-(4-fluorophenyP-5-propyl-pyridine
Step A: (±)-2,6-DiisopropV--3-ll-hvdroxy-2-(S)-toluylsulfoxyethyH-4-(4- fluorophenyP-5-propylpyridine A solution of lithium diisopropylamide was prepared by the addition of n- butyllithium (15 mL, 23 mmol, 1.6 M/hexane) to a solution of diisopropylamine (3 mL, 23 mmol) in anhydrous tetrahydrofuran (100 mL) at 0 °C. To this was added a solution of (S)-(-)-methyl p-tolylsulfoxide (3.6 g, 23 mmol) in anhydrous tetrahydrofuran (20 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- propyl-3-pyridinecarboxaldehyde (Example 101, Step A) (3.8 g, 11 mmol) in anhydrous tetrahydrofuran (50 mL) dropwise and with stirring. After stirring 15 min at 0 °C, the reaction mixture was quenched by the addition of saturated NH4CI
(5 mL). The solvent was removed in vacuo and the residue partitioned between CHCI3 (300 mL) and water (100 mL). The organic phase was washed with saturated NaHCθ3 (100 mL), water (100 mL) and brine (50 mL), dried over MgSθ4 and concentrated. The crude product consisted of a 1.3:1 ratio of diastereomers which were separated by flash chromatography (step gradient 5%-15%-20% ethyl acetate/hexane), which afforded 1.5 g of the faster diastereomer (I), followed by 2.7 g of the slower diastereomer (II) and 0.83 g of a mixed fraction. Diastereomer II is recrystallized once from ethanol /hexane to afford fine white needles (1.7 g, 3.5 mmol, 30% yield). I: mp 225-227°C; Rf = 0.4 (30% ethyl acetate/hexane); iH NMR (CDCI3, 500 MHz): δ 7.23 (m, 4 H), 6.95 (m, 2 H), 6.63 (m, 1 H), 6.55 (m, 1 H), 5.03 (d, / = 11.0 Hz, 1 H), 4.53 (s, 1 H), 3.79 (m, 2 H), 3.11 (sept, J = 6.6 Hz, 1 H), 2.46 (s, 3 H), 2.30 (dd, / = 1.9, 14.1 Hz, 1 H), 2.01 (m, 2 H), 1.25 (m, 12 H), 1.16 (m, 2 H), 0.64 (t, / = 7.3 Hz, 3 H). FAB-MS: calcd for C29H36FNO2S, 481, found 482 (M+H). II: mp 205-206'C; Rf = 0.2 (30% ethyl acetate/hexane); iH NMR (CDCI3, 500 MHz): δ 7.38 (d, / = 8.2 Hz, 2 H), 7.24 (m, 2 H), 7.05 (m, 1 H), 7.03 (m, 1 H), 6.97 (m, 1 H), 6.87 (m, 1 H), 4.84 (dt, / = 2.7, 10.8 Hz, 1 H), 3.69 (sept, / = 6.6 Hz, 1 H), 3.49 (dd, / = 10.8, 13.1 Hz, 1 H), 3.14 (sept, / = 6.6 Hz, 1 H), 3.00 (d, / = 2.5 Hz, 1 H), 2.68 (dd, / = 2.5, 13.1 Hz, 1 H), 2.41 (s, 3 H), 2.10 (m, 2 H), 1.23 (m, 14 H), 0.69 (t, / = 7.3 Hz, 3 H). FAB-MS calcd for C29H36FNO2S, 481, found 482 (M+H).
Step B: (+)-2,6-Diisopropyl-3-(l-hvdroxyethyl)-4-(4-fluorophenyl)-5- propylpyridine A suspension of Raney nickel (20 g) in methanol (50 mL) was stirred under a hydrogen atmosphere for 1 hr. The suspension was cooled to 0 °C and treated with a solution of the intermediate II obtained in Step A (1.6 g, 3.3 mmol) in methanol (50 mL). The suspension was stirred vigorously under hydrogen at 0 °C for 16 hr. After purging with argon, the methanolic solution was decanted from the catalyst, the catalyst washed and decanted 3 more times with methanol. The combined decanted solution was filtered through celite and concentrated. Flash chromatography through a plug of silica (10% ethyl acetatehexane) afforded the title compound (99% e.e.) as a white solid (1.1 g, 3.2 mmol, 96%). iH NMR (CDCI3, 300 MHz): δ 7.11 (m, 3 H), 7.04 (m, 1 H), 4.64 (dq, / = 3.7, 6.6 Hz, 1 H), 3.73 (sept, / = 6.6 Hz, 1 H), 3.18 (sept, / = 6.6 Hz, 1 H), 2.15 (m, 2 H), 1.56 (d, / = 3.7 Hz, 1 H), 1.39 (d, / = 6.6 Hz, 3 H), 1.28 (m, 14 H), 0.73 (t, / = 7.35 Hz, 3 H). FAB-MS calcd for C22H30F O, 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, 8.71; N, 3.76; F, 5.73. [a]D = +41.5° (CHCI3). mp 101-103'C. Rf = 0.3 (10% ethyl acetate/hexane).
EXAMPLE 223
Figure imgf000331_0001
(+)-2,6-Diisopropyl-3-(l-hydroxyethvP-4-(4-fluorophenyl)-5-propyl-pyridine
Step A: 2,6-Diisopropyl-4-(4-fluorophenyI)-5-propyl-3-[(l-oxo-2- toluylsulfoxy)ethyl)lpyridine To a solution of diisopropylamine (4.8 mL, 36.7 mmol) in anhydrous tetrahydrofuran (160 mL) was added n-butyllithium (23 mL, 33.4 mmol, 1.45 M/THF) at 0°C. To the reaction mixture was added a solution of (S)-(-)-methyl p- tolylsulfoxide (5.65 g, 36.7 mmol) in anhydrous tetrahydrofuran (30 mL). The mixture was stirred for 1.5 hours, then treated with a solution of 2,6-diisopropyl-4- (4-fluorophenyl)-5-propyl-3-pyridinecarboxaldehyde (Example 101, Step A) (8.0 g, 24.4 mmol) in anhydrous tetrahydrofuran (100 mL) at 0°C. After stirring 15 minutes at 0°C, the reaction was quenched by addition of saturated ammonium chloride solution (8 mL). The solvent was removed in vacuo and the residue dissolved in choroform (480 mL). The organic phase was washed with water (2 x 160 mL) and brine (160 mL), dried over magnesium sulfate and concentrated. The residue was dissolved in dichloromethane (800 mL) and manganese (IV) dioxide (40 g, 464 mmol) is added. The suspension was stirred vigorously with a mechanical stirrer and refluxed for 16 hours. The manganese (IV) dioxide was removed by filtration through celite, washed with dichloromethane (100 mL) and the solvent removed in vacuo. Filtration through a pad of silica gel (7.5% diethyl ether- dichloromethane) afforded a white solid (10.2 g, 21.3 mmol, 87%). JH NMR (300 MHz, CDCI3): δ 7.39 (m, 2 H), 7.26 (m, 2 H), 7.05 (m, 4 H), 3.72 (d, / = 16 Hz, 1 H), 3.38 (d, / = 16 Hz, 1 H), 3.24 (sept, / = 6.6 Hz, 1 H), 2.59 (sept, / = 6.6 Hz, 1 H), 2.42 (s, 3 H), 2.32 (m, 2 H), 1.27 (m, 8 H), 1.20 (m, 8 H), 0.75 (t, / = 7.35 Hz, 3 H). FAB-MS: calculated for C29H34FNO2S, 479, found 480 (M+H). mp 140-142°C. Rf = 0.2 (20% ethyl acetate/hexane).
Step B: 2,6-Diisopropyl-3-(l-hvdroxy-2-(S)-toluylsuIfoxyethvP-4-(4- fluorophenyP-5-propylpyridine
To a solution of the intermediate obtained in Step A (5.8 g, 12.1 mmol) in anhydrous tetrahydrofuran (145 mL) at -78°C was added rapidly a solution of lithium aluminum hydride (169 mL, 169 mmol, 1.0 M/THF). After 15 minutes the reaction mixture became turbid and was slowly quenched at -78°C with water (6 mL) , 20% aqueous sodium hydroxide solution (6 mL) and water (18 mL). The reaction mixture was allowed to warm to room temperature and the resulting suspension was filtered through a pad of celite. The solvent was evaporated and the residue purified by silica gel chromatography (10% diethyl ether/dichloromethane) to afford a white solid (4.8 g, 10 mmol, 83%). XH NMR
(300 MHz, CDCI3): δ 7.41 (d, J = 8.5 Hz, 2 H), 7.27 (m, 2 H), 7.06 (d, / = 7 Hz, 2 H),
7.00 (m, 1 H), 6.89 (m, 1 H), 4.85 (dt, / = 2.2, 11 Hz, 1 H), 3.71 (sept, / = 6.6 Hz, 1 H), 3.51 (dd, / = 11, 13 Hz, 1 H), 3.16 (sept, / = 6.6 Hz, 1 H), 3.02 (d, / = 2.2 Hz, 1 H), 2.70 (dd, / = 2.2, 13 Hz, 1 H), 2.43 (s, 3 H), 2.12 (m, 2 H), 1.25 (m, 14 H), 0.71 (t, / = 7.35 Hz, 3 H). FAB-MS calculated for C29H36F O2S, 481, found 482 (M+H). mp 204- 206°C. Rf = 0.2 (30% ethyl acetate/hexane).
Step C: (+)-2,6-Diisopropyl-3-(l-hvdroxyethvD-4-(4-fluorophenvD-5- propylpyridine A suspension of Raney nickel (40 g, washed with 3 x lOOmL ethanol) in ethanol (80 mL) was stirred under hydrogen atmosphere for 1.5 hours. The suspension was treated with a solution of the intermediate obtained in Step B (4.1 g,
8.5 mmol) in ethanol (180 mL) at room temperature and stirred vigorously for 5 hours. The suspension was carefully filtered through celite and concentrated. Filtration through silica gel (CH2CI2) afforded the title compotmd (99% e.e.) as a white solid (2.74 g, 8 mmol, 94 %). iH NMR (300 MHz, CDCI3): δ 7.11 (m, 3 H), 7.04 (m, 1 H), 4.64 (dq, / = 3.7, 6.6 Hz, 1 H), 3.73 (sept, / = 6.6 Hz, 1 H), 3.18 (sept, / =
6.6 Hz, 1 H), 2.15 (m, 2 H), 1.56 (d, / = 3.7 Hz, 1 H), 1.39 (d, / = 6.6 Hz, 3 H), 1.28 (m, 14 H), 0.73 (t, / = 7.35 Hz, 3 H). FAB-MS calculated for (C22H31FNO, M+H) 344, found 344. Anal. Calcd for C22H30FNO: C, 76.93; H, 8.80; N, 4.08; F, 5.53; Found: C, 77.20; H, 8.97; N, 4.01; F, 5.60. [a]D = +39.4° (CH2CI2). mp 104-106°C. Rf = 0.4 (CH2CI2). EXAMPLE 224
Figure imgf000333_0001
(+)-2,6-Diisopropyl-3-(l-hydroxyethvP-4-(4-fluorophenyl)-5-propyl-pyridine
Step A: 2,6-Diisopropyl-3-(l-oxoethyl)-4-(4-fluorophenvD-5-propylpyridine
To (±)-2,6-diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5- propylpyridine (Example 101) (8.03 g, 23.4 mmol) in CH2CI2 (600 mL) was added pyridinium chlorochromate (10.08 g, 46.76 mmol) and celite (10.1 g) under argon. The reaction was stirred at room temperature for 16 hours. The reaction was added to a 1:1 mixture of diethyl ether /hexane (1 L), then filtered through a plug of silica. The pad was washed with 150 mL of diethyl ether and the combined filtrates were concentrated in vacuo to afford a white solid (7.95 g, 23.3 mmol, 98%). H NMR (300 MHz, CDCI3): δ 7.12 (m, 4 H), 3.26 (septet, / = 6.6 Hz, 1 H), 2.85 (septet, /
= 6.6 Hz, 1 H), 2.36 (m, 2 H), 1.97 (s, 3 H), 1.33 (m, 14 H), 0.774 (t, / = 7.4 Hz, 3 H). FAB-MS calcd for (C22H28 OF) 341, found 342 (M+H). mp 131-133'C. Rf = 0.5 (50% CH2Cl2/hexane).
Step B: (+)-2,6-Diisopropyl-3-(l-hvdroxyethyl)-4-(4-fluorophenyl)-5- propylpyridine To a solution of (lS,2R)-(+)-N-methylephedrine (31.1 g, 0.174 mol) in ether (208 mL) was added lithium aluminum hydride (lM/diethyl ether, 1.5 eq., 174 mL) dropwise at 0°C under argon. The reaction was refluxed for 1.5 h. turning from a clear solution to a white milky solution. The reaction was cooled to room temperature and then -78°C. The intermediate obtained in Step A (39.53g, 0.116 mmol) was dissolved in 400 mL of dry diethyl ether and cooled to 0°C for a dropwise addition to the reaction mixture (~2 mL/min., the temperature should not rise above -60°C). The reaction was kept at -78°C for 4.0 hours and then allowed to warm overnight. The reaction was quenched at 0°C with isopropanol (70 mL) and diluted with ether (700 mL), washed with water (4 x 500 mL), 10% HCl (2 x 500 mL), brine (2 x 500 mL) and dried with MgSθ4. Filtration and concentration afforded a residue which was filtered through a pad of silica (600 g, 10% diethyl ether/hexane) to give the title compound (97% e.e.) as a white solid (36.67 g, 107 mmol, 92%). iH NMR (300 MHz, CDCI3): δ 7.11 (m, 4 H), 4.67 (dq, / = 3.3, 6.6 Hz, 1 H), 3.74 (septet, / = 6.6 Hz, 1 H), 3.20 (septet, / = 6.6 Hz, 1 H), 2.17 (m, 2 H), 1.61 (d, / = 2.9 Hz, 1 H), 1.40 (d, / = 7.0 Hz, 3 H), 1.30 (m, 14 H), 0.741 (t, / = 7.4 Hz, 3 H). FAB-MS: calcd for (C22H30NOF) 343, found 344 (M+H). mp 102-104°C. Rf = 0.2 (60% CH2CI2 /hexane).
EXAMPLE 225
Figure imgf000334_0001
2-Isopropyl-3-hvdroxymethyl-4-(4-fluorophenvP-5-pentyl-6-(2-frflMs- phenylethyPpyridine
Step A: 2-Bromomethyl-3-pentyl-4-(4-fluorophenyP-5-(f-butyl- diphenylsiloxy)methyl-6-isopropylpyridine Prepared from the intermediate obtained in Example 200, Step B by the procedure described in Example 47, Step B. H NMR (300 MHz, CDCI3): δ 7.40 (m,
6H), 7.32 (m, 4H), 7.04 (m, 4H), 4.64 (s, 2H), 4.26 (s, 2H), 3.14 (sept, 6.8 Hz, IH), 2.38 (m, 2H), 1.34 (m, 2H), 1.17 (d, 7.0 Hz, 6H), 1.12 (m, 4H), 1.00 (s, 9H), 0.78 (t, 6.6 Hz, 3H).
Step B: 2-(D-ethylphosphono)methyl-3-pentyl-4-(4-fluorophenyl)-5-(f- butyldiphenylsiloxy)methyl-6-isopropylpyridine
A mixture of diethylphosphite (280 mg) and sodium metal (50 mg) in benzene (5 mL) was stirred overnight. A mixture of the sodium diethylphosphite solution (1 mL) and the intermediate obtained in Step A (110 mg, 0.17 mmol) in benzene (5 mL) was refluxed for 2 h. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium chloride solution (3 x 10 mL). Silica gel chromatography (70:30 hexanes/ethyl acetate) provided a yellow oil (80 mg, 67%). H NMR (300 MHz, CDC13): δ 7.41 (m, 6H), 7.32 (m, 4H), 7.04 (m, 4H), 4.25 (s, 2H), 4.15 (dq, 7.2 Hz,
4H), 3.49 (d, 22.4 Hz, 2H), 3.14 (sept, 6.8 Hz, IH), 2.38 (m, 2H), 1.30 (t, 7.2 Hz, 6H), 1.25 (m, 2H), 1.16 (d, 6.6 Hz, 6H), 1.10 (m, 4H), 0.99 (s, 9H), 0.77 (t, 6.8 Hz, 3H).
Step C: 2-(£ratts-2-PhenylethenvD-3-pentyl-4-(4-fluorophenyP-5-
(Nbutyldiphenylsiloxy)methyl-6-isopropylpyridine
Sodium hydride (8 mg) was added to a mixture of the intermediate obtained in Step B (90 mg, 128 μmol) and benzaldehyde (20 mg) in THF (2.7 mL). After 15 min. the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. Silica gel chromatography (97:3 hexanes/ethyl acetate) provided a yellow oil (100 mg). αH NMR (300 MHz, CDCI3): δ 8.00 (d, 15.4 Hz,
IH), 7.61 (m, 2H), 7.45-7.27 (m, 14H), 7.04 (m, 4H), 4.29 (s, 2H), 3.20 (sept, 6.4 Hz, IH), 2.38 (m, 2H), 1.40 (m, 2H), 1.25 (d, 6.6 Hz, 6H), 1.18 (m, 4H), 1.00 (s, 9H), 0.81 (m, 3H).
Step D: 2-(trflns-2-PhenylethenvP-3-pentyl-4-(4-fluorophenyl)-5- hydroxymethyl-6-isopropylpyridine The title compound was prepared from the intermediate obtained in
Step C by the procedure described in Example 198, Step D. Silica gel chromatography (94:6 hexanes/ethyl acetate) provided a yellow oil (24 mg, 38%). αH NMR (300 MHz, CDCI3): δ 8.02 (d, 15.5 Hz, IH), 7.63 (m, 2H), 7.43-7.31 (m, 4H),
7.16 (m, 4H), 4.38 (s, 2H), 3.48 (sept, 6.6 Hz, IH), 2.41 (m, 2H), 1.42 (d, 6.6 Hz, 6H), 1.4 (m, 2H), 1.19 (m, 4H), 0.82 (t, 6.8 Hz, 3H). FAB-MS: calculated for C28H32FNO 417; found 418 (M+H). Rf- 0.13 (90:10 hexanes/ethyl acetate). Anal, calculated for C28H32FNO: C, 80.54; H, 7.72; N, 3.35. Found: C, 80.34; H, 7.79; N, 3.10. mp 98- 100°C.
EXAMPLE 226
Figure imgf000335_0001
2-Isopropyl-3-hvdroxymethyl-4-(4-fluorophenvP-5-pentyl-6-(2-methyl- propenyPpyridine
The title compound was prepared as a yellow oil from the intermediate obtained in Example 225, Step B by the procedure described in Example 225, Step C and Example 198, Step D. The product was obtained as an inseparable mixture of the title compound and the corresponding deconjugated olefin in a ratio of 84:16. iH NMR (300 MHz, CDCI3): δ 7.16 (m, 4H), 6.43 (s, IH), 4.82 (s, IH, minor isomer),
4.60 (s, IH, minor isomer), 4.36 (s, 2H), 3.58 (s, 2H, minor isomer), 3.46 (sept, 6.6 Hz, IH), 2.26 (m, 2H), 2.07 (s, 3H), 1.99 (s, 3H), 1.82 (s, 3H, minor isomer), 1.35 (d, 7.0 Hz, 6H), 1.28 (m, 2H), 1.13 (m, 4H), 0.79 (t, 6.8 Hz, 3H). FAB-MS: calculated for C24H32FNO 369; found 370 (M+H). Rf = 0.16 (90:10 hexanes/ethyl acetate). Anal, calculated for C24H32FNO: C, 78.01; H, 8.73; N, 3.79. Found: C, 77.73; H, 8.86; N, 3.97.
