WO2003011807A1 - Nouveaux derives d'acide carboxylique et leur utilisation comme antidiabetiques, etc. - Google Patents

Nouveaux derives d'acide carboxylique et leur utilisation comme antidiabetiques, etc. Download PDF

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WO2003011807A1
WO2003011807A1 PCT/DK2002/000471 DK0200471W WO03011807A1 WO 2003011807 A1 WO2003011807 A1 WO 2003011807A1 DK 0200471 W DK0200471 W DK 0200471W WO 03011807 A1 WO03011807 A1 WO 03011807A1
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Prior art keywords
phenyl
allyloxy
bis
acetic acid
chloro
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PCT/DK2002/000471
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English (en)
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Lone Jeppesen
Paul Stanley Bury
John Patrick Mogensen
Ingrid Pettersson
Per Sauerberg
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Novo Nordisk A/S
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Priority to BR0211414-3A priority Critical patent/BR0211414A/pt
Priority to EP02745186A priority patent/EP1414778A1/fr
Priority to IL15954702A priority patent/IL159547A0/xx
Priority to JP2003517001A priority patent/JP2004536150A/ja
Priority to CA002452665A priority patent/CA2452665A1/fr
Priority to PL02366401A priority patent/PL366401A1/xx
Priority to MXPA04000891A priority patent/MXPA04000891A/es
Priority to HU0401575A priority patent/HUP0401575A2/hu
Priority to KR10-2004-7001417A priority patent/KR20040019087A/ko
Publication of WO2003011807A1 publication Critical patent/WO2003011807A1/fr
Priority to NO20040389A priority patent/NO20040389L/no

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    • 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
    • C07D307/38—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • 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
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    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • 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
    • C07D277/22—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present invention relates to novel vinyl carboxyiic acid derivatives, to the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions compris- ing the compounds and to a method of treatment employing these compounds and compositions. More specifically, the compounds of the invention can be utilised in the treatment and/or prevention of conditions mediated by the Peroxisome Proliferator-Activated Receptors (PPAR), in particular the PPAR ⁇ suptype.
  • PPAR Peroxisome Proliferator-Activated Receptors
  • Coronary artery disease is the major cause of death in Type 2 diabetic and metabolic syndrome patients (i.e. patients that fall within the 'deadly quartet' category of impaired glucose tolerance, insulin resistance, hypertriglyceridaemia and/or obesity).
  • hypolipidaemic fibrates and antidiabetic thiazolidinediones separately display moderately effective triglyceride-lowering activities although they are neither potent nor effi- cacious enough to be a single therapy of choice for the dyslipidaemia often observed in Type 2 diabetic or metabolic syndrome patients.
  • the thiazolidinediones also potently lower circulating glucose levels of Type 2 diabetic animal models and humans.
  • the fibrate class of compounds are without beneficial effects on glycaemia.
  • thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased and decreased expression of specific enzymes and apolipoproteins respectively, both key-players in regulation of plasma triglyceride content.
  • Fibrates on the one hand, are PPAR ⁇ activators, acting primarily in the liver.
  • Thiazolidinediones on the other hand, are high affinity ligands for PPAR ⁇ acting primarily on adipose tissue.
  • Adipose tissue plays a central role in lipid homeostasis and the maintenance of energy balance in vertebrates.
  • Adipocytes store energy in the form of triglycerides during periods of nutritional affluence and release it in the form of free fatty acids at times of nutritional deprivation.
  • white adipose tissue is the result of a continuous differentiation process throughout life.
  • Much evidence points to the central role of PPAR ⁇ activation in initiating and regulating this cell differentiation.
  • Several highly specialised proteins are induced during adipocyte differentiation, most of them being involved in lipid storage and metabolism. The exact link from activation of PPAR ⁇ to changes in glucose metabolism, most notably a decrease in insulin resistance in muscle, has not yet been clarified.
  • a possible link is via free fatty acids such that activation of PPAR ⁇ induces Lipoprotein Lipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoA Synthetase (ACS) in adipose tissue but not in muscle tissue.
  • LPL Lipoprotein Lipase
  • FATP Fatty Acid Transport Protein
  • ACS Acyl-CoA Synthetase
  • PPAR ⁇ is involved in stimulating ⁇ -oxidation of fatty acids.
  • a PPAR ⁇ - mediated change in the expression of genes involved in fatty acid metabolism lies at the basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to liver and kidney and which can lead to hepatocarcinogenesis in rodents.
  • the phenomenon of peroxisome proliferation is not seen in man.
  • PPAR ⁇ is also involved in the control of HDL cholesterol levels in rodents and humans. This effect is, at least partially, based on a PPAR ⁇ -mediated transcriptional regulation of the major HDL apolipoproteins, apo A-l and apo A-ll.
  • hypotriglyceridemic action of fibrates and fatty acids also involves PPAR ⁇ and can be summarised as follows: (I) an increased lipolysis and clearance of remnant particles, due to changes in lipoprotein lipase and apo C-lll levels, (II) a stimulation of cellular fatty acid uptake and their subsequent conversion to acyl-CoA derivatives by the induction of fatty acid binding protein and acyl-CoA synthase, (III) an induction of fatty acid ⁇ -oxidation pathways, (IV) a reduction in fatty acid and triglyceride synthesis, and finally (V) a decrease in VLDL production.
  • both enhanced catabolism of triglyceride-rich particles as well as reduced secretion of VLDL particles constitutes mechanisms that contribute to the hypolipidemic effect of fibrates.
  • PPAR ⁇ activation was initially reported not to be involved in modulation of glucose or triglyceride levels. (Berger et al., / Biol. Chem. , 1999, Vol 274, pp. 6718-6725). Later it has been shown that PPAR ⁇ activation leads to increased levels of HDL cholesterol in dbldb mice (Leibowitz et al. FEBS letters 2000, 473, 333-336).
