Title of Invention

N-ACYL NITROGEN HETEROCYCLES AS LIGANDS OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS

Abstract

Compounds of the formula (I) provide pharmacological agents which bind to Peroxisome Proliferator-Activated Receptors (PPARs). Accordingly, the compounds of the instant invention are useful for the treatment of conditions mediated by the PPAR receptor activity in mammals. Such conditions include dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, ulcerative colitis, Crohn's disease, and conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, and Syndrome X.

Full Text

N-ACYL NITROGEN HETEROCYCLES AS LIGANDS OF PEROXISOME PROUFERATOR-ACTIVATED RECEPTORS The present invention relates to heterocyclic compounds, to pharmaceutical compositions containing them, and to methods of treating conditions mediated by the Peroxisome Prolrferator-Activated Receptor (PPAR) activity by employing such compounds. R1 is hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloatkyl; R2 is hydrogen, hydroxy, oxo, optionally substituted alkyl, aryl, aralkyl, alkoxy, aryioxy, aralkoxy, alkylthio, arylthio or aralkylthio; R3 is hydrogen; or R2 and R3 combined are alkylene which together with the carbon atoms to which they are attached form a fused 5- to 7-membered ring; or R2 and R3 combined are a bond between the carbon atoms to which they are attached; n is zero or an integer of 1 or 2; Ya is hydrogen; or Ya and R2 combined are a bond between the carbon atoms to which they are attached; R4a is hydrogen; or R4a and Ya combined are a bond between the carbon atoms to which they are attached; R" is hydrogen, optionally substituted alkyl, alkoxy or halogen; rn is an integer of 1 or 2; Yb is hydrogen; R4b is hydrogen; or R4b and Yb combined are a bond between the carbon atoms to which they are attached; R and R' are independently hydrogen, halogen, optionally substituted aikyl, alkoxy, aralkyl or heteroaralkyl; or R and R' combined together with the carbon atoms to which they are attached form an optionally substituted fused 5* to 6-membered aromatic or heteroaromatic ring provided that R and R' are attached to carbon atoms adjacent to each other; or R-C and R -C may independently be replaced by nitrogen; X, is -Z-(CH2)p-Q-W wherein Z is a bond, O, S, S(O) or S(O)2 or Z is -C(0)NR5- in which R5 is hydrogen, alkyl or aralkyl; p is an integer from 1 to 8; Q is a bond; or Q is -0(CH2)r or -S(CH2)r in which r is zero or an integer from 1 to 8; or Q is -O(CH2)^0., -S(CH2)14»0-f -S(CH2)^S- or -C(O)-; or Q is-C(0)NR6-in which R6 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or Q is -NRr-, -NR7C(O) -NR7C(O)NR8- or -NR7C(O)O- in which R7 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R6 is hydrogen, alkyl or aralkyl; W is cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; or W and R6 taken together with the nitrogen atom to which they are attached form a 8- to 12-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur, X2 is -C(R9)2, O.Sor -NR10, in which Re is hydrogen or lower alkyl; R10 is hydrogen, alkyl or araikyi; provided that W is not 2-methylquinolin-4-yl when Z is O, p is 1, Q is a bond, X2 is -C(R9)2 in which R9 is hydrogen, and Xt is located at the 4-position; or W is not 2-butyl-4-chloro-5-hydroxymethylimidazol-1-yl when Z is a bond, p is 1, Q is a bond, X2 is -NR10 in which R10 is hydrogen, and Xt is located at the 4-position; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. The compounds of the present invention bind to the Peroxisome Proliferator-Activated Receptors (PPARs) and, thus, the present invention provides pharmaceutical agents for the treatment of conditions mediated by the PPAR activity in mammals. Such conditions include dysfipidemia, hyperlipidemia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases (IBDs), ulcerative colitis, Crohn's disease, and conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated such as type-1 and type-2 diabetes, and Syndrome X. Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group, e.g., wherein an attachment point of a certain group is limited to a specific atom within that group, the point of attachment is defined by an arrow at the specific atom. The term "optionally substituted alkyl" refers to unsubstituted or substituted straight or branched chain hydrocarbon groups having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, f-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halo, hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfonamido, nitro, cyano, carboxy, alkoxycarbonyl, aryl, alkenyl, alkynyl, aralkoxy, guanidino, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolkfyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like. The term "lower alkyT refers to those alkyl groups as described above having 1 to 7, preferably 1 to 4 carbon atoms. The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine. The term "alkenyl" refers to any of the above alky! groups having at least two carbon atoms and further containing a carbon to carbon double bond at the point of attachment. Groups having two to four carbon atoms are preferred. The term "alkynyl" refers to any of the above alkyl groups