EXAMPLE 227
Figure imgf000336_0001
2-Isopropyl-3-hydroxymethy_-4-(4-fluorophenvD-5-pentyl-6-(2-phenyl- ethyPpyridine
The title compound was prepared as a yellow oil from the intermediate obtained in Example 225, Step D by the procedure described in Example 1, Step H. XH NMR (300 MHz, CDCI3): δ 7.29-7.19 (m, 5H), 7.14 (s, 2H), 7.12 (s, 2H), 4.34 (s,
2H), 3.44 (sept, 6.6 Hz, IH), 3.18-3.10 (m, 4H), 2.20 (m, 2H), 1.35 (d, 6.6 Hz, 6H), 1.22 (m, 2H), 1.08 (m, 4H), 0.76 (t, 6.8 Hz, 3H). FAB-MS: calculated for C28H34FNO 419; found 420 (M+H). Rf = 0.21 (90:10 hexanes/ethyl acetate). Anal, calculated for C28H34FNO: C, 80.18; H, 8.17; N, 3.34. Found: C, 80.12; H, 8.15; N, 3.24. EXAMPLE 228
Figure imgf000337_0001
2-Isopropyl-3-hydroxymethyl-4-(4-fluorophenvP-5-pentyl-6-(2-methyl- propyPpyridine
The title compound was prepared as a colorless crystalline solid from the intermediate obtained in Example 226 by the procedure described in Example 1, Step H. XH NMR (300 MHz, CDC13): δ 7.15 (m, 4H), 4.33 (d, 5.2 Hz, 2H), 3.41 (sept,
6.6 Hz, IH), 2.67 (d, 7.0 Hz, 2H), 2.34 (m, 2H), 2.25 (m, 2H), 1.32 (d, 6.6 Hz, 6H), 1.20 (m, 2H), 1.12 (m, 4H), 0.99 (d, 6.6 Hz, 6H), 0.78 (t, 6.6 Hz, 3H). FAB-MS: calculated for C24H34FNO 371; found 372 (M+H). Rf = 0.77 (90:10 hexanes/ethyl acetate). Anal, calculated for C24H34FNO: C, 77.59; H, 9.22; N, 3.77. Found: C, 77.49; H, 9.20; N, 3.73.
EXAMPLE 229
Figure imgf000337_0002
2-Isopropyl-3-hvdroxymethyl-4-(4-fluorophenvP-5-pentyl-6-(3-methyl- butvPpyridine
The title compound was prepared as a yellow oil from the intermediate obtained in Example 225, Step B by the procedures described in Example 225, Steps C and D, and Example 1, Step H. :H NMR (300 MHz, CDCI3): δ 7.14 (m, 4H), 4.34 (d, 3.7 Hz, 2H), 3.41 (sept, 6.8 Hz, IH), 2.80 (m, 2H), 2.26 (m, 2H), 1.68 (m, 3H), 1.33 (d, 6.6 Hz, 6H), 1.29 (m, 2H), 1.12 (m, 4H), 0.98 (d, 6.3 Hz, 6H), 0.79 (t, 6.6 Hz, 3H). FAB-MS: calculated for C25H36FNO 385; found 386 (M+H). Rf = 0.15 (90:10 hexanes/ethyl acetate). Anal, calculated for C25H36FNO: C, 77.88; H, 9.41; N, 3.63. Found: C, 77.62; H, 9.13; N, 3.42.
EXAMPLE 230
Figure imgf000338_0001
2-Isopropyl-3-hvdroxymethyl-4-(4-fluorophenvP-5,6,7,8-tetrahydro-8,8- dimethylquinoline
Step A: 2-[(4-Fluorophenyl)methylenel-4-methyl-3-oxopentanoic acid
To a solution of ethyl isobutyryl acetate (30 g, 0.190 mol) in ethanol (75 mL) was added cyclohexane (120 mL), acetic acid (0.6 mL), piperidine (0.6 mL), and 4- fluorobenzaldehyde (20.35 mL, 0.190 mol). The reaction was heated at reflux with a
Dean-Starck trap for 5 hours. The mixture was poured into 200 mL of diethyl ether and washed with brine (1 x 75 mL). The organic layer was dried with MgSθ4, filtered, and concentrated to afford an orange oil. The product was taken directly to the next step without any further purification. Rf = 0.1 (50% CH2CI2/ hexane).
Step B: 2-Isopropyl-3-carboethoxy-4-(4-fluorophenyl)-5,6,7,8-tetrahydro-8,8- dimethylquinoline
To a solution of lithium bis(tiimethylsilyl)amide (1.0 M/THF, 2 eq. 13.6 mL) in THF (15 mL) was added 2,2-dimethylcyclohexanone (1.88 mL, 13.6 mmol) at -
78°C. The reaction was stirred for 15 minutes, and then the intermediate obtained in Step A (3 g, 11.4 mmol) was added dropwise. The reaction was stirred overnight and allowed to warm to room temperature. To the crude product was added acetic acid (19.4 mL), ammonium acetate (2.62 g, 34.0 mmol) and copper acetate (5.14 g, 28.3 mmol). The reaction mixture was heated at 100°C and the THF was removed by distillation. The reaction was heated to 130°C and allowed to reflux for 24 hours. Ethyl acetate (100 mL) was added and washed with sodium bicarbonate (2 x 30 mL), water (2 x 20 mL), brine (2 x 20 mL), dried with MgSθ4, filtered, and concentrated to afford an oil. Flash chromatography (5 % ethyl acetate/hexane) afforded a white solid (1.36 g, 3.7 mmol, 32%). iH NMR (300 MHz, CDCI3): δ 7.17 (m, 2 H), 7.08 (m, 2 H), 3.98 (q, / = 7.4 Hz, 2 H), 3.03 (septet, / = 7.0 Hz, 1 H), 2.35 (t, / = 5.9 Hz, 2 H), 1.70 (m, 4 H), 1.36 (s, 6 H), 1.31 (d, / = 4.1 Hz, 6 H), 0.965 (t, / = 7.4 Hz, 3 H). FAB-MS: calculated for (C23H28FNO) 369, found 370 (M+H). mp 124-
126°C. Rf = 0.6 (50% CH2CI2 /hexane).
Step C: 2-Isopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5,6,7,8-tetrahvdro-
8,8-dimethylquinoIine
To the intermediate obtained in Step B (1.32 g, 3.6 mmol) in THF (35 mL) was added lithium aluminum hydride (1 M/THF, 2 eq., 7.2 mL) dropwise. The reaction was refluxed for 1.5 hours and cooled to room temperature. Then the reaction was quenched with water and the THF was evaporated. The residue was partitioned between diethyl ether (150 mL) and water (100 mL). The organic layer was washed with brine (1 x 100 mL), dried with MgSθ4, filtered, and concentrated to afford a solid. Flash chromatography (40% CH2CI2 /hexane) afforded the title compound as a white solid (808 mg, 2.5 mmol, 70%). !H NMR (300 MHz, CDCI3): δ 7.13 (d, / = 7.0 Hz, 4 H), 4.36 (d, / = 5.5 Hz, 2 H), 3.42 (septet, / = 6.6 Hz, 1 H), 2.24
(t, / = 5.5 Hz, 2 H), 1.67 (m, 4 H), 1.32 (m, 13 H). FAB-MS: calculated for (C21H26FNO) 327, found 328 (M+H). mp 146-149°C. Rf = 0.2 (50% CH2CI2 / hexane) .
EXAMPLE 231
Figure imgf000339_0001
2-Isopropyl-3-(l-hvdroxyethvP-4-(4-fluorophenyl)-5,6,7,8-tetrahydro-8,8- dimethylquinoline Step A: 2-Isopropyl-3-carboxaldehvde-4-(4-fluorophenyP-5,6,7,8-tetrahydro-
8,8-dimethylquinoline
To a solution of 2-isopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5,6,7,8- tetrahydro-8,8-dimethylquinoline (Example 230) (765 mg, 2.34 mmol) in dichloromethane (30 mL) was added Celite (1.01 g) and pyridinium chlorochromate
(1.01 g, 4.69 mmol). The reaction was stirred at room temperature for 2 hours and then added to a 1:1 diethyl ether/hexane solution (500 mL). The solution was passed through a pad of silica and washed several times with diethyl ether.
Concentration yielded a white solid (568 mg, 1.75 mmol, 75%). H NMR (300 MHz, CDCI3): δ 9.78 (s, 1 H), 7.15 (m, 4 H), 3.86 (septet, / = 6.6 Hz, 1 H), 2.31 (t, / = 5.9
Hz, 2 H), 1.70 (m, 4 H), 1.37 (s, 6 H), 1.30 (m, 6 H). FAB-MS: calculated for (C21H24FNO) 325, found 326 (M+H). mp 94-96°C. Rf = 0.7 (50% CH2CI2/ hexane).
Step B: 2-Isopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenvP-5,6,7,8-tetrahydro- 8,8-dimethylquinoline
To the intermediate obtained in Step A (508 mg, 1.56 mmol) in THF (20 mL) was added methylmagnesium bromide (0.57 mL, 3.0 M/ether, 1.1 eq.) dropwise at -78 °C. After 2 hours, the reaction was quenched with saturated ammonium chloride (30 mL) and diluted with dichloromethane (100 mL). The solid was filtered and the mother liquor was washed with water (1 x 50 mL), brine (1 x 50 mL), dried with MgSθ4, filtered, and concentrated to afford a white solid. Flash chromatography (50% dichloromethane/hexane) gave a white solid (205 mg, 0.6 mmol, 39%). iH NMR (300 MHz, CDCI3): δ 7.13 (m, 3 H), 7.01 (m, 1 H), 4.73, 4.71
(dq, / = 3.7, 6.6 Hz, 1 H), 3.74 (septet, / = 6.6 Hz, 1 H), 2.13 (q, / = 4.4 Hz, 2 H), 1.64 (m, 3 H), 1.31 (m, 17 H). FAB-MS: calculated for (C22H27FNO) 341, found 342 (M+H). mp 56.5-58.5°C. Rf = 0.2 (50% CH2CI2 /hexane).
EXAMPLE 232
Figure imgf000340_0001
2,6-Diisopropyl-3-hvdroxymethyl-4-(4-fluorophenvP-5-(l-butenyl)pyridine
The title compound was prepared from ethyl isobutyrylacetate,
4-fluorobenzaldehyde and 3-methyl-l-phenyl-2-butanone according to the procedures described in Example 230. iH NMR (300 MHz, CDCI3): δ 7.16 (m, 3 H), 6.91 (m, 6 H), 4.45 (d, / = 5.1 Hz, 2 H), 3.52 (sept., / = 6.6 Hz, 1 H), 2.86 (sept., / = 6.6 Hz, 1 H), 1.55 (s, 1 H), 1.36 (m, 6 H), 1.17 (d, / = 6.6 Hz, 6 H). FAB-MS: calculated for (C24H26FNO) 363, found 364 (M+H). mp 115-117βC. Rf = 0.3 (60% CH2C_2/hexane).
EXAMPLE 233
Figure imgf000341_0001
2,6-Diisopropyl-3-(l-hvdroxyethyP-4-(4-fluorophenyP-5-phenylpyridine The title compound was prepared according to the procedures described in Example 231. JH NMR (300 MHz, CDCI3): δ 7.14 (m, 3 H), 6.88 (m, 6
H), 4.80 (dq, / = 7.0, 3.7 Hz, 1 H), 3.84 (sept., / = 6.6 Hz, 1 H), 2.79 (sept., / = 6.6 Hz, 1 H), 1.66 (d, / = 3.7 Hz, 1 H), 1.48 (d,/ = 7.0 Hz, 3 H), 1.39 (m, 6 H). FAB-MS: calculated for (C25H28FNO) 377, found 378 (M+H). mp 155-157°C. Rf = 0.4 (60% CH2Cl2/hexane).
EXAMPLE 234
Figure imgf000341_0002
2-Isopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-7,7-dimethyl-5H-cvclo- pentafblpyridine
The title compound was prepared from ethyl isobutyrylacetate, 4 fluorobenzaldehyde and 2,2-dimethylcyclopentanone according to the procedures described in Example 230. JH NMR (300 MHz, CDCI3): δ 7.29 (m, 2 H), 7.14 (m, 2 H), 4.49 (d, / = 5.2 Hz, 2 H), 3.46 (sept., / = 6.6 Hz, 1 H), 2.56 (t, / = 7.0 Hz, 2 H), 1.90 (t, / = 7.0 Hz, 2 H), 1.34 (m, 13 H). FAB-MS: calculated for (C20H24FNO) 313, found 314 (M+H). mp 141-143°C. Rf = 0.1 (60% CH2CI2 /hexane).
EXAMPLE 235
Figure imgf000342_0001
2-Isopropyl-3-(l-hvdroxyethvP-4-(4-fluorophenyP-7,7-dimethyl-5H-cyclo- pentafblpyridine
The title compound was prepared according to the procedures described in Example 231. JH NMR (300 MHz, CDCI3): δ 7.15 (m, 4 H), 4.95 (dq, / = 6.6, 3.7 Hz,
1 H), 3.77 (sept., / = 6.6 Hz, 1 H), 2.44 (m, 2 H), 1.88 (t, / = 7.4 Hz, 2 H), 1.62 (d, / = 3.7 Hz, 1 H), 1.48 (d, / = 7.0 Hz, 3 H), 1.32 (m, 12 H). FAB-MS: calculated for (C21H26FNO) 327, found 328 (M+H). mp 90-92°C. Rf = 0.1 (60% CH2C_2/hexane).
EXAMPLE 236
Figure imgf000342_0002
2-Isopropyl-3-hvdroxymethyl-4-(4-fluorophenvP-5,6-dihvdro-6,6,8- trimethylquinoline
The title compound was prepared from ethyl isobutyrylacetate, 4 fluorobenzaldehyde and 2,4,4-trimethyl-2-cyclohexen-l-one according to the procedures described in Example 230. αH NMR (300 MHz, CDCI3): δ 7.16 (m, 4 H),
5.81 (s, 1 H), 4.41 (d, / = 5.2 Hz, 2 H), 3.45 (sept., / = 6.6 Hz, 1 H), 2.29 (s, 2 H), 2.16 (s, 3 H), 1.58 (s, 1 H), 1.35 (d, / = 6.6 Hz, 6 H), 0.95 (s, 6 H). FAB-MS: calculated for (C22H26FNO) 339, found 340 (M+H). mp 112-114'C. Rf = 0.2 (60% CH2CI2 /hexane).
EXAMPLE 237
Figure imgf000343_0001
2-Isopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5,6-dihydro-6<6,8- trimethylquinoline
The title compound was prepared according to the procedures described in Example 231. H NMR (300 MHz, CDCI3): δ 7.14 (m, 3 H), 7.00 ( m, 1 H), 5.78 (s, 1
H), 4.77 (dq, / = 6.6, 3.7 Hz, 1 H), 3.76 (sept., / = 6.6 Hz, 1 H), 2.18 (s, 2 H), 2.14 (s, 3 H), 1.61 (d, / = 3.7 Hz, 1 H), 1.43 (d, / = 6.6 Hz, 3 H), 1.33 (m, 6 H), 0.91 (s, 6 H). FAB-MS: calculated for (C23H28FNO) 353, found 354 (M+H). mp 117-119°C. Rf = 0.3 (60% CH2Cl2/hexane).
Figure imgf000343_0002
2,6-Diisopropyl-3-(l-hvdroxyethyP-4-(4-fluoro-2-hvdroxyphenvP-5-propylpyridine
Step A: 2,6-DiisopropyI-3-hvdroxymethyl-4-f(2-benzyloxy-4-fluoro)phenyl]-
5-prop-l-envPpyridine Prepared from the intermediate obtained in Example 166, Step B by the methods described in Example 160, Steps A-D. H NMR (300 MHz, CDCI3): δ 1.20-
1.34 (m, 12H), 1.56-1.59 (m, 3H), 1.68-1.74 (m, IH), 3.13-3.50 (m, 2H), 4.23-4.42 (m, 2H), 4.87-5.05 (m, 2H), 5.25-5.56 (m, IH), 5.23-6.03 (m, IH), 6.69-6.77 (m, 2H), 6.95- 7.08 (m, 3H), 7.22-7.27 (m, 3H). FAB-MS: calcd for (C28H32NO2F) 433; found 434 (M + 1). Rf = 0.30 (10% ethyl acetate-hexane).
Step B: 2,6-Diisopropyl-3-(l-hvdroxyethyP-4-(4-fluoro-2-hydroxyphenyl)-5- propylpyridine The title compound was prepared as two separable diastereomers from the intermediate obtained in Step A by the methods described 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: iH NMR (300 MHz, CDCI3): δ 0.75 (t, J = 7.2 Hz, 3H), 1.27-
1.40 (m, 17H), 1.66 (br s, IH), 2.02-2.12 (m, IH), 2.20-2.31 (m, IH), 3.21 (sept, J = 6.6 Hz, IH), 3.60 (sept, J = 6.6 Hz, IH), 4.94 (m, IH), 5.03 (br s, IH), 6.70-6.76 (m, 2H),
6.94-7.00 (m, IH); FAB-MS: calcd for (C22H30NO2F) 359, found 360 (M + 1). Rf =
0.29 (20% ethyl acetate-hexane). mp 152-153°C.
Diastereomer 1 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 1% (1% acetic acid, 99% ethanol) and 99% hexane at a flow rate of 150 mL/min. The sample was dissolved in chloroform (50 mg/mL) and 5 mL aliquots were injected at 40 min intervals. The effluent was monitored at 280 nm and two fractions (corresponding to the two enantiomers) were collected at (17-23 min,100% ee) and (23-32 min, 98% ee), respectively.
Diastereomer 2: H NMR (300 MHz, CDCI3): δ 0.75 (t, J = 7.2 Hz, 3H), 1.26-
1.31 (m, 14H), 1.38 (d, J = 6.9 Hz, 3H), 1.84-1.87 (m, IH), 2.05-2.14 (m, IH), 2.24-2.34 (m, IH), 3.20 (septet, J = 6.6 Hz, IH), 3.72 (septet, J = 6.6, IH), 4.58-4.65 (m, IH), 5.06 (br s, IH), 6.67-6.74 (m, 2H), 6.85-6.90 (m, IH); FAB-MS: calcd for (C22H30NO2F) 359, found 360 (M + 1). Rf = 0.19 (20% ether-hexanes). mp 157-159°C.
Figure imgf000345_0001
2,6-Diisopropyl-3-(l-hydroxymethyl)-4-(4-fluoro-2-hvdroxyphenyl)-5- propylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-
[(2-benzyloxy-4-fluoro)phenyl]-5-(prop-l-enyl)pyridine (Example 238, Step A) by the method described in Example 161, Step A (mp 138-141°C). 2H NMR (300 MHz, CDCI3): δ 0.76 (t, J = 7.2 Hz, 3H), 1.24-1.35 (m, 14H), 1.82 (br s, IH), 2.12-2.22 (m,
IH), 2.27-2.37 (m, IH), 3.24 (sept, J = 6.6 Hz, IH), 3.39 (sept, J = 6.6 Hz, IH), 4.29 (d, J = 11.4 Hz, IH), 4.52 (d, J = 10.8 Hz, IH), 5.72 (br s, IH), 7.70-6.77 (m, 2H), 6.94-7.00 (m, IH). FAB-MS: calcd for (C21H28NO2F) 345; found 346 (M + 1). Rf = 0.30 (10% ethyl acetate-hexane).
The racemate 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 1% (1% acetic acid, 99% ethanol) and 99% hexane at a flow rate of 100 mL/min. The sample was dissolved in mobile phase (5 mg/mL) and 3 mL aliquots were injected at 30 min intervals. The effluent was monitored at 280 nm and two fractions (corresponding to the two enantiomers) were collected at (24-36 min,100% ee) and (26-30 min, 95.5% ee), respectively.
EXAMPLE 240
Figure imgf000345_0002
2,6-Diisopropyl-3-(l-hvdroxyethvP-4-(4-fluoro-2-hvdroxyphenvP-5-ethylpyridine
Step A: 2,6-Diisopropyl-3-hydroxymethv.-4-f(2-benzyloxy-4-fluoro)phenyll-
5-ethenyl)pyridine Prepared from the intermediate obtained in Example 166, Step B by the methods described in Example 160, Steps A-D. iH NMR (300 MHz, CDCI3): δ 1.25-
1.33 (m, 12H), 1.66-1.70 (m, IH), 3.34-3.50 (m, 2H), 4.28-4.41 (m, 2H), 4.89-5.18 (m, 4H), 6.29-6.39 (m, IH), 6.67-6.78 (m, 2H), 7.23-7.25 (m, 3H). FAB-MS: calcd for (C27H30NO2F) 419; found 420 (M + 1). Rf = 0.29 (10% ethyl acetate-hexane).
Step B: 2,6-Diisopropyl-3-carboxaldehyde-4-[(2-benzyIoxy-4-fluoro)phenyl1-
5-ethenyl)pyridine Prepared from the intermediate obtained in Step A by the method described in Example 164, Step A. H NMR (300 MHz, CDCI3): δ 1.25-1.33 (m, 12H), 3.24 (sept, IH, J = 6.6 Hz), 3.89 (sept, IH, J = 6.6 Hz), 4.93-5.04 (m, 3H), 5.23 (dd, IH, J = 1.5, 11.4 Hz), 6.40 (dd, IH, J = 11.4, 17.7 Hz), 6.70-7.04 (m, 2H), 6.99-7.04 (m, IH), 7.10-7.14 (m, 2H), 7.24-7.29 (m, 3H), 9.82 (s, IH). FAB-MS: calcd for (C27H28 O2F) 417; found 418 (M + 1). Rf = 0.68 (10% ethyl acetate-hexane).
