EP2155687A1 - Inhibiteurs de diacylglycérol acyltransférase - Google Patents

Inhibiteurs de diacylglycérol acyltransférase

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Publication number
EP2155687A1
EP2155687A1 EP08759547A EP08759547A EP2155687A1 EP 2155687 A1 EP2155687 A1 EP 2155687A1 EP 08759547 A EP08759547 A EP 08759547A EP 08759547 A EP08759547 A EP 08759547A EP 2155687 A1 EP2155687 A1 EP 2155687A1
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EP
European Patent Office
Prior art keywords
phenyl
carbonyl
trifluoromethyl
amino
oxazole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08759547A
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German (de)
English (en)
Inventor
David Robert Bolin
Adrian Wai-Hing Cheung
Fariborz Firooznia
Matthew Michael Hamilton
Lee Apostle Mcdermott
Yimin Qian
Jenny Tan
Weiya Yun
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VIA Pharmaceuticals Inc
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VIA Pharmaceuticals Inc
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Publication date
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Publication of EP2155687A1 publication Critical patent/EP2155687A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to inhibitors of diacylglycerol acyltransferase.
  • the inhibitors are useful for the treatment of diseases such as obesity, type II diabetes mellitus, dyslipidemia and metabolic syndrome.
  • Triglycerides or triacylglycerols are the major form of energy storage in eukaryotic organisms. In mammals, these compounds are primarily synthesized in three tissues: the small intestine, liver, and adipocytes. Triglycerides or triacylglycerols support the major functions of dietary fat absorption, packaging of newly synthesized fatty acids and storage in fat tissue (see Subauste and Burant, Current Drug Targets - Immune, Endocrine & Metabolic Disorders (2003) 3, 263-270).
  • Diacylglycerol O-acyltransferase also known as diglyceride acyltransferase or DGAT
  • DGAT is a key enzyme in triglyceride synthesis.
  • DGAT catalyzes the final and rate-limiting step in triacylglycerol synthesis from 1,2-diacylglycerol (DAG) and long chain fatty acyl CoA as substrates.
  • DAG 1,2-diacylglycerol
  • DGAT plays an essential role in the metabolism of cellular diacylglycerol and is critically important for triglyceride production and energy storage homeostasis (see Mayorek et al, European Journal of Biochemistry (1989) 182, 395-400).
  • DGAT has a specificity for sn-1,2 diacylglycerols and will accept a wide variety of fatty acyl chain lengths (see Farese et al, Current Opinions in Lipidology (2000) 11, 229-234). DGAT activity levels increase in fat cells as they differentiate in vitro and recent evidence suggests that DGAT may be regulated in adipose tissue post-transcriptionally (see Coleman et al, Journal of Molecular Biology (1978) 253, 7256-7261 and Yu et al, Journal of Molecular Biology (2002) 277, 50876-50884).
  • DGAT activity is primarily expressed in the endoplasmic reticulum (see Colman, Methods in Enzymology (1992) 209, 98-104). In hepatocytes, DGAT activity has been shown to be expressed on both the cytosolic and luminal surfaces of the endoplasmic reticular membrane (see Owen et al, Biochemical Journal (1997) 323 (pt 1), 17-21 and Waterman et al, Journal of Lipid Research (2002) 43, 1555-156).
  • DGATl Two forms of DGAT have been cloned and are designated DGATl and DGAT2 (see Cases et al, Proceedings of the National Academy of Science, USA (1998) 95, 13018-
  • mice Although unable to express a functional DGAT enzyme (Dgat-/- mice), are viable and continue to synthesize triglycerides (see Smith et al, Nature Genetics (2000) 25, 87- 90). This would suggest that multiple catalytic mechanisms contribute to triglyceride synthesis, such as DGAT2.
  • An alternative pathway has also been shown to form triglycerides from two diacylglycerols by the action of diacylglycerol transacylase (see Lehner and Kuksis, Progress in Lipid Research (1996) 35, 169-210).
