US20050240049A1 - Process for the preparation of substituted tetralin and substituted indane derivatives - Google Patents

Process for the preparation of substituted tetralin and substituted indane derivatives Download PDF

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US20050240049A1
US20050240049A1 US11/110,459 US11045905A US2005240049A1 US 20050240049 A1 US20050240049 A1 US 20050240049A1 US 11045905 A US11045905 A US 11045905A US 2005240049 A1 US2005240049 A1 US 2005240049A1
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formula
compound
alkyl
yield
reacting
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US11/110,459
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Fan Zhang-Plasket
Hua Zhong
Frank Villani
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Janssen Pharmaceutica NV
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Fan Zhang-Plasket
Hua Zhong
Frank Villani
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Priority to US11/110,459 priority Critical patent/US20050240049A1/en
Publication of US20050240049A1 publication Critical patent/US20050240049A1/en
Assigned to JANSSEN PHARMACEUTICA N.V. reassignment JANSSEN PHARMACEUTICA N.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ZHONG, HUA, VILLANI, FRANK, ZHANG-PLASKET, FAN
Priority to US11/958,618 priority patent/US7576238B2/en
Priority to US12/501,833 priority patent/US20090326258A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
    • C07C303/08—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups by reaction with halogenosulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26—Separation; Purification; Stabilisation; Use of additives
    • C07C319/28—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to a novel processes for the preparation of substituted tetralin and substituted indane derivatives.
  • the substituted tetralin and substituted indane derivatives are PPAR alpha agonists, useful for elevating serum levels of high density lipoproteins (HDL), improving levels of intermediate density lipoproteins (IDL), and lowering serum levels of triglycerides, low density lipoproteins (LDL), atherogenic molecules, and/or free fatty acids (FFA).
  • the substituted tetralin and substituted indane compounds are further useful in treating hypertriglyceridemia, raising levels of HDL, lowering levels of LDL, and/or lowering total cholesterol.
  • the present invention is further directed to novel processes for the preparation of intermediates in the preparation of the substituted tetralin and substituted indane derivatives.
  • the present invention is directed to novel processes for the preparation of substituted tetralin and substituted indane derivatives.
  • the substituted tetralin and substituted indane derivatives and their use for the treatment of PPAR alpha-mediated diseases including, but not limited to dyslipidemia, cardiovascular disorders, impaired glucose tolerance, hyperinsulinemia, hyperglycemia, insulin resistance, early, intermediate or late Type II diabetes (NIDDM), complications thereof and/or Syndrome X are disclosed in U.S. patent application Ser. No. 10/688,380, filed Oct. 17, 2003, U.S. patent application Ser. No. 10/688,379, filed Oct. 17, 2003 and U.S. patent application Ser. No. 10/688,572 filed Oct. 17, 2003, which are incorporated by reference herein in their entirety.
  • the present invention is directed to a process for the preparation of compounds of formula (L) wherein
  • the present invention is further directed to a process for the preparation of compounds of formula (L) wherein
  • the present invention is further directed to a process for the preparation of compounds of formula (L) wherein
  • the present invention is further directed to a process for the preparation of compounds of formula (Lc) wherein
  • the present invention is further directed to a process for the preparation of a compound of formula (Lc) wherein
  • a process for the preparation of a compound of formula (Ld) wherein Q a is OH or OPg 2 , wherein Pg 2 is a carboxylic acid protecting group In another embodiment of the present invention is a process for the preparation of a compound of formula (Ld) wherein Q a is OPg 2 wherein Pg 2 is a carboxylic acid protecting group.
  • the present invention is further directed to a novel process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof,
  • the present invention is further directed to a process for the preparation of the compound of formula (Le) wherein Q b is selected from the group consisting of C 1-6 alkoxy, wherein the C 1-6 alkoxy is not substituted with amino; comprising (a) reacting a compound of formula (Ld) with (S)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, at a temperature in the range of from about 35° C. to about 0° C.; to yield the corresponding (R,S) diastereomeric salt, the compound of formula (XX); (b) reacting the (R,S) diastereomeric salt, the compound of formula (XX), with an inorganic base, to yield the corresponding compound of formula (Le).
  • the present invention is further directed to a process for the preparation of the compound of formula (Le) wherein Q b is selected from the group consisting of C 1-6 alkoxy, wherein the C 1-6 alkoxy is not substituted with amino; comprising (a) reacting a compound of formula (Ld) with (R)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35° C., preferably at a temperature greater than about 45° C.; or in THF at about room temperature, to yield the corresponding (R,R) diastereomeric salt, the compound of formula (XXI). (b) reacting the (R,R) diastereomeric salt, the compound of formula (XXI) with an inorganic base, to yield the corresponding compound of formula (Le).
  • the present invention is further directed to a process for the preparation of the compound of formula (Lf) wherein Q b is selected from the group consisting of C 1-6 alkoxy, wherein the C 1-6 alkoxy is not substituted with amino; comprising (a) reacting a compound of formula (Ld) with (S)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35° C., preferably at a temperature greater than about 45° C.; or in THF at about room temperature; to yield the corresponding (S,S) diastereomeric salt, the compound of formula (XXII). (b) reacting the (S,S) diastereomeric salt, the compound of formula (XXI) with an inorganic base, to yield the corresponding compound of formula (Lf).
  • the present invention is further directed to a process for the preparation of the compound of formula (Lf) wherein Q b is selected from the group consisting of C 1-6 alkoxy, wherein the C 1-6 alkoxy is not substituted with amino; comprising (a) reacting a compound of formula (Ld) with (R)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, at a temperature in the range of from about 35° C.
  • the present invention is further directed to a novel crystalline salt of the compound of formula (IIa), more specifically, an N,N′-dibenzylethylenediamine (benzathine) salt of the compound of formula (IIa).
  • the present invention is further directed to an N,N′-dibenzylethylenediamine salt of the compound of formula (IIa) wherein the ratio of the compound of formula (IIa) to the N,N′-dibenzylethylenediamine is 1:1.
  • the present invention is further directed to a process for the preparation of the benzathine salt of the compound of formula (IIa).
  • the present invention is further directed to a compound prepared according to any of the processes described herein.
  • Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound prepared according to any of the processes described herein.
  • An illustration of the invention is a pharmaceutical composition made by mixing a compound prepared according to any of the processes described herein and a pharmaceutically acceptable carrier.
  • Illustrating the invention is a process for making a pharmaceutical composition comprising mixing a compound prepared according to any of the processes described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises the compound: or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof.
  • the pharmaceutical composition comprises the compound:
  • Exemplifying the present invention are methods of treating a PPAR alpha-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound prepared according to any of the processes described herein or a pharmaceutical composition as described above.
  • HDL high density lipoproteins
  • IDL intermediate density lipoproteins
  • LDL low density lipbproteins
  • FFA free fatty acids
  • exemplifying the invention are methods for treating dyslipidemia, cardiovascular disorders, impaired glucose tolerance, hyperinsulinemia, hyperglycemia, insulin resistance, early, intermediate or late Type II diabetes (NIDDM), complications thereof, or Syndrome X, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound prepared according to any of the processes described herein or a pharmaceutical composition as described above.
  • NIDDM Type II diabetes
  • phase I hyperlipidemia phase I hyperlipidemia
  • pre-clinical hyperlipidemia phase II hyperlipidemia
  • hypertension CAD (coronary artery disease); coronary heart disease; hypertriglyceridemia; lowering serum levels of low-density lipoproteins (LDL), IDL, and/or small-density LDL and other atherogenic molecules, or molecules that cause atherosclerotic complications, thereby reducing cardiovascular complications; elevating serum levels of high-density lipoproteins (HDL); lowering serum levels of triglycerides, LDL, and/or free fatty acids; and/or lowering FPG/HbA1c.
  • LDL low-density lipoproteins
  • IDL IDL
  • small-density LDL and other atherogenic molecules or molecules that cause atherosclerotic complications, thereby reducing cardiovascular complications
  • elevating serum levels of high-density lipoproteins (HDL) lowering serum levels of triglycerides, LDL, and/or free
  • Another example of the invention is the use of a compound prepared according to any of the processes described herein in the preparation of a medicament for treating (a) dyslipidemia, (b) cardiovascular disorders, (c) impaired glucose tolerance, (d) hyperinsulinemia, (e) hyperglycemia, (f) insulin resistance, (g) early Type II diabetes (NIDDM), (h) intermediate Type II diabetes (NIDDM), (i) late Type II diabetes (NIDDM), (j) complications of Type II diabetes or (k) Syndrome X, in a subject in need thereof.
  • Alkyl includes optionally substituted straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group.
  • Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on.
  • alkyl also includes cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Alkenyl includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon double bond (Sp 2 ).
  • Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on.
  • Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl are grouped as alkynyls herein.
  • alkenyl also includes cycloalkenyl. Cis and trans or (E) and (Z) forms are included within the invention.
  • Alkynyl includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon triple bond (sp).
  • Alkynyls include ethynyl, propynyls, butynyls, and pentynyls.
  • Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein.
  • Alkynyl does not include cycloalkynyl.
  • Alkoxy includes an optionally substituted straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.
  • Aminoalkyl “Aminoalkyl”, “thioalkyl”, and “sulfonylalkyl” are analogous to alkoxy, replacing the terminal oxygen atom of alkoxy with, respectively, NH (or NR), S, and SO 2 .
  • Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl, and so on.
  • Aryl includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, indenyl, and so on, any of which may be optionally substituted.
  • Aryl also includes arylalkyl groups such as benzyl, phenethyl, and phenylpropyl.
  • Aryl includes a ring system containing an optionally substituted 6-membered carbocyclic aromatic ring, said system may be bicyclic, bridge, and/or fused. The system may include rings that are aromatic, or partially or completely saturated.
  • ring systems include indenyl, pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on.
  • Heterocyclyl includes optionally substituted aromatic and nonaromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom moiety (SO 2 , CO, CONH, COO) in the ring.
  • a heterocyclic radical may have a valence connecting it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom, such as N-piperidyl or 1-pyrazolyl.
  • a monocyclic heterocyclyl has between 5 and 7 ring atoms, or between 5 and 6 ring atoms; there may be between 1 and 5 heteroatoms or heteroatom moieties in the ring, and preferably between 1 and 3, or between 1 and 2.
  • a heterocyclyl may be saturated, unsaturated, aromatic (e.g., heteroaryl), nonaromatic, or fused.
  • Heterocyclyl also includes fused, e.g., bicyclic, rings, such as those optionally condensed with an optionally substituted carbocyclic or heterocyclic five- or six-membered aromatic ring.
  • heteroaryl includes an optionally substituted six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms condensed with an optionally substituted five- or six-membered carbocyclic or heterocyclic aromatic ring.
  • Said heterocyclic five- or six-membered aromatic ring condensed with the said five- or six-membered aromatic ring may contain 1, 2 or 3 nitrogen atoms where it is a six-membered ring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur where it is a five-membered ring.
  • heterocyclyls include thiazoylyl, furyl, thienyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl.
  • heterocyclyls or heterocyclic radicals include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, thienyl,and more preferably, piperidyl or morpholinyl.
  • heteroaryl examples include thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl.
  • “Acyl” refers to a carbonyl moiety attached to either a hydrogen atom (i.e., a formyl group) or to an optionally substituted alkyl or alkenyl chain, or heterocyclyl.
  • Halo or “halogen” includes fluoro, chloro, bromo, and iodo, and preferably fluoro or chloro as a substituent on an alkyl group, with one or more halo atoms, such as trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethoxy, or fluoromethylthio.
  • Alkanediyl or “alkylene” represents straight or branched chain optionally substituted bivalent alkane radicals such as, for example, methylene, ethylene, propylene, butylene, pentylene or hexylene.
  • Alkenediyl represents, analogous to the above, straight or branched chain optionally substituted bivalent alkene radicals such as, for example, propenylene, butenylene, pentenylene or hexenylene. In such radicals, the carbon atom linking a nitrogen preferably should be saturated.
  • Aroyl refers to a carbonyl moiety attached to an optionally substituted aryl or heteroaryl group, wherein aryl and heteroaryl have the definitions provided above.
  • benzoyl is phenylcarbonyl.
  • two radicals, together with the atom(s) to which they are attached may form an optionally substituted 4- to 7-, 5- to 7-, or a 5- to 6-membered ring carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic.
  • Said rings may be as defined above in the Summary of the Invention section.
  • Enantiomer excess or “ee”, usually expressed as a percentage, describes the excess of one enantiomer over the other.
  • the percentage enantiomer excess, ee 100(Xr ⁇ Xs)/(Xr+Xs), where Xr>Xs.
  • ee 100(2X-1), where X is the mole fraction of the dominant enantiomer in the mixture.
  • Xr and Xs represent the mole fraction of (R)-enantiomer and (S)-enantiomer respectively in the mixture.
  • “Pharmaceutically acceptable salts, esters, and amides” include carboxylate salts, amino acid addition salts, esters, and amides which are within a reasonable benefitrisk ratio, pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. These salts, esters, and amides may be, for example, C 1-8 alkyl, C 3-8 cycloalkyl, aryl, C 2-10 heteroaryl, or C 2-10 non-aromatic heterocyclic salts, esters, and amides. Salts, free acids, and esters are more preferable than amides on the terminal carboxylate/carboxylic acid group on the left of formula (I).
  • Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate.
  • alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
  • alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium
  • non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
  • amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
  • Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C 1-6 alkyl amines and secondary di(C 1-6 alkyl) amines.
  • Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms.
  • Preferred amides are derived from ammonia, C 1-3 alkyl primary amines, and di(C 1-2 alkyl)amines.
  • Representative pharmaceutically acceptable esters of the invention include C 1-7 alkyl, C 5-7 cycloalkyl, phenyl, and phenyl(C 1-6 )alkyl esters.
  • Preferred esters include methyl and ethyl esters.
  • eachradical includes substituted radicals is of that type and monovalent, bivalent, and multivalent radicals as indicated by the context.
  • the context will indicate that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (bivalent) or more hydrogen atoms removed (multivalent).
  • Radicals or structure fragments as defined herein are understood to include substituted radicals or structure fragments.
  • Hydrocarbyls include monovalent radicals containing carbon and hydrogen such as alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whether aromatic or unsaturated), as well as corresponding bivalent (or multi-valent) radicals such as alkylene, alkenylene, phenylene, and so on.
  • Heterocarbyls include monovalent and bivalent (or multi-valent) radicals containing carbon, optionally hydrogen, and at least one heteroatom.
  • Examples of monovalent heterocarbyls include acyl, acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl, and so on.
  • alkyl should be understood to include substituted alkyl having one or more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents may be the same (dihydroxy, dimethyl) or different (chlorofluoro-, chlorobenzyl- or aminomethyl-substituted).
  • substituted alkyl examples include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, trifluoromethyl, and 3-iodocyclopentyl), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl), aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and 2-aminopropyl), alkylalkyl, and so on.
  • haloalkyl such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, trifluoromethyl, and 3-iodocyclopentyl
  • hydroxyalkyl such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl
  • aminoalkyl such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and 2-aminopropyl
  • a di(C 1-6 alkyl)amino group includes independently selected alkyl groups, to form, for example, methylpropylamino and isopropylmethylamino, in addition dialkylamino groups having two of the same alkyl group such as dimethylamino or diethylamino.
  • aprotic solvent shall mean any solvent that does not yield a proton. Suitable examples include, but are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.
  • nitrogen protecting group shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction.
  • Suitable nitrogen protecting groups include, but are not limited to carbamates—groups of the formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH 2 ⁇ CH—CH 2 —, and the like; amides—groups of the formula —C(O)—R′ wherein R′ is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives—groups of the formula —SO 2 —R′′ wherein R′′ is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenz
  • carboxylic acid protecting group shall mean a group which may be attached to —C(O)O— portion of the carboxylic acid to protect said carboxylic acid from participating in a reaction and which may be readily removed following the reaction.
  • Suitable carboxylic acid protecting groups include, but are not limited C 1-7 alkyl, C 5-7 Cycloalkyl, phenyl, phenylC 1-6 alkyl, and the like.
  • Other suitable carboxylic acid protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the enantiomeric excess of the desired enantiomer of formula (I) is at least about 90% ee, more preferably, at least about 96% ee, most preferably, about 99% ee.
  • reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • a particular group is “substituted” (e.g., phenyl, aryl, aralkyl, heteroaryl), that group may have one or more substituents, preferably from one to three substituents, more preferably from one to two substituents, independently selected from the list of substituents.
  • substituents preferably from one to three substituents, more preferably from one to two substituents, independently selected from the list of substituents.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount means that 15 amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • R 1 and R 2 in the compound of formula (I), (a) one of R 1 and R 2 is methyl or ethyl; (b) each of R 1 and R 2 is methyl; (c) R 1 and R 2 taken together are cyclobutyl or cyclopentyl; (d) R 3 is H; (e) R 4 is H or C 2-7 alkyl; (e) R 4 is H or C 2-5 alkyl; (f) R 4 is ethyl; (g) R 4 is H; (h) n is 1; (i) 2; (j) at least one of R 5 and R 7 is H; (k) R 6 is C 1-4 alkyl, halomethoxy, or halothiomethoxy (i.e —S-(halomethyl)); (I) R 6 is t-butyl, isopropyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethoxy (i.e.
  • R 3 is H, R 4 is C 2-7 alkyl;
  • R 4 is C 2-5 alkyl;
  • R 6 is cyclopropylmethyl, isopropyl, isobutyl, methylethylamino, or diethylamino;
  • R 15 is C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene), (C 1-3 alkoxyacyl)(C 1-6 alkylene), C 1-6 alkoxy, C 3-7 alkenyl, or C 3-8 alkynyl;
  • R 6 is trifluoromethylthio or trifluoromethoxy; or (t) any combination of the above.
  • the compound of formula (I) selected from the group consisting of 2- ⁇ 6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid; 2- ⁇ 6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3fluoro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl ⁇ -2-methylpropionic acid; 2- ⁇ 6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-chloro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid; 2- ⁇ 6-[1-Ethyl-3-(4-ylsulfanyl ⁇ -2-methyl
  • the compound of formula (I) selected from the group consisting of 2- ⁇ 6-[1-Ethyl-3-(4-methyl propionic acid; 2- ⁇ 6-[3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl ⁇ -2-methylpropionic acid; 2- ⁇ 2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl ⁇ -2-methylpropionic acid; 2- ⁇ 2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsulfanyl ⁇ -2-methylpropionic acid; and 2-Methyl-2- ⁇ 2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl ⁇ propi
  • c is 0. In another embodiment of the present invention n is 1 and X is bound at the 5-position. In yet another embodiment of the present invention n is 2 and X is bound at the 6- or 7-position, preferably at the 6-position.
  • n is 1 and R 3 is hydrogen or is other than hydrogen and is bound at the 4-, 6- or 7-position
  • n is 1 and R 3 is hydrogen or is other than hydrogen and is bound at the 4-, 6- or 7-position
  • —X—C(R 1 R 2 )—C(O)-Q group is bound at the 5-position.
  • n is 1 and R 3 is hydrogen or is other than hydrogen and is bound at the 4-, 6- or 7- position
  • the —X—C(R 1 R 2 )—C(O)—OH group is bound at the 5-position.
  • n is 1 and R 3 is other than hydrogen and is bound at the 5-position
  • —X—C(R 1 R 2 )—C(O)-Q group is bound at the 6-position.
  • n is 1 and R 3 is other than hydrogen and is bound at the 5-position
  • the —X—C(R 1 R 2 )—C(O)—OH group is bound at the 6-position.
  • Q is Opg 2 or N(Pg 3 Pg 4 ), wherein Pg 2 is a carboxylic acid protecting group as readily understood by one skilled in the art, including, but not limited to, C 1-7 alkyl, C 5-7 cycloalkyl, phenyl, phenylC 1-6 alkyl, and the like; and Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; alternatively Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3 ioheteroaryl or C 3-10 non-aromatic heterocyclic, preferably a 5- or 6-membered heterocyclic or heteroaromatic ring moiety containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms.
  • Q is OPg 2 , wherein Pg 2 is a carboxylic acid protecting group.
  • Q is selected from the group consisting of hydroxy, unsubstituted C 1-6 alkoxy, amino, unsubstituted C 1-4 alkylamino and di(unsubstitutedC 1-4 alkyl)amino.
  • Q is selected from the group consisting of hydroxy, methoxy, ethoxy, ispropyloxy, n-butyloxy, t-butoxy, amino, methylamino and dimethylamino.
  • Q is C 1-6 alkoxy, wherein the C 1-6 alkoxy is not substituted with amino.
  • Q is selected from the group consisting of methoxy, ethoxy and t-butoxy.
  • the present invention is directed to a process for the preparation of compounds of formula (L) wherein Q, X, R 1 , R 2 , R 3 , n and R 4 are as herein defined.
  • the compounds of formula (L) are useful as intermediates in the preparation of compounds of formula (I).
  • a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted (for example, protected) according to known methods, to yield the corresponding compound of formula (IV), wherein Pg 1 is a nitrogen protecting group which is inert to CISO 3 H, such as, Alloc (CH 2 ⁇ CHCH 2 —O—C(O)—), acetyl (CH 3 —C(O)—), (C 14 alkyl)-C(O)—, and the like.
  • the compound of formula (III) is reacted with a suitably selected protecting reagent such as Alloc-Cl (CH 2 ⁇ CHCH 2 —O—C(O)—Cl), Alloc 2 O (CH 2 ⁇ CHCH 2 —OC(O)—O—C(O)O—CH 2 CH ⁇ CH 2 ), AcCl (CH 3 —C(O)—Cl), Ac 2 O (CH 3 —C(O)—O—C(O)—CH 3 ), and the like.
  • the compound of formula (III) is reacted with a Alloc-Cl, or Alloc 2 O
  • the corresponding protecting group Pg 1 is Alloc.
  • Pg 1 is selected from Alloc or acetyl.
  • the compound of formula (IV) is reacted with a suitable substituted compound of formula (V), wherein R 4a is R 4 other than hydrogen and wherein J is Br, Cl, or I, a known compound or compound prepared by known methods, in the presence of a base such as NaH, n-butyl lithium, LDA, LHMDS, and the like, in a polar aprotic solvent such as THF, dioxane, MTBE, and the like, to yield the corresponding compound of formula (VI).