Step C: 2,6-Diisopropyl-3-(2-hydroxyethvP-4-[(2-hydroxy-4-fluoro)phenyl1-5- ethyPpyridine
To an oven-dried 250 mL three-neck round bottom flask equipped with a thermometer were added copper(I) iodide (3.21 g, 16.9 mmol) and toluene (40 mL) under an argon atmosphere. The slurry was cooled to an internal temperature of 0°C . Methyllithium (1.4M in ether, 25 mL, 0.03314 mol) was added at a rate to maintain reaction temperature <5°C. The reaction was then allowed to stir at 0°C for 50 min. At the end of this time the intermediate from Step B (1.33 g, 3.19 mmol) in 10 mL toluene was added via syringe at a rate to maintain reaction temperature <5°C. The syringe was rinsed with an additional 4 mL toluene and this rinse was added to the reaction mixture at a rate to maintain reaction temperature <5°C. The reaction was stirred at 0°C for 35 min. The reaction was then quenched by the addition of a saturated solution of ammonium chloride (20 mL) and was allowed to stir for 36 h at 25°C. The reaction mixture was poured into a separtory funnel and was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was then concentrated to yield the crude intermediate (1.4 g, yellow oil, 9:1 ratio of diastereomers). The crude intermediate was dissolved in a mixture of ethanol (30 mL) and tetrahydrofuran (10 mL) under argon, treated with 10% palladium on carbon (140 mg), and was 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 was purified by flash chromatography (12-15% ethyl acetate-hexane) to yield 1.0 g of the title compound as two separate diastereomers. Diastereomer 1: JH NMR (300 MHz, CDCI3): δ 0.91 (t, J = 7.4 Hz, 3H), 1.28-
1.40 (m, 15H), 1.70 (d, J = 3.9 Hz, IH), 2.12-2.24 (m, IH), 2.29-2.41 (m, IH), 3.24 (sept, J = 6.6 Hz, IH), 3.61 (sept, J = 6.6 Hz, IH), 4.89-5.00 (m, IH), 5.10 (br s, IH), 6.70-6.76 (m, 2H), 6.96-7.01 (m, IH); FAB-MS: calcd for (C21H28NO2F) 345, found
346 (M + 1). Rf = 0.43 (30% ether-hexane). mp 190-191°C. Diastereomer 1 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 1% (1% acetic acid, 99% ethanol) and 99% hexane at a flow rate of 100 mL/min. The sample (1 g) was dissolved in a mixture of CH2CL2 (40 mL), ethanol (1 mL), and 10 mL of the mobile phase. The mixture was injected and the effluent was monitored at 280 nm and two fractions (corresponding to the two enantiomers) were collected at (27-29 min, 99.8% ee) and (37-57 min, 99.4% ee), respectively. Fraction 1 (27-29 min): [α]25D +4.7° (c = 0.54, CH2C-2)-
Diastereomer 2: iH NMR (300 MHz, CDCI3): δ 0.89 (t, J = 7.5 Hz, 3H), 1.26- 1.38 (m, 15H), 1.92 (d, J = 3 Hz, IH), 2.12-2.25 (m, IH), 2.31-2.43 (m, IH), 3.23 (septet, J = 6.6 Hz, IH), 3.72 (septet, J = 6.6, IH), 4.56-4.63 (m, IH), 5.14 (br s, IH), 6.68-6.74 (m, 2H), 6.85-6.91 (m, IH); FAB-MS: calcd for (C21H28NO2F) 345, found 346 (M + 1). Rf = 0.27 (30% ether-hexane). mp 201-202°C.
EXAMPLE 241
Figure imgf000347_0001
3,5-Diisopropyl-2-hvdroxymethyl-6-propyl-4'-fluoro-2'-hvdroxy-l,r-biphenyl Step A: Dimethyl 4,6-diethyI-2-hvdroxy-l,3-benzenedicarboxylate
A mixture of dimethyl 1,3-acetonedicarboxylate (200 g, 1.15 mol), 3,5- heptanedione (140 g, 1.09 mol) and sodium methoxide (70 g, 1.25 mol) in methanol (1.5 L) was held at reflux overnight. Methanol was removed via rotary evaporation and the resulting orange sludge was partitioned between diethyl ether (1 L) and 10 % aqueous hydrochloric acid (1 L). The separated aqueous layer was extracted with diethyl ether (0.5 L x 2). The combined organic portions were washed with saturated aqueous sodium chloride (0.1 L), dried over sodium sulfate, filtered through a pad of silica (40 mm x 100 mm) and concentrated in vacuo. The crude oil was purified via vacuum distillation at 0.25 Torr to afford the clean product as translucent yellow oil (bp: 125-145°C, 202 g, 70 %): iH NMR (300 MHz, CDCI3): δ 1.20 (t, J = 7.4 Hz, 6H), 2.71 - 2.80 (m, 4H), 3.95 (s, 6H), 6.64 (s, IH), 11.67 (s, IH). 13C NMR (75 MHz, CDCI3): δ 15.42, 28.31, 52.27, 115.22, 121.91, 148.63, 159.71, 169.86. EI-MS: calculated for C14H18O5 266; found 266 (M+). Anal, calc for C14H18O5: C, 63.15; H, 6.81. Found: C, 63.23; H, 6.92. Rf = 0.38 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A=0.05 % aqueous trifluoroacetic acid, B=CH3CN; linear gradient: 50%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 14.4 min (100.0 area %).
Step B: Dimethyl 4,6-diethyl-2-methoxy-l ,3-benzenedicarboxylate A mixture of the crude intermediate obtained in Step A (241.6 g, 0.91 mol), potassium carbonate (204 g, 1.48 mol) and dimethyl sulfate (129 mL, 1.37 mol) in acetone (1 L) was stirred vigorously overnight. After six hours at reflux, the reaction was cooled to room temperature, additional dimethyl sulfate (43 mL, 0.46 mol) was added, and reflux was continued overnight. The mixture was filtered through a pad of Celite, diethyl ether (1 L) was used to wash the Celite pad, and the combined filtrates were concentrated in vacuo. The resulting crude oil was purified via vacuum distillation to afford the pure product as a translucent yellow oil (bp:
180-190°C, 178.1 g, 58 % (2 steps)): iH NMR (300 MHz, CDCI3): δ 1.16-1.25 (m, 6H),
2.55-2.66 (m, 4H), 3.81 (s, 3H), 3.91 (s, 6H), 6.89 (s, IH). Rf = 0.34 (9:1 hexanes.ethyl acetate).
Step C: Dimethyl 4,6-diisoprop yl-2-methoxy-l ,3-benzenedicarboxylate
A solution of diisopropylamine (26.7 mL, 0.20 mol) in dry tetrahydrofuran (0.2 L) at -78°C under an argon atmosphere was treated with slow addition of n-butyllithium (2.47M in hexanes, 85.0 mL, 0.20 mol). After the reaction stirred for fifteen minutes, a solution of the intermediate from Step B (58.0 g, 0.16 mol) in dry tetrahydrofuran (0.2 L) was added to the solution of LDA over 45 minutes. Stirring was continued for 80 minutes while the internal temperature was held at -76°C. Neat iodomethane (13.2 mL, 0.21 mol) was added to the reaction mixture via syringe; two-thirds of the charge was transferred at the outset, the reaction was allowed to stir for 30 minutes, then the final third of the charge was added, followed by another 30 minutes of stirring. A second pot of LDA (0.2 mol) in dry tetrahydrofuran (0.2 L) was produced by the above procedure and was transferred to the reaction mixture via cannula over 45 minutes. Stirring was continued for 80 minutes at -76 °C then a second portion of neat iodomethane (13.2 mL, 0.21 mol) was added to the reaction mixture using the addition sequence described above. The cooling bath was removed and the reaction mixture was quenched with saturated aqueous ammonium chloride solution (0.4 L). The mixture was extracted with diethyl ether (3 x 0.4 L) and the combined organic portions were dried over magnesium sulfate, filtered through a plug of silica gel and concentrated in vacuo to afford the clean product as an off-white solid (60.2 g, 98 %). iH NMR (300 MHz, CDCI3): δ 1.24 (d, J = 6.6 Hz, 12H), 2.84-2.96 (m, 2H), 3.82 (s, 3H), 3.92 (s, 6H), 7.04 (s, IH). 3C NMR (75 MHz, CDCI3): δ 23.72, 31.36, 52.30, 63.56, 117.95, 125.66, 148.68, 153.76, 168.36. FAB-MS: calculated for C17H24O- 5308; found 309 ((M+H)+). Anal, calc for C17H24O5: C, 66.21; H, 7.84. Found: C, 66.22; H, 7.94. Rf = 0.3 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A=0.05 % aqueous trifluoroacetic acid, B=CH3CN; linear gradient: 50%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 16.2 min (97.6 area%). mp 70.5-71.5 °C.
Step D: Diisopropyl 4,6-diisopropyl-2-methoxy-l ,3-benzenedicarboxylate
Isopropanol (50 mL) was cautiously added to a flask charged with sodium hydride (95%, 0.33 g, 13.8 mmol). A solution of the intermediate obtained in Step C (8.5 g, 27.6 mmol) in isopropanol (100 mL) was added and the resulting mixture was held at reflux overnight. Additional sodium hydride (95%, 0.33 g, 13.8 mmol) and isopropanol (50 mL) were added to push the reaction to completion. Reflux was continued for five hours then the reaction mixture was cooled to ambient temperature and quenched with 10 % aqueous hydrochloric acid (60 mL). Isopropanol was removed in vacuo and the residual aqueous layer was extracted with diethyl ether (2 x 150 mL). The combined ethereal extracts were dried over magnesium sulfate, concentrated in vacuo, and chromatographed on silica (300 g) using dichloromethane:hexanes (1:1) as eluent to provide the clean product as a colorless crystalline solid (8.5 g, 85 %). iH NMR (300 MHz, CDCI3): δ 1.25 (d, J = 7.0 Hz, 12H), 1.37 (d, J = 6.3 Hz, 12H), 2.90-2.98 (m, 2H), 3.85 (s, 3H), 5.30 (septet, J = 6.3 Hz, 2H), 7.02 (s, IH). 13C NMR (75 MHz, CDCI3): δ 21.77, 23.74, 31.12, 63.59, 68.92, 117.78, 126.44, 148.08, 153.20, 167.40. FAB-MS: calculated for C21H32O5 364; found 365 ((M+H)+). Anal, calc for C21H32O5: C, 69.20; H, 8.85. Found: C, 69.23; H, 8.86. Rf = 0.42 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A=0.05 % aqueous trifluoroacetic acid, B = CH3CN; linear gradient: 50%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 24.4 min (96.6 area %). mp 68.0-69.0°C.
Step E: Diisopropyl 3,5-diisopropyl-2'-benzyloxy-4'-fluoro-l ,1 '-biphenyl-2,6- dicarboxylate A dry flask containing freshly ground magnesium turnings (2.88 g, 120 mmol) and a crystal of iodine was heated until a dark purple iodine atmosphere had formed. The flask was cooled to ambient temperature and a solution of 2- bromo-5-fluorophenyl benzyl ether (33.8 g, 120 mmol, Example 166, Step A) in dry tetrahydrofuran (60 mL) was added in several portions over 40 minutes at a rate sufficient to maintain reflux. Reflux was continued for 45 minutes, then the reaction was cooled to room temperature. This solution of Grignard reagent was transferred via syringe to a second flask containing a solution of the intermediate from Step D (11.0 g, 30.2 mmol) in dry benzene (66 mL). The reaction mixture was held at reflux for one hour, quenched with 10% aqueous hydrochloric acid (300 mL) and extracted with diethyl ether (3 x 300 mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give a brown oil which was subjected to flash column chromatography on silica (80 mm x 19.5") using a stepwise gradient elution of dichloromethane:hexanes (1:3, 1:2, 1:1, 4L each). The fractions containing the product were combined and concentrated to afford an inseparable mixture of the product and an unidentified side product in about a 1:1 ratio as a pale yellow gum (5.3 g, 33% mass balance). This material was not fully characterized and was used without further purification.
Step F: Isopropyl 3,5-diisopropyl-6-hydroxymethyl-2'benzyloxy-4'-fluoro-
1,1 '-biphenyl-2-carboxylate A mixture of the intermediate from Step E (5.83 g, 10.9 mmol) and Red-Al (3.3 mL, 10.9 mmol) in dry tetrahydrofuran (100 mL) was held at reflux for 2.5 hours. Additional Red-Al was added (in 3.3 mL aliquots) and reflux maintained until the lower Rf spot disappeared (21 hours, total 8 eq. Red-Al; i.e. the by-product from the previous step reacted faster than the desired diester). The reaction mixture was cooled to 0 °C, carefully quenched with water (14 mL), and vigorously stirred for 2 hours. The precipitated solids were removed via vacuum filtration through paper and the collected solids were washed with ethyl acetate (3 x 100 mL) and refiltered. The combined filtrates were washed with a 1:1 mixture of water and saturated aqueous sodium chloride (100 mL), followed by water (75 mL) and saturated aqueous sodium chloride (50 mL). The organic portion was separated, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography on silica (80 mm x 6") using hexanes:ethyl acetate (19:1) as eluent gave pure diisopropyl 3,5-diisopropyl-2'-benzyloxy-4'-fluoro-l,r-biphenyl-2,6- dicarboxylate (2.63 g, 4.92 mmol). This was resubjected to the reaction conditions with Red-Al (2.95 mL, 9.84 mmol) in dry tetrahydrofuran (45 mL). Additional Red- Al was added (in 2.95 mL aliquots) and reflux maintained until the reaction was complete (30 hours, total 12 eq. Red-Al). Worked up as above and subjected crude product to flash column chromatography on silica (40 mm x 7") using hexanes:ethyl acetate (19:1) as eluent to provide the desired product as a translucent colorless oil (1.25 g, 55 %). iH NMR (300 MHz, CDCI3): δ 0.91 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.3
Hz, 3H), 1.20-1.33 (m, 9H), 1.35 (d, J = 7.0 Hz, 3H), 1.91-2.00 (br s, IH), 2.94-3.07 (m, IH), 3.37-3.50 (m, IH), 4.24-4.46 (m, 2H), 4.84-5.06 (m, 3H), 6.73-6.87 (m, 2H), 7.01- 7.08 (m, 2H), 7.14-7.29 (m, 4H), 7.39 (s, IH). FAB-MS: calculated for C30H35O4F 478; found 479 ((M+H)+). Rf = 0.23 (9:1 hexanes:ethyl acetate).
Step G: Isopropyl 3,5-diisopropyl-6-formyl-2'-benzyloxy-4'-fluoro-l,l '- biphenyl-2-carboxylate A chilled (0°C) mixture of the intermediate from Step F (0.73 g, 1.52 mmol), Celite (1.46 g), and pyridinium chlorochromate (0.61 g, 2.84 mmol) in dry dichloromethane (30 mL) was stirred for 5 hours, while warming to room temperature. The mixture was diluted with ethyl acetate (30 mL) and hexane (60 mL) and filtered through a plug of silica (30 mm x 3"). Elution was continued with ethyl acetate:hexanes (1:1 mixture, 2 x 120 mL). The combined filtrates were concentrated in vacuo to afford the desired product as a clear colorless oil (0.72 g, 99 %). iH NMR (300 MHz, CDCI3): δ 0.90 (d, J = 6.3 Hz, 3H), 1.07 (d, J = 6.3 Hz,
3H), 1.23-1.36 (m, 12H), 2.99-3.10 (m, IH), 3.92-4.02 (m, IH), 4.85-5.06 (m, 3H), 6.65- 6.76 (m, 2H), 7.15-7.30 (m, 6H), 7.46 (s, IH), 9.84 (s, IH). FAB-MS: calculated for C30H33O4F 476; found 477 ((M+H)+). Rf = 0.47 (9:1 hexanes:ethyl acetate).
Step H: Isopropyl 3,5-diisopropyl-6-(prop-l-enyP-2'-benzyloxy-4'-fluoro-l ,1 '- biphenyl-2-carboxylate
A chilled (-70°C) suspension of (ethyl)triphenylphosphonium bromide (0.88 g, 2.37 mmol) in dry tetrahydrofuran (6 mL) was treated with dropwise addition of n-butyllithium (2.47M in hexanes, 1.04 mL, 2.56 mmol). The mixture was immediately warmed to 0 °C, stirred for 90 minutes at 0 °C, and recooled to -70 °C.
A solution of the intermediate from Step G (0.94 g, 1.97 mmol) in dry tetrahydrofuran (6 mL) was added to the solution of ylide over several minutes and the reaction mixture was warmed again to 0 °C and stirred for one hour. The reaction was quenched with water (3 mL) and diluted with ethyl acetate (25 mL). The organic portion was washed with saturated aqueous sodium chloride solution (2 x 15 mL). The combined aqueous portions were back-extracted with ethyl acetate (10 mL). The combined organic portions were dried over sodium sulfate and concentrated in vacuo to provide the crude solid which was subjected to flash column chromatography on silica (30 mm x 6") using hexanes:ethyl acetate (19:1) as eluent. The clean fractions were combined and concentrated in vacuo to afford the desired product as a pale yellow oil (0.81 g, 84 %). iH NMR (300 MHz, CDCI3): δ
0.84-0.92 (m, 3H), 1.02-1.59 (m, 18H), 2.96-3.31 (m, 2H), 4.82-4.97 (m, IH), 4.98 (s, 2H), 5.19-5.52 (m, IH), 6.07- 6.19 (m, IH), 6.57-6.69 (m, 2H), 7.05-7.31 (m, 7H). FAB- MS: calculated for C32H37O3F 488; found 489 (M+H)+. Rf = 0.58 (9:1 hexanes:ethyl acetate).
Step I: 3,5-Diisopropyl-2-hydroxymethyl-6-(prop-l-envP-2'-benzyloxy-4'- fluoro-l,l'-biphenyl
A reaction flask was charged with a suspension of lithium aluminum hydride (95%, 0.14 g, 3.3 mmol) in dry tetrahydrofuran (5 mL) and heated to reflux. A solution of the intermediate from Step H (0.80 g, 1.64 mmol) in dry tetrahydrofuran (10 mL) was added to the refluxing suspension dropwise from a syringe. The reaction mixture was held at reflux for 23 hours, cooled to ambient temperature and quenched using saturated aqueous sodium sulfate solution which was added dropwise until gas evolution stopped. The mixture was then diluted with ethyl acetate (15 mL), stirred for several minutes and filtered through a pad of Celite. The pad was washed copiously with additional ethyl acetate. The combined filtrates were concentrated in vacuo and subjected to flash column chromatography on silica (30 mm x 3") to afford the clean product as a clear oil (0.53 g, 75 %). iH NMR (300 MHz, CDCI3): δ 1.05-1.46 (m, 15H), 1.68-1.78 (br s, IH), 3.07-3.49 (m, 2H),
4.27-4.47 (m, 2H), 4.85-5.05 (m, 2H), 5.25-5.52 (m, IH), 5.92-6.08 (m, IH), 6.68-6.76 (m, 2H), 6.98-7.13 (m, 3H), 7.18-7.29 (m, 3H), 7.35 (s, IH). FAB-MS: calculated for C29H33O2F 432; found 432 (M)+. Rf = 0.29 (9:1 hexanes:ethyl acetate).
Step I: 3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-fluoro-2'-hvdroxy-l, - biphenyl
A mixture of the intermediate from Step I (0.53 g, 1.23 mmol), and 10% Pd/C (53 mg) in methanol (12 mL) was stirred under one atmosphere of hydrogen gas for 18 hours. The reaction mixture was then filtered through a pad of Celite and the pad was rinsed thoroughly with methanol (100 mL). The combined filtrates were concentrated in vacuo and subjected to flash column chromatography on silica (20 mm x 4") using hexanes:ethyl acetate (9:1) as eluent. In this manner, the pure product was obtained as a clear oil which slowly solidified to provide the title compounds as a white solid (0.37 g, 87 %). H NMR (300 MHz, CDCI3): δ 0.76
(t, J = 7.4 Hz, 3H), 1.16-1.36 (m, 15H), 2.11-2.42 (m, 2H), 3.12-3.25 (m, IH), 3.30-3.43 (m, IH), 4.29-4.47 (m, 2H), 6.69-6.80 (m, 2H), 7.00-7.07 (m, IH), 7.36 (s, IH). 3C
NMR (75 MHz, CDCI3): δ 14.65, 24.29, 24.34, 24.50, 24.58, 29.21, 32.18, 59.61, 103.6
(d, J=24.4 Hz), 107.6 (d, J=22.0 Hz), 123.50, 123.67 (d, J=2.4 Hz), 131.21 (d, J=9.8 Hz),
134.07, 134.66, 137.42, 146.30, 148.12, 154.26 (d, J=12.2 Hz), 163.01 (d, J=244.2 Hz).