  • a PPAR ⁇ agonist when dosed to insulin-resistant middle-aged obese rhesus monkeys caused a dramitic dose- dependent rise in serum HDL cholesterol while lowering the levels of small dense LDL, fasting triglycerides and fasting insulin (Oliver et al. PNAS 2001, 98, 5306-5311).
  • the same paper also showed that PPAR ⁇ activation increased the reverse cholesterol transporter ATP- binding cassette A1 and induced apolipoprotein A1 -specific cholesterol efflux.
  • Glucose lowering as a single approach does not overcome the macrovascular complications associated with Type 2 diabetes and metabolic syndrome.
  • Novel treatments of Type 2 diabetes and metabolic syndrome must therefore aim at lowering both the overt hy- pertriglyceridaemia associated with these syndromes as well as alleviation of hyperglycae- mia.
  • R 1 is pyridyl
  • R 2 is phenyl, thienyl, furyl, naphtyl, benzothienyl or pyridyl
  • R 3 is hydrogen or lower alkyl
  • diaryl acid derivatives and their pharmaceutical compositions are described as PPAR receptor ligands.
  • C 1-6 -alkyl as used herein, alone or in combination, represent a linear or branched, saturated hydrocarbon chain having the indicated number of carbon atoms. Examples of such groups include, but are not limited to methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, te/f-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.
  • C 3 . 6 -cycloalkyl as used herein, alone or in combination, represent a saturated monocyclic hydrocarbon group having the indicated number of carbon atoms.
  • C 2-6 -alkenyl represent an olefinically unsaturated branched or straight hydrocarbon group having from 2 to the specified number of carbon atoms and at least one double bond.
  • Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl and the like.
  • 6 -alkynyl as used herein, represent an unsaturated branched or straight hydrocarbon group having from 2 to the specified number of carbon atoms and at least one triple bond.
  • examples of such groups include, but are not limited to, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like.
  • C 4-6 -alkenynyl represent an unsaturated branched or straight hydrocarbon group having from 4 to the specified number of carbon atoms and both at least one double bond and at least one triple bond. Examples of such groups include, but are not limited to, 1-penten-4-ynyl, 3-penten-1-ynyl, 1 ,3-hexadiene-5-ynyl and the like.
  • C 1-6 -alkoxy refers to a straight or branched configuration linked through an ether oxygen having its free valence bond from the ether oxygen.
  • linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like.
  • branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy and the like.
  • C 3 . 6 -cycloalkoxy as used herein, alone or in combination, represent a saturated monocyclic hydrocarbon group having the indicated number of carbon atoms linked through an ether oxygen having its free valence bond from the ether oxygen.
  • Examples of cycloalkoxy groups are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • C 1-6 -alkylthio refers to a straight or branched monovalent substituent comprising a C 1-6 -alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom and having 1 to 6 carbon atoms e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio and the like.
  • C 3-6 -cycloalkylthio represent a saturated monocyclic hydrocarbon group having the indicated number of carbon atoms linked through a divalent sulfur atom having its free valence bond from the sulfur atom.
  • Examples of cycloalkoxy groups are cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
  • C 1-6 -alkylamino refers to a straight or branched monovalent substituent comprising a C 1-6 -alkyl group linked through amino having a free valence bond from the nitrogen atom e.g. methylamino, ethylamino, propylamino, butylamino, pentylamino and the like.
  • C 1-6 -cycloalkylamino as used herein, alone or in combination, represent a saturated monocyclic hydrocarbon group having the indicated number of carbon atoms linked through amino having a free valence bond from the nitrogen atom e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and the like.
  • C 1-6 -alkoxyC 1-6 -alky ' refers to Ci. e-alkyl as defined herein whereto is attached a C 1-6 -alkoxy as defined herein, e.g. methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like.
  • aryl refers to an aromatic monocyclic or an aromatic fused bi- or tricyclic hydrocarbon group e.g. phenyl, naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like.
  • arylene refers to divalent aromatic monocyclic or a divalent aromatic fused bi- or tricyclic hydrocarbon group e.g. phenylene, naphthylene and the like.
  • halogen means fluorine, chlorine, bromine or iodine.
  • perhalomethyl means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.
  • perhalomethoxy means trifluoromethoxy, trichloromethoxy, tribromo- methoxy or triiodomethoxy.
  • C ⁇ . 6 -dialkylamino refers to an amino group wherein the two hydrogen atoms independently are substituted with a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms; such as dimethylamino, N- ethyl-N-methylamino, diethylamino, dipropylamino, N-(n-butyl)-N-methylamino, di(n- pentyl)amino and the like.
  • acyl refers to a monovalent substituent comprising a C 1-6 - alkyl group linked through a carbonyl group; such as e.g. acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and the like.
  • heteroaryl refers to a monovalent substituent comprising a 5-7 membered monocyclic aromatic system or a 8-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g.
  • heteroaryloxy refers to a heteroaryl as defined herein linked to an oxygen atom having its free valence bond from the oxygen atom e.g. pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, pyrazinyloxy, pyrimidinyloxy, pyridazinyloxy, isothiazolyloxy, isoxazolyloxy, oxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, quinolinyloxy, isoquinolinyloxy, quinazolinyloxy, quinoxalinyloxy, indoltloxy, benzimidazolyloxy, benzofuranyloxy, pteridinyloxy and purinyloxy and the like.
  • aralkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with an aromatic carbohydride; such as benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl and the like.
  • aryloxy refers to phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
  • aralkoxy refers to a C 1-6 -alkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1- naphthylmethoxy, 2-(1-naphtyl)ethoxy and the like.
  • heteroarylkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with a heteroaryl group; such as (2- furyl)methyl, (3-furyl)methyl, (2-thienyl)methyi, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl- 1-(2-pyrimidyl)ethyI and the like.
  • heteroarylkoxy refers to a heteroarylalkyl as defined herein linked to an oxygen atom having its free valence bond from the oxygen atom, e.g. (2- furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl- 1-(2-pyrimidyl)ethyl linked to oxygen, and the like.
  • arylthio refers to an aryl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom, the aryl group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 -alkoxy; e.g. phenylthio, (4-methylphenyl)- thio, (2-chlorophenyl)thio and the like. Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
  • the present invention relates to compounds of the general formula (I):
  • X is aryl, fluorenyl or heteroaryl each of which is optionally substituted with one or more substituents selected from
  • Y is aryl or heteroaryl each of which is optionally substituted with one or more substituents selected from
  • Y is C 1-6 -alkyl, C 3 - 6 -cycIoalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4 . 6 -alkenynyl; and Ar is arylene which is optionally substituted with one or more halogen; and
  • Z is O or S
  • Q is -(CH 2 ) n - wherein n is 0, 1 , 2 or 3;
  • R-i is hydrogen or halogen
  • Ri is C ⁇ -6 -alkyl, C 3-6 -cycloalkyl, C ⁇ -6 -alkoxy, C 3-6 -cycloalkoxy each of which is optionally sub- stituted with one or more substituents selected from halogen, hydroxy, carboxy, amino or cyano; and
  • R 2 is hydrogen, C ⁇ -6 -alkyl, C -6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C -6 -alkenynyl or aryl;
  • X and Y independently is not a pyridine ring
  • the present invention is concerned with compounds of formula
  • the present invention is concerned with compounds of formula (I) wherein X is aryl, fluorenyl or heteroaryl each of which is optionally substituted with one or more substituents selected from
  • aryl, aryloxy or heteroaryl each of which is optionally substituted with halogen, perhalomethyl, perhalomethoxy or C 1-6 -alkyl.
  • the present invention is concerned with compounds of formula (I) wherein X is aryl, which is optionally substituted with one or more substituents selected from
  • halogen or • aryl, aryloxy or heteroaryl each of which is optionally substituted with halogen, perhalomethyl, perhalomethoxy or C 1-6 -alkyl.
  • the present invention is concerned with compounds of formula (I) wherein X is phenyl, which is optionally substituted with one or more substituents selected from • bromine; or
  • the present invention is concerned with compounds of formula (I) wherein X is heteroaryl, which is optionally substituted with one or more substituents selected from • halogen; or
  • the present invention is concerned with compounds of formula (I) wherein X is heteroaryl, which is optionally substituted with aryl. In another embodiment, the present invention is concerned with compounds of formula (I) wherein X is thiazolyl, which is optionally substituted with phenyl.
  • the present invention is concerned with compounds of formula (I) wherein X is fluorenyl.
  • the present invention is concerned with compounds of for- mula (I) wherein Y is aryl or heteroaryl each of which is optionally substituted with one or more substituents selected from
  • the present invention is concerned with compounds of formula (I) wherein Y is aryl or heteroaryl each of which is optionally substituted with one or more substituents selected from • halogen; or
  • aryl or heteroaryl each of which is optionally substituted with halogen, perhalomethyl, perhalomethoxy or C 1-6 -alkyl.
  • the present invention is concerned with compounds of formula (I) wherein Y is aryl, which is optionally substituted with one or more halogens.
  • the present invention is concerned with compounds of formula (I) wherein Y is phenyl, which is optionally substituted with one or more halogens.
  • the present invention is concerned with compounds of for- mula (I) wherein Y is heteroaryl, which is optionally substituted with one or more halogens. In another embodiment, the present invention is concerned with compounds of formula (I) wherein Y is C 1-6 -alkyl.
  • the present invention is concerned with compounds of formula (I) wherein Y is methyl. In another embodiment, the present invention is concerned with compounds of formula (I) wherein Ar is arylene, which is optionally substituted with one or more halogens. In another embodiment, the present invention is concerned with compounds of formula (I) wherein Ar is phenylene, which is optionally substituted with one or more halogens. In another embodiment, the present invention is concerned with compounds of formula (I) wherein Z is O.
  • the present invention is concerned with compounds of formula (I) wherein n is 1 or 2.
  • the present invention is concerned with compounds of formula (I) wherein R-i is hydrogen.
  • the present invention is concerned with compounds of formula (I) wherein R ⁇ is C 1-3 -alkyl.
  • the present invention is concerned with compounds of formula (I) wherein R ⁇ is C 1-3 -alkoxy. In another embodiment, the present invention is concerned with compounds of formula (I) wherein wherein R 2 is hydrogen or C 1-6 -alkyl.
  • the present invention is concerned with compounds of formula (I) wherein R 2 is hydrogen, methyl or ethyl.
  • the present invention is concerned with compounds of formula I wherein alkyl is methyl or ethyl. In another embodiment, the present invention is concerned with compounds of formula I wherein alkenyl is vinyl or 1-propenyl.
  • the present invention is concerned with compounds of formula I wherein alkynyl is 1-propynyl. In another embodiment, the present invention is concerned with compounds of formula I wherein alkenynyl is 1-pentene-4-yne.
  • the present invention is concerned with compounds of formula I wherein alkoxy is methoxy, ethoxy, isopropoxy or cyclopropoxy.
  • the present invention is concerned with compounds of formula I wherein aryl is phenyl.
  • the present invention is concerned with compounds of formula I wherein arylene is phenylene.
  • the present invention is concerned with compounds of formula I wherein halogen is fluorine, bromine or chlorine. In another embodiment, the present invention is concerned with compounds of formula I wherein perhalomethyl is trifluoromethyl.