  • Dgat-/- mice are resistant to diet-induced obesity and remain lean. When fed a high fat diet, Dgat-/- mice maintain weights comparable to mice fed a diet with regular fat content. Dgat-/- mice have lower tissue triglyceride levels. The resistance to weight gain seen in the knockout mice, which have a slightly higher food intake, is due to an increased energy expenditure and increased sensitivity to insulin and leptin (see Smith et al, Nature Genetics (2000) 25, 87-90, Chen and Farese, Trends in Cardiovascular Medicine (2000) 10, 188-192, Chen and Farese, Current Opinions in Clinical Nutrition and Metabolic Care (2002) 5, 359-363 and Chen et al, Journal of Clinical Investigation (2002) 109, 1049-1055).
  • Dgat-/- mice have reduced rates of triglyceride absorption, improved triglyceride metabolism, and improved glucose metabolism, with lower glucose and insulin levels following a glucose load, in comparison to wild-type mice (see Buhman et al, Journal of Biological Chemistry (2002) 277, 25474-25479 and Chen and Farese, Trends in Cardiovascular Medicine (2000) 10, 188-192).
  • Known inhibitors of DGAT include: dibenzoxazepinones (see Ramharack, et al, EP 1219716 and Burrows et al, 26 th National Medicinal Chemistry Symposium (1998) poster C-22), substituted amino-pyrimidino-oxazines (see Fox et al, WO2004047755), chalcones such as xanthohumol (see Tabata et al, Phyto chemistry (1997) 46, 683-687 and Casaschi et al, Journal of Nutrition (2004) 134, 1340-1346), substituted benzyl- phosphonates (see Kurogi et al, Journal of Medicinal Chemistry (1996) 39, 1433-1437, Goto, et al, Chemistry and Pharmaceutical Bulletin (1996) 44, 547-551, Ikeda, et al, Thirteenth International Symposium on Athersclerosis (2003), abstract 2P-0401, and Miyata, et al, JP 2004067635), aryl alky
  • Also known to be inhibitors of DGAT are: 2-bromo-palmitic acid (see Colman et al, Biochimica et Biophysica Acta (1992) 1125, 203-9), 2-bromo-octanoic acid (see Mayorek and Bar-Tana, Journal of Biological Chemistry (1985) 260, 6528-6532), roselipins (see Noriko et al, (Journal of Antibiotics (1999) 52, 815-826), amidepsin (see Tomoda et al, Journal of Antibiotics (1995) 48, 942-7), isochromophilone, prenylflavonoids (see Chung et al, Planta Medica (2004) 70, 258-260), polyacetylenes - A -
  • the present invention relates to DGAT inhibitors.
  • the invention provides compounds of the formula (I):
  • Ri is tert-butyl; phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; or
  • 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and R 2 is C or N; R 3 is C, N, O or S;
  • R 6 is halogen, lower alkyl, haloloweralkyl or alkoxy;
  • R 7 is N optionally substituted with lower alkyl; O; or absent;
  • Rs is C optionally substituted with lower alkyl;
  • R 9 is lower alkyl; alkoxy; hydroxyl; amine; lower alkyl amine; haloloweralkyl; lower alkoxy; lower alkenyloxy; cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, -C(O)OH, -C(O)O-lower alkyl and -C(O)O-lower alkyl-phenyl;
  • 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen,
  • 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, -C(O)OH, -C(O)O-lower alkyl and -C(O)O-lower alkyl-phenyl;
  • X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or
  • heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano
  • Y is phenyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano
  • heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano
  • cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or
  • 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or
  • n 1, 2 or 3; or pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • a method of treating obesity, type II diabetes or metabolic syndrome comprising the step of administering a therapeutically effective amount of a compound according to formula I to a patient in need thereof.
  • alkyl means, for example, a branched or unbranched, cyclic (i.e., “cycloalkyl”) or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical which may be substituted or unsubstituted.
  • cyclic the alkyl group is preferably C3 to C 12 , more preferably C 4 to C 10 , more preferably C 4 to C 7 .
  • the alkyl group is preferably Ci to C 10 , more preferably Ci to C 6 , more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and isopentyl), more preferably methyl.