  • a base such as NaH, n-butyl lithium, LDA, LHMDS, and the like
  • a polar aprotic solvent such as THF, dioxane, MTBE, and the like
  • the compound of formula (VI) is then reacted with ClSO 3 H, optionally in a polar organic solvent which is inert to ClSO 3 H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII).
  • a polar organic solvent which is inert to ClSO 3 H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII).
  • the compound of formula (IV) is reacted with ClSO 3 H, optionally in a polar organic solvent which is inert to ClSO 3 H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII) wherein R 4 is hydrogen.
  • a polar organic solvent which is inert to ClSO 3 H, such as DCM, DCE, acetonitrile, DMF
  • the compound of formula (VII) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), such as Zn, and the like, in the presence of an acid such as HCl, H 2 SO 4 , and the like, in an aprotic solvent such as acetonitrile, THF, dioxane, and the like; or with Zn in the presence of (CH 3 ) 2 SiCl 2 and DMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile, 1,2-dichloroethane, and the like; to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX).
  • a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII) such as Zn, and the like
  • the compound of formula (VII) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), such as LiAlH 4 , and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about reflux, to yield the corresponding compound of formula (VIII).
  • a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII) such as LiAlH 4 , and the like
  • organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like
  • the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII) is reacted with a reducing agent which is is capable of reducing the disulfide on the compound of formula (VIII), such as LiAlH 4 , LiBH 4 , NaBH 4 , and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (VIII), which is preferably not isolated.
  • a reducing agent which is is capable of reducing the disulfide on the compound of formula (VIII), such as LiAlH 4 , LiBH 4 , NaBH 4 , and the like
  • organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like
  • the compound of formula (VIII) is then reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (XI).
  • an organic base which is inert to the compound of formula (X)
  • DIPEA DIPEA
  • pyridine pyridine
  • an inorganic base which is inert to the compound of formula (X)
  • an inorganic base which is inert to the compound
  • the compound of formula (XI) is reacted to yield the corresponding compound of formula (L).
  • the compound of formula (XI) is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (L).
  • a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted (for example, protected) according to known methods, to yield the corresponding compound of formula (IV), wherein Pg 1 is a nitrogen protecting group which is inert to ClSO 3 H, such as, Alloc (CH 2 ⁇ CHCH 2 —O—C(O)—), acetyl (CH 3 —C(O)—), (C 1-4 alkyl)-C(O)—, and the like.
  • the compound of formula (III) is reacted with a suitably selected protecting reagent such as Alloc-Cl (CH 2 ⁇ CHCH 2 —O—C(O)—Cl), Alloc 2 O.
  • the compound of formula (IV) is reacted with a suitable substituted compound of formula (V), wherein R 4a is R 4 other than hydrogen and wherein J is Br, Cl, or I, a known compound or compound prepared by known methods, in the presence of a base such as NaH, n-butyl lithium, LDA, LHMDS, and the like, in a polar aprotic solvent such as THF, dioxane, MTBE, and the like, to yield the corresponding compound of formula (VI).
  • a base such as NaH, n-butyl lithium, LDA, LHMDS, and the like
  • a polar aprotic solvent such as THF, dioxane, MTBE, and the like
  • the compound of formula (VI) is then reacted with ClSO 3 H, optionally in a polar organic solvent which is inert to ClSO 3 H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII).
  • a polar organic solvent which is inert to ClSO 3 H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII).
  • the compound of formula (IV) is reacted with ClSO 3 H, optionally in a polar organic solvent which is inert to ClSO 3 H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII) wherein R 4 is hydrogen.
  • a polar organic solvent which is inert to ClSO 3 H, such as DCM, DCE, acetonitrile, DMF
  • the compound of formula (VII) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), such as Zn, and the like, in the presence of an acid such as HCl, H 2 SO 4 , and the like, in an aprotic solvent such as acetonitrile, THF, dioxane, and the like; or with Zn in the presence of (CH 3 ) 2 SiC 1-2 and DMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile, 1,2-dichloroethane, and the like; to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX).
  • a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII) such as Zn, and the like
  • the compound of formula (VII) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), such as LiAlH 4 , and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about reflux, to yield the corresponding compound of formula (VIII).
  • a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII) such as LiAlH 4 , and the like
  • organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like
  • the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), is de-protected according to known methods, such as those described in Protective Groucs in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Grouis in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (XIII).
  • the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), is reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (IX), such as LiAlH 4 , LiBH 4 , NaBH 4 , and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (VIII), which is preferably not isolated.
  • the compound of formula (VIII) is then de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (XIII).
  • the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (XII).
  • the compound of formula (XII) is then reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (XII), such as LiAlH 4 , LiBH 4 , NaBH 4 , and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (XIII).
  • a reducing agent which is capable of reducing the disulfide on the compound of formula (XII)
  • an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like
  • a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted (for example, protected) according to known methods, to yield the corresponding compound of formula (IV), wherein Pg 1 is a nitrogen protecting group which is inert to ClSO 3 H, such as, Alloc (CH 2 ⁇ CHCH 2 —O—C(O)—), acetyl (CH 3 —C(O)—), (C 1-4 alkyl)-C(O)—, and the like.
  • the compound of formula (III) is reacted with a suitably selected protecting reagent such as Alloc-Cl (CH 2 ⁇ CHCH 2 -Q-C(O)—Cl), Alloc 2 O.
  • the compound of formula (IV) is reacted with ClSO 3 H, optionally in a polar organic solvent which is inert to ClSO 3 H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VIIa) (i.e. the corresponding compound of formula (VII) wherein R 4 is hydrogen.).
  • a polar organic solvent which is inert to ClSO 3 H, such as DCM, DCE, acetonitrile, DMF
  • the compound of formula (VIIIa) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VIIa) such as Zn, and the like, in the presence of an acid such as HCl, H 2 SO 4 , and the like, in an aprotic solvent such as acetonitrile, THF, dioxane, and the like; or with Zn in the presence of (CH 3 ) 2 SiC 1-2 and DMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile, 1,2-dichloroethane, and the like; to yield a mixture of the corresponding compound of formula (VIIIa) (i.e. the corresponding compound of formula (VIII) wherein R 4 is hydrogen) and the corresponding compound of formula (IXa) (i.e. the corresponding compound of formula (IXa) wherein R 4 is hydrogen).
  • the compound of formula (VIIIa), isolated or in a mixture with the compound of formula (IXa) is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (XIIIa) (i.e. the corresponding compound of formula (XIII) wherein R 4 is hydrogen).
  • the compound of formula (XIIIa) is reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (La) (i.e. the corresponding compound of formula (L) wherein R 4 is hydrogen).
  • an organic base which is inert to the compound of formula (X)
  • an organic base such as TEA, DIPEA, pyridine, and the like
  • an inorganic base which is iner
  • the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), is reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (IXa), such as LiAlH 4 , LiBH 4 , NaBH 4 , and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (VIIIa).
  • a reducing agent which is capable of reducing the disulfide on the compound of formula (IXa)
  • an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like
  • the compound of formula (VIIIa) is then reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (XIa) (i.e.
  • the compound of formula (XIa) is then reacted to yield the corresponding compound of formula (La).
  • the compound of formula (XIa) is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (La).
  • the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (XIIa) (i.e. the corresponding compound of formula (XII) wherein R 4 is hydrogen).
  • the compound of formula (XIIa) is then reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (XIIa), such as LiAlH 4 , LiBH 4 , NaBH 4 , and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (XIIIa) (i.e. the corresponding compound of formula (XIII) wherein R 4 is hydrogen).
  • a reducing agent which is capable of reducing the disulfide on the compound of formula (XIIa)
  • an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like
  • the compound of formula (XIIIa) is then reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (La).
  • an organic base which is inert to the compound of formula (X)
  • an organic base such as TEA, DIPEA, pyridine, and the like
  • an inorganic base which is inert to the compound of formula (X)
  • the compound of formula (La) is reacted with a suitably substituted compound of formula (V), wherein R 4a is R 4 other than hydrogen and wherein J is Br, Cl, or I, a known compound or compound prepared by known methods, in the presence of a base such as NaH, n-butyl lithium, LDA, LHMDS, and the like, in a polar aprotic solvent such as THF, dioxane, MTBE, and the like, to yield the corresponding compound of formula (Lb).
  • a base such as NaH, n-butyl lithium, LDA, LHMDS, and the like
  • a polar aprotic solvent such as THF, dioxane, MTBE, and the like
  • the compound of formula (La) is reacted with a suitably substituted acylating agent capable of attaching an —C(O)—R 4b group onto the nitrogen of the compound of formula (La), wherein R 4b is selected from (C 1-4 straight chain alkylene)R 15 or (straight chain C 1-4 alkylene)R 16 , in the presence of an organic such as TEA, DIPEA, pyridine, and the like, or in the presence of an inorganic base such as NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (XVIII); the compound of formula (XVIII) is then reacted with a reducing agent capable of reducing the amide on the compound of formula (XVIII), such as borane, and the like, in a apro
  • a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted with a suitably substituted acylating capable of attaching an —C(O)O—R 4b group onto the nitrogen of the compound of formula (III), wherein R 4b is selected from (C 14 straight chain alkylene)R 15 or (straight chain C 14 alkylene)R 16 , for example an acid chloride of the formula Cl—C(O)—R 4b , a symmetric anhydride of the formula R 4b —C(O)—O—C(O)—R 4b , and the like, in the presence of an organic base, preferably a tertiary amine base such as TEA, DIPEA, pyridine, and the like, in an aprotic solvent such as THF, DMF, dioxane, ethyl acetate, and the like; or in the presence of an organic or inorganic base such as NaOH, KOH, Na 2 CO
  • the compound of formula (XIV) is reacted with ClSO 3 H, optionally in a polar organic solvent which is inert to ClSO 3 H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (XV).
  • a polar organic solvent which is inert to ClSO 3 H, such as DCM, DCE, acetonitrile, DMF
  • the compound of formula (XV) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (XV), such as Zn, and the like, in the presence of an acid such as HCl, H 2 SO 4 , and the like, optionally in an aprotic solvent such as acetonitrile, THF, dioxane, and the like; or with Zn in the presence of (CH 3 ) 2 SiC 1-2 and DMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile, 1,2-dichloroethane, and the like; to yield a mixture of the compound of formula (XVI) and the compound of formula (XVII).
  • a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (XV) such as Zn, and the like
  • the compound of formula (XVI), isolated or in a mixture with the compound of formula (XVII) is reacted with a reducing agent which is capable of reducing the amide on the compound of formula (XVI), such as LiAlH 4 , borane, and the like, in an aprotic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, to yield the corresponding compound of formula (XIIIb) (i.e. the corresponding compound of formula (XIII) wherein R 4 is other than hydrogen).
  • the reducing agent is LiAlH 4
  • the compound(s) is reduced at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature.
  • the compound of formula (XVII), isolated or in a mixture with the compound of formula (XVI) is reacted with a reducing agent which is capable of reducing the amide on the compound of formula (XVII) and the disulfide on the compound of formula (XVII), such as LiAlH 4 , borane, and the like, in an aprotic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, to yield the corresponding compound of formula (XIIIb).
  • a reducing agent is LiAlH 4
  • the compound(s) is reduced at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature.
  • the compound of formula (XIIIb) is reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, methanol, ethanol, and the like, to yield the corresponding compound of formula (Lc) (i.e. the corresponding compound of formula (L) wherein R 4 is selected from (C 2-5 straight chain alkylene)R 15 or (straight chain C 2-5 alkylene)R 16 ).
  • an organic base which is inert to the compound
  • the present invention is further directed to a process for the preparation of compounds of formula (I) wherein R 1 , R 2 , X, R 3 , n, R 4 , c, R 5 , R 6 and R 7 are as herein defined.
  • the compounds of formula (I) are useful as PPAR alpha agonists, more specifically as selective PPAR alpha agonists.
  • PPAR alpha agonists are useful for the treatment, prevention, or inhibiting the progression of one or more of the following conditions or diseases: phase I hyperlipidemia; pre-clinical hyperlipidemia; phase II hyperlipidemia; hypertension; CAD (coronary artery disease); coronary heart disease; hypertriglyceridemia; lowering serum levels of low-density lipoproteins (LDL), IDL, and/or small-density LDL and other atherogenic molecules, or molecules that cause atherosclerotic complications, thereby reducing cardiovascular complications; elevating serum levels of high-density lipoproteins (HDL); lowering serum levels of triglycerides, LDL, and/or free fatty acids; and/or lowering FPG/HbA1c.
  • LDL low-density lipoproteins
  • HDL high-density lipoproteins
  • HDL high-density lipoproteins
  • triglycerides LDL, and/or free fatty acids
  • the compound of formula (I) may be prepared by reacting a suitably substituted compound of formula (L) with a suitably substituted isocyanate, a compound of the formula (XIX) according to known methods.
  • a suitably substituted isocyanate a compound of formula (XIX)
  • X is S, R 1 is methyl, R 2 is methyl, Q is OH or OPg 2 , the —X—C(R 1 R 2 )—C(O)-Q is bound at the 5- position, R 3 is hydrogen, n is 1 and R 4 is ethyl.
  • X is S, R 1 is methyl, R 2 is methyl, Q is OPg 2 , Pg 2 is t-butyl, the —X—C(R 1 R 2 )—C(O)-Q is bound at the 5- position, R 3 is hydrogen, n is 1 and R 4 is ethyl.
  • the present invention is further directed to a process for the preparation of the compound of formula (Le) wherein Q b is selected from the group consisting of C 1-6 alkoxy, wherein the C 1-6 alkoxy is not substituted with amino.
  • Q b is unsubstituted C 1-6 alkoxy, more preferably, Q b is selected from the group consisting of methoxy, ethoxy and t-butoxy.
  • the compound of formula (Le) may be prepared according to the process outlined in Scheme 5.
  • a compound of formula (Ld) is reacted with (S)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol such as methanol, ethanol, and the like, preferably ethanol; or in acetone, at a temperature in the range of from about 35° C. to about 0° C., to yield the corresponding (R,S) diastereomeric salt, the compound of formula (XX).
  • an alcohol such as methanol, ethanol, and the like, preferably ethanol; or in acetone
  • the compound of formula (Le) is prepared with an enantiomeric excess in the range of from about 70 % ee to about 90 % ee.
  • the diasteromeric salt of the compound of formula (Le) may be further re-slurrried in or recrystallized from an organic solvent such as methanol, ethanol, acetone, and the like.
  • the compound of formula (Le) may alternatively be prepared according to the process outlined in Scheme 6.
  • a compound of formula (Ld) is reacted with (R)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35° C., preferably at a temperature greater than about 45° C.; or in THF at about room temperature; to yield the corresponding (R,R) diastereomeric salt, the compound of formula (XXI).
  • the (R,R) diastereomeric salt, the compound of formula (XXI), is reacted with an inorganic base such as NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , and the like to yield the corresponding compound of formula (Le).
  • an inorganic base such as NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , and the like to yield the corresponding compound of formula (Le).
  • the compound of formula (Le) is prepared with an enantiomeric excess in the range of from about 70 % ee to about 90 % ee.
  • the diasteromeric salt of the compound of formula (Le) may be further re-slurrried in or recrystallized from an organic solvent such as methanol, ethanol, acetone, and the like.
  • a compound of formula (Lf) may be similarly prepared by reacting a compound of formula (Ld) with (R)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol such as methanol, ethanol, and the like, preferably ethanol; or in acetone, at a temperature in the range of from about 35° C. to about 0° C.; to yield the corresponding (S,R) diastereomeric salt which is then reacted with an inorganic base such as NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , and the like, to yield the corresponding compound of formula (Lf).
  • an alcohol such as methanol, ethanol, and the like, preferably ethanol; or in acetone
  • the S-enantiomer of the compound of formula (Ld) may be prepared by reacting a compound of formula (Ld) with (S)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35° C., preferably at a temperature greater than about 45° C.; or in THF at about room temperature; to yield the corresponding (S,S) diastereomeric salt which is then reacted with an inorganic base such as NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , and the like, to yield the corresponding compound of formula (Lf).
  • an inorganic base such as NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , and the like
  • the present invention is further directed to a novel crystalline salt of the compound of formula (IIa) more specifically a crystalline N,N′-dibenzylethylenediamine (benzathine) salt of the compound of formula (IIa).
  • a novel crystalline salt of the compound of formula (IIa) more specifically a crystalline N,N′-dibenzylethylenediamine (benzathine) salt of the compound of formula (IIa).
  • the crystalline benzathine salt of the compound of formula (IIa) may be characterized by the major peaks of its X-ray diffraction peaks, as listed in Table 1, below.
  • the X-ray diffraction pattern was measured as follows.
  • the crystalline benzathine salt of the compound of formula (IIa) was backloaded into a conventional X-ray holder.
  • the sample was scanned from 3 to 35 °2 ⁇ at a step size of 0.0165 °2 ⁇ and a time per step of 10.16 seconds.
  • the effective scan speed was 0.2067°/s. Instrument voltage and current settings of 45 kV and 40 mA were employed.
  • the present invention is further directed to a process for the preparation of the benzathine salt of the compound of formula (IIa). More particularly, the compound of formula (lha) is reacted with N,N′-dibenzylethylenediamine, in an aprotic solvent such as isopropyl acetate, ethyl acetate, MTBE, and the like, preferably in isopropyl acetate, preferably, at a temperature less than about 5° C., more preferably, at a temperature in the range of from about 5° C. to about ⁇ 5° C., yield the corresponding N,N′-dibenzylethylenediame (benzathine) salt of the compound of formula (IIa).
  • an aprotic solvent such as isopropyl acetate, ethyl acetate, MTBE, and the like, preferably in isopropyl acetate, preferably, at a temperature less than about 5° C., more preferably,
  • the filtrate was placed in a separatory funnel and the aqueous layer was separated.
  • the organic layer was washed once with water (500 mL) and once with brine (500 mL).
  • the ethyl acetate layer was evaporated in vacuo to half of its original volume and then diluted with heptane (1000 mL) while stirring to produce a white suspension.
  • the solid was collected by vacuum filtration and washed twice with portions of heptane (300 mL). The second crop of the product was obtained as white crystalline solid.
  • N-acetyl-2-aminoindan (0.96 mol, 167.70 g) and acetonitrile (490 mL).
  • the reaction mixture was stirred and cooled in an ice-bath to about 3-5° C. and ClSO 3 H (3.83 mol, 440 g) was added slowly.
  • the first 30% of the reagent was added over 30 minutes while maintaining the reaction temperature below 15° C.
  • the ice-bath was then removed and the reaction mixture was warmed to room temperature.
  • the remaining 70% of the reagent was added over 30 minutes and the temperature of the reaction solution rose to 80° C.
  • the yellow reaction solution was stirred at 50° C. for about 20 hours.
  • the reaction solution was cooled to 30° C. and slowly poured into a vigorously stirred mixture of ice (1620 g), water (945 mL), and acetonitrile (135 mL) in an ice-bath over about 10-15 minutes.
  • the temperature of the quenching mixture dropped from 5° C. to ⁇ 6° C.
  • a white solid precipitated and the mixture was stirred at about 0-5° C. for 30 minutes.
  • the solid was collected by vacuum filtration and slurried 4 times with a cold mixture of water (4 ⁇ 300 mL).
  • the pH of the last slurry was around 2-3.
  • the solid was then slurried with cold acetone (300 mL) (5-7° C.), collected by filtration, and finally rinsed with of cold acetone (200 mL).
  • the solid product was air-dried for 4 hours, followed by drying in a vacuum oven at room temperature for 48 hours. The product was obtained as a white solid.
  • the reaction was then cooled to about 30-36° C. over 30 minutes while stirring.
  • the reaction mixture was filtered into a 500 mL one-necked round-bottomed flask through a frited glass funnel to remove the Zn residue.
  • the reaction flask was rinsed with EtOAc (25 mL).
  • the mixture was concentrated on a rotavapor under reduced pressure at about 45-50° C. bath temperature to remove most of the organic solvents.
  • the concentrated aqueous solution was mixed with of EtOAc (150 mL), followed by the addition of H 2 O. (75 mL). After stirring for 15 minutes, the layers were separated. The organic layer was washed four times with H 2 O. (3 ⁇ 75 mL).
  • the organic layer was concentrated on a rotavapor at 60° C. to 1 ⁇ 4 of its original volume (about 40 mL). Most of the precipitated white solid was dissolved by heating to reflux. The mixture was then diluted with MTBE (75 mL). The mixture was stirred at ambient temperature for 18 hours. The solid product was collected by vacuum filtration, washed with MTBE (20 mL), dried under nitrogen for 4 hours, then in a vacuum oven at about 40-45° C. for 24 h. The product was obtained as an off-white solid.
  • the suspension in toluene was warmed to 90° C. for 15 minutes and stirred at room temperature for 20 hours.
  • the solid product was collected by vacuum filtration, rinsed with toluene (20 mL), air-dried for 2 hours, and further dried in a vacuum oven at 60° C. for 2 days. The product was obtained as an off-white solid.
  • N-(5-Mercapto-indan-2-yl)-acetamide (330.0 g, 1.59 mol) was dissolved in a warm THF (1.65 L) at 50° C. The solution was then slowly added to LAH solution (1 M in THF) (2.385 L, 2.385 mol) at about 60-66° C. over 25 minutes to allow gentle reflux and slow gas evolution. After addition, the light yellow suspension was stirred under reflux for 4 hours. The reaction was cooled to about 5-7° C. in an ice-water bath. The reaction was quenched by the slow addition of methanol (203.7 g, 6.36 mol) under a nitrogen atmosphere and the reaction temperature was maintained below 25° C. by adjusting the addition rate.
  • the filter cake was suspended in EtOAc (2 L) and stirred for 30 minutes. The suspension was filtered through a 3L coarse frit funnel. The filtrate was combined with the crude concentrated THF solution obtained above. The combined organic layer was washed with H 2 O. (2 L). After separation of layers, the organic layer was concentrated in vacuo at 50° C. to remove the most of volatiles. The concentrated solution was diluted with anhydrous ethanol (800 mL) and re-concentrated to yield a purple oil. The crude product was used for the next step without further purification.