  • the present invention is concerned with compounds of formula I wherein heteroaryl is, thiazolyl.
  • the present invention is concerned with compounds of formula I wherein aralkyl is benzyl.
  • the present invention is concerned with compounds of formula I wherein aryloxy is phenoxy.
  • the present invention is concerned with compounds of formula I wherein aralkoxy is benzyloxy. In another embodiment, the present invention is concerned with compounds of formula I wherein the substituents R- ⁇ and Y are arranged in a trans-configuration.
  • the present invention is concerned with compounds of formula I wherein the substituents R-i and Y are arranged in a cis-configuration.
  • the present invention is concerned with compounds of formula I which is a PPAR ⁇ agonist.
  • the present invention is concerned with compounds of formula I which selective PPAR ⁇ agonist.
  • Examples of specific compounds of the invention are: 3- ⁇ 3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl ⁇ -propionic acid ethyl ester, 3- ⁇ 3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl ⁇ -propionic acid, 3- ⁇ 3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl ⁇ -acetic acid ethyl ester, 3- ⁇ 3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl ⁇ -acetic acid, 3- ⁇ 4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl ⁇ -propionic acid ethyl ester, 3- ⁇ 4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl ⁇ -propionic
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaph- thoates, glycero
  • inorganic or organic acid addition salts include the pharmaceutically accept- able salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium, zinc, calcium salts and the like.
  • amines and organic amines include ammonium, methylamine, di- methylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine, tetrame- thylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N-methyl-D-glucamine, guanidine and the like.
  • cationic amino acids include lysine, arginine, histidine and the like.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula I with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, so- dium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, ni- trie acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, ni- trie acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, enzymatic resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, (R)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like.
  • the compound of formula I may be con- verted to a 1 :1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the dia-stereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula I may be prepared by hydrolysing the pure diastereomeric amide.
  • Various polymorphs of compound of general formula I forming part of this invention may be prepared by crystallization of compound of formula I under different conditions.
  • Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formula (I).
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the invention also encompasses active metabolites of the present compounds.
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula I or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents. Furthermore, the invention relates to the use of compounds of the general formula I or their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR) such as the conditions mentioned above.
  • PPAR Peroxisome Proliferator-Activated Receptors
  • the present invention relates to a method of treating and/or preventing Type I or Type II diabetes.
  • the present invention relates to the use of one or more compounds of the general formula I or pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type I or Type II diabetes.
  • the present compounds are useful for the treatment and/or prevention of IGT. In a still further aspect, the present compounds are useful for the treatment and/or prevention of Type 2 diabetes.
  • the present compounds are useful for the delaying or prevention of the progression from IGT to Type 2 diabetes.
  • the present compounds are useful for the delaying or pre-vention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.
  • the present compounds reduce blood glucose and triglyceride levels and are accordingly useful for the treatment and/or prevention of ailments and disorders such as diabetes and/or obesity.
  • the present compounds are useful for the treatment and/or prophylaxis of insulin resistance (Type 2 diabetes), impaired glucose tolerance, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, insulin resistance, hypergly- caemia, atherosclerosis, hyperlipidemia, coronary artery disease, myocardial ischemia and other cardiovascular disorders.
  • the present compounds are effective in decreasing apoptosis in mammalian cells such as beta cells of Islets of Langerhans.
  • the present compounds are useful for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis.
  • the present compounds may also be useful for improving cognitive functions in dementia, treating diabetic complications, psoriasis, polycystic ovarian syndrome (PCOS) and prevention and treatment of bone loss, e.g. osteoporosis.
  • PCOS polycystic ovarian syndrome
  • the present compounds may also be administered in combination with one or more further pharmacologically active substances eg., selected from antiobesity agents, antidiabet- ics, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • further pharmacologically active substances eg., selected from antiobesity agents, antidiabet- ics, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotro- pin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) an- tagonists, urocortin agonists, ⁇ 3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradren
  • CART cocaine amp
  • the antiobesity agent is leptin. In another embodiment the antiobesity agent is dexamphetamine or amphetamine. In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine.
  • the antiobesity agent is sibutramine. In a further embodiment the antiobesity agent is orlistat. In another embodiment the antiobesity agent is mazindol or phentermine.
  • Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise sulphonylureas, bigua- nides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, po- tassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to
  • DPP-IV dipeptidyl peptidase- IV
  • inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis include glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as HMG CoA inhibitors (statins), com- pounds lowering food intake, RXR agonists and agents acting on the ATP-dependent potassium channel of the ⁇ -cells.
  • the present compounds are administered in combination with insulin.
  • the present compounds are administered in combination with a sulphonylurea eg. tolbutamide, glibenclamide, glipizide or glicazide.
  • a sulphonylurea eg. tolbutamide, glibenclamide, glipizide or glicazide.
  • the present compounds are administered in combination with a biguanide eg. metformin.
  • the present compounds are administered in combination with a meglitinide eg. repaglinide or senaglinide.
  • a meglitinide eg. repaglinide or senaglinide.
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor eg. miglitol or acarbose.
  • the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg. tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg. tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
  • the present compounds may be administered in combination with nateglinide.
  • the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofi- brate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofi- brate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofi- brate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • the present compounds are administered in combination with more than one of the above-mentione
  • a sulphony- lurea and metformin in combination with a sulphony- lurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing
  • the present invention also relates to a process for the preparation of the above said novel compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with phar- maceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate orglyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, trans- dermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • the carrier may contain additives such as solubilizing agents, e.g.
  • propylene glycol propylene glycol
  • surfactants such as lecithin (phosphatidylcholine) or cyclodextrin
  • preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • the pharmaceutical composition of the invention may comprise the compound of formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.