  • alkyl as used herein includes alkyl (branched or unbranched), substituted alkyl (branched or unbranched), alkenyl (branched or unbranched), substituted alkenyl (branched or unbranched), alkynyl (branched or unbranched), substituted alkynyl (branched or unbranched), cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloalkynyl and substituted cycloalkynyl.
  • the "cycloalkyl" moieties can optionally be substituted with one, two, three or four substituents, wherein each substituent is independently, for example, hydroxy, alkyl, alkoxy, halogen or amino, unless otherwise specifically indicated.
  • cycloalkyl moieties include, but are not limited to, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclopentenyl, optionally substituted cyclohexyl, optionally substituted cyclohexylene, optionally substituted cycloheptyl, optionally substituted adamantyl and the like or those which are specifically exemplified herein.
  • heterocycloalkyl denotes a cyclic alkyl ring, wherein one, two or three of the carbon ring atoms is replaced by a heteroatom such as N, O or S.
  • heterocycloalkyl groups include, but are not limited to, morpholyl, thiomorpholyl, piperazyl, piperidyl, tetrahydrofuryl, pyrrolidyl, oxazolyl, lH-pyrazolyl, lH-tetrazolyl and the like.
  • the heterocycloalkyl groups may be unsubstituted or substituted.
  • lower alkyl means, for example, a branched or unbranched, cyclic (e.g., “cycloloweralkyl”) or acyclic, saturated or unsaturated hydrocarbyl radical wherein said cyclic lower alkyl group is C3, C 4 , C 5 , C 6 or C 7 , and wherein said acyclic lower alkyl group is C 1 , C 2 , C3 or C 4 , and is preferably selected from methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
  • cyclic e.g., "cycloloweralkyl”
  • acyclic, saturated or unsaturated hydrocarbyl radical wherein said cyclic lower alkyl group is C3, C 4 , C 5 , C 6 or C 7 , and wherein said acyclic lower alkyl group is C 1 , C
  • aryl means a carbocyclic aromatic group. Examples of aryl groups are phenyl, naphthyl and the like. A particularly preferred examples of aryl is phenyl.
  • heteroaryl alone or in combination with other groups, means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, and S, the remaining ring atoms being C.
  • One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group.
  • the heteroaryl group described above may be substituted independently with one, two, or three substituents, preferably one or two substituents such as, for example, halogen, hydroxy, Ci_6 alkyl, halo Ci_6 alkyl, Ci_6 alkoxy, Ci_6 alkyl sulfonyl, Ci_6 alkyl sulfinyl, Ci_6 alkylthio, amino, amino Ci_6 alkyl, mono- or di-substituted amino-Ci_6 alkyl, nitro, cyano, oxo, acyl, carbamoyl, mono- or di-substituted amino, aminocarbonyl, mono- or di-substituted amino-carbonyl, aminocarbonyl Ci_6 alkoxy, mono- or di- substituted amino-carbonyl-Ci_6 alkoxy, hydroxy- Ci_6 alkyl, carboxyl, Ci_6 alkoxy carbonyl, aryl Ci_6 alk
  • Preferred examples of 5- or 6-membered heteroaryl are pyridyl, pyrimidyl, thiophenyl, oxadiazolyl, pyrazolyl, oxazolyl, triazolyl, tetrazolyl and lH-tetrazolyl.
  • Preferred examples of 5- or 6-membered heterocycloalkyl are tetrahydrofuryl, pyrrolidyl, piperidyl and piperazyl.
  • the alkyl and aryl groups may be substituted or unsubstituted. Where substituted, there will generally be, for example, 1 to 3 substituents present, preferably 1 substituent.
  • Substituents may include, for example: carbon-containing groups such as alkyl, aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g.
  • oxygen-containing groups such as alcohols (e.g. hydroxyl, hydroxyalkyl, aryl(hydroxyl)alkyl), ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl), aldehydes (e.g. carboxaldehyde), ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arycarbonylalkyl), acids (e.g. carboxy, carboxyalkyl), acid derivatives such as esters (e.g.