  • FTIR (KBr): 3211 (br.), 1716, 1516, 1454, 1416, 1377, 1330, 1263, 1233, 1176, 1136, 1098, 1045, 946, 918, 861, 826, 766, 712, 697, 673, 638, 563, 508 cm ⁇ 1 .
  • the crude solid with 86% ee was dissolved in 95% ethanol (165 mL) at 60° C. The solution was cooled slowly to 20° C. and stirred at this temperature for 18 hours. The solid was collected by vacuum filtration to yield the product as a white granular solid with 99.5% ee.
  • FTIR (KBr): 2980, 2934, 1717, 1629, 1576, 1510, 1458, 1405, 1368, 1279, 1257, 1230, 1148, 1121, 1101, 1044, 848, 830, 801, 758, 679, 643, 525 cm ⁇ 1 .
  • the diastereomeric salt prepared in Example 7 above (357 g, 0.635 mol) was charged into a mixture of isopropyl acetate (2 L) and 50% of NaOH (102 g, 1.28 mol) in water (0.8 L). The mixture was stirred until all solids dissolved. After removal of the bottom aqueous layer, the isopropyl acetate layer was washed with water 3 times until the pH of the aqueous phase was about 7. The organic solution was concentrated at 60° C. to remove about 3 ⁇ 4 of the isopropyl acetate. 1 L of fresh isopropyl acetate was added and the amount of residual water in the solution was assayed by KF. The solution was used for the next step directly.
  • FTIR ReactIR, neat: 2971, 2933, 2838, 1721, 1474, 1461, 1385, 1366, 1343, 1275, 1256, 1146, 1121, 1036, 1009, 942, 847, 820, 752, 706 cm ⁇ 1 .
  • N,N′-Dibenzylethylenediamine (0.26 g, 1.08 mmol) was added to t-butyl methyl ether solution of 2- ⁇ 2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl ⁇ -2-methyl-propionic acid (0.52 g, 1.08 mmol).
  • iPrOAc was added to the resulted cloudy solution. The solution was kept in the refrigerator overnight ( ⁇ 20 hours). The solids precipitated were collected by filtration. 1 H NMR analysis and the melting point measurement of the isolated solids confirmed the formation of the salt with 1:1 mole ratio of acid and N,N′-dibenzylethylenediamine.
  • the solid was filtered and rinsed with a chilled mixture of iPrOAc/heptane (1 ⁇ 2, 90 mL). The solid was air-dried at the ambient temperature overnight to yield a solid with 99.1% ee.
  • FTIR (KBr): 3310(broad), 2972, 2849, 1638, 1606, 1539, 1510, 1458, 1418, 1389, 1351, 1264, 1244, 1199, 1162, 842, 816, 748, 698.81, 668 cm ⁇ 1 .
  • Racemic tert-Butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate (0.30 mmol) and (S)-( ⁇ )-2-(4-hydroxyphenoxy)propionic acid (0.30 mmol) were mixed into THF (2 mL) and heated to 50° C. to a clear solution. The reaction mixture was then cooled to the ambient temperature and stirred overnight.
  • Racemic tert-Butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate (17 g, 51 mmol) and (S)-( ⁇ )-2-(4-hydroxyphenoxy)propionic acid (4.6 g, 25 mmol) were dissolved in acetone (55 mL), each separately. The solutions were then mixed and stirred at the ambient temperature overnight. The resulting thick suspension was heated to 55° C. for 6 h, 40° C. for 18 h, then heated to 50° C.
  • reaction mixture was partitioned between EtOAc and H 2 O, the aqueous phase extracted with EtOAc, the organic extracts combined, washed with H 2 O, brine, dried over Na 2 SO 4 , filtered and the solvent removed under reduced pressure to yield a crude oil, which was purified by reverse-phase semi-prep HPLC eluting with a MeCN—H 2 O. gradient to yield 2-(6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester as an oil.
  • the residual oil was further azeotroped with MeOH (3 ⁇ ) to yield a mixture of 2-(6-ethylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester and it's borane complex as an oil.
  • Example 21 2- ⁇ 6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-phenyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl ⁇ -2-methylpropionic acid, the compound of Example 21 was additionally prepared, as a white solid, according to the procedure described in Example 14, by selecting and substituting suitable reagents in Steps F, G and H, as appropriate.

Abstract

The present invention relates to novel processes for the preparation of substituted tetralin. and substituted indane derivatives. The present invention is further directed to novel processes for the preparation of intermediates in the preparation of the substituted tetralin and substituted indane derivatives.

Description

    CROSS REFERENCE TO RELATED APPLICATION
  • This application claims the benefit of U.S. Provisional Application No. 60/564,159, filed Apr. 21, 2004, which is incorporated by reference herein.
    • FIELD OF THE INVENTION
  • The present invention relates to a novel processes for the preparation of substituted tetralin and substituted indane derivatives. The substituted tetralin and substituted indane derivatives are PPAR alpha agonists, useful for elevating serum levels of high density lipoproteins (HDL), improving levels of intermediate density lipoproteins (IDL), and lowering serum levels of triglycerides, low density lipoproteins (LDL), atherogenic molecules, and/or free fatty acids (FFA). The substituted tetralin and substituted indane compounds are further useful in treating hypertriglyceridemia, raising levels of HDL, lowering levels of LDL, and/or lowering total cholesterol. The present invention is further directed to novel processes for the preparation of intermediates in the preparation of the substituted tetralin and substituted indane derivatives.
    • SUMMARY OF THE INVENTION
  • The present invention is directed to novel processes for the preparation of substituted tetralin and substituted indane derivatives. The substituted tetralin and substituted indane derivatives and their use for the treatment of PPAR alpha-mediated diseases including, but not limited to dyslipidemia, cardiovascular disorders, impaired glucose tolerance, hyperinsulinemia, hyperglycemia, insulin resistance, early, intermediate or late Type II diabetes (NIDDM), complications thereof and/or Syndrome X are disclosed in U.S. patent application Ser. No. 10/688,380, filed Oct. 17, 2003, U.S. patent application Ser. No. 10/688,379, filed Oct. 17, 2003 and U.S. patent application Ser. No. 10/688,572 filed Oct. 17, 2003, which are incorporated by reference herein in their entirety.
  • The present invention is directed to a process for the preparation of compounds of formula (L)
    Figure US20050240049A1-20051027-C00001
    wherein
      • Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic;
      • each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
      • wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
      • alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
      • n is an integer from 1 to 2;
      • X is S;
      • provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
      • R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
      • each R9 and R10 is independently C1-6alkyl;
      • R4 is H or —(C15straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)—, (C1-3alkoxyacyl)(C1-6alkylene)—, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
      • wherein R4 has no more than 9 carbon atoms;
      • alternatively, R4 is —(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
      • wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
      • comprising
        Figure US20050240049A1-20051027-C00002
        reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to CISO3H;
        Figure US20050240049A1-20051027-C00003
        reacting the compound of formula (IV) with a suitably substituted compound of formula (V) wherein R4a is R4 other than hydrogen and wherein J is Br, Cl or l, in the presence of a base, to yield the corresponding compound of formula (VI); and then reacting the compound of formula (VI) with CISO3H, to yield the corresponding compound of formula (VII);
      • alternatively, reacting the compound of formula (IV) with CISO3H, to yield the corresponding compound of formula (VII) wherein R4 is hydrogen;
        Figure US20050240049A1-20051027-C00004
        reacting the compound of formula (VII) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX);
        Figure US20050240049A1-20051027-C00005
        reacting the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), with a suitably substituted compound of formula (X), wherein W is Br, Cl or l, in the presence of a base, to yield the corresponding compound of formula (XI);
      • alternatively, reacting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), with a reducing agent capable of reducing the disulfide on compound of formula (IX), to yield the corresponding compound of formula (VIII); and then reacting the compound of formula (VIII) with a suitably substituted compound of formula (X), wherein W is Br, Cl or l, in the presence of a base, to yield the corresponding compound of formula (XI);
        Figure US20050240049A1-20051027-C00006
        reacting the compound of formula (XI), to yield the corresponding compound of formula (L).
  • The present invention is further directed to a process for the preparation of compounds of formula (L)
    Figure US20050240049A1-20051027-C00007
    wherein
      • Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic;
      • each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
      • wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
      • alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
      • n is an integer from 1 to 2;
      • X is S;
      • provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
      • R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10, or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
      • each R9 and R10 is independently C1-6alkyl;
      • R4 is H or —(C1-5straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)—, (C1-3alkoxyacyl)(C1-6alkylene)—, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
      • wherein R4 has no more than 9 carbon atoms;
      • alternatively, R4 is —(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
      • wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
      • comprising
        Figure US20050240049A1-20051027-C00008
        reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to CISO3H;
        Figure US20050240049A1-20051027-C00009
        reacting the compound of formula (IV) with a suitably substituted compound of formula (V) wherein R4a is R4 other than hydrogen and wherein J is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (VI); and then reacting the compound of formula (VI) with CISO3H, to yield the corresponding compound of formula (VII);
      • alternatively, reacting the compound of formula (IV) with CISO3H, to yield the corresponding compound of formula (VII) wherein R4 is hydrogen;
        Figure US20050240049A1-20051027-C00010
        reacting the compound of formula (VII) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX);
        Figure US20050240049A1-20051027-C00011
        de-protecting the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), to yield the corresponding compound of formula (XIII);
      • alternatively, de-protecting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), to yield a corresponding compound of formula (XII); and then reducing the compound of formula (XII) with a reducing agent capable of reducing the disulfide on compound of formula (XII), to yield the corresponding compound of formula (XIII);
      • alternatively still, reacting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), with a reducing agent capable of reducing the disulfide on compound of formula (IX), to yield the corresponding compound of formula (VIII); and then de-protecting the compound of formula (VIII), to yield the corresponding compound of formula (XIII);
        Figure US20050240049A1-20051027-C00012
        reacting the compound of (XIII) with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (L).
  • The present invention is further directed to a process for the preparation of compounds of formula (L)
    Figure US20050240049A1-20051027-C00013
    wherein
      • Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic;
      • each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
      • wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
      • alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
      • n is an integer from 1 to 2;
      • X is S;
      • provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
      • R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
      • each R9 and R10 is independently C1-6alkyl;
      • R4 is —(C1-5straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)—, (C1-3alkoxyacyl)(C1-6alkylene)—, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
      • wherein R4 has no more than 9 carbon atoms;
      • alternatively, R4 is —(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
      • wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
      • comprising
        Figure US20050240049A1-20051027-C00014
        reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to CISO3H;
        Figure US20050240049A1-20051027-C00015
        reacting the compound of formula (IV) with CISO3H, to yield the corresponding compound of formula (VIIa);
        Figure US20050240049A1-20051027-C00016
        reacting thecompound of formula (VIIa) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VIIa), to yield a mixture of the corresponding compound of formula (VIIIa) and the corresponding compound of formula (IXa);
        Figure US20050240049A1-20051027-C00017
        de-protecting the compound of formula (VIIIa), isolated or in a mixture with the compound of formula (IXa), to yield the corresponding compound of formula (XIIIa); and then reacting the compound of formula (XIIIa) with a suitably substituted compound of formula (X), wherein W is Cl, Br or I, in the presence of a base, to yield the corresponding compound of formula (La);
      • alternatively, reacting the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), with a reducing agent capable of reducing the disulfide on the compound of formula (IXa), to yield the corresponding compound of formula (VIIIa); then reacting the compound of formula (VIIIa) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (XIa); and then reacting the compound of formula (XIa), to yield the corresponding compound of formula (La);
      • alternatively still, de-protecting the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), to yield the corresponding compound of formula (XIIa); then reacting the compound of formula (XIIa) with a reducing agent capable of reducing the disulfide on the compound of formula (XIIa), to yield the corresponding compound of formula (XIIIa); and then reacting the compound of formula (XIIIa) with a suitably substituted compound is of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (La);
        Figure US20050240049A1-20051027-C00018
        reacting the compound of formula (La) with a suitably substituted compound of formula (V) wherein R4a is R4 other than hydrogen and wherein J is Br, Cl or I, to yield the corresponding compound of formula (Lb);
      • alternatively, reacting the compound of formula (La) with a suitably substituted acylating agent capable of attaching an —C(O)—R4b group onto the nitrogen of the compound of formula (La), wherein R4b is selected from (C1-4straight chain alkylene)R15 or (straight chain C1-4alkylene)R16, in the presence of a base, to yield the corresponding compound of formula (XVIII); and then reacting the compound of formula (XVIII) with a reducing agent capable of reducing the amide on the compound of formula (XVIII), to yield the corresponding compound of formula (Lb).
  • The present invention is further directed to a process for the preparation of compounds of formula (Lc)
    Figure US20050240049A1-20051027-C00019
    wherein
      • Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic;
      • each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
      • wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
      • alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
      • n is an integer from 1 to 2;
      • X is S;
      • provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
      • R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
      • each R9 and R10 is independently C1-6alkyl;
      • R4b is —(C1-4straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)—, (C1-3alkoxyacyl)(C1-6alkylene)—, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
      • wherein R4b has no more than 8 carbon atoms;
      • alternatively, R4b is —(straight chain C1-4alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
      • wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
      • comprising
        Figure US20050240049A1-20051027-C00020
        reacting a suitably substituted compound of formula (III) with a suitably substituted acylating agent capable of attaching an —C(O)—R4b group onto the nitrogen of the compound of formula (III), in the presence of a base, to yield the corresponding compound of formula (XIV);
        Figure US20050240049A1-20051027-C00021
        reacting the compound of formula (XIV) with CISO3H, to yield the corresponding compound of formula (XV);
        Figure US20050240049A1-20051027-C00022
        reacting the compound of formula (XV) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (XV), to yield a mixture of the corresponding compound of formula (XVI) and the corresponding compound of formula (XVII);
        Figure US20050240049A1-20051027-C00023
        reacting the compound of formula (XVI), isolated or in a mixture with the compound of formula (XVII), with a reducing agent capable of reducing the amide on the compound of formula (XVI), to yield the corresponding compound of formula (XIIIb);
      • alternatively, reacting the compound of formula (XVII), isolated or in a mixture with the compound of formula (XVI), with a reducing agent capable of reducing the amide and the disulfide on the compound of formula (XVII), to yield the corresponding compound of formula (XIIIb);
        Figure US20050240049A1-20051027-C00024
        reacting the compound of formula (XIIIb) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (Lc).
  • The present invention is further directed to a process for the preparation of a compound of formula (Lc)
    Figure US20050240049A1-20051027-C00025
    wherein
      • Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic;
      • each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
      • wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
      • alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
      • n is an integer from 1 to 2;
      • X is S;
      • provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
      • R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
      • each R9 and R10 is independently C1-6alkyl;
      • R4b is —(C1-4straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)—, (C1-3alkoxyacyl)(C1-6alkylene)—, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
      • wherein R4b has no more than 8 carbon atoms;
      • alternatively, R4b is —(straight chain C1-4alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
      • wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
      • comprising
        Figure US20050240049A1-20051027-C00026
        reacting a suitably substituted compound of formula (III) with a suitably substituted acylating agent capable of attaching an —C(O)—R4b group onto the nitrogen of the compound of formula (III), in the presence of a base, to yield the corresponding compound of formula (XIV);
        Figure US20050240049A1-20051027-C00027
        reacting the compound of formula (XIV) with CISO3H, to yield the corresponding compound of formula (XV);
        Figure US20050240049A1-20051027-C00028
        reacting the compound of formula (XV) with a reducing agent capable of reducing the chlorosulfonyl group and the amide group on the compound of formula (XV), to yield the corresponding compound of formula (XIIIb);
        Figure US20050240049A1-20051027-C00029
        reacting the compound of formula (XIIIb) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (Lc).
  • In an embodiment of the present invention is a process for the preparation of a compound of formula (Ld)
    Figure US20050240049A1-20051027-C00030
    wherein Qa is OH or OPg2, wherein Pg2is a carboxylic acid protecting group. In another embodiment of the present invention is a process for the preparation of a compound of formula (Ld) wherein Qa is OPg2 wherein Pg2 is a carboxylic acid protecting group.
  • The present invention is further directed to a novel process for the preparation of a compound of formula (I)
    Figure US20050240049A1-20051027-C00031
    or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof,
      • wherein
      • each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
      • wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
      • alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
      • n is an integer from 1 to 2;
      • X is S;
      • provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
      • R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
      • each R9 and R10 is independently C1-6alkyl;
      • R4 is H or —(C1-5straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)—, (C1-3alkoxyacyl)(C1-6alkylene)—, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
      • wherein R4 has no more than 9 carbon atoms;
      • alternatively, R4 is —(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
      • c is an integer from 0 to 1;
      • each of R5 and R7 is independently selected from H, C1-6alkyl, halo, cyano, nitro, COR11, COOR11, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR11R12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
      • R6 is selected from C1-6alkyl, halo, cyano, nitro, COR13, COOR13, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR13R14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
      • alternatively, R5 and R6 or R6 and R7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C3-4alkylene (for example, —(CH2)3— or —(CH2)4—), C3-4alkenylene (for example, —CH═CH—CH2— or —CH═CH—CH═CH—) or (CHI1-2)pN(CH1-2)q;
      • p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
      • each R11, R12, R13 and R14 is independently H or C1-6alkyl;
      • wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
      • comprising
        Figure US20050240049A1-20051027-C00032
      • reacting a compound of formula (L), wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic; to yield the corresponding compound of formula (I).
  • In an embodiment of the present invention is a process for the preparation of a compound of formula (II)
    Figure US20050240049A1-20051027-C00033
    also known as 2-[[2-[ethyl[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]amino]-2,3-dihydro-1H-inden-5-yl]thio]-2-methyl-propanoic acid or 2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionic acid.
  • In another embodiment of the present invention is a process for the preparation of a compound of formula (IIa)
    Figure US20050240049A1-20051027-C00034
    also known as 2-[[(2R)-2-[ethyl[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]amino]-2,3-dihydro-1H-inden-5-yl]thio]-2-methyl-propanoic acid or 2-{(2R)-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionic acid.
  • The present invention is further directed to a process for the preparation of the compound of formula (Le)
    Figure US20050240049A1-20051027-C00035
    wherein Qb is selected from the group consisting of C1-6alkoxy, wherein the C1-6alkoxy is not substituted with amino; comprising
    Figure US20050240049A1-20051027-C00036
    (a) reacting a compound of formula (Ld) with (S)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, at a temperature in the range of from about 35° C. to about 0° C.; to yield the corresponding (R,S) diastereomeric salt, the compound of formula (XX);
    Figure US20050240049A1-20051027-C00037
    (b) reacting the (R,S) diastereomeric salt, the compound of formula (XX), with an inorganic base, to yield the corresponding compound of formula (Le).
  • The present invention is further directed to a process for the preparation of the compound of formula (Le)
    Figure US20050240049A1-20051027-C00038
    wherein Qb is selected from the group consisting of C1-6alkoxy, wherein the C1-6alkoxy is not substituted with amino; comprising
    Figure US20050240049A1-20051027-C00039
    (a) reacting a compound of formula (Ld) with (R)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35° C., preferably at a temperature greater than about 45° C.; or in THF at about room temperature, to yield the corresponding (R,R) diastereomeric salt, the compound of formula (XXI).
    Figure US20050240049A1-20051027-C00040
    (b) reacting the (R,R) diastereomeric salt, the compound of formula (XXI) with an inorganic base, to yield the corresponding compound of formula (Le).
  • The present invention is further directed to a process for the preparation of the compound of formula (Lf)
    Figure US20050240049A1-20051027-C00041
    wherein Qb is selected from the group consisting of C1-6alkoxy, wherein the C1-6alkoxy is not substituted with amino; comprising
    Figure US20050240049A1-20051027-C00042
    (a) reacting a compound of formula (Ld) with (S)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35° C., preferably at a temperature greater than about 45° C.; or in THF at about room temperature; to yield the corresponding (S,S) diastereomeric salt, the compound of formula (XXII).
    Figure US20050240049A1-20051027-C00043
    (b) reacting the (S,S) diastereomeric salt, the compound of formula (XXI) with an inorganic base, to yield the corresponding compound of formula (Lf).
  • The present invention is further directed to a process for the preparation of the compound of formula (Lf)
    Figure US20050240049A1-20051027-C00044
    wherein Qb is selected from the group consisting of C1-6alkoxy, wherein the C1-6alkoxy is not substituted with amino; comprising
    Figure US20050240049A1-20051027-C00045
    (a) reacting a compound of formula (Ld) with (R)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, at a temperature in the range of from about 35° C. to about 0° C.; to yield the corresponding (S,R) diastereomeric salt, the compound of formula (XXIII);
    Figure US20050240049A1-20051027-C00046
    (b) reacting the (S,R) diastereomeric salt, the compound of formula (XXIII) with an inorganic base, to yield the corresponding compound of formula (Lf).
  • The present invention is further directed to a novel crystalline salt of the compound of formula (IIa), more specifically, an N,N′-dibenzylethylenediamine (benzathine) salt of the compound of formula (IIa). The present invention is further directed to an N,N′-dibenzylethylenediamine salt of the compound of formula (IIa) wherein the ratio of the compound of formula (IIa) to the N,N′-dibenzylethylenediamine is 1:1. The present invention is further directed to a process for the preparation of the benzathine salt of the compound of formula (IIa).
  • The present invention is further directed to a compound prepared according to any of the processes described herein.
  • Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound prepared according to any of the processes described herein. An illustration of the invention is a pharmaceutical composition made by mixing a compound prepared according to any of the processes described herein and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing a compound prepared according to any of the processes described herein and a pharmaceutically acceptable carrier.
  • In one embodiment, the pharmaceutical composition comprises the compound:
    Figure US20050240049A1-20051027-C00047
    or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof.
  • In another embodiment, the pharmaceutical composition comprises the compound:
    Figure US20050240049A1-20051027-C00048
  • Exemplifying the present invention are methods of treating a PPAR alpha-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound prepared according to any of the processes described herein or a pharmaceutical composition as described above. Further exemplifying the present invention are methods of elevating serum levels of high density lipoproteins (HDL), improving levels of intermediate density lipoproteins (IDL), lowering serum levels of triglycerides, low density lipbproteins (LDL), atherogenic molecules, and/or free fatty acids (FFA), treating hypertriglyceridemia, raising levels of HDL, lowering levels of LDL, and/or lowering total cholesterol, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound prepared according to any of the processes described herein or a pharmaceutical composition as described above.