  • the compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of diseases related to the regulation of blood sugar.
  • Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the compounds of the invention are effective over a wide dosage range.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of ad- ministration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
  • the compounds used as starting materials are either known compounds or compounds which can readily be prepared by methods known per se.
  • the structures of the com- pounds are confirmed by either elemental analysis (MA) nuclear magnetic resonance (NMR), mass spectrometry (MS) or optical rotation. NMR shifts ( ⁇ ) are given in parts per million (ppm) and only selected peaks are given, mp is melting point and is given in °C.
  • Column chromatography was carried out using the technique described by W.C. Still et al, J. Org. Chem. 1978, 43, 2923-2925 on Merck silica gel 60 (Art 9385). The optical rotation was measured on a Advanced Laser Polarimeter.
  • 3,3 ⁇ Bis-(4-bromophenyl)prop-2-en-1-ol was prepared as described in example 1 , step A-B.
  • Step C 1) To an ice-cooled solution of 3-(p-hydroxyphenyl)-propionic acid (8.3 g, 50.0 mmol) in ethanol (100 mL) was dropwise added thionyl chloride (3.7 mL, 50.7 mmol). The mixture was stirred at room temperature over night, concentrated in vacuo and the residue purified by kugelrohr distillation, to give 9.6 g (99%) of 3-(4-hydroxy-phenyl)-propionic acid ethyl ester as a colourless oil.
  • Step A To a solution of 3- ⁇ 4-[3,3-bis-(4-bromo-phenyl)-allyloxy]-phenyl ⁇ -propionic acid ethyl ester (example 5) (1.0 g, 2.0 mmol) in toluene (20 mL) and ethanol (50 mL) was added 1 N NaOH (10.0 mL) and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated in vacuo and 1N HCI added. The product was extracted with ethyl acetate (x 3). The organic layers were combined, washed with water, dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was recrystalised from warm ethanol (100 mL), witch was concentrated to 60 mL, and cooled, to give 600 mg (56 %) of the title compound.
  • Step C Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (504 mg, 2.0 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (404 mg, 2.0 mmol), methyl 4- hydroxyphenylacetate (250 mg, 1.5 mmol) and 3,3-bis-(4-bromophenyl)prop-2-en-1-ol (552 mg, 1.5 mmol) in dry THF (10 ml), the mixture stirred for 1 h, filtered and concentrated in vacuo. The crude product was then purified by column chromatography on silica (toluene eluent).
  • Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (0.94 ml, 786 mg, 3.0 mmol), methyl 4-hydroxyphenylacetate (332 mg, 2.0 mmol) and (E)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol (578 mg, 2.0 mmol) in dry THF (25 ml), the mixture was stirred for 1h. The mixture was filtered and concentrated I vacuo. The residue was purified by flash chromatography on silica gel (toluene as eluent) to give 710 mg (81%) of the title compound.
  • Step A To a solution of (E)- ⁇ 4-[3-(4-bromo-phenyl)-3-phenyl-allyloxy]-phenyl ⁇ -acetic acid ethyl ester (example 11) (700 mg, 1.6 mmol) in THF (5 m) and ethanol (5 ml) was added 1 N NaOH (5.0 ml) and the reaction mixture was stirred for 1 h at 60°C for 1h and at room tern- perature over night. The reaction mixture was added water and the organic solvent evaporated. 1 N HCI was added to pH -1-2 and the product extracted with dichloro- methane/isopropanol (19:1). The combined organic phases were dried (MgSO ), filtered and concentrated in vacuo. The residue was suspended in toluene/petroleum ether (1 :1) and 490 mg (70%) of the title compound was isolated by filtration.
  • Step C Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (0.94 ml, 786 mg, 3.0 mmol), methyl 4-hydroxyphenylacetate (332 mg, 2.0 mmol) and (Z)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol (578 mg, 2.0 mmol) in dry THF (25 ml), the mixture was stirred for 1h. The mixture was filtered and concentrated I vacuo. The residue was purified by flash chromatography on silica gel (toluene as eluent) to give 650 mg (74%) of the title compound.
  • Step B A 1M solution of DIBAL-H in toluene (15 ml, 15 mmol) was added dropwise, at -
  • azodicarboxylic dipiperidide (353 mg, 1.4 mmol) was added at 0-5 °C to a stirred solution of tributylphosphine (0.4 mL, 1.4 mmol), ethyl 3- hydroxyphenylacetate (120 mg, 0.7 mmol) and (E)- 3-(4'-bromo-biphenyl-4-yl)-but-2-en-1-ol (200 mg, 0.7 mmol) in dry THF (10 ml), the mixture stirred for 16 h, filtered and concentrated in vacuo.
  • azodicarboxylic dipiperidide (353 mg, 1.4 mmol) was added at 0-5 °C to a stirred solution of tributylphosphine (0.4 mL, 1.4 mmol), methyl 4- hydroxyphenylacetate (110 mg, 0.7 mmol) and (E)- 4-(4'-Bromo-biphenyl-4-yl)-but-2-en-1-ol (example 22 step A-B)(200 mg, 0.7 mmol) in dry THF (10 mL), the mixture stirred for 16 h, filtered and concentrated in vacuo. The crude product was then purified by column chromatography on silica (eluent: 20 % ethyl acetate in heptane) to give 264 mg (84%) of the title compound.
  • Step A-C The title compound was prepared by a method analogous to that described in example 14, using (4-fluorophenyl)-(2-phenyl-1 ,3-thiazol-5-yl)-methanone as starting material.
  • Step A The title compound was prepared by a method analogous to that described in example 2, using (E)- ⁇ 3-chIoro-4-[3-(4-fluoro-phenyl)-3-(2-phenyl-thiazol-5-yl)-allyIoxy]-phenyl ⁇ - acetic acid ethyl ester (example 26) as starting material.