FAB-MS: calculated for C22H29O2F 344; found 344 (M)+. Anal, calc for C22H29O2F: C, 76.71; H, 8.49. Found: C, 76.66; H, 8.34. Rf = 0.41 (4:1 hexanes:ethyl acetate). HPLC: (C-18, A=0.05 % aqueous trifluoroacetic acid, B=CH3CN; linear gradient: 50%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 17.1 min (97.5 area %). mp 127.5 - 129.0°C.
EXAMPLE 242
Figure imgf000353_0001
3,5-Diisopropyl-2-(l-hydroxyethyl)-6-propyl-4'-fluoro-2'-hydroxy-l,r-biphenyl
Step A: 3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-fluoro-2'-benzyloxy-
1,1 '-biphenyl
A mixture of the racemic compound prepared in Example 241 (293 mg, 851 μmol), benzyl bromide (110 μL, 925 μmol), and potassium carbonate (303 mg, 2.19 mmol) in acetone (29 mL) was heated to reflux for 3 h. The mixture was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with
Et2θ (3 x 50 mL). Silica gel chromatography (90:10 hexane/ethyl acetate) provided a colorless oil (0.369 g, 100%). NMR (CDCI3, 300 MHz): δ 7.34 (s, IH), 7.23 (m, 3H), 7.12 (m, IH), 7.03 (m, 2H), 6.84-6.75 (m, 2H), 5.04 (d, 12.1 Hz, IH), 4.94 (d, 12.1 Hz, IH), 4.38 (dd, 11.4 Hz, 8.5 Hz, IH), 4.25 (dd, 11.4 Hz, 3.3 Hz, IH), 3.39 (sept, 6.9 Hz, IH), 3.18 (sept, 6.9 Hz, IH), 2.30-2.40 (m, IH), 2.09-2.20 (m, IH), 1.65 (dd, 8.5 Hz, 3.3 Hz, IH), 1.26-1.34 (m, 14H), 0.72 (t, 7.4 Hz, 3H).
Step B: 3,5-Diisopropyl-2-formyl-6-propyl-4'-fluoro-2'-benzyloxy-l,r- biphenyl
Prepared from the intermediate obtained in Step A by the procedure described in Example 218, Step A. Silica gel chromatography (95:5 hexane/EtOAc) provided a colorless crystalline solid (0.323 g, 88%). αH NMR (CDCI3, 300 MHz): δ
9.74 (s, IH), 7.41 (s, IH), 7.22-7.28 (m, 3H), 7.06-7.13 (m, 3H), 6.72-6.80 (m, 2H), 5.00 (s, 2H), 3.91 (sept, 6.8 Hz, IH), 3.23 (sept, 6.7 Hz, IH), 2.37-2.46 (m, IH), 2.17-2.27
(m, IH), 1.20-1.36 (m, 14H), 0.73 (t, 7.4 Hz, 3H). FAB-MS: calculated for C29H33FO2
432; found 433 (M+H).
Step C: 3,5-Diisopropy 1-2- ( 1 -hy drox yeth yl)-6-pr opy 1-4 '-fluoro-2 '-benzy loxy- l,l'-biphenyl
Methyl lithium (2.7 mL of 1.4 M solution in Et2θ, 3.78 mmol) was added dropwise over five minutes to a cooled (ice-water bath) suspension of Cul (715 mg,
3.75 mmol, purified by extraction with THF) in toluene (10.8 mL) such that the internal temperature of the mixture was <3°C. The addition produced first a yellow-orange suspension and then a colorless solution. After 25 minutes the mixture was again a yellow-orange suspension. A solution of the intermediate obtained in Step B (306 mg, 707 μmol) in toluene (1 mL) was added dropwise over four minutes such that the internal temperature of the mixture was <2°C. After 30 minutes 1/3 saturated aqueous NH4OH solution (40 mL) was added. After an additional 60 minutes the mixture was diluted with saturated aqueous NH4CI solution (40 mL) and extracted with Et2θ (3 x 40 mL). Silica gel chromatography
(83:17 hexane/EtOAc) provided a colorless solid (0.290 g, 91%). The product was a mixture of diastereomers in a ratio of 93:7 as judged by HPLC. H NMR (CDCI3, 300 MHz, only peaks corresponding to the major diastereomer were visible): δ 7.35 (s, IH), 7.22-7.24 (m, 3H), 7.11 (dd, 8.1 Hz, 7.0 Hz, IH), 7.04 (m, 2H), 6.70-6.78 (m, 2H), 4.99 (d, 2.6 Hz, 2H), 4.83 (qd, Jq=6.8 Hz, Jd=2.8 Hz, IH), 3.84 (sept, 6.8 Hz,
IH), 3.14 (sept, 6.9 Hz, IH), 2.29 (m, IH), 2.07 (m, IH), 1.74 (d, 2.9 Hz, IH), 1.25-1.35 (m, 17H), 0.70 (t, 7.4 Hz, 3H). EI-MS: calculated for C30H37FO2 448; found 448
(M+).
Step D: 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-propyl-4'-fluoro-2'-hydroxy-
1,1 '-biphenyl The title compound was prepared from the intermediate obtained in Step C by the procedure described in Example 1, Step H. Silica gel chromatography (83:17 hexane/EtOAc) provided two colorless solids (0.229 g, 99%).
Diastereomer 1 was obtained as a colorless crystalline solid (0.214 g, 92%). iH NMR (CDCI3, 300 MHz): δ 7.37 (s, IH), 7.03 (m, IH), 6.72 (m, 2H), 4.80-4.89 (m, 2H), 3.79 (sept, 6.8 Hz, IH), 3.14 (sept, 6.8 Hz, IH), 2.31 (m, IH), 2.08 (m, IH), 1.64 (d, 3.3 Hz, IH), 1.41 (d, 7.0 Hz, 3H), 1.26-1.31 (m, 14H), 0.74 (t, 7.4 Hz, 3H). FAB- MS: calculated for C23H31FO2 358; found 341 (M-OH). mp 149-150°C. Rf = 0.25
(83:17 hexane/ethyl acetate).
Diastereomer 1 (212 mg) was resolved into its constituent enantiomers as follows: a Waters Prep LC 4000 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 1% butanol and 99% heptane at a flow rate of 100 mL/min. The sample was dissolved in dichloromethane (70 mg/mL) and 1 mL aliquots were injected at 40 min intervals. The effluent was monitored at 285 nm and two fractions (corresponding to the two enantiomers) were collected at (19-23 min,100% ee) and (30-37 min, >98% ee), respectively.
Enantiomer 1 was obtained as a colorless solid (78 mg). H NMR (CDCI3, 300 MHz): δ 7.37 (s, IH), 7.02 (m, IH), 6.71 (m, 2H), 4.77-4.89 (m, 2H), 3.77 (m, IH), 3.14 (sept, 6.8 Hz, IH), 2.31 (m, IH), 2.08 (m, IH), 1.63 (d, 2.9 Hz, IH), 1.41 (d, 6.6 Hz, 3H), 1.26-1.31 (m, 14H), 0.74 (t, 7.2 Hz, 3H). FAB-MS: calculated for C23H31FO2 358; found 341 (M-OH).
Enantiomer 2 was obtained as a colorless solid (74 mg). 1H NMR (CDCI3,
300 MHz): δ 7.38 (s, IH), 7.03 (m, IH), 6.72 (m, 2H), 4.80-4.90 (m, 2H), 3.79 (sept, 6.6
Hz, IH), 3.14 (sept, 6.7 Hz, IH), 2.30 (m, IH), 2.07 (m, IH), 1.63 (d, 3.3 Hz, IH), 1.41 (d, 6.6 Hz, 3H), 1.26-1.31 (m, 14H), 0.74 (t, 7.2 Hz, 3H). FAB-MS: calculated for 23H31FO2 358; found 341 (M-OH).
Diastereomer 2 was obtained as a colorless crystalline solid (15.3 mg, 7%). 2H NMR (CDCI3, 300 MHz): δ 7.37 (s, IH), 6.92 (m, H), 6.70 (m, 2H), 5.1 (br s, IH),
4.64 (q, 6.7 Hz, IH), 3.85 (sept, 6.7 Hz, IH), 3.14 (sept, 6.8 Hz, IH), 2.32 (m, IH), 2.09 (m, IH), 1.8 (br s, IH), 1.37 (d, 6.6 Hz, 3H), 1.24-1.30 (m, 14H), 0.74 (t, 7.2 Hz, 3H). FAB-MS: calculated for C23H31FO2 358; found 341 (M-OH). mp 179-180°C.
Figure imgf000356_0001
(+)-3,5-Diisopropyl-2-(l-hvdroxyethvP-6-pentyl-4'-fluoro-l,l'-biphenyl
Step A: 3,5-Diisopropyl-2-(l-oxoethyl)-6-pentyl-4'-fluoro-l,l '-biphenyl
A mixture of 3,5-diisopropyl-2-(l-hydroxyethyl)-6-pentyl-4'-fluoro-l,r- biphenyl (Example 192, 13.7 g, 37.1 mmol), Celite (26 g), and pyridinium chlorochromate (14.9 g, 69.3 mmol) in dichloromethane (750 mL) was stirred for 45 minutes. The mixture was diluted with ethyl acetate (750 mL) and hexane (1.5 L) and filtered through a plug of silica (100 mm x 2") topped with Celite (100 mm x 0.5"). Elution was continued with ethyl acetate:hexanes (1:1 mixture, 3L x 2). The combined filtrates were concentrated in vacuo to afford the desired product as a white solid (13.5 g, 99 %). iH NMR (300 MHz, CDCI3): δ 0.75 - 0.80 (m, 3H), 1.06 - 1.31 (m, 18H), 1.95 (s, 3H), 2.33 - 2.39 (m, 2H), 2.78 (septet, J = 7.0 Hz, IH), 3.18 (septet, J = 7.0 Hz, IH), 7.03 - 7.09 (m, 2H), 7.17 - 7.22 (m, 2H) 7.26 (s, IH). i3C NMR (75 MHz, CDCI3): δ 13.75, 22.02, 24.32, 24.37, 28.99, 29.10, 29.28, 30.60, 31.04,
32.06, 33.03, 114.85 (d, J = 20.8 Hz, 2C), 122.06, 132.03 (d, J = 7.3 Hz, 2C), 135.52 (d, J = 2.4 Hz, IC) 135.58, 135.76, 140.13, 140.85, 147.66 161.99 (d, J = 246.6 Hz, IC), 208.23. EI-MS: calculated for C25H33OF 368; found 368 (M+). Anal, calc for C25H33OF: C, 80.86; H, 8.96. Found: C, 81.04; H, 9.06. Rf = 0.65 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A = 0.05 % aqueous trifluoroacetic acid, B = CH3CN; linear gradient: 75%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 22.7 min (94.0 area %). mp 123.0-124.5°C.
Step B: (+)-3,5-Diisopropyl-2-(l-hvdroxyethvP-6-pentyl-4,-fluoro-l,l'- biphenyl A mixture of (lS,2R)-(+)-N-methylephedrine (13.9 g, 77.3 mmol) in diethyl ether (225 mL) at 0 °C under an argon atmosphere was treated with slow addition of lithium aluminum hydride (IM in diethyl ether, 77.3 mL, 77.3 mmol). The mixture was held at reflux for one hour and then cooled to -75 °C. A solution of the intermediate from Step A (13.5 g, 36.7 mmol) in diethyl ether (500 mL, 50 mL rinse) was then added to the reaction mixture in such a manner that the internal temperature did not rise above -68 °C. The reaction stirred for 3 hours at -75 °C and was warmed to ambient temperature overnight. The reaction was cooled to 0 °C, quenched by adding water (500 mL), and diluted with diethyl ether (750 mL). The aqueous portion was separated and back-extracted with diethyl ether (200 mL). The combined organic portions were washed with water (2 x 500 mL), 10 % aqueous hydrochloric acid (500 mL), and saturated aqueous sodium chloride (2 x 500 mL), dried over sodium sulfate, filtered through a pad of silica (80 mm x 1.25") and concentrated in vacuo. The resulting solid was recrystallized from ethanol:water (2:1) and dried in vacuo with several minutes of heating to provide the title compound as a fine white powder (11.08 g, 82 %). iH NMR (300 MHz, CDCI3): δ 0.75 - 0.80 (m, 3H), 1.02 - 1.31 (m, 19H), 1.40 (d, J = 6.6 Hz, 3H), 2.17 - 2.22
(m, 2H), 3.08 - 3.18 (m, IH), 3.83 - 3.92 (m, IH), 4.66 - 4.73 (m, IH), 7.05 - 7.23 (m, 4H), 7.32 (s, IH). 13C NMR (75 MHz, CDCI3): δ 13.88, 22.02, 23.38, 24.23, 24.56,
24.63, 25.09, 28.68, 28.96, 29.92, 31.04, 32.23, 68.91, 114.80 (d, J = 20.8 Hz, IC), 115.02 (d, J = 20.8 Hz, IC), 124.27, 130.40 (d, J = 8.5 Hz, IC), 131.25 (d, J = 7.3 Hz, IC), 135.53, 136.98, 137.73 (d, J = 2.4 Hz, IC), 139.02, 145.82 (2C), 161.68 (d, J = 245.4 Hz, IC). FAB-MS: calculated for C25H35OF 370; found 370 (M+). Anal, calc for C25H35OF: C, 81.03; H, 9.52. Found: C, 81.15; H, 9.68. Rf = 0.36 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A = 0.05 % aqueous trifluoroacetic acid, B = CH3CN; linear gradient: 75%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 22.6 min (98.3 area %), (Daicel Chiralcel OD-H; isocratic 99:1 hexanes:methyl f-butyl ether; 254 nm, 1.5 mL/min); R.T. 6.20 min.(97.2 area %), 8.37 min. (0.36 area %); 99.5 % e.e. [a]D = +26.9° (c = 0.00196 g/mL, CH2CI2). mp 108.5-109.5°C.
EXAMPLE 244
Figure imgf000357_0001
(+)-3,5-DiisopropyI-2-(l-hvdroxyethyl)-6-ethyl-4'-fluoro-l,l'-biphenyl Step A: Dimethyl 4,6-diethyl-2-trifluoromethanesulfonyloxy-l,3- benzenedicarboxylate
A solution of 90 g (338 mmol) of dimethyl 4,6-diethyl-2-hydroxy-l,3- benzenedicarboxylate (Example 241, Step A) in dichloromethane (1 L) was treated with pyridine (109 mL, 1.35 mol). The mixture was stirred under argon at 0°C and treated dropwise with triflic anhydride (83 mL, 507 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hours. Then was washed with
5% HCl (1.5 L), water (1 L), saturated sodium bicarbonate (2 x 500 mL), and dried with MgSθ4. Filtration and concentration afforded a dark oil (129.7 g, 326 mmol, 96%). Rf = 0.4 (10% ethyl acetate/hexane). iH NMR (300 MHz, CDCI3): δ 7.20 (s,
1 H), 3.93 (s, 6 H), 2.74 (q, / = 7.4 Hz, 4 H), 1.22 (t, / = 4.8 Hz, 6 H). FAB-MS: calculated for (C15H27F3O7) 398, found 399 (M+H).
Step B: 3,5-Diethyl-2,6-dicarboxymethyl-4'-fluoro-l,l'-biphenyl To a solution of the intermediate obtained in Step A (129.7 g, 326 mmol) in dioxane (2.5 L) was added 4-fluorobenzene boronic acid (68.4 g, 492 mmol), potassium phosphate (145 g, 683 mmol), potassium bromide (58.1 g, 488 mmol), tetrakis(triphenylphosphine)palladium (18.8 g, 16.3 mmol), and water (20 mL). The reaction mixture was stirred under argon at reflux for 24 hrs. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The oily residue was filtered twice through a pad of silica (700 g, 40% dichloromethane/hexane) to afford a yellow solid. Recrystallization from hexane afforded a white solid (52.6 g,
153 mmol, 47%). mp = 98-99°C. Rf = 0.4 (10% ethyl acetate/hexane). JH NMR
(300 MHz, CDCI3): δ 7.26 (m, 2 H), 7.17 (s, 1 H), 7.04 (m, 2 H), 3.49 (s, 6 H), 2.67 (q,J = 7.7 Hz, 4 H), 1.25 (t, / = 7.7 Hz, 6 H). FAB-MS: calculated for (C20H21FO4) 344, found 345 (M+H).
Step C: 3,5-Diisopropy l-2,6-dicarboxymethyl-4'-fluoro- 1 , 1 '-biphenyl
A solution of diisopropylamine (22.7 mL, 0.174 mol) in dry tetrahydrofuran (0.2 L) at -78°C under an argon atmosphere was treated with slow addition of n- butyllithium (2.5M in hexanes, 70 mL, 0.174 mol). After the reaction stirred for fifteen minutes, a solution of the intermediate from Step B (46.0 g, 0.133 mol) in dry tetrahydrofuran (0.2 L) was added to the solution of LDA over 15 minutes. Stirring was continued for 30 minutes while the temperature was held at -78°C. Neat iodomethane (11.2 mL, 0.180 mol) was added to the reaction mixture via syringe; two-thirds of the charge was transferred at the outset, the reaction was allowed to stir for 20 minutes, then the final third of the charge was added, followed by another 10 minutes of stirring. A second pot of LDA (0.174 mol) in dry tetrahydrofuran (0.2 L) was produced by the above procedure and was transferred to the reaction mixture via cannula over 15 minutes. Stirring was continued for 30 minutes at -78 °C then a second portion of neat iodomethane (11.2 mL, 0.180 mol) was added to the reaction mixture using the addition sequence described above. The cooling bath was removed and the reaction mixture was quenched with saturated aqueous ammonium chloride solution (0.4 L). The mixture was extracted with diethyl ether (3 x 0.4 L) and the combined organic portions were dried over magnesium sulfate and concentrated in vacuo to afford an oil, which crystallized upon standing. The white solid was washed with a small portion of hexane (41.7 g, 84 %). mp 128-130°C. Rf = 0.5 (10% ethyl acetate/hexane). iH NMR (300 MHz, CDCI3): δ 7.33 (s, 1 H), 7.26 (m, 2 H), 7.03 (m, 2 H), 3.49 (s, 6 H), 2.97 (sept, / = 6.6 Hz, 2 H), 1.29 (d, / = 7.0 Hz, 6 H). FAB-MS: calculated for (C22H25FO4) 372, found 373 (M+H).
Step D: 3,5-Diisopropy.-2-hyd-θxymethy_-6-carboxymethyl-4'-fluoro-l, - biphenyl To a solution of the intermediate obtained in Step C (37.3 g, 100 mmol) in anhydrous tetrahydrofuran (350 mL) stirred under argon at 0°C was added a solution of 3.4M of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (Red-Al) (105 L, 204 mmol, 65 wt% in toluene) via syringe over 20 mm. The reaction mixture was allowed to stir at room temperature for 24 hr, then cooled 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 (500 g silica) via step gradient. Elution with 5% diethyl ether/hexane affords 9.8 g (26.3 mmol, 28%) of recovered starting material and elution with 40% diethyl ether(Et2θ) /hexane affords the desired product as a white solid (26.8 g, 77.8 mmol, 78%). mp 124- 126°C. Rf = 0.2 (10% ethyl acetate/hexane). iH NMR (300 MHz, CDCI3): δ 7.35 (s,
1 H), 7.27 (m, 2 H), 7.08 (m, 2 H), 4.44 (d, / = 5.5 Hz, 2 H), 3.43 (m, 4 H), 2.92 (sept, / = 6.6 Hz, 1 H), 1.59 (s, 1 H), 1.28 (m, 12 H). FAB-MS: calculated for (C21H25FO3)
344, found 345 (M+H).
Step E: 3,5-Diisopropyl-2-carboxaldehvde-6-carboxymethyl-4'-fluoro-l, - biphenyl To a solution of the intermediate obtained in Step D (26.8 g, 77.8 mmol) in dichloromethane (400 mL) was added celite (33.6 g). The suspension was stirred at room temperature and treated with pyridinium chlorochromate (PCC) (33.6 g, 15.6 mmol) in three portions. The suspension was stirred at room temperature for 2 hr, then poured into 1:1 diethyl ether/hexane (1 L), filtered through a pad of silica, the pad was washed with diethyl ether (600 mL) and the combined eluent concentrated to afford an gummy oil (23.3 g, 68.1 mmol, 87%): Rf = 0.4 (10% ethyl acetate/hexane). iH NMR (300 MHz, CDCI3): δ 9.87 (s, 1 H), 7.36 (s, 1 H), 7.28 (m, 2 H), 7.15 (m, 2 H), 3.48 (s, 3 H), 3.89 (sept, / = 6.6 Hz, 1 H), 3.10 (sept, / = 6.6 Hz, 1 H), 1.35 (m, 12 H); FAB-MS calcd for (C21H23FO3) 342, found 343 (M+H).