  • Further exemplifying the invention are methods for treating dyslipidemia, cardiovascular disorders, impaired glucose tolerance, hyperinsulinemia, hyperglycemia, insulin resistance, early, intermediate or late Type II diabetes (NIDDM), complications thereof, or Syndrome X, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound prepared according to any of the processes described herein or a pharmaceutical composition as described above.
  • Further exemplifying the invention are methods for the treatment, prevention, or for inhibiting the progression of one or more of the following conditions or diseases: phase I hyperlipidemia; pre-clinical hyperlipidemia; phase II hyperlipidemia; hypertension; CAD (coronary artery disease); coronary heart disease; hypertriglyceridemia; lowering serum levels of low-density lipoproteins (LDL), IDL, and/or small-density LDL and other atherogenic molecules, or molecules that cause atherosclerotic complications, thereby reducing cardiovascular complications; elevating serum levels of high-density lipoproteins (HDL); lowering serum levels of triglycerides, LDL, and/or free fatty acids; and/or lowering FPG/HbA1c.
  • Another example of the invention is the use of a compound prepared according to any of the processes described herein in the preparation of a medicament for treating (a) dyslipidemia, (b) cardiovascular disorders, (c) impaired glucose tolerance, (d) hyperinsulinemia, (e) hyperglycemia, (f) insulin resistance, (g) early Type II diabetes (NIDDM), (h) intermediate Type II diabetes (NIDDM), (i) late Type II diabetes (NIDDM), (j) complications of Type II diabetes or (k) Syndrome X, in a subject in need thereof.
    • DETAILED DESCRIPTION OF THE INVENTION
  • “Alkyl” includes optionally substituted straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on. As used herein, alkyl also includes cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • “Alkenyl” includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon double bond (Sp2). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein. As used herein, alkenyl also includes cycloalkenyl. Cis and trans or (E) and (Z) forms are included within the invention.
  • “Alkynyl” includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon triple bond (sp). Alkynyls include ethynyl, propynyls, butynyls, and pentynyls. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkynyl does not include cycloalkynyl.
  • “Alkoxy” includes an optionally substituted straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.
  • “Aminoalkyl”, “thioalkyl”, and “sulfonylalkyl” are analogous to alkoxy, replacing the terminal oxygen atom of alkoxy with, respectively, NH (or NR), S, and SO2. Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl, and so on.
  • “Aryl” includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, indenyl, and so on, any of which may be optionally substituted. Aryl also includes arylalkyl groups such as benzyl, phenethyl, and phenylpropyl. Aryl includes a ring system containing an optionally substituted 6-membered carbocyclic aromatic ring, said system may be bicyclic, bridge, and/or fused. The system may include rings that are aromatic, or partially or completely saturated. Examples of ring systems include indenyl, pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on.
  • “Heterocyclyl” includes optionally substituted aromatic and nonaromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom moiety (SO2, CO, CONH, COO) in the ring. Unless otherwise indicated, a heterocyclic radical may have a valence connecting it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom, such as N-piperidyl or 1-pyrazolyl. Preferably a monocyclic heterocyclyl has between 5 and 7 ring atoms, or between 5 and 6 ring atoms; there may be between 1 and 5 heteroatoms or heteroatom moieties in the ring, and preferably between 1 and 3, or between 1 and 2. A heterocyclyl may be saturated, unsaturated, aromatic (e.g., heteroaryl), nonaromatic, or fused.
  • Heterocyclyl also includes fused, e.g., bicyclic, rings, such as those optionally condensed with an optionally substituted carbocyclic or heterocyclic five- or six-membered aromatic ring. For example, “heteroaryl” includes an optionally substituted six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms condensed with an optionally substituted five- or six-membered carbocyclic or heterocyclic aromatic ring. Said heterocyclic five- or six-membered aromatic ring condensed with the said five- or six-membered aromatic ring may contain 1, 2 or 3 nitrogen atoms where it is a six-membered ring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur where it is a five-membered ring.
  • Examples of heterocyclyls include thiazoylyl, furyl, thienyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. For example, preferred heterocyclyls or heterocyclic radicals include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, thienyl,and more preferably, piperidyl or morpholinyl.
  • Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl.
  • “Acyl” refers to a carbonyl moiety attached to either a hydrogen atom (i.e., a formyl group) or to an optionally substituted alkyl or alkenyl chain, or heterocyclyl.
  • “Halo” or “halogen” includes fluoro, chloro, bromo, and iodo, and preferably fluoro or chloro as a substituent on an alkyl group, with one or more halo atoms, such as trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethoxy, or fluoromethylthio.
  • “Alkanediyl” or “alkylene” represents straight or branched chain optionally substituted bivalent alkane radicals such as, for example, methylene, ethylene, propylene, butylene, pentylene or hexylene.
  • “Alkenediyl” represents, analogous to the above, straight or branched chain optionally substituted bivalent alkene radicals such as, for example, propenylene, butenylene, pentenylene or hexenylene. In such radicals, the carbon atom linking a nitrogen preferably should be saturated.
  • “Aroyl” refers to a carbonyl moiety attached to an optionally substituted aryl or heteroaryl group, wherein aryl and heteroaryl have the definitions provided above. In particular, benzoyl is phenylcarbonyl.
  • As defined herein, two radicals, together with the atom(s) to which they are attached may form an optionally substituted 4- to 7-, 5- to 7-, or a 5- to 6-membered ring carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic. Said rings may be as defined above in the Summary of the Invention section.
  • “Enantiomer excess” or “ee”, usually expressed as a percentage, describes the excess of one enantiomer over the other. The percentage enantiomer excess, ee=100(Xr−Xs)/(Xr+Xs), where Xr>Xs. Alternatively, ee=100(2X-1), where X is the mole fraction of the dominant enantiomer in the mixture. Please note that Xr and Xs represent the mole fraction of (R)-enantiomer and (S)-enantiomer respectively in the mixture.
  • “Pharmaceutically acceptable salts, esters, and amides” include carboxylate salts, amino acid addition salts, esters, and amides which are within a reasonable benefitrisk ratio, pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. These salts, esters, and amides may be, for example, C1-8alkyl, C3-8cycloalkyl, aryl, C2-10heteroaryl, or C2-10non-aromatic heterocyclic salts, esters, and amides. Salts, free acids, and esters are more preferable than amides on the terminal carboxylate/carboxylic acid group on the left of formula (I). Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C1-6alkyl amines and secondary di(C1-6alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C1-3alkyl primary amines, and di(C1-2alkyl)amines. Representative pharmaceutically acceptable esters of the invention include C1-7 alkyl, C5-7cycloalkyl, phenyl, and phenyl(C1-6)alkyl esters. Preferred esters include methyl and ethyl esters.
  • As used herein, all hydrocarbon radicals, whether saturated, unsaturated or aromatic, and whether or not cyclic, straight chain, or branched, and also similarly with all heterocyclic radicals, eachradical includes substituted radicals is of that type and monovalent, bivalent, and multivalent radicals as indicated by the context. The context will indicate that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (bivalent) or more hydrogen atoms removed (multivalent).
  • Radicals or structure fragments as defined herein are understood to include substituted radicals or structure fragments. Hydrocarbyls include monovalent radicals containing carbon and hydrogen such as alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whether aromatic or unsaturated), as well as corresponding bivalent (or multi-valent) radicals such as alkylene, alkenylene, phenylene, and so on. Heterocarbyls include monovalent and bivalent (or multi-valent) radicals containing carbon, optionally hydrogen, and at least one heteroatom. Examples of monovalent heterocarbyls include acyl, acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl, and so on. Using “alkyl” as an example, “alkyl” should be understood to include substituted alkyl having one or more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents may be the same (dihydroxy, dimethyl) or different (chlorofluoro-, chlorobenzyl- or aminomethyl-substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, trifluoromethyl, and 3-iodocyclopentyl), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl), aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and 2-aminopropyl), alkylalkyl, and so on. A di(C1-6alkyl)amino group includes independently selected alkyl groups, to form, for example, methylpropylamino and isopropylmethylamino, in addition dialkylamino groups having two of the same alkyl group such as dimethylamino or diethylamino.
  • Only stable compounds are intended. For example, where there is an NR11R12 group, and R can be an alkenyl group, the double bond is at least one carbon removed from the nitrogen to avoid enamine formation. Similarly, where —(CH2)p—N—(CH2)q— can be unsaturated, the appropriate hydrogen atom(s) is(are) included or omitted, as shown in —(CH2)—N═(CH)—(CH2)— or —(CH2)—NH—(CH)═(CH)—.
  • Unless otherwise noted, when naming substituents such as X and R3, the following numbering of the indane and tetralin, respectively, will be applied.
    Figure US20050240049A1-20051027-C00049
  • As used herein, unless otherwise noted, the term “aprotic solvent” shall mean any solvent that does not yield a proton. Suitable examples include, but are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.
  • As used herein, unless otherwise noted, the term “nitrogen protecting group” shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamates—groups of the formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH2═CH—CH2—, and the like; amides—groups of the formula —C(O)—R′ wherein R′ is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives—groups of the formula —SO2—R″ wherein R″ is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Grouis in Organic Synthesis, John Wiley & Sons, 1991.
  • As used herein, unless otherwise noted, the term “carboxylic acid protecting group” shall mean a group which may be attached to —C(O)O— portion of the carboxylic acid to protect said carboxylic acid from participating in a reaction and which may be readily removed following the reaction. Suitable carboxylic acid protecting groups include, but are not limited C1-7alkyl, C5-7Cycloalkyl, phenyl, phenylC1-6alkyl, and the like. Other suitable carboxylic acid protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • In the process for the preparation of the compounds of formula (I), application of the present invention to a mixture of enantiomers of the compound of formula (L), substantially free of the S enantiomer, will result in the production of a mixture of enantiomers of formula (I), substantially free of the S enantiomer. Similarly, in the process for the preparation of the compounds of formula (I), application of the present invention to a mixture of enantiomers of formula (L), substantially free of the R enantiomer, will result in the production of a mixture of enantiomers of formula (I), substantially free of the R enantiomer. Preferably, the enantiomeric excess of the desired enantiomer of formula (I) is at least about 90% ee, more preferably, at least about 96% ee, most preferably, about 99% ee.
  • To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.
  • One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
  • Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • With reference to substituents, the term “independently” means that when more than one of such substituents is possible, such substituents may be the same or different from each other.
  • When a particular group is “substituted” (e.g., phenyl, aryl, aralkyl, heteroaryl), that group may have one or more substituents, preferably from one to three substituents, more preferably from one to two substituents, independently selected from the list of substituents.
  • The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • The term “therapeutically effective amount” as used herein, means that 15 amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • Abbreviations used in the specification, particularly the Schemes and Examples, are as follows:
    Ac = Acetyl (i.e. —C(O)—CH3)
    ACN or MeCN = Acetonitrile
    Alloc = CH2═CHCH2—O—C(O)—
    DCE = Dichloroethane
    DCM = Dichloromethane
    DIPEA or DIEA = Diisopropylethylamine
    DMA = Dimethylacetamide
    DMF = N,N-Dimethytformamide
    DMSO = Dimethyl sulfoxide
    % ee = Percent Enantiomeric Excess
    Et3N or TEA = Triethylamine
    EtOAc = Ethyl acetate
    EtOH = Ethanol
    FTIR = Fourier Transform Infra-Red
    HPLC = High Pressure Liquid Chromatography
    iPrOAc = Isopropyl acetate
    KF = Karl-Fisher (% water measurement)
    LAH = Lithium Aluminum Hydride
    LDA = Lithium Diisopropylamide
    LHMDS = Lithium bis(trimethylsilyl)amide
    MeOH = Methanol
    mp = Melting Point
    MS = Mass Spectroscopy
    MTBE = Methyl-t-butyl ether
    MTr = 2,3,6-trimethyl-4-methoxy-phenyl-sulfonyl
    NMR = Nuclear Magnetic Resonance
    Pd(PPh3)4 = Palladium (0) Tetrakis(triphenylphosphine)
    TFA = Trifluoroacetic Acid
    THF = Tetrahydrofuran
  • In an embodiment of the present invention, in the compound of formula (I), (a) one of R1 and R2 is methyl or ethyl; (b) each of R1 and R2 is methyl; (c) R1 and R2 taken together are cyclobutyl or cyclopentyl; (d) R3 is H; (e) R4 is H or C2-7alkyl; (e) R4 is H or C2-5alkyl; (f) R4 is ethyl; (g) R4 is H; (h) n is 1; (i) 2; (j) at least one of R5 and R7 is H; (k) R6 is C1-4alkyl, halomethoxy, or halothiomethoxy (i.e —S-(halomethyl)); (I) R6 is t-butyl, isopropyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethoxy (i.e. —S—CF3), difluoromethoxy, or dimethylamino; (m) R3 is H, R4 is C2-7alkyl; (n) R4 is C2-5alkyl; (o) R6 is cyclopropylmethyl, isopropyl, isobutyl, methylethylamino, or diethylamino; (p) the (S) enantiomer at the C-2 position on the indane or tetralin; (q) the (R) entantiomer at the. C-2 position on the indane or tetralin; (r) where R15 is C1-7 alkyl, [di(C1-2alkyl)amino](C1-6alkylene), (C1-3alkoxyacyl)(C1-6alkylene), C1-6alkoxy, C3-7alkenyl, or C3-8alkynyl; (s) R6 is trifluoromethylthio or trifluoromethoxy; or (t) any combination of the above.
  • In another embodiment of the present invention, the compound of formula (I) selected from the group consisting of 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3fluoro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-chloro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid; 2-{6-[1-Ethyl-3-(4-ylsulfanyl}-2-methylpropionic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5, 6,7,8tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-trifluoromethoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid; 2-{6-[1-Ethyl-3-(4-hydroxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid; 2-{6-[(4-Aminophenyl)-1-ethyl-ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid and 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-4-trifluoromethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid.
  • In another embodiment of the present invention the compound of formula (I) selected from the group consisting of 2-{6-[1-Ethyl-3-(4-methyl propionic acid; 2-{6-[3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionic acid; and 2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propionic acid.
  • In an embodiment of the present invention c is 0. In another embodiment of the present invention n is 1 and X is bound at the 5-position. In yet another embodiment of the present invention n is 2 and X is bound at the 6- or 7-position, preferably at the 6-position.
  • In an embodiment of the present invention, wherein n is 1 and R3 is hydrogen or is other than hydrogen and is bound at the 4-, 6- or 7-position, then the —X—C(R1R2)—C(O)-Q group is bound at the 5-position. In another embodiment of the present invention, wherein n is 1 and R3 is hydrogen or is other than hydrogen and is bound at the 4-, 6- or 7- position, then the —X—C(R1R2)—C(O)—OH group is bound at the 5-position.
  • In an embodiment of the present invention, wherein n is 1 and R3 is other than hydrogen and is bound at the 5-position, then the —X—C(R1R2)—C(O)-Q group is bound at the 6-position. In another embodiment of the present invention, wherein n is 1 and R3 is other than hydrogen and is bound at the 5-position, then the —X—C(R1R2)—C(O)—OH group is bound at the 6-position.
  • In an embodiment of the present invention Q is Opg2 or N(Pg3Pg4), wherein Pg2 is a carboxylic acid protecting group as readily understood by one skilled in the art, including, but not limited to, C1-7alkyl, C5-7cycloalkyl, phenyl, phenylC1-6alkyl, and the like; and Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; alternatively Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3 ioheteroaryl or C3-10non-aromatic heterocyclic, preferably a 5- or 6-membered heterocyclic or heteroaromatic ring moiety containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. In another embodiment of the present invention Q is OPg2, wherein Pg2 is a carboxylic acid protecting group.
  • In an embodiment of the present invention Q is selected from the group consisting of hydroxy, unsubstituted C1-6alkoxy, amino, unsubstituted C1-4alkylamino and di(unsubstitutedC1-4alkyl)amino. In another embodiment of the present invention Q is selected from the group consisting of hydroxy, methoxy, ethoxy, ispropyloxy, n-butyloxy, t-butoxy, amino, methylamino and dimethylamino. In yet another embodiment of the present invention Q is C1-6alkoxy, wherein the C1-6alkoxy is not substituted with amino. In yet another embodiment of the present invention, Q is selected from the group consisting of methoxy, ethoxy and t-butoxy.
  • The present invention is directed to a process for the preparation of compounds of formula (L)
    Figure US20050240049A1-20051027-C00050
    wherein Q, X, R1, R2, R3, n and R4 are as herein defined. The compounds of formula (L) are useful as intermediates in the preparation of compounds of formula (I).
  • Compounds of formula (L) may be prepared according to the process outlined in Scheme 1.
    Figure US20050240049A1-20051027-C00051
  • Accordingly, a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted (for example, protected) according to known methods, to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to CISO3H, such as, Alloc (CH2═CHCH2—O—C(O)—), acetyl (CH3—C(O)—), (C14alkyl)-C(O)—, and the like. For example, the compound of formula (III) is reacted with a suitably selected protecting reagent such as Alloc-Cl (CH2═CHCH2—O—C(O)—Cl), Alloc2O (CH2═CHCH2—OC(O)—O—C(O)O—CH2CH═CH2), AcCl (CH3—C(O)—Cl), Ac2O (CH3—C(O)—O—C(O)—CH3), and the like. Wherein the compound of formula (III) is reacted with a Alloc-Cl, or Alloc2O, the corresponding protecting group Pg1 is Alloc. Preferably, Pg1 is selected from Alloc or acetyl.
  • The compound of formula (IV) is reacted with a suitable substituted compound of formula (V), wherein R4a is R4 other than hydrogen and wherein J is Br, Cl, or I, a known compound or compound prepared by known methods, in the presence of a base such as NaH, n-butyl lithium, LDA, LHMDS, and the like, in a polar aprotic solvent such as THF, dioxane, MTBE, and the like, to yield the corresponding compound of formula (VI). The compound of formula (VI) is then reacted with ClSO3H, optionally in a polar organic solvent which is inert to ClSO3H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII).
  • Alternatively, the compound of formula (IV) is reacted with ClSO3H, optionally in a polar organic solvent which is inert to ClSO3H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII) wherein R4 is hydrogen.
  • The compound of formula (VII) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), such as Zn, and the like, in the presence of an acid such as HCl, H2SO4, and the like, in an aprotic solvent such as acetonitrile, THF, dioxane, and the like; or with Zn in the presence of (CH3)2SiCl2 and DMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile, 1,2-dichloroethane, and the like; to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX).
  • Alternatively, wherein the compound of formula (VII) Pg1 is tosyl or MTr, the compound of formula (VII) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), such as LiAlH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about reflux, to yield the corresponding compound of formula (VIII).
  • The compound of formula (VIII), isolated or in a mixture with the compound of formula (IX) is reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (XI).
  • Alternatively, the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII) is reacted with a reducing agent which is is capable of reducing the disulfide on the compound of formula (VIII), such as LiAlH4, LiBH4, NaBH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (VIII), which is preferably not isolated. The compound of formula (VIII) is then reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (XI).
  • The compound of formula (XI) is reacted to yield the corresponding compound of formula (L). For example, the compound of formula (XI) is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (L).
  • Compounds of formula (L) may alternatively be prepared according to the process outlined in Scheme 2.
    Figure US20050240049A1-20051027-C00052
  • Accordingly, a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted (for example, protected) according to known methods, to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to ClSO3H, such as, Alloc (CH2═CHCH2—O—C(O)—), acetyl (CH3—C(O)—), (C1-4alkyl)-C(O)—, and the like. For example, the compound of formula (III) is reacted with a suitably selected protecting reagent such as Alloc-Cl (CH2═CHCH2—O—C(O)—Cl), Alloc2O. (CH2═CHCH2—OC(O)—O—C(O)O—CH2CH═CH2), AcCl (CH3—C(O)—Cl), Ac2O. (CH3—C(O)—O—C(O)—CH3), and the like. Wherein the compound of formula (III) is reacted with a Alloc-Cl, or Alloc2O, the corresponding protecting group Pg1 is Alloc. Preferably, Pg1 is selected from Alloc or acetyl.
  • The compound of formula (IV) is reacted with a suitable substituted compound of formula (V), wherein R4a is R4 other than hydrogen and wherein J is Br, Cl, or I, a known compound or compound prepared by known methods, in the presence of a base such as NaH, n-butyl lithium, LDA, LHMDS, and the like, in a polar aprotic solvent such as THF, dioxane, MTBE, and the like, to yield the corresponding compound of formula (VI). The compound of formula (VI) is then reacted with ClSO3H, optionally in a polar organic solvent which is inert to ClSO3H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII).
  • Alternatively, the compound of formula (IV) is reacted with ClSO3H, optionally in a polar organic solvent which is inert to ClSO3H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII) wherein R4 is hydrogen.
  • The compound of formula (VII) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), such as Zn, and the like, in the presence of an acid such as HCl, H2SO4, and the like, in an aprotic solvent such as acetonitrile, THF, dioxane, and the like; or with Zn in the presence of (CH3)2SiC1-2 and DMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile, 1,2-dichloroethane, and the like; to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX).
  • Alternatively, wherein the compound of formula (VII) Pg1 is tosyl or MTr, the compound of formula (VII) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), such as LiAlH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about reflux, to yield the corresponding compound of formula (VIII).
  • The compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), is de-protected according to known methods, such as those described in Protective Groucs in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Grouis in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (XIII).
  • Alternatively, the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), is reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (IX), such as LiAlH4, LiBH4, NaBH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (VIII), which is preferably not isolated. The compound of formula (VIII) is then de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (XIII).
  • Alternatively still, the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (XII). The compound of formula (XII) is then reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (XII), such as LiAlH4, LiBH4, NaBH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (XIII).
  • The compound of formula (XIII) reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (L).
  • Compounds of formula (L) wherein R4 is other than hydrogen may alternatively be prepared according to the process outlined in Scheme 3.