  • the title compound was prepared by a method analogous to that described in example 14, using (1 , -biphenyl)-4-yl-(2-phenyl-1 ,3-thiazol-5-yl)-methanone as starting material.
  • the title compound was prepared by a method analogous to that described in ex- ample 14, using (1 ,1 ' -biphenyl)-4-yl-(2-phenyl-1 ,3-thiazol-5-yl)-methanone as starting material.
  • the PPAR transient transactivation assays are based on transient transfection into human HEK293 cells of two plasmids encoding a chimeric test protein and a reporter protein respectively.
  • the chimeric test protein is a fusion of the DNA binding domain (DBD) from the yeast GAL4 transcription factor to the ligand binding domain (LBD) of the human PPAR pro- teins.
  • DBD DNA binding domain
  • LBD ligand binding domain
  • the GAL4 DBD will direct the chimeric protein to bind only to Gal4 enhancers (of which none existed in HEK293 cells).
  • the reporter plas- mid contained a Gal4 enhancer driving the expression of the firefly luciferase protein.
  • HEK293 cells expressed the GAL4-DBD-PPAR-LBD fusion protein.
  • the fusion protein will in turn bind to the Gal4 enhancer controlling the luciferase expression, and do nothing in the absence of ligand.
  • luciferase protein Upon addition to the cells of a PPAR ligand luciferase protein will be produced in amounts corresponding to the activation of the PPAR protein. The amount of luciferase protein is measured by light emission after addition of the appropriate substrate.
  • HEK293 cells were grown in DMEM + 10% FCS. Cells were seeded in 96-well plates the day before transfection to give a confluency of 50-80 % at transfection. A total of 0,8 ⁇ g DNA containing 0,64 ⁇ g pM1oc/ ⁇ LBD, 0,1 ⁇ g pCMV ⁇ Gal, 0,08 ⁇ g pGL2(Gal4) 5 and 0,02 ⁇ g pADVANTAGE was transfected per well using FuGene transfection reagent according to the manufacturers instructions (Roche). Cells were allowed to express protein for 48 h followed by addition of compound.
  • Plasmids Human PPAR ⁇ , ⁇ and ⁇ was obtained by PCR amplification using cDNA synthesized by reverse transcription of mRNA from human liver, adipose tissue and plancenta respectively. Amplified cDNAs were cloned into pCR2.1 and sequenced.
  • the ligand binding domain (LBD) of each PPAR isoform was generated by PCR (PPAR ⁇ : aa 167 - C-terminus; PPAR ⁇ : aa 165 - C-terminus; PPAR ⁇ : aa 128 - C-terminus) and fused to the DNA binding domain (DBD) of the yeast transcription factor GAL4 by subcloning fragments in frame into the vector pM1 (Sadowski et al. (1992), Gene 118, 137) generating the plasmids pMl ⁇ LBD, pMl ⁇ LBD and pM1 ⁇ . Ensuing fusions were verified by sequencing.
  • the reporter was constructed by inserting an oligonucleotide encoding five repeats of the GAL4 recognition sequence (5 x CGGAGTACTGTCCTCCG(AG)) (Webster et al. (1988), Nucleic Acids Res. 16, 8192) into the vector pGL2 promotor (Promega) generating the plasmid pGL2(GAL4) 5 .
  • pCMV ⁇ Gal was purchased from Clontech and pADVANTAGE was purchased from Promega.
  • Luciferase assay Medium including test compound was aspirated and 100 ⁇ l PBS incl. 1mM Mg++ and Ca++ was added to each well. The luciferase assay was performed using the LucLite kit according to the manufacturers instructions (Packard Instruments). Light emission was quantified by counting on a Packard LumiCounter. To measure ⁇ - galactosidase activity 25 ⁇ l supernatant from each transfection lysate was transferred to a new microplate. ⁇ -galactosidase assays were performed in the microwell plates using a kit from Promega and read in a Labsystems Ascent Multiscan reader. The ⁇ -galactosidase data were used to normalize (transfection efficiency, cell growth etc.) the luciferase data.

Abstract

L'invention concerne de nouveaux composés représentés par la formule générale (I), l'utilisation de ces composés comme compositions pharmaceutiques, des compositions pharmaceutiques comprenant ces composés, et des méthodes de traitement utilisant ces composés et ces compositions. Les composés de l'invention peuvent être utilisés dans le traitement et/ou la prévention d'états pathologiques associés aux récepteurs activés proliférateurs du peroxysome (PPAR), en particulier au sous-type PPARδ.
PCT/DK2002/000471 2001-07-30 2002-07-05 Nouveaux derives d'acide carboxylique et leur utilisation comme antidiabetiques, etc. WO2003011807A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
BR0211414-3A BR0211414A (pt) 2001-07-30 2002-07-05 Composto, uso do mesmo, composição farmacêutica, e, métodos para o tratamento e/ou prevenção de condições mediadas pelos receptores nucleares e de diabetes tipo i, diabetes tipo ii, tolerância à glicose, resistência à insulina ou obesidade prejudicadas
EP02745186A EP1414778A1 (fr) 2001-07-30 2002-07-05 Nouveaux derives d'acide carboxylique et leur utilisation comme antidiabetiques, etc.
IL15954702A IL159547A0 (en) 2001-07-30 2002-07-05 Novel vinyl carboxylic acid derivatives and their use as antidiabetics
JP2003517001A JP2004536150A (ja) 2001-07-30 2002-07-05 新規なビニル、カルボン酸誘導体および抗生物質などとしてのそれらの使用
CA002452665A CA2452665A1 (fr) 2001-07-30 2002-07-05 Nouveaux derives d'acide carboxylique et leur utilisation comme antidiabetiques, etc.