  • alcohols e.g. hydroxyl, hydroxyalkyl, aryl(hydroxyl)alkyl
  • ethers e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl
  • aldehydes e.g. carboxaldehyde
  • ketones e.g. alkyl
  • nitrogen-containing groups such as amines (e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl), azides, nitriles (e.g. cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols, thioethers, sulfoxides and sulfones (e.g.
  • alkylthio alkylsulfinyl, alkylsulfonyl, alky It hio alkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, arylthio, arysulfinyl, arysulfonyl, arythioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); and heterocyclic groups containing one or more, preferably one, heteroatom, (e.g.
  • the lower alkyl groups may be substituted or unsubstituted, preferably unsubstituted. Where substituted, there will generally be, for example, 1 to 3 substitutents present, preferably 1 substituent.
  • alkoxy means, for example, alkyl-O- and "alkoyl” means, for example, alkyl-CO-. Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by, for example, one or more alkyl groups.
  • halogen means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical, and more preferably a fluorine or chlorine radical.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.
  • acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like.
  • Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
  • the compounds of formula I can also be solvated, e.g. hydrated.
  • the solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration).
  • pharmaceutically acceptable salts also includes physiologically acceptable solvates.
  • the compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereio isomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • asymmetric carbon atom means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention the asymmetric carbon atom can be of the "R" or "S" configuration.
  • the term "optionally substituted with one to four substituents" defines a group which has one to four substituents, preferably one to three, more preferably one to two, and even more preferably one.
  • Ri is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and and wherein both R 7 and Rs are not absent; with the proviso that in case R 2 and R 4 are at the same time C, then R3 is C, N or S and R 5 is C, O or S.
  • Ri is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and and wherein both R 7 and Rs are not absent; with the proviso that in case R 2 and R 4 are at the same time C, then R3 is C, N or S and R 5 is C, O or S.
  • Ri is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and
  • R 2 is C
  • R 3 is O
  • R 4 Is C; R 5 is N; and wherein both R 7 and Rs are not absent.
  • Ri is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; or
  • 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ;
  • R 2 is C;
  • R 3 is O;
  • R 4 Is C; R 5 is N; and wherein both R 7 and Rs are absent.
  • Ri is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 .
  • Ri is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 .
  • Ri is phenyl, fluorophenyl, chlorophenyl, bromophenyl, thiophenyl, pyridyl, trifluoromethoxyphenyl or tert-butyl.
  • Ri is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; and X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
  • Y is cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or
  • 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
  • Ri is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ; and X is 5- or 6-membered optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
  • Ri is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ;
  • X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
  • Ri is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ; and X is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
  • Ri is phenyl, optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ;
  • Y is phenyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
  • Ri is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -0-CF 3 ;
  • Y is phenyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
  • Ri is phenyl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and -O-CF 3 ;
  • Y is cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
  • Ri is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from halogen, lower alkyl, alkoxy and
  • Y is cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
  • X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; and Y is phenyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; heteroaryl; cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or
  • X is 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano;
  • Y is phenyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; heteroaryl; cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or -N(CH 2 ) n )N.
  • X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; and Y is phenyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
  • X is 5- or 6-membered aryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heteroaryl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; and Y is cycloloweralkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano; or 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, halogen and cyano.
  • R 9 is lower alkyl; alkoxy; hydroxyl; lower alkyl amine; cycloloweralkyl optionally substituted with one to four substituents independently selected from loweralkyl, hydroxy, halogen, -C(O)OH,
  • 5- or 6-membered heterocycloalkyl optionally substituted with one to four substituents independently selected from lower alkyl, hydroxy, halogen, -SO 2 -loweralkyl, -C(O)OH, -C(O)O-lower alkyl and -C(O)O-lower alkyl- phenyl;
  • -N-cycloalkyl optionally substituted with -C(O)OH; -N-CH(lower alkyl)C(O)OH; or -N-(cycloalkyl)C(O)OH.