    Figure US20050240049A1-20051027-C00053
    Figure US20050240049A1-20051027-C00054
  • Accordingly, a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted (for example, protected) according to known methods, to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to ClSO3H, such as, Alloc (CH2═CHCH2—O—C(O)—), acetyl (CH3—C(O)—), (C1-4alkyl)-C(O)—, and the like. For example, the compound of formula (III) is reacted with a suitably selected protecting reagent such as Alloc-Cl (CH2═CHCH2-Q-C(O)—Cl), Alloc2O. (CH2═CHCH2—OC(O)—O—C(O)O—CH2CH═CH2), AcCl (CH3—C(O)—Cl), Ac2O. (CH3—C(O)—O—C(O)—CH3), and the like. Wherein the compound of formula (III) is reacted with a Alloc-Cl, or Alloc2O, the corresponding protecting group Pg1 is Alloc. Preferably, Pg1 is selected from Alloc or acetyl.
  • The compound of formula (IV) is reacted with ClSO3H, optionally in a polar organic solvent which is inert to ClSO3H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VIIa) (i.e. the corresponding compound of formula (VII) wherein R4 is hydrogen.).
  • The compound of formula (VIIIa) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VIIa) such as Zn, and the like, in the presence of an acid such as HCl, H2SO4, and the like, in an aprotic solvent such as acetonitrile, THF, dioxane, and the like; or with Zn in the presence of (CH3)2SiC1-2 and DMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile, 1,2-dichloroethane, and the like; to yield a mixture of the corresponding compound of formula (VIIIa) (i.e. the corresponding compound of formula (VIII) wherein R4 is hydrogen) and the corresponding compound of formula (IXa) (i.e. the corresponding compound of formula (IXa) wherein R4 is hydrogen).
  • The compound of formula (VIIIa), isolated or in a mixture with the compound of formula (IXa) is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (XIIIa) (i.e. the corresponding compound of formula (XIII) wherein R4 is hydrogen). The compound of formula (XIIIa) is reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (La) (i.e. the corresponding compound of formula (L) wherein R4 is hydrogen).
  • Alternatively, the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), is reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (IXa), such as LiAlH4, LiBH4, NaBH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (VIIIa). The compound of formula (VIIIa) is then reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (XIa) (i.e. the corresponding compound of formula (XI) wherein R4 is hydrogen). The compound of formula (XIa) is then reacted to yield the corresponding compound of formula (La). For example, the compound of formula (XIa) is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (La).
  • Alternatively still, the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, to yield the corresponding compound of formula (XIIa) (i.e. the corresponding compound of formula (XII) wherein R4 is hydrogen). The compound of formula (XIIa) is then reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (XIIa), such as LiAlH4, LiBH4, NaBH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (XIIIa) (i.e. the corresponding compound of formula (XIII) wherein R4 is hydrogen). The compound of formula (XIIIa) is then reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (La).
  • The compound of formula (La) is reacted with a suitably substituted compound of formula (V), wherein R4a is R4 other than hydrogen and wherein J is Br, Cl, or I, a known compound or compound prepared by known methods, in the presence of a base such as NaH, n-butyl lithium, LDA, LHMDS, and the like, in a polar aprotic solvent such as THF, dioxane, MTBE, and the like, to yield the corresponding compound of formula (Lb). Alternatively, the compound of formula (La) is reacted with a suitably substituted acylating agent capable of attaching an —C(O)—R4b group onto the nitrogen of the compound of formula (La), wherein R4b is selected from (C1-4 straight chain alkylene)R15 or (straight chain C1-4alkylene)R16, in the presence of an organic such as TEA, DIPEA, pyridine, and the like, or in the presence of an inorganic base such as NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (XVIII); the compound of formula (XVIII) is then reacted with a reducing agent capable of reducing the amide on the compound of formula (XVIII), such as borane, and the like, in a aprotic organic solvent such as THF, dioxane, MTBE, and the like, to yield the corresponding compound of formula (Lb).
  • Compounds of formula (L) wherein R4 is other than hydrogen, (C1 straight chain alkylene)R15 or (straight chain C1alkylene)R16 may be prepared according to the process outlined in Scheme 4.
    Figure US20050240049A1-20051027-C00055
  • Accordingly, a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted with a suitably substituted acylating capable of attaching an —C(O)O—R4b group onto the nitrogen of the compound of formula (III), wherein R4b is selected from (C14 straight chain alkylene)R15 or (straight chain C14 alkylene)R16, for example an acid chloride of the formula Cl—C(O)—R4b, a symmetric anhydride of the formula R4b—C(O)—O—C(O)—R4b, and the like, in the presence of an organic base, preferably a tertiary amine base such as TEA, DIPEA, pyridine, and the like, in an aprotic solvent such as THF, DMF, dioxane, ethyl acetate, and the like; or in the presence of an organic or inorganic base such as NaOH, KOH, Na2CO3, NaHCO3, K2CO3, KHCO3, TEA, DIPEA, pyridine, and the like, in a mixture of an aprotic solvent and water, to yield the corresponding compound of formula (XIV).
  • The compound of formula (XIV) is reacted with ClSO3H, optionally in a polar organic solvent which is inert to ClSO3H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (XV).
  • The compound of formula (XV) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (XV), such as Zn, and the like, in the presence of an acid such as HCl, H2SO4, and the like, optionally in an aprotic solvent such as acetonitrile, THF, dioxane, and the like; or with Zn in the presence of (CH3)2SiC1-2 and DMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile, 1,2-dichloroethane, and the like; to yield a mixture of the compound of formula (XVI) and the compound of formula (XVII).
  • One skilled in the art will recognize that when the compound of formula (XV) is reacted with a reducing agent capable of reducing the chlorosulfonyl group and the amide group on the compound of formula (XV), such as LiAlH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about reflux, then the compound of formula (XV) is reacted to yield the corresponding compound of formula (XIIIb) in one step.
  • The compound of formula (XVI), isolated or in a mixture with the compound of formula (XVII) is reacted with a reducing agent which is capable of reducing the amide on the compound of formula (XVI), such as LiAlH4, borane, and the like, in an aprotic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, to yield the corresponding compound of formula (XIIIb) (i.e. the corresponding compound of formula (XIII) wherein R4 is other than hydrogen). Wherein the reducing agent is LiAlH4, the compound(s) is reduced at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature.
  • Alternatively, the compound of formula (XVII), isolated or in a mixture with the compound of formula (XVI) is reacted with a reducing agent which is capable of reducing the amide on the compound of formula (XVII) and the disulfide on the compound of formula (XVII), such as LiAlH4, borane, and the like, in an aprotic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, to yield the corresponding compound of formula (XIIIb). Wherein the reducing agent is LiAlH4, the compound(s) is reduced at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature.
  • The compound of formula (XIIIb) is reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, methanol, ethanol, and the like, to yield the corresponding compound of formula (Lc) (i.e. the corresponding compound of formula (L) wherein R4 is selected from (C2-5 straight chain alkylene)R15 or (straight chain C2-5 alkylene)R16).
  • The present invention is further directed to a process for the preparation of compounds of formula (I)
    Figure US20050240049A1-20051027-C00056
    wherein R1, R2, X, R3, n, R4, c, R5, R6 and R7 are as herein defined. The compounds of formula (I) are useful as PPAR alpha agonists, more specifically as selective PPAR alpha agonists. PPAR alpha agonists are useful for the treatment, prevention, or inhibiting the progression of one or more of the following conditions or diseases: phase I hyperlipidemia; pre-clinical hyperlipidemia; phase II hyperlipidemia; hypertension; CAD (coronary artery disease); coronary heart disease; hypertriglyceridemia; lowering serum levels of low-density lipoproteins (LDL), IDL, and/or small-density LDL and other atherogenic molecules, or molecules that cause atherosclerotic complications, thereby reducing cardiovascular complications; elevating serum levels of high-density lipoproteins (HDL); lowering serum levels of triglycerides, LDL, and/or free fatty acids; and/or lowering FPG/HbA1c.
  • More specifically, the compound of formula (I) may be prepared by reacting a suitably substituted compound of formula (L) with a suitably substituted isocyanate, a compound of the formula (XIX)
    Figure US20050240049A1-20051027-C00057
    according to known methods. One skilled in the art will recognize that in reacting the compound of formula (L) with a suitably substituted isocyanate, a compound of formula (XIX), it may be necessary or desirable to protect reactive groups on the compound of formula (L), according to known methods. For example, it may be necessary or desirable to protect the carboxylic acid or amide on the compound of formula (L) when Q is OH or NH2, respectively. One skilled in the art will further recognize that wherein the compound of formula (L) Q is OPg2, NH or N(Pg3Pg4), the compound of formula (L) is reacted with a suitably substituted isocyanate, a compound of formula (XIX), according to known methods, to yield an intermediate which is then de-protected according to known methods to yield the corresponding compound of formula (I).
  • In an embodiment of the present invention is a process for the preparation of a compound of formula (L) wherein X is S, R1 is methyl, R2 is methyl, Q is OH or OPg2, the —X—C(R1R2)—C(O)-Q is bound at the 5- position, R3 is hydrogen, n is 1 and R4 is ethyl. In another embodiment of the present invention is a process for the preparation of a compound of formula (L) wherein X is S, R1 is methyl, R2 is methyl, Q is OPg2, Pg2is t-butyl, the —X—C(R1R2)—C(O)-Q is bound at the 5- position, R3 is hydrogen, n is 1 and R4 is ethyl.
  • In another embodiment of the present invention is a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, C1-6ester or C1-6amide thereof, wherein X is S, R1 is methyl, R2 is methyl, wherein —X—C(R1R2)—C(O)—OH is bound at the 5- position, R3 is hydrogen, n is 1, R4 is ethyl, c is 0, R5 is hydrogen, R6 is trifluoromethoxy and R7 is hydrogen.
  • The present invention is further directed to a process for the preparation of the compound of formula (Le)
    Figure US20050240049A1-20051027-C00058
    wherein Qb is selected from the group consisting of C1-6alkoxy, wherein the C1-6alkoxy is not substituted with amino. Preferably, Qb is unsubstituted C1-6alkoxy, more preferably, Qb is selected from the group consisting of methoxy, ethoxy and t-butoxy.
  • More specifically, the compound of formula (Le) may be prepared according to the process outlined in Scheme 5.
    Figure US20050240049A1-20051027-C00059
  • Accordingly, a compound of formula (Ld) is reacted with (S)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol such as methanol, ethanol, and the like, preferably ethanol; or in acetone, at a temperature in the range of from about 35° C. to about 0° C., to yield the corresponding (R,S) diastereomeric salt, the compound of formula (XX).
  • The (R,S) diastereomeric salt, the compound of formula (XX), is r eacted with an inorganic base such as NaOH, KOH, Na2CO3, K2CO3, and the like to yield the corresponding compound of formula (Le).
  • Preferably, the compound of formula (Le) is prepared with an enantiomeric excess in the range of from about 70 % ee to about 90 % ee. One skilled in the art will recognize that wherein a greater % ee is desired, the diasteromeric salt of the compound of formula (Le) may be further re-slurrried in or recrystallized from an organic solvent such as methanol, ethanol, acetone, and the like.
  • The compound of formula (Le) may alternatively be prepared according to the process outlined in Scheme 6.
    Figure US20050240049A1-20051027-C00060
  • Accordingly, a compound of formula (Ld) is reacted with (R)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35° C., preferably at a temperature greater than about 45° C.; or in THF at about room temperature; to yield the corresponding (R,R) diastereomeric salt, the compound of formula (XXI).
  • The (R,R) diastereomeric salt, the compound of formula (XXI), is reacted with an inorganic base such as NaOH, KOH, Na2CO3, K2CO3, and the like to yield the corresponding compound of formula (Le).
  • Preferably, the compound of formula (Le) is prepared with an enantiomeric excess in the range of from about 70 % ee to about 90 % ee. One skilled in the art will recognize that wherein a greater % ee is desired, the diasteromeric salt of the compound of formula (Le) may be further re-slurrried in or recrystallized from an organic solvent such as methanol, ethanol, acetone, and the like.
  • One skilled in the art will further recognize that the S-enantiomer of the compound of formula (Ld), a compound of formula (Lf)
    Figure US20050240049A1-20051027-C00061
    may be similarly prepared by reacting a compound of formula (Ld) with (R)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol such as methanol, ethanol, and the like, preferably ethanol; or in acetone, at a temperature in the range of from about 35° C. to about 0° C.; to yield the corresponding (S,R) diastereomeric salt which is then reacted with an inorganic base such as NaOH, KOH, Na2CO3, K2CO3, and the like, to yield the corresponding compound of formula (Lf).
  • Alternatively, the S-enantiomer of the compound of formula (Ld) (i.e. the compound of formula (Lf)) may be prepared by reacting a compound of formula (Ld) with (S)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35° C., preferably at a temperature greater than about 45° C.; or in THF at about room temperature; to yield the corresponding (S,S) diastereomeric salt which is then reacted with an inorganic base such as NaOH, KOH, Na2CO3, K2CO3, and the like, to yield the corresponding compound of formula (Lf).
  • The present invention is further directed to a novel crystalline salt of the compound of formula (IIa)
    Figure US20050240049A1-20051027-C00062
    more specifically a crystalline N,N′-dibenzylethylenediamine (benzathine) salt of the compound of formula (IIa). In an embodiment of the present invention is a crystalline N.N′-dibenzylethylenediamine salt of the compound of formula (IIa) wherein the ratio of the compound of formula (IIa) to the N,N′-dibenzylethylenediamine is 1:1.
  • The crystalline benzathine salt of the compound of formula (IIa) may be characterized by the major peaks of its X-ray diffraction peaks, as listed in Table 1, below. The X-ray diffraction pattern was measured as follows. The crystalline benzathine salt of the compound of formula (IIa) was backloaded into a conventional X-ray holder. Using an X-Celerator detector, the sample was scanned from 3 to 35 °2θ at a step size of 0.0165 °2θ and a time per step of 10.16 seconds. The effective scan speed was 0.2067°/s. Instrument voltage and current settings of 45 kV and 40 mA were employed.
    TABLE 1
    XRD - Compound of formula (IIa) Benzathine Salt
    Position [°2θ] d-spacing [Å] Relative Intensity [%]
    6.3894 13.8336 17.39
    8.0423 10.9938 13.38
    12.157 7.2803 19.22
    16.012 5.5354 15.74
    17.929 4.9475 20.77
    18.048 4.9151 14.20
    19.038 4.6618 100.00
    19.2656 4.6072 26.28
    20.325 4.3694 10.65
    21.943 4.0508 16.85
    22.190 4.0063 18.63
    22.330 3.9815 12.37
  • The present invention is further directed to a process for the preparation of the benzathine salt of the compound of formula (IIa). More particularly, the compound of formula (lha) is reacted with N,N′-dibenzylethylenediamine, in an aprotic solvent such as isopropyl acetate, ethyl acetate, MTBE, and the like, preferably in isopropyl acetate, preferably, at a temperature less than about 5° C., more preferably, at a temperature in the range of from about 5° C. to about −5° C., yield the corresponding N,N′-dibenzylethylenediame (benzathine) salt of the compound of formula (IIa).
  • The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.
    • EXAMPLE 1 N-Indan-2-yl-acetamide
  • Figure US20050240049A1-20051027-C00063
  • To a cooled mixture of 2-aminoindan (1.2 mol, 160.00 g) in ethyl acetate (1019 mL) at about 5-7° C. was added a solution of Na2CO3 (2.4 mol, 254.65 g) in water (1528 mL) while stirring, followed by the addition of a solution of acetyl chloride (1.32 mol, 109.19 g) slowly over 2 hours. The reaction temperature was maintained below 10° C. by adjusting the addition rate. During the addition, a suspension was formed. After the addition of acetyl chloride, the mixture was stirred at the room temperature for 1 hour. The precipitated solid was collected by vacuum filtration and the filter cake was washed with water (200 mL), EtOAc (200 mL), and air-dried for 48 hours. The first crop of the product was obtained as a white crystalline solid.
  • The filtrate was placed in a separatory funnel and the aqueous layer was separated. The organic layer was washed once with water (500 mL) and once with brine (500 mL). The ethyl acetate layer was evaporated in vacuo to half of its original volume and then diluted with heptane (1000 mL) while stirring to produce a white suspension. The solid was collected by vacuum filtration and washed twice with portions of heptane (300 mL). The second crop of the product was obtained as white crystalline solid.
  • mp 127-129° C.
  • 1H NMR (300 MHz, CDCl3) δ 7.13 (m, 4H), 6.99 (br d, 1H), 4.57 (m, 1H), 3.19 (dd, J ═16.1, 7.3 Hz, 2H), 2.78 (dd, J=16.0, 5.1 Hz, 2H), 1.85 (s, 3H).
  • 13C NMR (300 MHz, CDCl3) δ 170.7, 141.4, 127.01, 125.1, 51.0, 41.2, 23.5.
  • MS (ESI): m/z 176.2 (MH+).
  • Elemental Analysis for C11H13NO:
  • Calculated: C, 75.40; H, 7.48; N, 7.99
  • Found: C, 75.13; H, 7.73; N, 7.96.
    • EXAMPLE 2 2-Acetylamino-indan-5-sulfonyl chloride
  • Figure US20050240049A1-20051027-C00064
  • To a 2 L 3-necked glass reaction flask equipped with stirrer, condenser, thermocouple, 500 mL addition funnel and nitrogen inlet was added N-acetyl-2-aminoindan (0.96 mol, 167.70 g) and acetonitrile (490 mL). The reaction mixture was stirred and cooled in an ice-bath to about 3-5° C. and ClSO3H (3.83 mol, 440 g) was added slowly. The first 30% of the reagent was added over 30 minutes while maintaining the reaction temperature below 15° C. The ice-bath was then removed and the reaction mixture was warmed to room temperature. The remaining 70% of the reagent was added over 30 minutes and the temperature of the reaction solution rose to 80° C. at the end of the addition. The yellow reaction solution was stirred at 50° C. for about 20 hours. The reaction solution was cooled to 30° C. and slowly poured into a vigorously stirred mixture of ice (1620 g), water (945 mL), and acetonitrile (135 mL) in an ice-bath over about 10-15 minutes. The temperature of the quenching mixture dropped from 5° C. to −6° C. A white solid precipitated and the mixture was stirred at about 0-5° C. for 30 minutes. The solid was collected by vacuum filtration and slurried 4 times with a cold mixture of water (4×300 mL). The pH of the last slurry was around 2-3. The solid was then slurried with cold acetone (300 mL) (5-7° C.), collected by filtration, and finally rinsed with of cold acetone (200 mL). The solid product was air-dried for 4 hours, followed by drying in a vacuum oven at room temperature for 48 hours. The product was obtained as a white solid.
  • mp 158-160° C.
  • 1H NMR (300 MHz, DMSO-d6) δ 8.53 (br s, 1H), 7.45 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 4.45 (br m, 1H), 3.15 (m, 2H), 2.77 (dd, J=16.2, 5.7 Hz, 2H), 1.85 (s, 3H).
  • 13C NMR (300 MHz, DMSO-d6) δ 169.6, 145.3, 142.3, 140.9, 123.9, 123.7, 121.6, 50.2, 38.6, 38.4, 22.2.
  • MS (ESI): m/z 274.0 (MH+)
  • Elemental Analysis for C11H12ClNO3S.0.1H2O:
  • Calculated: C, 47.95; H, 4.47; Cl, 12.87; N, 5.09; S, 11.64; KF, 0.66%
  • Found: C, 47.61; H, 4.49; Cl, 12.50; N, 5.13; S, 11.50; KF, 0.67%
    • EXAMPLE 3 N-(5-Mercapto-indan-2-yl)-acetamide
  • Figure US20050240049A1-20051027-C00065
  • A suspension of zinc (22.94 g, 0.35 mol) and 2-acetylamino-indan-5-sulfonyl chloride (93% weight) (29.45 g, 0.10 mol) in acetonitrile (200 mL) in a 1 Liter four-necked round-bottomed flask equipped with a condenser, a thermometer, an addition funnel, and a mechanical stirrer was heated to about 50-60° C. The heating source was removed and to the warm suspension was added concentrated HCl (59.20 g, 0.60 mol) slowly over 1 hour. The addition rate was adjusted to maintain the reaction temperature between about 70-75° C. A gentle gas (H2) evolution was observed throughout the addition of HCl. The reaction was then cooled to about 30-36° C. over 30 minutes while stirring. The reaction mixture was filtered into a 500 mL one-necked round-bottomed flask through a frited glass funnel to remove the Zn residue. The reaction flask was rinsed with EtOAc (25 mL). The mixture was concentrated on a rotavapor under reduced pressure at about 45-50° C. bath temperature to remove most of the organic solvents. The concentrated aqueous solution was mixed with of EtOAc (150 mL), followed by the addition of H2O. (75 mL). After stirring for 15 minutes, the layers were separated. The organic layer was washed four times with H2O. (3×75 mL). After separation of layers, the organic layer was concentrated on a rotavapor at 60° C. to ¼ of its original volume (about 40 mL). Most of the precipitated white solid was dissolved by heating to reflux. The mixture was then diluted with MTBE (75 mL). The mixture was stirred at ambient temperature for 18 hours. The solid product was collected by vacuum filtration, washed with MTBE (20 mL), dried under nitrogen for 4 hours, then in a vacuum oven at about 40-45° C. for 24 h. The product was obtained as an off-white solid.
  • mp 128-129.5° C.
  • 1H NMR (300 MHz, DMSO-d6) δ 8.12 (br d, J=6.6 Hz, 1H), 7.15 (s, 1H), 7.08 (brs, 2H), 5.18 (s, 1H), 4.41 (m, 1H), 3.09 (m, 2H), 2.69 (m, 2H), 1.79 (s, 3H).
  • 13C NMR (300 MHz, DMSO-d6) δ 168.9, 142.4, 138.2, 129.2, 126.6, 125.0,124.8, 49.9, 38.9, 38.5, 22.5.