PL02366401A PL366401A1 (en) 2001-07-30 2002-07-05 Novel vinyl carboxylic acid derivatives and their use as antidiabetics etc.
MXPA04000891A MXPA04000891A (es) 2001-07-30 2002-07-05 Nuevos derivados de acido vinilcarboxilico y su uso como antidiabeticos.
HU0401575A HUP0401575A2 (hu) 2001-07-30 2002-07-05 Új vinil-karbonsav-származékok és ezek alkalmazása cukorbetegség ellen és ezeket tartalmazó gyógyszerkészítmények
KR10-2004-7001417A KR20040019087A (ko) 2001-07-30 2002-07-05 신규 비닐 카르복실산 유도체 및 항당뇨제 등으로서그들의 사용
NO20040389A NO20040389L (no) 2001-07-30 2004-01-29 Nye vinylkarboksylsyrederivater og deres anvendelse som antidiabetika

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DKPA200101154 2001-07-30
DKPA200101154 2001-07-30

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EP (1) EP1414778A1 (fr)
JP (1) JP2004536150A (fr)
KR (1) KR20040019087A (fr)
CN (1) CN1537093A (fr)
BR (1) BR0211414A (fr)
CA (1) CA2452665A1 (fr)
CZ (1) CZ2004133A3 (fr)
HU (1) HUP0401575A2 (fr)
IL (1) IL159547A0 (fr)
MX (1) MXPA04000891A (fr)
NO (1) NO20040389L (fr)
PL (1) PL366401A1 (fr)
RU (1) RU2004105956A (fr)
WO (1) WO2003011807A1 (fr)
ZA (1) ZA200400161B (fr)

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WO2004022533A1 (fr) * 2002-09-05 2004-03-18 Novo Nordisk A/S Nouveaux derives d'acide vinylcarboxylique et leur utilisation therapeutique
WO2004037776A3 (fr) * 2002-10-28 2004-06-10 Novo Nordisk As Nouveaux composes, leur preparation et leur utilisation
WO2004113266A1 (fr) * 2003-06-20 2004-12-29 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Derives d'acides de phenylalkyle et de phenoxyalkyle pour le traitement de l'hyperglycemie et de l'hypertriglyceridemie typiques du diabete de type ii et procede de preparation desdits derives
WO2005030694A1 (fr) * 2003-09-19 2005-04-07 Janssen Pharmaceutica, N.V. Acides 4-((phenoxyalkyl)thio)-phenoxyacetiques et analogues
WO2005042478A2 (fr) * 2003-09-19 2005-05-12 Janssen Pharmaceutica, N.V. Acides 4-((phenoxyalkyl)thio)-phenoxyacetiques et analogues
WO2007071766A2 (fr) * 2005-12-22 2007-06-28 Transtech Pharma Nouveaux composes, leur preparation et leur utilisation
JP2007536342A (ja) * 2004-05-05 2007-12-13 ノボ　ノルディスク　アクティーゼルスカブ 新規の化合物、その製法と使用
US7678786B2 (en) 2006-04-18 2010-03-16 Janssen Pharmaceutica Nv Benzoazepin-oxy-acetic acid derivatives as PPAR-delta agonists used for the increase of HDL-C, lower LDL-C and lower cholesterol
US7709682B2 (en) 2005-09-14 2010-05-04 Janssen Pharmaceutica N.V. Lysine salts of 4-((phenoxyalkyl)thio)-phenoxyacetic acid derivatives
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
WO2022020376A1 (fr) * 2020-07-22 2022-01-27 Reneo Pharmaceuticals, Inc. Agoniste de ppar-delta cristallin
US11931365B2 (en) 2022-01-25 2024-03-19 Reneo Pharmaceuticals, Inc. Use of PPAR-delta agonists in the treatment of disease

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KR100693132B1 (ko) * 2006-06-23 2007-03-14 동해전장 주식회사 정션박스내에 삽입된 릴레이의 동작 검사 장치
US20120168303A1 (en) * 2011-01-05 2012-07-05 Sueng-Nien Kao Salt water activated emergency lighting device
CN103467409B (zh) * 2013-09-03 2015-01-07 浙江医药高等专科学校 取代的四氮唑羧酸类化合物及其用途
CN103467408B (zh) * 2013-09-03 2015-01-21 浙江医药高等专科学校 一类四氮唑羧酸类化合物及其用途
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CN103467407B (zh) * 2013-09-03 2015-04-22 浙江医药高等专科学校 四氮唑羧酸类化合物及其用途
CN103467406B (zh) * 2013-09-03 2014-12-17 浙江医药高等专科学校 卤素取代的四氮唑羧酸类化合物、其制备方法和用途

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US7091245B2 (en) 2002-09-05 2006-08-15 Novo Novdisk A/S Compounds, their preparation and use
WO2004022533A1 (fr) * 2002-09-05 2004-03-18 Novo Nordisk A/S Nouveaux derives d'acide vinylcarboxylique et leur utilisation therapeutique
WO2004037776A3 (fr) * 2002-10-28 2004-06-10 Novo Nordisk As Nouveaux composes, leur preparation et leur utilisation
WO2004113266A1 (fr) * 2003-06-20 2004-12-29 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Derives d'acides de phenylalkyle et de phenoxyalkyle pour le traitement de l'hyperglycemie et de l'hypertriglyceridemie typiques du diabete de type ii et procede de preparation desdits derives
US8106095B2 (en) 2003-09-19 2012-01-31 Janssen Pharmaceutica N.V. 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
NO337041B1 (no) * 2003-09-19 2016-01-11 Janssen Pharmaceutica Nv 4-((fenoksyalkyl)tio)-fenoksyeddiksyrer og analoger, farmasøytisk preparat samt anvendelse av forbindelsene
WO2005042478A2 (fr) * 2003-09-19 2005-05-12 Janssen Pharmaceutica, N.V. Acides 4-((phenoxyalkyl)thio)-phenoxyacetiques et analogues