  • Rg is hydro xyl, tert-butyl, carboxy-ethyl, 2,2-dimethyl-2-carboxy-ethyl, 2-cyclopentyl-2-carboxy-ethyl, 2-cyclohexyl-2- carboxyethyl, cyclopropyl, cyclopentenyl, tetrahydrofuryl, methoxy, ethoxy, isobutyloxy, methoxymethyl, trifluoromethyl, isopropyloxy, methyl, ethyl, propyl, butyl, 2,2- dimethyl-propyl, 2,2-dimethyl-propyloxy, 3,3-dimethyl-propyl, 4-methyl-pentanol, methyl-cyclopentyl, carboxy-cyclohexyl, methoxycarbonyl-cyclohexyl, carboxy- cyclopentyl, ethoxycarbonyl-cyclopentyl
  • Rg is 2,2-dimethyl-2-carboxy- ethyl, carboxy-cyclohexyl, carboxy-cyclopentyl, cyclopropyl or tert-butyl-sulfonyl- amino.
  • Preferred examples of compounds of formula (I) are:
  • the invention also relates to a pharmaceutical composition, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the invention also relates to a method of treating obesity, type II diabetes, dyslipidemia or metabolic syndrome, comprising the step of administering a therapeutically effective amount of a compound of formula (I) to a patient in need thereof.
  • the configuration of 3-amino- pyrrolidine can be (R) or (S)-stereoisomer.
  • the stereochemistry of pyrrolidin-3-yl-carbamic acid tert-butyl ester can be (R) or (S)-conf ⁇ guration.
  • amide formation of an aryl- substituted five membered ring heterocyclic carboxylic acid (compound xvi, where Zi can be carbon or nitrogen, Xi and Yi can be oxygen, nitrogen, or sulfur, R can be halogen, lower alkyl, fluorine substituted alkyl or alkoxy group) with an aryl amine xvii can be carried out by using general amide coupling methods such as acid chloride, mixed anhydride or coupling reagents. It is understood that a variety of coupling reagents such as EDCI, PyBroP ® and many others can be applied.
  • compound xvii is meant to encompass those represented by compounds iii, v, vii and xv with the different cyclic amines being represented by spacer Q.
  • the nitrogen that links spacer Q and the tert-butyloxycarbonyl group can be part of the ring (e.g. compound v) or outside of the ring (e.g. compound vii).
  • the tert- butyloxycarbonyl group in the coupling product can be cleaved under acidic condition to generate the corresponding amine xviii.
  • heterocyclic carboxylic acid xvi can also be coupled with amine ix, xi and xiii under the same amide formation conditions.
  • the esters of the amide coupling product can further be hydrolyzed to generate the corresponding carboxylic acids.
  • XXIV The key intermediate xviii in Scheme 3 can be functionalized to form various amides, carbamates and ureas.
  • compound xviii can be treated with acyl chloride or carboxylic acid to form amide xix (R' can be cyclic or acyclic alkyl group).
  • R' can be cyclic or acyclic alkyl group.
  • compound xviii can be treated with isocyanate or alkylaminocarbonyl chloride.
  • the reaction of xviii with alkoxycarbonyl chloride will generate carbamate xxi.
  • xviii can be treated with anhydride xxiii (E can be cyclic or acyclic alkyl group) to form carboxylic acid xxiv.
  • anhydride xxiii E can be cyclic or acyclic alkyl group
  • the direct coupling of xviii with dicarboxylic acid xxii using coupling reagents can also lead to xxiv.
  • the dicarboxylic acid in xxii can be transformed to a mono-ester mono- carboxylic acid which can be coupled with xviii, and the cleavage of the resulting ester will generate compound xxiv.
  • the dicarboxylic acid when spacer E is cyclic, can be in cis or trans- conformation.
  • spacer E when spacer E has stereogenic centers, single enantiomers of compound xxiv can be prepared through chiral separation.
  • Shown in Scheme 7 is a general method to prepare claimed compounds with an ether linkage.
  • the nitro group in xxxi can be reduced and the resulting amine can be coupled with heterocyclic carboxylic acid xvi to generate compound xxxii.
  • tert- butyloxycarbonyl group in xxxii can be cleaved under acidic condition and the resulting amine can be functionalized to generate compound xxxiii, where R represents alkyl, alkoxy, cycloalkyl, and alkyl/cycloalkyl with carboxylic acid.