Step F: 3,5-Diisopropyl-2-carboxymethyl-6-ethenyl-4'-fluoro-l, -biphenyl
Methyltriphenylphosphonium bromide (15.5 g, 43.4 mmol) was suspended in anhydrous THF (250 mL) under argon and stirred at -78°C. A 1.6 M solution of n-butyllithium in hexanes (25 mL, 40.2 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 (11.4 g, 33.3 mmol) in THF (100 mL). The reaction mixture was allowed to stir at 0°C for 1 hr, then quenched by the addition of water (30 mL). The THF was removed in vacuo, the residue partitioned between diethyl ether (400 mL) and water (400 mL). The organic layer was washed with brine (100 mL), dried over MgSθ4 and concentrated. Flash chromatography through silica (5% diethyl ether/hexane) affords a solid (10.3 g, 30.3 mmol, 91%) (E, Z mixture). iH NMR (300 MHz, CDCI3): δ 7.31 (s, 1 H), 7.16 (m, 2 H), 7.02 (m, 2 H), 6.10 (dd, / = 6.3, 11.4 Hz, 1 H), 6.04 (dd, /
= 1.8, 13.6 Hz, 1 H), 5.48 (dd, / = 1.8, 19.9 Hz, 1 H), 3.46 (s, 3 H), 3.35 (sept, / = 6.6 Hz, 1 H), 2.93 (sept, / = 6.6 Hz, 1 H), 1.29 (m, 12 H). EI-MS calculated for (C22H25FO2) 340, found 340 (M+). mp 58-61°C. Rf = 0.6 (10% ethyl acetate/hexane).
Step G: 3,5-Diisopropyl-2-hvdroxymethyl-6-ethenyl-4,-fluoro-l, -biphenyl
The intermediate obtained in Step F (10.0 g, 29.4 mmol) was dissolved in anhydrous THF (150 mL) under argon and treated dropwise at room temperature with lithium aluminum hydride (1.0 M in THF, 41 mL, 41 mmol). The reaction mixture was stirred at reflux for 2 hours, cooled to room temperature and quenched by the addition of 30 mL H2O. The THF was removed in vacuo, the residue partitioned between diethyl ether (400 mL) and water (3 x 400 mL). The organic layer was washed with brine (300 mL), dried over MgSθ4 and concentrated. Flash chromatography through silica (5% diethyl ether/hexane) affords a solid (7.7 g, 24.7 mmol, 84%). iH NMR (300 MHz, CDCI3): δ 7.38 (s, 1 H),
7.14 (m, 4 H), 6.35 (dd, / = 6.3, 11.4 Hz, 1 H), 5.20 (dd, / = 1.8, 13.6 Hz, 1 H), 4.98 (dd, / = 1.8, 19.9 Hz, 1 H), 4.40 (d, / = 5.5 Hz, 2 H), 3.39 (m, 2 H), 1.29 (m, 12 H). FAB-MS calculated for (C21H25FO) 312, found 312 (M+). mp 97-99"C. Rf = 0.1 (50% dichloromethane / hexane) .
Step H: 3,5-Diisopropyl-2-hvdroxymethyl-6-ethyl-4'-fluoro-l,l'-biphenyl
The intermediate obtained in Step G (7.7 g, 24.7 mmol) was dissolved in absolute ethanol (200 mL) under argon, treated with 10% palladium on carbon (610 mg, 0.1 eq), then 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 (7.7 g, 25 mmol, 99%). H NMR (300 MHz, CDCI3): δ 7.32 (s, 1 H), 7.15 (m, 4 H), 4.33 (m, 2 H), 3.39 (septet, / = 7 Hz, 1 H), 3.32 (septet, / =
7 Hz, 1 H), 2.37 (q, / = 7.7 Hz, 2 H), 1.29 (m, 13 H), 0.92 (t, / = 7.7 Hz, 3 H). FAB-MS calculated for (C21H27FO) 314, found 314 (M+). mp 106-108°C. Rf = 0.1 (50% dichloromethane /hexane).
Step I: 3,5-Diisopropyl-2-(l-hvdroxyethvP-6-ethyl-4'-fluoro-l,l'-biphenyl
The intermediate obtained in Step H (7.65 g, 24.3 mmol) was dissolved in dichloromethane (250 mL), treated with celite (10.5 g). The suspension was stirred at room temperature and treated with pyridinium chlorochromate (PCC) (10.5 g, 48.7 mmol). Stirring was continued at room temperature for 2 hrs. The suspension was poured into 1:1 diethyl ether/hex (1 L), filtered through a pad of silica, the pad washed with diethyl ether (600 mL) and the combined eluent concentrated to afford a solid (7.25 g, 23.2 mmol, 95%).
The intermediate (7.25 g, 23.2 mmol) was dissolved in THF (75 mL) at 0°C under argon atmosphere and treated dropwise with Methyl magnesium bromide (3 M, 1.3 eq, 10.1 mL). The reaction was stirred for 1 hr. The reaction was quenched with saturated ammonium chloride (7 mL) and the THF was evaporated in vacuo to afford an oil. The product was partitioned between water (100 mL) and diethyl ether (250 mL) and the organic layer was dried with MgSOj, filtered, and concentrated to yield a white solid. Flash chromatography using silica gel (60% CH2Cl2/hexane) afforded a white solid (7.2 g, 22 mmol, 99%). mp 138-140°C; Rf = 0.1 (50% CH2Cl2/hexane); iH NMR (300 MHz, CDCI3): δ 7.34 (s, 1 H), 7.15 (m, 4 H), 4.69 (dq, / = 2.9, 7 Hz, 1 H), 3.88 (septet, / = 7 Hz, 1 H), 3.17 (septet, / = 6.6 Hz, 1 H), 2.28 (q, / = 7.4 Hz, 2 H), 1.64 (d, / = 2.9 Hz, 1 H), 1.39 (d, / = 6.6 Hz, 3 H), 1.27 (m, 12 H), 0.89 (t, / = 7.4 Hz, 3 H); FAB-MS calcd for (C22H29FO) 328, found 328 (M+). Step I: 3,5-Diisopropyl-2-(l-oxoethvP-6-ethyl-4'-fluoro-l,l'-biphenyl
The intermediate obtained in Step I (7.23 g, 22 mmol) in dichloromethane (100 mL) was added pyridinium chlorochromate (9.49 g, 44 mmol) and celite (9.49 g) under argon. The reaction was stirred at room temperature for 24 hours. The reaction was added to a 1:1 mixture of diethyl ether/hexane (1 L), then filtered through a plug of silica. The pad was washed with 650 mL of diethyl ether and the combined filtrates were concentrated in vacuo to afford a white solid (7.18 g, 22 mmol, 99%). mp 121-23°C; Rf = 0.3 (50% CH2CI2 /hexane); JH NMR (300 MHz, CDCI3): δ 7.27 (s, 1 H), 7.21 (m, 2 H), 7.07 (m, 2 H), 3.22 (septet, / = 7 Hz, 1 H), 2.78
(septet, / = 7 Hz, 1 H), 2.43 (q, / = 7.4 Hz, 2 H), 1.96 (s, 3 H), 1.28 (m, 12 H), 0.930 (t, / = 7.7 Hz, 3 H); FAB-MS calcd for (C22H27FO) 326, found 327 (M+H).
Step K: (+)-3,5-Diisopropyl-2-(l-hvdroxyethvP-6-ethyl-4'-fluoro-l,l'-biphenyl
To a solution of (lS,2R)-(+)-N-methylephedrine (6.29 g, 35.1 mol) in diethyl ether (45 mL) was added lithium aluminum hydride (lM/diethyl ether, 1.5 eq., 35 mL) dropwise at 0°C under argon. The reaction was refluxed for 1.5 h. turning from a clear solution to a white milky solution. The reaction was cooled to room temperature and then -78°C. The intermediate obtained in Step J (6.64 g, 20.3 mmol) was dissolved in 60 mL of dry diethyl ether for a dropwise addition to the reaction mixture (~2 mL/min., the temperature should not rise above -60°C). The reaction was kept at -78°C for 2.0 hours and then allowed to warm overnight. The reaction was quenched at 0°C with water (30 mL) and diluted with diethyl ether (250 mL), washed with water (3 x 200 mL), brine (100 mL) and dried with MgSθ4.
Filtration and concentration afford a residue which was filtered through a pad of silica (400 g, 80% dichloromethane /hexane) to give the titled compound (99% e.e.) as a white solid (5.85 g, 17.8 mmol, 88%). mp 143-145°C; Rf = 0.1 (50% CH2Cl2/hexane); H NMR (300 MHz, CDCI3): δ 7.34 (s, 1 H), 7.15 (m, 4 H), 4.68 (dq, / = 3.3, 7 Hz, 1 H), 3.88 (septet, / = 7 Hz, 1 H), 3.18 (septet, / = 7 Hz, 1 H), 2.29 (q, / = 7.7 Hz, 2 H), 1.68 (s, 1 H), 1.37 (d, / = 4.8 Hz, 3 H), 1.26 (m, 12 H), 0.890 (t, / = 7.4 Hz, 3 H); FAB-MS calcd for (C22H29FO) 328, found 328 (M+); Anal. Calcd for C22H29FO: C, 80.45; H, 8.90; F, 5.78. Found: C, 80.19; H, 8.77; F, 5.84; [α]22 = +26.6. EXAMPLE 245
Figure imgf000363_0001
(+)-3,5-Diisopropyl-2-(l-hydroxyethyl)-6-propyl-4'-fluoro-l,l'-biphenyl
The title compound (99% ee) was prepared from the intermediate obtained in Step E, Example 244 and ethyl triphenylphosphonium bromide according to the procedures described in Example 244, Steps F-K. H NMR (300 MHz, CDCI3): δ
7.33 (s, 1 H), 7.14 (m, 4 H), 4.70 (dq, / = 2.9, 7 Hz, 1 H), 3.88 (septet, / = 6.62 Hz, 1 H), 3.14 (septet, / = 6.62 Hz, 1 H), 2.18 (m, 2 H), 1.67 (d, / = 2.9 Hz, 1 H), 1.37 (d, / = 7 Hz, 3 H), 1.29 (m, 14 H), 0.719 (t, / = 7 Hz, 3 H); FAB-MS calcd for (C23H31FO) 342, found 342 (M+); Anal. Calcd for C23H31FO: C, 80.66; H, 9.12; F, 5.55. Found: C, 80.71; H, 8.99; F, 5.34; [α]22 = +23.8. mp 114-116'C; Rf = 0.1 (50% CH2CI2 /hexane).
EXAMPLE 246
Figure imgf000363_0002
3,5-Diisopropyl-2-(l-hvdroxyethvP-6-ethyl-4'-fluoro-2'-hydroxy-l,l'-biphenyl
Step A: Di-ter t-butyl 4,6-diethyI-2-hydroxy-l ,3-benzenedicarboxylate
A mixture of di-tert-butyl 1,3-acetonedicarboxylate (10 g, 38.7 mmol), 3,5-heptanedione (6.5 g, 50.3 mmol) and sodium methoxide (2.7 g, 50.3 mmol) in methanol (100 mL) was stirred at room temperature overnight. Methanol was removed via rotary evaporation and the resulting orange sludge was partitioned between diethyl ether (100 mL) and 10 % aqueous hydrochloric acid (100 mL). The separated aqueous layer was extracted with diethyl ether (50 mL x 2). The combined organic portions were washed with saturated aqueous sodium chloride (20 mL), dried over sodium sulfate, filtered through a pad of silica (20 mm x 40 mm) and concentrated in vacuo to yield a yellow oil (13.23 g, 97 %): JH NMR (300 MHz, CDCI3): δ 1.20 (t, 6H), 1.60 (s, 18H) 2.74 (q, 4H), 6.55 (s, IH), 11.73 (s, IH).
Step B: Di-tert-butyl 3,5-diisopropyl-2'-benzyloxy-4'-fluoro-l,r-biphenyl-2,6- dicarboxylate
The title compound was prepared from the intermediate obtained in Step A by the methods described in Example 241, Steps B, C, and E. iH NMR (300 MHz, CDCI3): δ 1.15 (s, 18H), 1.27 (dd, J=5.15, 1.65 Hz, 12 H), 3.06 (m, 2H), 4.95 (s,
2H), 6.65 (m, 2H), 7.27 (m, 7H).
Step C: 3,5-Diisopropyl-2'-benzyloxy-4'-fluoro-l,r-biphenyI-2,6-dicarboxylate
To a solution of 14.37 g (25.53 mmol) of the intermediate obtained in Step B in dichloromethane (150 mL) at 0°C was added trifluoroacetic acid (20 mL, 259.60 mmol). This reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated to dryness and the residue was partioned between diethyl ether and aqueous sodium hydroxide. The organic layer was removed, washed with aqueous sodium hydroxide and the two aqueous layers were combined. The combined aqueous layers were washed with diethyl ether (lx) then made acidic by addition of HCl (10%) and extracted with diethyl ether (3x). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to yield an off-white solid. The crude product was taken directly to the next step without any further purification.
Step D: Dimethyl 3,5-diisopropyl-2'-benzyloxy-4'-fluoro-l ,1 '-biphenyl-2,6- dicarboxylate
To a suspension of 7.17 g (15.93 mmol) of the intermediate obtained in Step C in dichloromethane (200 mL) at 0°C was added solid potassium carbonate (10.05 g, 72.71 mmol) followed by iodomethane (5.0 mL, 80.31 mmol). The mixture was allowed to warm to room temperature. After stirring for 1 day the mixture was diluted with water and extracted with diethyl ether (3x). The combined extracts were washed with brine (lx), dried over magnesium sulfate, filtered and concentrated to yield an off-white solid. JH NMR (300 MHz, CDCI3): δ 1.22 (dd, 1=4.41, 2.4 Hz, 12H), 2.94 (m, 2H), 3.39 (s, 6H), 4.93 (s, 2H), 6.55 (m, 2H), 7.05 ( , IH), 7.18 (m, 6H).
Step E: 3>5-Diisopropyl-2-(l-hydroxyethvP-6-ethyl-4'-fluoro-2'-hydroxy-l,l'- biphenyl The title compound was prepared from the intermediate obtained in Step D by the methods described in Example 241 steps F-I (using ethyl triphenylphosphonium bromide in Step H) followed by Example 242 steps B-D. Silica gel chromatography (90% hexane/ 10% EtOAc) provided two colorless solids (1.129g, 84%). Diastereomer 1 was obtained as a colorless crystalline solid (1.029g, 77%). iH NMR (300 MHz, CDCI3): δ 0.89 (t, J=7.36 Hz, 3H), 1.28 (m, 12H), 1.40 (d, J=6.62
Hz,3H), 1.63 (bs, IH), 2.29 (m, 2H), 3.17 (m, IH), 3.78 (m, IH), 4.84 (m, IH), 6.70 (m, 2H), 7.03 (m, IH), 7.38 (s, IH). FAB-MS: calculated for C22H29O2F, 344; found 367
[M+Na]. mp 174-175°C. Diastereomer 1 (1.029 g) was resolved into its constituent enantiomers as follows: a Waters Prep LC 4000 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 0.75% butanol and 99.25% hexane at a flow rate of 100 mL/min.
The sample was dissolved in dichloromethane (20 mg/mL) and the sample was injected in one injection. The effluent was monitored at 285 nm and two fractions
(corresponding to the two enantiomers) were collected at (26-32 min,≥98% ee) and
(34-48 min, >99% ee), respectively.
Enantiomer 1 was obtained as a colorless solid (480 mg). iH NMR (300
MHz, CDCI3): δ 0.89 (t, J=7.54 Hz, 3H), 1.28 (m, 12H), 1.40 (d, J=5.14 Hz, 3H), 1.65 (bs, IH), 2.19 (m, IH), 2.35 (m, IH), 3.17 (m, IH), 3.78 (m, IH), 4.85 (m, IH), 6.71 (m, 2H), 7.03 (m, IH), 7.38 (s, IH). mp condenses at 57-59°C.
Enantiomer 2 was obtained as a colorless solid (483 mg). iH NMR (300 MHz, CDCI3): δ 0.89 (t, J=7.36 Hz, 3H), 1.28 (m, 12H), 1.39 (d, J=6.99 Hz, 3H), 1.63
(bs, IH), 2.29 (m, 2H), 3.17 (m, IH), 3.78 (m, IH), 4.84 (m, IH), 6.70 (m, 2H), 7.03 (m, IH), 7.38 (s, IH). FAB-MS: calculated for C22H29O2F- 344; found 367 [M+Na). mp condenses at 57-59°C.
Diastereomer 2 was obtained as a colorless crystalline solid (100 mg, 7%). αH NMR (CDCI3, 300 MHz): δ 0.88 (t, J=7.54 Hz, 3H), 1.27 (m, 12H), 1.36 (d, J=6.62
Hz, 3H), 1.8 (bs, IH), 2.19 (m, IH), 2.39 (m, IH), 3.16 (m, IH), 3.84 (m. IH), 4.63 (q, J=6.62 Hz, IH), 5.09 (bs, IH), 6.69 (m, 2H), 6.92 (t, J=7.35 Hz, IH), 7.37 (s, IH). mp 183-184°C. EXAMPLE 247
Figure imgf000366_0001
3>5-Diisopropyl-2-(l-hydroxyethyl)-6-pentyl-4'-fluoro-2'-hydroxy-l,l'-biphenyl
Step A: 3,5-Diisopropyl-2-hydroxymethyl-6-(pent-l-enyP-2'-benzyloxy-4'- fluoro-1,1 '-biphenyl
The desired compound was prepared from dimethyl 3,5-diisopropyl-2 - benzyloxy-4'-fluoro-l, -biphenyl-2,6-dicarboxylate (Example 246, Step D) by the procedure described in Example 241, Steps F - I (using pentyl triphenylphosphonium bromide in Step H). The pure product obtained was a clear oil (4.73 g, 52 % over 4 steps). iH NMR (300 MHz, CDCI3): δ 0.67 - 0.78 (m, 3H),
1.09 - 1.34 (m, 14H), 1.66 - 1.88 (m, 3H), 3.16 - 3.46 (m, 2H), 4.29 - 4.44 (m, 2H), 4.88 - 5.04 (m, 2H), 5.27 - 5.41 (m, IH), 5.94 - 6.01 (m, IH), 6.69 - 6.78 (m, 2H), 7.00 - 7.06 (m, 3H), 7.22 - 7.26 (m, 3H), 7.35 (s, IH). 13c NMR (75 MHz, CDCI3): δ 14.18, 14.52, 22.89, 23.05, 24.39, 24.64, 24.94, 25.11, 25.38, 29.73, 30.50, 30.66, 31.68, 35.85, 60.78, 71.07, 71.45, 102.25, 102.59, 108.08, 108.37, 122.33, 122.54, 127.11, 127.22, 127.92, 128.11, 128.51, 129.16, 132.70, 132.83, 133.39, 134.06, 135.96, 136.96, 137.29, 137.35, 147.48, 147.63, 147.79, 156.90, 156.93, 163.26 (d, J = 246.6 Hz, IC). FAB-MS: calculated for C31H37O2F 460; found 460 (M+). Anal, calc for C31H37O2F: C, 80.83; H, 8.10. Found: C, 80.91; H, 8.01. Rf = 0.34 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A = 0.05 % aqueous trifluoroacetic acid, B = CH3CN; linear gradient: 80%-100% B over 20 min; 254 nm, 1 mL/min): R.T. 14.8 min (37.7 area %), 15.2 min (56.0 area %); 93.7 % purity (cis- and trans-).
Step B: 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-pentyI-4'-fluoro-2'-hydroxy- lΛ'-biphenyl
The title compound was prepared from the intermediate obtained in Step A utilizing the procedures outlined in Example 242, Steps B-D. The crude product was subjected to flash column chromatography on silica (50 mm x 6") using hexanes:ethyl acetate (19:1 and 9:1) as eluent to separate the diastereomers (2.19 g, 90 %, 75 % over 3 steps).
Diastereomer 1 was obtained as a white solid (2.03 g, 83 %). iH NMR (300 MHz, CDCI3): δ 0.78 (t, J = 6.6 Hz, 3H), 0.96 - 1.23 (m, 19H), 1.41 (d, J = 7.0 Hz, 3H),
2.04 - 2.37 (m, 2H), 3.09 - 3.19 (m, IH), 3.74 - 3.84 (m, IH), 4.81 - 4.90 (m, 2H), 6.68 - 6.75 (m, 2H), 6.99 - 7.06 (m, IH), 7.37 (s, IH). 13C NMR (75 MHz, CDCI3): δ 13.83, 21.94, 23.83, 24.27, 24.38, 24.50, 24.88, 28.70, 29.05, 29.80, 30.76, 32.20, 68.21, 102.98 (d, J = 24.4 Hz, IC), 107.33 (d, J = 20.8 Hz, IC), 123.58 (d, J = 2.4 Hz, IC), 125.45, 130.70 (d, J = 9.8 Hz, IC), 131.78, 137.45, 138.55, 146.48, 146.94, 154.29 (d, J = 6.1 Hz, IC), 163.04 (d, J = 244.2 Hz, IC). FAB-MS: calculated for C25H35O2F 386; found 409 (M+Na)+. Anal, calc for C25H35O2F: C, 77.68; H, 9.13. Found: C, 77.38; H, 9.20. Rf = 0.30 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A = 0.05 % aqueous trifluoroacetic acid, B = CH3CN; linear gradient: 70%-100% B over 30 min; 254 nm, 1 mL/min):
R.T. 12.9 min (91.3 area %); (silica, A = hexanes, B = isopropanol, isocratic run: 3 % B over 15 min; 254 nm, 1 mL/min): R.T. 5.1 min (100 area %). mp 122.5-124.0°C.