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US9724322B2 (en) 2003-09-19 2017-08-08 Janssen Pharmaceutica N.V. 4-(phenoxyalkyl)thio)-phenoxyacetic acids and analogs
EA009119B1 (ru) * 2003-09-19 2007-10-26 Янссен Фармацевтика Н. В. 4-((феноксиалкил)тио)феноксиуксусные кислоты и аналоги
US7301050B2 (en) 2003-09-19 2007-11-27 Janssen Pharmaceutical N.V. 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
NO338511B1 (no) * 2003-09-19 2016-08-29 Janssen Pharmaceutica Nv 4-((Fenoksyalkyl)tio)-fenoksyeddiksyrer og analoger
EA012241B1 (ru) * 2003-09-19 2009-08-28 Янссен Фармацевтика, Н.В. 4-((феноксиалкил)тио)феноксиуксусные кислоты и их аналоги
EP2100877A1 (fr) * 2003-09-19 2009-09-16 Janssen Pharmaceutica, N.V. Acides et analogues 4-((Phénoxyalkyl)thio)-phénoxyacétique
WO2005030694A1 (fr) * 2003-09-19 2005-04-07 Janssen Pharmaceutica, N.V. Acides 4-((phenoxyalkyl)thio)-phenoxyacetiques et analogues
US7635718B2 (en) 2003-09-19 2009-12-22 Janssen Pharmaceutica Nv 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
US8258177B2 (en) 2003-09-19 2012-09-04 Janssen Pharmaceutica, N.V. 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
WO2005042478A3 (fr) * 2003-09-19 2005-07-21 Janssen Pharmaceutica Nv Acides 4-((phenoxyalkyl)thio)-phenoxyacetiques et analogues
EP2243766A3 (fr) * 2003-09-19 2011-02-16 Janssen Pharmaceutica N.V. Acides et analogues 4-(phénoxyalkyl)thio)-phénoxyacétique
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US7598292B2 (en) 2003-09-19 2009-10-06 Janssen Pharmaceutica, N.V. 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
JP2007536342A (ja) * 2004-05-05 2007-12-13 ノボ　ノルディスク　アクティーゼルスカブ 新規の化合物、その製法と使用
US8053598B2 (en) 2004-05-05 2011-11-08 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US8669288B2 (en) 2005-09-14 2014-03-11 Janssen Pharmaceutica N.V. Lysine salts of 4-((phenoxyalkyl)thio)-phenoxyacetic acid derivatives
US7709682B2 (en) 2005-09-14 2010-05-04 Janssen Pharmaceutica N.V. Lysine salts of 4-((phenoxyalkyl)thio)-phenoxyacetic acid derivatives
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
EA015717B1 (ru) * 2005-12-22 2011-10-31 ХАЙ ПОЙНТ ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи Феноксиуксусные кислоты в качестве активаторов ppar дельта
US10947180B2 (en) 2005-12-22 2021-03-16 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
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US11420929B2 (en) 2005-12-22 2022-08-23 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
US7943613B2 (en) 2005-12-22 2011-05-17 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US10471066B2 (en) 2005-12-22 2019-11-12 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
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WO2007071766A2 (fr) * 2005-12-22 2007-06-28 Transtech Pharma Nouveaux composes, leur preparation et leur utilisation
US9663481B2 (en) 2005-12-22 2017-05-30 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPARδ agonists
WO2007071766A3 (fr) * 2005-12-22 2007-09-13 Novo Nordisk As Nouveaux composes, leur preparation et leur utilisation
US8362016B2 (en) 2005-12-22 2013-01-29 High Point Pharmaceuticals, Llc Phenyl propionic acids as PPAR delta activators
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US8633184B2 (en) 2006-04-18 2014-01-21 Janssen Pharmaceutica N.V. Benzoazepin-oxy-acetic acid derivatives as PPAR-delta agonists used for the increase of HDL-C, lower LDL-C and lower cholesterol
US7678786B2 (en) 2006-04-18 2010-03-16 Janssen Pharmaceutica Nv Benzoazepin-oxy-acetic acid derivatives as PPAR-delta agonists used for the increase of HDL-C, lower LDL-C and lower cholesterol
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
WO2022020376A1 (fr) * 2020-07-22 2022-01-27 Reneo Pharmaceuticals, Inc. Agoniste de ppar-delta cristallin
US11267795B2 (en) 2020-07-22 2022-03-08 Reneo Pharmaceuticals, Inc. Crystalline PPAR-delta agonist
US11713301B2 (en) 2020-07-22 2023-08-01 Reneo Pharmaceuticals, Inc. Crystalline PPARδ agonist
US11931365B2 (en) 2022-01-25 2024-03-19 Reneo Pharmaceuticals, Inc. Use of PPAR-delta agonists in the treatment of disease

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PL366401A1 (en) 2005-01-24
EP1414778A1 (fr) 2004-05-06
JP2004536150A (ja) 2004-12-02
IL159547A0 (en) 2004-06-01
KR20040019087A (ko) 2004-03-04
HUP0401575A2 (hu) 2004-11-29
BR0211414A (pt) 2004-08-17
CN1537093A (zh) 2004-10-13
NO20040389L (no) 2004-01-29
ZA200400161B (en) 2004-08-18
CZ2004133A3 (cs) 2004-06-16
CA2452665A1 (fr) 2003-02-13
MXPA04000891A (es) 2004-05-21
RU2004105956A (ru) 2005-03-27

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