  • an effective amount of any one of the compounds of this invention or a combination of any of the compounds of this invention or a pharmaceutically acceptable salt thereof is administered via any of the usual and acceptable methods known in the art, either singly or in combination.
  • the compounds or compositions can thus be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form or solid, liquid or gaseous dosages, including tablets and suspensions.
  • buccal cavity e.g., buccal cavity
  • parenterally e.g., intramuscularly, intravenously, or subcutaneously
  • rectally e.g., by suppositories or washings
  • transdermally e.g., skin electroporation
  • the administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.
  • the therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration.
  • Useful pharmaceutical carriers for the preparation of the compositions hereof can be solids, liquids or gases; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like.
  • the carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • formulations for intravenous administration comprise sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution, and rendering the solution sterile.
  • Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
  • the compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like.
  • Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.
  • the invention also relates to a process for the preparation of a compound of formula (I) comprising one of the following reactions:
  • Ri to R9, X and Y are as defined above, wherein Hal represents F, Cl, Br or I, and wherein R represents hydrogen, alkyl or cycloalkyl.
  • the invention also relates to a compound of formula (I) for use as therapeutically active substance.
  • the invention also relates to a pharmaceutical composition, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the invention also relates to the use of a compound of formula (I) for the preparation of medicaments for the treatment or prophylaxis of obesity, type II diabetes, dyslipidemia or metabolic syndrome, and preferably type II diabetes.
  • the invention also relates to compounds of formula (I) for use as medicaments for the treatment and prophylaxis of obesity, type II diabetes, dyslipidemia or metabolic syndrome, and preferably type II diabetes.
  • the invention also relates to a compound according of formula (I), when manufactured according to a process according to the invention.
  • the invention also relates to a method of treating obesity, type II diabetes, dyslipidemia or metabolic syndrome, and preferably type II diabetes, comprising the step of administering a therapeutically effective amount of a compound of formula (I) to a patient in need thereof.
  • the dose of a compound of the present invention depends on a number of factors, such as, for example, the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian.
  • Such an amount of the active compound as determined by the attending physician or veterinarian is referred to herein, and in the claims, as a "therapeutically effective amount".
  • the dose of a compound of the present invention is typically in the range of about 1 to about 1000 mg per day.
  • the therapeutically effective amount is in an amount of from about 1 mg to about 500 mg per day.
  • a compound of formula I can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet
  • a compound of formula I can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:
  • 2,2-Dimethyl-3-(piperidine-4-yl)-propionic acid methyl ester (156 mg, 0.78 mmol) from above was mixed with 2-chloro-5-nitropyridine (124 mg, 0.78 mol) in tetrahydrofuran (2 mL) containing triethylamine (0.24 mL). The mixture was heated in a microwave at 140 0 C for 30 minutes. The mixture was extracted with ethyl acetate and water. The organic layer was washed with brine and dried.
  • (R)-3-(5-amino-pyridin-2- ylamino)-pyrrolidine-l-carboxylic acid tert-butyl ester was prepared by the hydrogenation of (R)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-l-carboxylic acid tert- butyl ester. This material was used in the next step without further purification.
  • racemic [l-(5-amino- pyridin-2-yl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester was prepared by the hydrogenation of racemic [l-(5-nitro-pyridin-2-yl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester. This material was directly used in the next step without further purification.
  • racemic l-(5-amino-pyridin-2-yl)-pyrrolidine-3-carboxylic acid methyl ester was prepared by the hydrogenation of racemic l-(5-nitro-pyridin-2-yl)-pyrrolidine-3-carboxylic acid methyl ester. This material was directly used in the next step without further purification.
  • 5-phenyl-2-propyl-2H-pyrazole-3- carboxylic acid was prepared from 5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester and 1-iodopropane.
  • LCMS calcd for C13H14N2O2 (m/e) 230, obsd 229 (M-H).
  • reaction mixture was filtered through a plug of Celite and evaporated under reduced pressure to give 4-(4-amino-phenyl)-piperazine-l-carboxylic acid tert-butyl ester that was used in the in the next step without further purification.