Diastereomer 1 (1.92 g) was resolved into its constituent enantiomers as follows: a Waters Prep LC 4000 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 0.75% butanol and 99.25% hexane at a flow rate of 100 mL/min. The sample was dissolved in dichloromethane (40 mg/mL) and the sample was loaded in two injections. The effluent was monitored at 285 nm and two fractions (corresponding to the two enantiomers) were collected.
Enantiomer 1 was obtained as a white crystalline solid (0.78 g). iH NMR (300 MHz, CDCI3): δ 0.78 (t, J = 6.6 Hz, 3H), 0.96 - 1.23 (m, 19H), 1.41 (d, J = 7.0
Hz,3H), 2.04 - 2.37 (m, 2H), 3.09 - 3.19 (m, IH), 3.74 - 3.84 (m, IH), 4.81 - 4.90 (m,
2H), 6.68 - 6.75 (m, 2H), 6.99 - 7.06 (m, IH), 7.37 (s, IH). 13C NMR (75 MHz, CDCI3): δ 13.83, 21.94, 23.83, 24.27, 24.38, 24.50, 24.88, 28.70, 29.05, 29.80, 30.76,
32.20, 68.21, 102.98 (d, J = 24.4 Hz, IC), 107.33 (d, J = 20.8 Hz, IC), 123.58 (d, J = 2.4 Hz, IC), 125.45, 130.70 (d, J = 9.8 Hz, IC), 131.78, 137.45, 138.55, 146.48, 146.94, 154.29 (d, J = 6.1 Hz, IC), 163.04 (d, J = 244.2 Hz, IC). FAB-MS: calculated for C25H35O2F 386; found 409 (M+Na)+. Anal, calc for C25H35O2F: C, 77.68; H, 9.13. Found: C, 77.74; H, 9.00. Rf = 0.30 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A = 0.05 % aqueous trifluoroacetic acid, B = CH3CN; linear gradient: 70%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 12.8 min (94.9 area %); (BRB-9668, 99 % (1 % butanol in hexanes), 5 min, 285 nm, 2mL/min): R.T. 2.6 min (100 area %, 100 % e.e.). [a]D = -14.3° (c = 0.00200 g/mL, CH2CI2). mp 105.0-106.5°C. Enantiomer 2 was obtained as a white flaky solid (0.73 g). iH NMR (300
MHz, CDCI3): δ 0.78 (t, J = 6.6 Hz, 3H), 0.96 - 1.23 (m, 19H), 1.41 (d, J = 7.0 Hz,3H),
2.04 - 2.37 (m, 2H), 3.09 - 3.19 (m, IH), 3.74 - 3.84 (m, IH), 4.81 - 4.90 (m, 2H), 6.68 - 6.75 (m, 2H), 6.99 - 7.06 (m, IH), 7.37 (s, IH). 13c NMR (75 MHz, CDCI3): δ 13.83, 21.94, 23.83, 24.27, 24.38, 24.50, 24.88, 28.70, 29.05, 29.80, 30.76, 32.20, 68.21, 102.98 (d, J = 24.4 Hz, IC), 107.33 (d, J = 20.8 Hz, IC), 123.58 (d, J = 2.4 Hz, IC), 125.45, 130.70 (d, J = 9.8 Hz, IC), 131.78, 137.45, 138.55, 146.48, 146.94, 154.29 (d, J = 6.1 Hz, IC), 163.04 (d, J = 244.2 Hz, IC). FAB-MS: calculated for C25H35O2F 386; found 409 (M+Na)+. Anal, calc for C25H35O2F: C, 77.68; H, 9.13. Found: C, 77.64; H, 9.06. Rf
= 0.30 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A = 0.05 % aqueous trifluoroacetic acid, B = CH3CN; linear gradient: 70%-100% B over 30 min; 254 nm, 1 mL/min):
R.T. 12.8 min (94.7 area %); (BRB-9668, 99 % (1 % butanol in hexanes), 5 min, 285 nm, 2mL/min): R.T. 1.7 min (0.51 area %), 2.9 min (0.97 area %), 4.0 min (98.5 area %, 98 % e.e.). [a]D = +16.0° (c = 0.00200 g/mL, CH2CI2). mp 103.5-105.5°C.
Diastereomer 2 was obtained as a white solid (0.16 g, 7 %). iH NMR (CDCI3, 300 MHz): δ 0.78 (t, J = 6.6 Hz, 3H), 0.96 - 1.33 (m, 19H), 1.37 (d, J = 6.6
Hz,3H), 2.05 - 2.38 (m, 2H), 3.09 - 3.19 (m, IH), 3.80 - 3.89 (m, IH), 4.61 - 4.68 (m,
IH), 4.75 - 5.25 (br s, IH), 6.66 - 6.74 (m, 2H), 6.90 - 6.96 (m, IH), 7.37 (s, IH). 13c NMR (75 MHz, CDCI3): δ 13.83, 21.94, 23.43, 24.08, 24.48, 24.56, 24.98, 28.70, 29.04,
29.80, 30.76, 32.19, 68.89, 102.80 (d, J = 24.4 Hz, IC), 107.36 (d, J = 22.0 Hz, IC), 123.24 (d, J = 2.4 Hz, IC), 125.64, 131.25 (d, J = 9.8 Hz, IC), 131.56, 137.08, 138.44, 146.81, 146.84, 154.37 (d, J = 12.2 Hz, IC), 163.03 (d, J = 244.2 Hz, IC). FAB-MS: calculated for C25H35O2F 386; found 409 (M+Na)+. Anal, calc for C25H35O2F: C, 77.68; H, 9.13. Found: C, 77.70; H, 9.12. Rf = 0.17 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A = 0.05 % aqueous trifluoroacetic acid, B = CH3CN; linear gradient: 70%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 17.6 min (86.9 area %); (silica, A = hexanes, B = isopropanol, isocratic run: 3 % B over 15 min; 254 nm, 1 mL/min): R.T. 4.9 min (100 area %). mp 148.0-150.0°C. EXAMPLE 248
Figure imgf000368_0001
(+)-3,5-Diisopropyl-2-f(p-methylbenzyloxy)methyll-6-(l-hydroxyethyl)-4'-fluoro- Ll'-biphenyl Step A: 3,5-Diisopropyl-2-f(^-methvIbenzyloxy)methyll-6-hydroxymethyl-4'- fluoro- 1 ,1 '-biphenyl
To a solution of 3,5-diisopropyl-2-hydroxymethyl-6-carboxymethyl-4'- fluoro-1,1 '-biphenyl (Example 244, Step D) (4.09 g, 11.9 mmol) in THF (70 mL) was added at room temperature sodium hydride (0.85 g, 35.4 mmol) in portions. The reaction mixture was stirred for 10 min. and then treated with α-bromo-p-xylene
(2.64 g, 14.3 mmol). The reaction mixture was heated at reflux for 24 hrs then cooled to room temperature and quenched with water (30 mL). The solvent was removed in vacuo and the residue partitioned between diethyl ether (300 mL) and water (200 mL). The ether layer was dried (MgSθ4) and concentrated, the residue was purified through silica (70% CH2CI2 /hexane) which afforded a white solid (4.5 g, 10.3 mmol, 84%). The product was dissolved in THF (40 mL) was treated with lithium aluminum hydride (19.8 mL, 19.8 mmol, 1.0M in THF). The reaction mixture was heated at reflux for 2 hrs then allowed to cool to room temperature. The mixture was quenched with water (6 mL), and the solvent was removed in vacuo. The residue was partitioned between diethyl ether (200 mL) and water (300 mL). The organic layer was washed with water (3 X 300mL), brine (100 mL), dried (MgSθ4), filtered and concentrated. The residue was filtered through a cake of silica (CH2CI2, lL) and evaporated to afford a white solid (3.26 g, 7.7 mmol, 78%). mp 99-lθrC; Rf = 0.07 (80% CH2CI2 /hexane); iH NMR (300 MHz, CDCI3): δ 7.38 (s, 1 H), 7.24 (m, 2 H), 7.09 (m, 6 H), 4.36 (d, / = 5.5 Hz, 2 H), 4.27 (s, 2 H), 4.11 (s, 2 H), 3.42 (septet, / = 6.6 Hz, 1 H), 3.32 (septet, / = 6.6 Hz, 1 H), 2.35 (s, 3 H), 1.60 (s, 1 H), 1.22 (m, 12 H); FAB-MS calcd for (C28H33FO2) 420, found 403 (M-OH).
Step B: (+)-3,5-Diisopropyl-2-[(p-methylbenzyloxy)methyll-6-(l- hydroxyethyl)-4'-fluoro-l,l'-biphenyl The title compound was prepared by subjecting the intermediate obtained in Step A to the procedures described in Example 244, Steps I-K. mp 84-86°C; Rf = 0.1 (80% CH2Cl2/hexane); iH NMR (300 MHz, CDCI3): δ 7.39 (s, 1 H), 7.27 (m, 2 H), 7.09 (m, 6 H), 4.76 (dq, / = 1.5, 7 Hz, 1 H), 4.22 (s, 2 H), 4.03 (s, 2 H), 3.89 (septet, / = 6.6 Hz, 1 H), 3.26 (septet, / = 6.6 Hz, 1 H), 2.35 (s, 3 H), 1.66 (s, 1 H), 1.40 (d, / = 6.6 Hz, 3 H), 1.26 (m, 12 H); FAB-MS calcd for (C29H35FO2) 434, found 417 (M-OH); Anal. Calcd for C29H35FO2: C, 80.15; H, 8.12; F, 4.37. Found: C, 80.10; H, 8.30; F, 4.24; [α]22 = +30.7.
Figure imgf000370_0001
(+)-3,5-Diisopropyl-2-[(p-tolylthio)methvn-6-(l-hydroxyethyP-4'-fluoro-l,l'- biphenyl
The title compound was prepared from p-thiocresol and 3,5-diisopropyl-2- hydroxymethyl-6-carboxymethyl-4'-fluoro-l,l '-biphenyl (Example 244, Step D), according to the procedures described in Example 47, Steps B and C, followed by the procedures described in Example 244, Steps I-K. Rf = 0.36 (70% CH2C_2/hexane); iH NMR (300 MHz, CDCI3): δ 7.40 (s, 1 H), 7.28 (m, 2 H), 7.11 (m, 6 H), 4.76 (dq, / = 1.8, 7 Hz, 1 H), 3.92 (septet, / = 6.6 Hz, 1 H), 3.78 (s, 2 H), 3.26 (septet, / = 6.6 Hz, 1 H), 2.36 (s, 3 H), 1.66 (s, 1 H), 1.40 (d, / = 6.6 Hz, 3 H), 1.28 (m, 12 H); FAB-MS calcd for (C28H33FOS) 436, found 436 (M+); Anal. Calcd for C29H35FOS: C, 77.02; H, 7.62; S, 7.34; F, 4.35. Found: C, 76.90; H, 7.77; S, 7.30; F, 4.37; [αj22 = +32.2.
EXAMPLE 250
Figure imgf000370_0002
(+)-3,5-Diisopropyl-2-[(4-methoxythiophenyl)methyn-6-(l-hydroxyethyP-4'-fluoro- 1,1 '-biphenyl The title compotmd was prepared from 4-methoxy thiophenol and 3,5-diiso- propyl-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-l, -biphenyl (Example 244, Step D), according to the procedures described in Example 47, Steps B and C, followed by the procedures described in Example 244, Steps I-K. Rf = 0.23 (70% CH2CI2 /hexane); mp 140-2°C; iH NMR (300 MHz, CDCI3): δ 7.36 (s, 1 H), 7.30 (m, 2 H), 7.08 (m, 4 H), 6.75 (m, 2 H), 4.72 (q, / = 7 Hz, 1 H), 3.89 (septet, / = 7 Hz, 1 H), 3.78 (s, 3 H), 3.68 (m, 2 H), 3.38 (septet, / = 7 Hz, 1 H), 1.57 (m, 1 H), 1.40 (d, / = 6.6 Hz, 3 H), 1.31 (m, 12 H); FAB-MS calcd for (C28H33FO2S) 452, found 452 (M+); Anal. Calcd for C28H33FO2S: C, 74.30; H, 7.35; S, 7.08; F, 4.20. Found: C, 74.06; H, 7.46; S, 6.87; F, 4.09; [α]22 = +24.5.
EXAMPLE 251
Figure imgf000371_0001
(+)-3,5-Diisopropyl-2-f(4-thiomethylthiophenyl)-methyll-6-(l-hydroxyethyl)-4,- fluoro-1,1 '-biphenyl
The title compound was prepared from 4-(methylthio)phenol and 3,5-diiso- propyl-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-l,l'-biphenyl (Example 244, Step D), according to the procedures described in Example 47, Steps B and C, followed by the procedures described in Example 244, Steps I-K. Rf = 0.52 (90% CH2Cl2/hexane); mp 157-9°C; αH NMR (300 MHz, CDCI3): δ 7.37 (s, 1 H), 7.30 (m, 2 H), 7.12 (m, 6 H), 4.71 (q, / = 7 Hz, 1 H), 3.90 (septet, / = 7 Hz, 1 H), 3.75 (d, / = 11 Hz, 1 H), 3.70 (d, / = 11 Hz, 1 H), 3.33 (septet, / = 7 Hz, 1 H), 2.46 (s, 3 H), 1.58 (s, 1 H), 1.40 (d, / = 6.6 Hz, 3 H), 1.29 (m, 12 H); EI-MS calcd for (C28H33FOS2) 468, found 468 (M+); Anal. Calcd for C28H33FOS2: C, 71.76; H, 7.10; S, 13.68; F, 4.05. Found: C, 71.54; H, 7.22; S, 13.26; F, 4.17; [α]22 = +40.6. EXAMPLE 252
Figure imgf000372_0001
(+)-3,5-Diisopropyl-2-[(4-trifluoromethylthiophenyl)-methyll-6-(l-hydroxyethyI)- 4'-fluoro-l ,1 '-biphenyl
The title compound was prepared from 4-(trifluoromethyl)benzene thiol and 3,5-diisopropyl-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-l,l'-biphenyl (Example 244, Step D), according to the procedures described in Example 47, Steps B and C, followed by the procedures described in Example 244, Steps I-K. Rf = 0..39 (80% CH2C_2/hexane); mp 171-3°C; !H NMR (300 MHz, CDCI3): δ 7.45 (s, 1 H), 7.42 (s, 1 H), 7.39 (s, 1 H), 7.30 (m, 1 H), 7.09 (m, 5 H), 4.72 (q, / = 7 Hz, 1 H), 3.91 (septet, / = 7 Hz, 1 H), 3.83 (d, / = 11 Hz, 1 H), 3.78 (d, / = 11 Hz, 1 H), 3.28 (septet, / = 7 Hz, 1 H), 1.60 (s, 1 H), 1.41 (d, / = 6.6 Hz, 3 H), 1.29 (m, 12 H); FAB-MS calcd for (C28H30F4OS) 490, found 490 (M+); Anal. Calcd for C28H30F4OS: C, 68.55; H,
6.16; S, 6.53; F, 15.49. Found: C, 68.67; H, 6.15; S, 6.56; F, 15.33; [α]22 = +25.6.
EXAMPLE 253
Figure imgf000372_0002
(+)-3,5-Diisopropyl-2-[(4-trifluoromethoxythiophenyl)-methyll-6-(l-hydroxyethyP- 4'-fluoro-l, -biphenyl The title compound was prepared from 4-(trifluoromethoxy)benzene thiol and 3,5-diisopropyl-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-l,l'-biphenyl
(Example 244, Step D), according to the procedures described in Example 47, Steps B and C, followed by the procedures described in Example 244, Steps I-K. Rf = 0.39 (80% CH2Cl2/hexane); mp 124-6°C; iH NMR (300 MHz, CDCI3): δ 7.38 (s, 1 H), 7.30 (m, 2 H), 7.09 (m, 6 H), 4.73 (q, / = 7 Hz, 1 H), 3.91 (septet, / = 7 Hz, 1 H), 3.78 (d, / = 11 Hz, 1 H), 3.73 (d, / = 11 Hz, 1 H), 3.31 (septet, / = 7 Hz, 1 H), 1.60 (s, 1 H), 1.41 (d, J = 7 Hz, 3 H), 1.28 (m, 12 H); FAB-MS calcd for (C28H30F4O2S) 506, found 506 (M+); Anal. Calcd for C28H30F4O2S: C, 66.39; H, 5.97; S, 6.33; F, 15.00. Found: C, 66.71; H, 6.06; S, 6.22; F, 15.24; [α]22 = +25.8.
EXAMPLE 254
Figure imgf000373_0001
(+)-3,5-Diisopropyl-2-f(4-fluorothiophenyl)-methyl1-6-(l-hydroxyethyl)-4'-fluoro- 1,1 '-biphenyl
The title compound was prepared from 4-fluorothiolphenol and 3,5-diiso- propyl-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-l,l '-biphenyl (Example 244, Step D), according to the procedures described in Example 47, Steps B and C, followed by the procedures described in Example 244, Steps I-K. Rf = 0.35 (70% CH2Cl2/hexane); mp 138-140°C; iH NMR (300 MHz, CDCI3): δ 7.37 (s, 1 H), 7.30 (m, 2 H), 7.05 (m, 4 H), 6.90 (m, 2 H), 4.71 (q, / = 7 Hz, 1 H), 3.90 (septet, / = 6.6 Hz, 1 H), 3.72 (m, 2 H), 3.33 (septet, / = 6.6 Hz, 1 H), 1.52 (s, 1 H), 1.39 (d, / = 6.6 Hz, 3 H), 1.27 (m, 12 H); FAB-MS calcd for (C28H30FO2S) 506, found 506 (M+); Anal. Calcd for C28H33FO2S: C, 74.30; H, 7.35; S, 7.08; F, 4.20. Found: C, 74.06; H, 7.46; S, 6.87; F, 4.09; [α]22 = +17.6. EXAMPLE 255
Figure imgf000374_0001
3,5-Diisopropyl-2-(thiophenylmethyl)-6-(hydroxymethyl)-4'-fluoro-l, -biphenyl
A suspension of Wang-resin (100 g, 1.09 mmol/g hydroxylated) was suspended in 1 L of a solution of 4N HCl in dioxane and gently stirred at room temperature for two days. After filtration, the chlorinated resin was washed 6 times with each of the following solvents; dioxane, isopropanol and finally THF. The resin was then dried at 60°C overnight. From this resin, 2.5 g (2.2 mmol based on the chlorine content detected by elemental analysis) was suspended in DMF (25 mL) and stirred at room temperature for 5 minutes, then the DMF was decanted off for the addition of a solution of 3,5-diisopropyl-2-hydroxymethyl-6-carboxymethyl-4'- fluoro-1,1 '-biphenyl (Example 244, Step D) (1.13 g, 3.3 mmol) in DMF (25 mL), followed by a solution of sodium hydride (60 % in mineral oil, 170 mg, 3.3 mmol) in DMF (12.5 mL). The suspension was stirred at room temperature for two days under an argon atmosphere. The suspension was then filtered and the resulting resin was successively washed 10 times with each of the following solvents; DMF, a mixture THF/ water (1:1), THF and finally with CH2CI2. The resin residue was then treated with a solution of lithium aluminum hydride (1 M in THF, 15 mL, 15 mmol) and heated at reflux for 2 days. The suspension was filtered and the resulting residue was washed successively 10 times with each of the following solvents; THF, a mixture of THF/water (1:1), a mixture of THF/water (2:1), THF and finally with CH2CI2. The residue was suspended in THF (25 mL) and slowly treated with PBr3 (835 μL, 8.7 mmol) at room temperature. The resin was filtered out and washed 10 times with each of the following solvents; THF, mixture of THF/ IN sodium bicarbonate (1:1), THF/water (1:1), THF and finally CH2CI2, then dried at 60°C overnight which afforded 2.25 g of resin (0.62 mmol/g based on the bromine content detected by elemental analysis). To 25 mg of this intermediate coupled with a resin was added thiophenol (26.4 mg, 0.24 mmol) in dry THF (500 μL) and N-methylmorpholine (26 μL, 0.24 mmol), then the suspension was refluxed for 8 hours. After filtration, the resin was washed successively 10 times with each of the following solvents; THF, a mixture of THF/water (1:1) and THF. The resin was then suspended in a mixture of TFA and CH2CI2 (1:1) and stirred at room temperature for one hour. The resin was filtered off and the solvent recovered then evaporated. The residue was dissolved in a mixture of methanol and acetonitrile (1:1) and one drop of diisopropylethylamine, then stirred for one hour; HPLC: 12.5 min (Hypersil BDS-C18, 5μm, 125 x 2 mm/Hewlett Packard, Flow 0.5 mL, 0-13 min 30-90%C, 13-15 min 90%C, Solvent A: Water/0.1% TFA; Solvent B: Acetonitrile). After evaporation of the solvent, the remaining residue was transferred in a microtiterplate for testing.