  • MS (ESI): m/z 208.2 (MH+)
  • Elemental Analysis for C11H13NOS:
  • Calculated: C, 63.73; H, 6.32; N, 6.76; S, 15.47
  • Found: C, 63.48; H, 6.50; N, 6.64; S, 15.56
    • EXAMPLE 4 N-[5-(2-Acetylamino-indan-5-yldisulfanyl)-indan-2-yl]-acetamide
  • Figure US20050240049A1-20051027-C00066
  • To a suspension of zinc (28.60 g, 0.44 mol) and 2-acetylamino-indan-5-sulfonyl chloride (40.00 g, 0.146 mol) in acetonitrile (400 mL) in a three-necked round-bottomed flask equipped with a magnetic stirrer, an addition funnel, and a thermometer was added a solution of dichlorodimethylsilane (44.2 mL, 0.365 mol) in acetonitrile (50 mL) at room temperature over 1 hour. The reaction temperature increased to 66° C. during the addition. After addition, the reaction mixture was stirred at room temperature for 20 hours and some solids were formed.
  • THF (100 mL) was added to dissolve the suspension and the excess Zn was removed by decantation and rinsed with THF (20 mL. The crude ACN/THF solution was extracted with heptane (3×300 mL) to remove the silane byproducts. The ACN/THF layer was concentrated and re-dissolved in EtOAc (300 mL) and H2O (150 mL). The mixture was stirred for 10 minutes and the layers were separated. The organic layer was washed with H2O. (2×200 mL), brine (200 mL), and then concentrated to the half of its original volume. The solution was diluted with toluene (200 mL) and concentrated again to remove all EtOAc. The suspension in toluene was warmed to 90° C. for 15 minutes and stirred at room temperature for 20 hours. The solid product was collected by vacuum filtration, rinsed with toluene (20 mL), air-dried for 2 hours, and further dried in a vacuum oven at 60° C. for 2 days. The product was obtained as an off-white solid.
  • mp 165-168° C. (soften at 137° C.)
  • 1H NMR (300 MHz, DMSO-d6) δ 8.13 (d, J=7.7 Hz, 2H), 7.38 (s, 2H), 7.30 (d, J=7.9 Hz, 2H), 7.22 (d, J=7.7 Hz, 2H), 4.42 (br m, 2H), 3.15 (m, 2H), 3.11 (m, 2H), 2.71 (dd, J=16.2, 5.3 Hz, 4H), 1.78 (s, 6H).
  • 13C NMR (300 MHz, DMSO-d6) δ 168.8, 142.9, 141.4, 133.7, 126.1, 125.3, 124.0, 49.9, 38.9, 38.6, 22.5.
  • MS (ESI): m/z 413.1 (MH+)
    • EXAMPLE 5 tert-Butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate
  • Figure US20050240049A1-20051027-C00067
  • N-(5-Mercapto-indan-2-yl)-acetamide (330.0 g, 1.59 mol) was dissolved in a warm THF (1.65 L) at 50° C. The solution was then slowly added to LAH solution (1 M in THF) (2.385 L, 2.385 mol) at about 60-66° C. over 25 minutes to allow gentle reflux and slow gas evolution. After addition, the light yellow suspension was stirred under reflux for 4 hours. The reaction was cooled to about 5-7° C. in an ice-water bath. The reaction was quenched by the slow addition of methanol (203.7 g, 6.36 mol) under a nitrogen atmosphere and the reaction temperature was maintained below 25° C. by adjusting the addition rate. After quenching, the resulted green suspension was cooled to 5-7° C. and treated with tert-butyl 2-bromo-2-methylpropionate (354.7 g, 1.59 mol). The resulted mixture was warmed to room temperature while stirring and then maintained with stirring at room temperature for 2 hours. The reaction mixture was treated by the slow addition of H2O. (90.6 mL) and 15% of aqueous NaOH (90.6 mL) sequentially. The resulted granular solid was removed by vacuum filtration through a 3L coarse frit funnel lined with Celite filter aid. The filter cake was rinsed twice with THF (2×500 mL). The combined filtrate was concentrated in vacuo to remove about 70-80% of THF. The filter cake was suspended in EtOAc (2 L) and stirred for 30 minutes. The suspension was filtered through a 3L coarse frit funnel. The filtrate was combined with the crude concentrated THF solution obtained above. The combined organic layer was washed with H2O. (2 L). After separation of layers, the organic layer was concentrated in vacuo at 50° C. to remove the most of volatiles. The concentrated solution was diluted with anhydrous ethanol (800 mL) and re-concentrated to yield a purple oil. The crude product was used for the next step without further purification.
  • MS (ESI): m/z 336.1 (MH+)
    • EXAMPLE 6 (S)-2-(4-hvdroxyphenoxy)propionic acid
  • Figure US20050240049A1-20051027-C00068
  • To (R)-2-chloropropionic acid (200 g, 1.81 mol) was added a solution of 50% NaOH (147.4 g, 1.84 mol) in water (520 mL) with the internal temperature below 25° C. In another flask, water (800 mL) and hydroquinone (811.8 g, 7.38 mol) were mixed. To the water/hydroquinone mixture was added 50% NaOH (1179.6 g, 14.71 mol), then the above (R)-2-chloropropionate sodium salt solution was added to the mixture, keeping the internal temperature below 55° C. The reaction mixture was heated at about 55-60° C. for an additional 2 h.
  • The reaction mixture was then cooled down to 5° C. To the reaction mixture was added concentrated HCl (1090 mL, 13.28 mol) while maintaining the temperature at about 15-30° C. to adjust the pH to about 4.3. The excess solid hydroquinone was removed by extraction with methyl isobutyl ketone three times (1200 mL, 200 mL×2). The resulting aqueous layer was further acidified to pH 1 with concentrated HCl (140 mL, 1.7 mol). Most of the (S)-2-(4-hydroxylphenoxy)propionic acid became solid at this point. (S)-2-(4-hydroxylphenoxy)propionic acid was then extracted into isopropyl acetate (800 mL and 400 mL). Water (325 mL) was added to the isopropyl acetate solution and the isopropyl acetate was removed azeotropically. The aqueous solution was adjusted to pH about 2.2 with 50% NaOH, then cooled down slowly to 20° C. The crude solid was collected by vacuum filtration and the filter cake was washed with small amount of water. The crude solid was recrystallized from water (230 mL) to yield the title compound as a white granular solid of 100% ee.
  • mp 139-140° C.
  • Optical rotation: [α]20 D=−38.5 (c 1.0, MeOH)
  • MS: m/z(ESI−): 181.12 (M-H)−, m/z (ESI+): 204.96 (M+Na)+
  • 1H NMR (300 MHz, DMSO-d6) δ 12.85 (brs, 1H), 8.95 (brs, 1H), 6.68 (m, 4H), 4.62 (q, J=6.8 Hz, 1H), 1.44 (d, J=6.8 Hz, 3H).
  • 13C NMR (300 MHz, DMSO-d6) δ 173.8, 151.9, 150.6, 116.4, 116.0, 72.7, 18.7,
  • FTIR (KBr): 3211 (br.), 1716, 1516, 1454, 1416, 1377, 1330, 1263, 1233, 1176, 1136, 1098, 1045, 946, 918, 861, 826, 766, 712, 697, 673, 638, 563, 508 cm−1.
  • Elemental Analysis for C9H10O4:
  • Calculated: C: 59.34H: 5.93
  • Found: C: 59.24H: 5.83
    • EXAMPLE 7 (R)-(−)-tert-Butyl 2-(2-ethylamino-indan-5-visulfanyl)-2-methyl-Propionate, (S)-(−)-2-(4-hydroxyphenoxy)propionic acid salt
  • Figure US20050240049A1-20051027-C00069
  • A solution of (S)-(−)-2-(4-hydroxyphenoxy)propionic acid (46.7 g) in 95% EtOH (200 mL) was warmed to about 30-35° C. To the solution was added a solution of the crude dark purple oil prepared in Example 5 above (94.5 g, 0.25 mol, 89% pure) in 95% EtOH (227 mL). After addition, the mixture was stirred and cooled down to 0° C. at the rate of less than 5° C. per hour. The suspension was then stirred at 0° C. for 2 hours, the solid was collected by vacuum filtration.
  • The crude solid with 86% ee was dissolved in 95% ethanol (165 mL) at 60° C. The solution was cooled slowly to 20° C. and stirred at this temperature for 18 hours. The solid was collected by vacuum filtration to yield the product as a white granular solid with 99.5% ee.
  • mp 145.6-147.0° C.
  • Optical rotation: [α]20 D=−22.8 (c 1.0, MeOH).
  • 1H NMR (300 MHz, DMSO-d6) δ 7.26 (m, 3H), 6.62 (m, 4H), 4.35 (q, J=6.8 Hz, 1H), 3.14 (m, 2H), 3.74 (p, J=7.2 Hz, 1H), 2.87 (dd, J=6.7 Hz, 16.3 Hz, 2H), 2.76 (q, J=7.3 Hz, 2H), 1.36 (s, 9H), 1.35 (s, 6H), 1.34 (d, J=6.8 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H).
  • 13C NMR (300 MHz, DMSO-d6) δ 175.8, 172.4, 151.5, 151.2, 142.3, 141.3, 135.5, 132.9, 129.4, 125.0, 115.9, 115.7, 80.7, 74.8, 57.4, 51.2, 41.0, 36.4, 27.8, 26.1, 19.3, 12.3.
  • FTIR (KBr): 2980, 2934, 1717, 1629, 1576, 1510, 1458, 1405, 1368, 1279, 1257, 1230, 1148, 1121, 1101, 1044, 848, 830, 801, 758, 679, 643, 525 cm−1.
  • Elemental Analysis for C28H39NO6S.0.43 EtOH:
  • Calculated: C: 64.19, H: 7.66, N: 2.13, S: 5.49
  • Found: C: 64.12, H: 7.87, N: 2.18, S: 5.89
    • EXAMPLE 8 (R)-(−)-tert-Butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate
  • Figure US20050240049A1-20051027-C00070
  • The diastereomeric salt prepared in Example 7 above (357 g, 0.635 mol) was charged into a mixture of isopropyl acetate (2 L) and 50% of NaOH (102 g, 1.28 mol) in water (0.8 L). The mixture was stirred until all solids dissolved. After removal of the bottom aqueous layer, the isopropyl acetate layer was washed with water 3 times until the pH of the aqueous phase was about 7. The organic solution was concentrated at 60° C. to remove about ¾ of the isopropyl acetate. 1 L of fresh isopropyl acetate was added and the amount of residual water in the solution was assayed by KF. The solution was used for the next step directly.
  • An analytical sample was obtained as clear oil by simple concentration of a small amount of the crude solution.
  • Optical Rotation: [α]20 D=−17.1 (c 1.0, MeOH).
  • MS (APCl): m/z 336.3 (MH+).
  • 1H NMR (300 MHz, DMSO-d6) δ 7.26 (s, 1H), 7.19 (m, 2H), 3.50 (p, J=6.8 Hz, 1H), 3.04 (dt, J=16 Hz, 6.5 Hz, 2H), 2.64 (m, 2H), 2.57 (q, J=7.0 Hz, 2H), 1.36 (s, 9H), 1.34 (s, 6H), 1.01 (t, J=7.0 Hz, 3H).
  • 13C NMR (300 MHz, DMSO-d6) δ 172.0, 143.8, 142.8, 134.5, 132.6, 128.2, 124.6, 80.2, 59.2, 50.7, 41.7, 39.3, 27.4, 25.7, 15.2.
  • FTIR (ReactIR, neat): 2971, 2933, 2838, 1721, 1474, 1461, 1385, 1366, 1343, 1275, 1256, 1146, 1121, 1036, 1009, 942, 847, 820, 752, 706 cm−1.
  • Elemental Analysis for C19H29NO2S:
  • Calculated: C, 68.02; H, 8.71; N, 4.17; S, 9.56
  • Found: C, 67.94,H, 8.93, N, 4.09, S, 9.54.
    • EXAMPLE 9 (R)-(+)-tert-Butyl 2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionate
  • Figure US20050240049A1-20051027-C00071
  • To a solution of tert-butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate (182 g, 0.544 mol) was added 4-(trifluoromethoxy)phenyl isocyanate (115 g, 0.556 mol) and the reaction temperature was maintained at about 15-20° C. After addition, the clear solution was stirred for 15 minutes at about 15-20° C. The solution was used for the next step directly.
  • An analytical sample was obtained as a white solid by simple concentration of a small amount of the crude solution.
  • mp 95.4-97.8° C.
  • Optical rotation: [a]20 D=+3.4 (c 1.0, MeOH).
  • MS (APCI): m/z 280.2(30% ), 306.2(100% ), 437.3(50% ), 483.1(20%).
  • 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.61 (d, J=9.2 Hz, 2H), 7.27 (m, 5H), 4.91 (p, J=8.2 Hz, 1H), 3.37 (q, J=6.8 Hz, 2H), 3.08 (m, 4H), 1.38 (s, 9H), 1.36 (s, 6H), 1.09 (t, J=6.8 Hz, 3H).
  • 13C NMR (300 MHz, DMSO-d6) δ 15.5, 26.1, 27.8, 36.6, 38.4, 51.2, 56.8, 80.7, 120.6 (q, J=225 Hz, OCF3), 121.4, 121.5, 124.9, 129.1, 132.8, 135.3, 140.2, 142.3, 143.0, 143.3, 154.9, 172.5,
  • FTIR (KBr): 3297, 2974, 2933, 1724, 1636, 1605, 1511, 1419, 1369, 1270, 1229, 1198, 1148, 1122, 845, 817, 756, 561 cm−1.
  • Elemntal Analysis for C27H33F3N2O4S:
  • Calculated: C, 60.21; H, 6.18; N, 5.20; F, 10.58; S, 5.95
  • Found: C, 59.87; H, 6.22; N, 5.08; F, 10.86; S, 5.94.
    • EXAMPLE 10 (R)-(+)-2-{2-[1-Ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionic acid
  • Figure US20050240049A1-20051027-C00072
  • To a solution of tert-butyl 2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionate (288 g, 0.534 mol) was added a solution of sulfuric acid (535 g, 5.34 mol) in isopropyl acetate (0.7 L) while maintaining the reaction temperature at about 15-20° C. The clear solution was stirred at 15° C. for 1 hour after the addition. To the reaction mixture was added cold water (0.94 L). After removal of the acidic aqueous layer, the isopropyl acetate layer was washed until the pH of the aqueous layer reached 3. The solution was used in the next step without isolation.
  • An analytical sample was obtained as a white foam by simple concentration of a small amount of the crude solution.
  • mp 57° C.
  • Optical rotation: [α]20 D=+7.7 (c 1.0, MeOH).
  • MS (APCI): m/z: 483.1(MH+).
  • 1H NMR (300 MHz, DMSO-d6) δ 12.43 (br s, 1H), 8.49 (s, 1H), 7.61 (d, J=9.5, 2H), 7.27 (m, 5H), 4.91 (p, J=8.4 Hz, 1H), 3.39 (m, 2H), 3.08 (m, 4H), 1.38 (s, 6H), 1.10 (t, J=6.9 Hz, 3H).
  • 13C NMR (300 MHz, DMSO-d6) δ 175.2, 154.9, 143.2, 143.0, 142.3, 140.2, 135.1, 132.6, 129.4, 125.0, 121.5, 121.3, 120.6 (q, J=255 Hz, OCF3), 56.8, 51.0, 38.4, 36.5, 26.0, 15.5.
  • FTIR (KBr): 3395, 2977, 2935, 1703, 1641, 1511, 1420, 1265, 1200, 1161, 1016, 841, 815, 755 cm−1.
  • Elemental Analysis for C23H25F3N2O4S:
  • Calculated: C, 57.25; H, 5.22; N, 5.81; F, 11.81; S, 6.65.
  • Found: C, 57.00; H, 5.47; N, 5.41; F, 11.75; S, 6.23.
    • EXAMPLE 11 (R)-(+)-2-{2-[1-Ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionic acid, N,N′-dibenzylethylenediamine salt
  • Figure US20050240049A1-20051027-C00073
    Seeds Preparation:
  • N,N′-Dibenzylethylenediamine (0.26 g, 1.08 mmol) was added to t-butyl methyl ether solution of 2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionic acid (0.52 g, 1.08 mmol). iPrOAc was added to the resulted cloudy solution. The solution was kept in the refrigerator overnight (˜20 hours). The solids precipitated were collected by filtration. 1H NMR analysis and the melting point measurement of the isolated solids confirmed the formation of the salt with 1:1 mole ratio of acid and N,N′-dibenzylethylenediamine.
  • Salt Preparation:
  • A solution of 2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionic acid (218.51 g, 0.453 mol) in isopropyl acetate (859 mL) was cooled to about −5 to 0° C. and N,N′-dibenzylethylenediamine (112 g, 0.453 mol) was added over 1 hour. The internal reaction temperature was maintained under 0° C. Heptane (513 mL) was added to the solution until the solution became cloudy. The seeds were added while stirring. The cloudy mixture changed to a uniform suspension within one hour. Additional heptane (60 mL) was then added. After stirred for 1 h, more heptane (180 mL) was added. The suspension was stirred overnight (18 hours) at 0° C.
  • The solid was filtered and rinsed with a chilled mixture of iPrOAc/heptane (½, 90 mL). The solid was air-dried at the ambient temperature overnight to yield a solid with 99.1% ee.
  • mp 99-102° C.
  • Optical rotation: [a]20 D═+7.7 (c 1.0, MeOH).
  • MS (APCI): m/z 483.8(MH+).
  • 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.63 (m, 2H), 7.28 (m, 15H), 6.99 (br s, 3H), 4.91 (p, J=8.5 Hz, 1H), 3.80 (s, 4H), 3.37 (q, J=6.9 Hz, 2H), 3.05 (d, J=7.6 Hz, 4H), 2.77 (s, 4H), 1.33 (s, 6H), 1.09 (t, J=6.9 Hz, 3H).
  • 13C NMR (300 MHz, DMSO-d6) δ 176.6, 154.9, 142.9, 142.1, 141.9, 140.3, 138.8, 134.7, 132.2, 131.3, 128.8, 128.5,127.4, 124.7, 121.4, 121.4, 120.2 (q, J=255 Hz, OCF3), 56.8, 52.9, 52.2, 46.7, 38.3, 36.5, 36.4, 27.3, 15.5.
  • FTIR (KBr): 3310(broad), 2972, 2849, 1638, 1606, 1539, 1510, 1458, 1418, 1389, 1351, 1264, 1244, 1199, 1162, 842, 816, 748, 698.81, 668 cm−1.
  • Elemental Analysis for C39H45F3N4O4S:
  • Calculated: C 64.80; H 6.27; N, 7.75; F 7.88; S, 4.44
  • Found: C, 64.65; H, 6.35; N, 7.61; F, 8.12, S, 4.51.
    • EXAMPLE 12 (S)-(+)-tert-Butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate, (S)-(−)-2-(4-hydroxyphenoxy)propionic acid salt
  • Figure US20050240049A1-20051027-C00074
  • Racemic tert-Butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate (0.30 mmol) and (S)-(−)-2-(4-hydroxyphenoxy)propionic acid (0.30 mmol) were mixed into THF (2 mL) and heated to 50° C. to a clear solution. The reaction mixture was then cooled to the ambient temperature and stirred overnight. White crystalline solid precipitated and determined to be the enriched diastereomeric salt (S)-(+)-tert-Butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate and (S)-(−)-2-(4-hydroxyphenoxy)propionic acid at 48% ee by chiral HPLC.
    • EXAMPLE 13 (S)-(+)-tert-Butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-prolionate. (S)-(−)-2-(4-hydroxyphenoxy)propionic acid salt
  • Figure US20050240049A1-20051027-C00075
  • Racemic tert-Butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate (17 g, 51 mmol) and (S)-(−)-2-(4-hydroxyphenoxy)propionic acid (4.6 g, 25 mmol) were dissolved in acetone (55 mL), each separately. The solutions were then mixed and stirred at the ambient temperature overnight. The resulting thick suspension was heated to 55° C. for 6 h, 40° C. for 18 h, then heated to 50° C. and filtered to yield a solid which was determined to be enriched with the diastereomeric salt (S)-(+)-tert-Butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate and (S)-(−)-2-(4-hydroxyphenoxy)propionic at 22% ee. The enriched salt was re-crystallized from acetone twice, to yield the title compound salt (S,S) salt in 94% ee.
  • 1H NMR for 94% ee sample (300 MHz, DMSO-d6) δ 7.26 (m, 3H), 6.62 (m, 4H), 4.35 (q, J=6.8 Hz, 1H), 3.14 (m, 2H), 3.74 (p, J=7.2 Hz, 1H), 2.87 (dd, J=6.7 Hz, 16.3 Hz, 2H), 2.76 (q, J=7.3 Hz, 2H), 1.36 (s, 9H), 1.35 (s, 6H), 1.34 (d, J=6.8 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H).
  • m.p. for 80% ee sample isolated after first recrystallization as described above: 157-159° C. (DSC)
    • EXAMPLE 14 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthale-2-ylsulfanyl}-2-methylpropionic acid
  • Figure US20050240049A1-20051027-C00076
    STEP A. 7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine
  • To a solution of 7-methoxy-2-tetralone (12.4 g; 70.7 mmol) dissolved in MeOH (350 mL) was added ammonium acetate (82 g; 1.06 mol) and the reaction was stirred for 30 min at room temperature. To the reaction was then added sodium cyanoborohydride (21.5 g; 353 mmol) and the reaction was refluxed for 1 h. Upon completion of the reaction, the reaction was cooled and the solvent removed under reduced pressure. The residue was diluted with EtOAc and 1 N NaOH was added to quench the reaction. The aqueous phase was separated and the organic phase washed with H2O, brine, dried over Na2SO4, filtered, and the solvent removed under reduced pressure to yield 7-methoxy-1,2,3,4-tetrahydronapthalen-2-ylamine as a dark oil.
  • MS, m/z: 178 (M+1) C11H15NO.
  • STEP B. N-(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide
  • To a stirred suspension of 7-methoxy-1,2,3,4-tetrahydronapthalen-2-ylamine (2.54 g; 14.3 mmol) in CH2Cl2 (20 mL) was added DIEA (3.4 mL) and the reaction mixture was cooled to 0° C. Acetyl chloride (1.22 mL; 17.1 mmol) was added dropwise at 0° C. and the reaction was allowed to warm to room temperature, then stirred for 18 h. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield a crude solid. Purification by flash chromatography (SiO2) eluting with hexanes-EtOAc yielded N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide as a white solid.