  • reaction mixture was stirred at room temperature for 3 hr. Another portion of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.5 eq) was added. The reaction mixture was stirred at 50 0 C for 3 hr and at room temperature for 3.5 days.
  • 2-phenyl-5-trifluoromethyl- oxazole-4-carboxylic acid (r,2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-5-yl)-amide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6- tetrahydro-2H-[l,2']bipyridinyl-5'-yl)-amide trifluoro acetate salt was prepared from methyl- ⁇ 5'-[(2-phenyl-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4, 5, 6-tetrahydro- 2H-[l,2']bipyridinyl-4-yl ⁇ -carbamic acid tert-butyl ester.
  • the crude mixture was diluted in methanol (100 mL), loaded onto silica gel and purified using Isco chromatography (eluting with ethyl acetate and hexanes) to give 4-(4- ⁇ [l-(2- chloro-phenyl)-3 -trifluoromethyl- 1 H-pyrazo le-carbonyl] -amino ⁇ -phenyl)-piperidine- 1 - carboxylic acid tert-butyl ester.
  • the NMR spectrum obtained on the sample is compatible with its structure.
  • Racemic tr ⁇ /?5-2- ⁇ 4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl- 4-carbonyl ⁇ -cyclopentanecarboxylic acid from above was separated by chiral SFC to afford (1 S,2S)-2- ⁇ 4'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl- 4-carbonyl ⁇ -cyclopentanecarboxylic acid (or enantiomer). [ ⁇ ]o: +37.6° in CHCI3.
  • racemic trans-2- ⁇ 4' -[(2-pheny ⁇ - 5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl ⁇ - cyclopentanecarboxylic acid racemic 2- ⁇ 4'-[(2-phenyl-5-trifluoromethyl-oxazole- 4-carbonyl)-amino]-biphenyl-4-carbonyl ⁇ -cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic trans-2-(4'- amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid.
  • racemuc 2- ⁇ 4'-[(2-phenyl-5-trifluoromethyl-oxazole- 4-carbonyl)-amino]-biphenyl-4-carbonyl ⁇ -cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic trans-2-(4'- amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid.
  • racemic trans-2- ⁇ 4' -[(2-pheny ⁇ - 5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl ⁇ - cyclopentanecarboxylic acid racemic 2- ⁇ 4'-[(2-phenyl-5-trifluoromethyl-oxazole- 4-carbonyl)-amino]-biphenyl-4-carbonyl ⁇ -cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic c ⁇ -2-(4'-amino- biphenyl-4-carbonyl)-cyclohexanecarboxylic acid.
  • racemic trans-2- ⁇ 4'-[(2-phQny ⁇ - 5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl ⁇ - cyclopentanecarboxylic acid racemic 2- ⁇ 4'-[(2-phenyl-5-trifluoromethyl-oxazole- 4-carbonyl)-amino]-biphenyl-4-carbonyl ⁇ -cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and czs-2-(4'-amino- biphenyl-4-carbonyl)-cyclohexanecarboxylic acid.
  • the resulting aminopyridine derivative was reacted with 2-phenyl-5-trifluoromethyl-oxazole-4- carbonyl chloride (prepared from the corresponding carboxylic acid (128.5 mg, 0.5 mmol), oxalyl chloride and catalytic amount of N,N-dimethylformamide) at room temperature. After concentration, the residue was partitioned between methylene chloride and water. The organic layer was washed with aqueous citric acid solution and dried over sodium sulfate. The solvents were evaporated and the residue was dried in vacuum.
  • 2-phenyl-5-trifluoromethyl-oxazole-4- carbonyl chloride prepared from the corresponding carboxylic acid (128.5 mg, 0.5 mmol), oxalyl chloride and catalytic amount of N,N-dimethylformamide

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Abstract

L'invention concerne des composés de la formule (I) ainsi que des sels pharmaceutiquement acceptables de ceux-ci, les substituants étant ceux décrits dans l'invention. Ces composés, et les compositions pharmaceutiques les contenant, sont utiles pour le traitement de maladies telles que, par exemple, l'obésité, le diabète sucré de type II et le syndrome métabolique.
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