The compounds identified in the following Table as Examples 256-288 were prepared analogously to the compound of Example 255.
Table of Exemplary Compounds 255-288
Figure imgf000375_0001
Figure imgf000376_0001
HPLC: The Retention times (R.T.) for the compounds shown in the above table of exemplary compounds 255-290 were measured in minutes according to one of the three methods described below:
(I) Hypersil BDS-C18, 5μm, 125 x 2 mm/Hewlett Packard, Flow 0.5 mL, 0-13 min 30-90%C, 13-15 min 90% C, Solvent A: Water/0.1% TFA; Solvent B: Acetonitrile. (H) Hypersil BDS-C18, 5μm, 125 x 2 mm/Hewlett Packard, Flow 0.5 mL, 0-
13 min 30-90%C, 13-25 min 90% C, Solvent A: Water/0.1% TFA; Solvent B:
Acetonitrile.
(IH) NPS ODS-1, 1.5mm, 33 x 4.6 mm/Micra, Flow 1.0 mL, 0-8 min 15-70% C,
Solvent A: Water/0.1% TFA; Solvent B: Acetonitrile. The estimated purity numbers were determined by comparison of peak areas, not by reference to standards.
The pharmaceutical utility of compounds of this invention is indicated by the following assay for glucagon receptor activity.
The affinity for the glucagon receptor of compounds of the present invention is determined by the glucagon receptor binding assay. Membranes were prepared from Chinese Hamster Ovary cells expressing the glucagon receptor (CHO-HGR) by scraping the cells into hypotonic lysis buffer (10 mM Tris, pH 7.4, 2 mM EDTA, 5 mM MgCl2 and 1 mM PMSF) and subjecting the material to Polytron homogenization. Nuclei were removed by a 15-min 800 x g centrifugation step conducted at 4°C. Membranes containing the receptor were collected by centrifugation at 15,000 x g for 15 min at 4°C. The membranes were washed once in lysis buffer and suspended in 0.25 M sucrose, 10 mM Tris, 5 mM EDTA, pH 7.4. The membranes were used in ligand binding studies as reported (Yoo- Warren, H. , Willse, A.G., Hancock, N., Hull, J., McCaleb, M., and Livingston, J. Regulation of Rat Glucagon Receptor Expression. Biochem. Biophysical Res. Commun. 1994, 205, 347-353). In brief, 10 ug of membrane protein was incubated in 130 μl of binding buffer that consisted of 20 mM Tris, pH 7.4, 1 mM EDTA, 1 mg/ml BSA, and 1 mg/ml bacitracin. The membrane suspension was placed in each well of a 96-well filtration plate (glass fiber type C, Millipore). Twenty μl of test compound was added to each well to give final concentrations ranging from 2 nM to 20 μM. Following the addition of test compound, 50 μl of l25l-glucagon (9 fmol) (NEN) was added to each well. Control wells contained membranes, 0.5% DMSO (solvent for test compounds), radiolabeled glucagon without and with excess native glucagon (1 μM) to establish nonspecific binding. The plates were incubated for 60 min at room temperature, and then filtered on a Millipore vacuum apparatus. Following a wash step with ice-cold PBS/0.1% BSA, the filters were punched into test tubes, and the membrane bound radioactivity was determined. An IC50 value
(the concentration of test compound needed to reduce membrane binding of radiolabelled glucagon by 50%) was calculated for each compound. If 20 μM compound did not reduce glucagon binding by 50%, the % reduction at 20 μM was reported in place of an IC50 value. The binding characteristics for compounds of this invention are shown in Table 1(C).
Table 1(C)
Figure imgf000378_0001
Figure imgf000379_0001
Figure imgf000380_0001
Figure imgf000381_0001
Figure imgf000382_0001
Figure imgf000383_0001
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000386_0001
Figure imgf000387_0001
Preferred phenyl pyridine compounds of general formula (IC) and more particularly of general formula IB are shown in the following list:
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-hydroxyρhenyl)-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-burylpyridine; 2,6-Diisopropyl- 3-hydroxymethyl-4-phenyl-5-pentylpyridine; 2,6-DiisopropyI- 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-hydroxymethyl- pyridine; 2,6-Diisopropyl-3-[(/ olylthio)methyl]-4-(4-chlorophenyl)-5-hydroxymethyl- pyridine; 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- hy droxymethy 1-py rid ine; 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-(l-hydroxyethyl)-4-phenyl-5-ethylpyridine;
2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-ethylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-chlorophenyl)-5-ethylpyridine; 2/6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-methylphenyl)-5-ethylpyridine; 2,6-Diisopropyl-3-ι 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 l-hydroxyethyl)-4-phenyl-5-butylpyridine; 2,6-Diisopropyl-3- l-hydroxyethyl)-4-(4-fluorophenyl)-5-butylpyridine; 2,6-Diisopropyl-3- l-hydroxyethyl)-4-(4-chlorophenyl)-5-butylpyridine; 2,6-Diisopropyl-3- l-hydroxyethyl)-4-(4-methylphenyl)-5-butylpyridine; 2,6-Diisopropyl-3- l-hydroxyethyl)-4-(2-hydroxyphenyl)-5-butylpyridine; 2,6-Diisopropyl-3- l-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-butylpyridine; 2,6-Diisop ropy 1-3 l-hydroxyethyl)-4-phenyl-5-pentylpyridine; 2,6-Diisopropyl-3- l-hydroxyethyl)-4-(4-fluorophenyl)-5-pentylpyridine; 2,6-Diisopropyl-3-ι l-hydroxyethyl)-4-(4-chlorophenyl)-5-pentylpyridine; 2,6-Diisopropyl-3- l-hydroxyethyl)-4-(4-methylphenyl)-5-pentylpyridine; 2,6-Diisopropyl-3- l-hydroxyethyl)-4-(2-hydroxyphenyl)-5-pentylpyridine; 2,6-Diisopropyl-3- l-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-pentylpyridine; 2,6-Diisopropyl-3 l-hydroxyethyl)-4-phenyl-5-hexylpyridine; 2,6-Diisopropyl-3-ι l-hydroxyethyl)-4-(4-fluorophenyl)-5-hexyl-pyridine; 2,6-Diisopropyl-3 l-hydroxyethyl)-4-(4-chlorophenyl)-5-hexylpyridine; 2,6-Diisopropyl-3 l-hydroxyethyl)-4-(4-methylphenyl)-5-hexylpyridine; 2,6-Diisopropyl-3- l-hydroxyethyl)-4-(2-hydroxyphenyl)-5-hexylpyridine;
2,6-Diisopropyl-3- l-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5-hexylpyridine;
2,6-Diisopropyl-3- (p-tolylthio)methyl]-4-phenyl-5-(l-hydroxyethyl)-pyridine;
2,6-Diisopropyl-3- (p-tolylthio)methyl]-4-(4-fluorophenyl)-5-(l-hydroxyethyl)- pyridine; 2,6-Diisopropyl-3- (p-tolylthio)methyl]-4-(4-chlorophenyl)-5-(l-hydroxyethyl)- pyridine; 2,6-Diisopropyl-3 (p-tolylthio)methyl]-4-(4-methylphenyl)-5-(l-hydroxyethyl)- pyridine; 2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(2-hydroxyphenyl)-5-(l-hydroxyethyl)- pyridine; 2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(2-hydroxy-4-fluorophenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-phenyl-5-(l-hydroxyethyl)- pyridine;
2,6-Diisopropyl-3-[((4-fluoroρhenyl)thio)methyl]-4-(4-fluorophenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-chlorophenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-methylphenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(2-hydroxyphenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(2-hydroxy-4-fluorophenyl)-5- (l-hydroxyethyl)-pyridine.
Preferred biphenyl compounds of general formula (IC) and more particularly of general formula ID are shown in the following list:
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-l,l '-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-fluoro-l, -biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-chloro-l,F-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-methyl-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-2'-hydroxy-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-2'-hydroxy-4'-fluoro-l,l '-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-l,r-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-fluoro-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-chloro-l, -biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-methyl-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-propyl-2'-hydroxy-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-2'-hydroxy-4'-fluoro-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-chloro-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-methyl-l, -biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-butyl-2'-hydroxy-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-butyl-2'-hydroxy-4'-fluoro-l, -biphenyl; 3,5-Diisopropy 1-2-hy droxymethy 1-6-pentyl-l ,1 '-biphenyl; 3,5-Diisopropy 1-2-hy d roxy methy 1-6-pen ty l-4'-fluor o- 1 , 1 '-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-chloro-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-methyl-l, -biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-2'-hydroxy-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-2'-hydroxy-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-fluoro-l,r-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-chloro-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-methyl-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-2'-hydroxy-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-2'-hydroxy-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-l,l'-biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-4'-chloro-l, -biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-4'-methyl-l,l'-biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-2'-hydroxy-l,l'-biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-2'-hydroxy-4'-fluoro-l, - biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-l,l'-biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-4'-fluoro-l,l'- biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-4'-chloro-l, - biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-4'-methyl-l, - biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-2'-hydroxy-l,l'- biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-2'-hydroxy-4'- fluoro- 1 , 1 '-biphenyl; 3,5-Diisopropyl-2 (l-hydroxyethyl)-6-ethyl-l,l'-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-ethy l-4'-fluoro-l ,1 '-biphenyl; 3,5-Diisopropyl-2 (l-hydroxyethyl)-6-ethyl-4'-chloro-l, -biphenyl; 3,5-Diisopropyl-2 (l-hydroxyethyl)-6-ethyl-4'-methyl-l,l'-biphenyl; 3,5-Diisopropyl-2 (l-hydroxyethyl)-6-ethyl-2'-hydroxy-l,l'-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-ethyl-2'-hydroxy-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-propyl-l,l '-biphenyl; 3,5-Diisopropyl-2 (l-hydroxyethyl)-6-propyl-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-propyl-4'-chloro-l,l'-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-propyl-4'-methyl-l,l'-biphenyl; 3,5-Diisopropyl-2 ( 1 -hy d roxyethy l)-6-propy 1-2 '-hydroxy- 1 , 1 '-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-propyl-2'-hydroxy-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2- ( 1 -hydroxy ethy l)-6-buty 1-1 , 1 '-biphenyl; 3,5-Diisopropyl-2 (l-hydroxyethyl)-6-butyl-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-butyl-4'-chloro-l,l'-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-butyl-4'-methyl-l,l'-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-butyl-2'-hydroxy-l,l'-biphenyl; 3,5-Diisopropyl-2-ι ( 1 -hydroxy ethy 1 )-6-buty l-2'-hyd roxy-4'- fluoro- 1 , 1 '-biphenyl; 3,5-Diisopropyl-2- ( 1 -hy droxyethy l)-6-penty 1-1 , 1 '-biphenyl; 3,5-Diisopropyl-2 (l-hydroxyethyl)-6-pentyl-4'-fluoro-l,l '-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-pentyl-4'-chloro-l ,1 '-biphenyl; 3,5-Diisopropyl-2 (l-hydroxyethyl)-6-pentyl-4'-methyl-l,l'-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-pentyl-2'-hydroxy-l,l'-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-pentyl-2'-hydroxy-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2 ( 1 -hy d roxyethy l)-6-hexy 1- 1 , 1 '-biphenyl; 3,5-Diisopropyl-2 (l-hydroxyethyl)-6-hexyl-4'-fluoro-l, -biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-hexyl-4'-chloro-l,l'-biphenyl; 3,5-Diisopropyl-2- (1-hydroxyethyl )-6-hexyl-4'-methy 1-1,1 '-biphenyl; 3,5-Diisopropyl-2- ( 1-hy droxyethy l)-6-hexy 1-2 '-hydroxy- 1 , 1 '-biphenyl; 3,5-Diisopropyl-2- (l-hydroxyethyl)-6-hexyl-2'-hydroxy-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2 [(p-tolylthio)methyl]-6-(l-hydroxyethyl)-l,l'-biphenyl; 3,5-Diisopropyl-2 [(p-tolylthio)methyl]-6-(l-hydroxyethyl)-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2- [(p-tolylthio)methyl]-6-(l-hydroxyethyl)-4'-chloro-l,l'-biphenyl; 3,5-Diisopropyl-2 [(p-tolylthio)methyl]-6-(l-hydroxyethyl)-4'-methyl-l, -biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(l-hydroxyethyl)-2'-hydroxy-l,l'- biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(l-hydroxyethyl)-2'-hydroxy-4'-fluoro-
1,1 '-biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-l, -biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-4'-fluoro-l, - biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-4'-chloro-l, - biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-4'-methyl-l,l'- biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-2'-hydroxy-
1,1 '-biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-2'-hydroxy-4'- fluoro- 1 ,1 '-biphenyl.
Other embodiments of the invention will be apparent to the skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

Claims

We claim:
1. Substituted pyridines of the general formula (IA),
Figure imgf000394_0001
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 -NRIR2,
wherein
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
has the above-mentioned meaning
and
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 stiaight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR3R4,
wherein
Rβ and R^ are identical or different and have the meaning given above for Rl 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 R are identical or different and have the meaning given above for Rl 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
R9 Rιo
R7— X or R8
wherein R'7 and R^ 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 benzocondensed, 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 - NRllRl2,
wherein
RU and Rl2 are identical or different and have the meaning given above for R 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
RlO 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
Rl3 and Rl4 are identical or different and have the meaning given above for Rl and R2, or
R9 and RlO 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 -NRIR2,
wherein
Rl 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
R^ and R4 are identical or different and have the meaning given above for Rl 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 Rβ are identical or different and have the meaning given above for Rl 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,
stands for a radical of the formula
R9 R10
R7— X- or
wherein R7 and Rβ 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 -NRHR 2,
wherein
RU and R 2 are identical or different and have the meaning given above for Rl 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
RlO 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
Rl3 and Rl4 are identical or different and have the meaning given above for R and R2, or
R9 and Rly 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
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
in this case stands for straight-chain or branched alkoxy with up to 5 carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy,
stands for a radical of the formula
R9 R10
R7— X or R8 V
wherein
R7 and R^ 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,
R" denotes hydrogen, and
RlO 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 RlO 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)
Figure imgf000402_0001
in which
A, E, L, and T have the above-mentioned meanings,
and R15 stands for stiaight-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)
Figure imgf000403_0001
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 Rβ are the same or different and denote hydrogen, phenyl, or stiaight-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
Rβ denotes hydrogen or straight-chain or branched alkyl with up to 6 carbon atoms or phenyl,
Rl 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, stiaight-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 -OR^, -SR', -SO2R , 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 R^u are identical or different and have the above-indicated meaning of R2 and R^,
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 Rβ 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
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,
Rl 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
R denotes hydrogen or straight-chain or branched alkyl with up to 3 carbon atoms,
Rl 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 -SO2 8,
wherein
R6, R7, and R° 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)
Figure imgf000409_0001
in which
A, D, L, and T have the indicated meaning, and
RU stands with up to 4 carbon
Figure imgf000410_0001
are reacted with compounds of general formula (HI)
Rl-E-Z (HI)
in which
Rl 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 RU,
[B] compounds of general formula (H) are next converted by reactions with compounds of general formula (IV)
R12 S Cl (IV)
II
O in which
R stands for straight-chain alkyl with up to 4 carbon atoms,
into compounds of general formula (V) 1
Figure imgf000411_0001
in which
A, D, L, T, RU, and Rl2 have the indicated meaning,
and these are then reacted with compounds of general formula (VI)
R -E-V-H (VI)
in which
Rl, E, and V have the indicated meaning,
and reductive separation is carried out,
and optionally, the groups listed under substituents A, L, T, and R 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 IA
Figure imgf000412_0001
1A wherein
Ria and R " independently represent trifluoromethyl, (Cl-Clθ)-alkyl, substituted (Ci-Cιo)-alkyl, (C2-Cio)-alkenyl, substituted (C2-Cio)-alkenyl, (C2-Cl0)-alkynyl, substituted (C2-Clθ)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)- cycloalkenyl, or (Cl -Co) -alkanoyl;
R2 represents (Cj-C^-alkyl, substituted (CrC10)-a-ky_, (C2-C10)- alkenyl, substituted (C2-C2o)-alkenyl,
Figure imgf000412_0002
substituted (C2- Cl0)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)- cycloalkyl-(Cι-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, l,3-dioxolan-2-yl, -C(0)NR4R5, or -S(0)mR7 wherein m is 0, 1, or 2;
R4 and R independently represent hydrogen, (Ci-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Cι-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl- (Cl-C6)-alkyl, or substituted naphthyl-(Cl-C6)-alkyl;
R4 and Rβ optionally may be joined together to form - (CH2)rA(CH2)s- wherein r and s are independently 1, 2, or 3; and wherein
A represents O, S(0)n, CHR6, or NR6; wherein n is 0, 1, or 2; and
R6 represents hydrogen, (Ci-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Ci-C6)-alkyl; R7 represents (Cι-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cι-
C6)-alkyl, substituted phenyl-(Cι-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci-C6)-alkyl, substituted pyridyl-(Cι-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cι-C6)-alkyl, or substituted naphthyl-(Cι- C6)-alkyl; R2 optionally may be joined to R^ to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and R ° are attached; Rβ represents hydroxy, trifluoroacetyl, (Cj-C^-alkanoyl, substituted
(Cχ-C6)-alkyl, or substituted (C3-Cg)-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R^ 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, (Cχ-Cg)-alkyl, substituted (Cj-
C^-alkyl, (C2-C )-alkenyl, substituted (C2-C )-alkenyl, (C -C )-alkynyl, substituted (C2-C^)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(0)R4, -OC(0)R4, -CO2R4 -NR4R5, -C(0)NR R5, or -S(0)mR7 wherein m is 0, 1, or 2; and pharmaceutically acceptable salts thereof.
22. A compound of claim 21, wherein in structural formula IA,
Rla and R^5 independently represent trifluoromethyl, (Ci-Cιo)-alkyl, substituted (Ci-Cio)-alkyl, (C2-Cio)-alkenyl, substituted (C2-Cιo)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl;
R2 represents (Cχ-Cχo)-alkyl, substituted (Cχ-Cχo)-alkyl, (C2-Cχo)- alkenyl or substituted (C -C o)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(0)NR4R5, or -S(0)mR7 wherein m is 0, 1, or 2;
R4 and R^ independently represent hydrogen, (Cχ-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)- alkyl, substituted phenyl-(Cχ-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cι-Cό)-alkyl, or substituted naphthyl-(Ci-C6)-alkyl;
R6 represents hydrogen, (Cl-C6)-alkyl, phenyl, or phenyl-(Cχ-C6)- alkyl; R7 represents (Cι-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-
C6)-alkyl, substituted phenyl-(Cχ-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci-C6)-alkyl, or substituted pyridyl-(Cι-C6)-alkyl;
R2 optionally may be joined to R^" to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R2 and ° are attached; Rβ represents (Cj-C ) alkanoyl, substituted (C|-C£)-alkyl, or substituted (C3-C )-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, (Cj-Cβj-alkyl,
(C2-C5)-alkenyl, (C2-C£)-alkynyl, (C3-C )-cycloalkyl, cyano, -OR4, or -
OC(0)R4, where R4 is hydrogen, ( -C6) alkyl, phenyl ( -Cβ) alkyl or substituted phenyl (Cχ-C6) alkyl.