  • MS, m/z: 220 (M+1) C13H17NO2.
  • STEP C. 6-Acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride
  • To chlorosulfonic acid (15 mL), cooled to −10° C. was added N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (1.44 g; 6.6 mmol). The reaction mixture was stirred at −10° C. for 15 min and quenched carefully by pouring over ice-water. The aqueous phase was extracted with CH2Cl2 (3X), the organic extracts combined, dried over Na2SO4, filtered and evaporated under reduced pressure to yield 6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride as a white solid.
  • 1H NMR (300 MHz, CDCl3): δ 7.68 (s, 1H), 6.78 (s, 1H), 5.53-5.56 (m, 1H), 4.22-4.31 (m, 1H), 4.00 (s, 3H), 3.18-3.26 (dd, 1H), 2.86-2.90 (m, 2H), 2.67-2.76 (dd, 1H), 2.04-2.12 (m, 1H), 2.00 (s, 1H), 1.73-1.82 (m, 2H).
  • MS, m/z: 318 (M+1) C13H16ClNO4S.
  • STEP D. N-(6-Mercaito-7-methoxy-1,2,3,4-tetrahydronaphthalen-2yl)acetamide
  • To a suspension of zinc dust (1.16 g; 17.7 mmol) and dimethylsilyl dichloride (2.4 mL; 17.7 mmol) in MeCN (40 mL) was added a solution of 6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride (1.13 g; 3.55 mmol) in MeCN/DCE (40/10 mL), at room temperature. The reaction suspension was then heated at 81° C. for 4 h, cooled to room temperature, filtered and the solvent evaporated under reduced pressure. The crude residue was purified by reverse-phase semi-prep HPLC eluting with a MeCN—H2O gradient to yield N-(6-mercapto-7-methoxy-1,2,3,4-tetrahydronaphthalen-2 yl)acetamide as a white solid and N-[6-(6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2yldisulfanyl)-7-methoxy-1,2,3,4,-tetrahydronaphthalen-2-yl]acetamide as a tan solid.
  • MS, m/z: 252 (M+1; S—H) C13H17NO2S & 501 (M+1; S—S) C26H32N2O4S2.
  • STEP E. 2-(6-Acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester
  • To a suspension of N-[6-(6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2yl]disulfanyl)-7-methoxy-1,2,3,4,-tetrahydronaphthalen-2-yl]acetamide (0.368 g; 0.73 mmol) in MeOH (10 mL) was added DMF (3 mL), K2CO3 (0.31 g; 2.26 mmol), tert-butyl 2-bromoisobutyrate (0.66 mL; 2.95 mmol) and NaBH4 (0.28 g; 7.34 mmol) and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between EtOAc and H2O, the aqueous phase extracted with EtOAc, the organic extracts combined, washed with H2O, brine, dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield a crude oil, which was purified by reverse-phase semi-prep HPLC eluting with a MeCN—H2O. gradient to yield 2-(6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester as an oil.
  • MS, m/z: 338 (M+1) C21H31NO4S.
  • STEP F. 2-(6-Ethylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester
  • To a solution of 2-(6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester (0.68 g; 1.74 mmol) in THF (15 mL) was added a solution of 1.0 M borane-THF (15 mL), dropwise at room temperature. The reaction mixture was allowed to stir for 18 h at room temeperature, then carefully quenched with MeOH (10 mL) and the solvent evaporated under reduced pressure. The residual oil was further azeotroped with MeOH (3×) to yield a mixture of 2-(6-ethylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester and it's borane complex as an oil.
  • MS, m/z: 380 (M+1) C21H33NO3S.
  • STEP G. 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl-2-methylpropionic acid tert butyl ester
  • To a mixture of 2-(6-ethylamino-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester and borane complex (0.054 g; 0.141 mmol) dissolved in CH2Cl2 (2 mL) was added 4-trifluoromethoxyphenyl isocyanate (0.063 mL; 0.284 mmol) and the reaction mixture as stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the crude residue was purified by reverse-phase semi-prep HPLC eluting with a MeCN—H2O. gradient to yield 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert butyl ester as an oil.
  • MS, M/Z: 527 ((M-C4H8)+1) C29H37F3N2O5S.
  • STEP H. 2-{6-[1-Ethyl-3-(4-trifluoromethoxyohenyl)ureidol-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl]-2-methylpropionic acid
  • To 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert butyl ester (0.02 g; 0.03 mmol) dissolved in CH2Cl2 (1.5 mL) was added TFA (1.5 mL) and the reaction mixture was stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure and the residue was purified by reverse-phase semi-prep HPLC eluting with a MeCN—H2O. gradient to yield 2-{6-[1ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid as a white solid.
  • 1H NMR (300 MHz, CD3OD): δ 7.45-7.48 (d, 2H), 7.15-7.18 (m, 3H), 6.71 (s, 1H), 4.43-4.79 (m, 1H), 3.75 (s, 3H), 3.43-3.45 (m, 2H), 2.88-3.08 (m, 4H), 1.99-2.03 (m, 2H), 1.38 (s, 6H), 1.25-1.52 (t, 3H).
  • MS, m/z: 526 (M+1) C25H29F3N2O5S.
  • The following compounds were similarly prepared according to the 15 procedure described in Example 14 above with selection and substitution of suitable reagents and reaction conditions.
    • EXAMPLE 15 2-{6-[3-(4-tert-Butylphenyl)1-ethylureidol-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylprooionic acid
  • Figure US20050240049A1-20051027-C00077
  • Prepared as an oil by replacing 4-trifluoromethoxyphenyl isocyanate with 4-tert-butylphenyl isocyanate in Step G above.
  • MS, m/z: 499 (M+1) C28H38N2O4S.
    • EXAMPLE 16 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl]-2-methylpropionic acid
  • Figure US20050240049A1-20051027-C00078
  • Prepared as a white solid by substituting 7-methoxy-2-tetralone with 7-fluoro-2-tetralone in STEP A above.
  • 1H NMR (300 MHZ, CDCL3): δ 7.46-7.51 (M, 2H), 7.25-7.28 (D, 1H), 7.17-7.20 (D, 2H), 6.92-6.95 (D, 1H), 4.43 (M, 1H), 3.42-3.49 (M, 2H), 2.90-3.11 (M, 4H), 2.02-2.07 (M, 2H), 1.45 (S, 6H), 1.25-1.31 (T, 3H).
  • MS, m/z: 515 (M+1) C24H26F4N2O4S.
    • EXAMPLE 17 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-chloro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl-2-methylpropionic acid
  • Figure US20050240049A1-20051027-C00079
  • Prepared as a white solid by substituting 7-methoxy-2-tetralone with 7-chloro-2-tetralone in STEP A above.
  • MS, m/z: 532 (M+1) C24H26ClF3N2O4S.
    • EXAMPLE 18 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-bromo-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methyylropionic acid
  • Figure US20050240049A1-20051027-C00080
  • Prepared as a white solid by substituting 7-methoxy-2-tetralone with 7-bromo-2-tetralone in STEP A above.
  • 1H NMR (300 MHz, CDCl3): δ 7.45-7.48 (m, 3H), 7.36 (s, 1H), 7.15-7.18 (d, 2H), 4.41-4.79 (m, 1H), 3.40-3.47 (m, 2H), 2.90-3.07 (m, 4H), 2.01-2.03 (m, 2H), 1.45 (s, 6H), 1.24-1.29 (t, 3H).
  • MS, m/z: 576 (M+1) C24H26BrF3N2O4S.
    • EXAMPLE 19 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl-2-methylpropionic acid
  • Figure US20050240049A1-20051027-C00081
  • Prepared as a white solid by substituting 7-methoxy-2-tetralone with 7-methyl-2-tetralone in STEP A above.
  • 1H NMR (300 MHz, CDCl3): δ 7.45-7.48 (m, 2H), 7.22 (s, 1H), 7.15-7.18 (d, 2H), 7.02 (s,1H), 4.41-4.79 (m, 1H), 3.40-3.47 (m, 2H), 2.85-3.03 (m, 4H), 2.39 (s, 3H), 2.01-2.03 (m, 2H), 1.41 (s, 6H), 1.24-1.29 (t, 3H).
  • MS, m/z: 511 (M+1) C25H29F3N2O4S.
    • EXAMPLE 20 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-trifluoromethoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl]-2-methylpropionic acid
  • Figure US20050240049A1-20051027-C00082
  • Prepared as white solid by substituting 7-methoxy-2-tetralone with 7-methyl-2-tetralone in STEP A above.
  • 1H NMR (300 MHz, CDCl3): δ 7.45-7.48 (d, 2H), 7.37 (s, 1H), 7.12-7.18 (m, 3H), 4.44 (m, 1H), 3.43-3.48 (m, 2H), 2.97-3.21 (m, 4H), 2.03-2.05 (m, 2H), 1.42 (s, 6H), 1.25-1.30 (t, 3H).
  • MS, m/z: 580 (M+1) C25H26F6N2O5S.
    • EXAMPLE 21 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureidol-3-phenyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid
  • Figure US20050240049A1-20051027-C00083
    STEP A. 2-(6-Acetylamino-3-Phenyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylprolionic acid tert-butyl ester
  • To 2-(6-acetylamino-3-bromo-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert-butyl ester (0.135 g; 0.30 mmol) dissolved in toluene (1.5 mL) was added phenylboronic acid (0.178 g; 1.46 mmol), Pd(PPh3)4 (15 mg; 0.013 mmol) and 2M Na2CO3 (0.61 mL) and the reaction mixture heated at 95° C. for 18 h. The reaction mixture was cooled, diluted with EtOAc, washed with H2O. (2×), brine, dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield a crude residue which was purified by flash chromatography (SiO2) eluting with a heptane-EtOAc gradient (50→100% ) to yield 2-(6-acetylamino-3-phenyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methyl-propionic acid tert-butyl ester as a clear oil.
  • MS, M/Z: 383 ((M-C4H8)+1) C26H33NO3S
  • 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-phenyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid, the compound of Example 21 was additionally prepared, as a white solid, according to the procedure described in Example 14, by selecting and substituting suitable reagents in Steps F, G and H, as appropriate.
  • 1H NMR (300 MHz, CDCl3): δ 7.45-7.48 (d, 2H), 7.29-7.38 (m, 6H), 7.15-7.18 (d, 2H), 7.10 (s, 1H), 4.46 (m, 1H), 3.44-3.49 (m, 2H), 2.98-3.06 (m, 4H), 2.04-2.06 (m, 2H), 1.26-1.30 (t, 3H), 1.14 (s, 6H).
  • MS, M/Z: 573 (M+1) C25H29F3N2O5S
  • While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations.and/or modifications as come within the scope of the following claims and their equivalents.

Claims (52)

1. A process for the preparation of a compound of formula (L)
Figure US20050240049A1-20051027-C00084
wherein
Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic;
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4 is H or —(C1-5straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)—, (C1-3alkoxyacyl)(C1-6alkylene)—, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4 has no more than 9 carbon atoms;
alternatively, R4 is —(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
Figure US20050240049A1-20051027-C00085
reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to ClSO3H;
Figure US20050240049A1-20051027-C00086
reacting the compound of formula (IV) with a suitably substituted compound of formula (V) wherein R4a is R4 other than hydrogen and wherein J is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (VI); and then reacting the compound of formula (VI) with ClSO3H, to yield the corresponding compound of formula (VII);
alternatively, reacting the compound of formula (IV) with ClSO3H, to yield the corresponding compound of formula (VII) wherein R4 is hydrogen;
Figure US20050240049A1-20051027-C00087
reacting the compound of formula (VII) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX);
Figure US20050240049A1-20051027-C00088
reacting the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (XI);
alternatively, reacting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), with a reducing agent capable of reducing the disulfide on compound of formula (IX), to yield the corresponding compound of formula (VIII); and then reacting the compound of formula (VIII) with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (XI);
Figure US20050240049A1-20051027-C00089
reacting the compound of formula (XI), to yield the corresponding compound of formula (L).
2. A process for the preparation of a compound of formula (I)
Figure US20050240049A1-20051027-C00090
or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof,
wherein
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4 is H or —(C1-5straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)—, (C1-3alkoxyacyl)(C1-6alkylene)—, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4 has no more than 9 carbon atoms;
alternatively, R4 is —(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R5 and R7 is independently selected from H, C1-6alkyl, halo, cyano, nitro, COR11, COOR11, C1-14alkoxy, C1-14alkylthio, hydroxy, phenyl, NR11R12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R6 is selected from C1-6alkyl, halo, cyano, nitro, COR13, COOR13, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR13R14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R5 and R6 or R6 and R7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C3-4alkylene, C3-4alkenylene or (CH1-2)pN(CH1-2)q;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R11, R12, R13 and R14 is independently H or C1-6alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising the process of claim 1 and further comprising
Figure US20050240049A1-20051027-C00091
reacting the compound of formula (L), to yield the corresponding compound of formula (I).
3. A process for the preparation of a compound of formula (I)
Figure US20050240049A1-20051027-C00092
or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof,
wherein
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4 is H or —(C1-5straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)—, (C1-3alkoxyacyl)(C1-6alkylene)—, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4 has no more than 9 carbon atoms;
alternatively, R4 is —(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R5 and R7 is independently selected from H, C1-6alkyl, halo, cyano, nitro, COR11, COOR11, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR11R12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R6 is selected from C1-6alkyl, halo, cyano, nitro, COR13, COOR13, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR13R14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R5 and R6 or R6 and R7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C3-4alkylene, C3-4alkenylene or (CH1-2)pN(CH1-2)q;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R11, R12, R13 and R14 is independently H or C1-6alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
Figure US20050240049A1-20051027-C00093
reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to ClSO3H;
Figure US20050240049A1-20051027-C00094
reacting the compound of formula (IV) with a suitably substituted compound of formula (V) wherein R4a is R4 other than hydrogen and wherein J is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (VI); and then reacting the compound of formula (VI) with ClSO3H, to yield the corresponding compound of formula (VII);
alternatively, reacting the compound of formula (IV) with ClSO3H, to yield the corresponding compound of formula (VII) wherein R4 is hydrogen;
Figure US20050240049A1-20051027-C00095
reacting the compound of formula (VII) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX);
Figure US20050240049A1-20051027-C00096
reacting the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), with a suitably substituted compound of formula (X), wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic; and wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (XI);
alternatively, reacting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), with a reducing agent capable of reducing the disulfide on compound of formula (IX), to yield the corresponding compound of formula (VIII); and then reacting the compound of formula (VIII) with a suitably substituted compound of formula (X), wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic; and wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (XI);
Figure US20050240049A1-20051027-C00097
reacting the compound of formula (XI), to yield the corresponding compound of formula (L);
Figure US20050240049A1-20051027-C00098
reacting the compound of formula (L), to yield the corresponding compound of formula (I).
4. The process of claim 1 wherein Q is OPg2, Pg2 is t-butyl, X is S, R1 is methyl, R2 is methyl, the —X—C(R1R2)—C(O)-Q group is bound at the 5-position, R3 is hydrogen, n is 1 and R4 is ethyl
5. The process of claim 2 wherein X is S, R1 is methyl, R2 is methyl, the —X—C(R1R2)—C(O)—OH group is bound at the 5-position, R3 is hydrogen, n is 1, R4 is ethyl, c is 0, R5 is hydrogen, R6 is trifluoromethoxy and R7 is hydrogen.
6. The process of claim 3 wherein X is S, R1 is methyl, R2 is methyl, the —X—C(R1R2)—C(O)—OH group is bound at the 5-position, R3 is hydrogen, n is 1, R4 is ethyl, c is 0, R5 is hydrogen, R6 is trifluoromethoxy and R7 is hydrogen.
7. A process for the preparation of a compound of formula (L)
Figure US20050240049A1-20051027-C00099
wherein
Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic;
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
x is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4 is H or —(C1-5straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)—, (C1-3alkoxyacyl)(C1-6alkylene)—, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4 has no more than 9 carbon atoms;
alternatively, R4 is -(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
wherein each of the. above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
Figure US20050240049A1-20051027-C00100
reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to ClSO3H;
Figure US20050240049A1-20051027-C00101
reacting the compound of formula (IV) with a suitably substituted compound of formula (V) wherein R4a is R4 other than hydrogen and wherein J is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (VI); and then reacting the compound of formula (VI) with ClSO3H, to yield the corresponding compound of formula (VII);
alternatively, reacting the compound of formula (IV) with ClSO3H, to yield the corresponding compound of formula (VII) wherein R4 is hydrogen;
Figure US20050240049A1-20051027-C00102
reacting the compound of formula (VII) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX);
Figure US20050240049A1-20051027-C00103
de-protecting the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), to yield the corresponding compound of formula (XIII);
alternatively, de-protecting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), to yield a corresponding compound of formula (XII); and then reducing the compound of formula (XII) with a reducing agent capable of reducing the disulfide on compound of formula (XII), to yield the corresponding compound of formula (XIII);
alternatively still, reacting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), with a reducing agent capable of reducing the disulfide on compound of formula (IX), to yield the corresponding compound of formula (VIII); and then de-protecting the compound of formula (VIII), to yield the corresponding compound of formula (XIII);
Figure US20050240049A1-20051027-C00104
reacting the compound of (XIII) with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (L).
8. A process for the preparation of a compound of formula (I)
Figure US20050240049A1-20051027-C00105
or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof,
wherein
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4 is H or —(C1-5straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)—, (C1-3alkoxyacyl)(C1-6alkylene)-, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4 has no more than 9 carbon atoms;
alternatively, R4 is -(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R5 and R7 is independently selected from H, C1-6alkyl, halo, cyano, nitro, COR11, COOR11, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR11R12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;.
R6 is selected from C1-6alkyl, halo, cyano, nitro, COR13, COOR13, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR13R14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R5 and R6 or R6 and R7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C3-4alkylene, C3-4alkenylene or (CH1-2)pN(CH1-2)q;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R11, R12, R13 and R14 is independently H or C1-6alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising the process of claim 7 and further comprising
Figure US20050240049A1-20051027-C00106
reacting the compound of formula (L), to yield the corresponding compound of formula (I).
9. A process for the preparation of a compound of formula (I)
Figure US20050240049A1-20051027-C00107
or a pharmaceutically acceptable salt, C1-6 ester or C1-6amide thereof,
wherein
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4 is H or —(C1-5straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)—, (C1-3alkoxyacyl)(C1-6alkylene)-, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4 has no more than 9 carbon atoms;
alternatively, R4 is -(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R5 and R7 is independently selected from H, C1-6alkyl, halo, cyano, nitro, COR11, COOR11, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR11R12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R6 is selected from C1-6alkyl, halo, cyano, nitro, COR13, COOR13, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR13R14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S; alternatively, R5 and R6 or R6 and R7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C3-4alkylene, C3-4alkenylene or (CH1-2)pN(CH1-2)q;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R11, R12, R13 and R14 is independently H or C1-6alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
Figure US20050240049A1-20051027-C00108
reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to ClSO3H;
Figure US20050240049A1-20051027-C00109
reacting the compound of formula (IV) with a suitably substituted compound of formula (V) wherein R4a is R4 other than hydrogen and wherein J is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (VI); and then reacting the compound of formula (VI) with ClSO3H, to yield the corresponding compound of formula (VII);
alternatively, reacting the compound of formula (IV) with ClSO3H, to yield the corresponding compound of formula (VII) wherein R4 is hydrogen;
Figure US20050240049A1-20051027-C00110
reacting the compound of formula (VII) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX);
Figure US20050240049A1-20051027-C00111
de-protecting the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), to yield the corresponding compound of formula (XIII);
alternatively, de-protecting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), to yield a corresponding compound of formula (XII); and then reducing the compound of formula (XII) with a reducing agent capable of reducing the disulfide on compound of formula (XII), to yield the corresponding compound of formula (XIII);
alternatively still, reacting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), with a reducing agent capable of reducing the disulfide on compound of formula (IX), to yield the corresponding compound of formula (VIII); and then de-protecting the compound of formula (VIII), to yield the corresponding compound of formula (XIII);
Figure US20050240049A1-20051027-C00112
reacting the compound of (XIII) with a suitably substituted compound of formula (X), wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic; and wherein W is Br, Cl or I; in the presence of a base, to yield the corresponding compound of formula (L);
Figure US20050240049A1-20051027-C00113
reacting the compound of formula (L), to yield the corresponding compound of formula (I).
10. The process of claim 7 wherein Q is OPg2, Pg2 is t-butyl, X is S, R1 is methyl, R2 is methyl, the —X—C(R1R2)—C(O)-Q group is bound at the 5-position, R3 is hydrogen, n is 1 and R4 is ethyl
11. The process of claim 8 wherein X is S, R1 is methyl, R2 is methyl, the —X—C(R1R2)—C(O)—OH group is bound at the 5-position, R3 is hydrogen, n is 1, R4 is ethyl, c is 0, R5 is hydrogen, R6 is trifluoromethoxy and R7 is hydrogen.
12. The process of claim 9 wherein X is S, R1 is methyl, R2 is methyl, the-X—C(R1R2)—C(O)—OH group is bound at the 5-position, R3 is hydrogen, n is 1, R4 is ethyl, c is 0, R5 is hydrogen, R6 is trifluoromethoxy and R7 is hydrogen.
13. A process for the preparation of a compound of formula (L)
Figure US20050240049A1-20051027-C00114
wherein
Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or and aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic;
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4 is —(C1-5straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)-, (C1-3alkoxyacyl)(C1-6alkylene)-, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4 has no more than 9 carbon atoms;
alternatively, R4 is -(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
Figure US20050240049A1-20051027-C00115
reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to ClSO3H;
Figure US20050240049A1-20051027-C00116
reacting the compound of formula (IV) with ClSO3H, to yield the corresponding compound of formula (VIIa);
Figure US20050240049A1-20051027-C00117
reacting the compound of formula (VIIa) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VIIa), to yield a mixture of the corresponding compound of formula (VIIIa) and the corresponding compound of formula (IXa);
Figure US20050240049A1-20051027-C00118
de-protecting the compound of formula (VIIIa), isolated or in a mixture with the compound of formula (IXa), to yield the corresponding compound of formula (XIIIa); and then reacting the compound of formula (XIIIa) with a suitably substituted compound of formula (X), wherein W is Cl, Br or I, in the presence of a base, to yield the corresponding compound of formula (La);
alternatively, reacting the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), with a reducing agent capable of reducing the disulfide on the compound of formula (IXa), to yield the corresponding compound of formula (VIIIa); then reacting the compound of formula (VIIIa) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (XIa); and then reacting the compound of formula (XIa), to yield the corresponding compound of formula (La);
alternatively still, de-protecting the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), to yield the corresponding compound of formula (XIIa); then reacting the compound of formula (XIIa) with a reducing agent capable of reducing the disulfide on the compound of formula (XIIa), to yield the corresponding compound of formula (XIa); and then reacting the compound of formula (XIIIa) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (La);
Figure US20050240049A1-20051027-C00119
reacting the compound of formula (La) with a suitably substituted compound of formula (V) wherein R4a is R4 other than hydrogen and wherein J is Br, Cl or I, to yield the corresponding compound of formula (Lb);
alternatively, reacting the compound of formula (La) with a suitably substituted acylating agent capable of attaching an —C(O)—R4b group onto the nitrogen of the compound of formula (La), wherein R4b is selected from (C1-4 straight chain alkylene)R15 or (straight chain C1-4alkylene)R16, in the presence of a base, to yield the corresponding compound of formula (XVIII); and then reacting the compound of formula (XVIII) with a reducing agent capable of reducing the amide on the compound of formula (XVIII), to yield the corresponding compound of formula (Lb).
14. A process for the preparation of a compound of formula (I)
Figure US20050240049A1-20051027-C00120
or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof,
wherein
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4 is H or —(C1-5straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)-, (C1-3alkoxyacyl)(C1-6alkylene)-, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4 has no more than 9 carbon atoms;
alternatively, R4 is -(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R5 and R7 is independently selected from H, C1-6alkyl, halo, cyano, nitro, COR11, COOR11, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR11R12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R6 is selected from C1-6alkyl, halo, cyano, nitro, COR13, COOR13, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR13R14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R5 and R6 or R6 and R7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C3-4alkylene, C3-4alkenylene or (CH1-2)pN(CH1-2)q;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R11, R12, R13 and R14 is independently H or C1-6alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising the process of claim 13 and further comprising
Figure US20050240049A1-20051027-C00121
reacting the compound of formula (L), to yield the corresponding compound of formula (I).
15. A process for the preparation of a compound of formula (I)
Figure US20050240049A1-20051027-C00122
or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof,
wherein
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4 is H or —(C1-5straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)-, (C1-3alkoxyacyl)(C1-6alkylene)-, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4 has no more than 9 carbon atoms;
alternatively, R4 is -(straight chain C1-5alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R5 and R7 is independently selected from H, C1-6alkyl, halo, cyano, nitro, COR11, COOR11, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR11R12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R6 is selected from C1-6alkyl, halo, cyano, nitro, COR13, COOR13, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR13R14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R5 and R6 or R6 and R7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C3-4alkylene, C3-4alkenylene or (CH1-2)pN(CH1-2)q;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R11, R12, R13 and R14 is independently H or C1-6alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
Figure US20050240049A1-20051027-C00123
reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to ClSO3H;
Figure US20050240049A1-20051027-C00124
reacting the compound of formula (IV) with ClSO3H, to yield the corresponding compound of formula (VIIa);
Figure US20050240049A1-20051027-C00125
reacting the compound of formula (VIIa) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VIIa), to yield a mixture of the corresponding compound of formula (VIIIa) and the corresponding compound of formula (IXa);
Figure US20050240049A1-20051027-C00126
de-protecting the compound of formula (VIIIa), isolated or in a mixture with the compound of formula (IXa), to yield the corresponding compound of formula (XIIIa); and then reacting the compound of formula (XIIIa) with a suitably substituted compound of formula (X), wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic; and wherein W is Br, Cl or I; in the presence of a base, to yield the corresponding compound of formula (La);
alternatively, reacting the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), with a reducing agent capable of reducing the disulfide on the compound of formula (IXa), to yield the corresponding compound of formula (VIIIa); then reacting the compound of formula (VIIIa) with a suitably substituted compound of formula (X) wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8Cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic; and wherein W is Br, Cl or I; in the presence of a base, to yield the corresponding compound of formula (XIa); and then reacting the compound of formula (XIa), to yield the corresponding compound of formula (La);
alternatively still, de-protecting the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), to yield the corresponding compound of formula (XIIa); then reacting the compound of formula (XIIa) with a reducing agent capable of reducing the disulfide on the compound of formula (XIIa), to yield the corresponding compound of formula (XIIIa); and then reacting the compound of formula (XIIIa) with a suitably substituted compound of formula (X), wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic; and wherein W is Br, Cl or I; in the presence of a base, to yield the corresponding compound of formula (La);
Figure US20050240049A1-20051027-C00127
reacting the compound of formula (La) with a suitably substituted compound of formula (V), wherein R4a is R4 other than hydrogen and wherein J is Br, Cl or I, to yield the corresponding compound of formula (Lb);
alternatively, reacting the compound of formula (La) with a suitably substituted acylating agent capable of attaching an —C(O)—R4b group onto the nitrogen of the compound of formula (La), wherein R4b is selected from (C1-4 straight chain alkylene)R15 or (straight chain C1-4alkylene)R16, in the presence of a base, to yield the corresponding compound of formula (XVIII); and then reacting the compound of formula (XVIII) with a reducing agent capable of reducing the amide on the compound of formula (XVIII), to yield the corresponding compound of formula (Lb);
Figure US20050240049A1-20051027-C00128
reacting the compound of formula (La) or the compound of formula (Lb), to yield the corresponding compound of formula (I).
16. The process of claim 13 wherein Q is OPg2, Pg2 is t-butyl, X is S, R1 is methyl, R2 is methyl, the —X—C(R1R2)—C(O)-Q group is bound at the 5-position, R3 is hydrogen, n is 1 and R4 is ethyl.
17. The process of claim 14 wherein X is S, R1 is methyl, R2 is methyl, the —X—C(R1R2)—C(O)—OH group is bound at the 5-position, R3 is hydrogen, n is 1, R4 is ethyl, c is 0, R5 is hydrogen, R6 is trifluoromethoxy and R7 is hydrogen.
18. The process of claim 15 wherein X is S, R1 is methyl, R2 is methyl, the —X—C(R1R2)—C(O)—OH group is bound at the 5-position, R3 is hydrogen, n is 1, R4 is ethyl, c is 0, R5 is hydrogen, R6 is trifluoromethoxy and R7 is hydrogen.
19. A process for the preparation of a compound of formula (Lc)
Figure US20050240049A1-20051027-C00129
wherein
Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic;
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4b is —(C1-4straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)-, (C1-3alkoxyacyl)(C1-6alkylene)-, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4b has no more than 8 carbon atoms;
alternatively, R4b is -(straight chain C1-4alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
Figure US20050240049A1-20051027-C00130
reacting a suitably substituted compound of formula (III) with a suitably substituted acylating agent capable of attaching an —C(O)—R4b group onto the nitrogen of the compound of formula (III), in the presence of a base, to yield the corresponding compound of formula (XIV);
Figure US20050240049A1-20051027-C00131
reacting the compound of formula (XIV) with ClSO3H, to yield the corresponding compound of formula (XV);
Figure US20050240049A1-20051027-C00132
reacting the compound of formula (XV) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (XV), to yield a mixture of the corresponding compound of formula (XVI) and the corresponding compound of formula (XVII);
Figure US20050240049A1-20051027-C00133
reacting the compound of formula (XVI), isolated or in a mixture with the compound of formula (XVII), with a reducing agent capable of reducing the amide on the compound of formula (XVI), to yield the corresponding compound of formula (XIIIb);
alternatively, reacting the compound of formula (XVII), isolated or in a mixture with the compound of formula (XVI), with a reducing agent capable of reducing the amide and the disulfide on the compound of formula (XVII), to yield the corresponding compound of formula (XIIIb);
Figure US20050240049A1-20051027-C00134
reacting the compound of formula (XIIIb) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (Lc).
20. A process for the preparation of a compound of formula (Ic)
Figure US20050240049A1-20051027-C00135
or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof,
wherein
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4b is —(C1-4straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)-, (C1-3alkoxyacyl)(C1-6alkylene)-, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4b has no more than 8 carbon atoms;
alternatively, R4b is -(straight chain C1-4alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R5 and R7 is independently selected from H, C1-6alkyl, halo, cyano, nitro, COR11, COOR11, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR11R1-2 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R6 is selected from C1-6alkyl, halo, cyano, nitro, COR13, COOR13, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR13R14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R5 and R6 or R6 and R7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C3-4alkylene, C3-4alkenylene or (CH1-2)pN(CH1-2)q;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R11, R12, R13 and R14 is independently H or C1-6alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising the process of claim 19 and further comprising
Figure US20050240049A1-20051027-C00136
reacting the compound of formula (Lc), to yield the corresponding compound of formula (Ic).
21. A process for the preparation of a compound of formula (I)
Figure US20050240049A1-20051027-C00137
or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof,
wherein
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4b is —(C1-4straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)-, (C1-3alkoxyacyl)(C1-6alkylene)-, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4b has no more than 8 carbon atoms;
alternatively, R4b is -(straight chain C1-4alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R5 and R7 is independently selected from H, C1-6alkyl, halo, cyano, nitro, COR11, COOR11, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR11R12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R6 is selected from C1-6alkyl, halo, cyano, nitro, COR13, COOR13, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR13R14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R5 and R6 or R6 and R7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C3-4alkylene, C3-4alkenylene or (CH1-2)pN(CH1-2)q;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R11, R12, R13 and R14 is independently H or C1-6alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
Figure US20050240049A1-20051027-C00138
reacting a suitably substituted compound of formula (III) with a suitably substituted acylating agent capable of attaching an —C(O)—R4b group onto the nitrogen of the compound of formula (III), in the presence of a base, to yield the corresponding compound of formula (XIV);
Figure US20050240049A1-20051027-C00139
reacting the compound of formula (XIV) with ClSO3H, to yield the corresponding compound of formula (XV);
Figure US20050240049A1-20051027-C00140
reacting the compound of formula (XV) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (XV), to yield a mixture of the corresponding compound of formula (XVI) and the corresponding compound of formula (XVII);
Figure US20050240049A1-20051027-C00141
reacting the compound of formula (XVI), isolated or in a mixture with the compound of formula (XVII), with a reducing agent capable of reducing the amide on the compound of formula (XVI), to yield the corresponding compound of formula (XIIIb);
alternatively, reacting the compound of formula (XVII), isolated or in a mixture with the compound of formula (XVI), with a reducing agent capable of reducing the amide and the disulfide on the compound of formula (XVII), to yield the corresponding compound of formula (XIIIb);
Figure US20050240049A1-20051027-C00142
reacting the compound of formula (XIIIb) with a suitably substituted compound of formula (X) wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3loheteroaryl or C3-10non-aromatic heterocyclic; and W is Br, Cl or I; in the presence of a base, to yield the corresponding compound of formula (Lc);
Figure US20050240049A1-20051027-C00143
reacting the compound of formula (Lc), to yield the corresponding compound of formula (Ic).
22. The process of claim 19 wherein Q is Opg2, Pg2 is t-butyl, X is S, R1 is methyl, R2 is methyl, wherein the —X—C(R1R2)—C(O)Q group is bound at the 5-position, R3 is hydrogen, n is 1 and R4 is ethyl
23. The process of claim 20 wherein X is S, R1 is methyl, R2 is methyl, the-X—C(R1R2)—C(O)—OH group is bound at the 5-position, R3 is hydrogen, n is 1, R4 is ethyl, c is 0, R5 is hydrogen, R6 is trifluoromethoxy and R7 is hydrogen.
24. The process of claim 21 wherein X is S, R1 is methyl, R2 is methyl, the-X—C(R1R2)—C(O)—OH group is bound at the 5-position, R3 is hydrogen, n is 1, R4 is ethyl, c is 0, R5 is hydrogen, R6 is trifluoromethoxy and R7 is hydrogen.
25. A process for the preparation of a compound of formula (Lc)
Figure US20050240049A1-20051027-C00144
wherein
Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic;
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4b is —(C1-4straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)-, (C1-3alkoxyacyl)(C1-6alkylene)-, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4b has no more than 8 carbon atoms;
alternatively, R4b is -(straight chain C1-4alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
Figure US20050240049A1-20051027-C00145
reacting a suitably substituted compound of formula (III) with a suitably substituted acylating agent capable of attaching an —C(O)—R4b group onto the nitrogen of the compound of formula (III), in the presence of a base, to yield the corresponding compound of formula (XIV);
Figure US20050240049A1-20051027-C00146
reacting the compound of formula (XIV) with ClSO3H, to yield the corresponding compound of formula (XV);
Figure US20050240049A1-20051027-C00147
reacting the compound of formula (XV) with a reducing agent capable of reducing the chlorosulfonyl group and the amide group on the compound of formula (XV), to yield the corresponding compound of formula (XIIIb);
Figure US20050240049A1-20051027-C00148
reacting the compound of formula (XIIIb) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (Lc).
26. A process for the preparation of a compound of formula (Ic)
Figure US20050240049A1-20051027-C00149
or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof,
wherein
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4b is —(C1-4straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)-, (C1-3alkoxyacyl)(C1-6alkylene)-, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4b has no more than 8 carbon atoms;
alternatively, R4b is -(straight chain C1-4alkylene)R16; wherein R16 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R5and R7 is independently selected from H, C1-6alkyl, halo, cyano, nitro, COR11, COOR11, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR11R12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R6 is selected from C1-6alkyl, halo, cyano, nitro, COR13, COOR13, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR13R14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R5 and R6 or R6 and R7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C3-4alkylene, C3-4alkenylene or (CH1-2)pN(CH1-2)q;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R11, R12, R13 and R14 is independently H or C1-6alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising the process of claim 25 and further comprising
Figure US20050240049A1-20051027-C00150
reacting the compound of formula (Lc), to yield the corresponding compound of formula (Ic).
27. A process for the preparation of a compound of formula (I)
Figure US20050240049A1-20051027-C00151
or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof, wherein
each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8;
wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl; and m is an integer from 1 to 6;
alternatively, R1 and R2 are taken together with the carbon atom to which theyare attached to form a C3-7cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;
R3 is H, C1-3alkoxy, C1-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3;
each R9 and R10 is independently C1-6alkyl;
R4b is —(C1-4straight chain alkylene)R15; wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene)-, (C1-3alkoxyacyl)(C1-6alkylene)-, C1-6alkoxy, C3-7alkenyl or C3-8alkynyl;
wherein R4b has no more than 8 carbon atoms;
alternatively, R4b is -(straight chain C1-4alkylene)R16; wherein R1-6 is C3-6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R5 and R7 is independently selected from H, C1-6alkyl, halo, cyano, nitro, COR11, COOR11, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR11R12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R6 is selected from C1-6alkyl, halo, cyano, nitro, COR13, COOR13, C1-4alkoxy, C1-4alkylthio, hydroxy, phenyl, NR13R14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R5 and R6 or R6 and R7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C3-4alkylene, C3-4alkenylene or (CH1-2)pN(CH1-2)q;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R11, R12, R13 and R14 is independently H or C1-6alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
Figure US20050240049A1-20051027-C00152
reacting a suitably substituted compound of formula (III) with a suitably substituted acylating agent capable of attaching an —C(O)—R4b group onto the nitrogen of the compound of formula (III), in the presence of a base, to yield the corresponding compound of formula (XIV);
Figure US20050240049A1-20051027-C00153
reacting the compound of formula (XIV) with ClSO3H, to yield the corresponding compound of formula (XV);
Figure US20050240049A1-20051027-C00154
reacting the compound of formula (XV) with a reducing agent capable of reducing the chlorosulfonyl group and the amide group on the compound of formula (XV), to yield the corresponding compound of formula (XIIIb);
Figure US20050240049A1-20051027-C00155
reacting the compound of formula (XIIIb) with a suitably substituted compound of formula (X) wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-10heteroaryl or C3-10non-aromatic heterocyclic; and W is Br, Cl or I; in the presence of a base, to yield the corresponding compound of formula (Lc);
Figure US20050240049A1-20051027-C00156
reacting the compound of formula (Lc), to yield the corresponding compound of formula (Ic).
28. The process of claim 25 wherein Q is OPg2, Pg2 is t-butyl, X is S, R1 is methyl, R2 is methyl, wherein the —X—C(R1R2)—C(O)Q group is bound at the 5-position, R3 is hydrogen, n is 1 and R4 is ethyl
29. The process of claim 26 wherein X is S, R1 is methyl, R2 is methyl, the-X—C(R1R2)—C(O)—OH group is bound at the 5-position, R3 is hydrogen, n is 1, R4 is ethyl, c is 0, R5 is hydrogen, R6 is trifluoromethoxy and R7 is hydrogen.
30. The process of claim 27 wherein X is S, R1 is methyl, R2 is methyl, the-X—C(R1R2)—C(O)—OH group is bound at the 5-position, R3 is hydrogen, n is 1, R4 is ethyl, c is 0, R5 is hydrogen, R6 is trifluoromethoxy and R7 is hydrogen.
31. A process for the preparation of a compound of formula (Le)
Figure US20050240049A1-20051027-C00157
wherein Qb is selected from the group consisting of C1-6alkoxy, wherein the C1-6alkoxy is not substituted with amino; comprising
Figure US20050240049A1-20051027-C00158
(a) reacting a compound of formula (Ld) with (S)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, at a temperature in the range of from about 35° C. to about 0° C.; to yield the corresponding (R,S) diastereomeric salt, the compound of formula (XX);
Figure US20050240049A1-20051027-C00159
(b) reacting the (R,S) diastereomeric salt, the compound of formula (XX), with an inorganic base, to yield the corresponding compound of formula (Le).
32. The process of claim 31 wherein Qb is t-butoxy.
33. A process for the preparation of a compound of formula (Le)
Figure US20050240049A1-20051027-C00160
wherein Qb is selected from the group consisting of C1-6alkoxy, wherein the C1-6alkoxy is not substituted with amino; comprising
Figure US20050240049A1-20051027-C00161
(a) reacting a compound of formula (Ld) with (R)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35° C.; or in THF at about room temperature; to yield the corresponding (R,R) diastereomeric salt, the compound of formula (XXI);
Figure US20050240049A1-20051027-C00162
(b) reacting the (R,R) diastereomeric salt, the compound of formula (XXI) with an inorganic base, to yield the corresponding compound of formula (Le).
34. The process of claim 33 wherein Qb is t-butoxy.
35. A process for the preparation of the compound of formula (Lf)
Figure US20050240049A1-20051027-C00163
wherein Qb is selected from the group consisting of C1-6alkoxy, wherein the C1-6alkoxy is not substituted with amino; comprising
Figure US20050240049A1-20051027-C00164
(a) reacting a compound of formula (Ld) with (S)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35° C.; or in THF at about room temperature; to yield the corresponding (S,S) diastereomeric salt, the compound of formula (XXII);
Figure US20050240049A1-20051027-C00165
(b) reacting the (S,S) diastereomeric salt, the compound of formula (XXI) with an inorganic base, to yield the corresponding compound of formula (Lf).
36. A process for the preparation of the compound of formula (Lf)
Figure US20050240049A1-20051027-C00166
wherein Qb is selected from the group consisting of C1-6alkoxy, wherein the C1-6alkoxy is not substituted with amino; comprising
Figure US20050240049A1-20051027-C00167
(a) reacting a compound of formula (Ld) with (R)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, at a temperature
in the range of from about 35° C. to about 0° C.; to yield the corresponding (S,R) diastereomeric salt, the compound of formula (XXIII);
Figure US20050240049A1-20051027-C00168
(b) reacting the (S,R) diastereomeric salt, the compound of formula (XXIII) with an inorganic base, to yield the corresponding compound of formula (Lf).
37. A crystalline N,N′-dibenzylethylenediamine salt of a compound of formula (IIa)
Figure US20050240049A1-20051027-C00169
38. The crystalline salt as in claim 37 wherein the ratio of the compound of formula (IIa) to the N,N′-dibenzylethylenediamine is 1:1.
39. A crystalline N,N′-dibenzylethylenediamine salt of a compound of formula (IIa)
Figure US20050240049A1-20051027-C00170
comprising the following X-ray diffraction peaks:
Position [°2θ] d-spacing [Å] Relative Intensity [%] 6.3894 13.8336 17.39 8.0423 10.9938 13.38 12.157 7.2803 19.22 16.012 5.5354 15.74 17.929 4.9475 20.77 18.048 4.9151 14.20 19.038 4.6618 100.00 19.2656 4.6072 26.28 20.325 4.3694 10.65 21.943 4.0508 16.85 22.190 4.0063 18.63 22.330 3.9815 12.37
40. A process for the preparation of a N,N′-dibenzylethylenediamine salt of a compound of formula (IIa)
Figure US20050240049A1-20051027-C00171
41. The process of claim 40 wherein the aprotic solvent is isopropyl alcohol.
42. The process of claim 41 wherein the compound of formula (IIa) is reacted with N,N′-dibenzylethylenediaine at a temperature less than about 5° C.
43. A compound of formula (IIa) comprising the structure:
Figure US20050240049A1-20051027-C00172
or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof.
44. The compound of claim 43 wherein said compound has an enantiomeric excess of at least about 90% .
45. The compound of claim 43 wherein said compound has an enantiomeric excess of at least about 96% .
46. The compound of claim 43 wherein said compound has an enantiomeric excess of at least about 99% .
47. A compound comprising the structure:
Figure US20050240049A1-20051027-C00173
48. The comnpound of claim 47 wherein said compound has an enantiomeric excess of at least about 90% .
49. The compound of claim 47 wherein said compound has an enantiomeric excess of at least about 96% .
50. The compound of claim 47 wherein said compound has an enantiomeric excess of at least about 99% .
51. A pharmaceutical composition comprising the compound of claim 43.
52. A pharmaceutical composition comprising the compound of claim 47.
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