23. A compound of claim 21, wherein in structural formula IA,
Ria and Rlb independently represent (Cχ-C6)-alkyl or (C2-C6)- alkenyl;
R2 represents (CrC10)-alkyl, substituted ( -C10) alkyl, (C2-C10)- alkenyl, or substituted (C2-Cιo)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to
3 of halogen or -S(0)mR7 wherein m=0,
R7 represents (Cι-C6)-alkyl, phenyl, substituted phenyl, phenyl (Ci- C6)-alkyl or substituted phenyl (Cχ-C6)-alkyl;
Rβ represents substituted (Cj-CfcJ-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, (CrC6)-alkyl, (C2-C6)-alkenyl, -OR4, or -OC(0)R4, where R4 is hydrogen or (Ci-Cβ) 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 IB
Figure imgf000415_0001
wherein
Ria and Rl" independently represent trifluoromethyl, (Cι-Ciθ)-alkyl, substituted (Cl-Cio)-alkyl, (C2-Cio)-alkenyl, substituted (C2-Cio)-alkenyl, (C2-Clθ)-alkynyl, substituted (C2-Cιo)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)- cycloalkenyl, or (Cι-C6)-alkanoyl;
R2 represents
Figure imgf000415_0002
(C2-Cχo)_ alkenyl, substituted (C -C o)-alkenyl, (C -Cχo)~alkynyl, substituted (C2- C10)-alkynyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, or substituted (C3-C6)- cycloalkyHCj-C^-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, l,3-dioxolan-2-yl, -C(0)NR4R5, or -S(0)mR7 wherein m is 0, 1, or 2;
R4 and Rβ independently represent hydrogen, (Ci-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci-C6)-alkyl, substituted phenyl-(Cι-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cι-C6)-alkyl, or substituted naphthyl-(Cι-C6)-alkyl;
R4 and R^ optionally may be joined together to form - (CH2)rA(CH2)s- wherein r and s are independently 1, 2, or 3; and wherein A represents O, S(0)n, CHR6, or NR6; wherein n is 0, 1, or 2; and
R6 represents hydrogen, (Ci-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cι-C6)-alkyl; R7 represents (Cχ-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci- Cό)-alkyl, substituted phenyl-(Cι-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci-C6)-alkyl, substituted pyridyl-(Cι-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Ci-C6)-alkyl, or substituted naphthyl-(Ci- C6)-alkyl; R^ optionally may be joined to V to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and Rl° are attached;
R3 represents hydroxy, trifluoroacetyl, (Cχ-C^)-alkanoyl, substituted (Cj-CgJ-alkyl, or substituted (C3-C6)-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R^ 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, (C- C^-alkyl, substituted (Cχ-C£)-alkyl, (C2-C£)-alkenyl, substituted (C2-C6)-alkenyl, (C2-
C^-alkynyl, substituted (C2-C£)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(0)R4, -OC(0)R4, -CO2R4 -NR4R5, -C(0)NR R5, or -S(0)mR7 wherein m is 0, 1, or 2; and pharmaceutically acceptable salts thereof.
28. A compound of claim 27, wherein in structural formula IB,
Ria and R " independently represent trifluoromethyl, (Ci-Cio)-alkyl, substituted (Ci-Cio)-alkyl, (C2-Cχo)-alkenyl, substituted (C2-Cιo)-alkenyl,
(C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl; R2 represents (CrC10)-alkyl, substituted (CrC10)-alkyl, (C2-C10)- alkenyl or substituted (C2-Cjo)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(0)NR R5, or -S(0)mR7 wherein m is 0,1, or 2; R4 and R^ independently represent hydrogen, (Ci-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(Cι-Cβ)- alkyl, substituted phenyl-(Cχ-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cι-C6)-alkyl, or substituted naphthyl-(Cχ-C6)-alkyl;
R6 represents hydrogen, (Cχ-C6)-alkyl, phenyl, or phenyl-(Cχ-C6)- alkyl;
R7 represents (Cχ-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cχ- C6)-alkyI, substituted phenyl-(Cι-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Cι-C6)-alkyl, or substituted pyridyI-(Cι-C6)-alkyl;
R2 optionally may be joined to R^ to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R2 and R ° are attached; R3 represents (Cχ-Cg) alkanoyl, substituted (Ci-CgJ-alkyl, or substituted (C3-Cg)-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, (Cj-C^-alkyl, (C2-C£)-alkenyl, (C2- C6)-alkynyl, (C3-C )-cycloalkyl, cyano, -OR4, or -OC(0)R4, where R4 is hydrogen, (Cι-C6) alkyl, phenyl (Cχ-C6) alkyl or substituted phenyl ( -Cό) alkyl.
29. A compound of claim 27, wherein in structural formula IB, Rla and Rlb independently represent (Cι-C6)-alkyl or (C2-C6)- alkenyl;
R2 represents (Cχ-Cχo)-alkyl, substituted (Cχ-Clθ) alkyl, (C2-Cχo)- alkenyl, or substituted (C2-C|Q) alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen or -S(0)mR7 wherein m=0;
R7 represents (Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl (Ci- C6)-alkyl or substituted phenyl (Ci-C6)-alkyl;
R3 represents substituted (Cχ-Cg)-alkyl or substituted (C3-C )- 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, (C C6)-alkyl, (C2-C6)-alkenyl, -OR4, or -OC(0)R4, where R4 is hydrogen or ( -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-Dϋsopropyl-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-butyl- pyridine;
2,6-Diisopropyl-3-hydroxymethyl-4-phenyI-5-pentylpyridine; 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-ρentylpyridine; 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-pentyl- pyridine; 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-hexyl- pyridine; 2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-phenyl-5-hydroxymethyl-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-fluorophenyl)-5-hydroxymethyl- pyridine; 2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-chlorophenyl)-5-hydroxymethyl- pyridine; 2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-methylphenyl)-5- hyd roxy methy 1-py rid ine; 2,6-Diisopropy 1-3- [ (p-toly lthio )methy 1] -4-(2-hy d roxypheny l)-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- hy droxymethy 1-py rid ine; 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-Diisopropy l-3-( 1 -hydroxyethyl)-4-pheny 1-5-ethylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-ethylpyridine;
2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-chlorophenyl)-5-ethylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-methylphenyl)-5-ethylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(2-hydroxyphenyl)-5-ethylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5- ethylpyridine;
2,6-Diisopropyl-3-(l-hydroxyethyl)-4-phenyl-5-propylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-propylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-chlorophenyl)-5-propylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-methylphenyl)-5-propylpyridine; 2,6-Diisopropyl-3-( 1 -hydroxyethy l)-4-(2-hy droxypheny l)-5-propy lpy ridine;
2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5- propylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-phenyl-5-butylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-butylρyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-chlorophenyl)-5-butylpyridine;
2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-methylphenyl)-5-butylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(2-hydroxyphenyl)-5-butylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5- butylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-phenyl-5-pentylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-pentylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-chlorophenyl)-5-pentylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-methylphenyl)-5-pentylpyridine;
2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(2-hydroxyphenyl)-5-pentylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5- pentylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-phenyl-5-hexylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)-5-hexyl-pyridine;
2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-chlorophenyl)-5-hexylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(4-methylphenyl)-5-hexylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(2-hydroxyphenyl)-5-hexylpyridine; 2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(2-hydroxy-4-fluorophenyl)-5- hexylpyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-phenyl-5-(l-hydroxyethyl)- pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-fluorophenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[( tolylthio)methyl]-4-(4-chlorophenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(4-methylphenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(2-hydroxyphenyl)-5-(l- hydroxyethyl)-pyridine;
2,6-Diisopropyl-3-[(p-tolylthio)methyl]-4-(2-hydroxy-4-fluorophenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-ρhenyl-5-(l- hydroxyethyP-pyridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-fluorophenyl)-5-(l- hy droxyethy 1 )-py ridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-chlorophenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(4-methylphenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(2-hydroxyphenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4-(2-hydroxy-4- fluorophenyl)-5-(l-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 IC
Figure imgf000421_0001
1 C wherein
R° represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (Cι-Cιo)-alkyl, substituted (Cι-Cιo)-alkyl, ( -C6)- alkoxy, (C3-C7)-cycloalkyl, phenyl-(Ci-C3)-alkoxy, (Cι-C6)-alkanoyloxy, (Cχ-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5;
R4 and R5 independently represent hydrogen, (Cι-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Cι-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cι-C6)-alkyl, substituted phenyl- (Cι-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cι-C6)-alkyl, or substituted naphthyl-(Ci-C6)-alkyl; R4 and R optionally may be joined together to form -
(CH2)rA(CH2)s- wherein r and s are independently 1, 2, or 3, and wherein A represents O, S(0)n, CHR6, or R6; wherein n is 0, 1, or 2; and R6 represents hydrogen, (Cχ-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cι-C6)-alkyl; Rla and R " independently represent trifluoromethyl, (Ci-Clθ)-alkyl, substituted (Cι-Clθ)-alkyl, (C2-Cιo)-alkenyl, substituted (C2-Cio)-alkenyl, (C2-Cιo)-alkynyl, substituted (C2-Cιo)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)- cycloalkenyl, or (Ci-C6)-alkanoyl;
R2 represents (Cj-CjoJ-alkyl, substituted (C1-C10)-alkyl, (C2-C10)- alkenyl, substituted (C2-Cio)-alkenyl, (C2-Cio)-alkynyl, substituted (C - C|o)-alkynyl/ (C3-C6)-cycloalkyl-(Cχ-C6)-alkyl, or substituted (C -C^)- cycloalkyl-(Cχ-C^)-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, l,3-dioxolan-2-yl, -C(0)NR4R5, or -S(0)mR7 wherein m is 0, 1, or 2; R7 represents (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cχ- C6)-alkyl, substituted phenyl-(Cι-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Cι-C6)-alkyl, substituted pyridyl-(Cι-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cι-C6)-alkyl, or substituted naphthyl-(Cχ- C6)-alkyl;
R2 optionally may be joined to Ri to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and Rib are attached;
R3 represents hydroxy, trifluoroacetyl, (Cχ-C )-alkanoyl, substituted (C-j-C^-alkyl, or substituted (C3-C )-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, (C- C^-alkyl, substituted (C C6)-alkyl, (C2-C6)-alkenyl, substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, substituted (C -C ,)-alkynyl, (C3-C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(0)R4, -OC(0)R4, -CO2R4, -NR R5, -C(0)NR4R5, or -S(0)mR7 wherein m is 0, 1, or 2 and pharmaceutically acceptable salts thereof.
35. A compound of claim 34, wherein in structural formula IC, R° represents hydrogen, halogen, trifluoromethyl or (Cl-Cio) alkyl;
R a and R independently represent trifluoromethyl, (Ci-Cio)-alkyl, substituted (Cι-Cιo)-alkyl, (C2-Cio)-alkenyl, substituted (C2-Cio)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl;
R2 represents (C|-Cχo)-alkyl, substituted (C^-CjQ^ lkyl, (C2-CJQ)- alkenyl or substituted (C2-Cχo)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(0)NR4R5, or -S(0)mR7 wherein m is 0,1, or 2;
R4 and R^ independently represent hydrogen, (Cl-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(Cχ-C6)- alkyl, substituted phenyl-(Cι-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Ci-C6)-alkyl, or substituted naphthyl-(Ci-C6)-alkyl;
R6 represents hydrogen, (Cι-C6)-alkyl, phenyl, or phenyl-(Cχ-C6)- alkyl; R7 represents (Cι-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cι-
C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Cι-C6)-alkyl, or substituted pyridyl-(Ci-C6)-alkyl;
R2 optionally may be joined to Ri to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R2 and Rib are attached;
R3 represents (Cχ-Cg) alkanoyl, substituted (C^-C^)-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, (Ci-C^-alkyl,
(C -C5)-alkenyl, (C2-Cg)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4, or -
OC(0)R4, where R4 is hydrogen, (Cχ-C6) alkyl, phenyl ( -Cό) alkyl or substituted phenyl (Cχ-C6) alkyl.
36. A compound of claim 34, wherein in structural formula IC, R° represents hydrogen; Rla and Rib independently represent (Ci-C6)-alkyl or (C2-C6)- alkenyl;
R2 represents (Cχ-Cιo)-alkyl, substituted (Cl-Cio) alkyl, (C2-CJQ)- alkenyl, or substituted (C2-Clθ)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen or -S(0)mR7 wherein m=0,
R7 represents (Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl (Ci- C6)-alkyl or substituted phenyl (Cι-C6)-alkyl; Rβ represents substituted
Figure imgf000424_0001
or substituted (C3-C )- 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(0)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 ID
Figure imgf000424_0002
wherein R^ represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (Cl-Cιo)-alkyl, substituted (Cχ-Clθ)-alkyl, ( -C6)- alkoxy, (C3-C7)-cycloalkyl, phenyl-(Ci-C3)-alkoxy, (Cι-C6)-alkanoyloxy, (Cχ-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5;
R4 and R^ independently represent hydrogen, (Ci-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Cι-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C -C6)-alkyl, substituted phenyl-(Cι-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Ci-C6)-alkyl, or substituted naphthyl-(Cι-C6)-alkyl;
R4 and R^ optionally may be joined together to form - (CH2)rA(CH2)s- wherein r and s are independently 1, 2, or 3, and wherein A represents O, S(0)n , CHR6, or NR6, wherein n is 0, 1, or 2; and
R6 represents hydrogen, (Cι-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Ci-C6)-alkyl;
Rla and Rib independently represent trifluoromethyl, (Ci-Clθ)-alkyl, substituted (Cl-Cio)-alkyl, (C2-Cio)-alkenyl, substituted (C2-Cio)-alkenyl, (C2-Cl0)-alkynyl, substituted (C2-Clθ)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)- cycloalkenyl, or (Ci-C6)-alkanoyl; R2 represents (CrC10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)- alkenyl, substituted (C2-Cχo)-alkenyl, (C2-Cχo)-alkynyl, substituted (C2- C o)-alkynyl, ^-CβJ-cycloalkyHCj-CβJ-alkyl, or substituted (C3-C^)- cycloalkyl-(Cχ-C )-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, l,3-dioxolan-2-yl, -C(0)NR R5, or -S(0)mR7 wherein m is 0, 1, or 2; R7 represents (Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cι-
C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci-C6)-alkyl, substituted pyridyl-(Ci-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cι-
C6)-alkyl;
R2 optionally may be joined to Rib to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R2 and Rib are attached; R3 represents hydroxy, trifluoroacetyl, (Cχ-C5)-alkanoyl, substituted
(Cχ-Cg)-alkyl, or substituted (C -C,5)-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl Rβ 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, (C- C^-alkyl, substituted
Figure imgf000426_0001
(C -
C^-alkynyl, substituted (C2-C^)-alkynyl, (C -C7)-cycloalkyl, cyano, nitro, trifluoromethyl, -OR4, -C(0)R4, -OC(0)R4, -CO2R4, -NR4R5, -C(0)NR4R5, or -S(0)mR7 wherein m is 0, 1, or 2; and pharmaceutically acceptable salts thereof.
41. A compound of claim 40, wherein in structural formula ID,
R° represents hydrogen, halogen, trifluoromethyl or (C1-C10) alkyl; R a and Rib independently represent trifluoromethyl, (Cι-Cιo)-alkyl, substituted (Ci-C o)-alkyl, (C2-Cιo)-alkenyl, substituted (C2-Cio)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl;
R2 represents (Cχ-Cχo)-alkyl, substituted (Cχ-C o)-alkyl, (C -CJQ)- alkenyl or substituted (C2-Cχo)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(0)NR4R5, or -S(0)mR7 wherein m is 0,l,or 2;
R4 and R^ independently represent hydrogen, (Ci-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(Cχ-C6)- alkyl, substituted phenyl-(Cχ-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(Cχ-C6)-alkyl; Rβ represents hydrogen, (Cχ-C6)-alkyl, phenyl, or phenyl-(Cχ-C6)- alkyl;
R7 represents (Cχ-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cχ- C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Cι-C6)-alkyl, or substituted pyridyl-(Cι-C6)-alkyl; R2 optionally may be joined to Rib to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R2 and Rib are attached;
Rβ represents (Cχ-C^) alkanoyl, substituted (Cχ-Cg)-alkyl, or substituted (C3-Cg)-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, (Cχ-C6)-alkyl, (C2-C6)-alkenyl, (C2-
C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR4, or -OC(0)R4, where R4 is hydrogen, ( -C6) alkyl, phenyl (Cl-C6) alkyl or substituted phenyl (Cχ-C6) alkyl.
42. A compound of claim 40, wherein in structural formula ID, represents hydrogen;
Rla and Rib independently represent (Cχ-C6)-alkyl or (C2-C6)- alkenyl; R2 represents (Cj-Cxo alkyl, substituted (C1-C10) alkyl, (C -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(0)mR7 wherein m=0;
R7 represents (Ci-C6)-alkyl, phenyl, substituted phenyl, phenyl (Ci- C6)-alkyl or substituted phenyl (Ci-C6)-alkyl;
R3 represents substituted (C}-C )-alkyl or substituted (C3-C£)- 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,
Figure imgf000427_0001
(C2-Cg)-alkenyl, -OR4, or -OC(0)R4, where R4 is hydrogen or (Cχ-C6) alkyl.
43. A compound of claim 40, selected from the following group of compounds: 3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-chloro-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-methyl-l,l '-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-2'-hydroxy-l,l '-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-2'-hydroxy-4'-fluoro-l,l '-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-fluoro-l,r-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-chloro-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-4'-methyl-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-propyl-2'-hydroxy-l,l '-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-propyl-2'-hydroxy-4'-fluoro-l, - biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-l, -biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-fluoro-l, -biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-chloro-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-methyl-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-2'-hydroxy-l, -biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-butyl-2'-hydroxy-4'-fluoro-l, - biphenyl;
3,5-Diisopropy 1-2-hy droxy methy 1-6-penty 1- 1 ,1 '-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-fluoro-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-chloro-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-methyl-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-2'-hydroxy-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-2'-hydroxy-4'-fluoro-l, - biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-fluoro-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-chloro-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-methyl-l,l'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-2'-hydroxy-l,l'-biphenyl;
3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-2'-hydroxy-4'-fluoro-l, - biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-l,l'-biphenyl;
3,5-DiisopropyI-2-[(p-tolylthio)methyl]-6-hydroxymethyl-4'-fluoro-l, - biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-4'-chloro-l,l'- biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-4'-methyl-l,l'- biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-hydroxymethyl-2'-hydroxy-l ,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-l,l'- 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-l,l'-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'- hy droxy- 1 , 1 '-biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-hydroxymethyl-2'- hydroxy-4'-fluoro-l, '-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-ethyl-l, -biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-ethyl-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-ethyl-4'-chloro-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-ethyl-4'-methyl-l,l'-biphenyl;
3,5-Diisopropyl-2-(l-hydroxyethyl)-6-ethyl-2'-hydroxy-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-ethyl-2'-hydroxy-4'-fluoro-l,l'- biphenyl;
3,5-Diisopropyl-2-(l-hydroxyethyl)-6-propyl-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-propyl-4'-fluoro-l,l'-biphenyl;
3,5-Diisopropyl-2-(l-hydroxyethyl)-6-propyl-4'-chloro-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-propyl-4'-methyl-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-propyl-2'-hydroxy-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-propyl-2'-hydroxy-4'-fluoro-l,l'- biphenyl;
3,5-Diisopropyl-2-(l-hydroxyethyl)-6-butyl-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-butyl-4'-fluoro-l, -biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-butyl-4'-chloro-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-butyl-4'-methyl-l,l '-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-butyl-2'-hydroxy-l,l '-biphenyl;
3,5-Diisopropyl-2-(l-hydroxyethyl)-6-butyl-2'-hydroxy-4'-fluoro-l,l'- biphenyl; 3,5-Diisopropyl-2-( 1 -hydroxy ethy l)-6-penty 1-1 , 1 '-biphenyl; 3,5-Diisopropy_-2-(l-hydroxyethyl)-6-pentyl-4'-fluoro-l,l '-biphenyl;
3,5-Diisopropyl-2-(l-hydroxyethyl)-6-pentyl-4'-chloro-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-pentyl-4'-methyl-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-pentyl-2'-hydroxy-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-pentyl-2'-hydroxy-4'-fluoro-l,r- biphenyl;
3,5-Diisopropyl-2-(l-hydroxyethyl)-6-hexyl-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-hexyl-4'-fluoro-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-hexyl-4'-chloro-l,l '-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-hexyl-4'-methyl-l,l'-biphenyl; 3,5-Diisopropyl-2-(l-hydroxyethyl)-6-hexyl-2'-hydroxy-l,l'-biphenyl;
3,5-Diisopropyl-2-(l-hydroxyethyl)-6-hexyl-2'-hydroxy-4'-fluoro-l,l'- biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(l-hydroxyethyl)-l,l'-biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(l-hydroxyethyl)-4'-fluoro-l,l'- biphenyl;
3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(l-hydroxyethyl)-4'-chloro-l,l'- biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(l-hydroxyethyl)-4'-methyl-l,l'- biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(l-hydroxyethyl)-2'-hydroxy-l,l'- biphenyl; 3,5-Diisopropyl-2-[(p-tolylthio)methyl]-6-(l-hydroxyethyl)-2'-hydroxy-4'- fluoro-1,1 '-biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-l,l'- biphenyl;
3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-4'- fluoro- 1 ,1 '-biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-4'- chloro-1 , 1 '-biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-4'- methyl-l,l'-biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-2'- hydroxy-1,1 '-biphenyl; 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-2'- hydroxy-4'-fluoro-l,l '-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
H 3 HC H (Remainder of molecule)
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