having at least two carbon atoms and further containing a carbon to carbon triple bond at the point of attachment. Groups having two to four carbon atoms are preferred. The term "alkylene" refers to a straight chain bridge of 1 to 6 carbon atoms connected by single bonds (e.g., -(CH2)x- wherein x is 1 to 6), which may be interrupted with one or more heteroatoms selected from oxygen, sulfur and nitrogen, and may be substituted with 1 to 3 substituents such as alkyl, alkoxy, halo, hydroxy, cycloalkyl, alkanoyl, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkyiamino, acylamino, carbamoyl, thiol, alkylthio, alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, carboxy, alkoxycarbonyl, aryl, aralkoxy, guanidino, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like The term "cycloalkyT refers to optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon groups of 3 to 12 carbon atoms, each of which may optionally be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, amino, alkylamino, dialkyiamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, alkyl- and arylsulfonyl, sulfonamido, heterocyclyl and the like. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like. Exemplary tricyclic hydrocarbon groups include bomyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1 ]heptenyl, 6,6-dimethylbicydo[3.1.1]heptyl, 2,6,64rimethylbicycJo[3.1.1 ]heptyl, bicydo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groups include adamantyl and the like. The term "alkoxy" refers to alkyl-O-. The term "acyl" refers to alkanoyl, aroyl, heteroaroyl, arylalkanoyl or heteroarylalkanoyl. The term "alkanoyl" refers to alkyl-C(O)-. The term "alkanoyloxy" refers to alkyl-C(0)-0-. The terms "alkyfamino" and "dialkytemino" refer to alkyl-NH- and (alkyl)2N-t respectively. The term "alkanoylamino" refers to alkyl-C(0)-NH-. The term "alkylthio" refers to alkyl-S-. The term "alkylaminothiocarbonyl" refers to alkyl-NHC(S)-. The term Iriafkylsilyr refers to (alkyl)3SiO- The term "trialkylsilyloxy" refers to (alkyl)3SiO-. The term "alkylthiono" refers to alkyl-S(O)-. The term "alkylsulfonyT refers to a!kyi-S(0)2-. The term "alkoxycarbonyT refers to alkyl-O-C(O)-. The term "alkoxycarbonyloxy" refers to alkyl-0-C(0)0. The term "carbamoyl" refers to alkyl-NHC(Oh (alkyl)2NC(0)-, aryl-NHC(O)-. alkyl(aryl)- NC(O)-, heteroaryl-NHC(O)-, alkyi(heteroaryI)-NC(0)-, aralkyl-NHC(O)- and alkyl(aralkyl)-NC(O). The term "aryl" refers to monocyclic or tricyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups, each of which may optionally be substituted by one to four substituents, such as alkyl, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, optionally substituted amino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, alkylthiono, alkyl- and arylsulfonyl, sulfonamkto, heterocycloyl and the like. The term "monocyclic aryl refers to optionally substituted phenyl as described under aryl. The term "aralkyl refers to an aryl group bonded directly through an alkyl group, such as benzyl. The term "aralkylthio" refers to aralkyl-S-. The term "aralkoxy" refers to an aryl group bonded directly through an alkoxy group. The term "arylsulfonyl" refers to aryl-S(0)2-. The term "arylthio" refers to aryl-S-. The term "aroyl" refers to aryl-C(O)-. The term "aroylamino" refers to aryl-C(0)-NH-. The term "aryloxycarbonyl" refers to aryl-O-C(O)-. The term "heterocyclyr or "heterocyclo" refers to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic cyclic group, for example, which is a 4- to 7-membered monocyclic, 7- to 12-membered bicycfic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The heterocyclic group may be attached at a heteroatom or a carbon atom. Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, triazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, rsoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyi, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyt, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyi, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dk>xolane and tetrahydro-1,l-dioxothienyl and the like. Exemplary bicyclic heterocyclic groups include indolyl, dihydroidolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyi, benzothiazinyl, quinudidinyl, quinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, tsoquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, benzimidazolyf, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyi, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2f3-c}pyridinyl, furo[3,2-b]-pyridinyIJ or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl)l phthalazinyl and the like-Exemplary tricyclic heterocyclic groups include carbazolyl, dibenzoazepinyt, dithienoazepinyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyi, phenoxazinyl, phenothiazinyl, xanthenyl, carbolinyl and the like. The term "heterocyclyT includes substituted heterocyclic groups. Substituted heterocyclic groups refer to heterocyclic groups substituted with 1, 2 or 3 substituents selected from the group consisting of: (a) alkyl; (b) hydroxy (or protected hydroxy); (c) halo; (d) oxo (i.e. =0); (e) optionally substituted amino, alkylamino or dialkylamino; (f) alkoxy; (g) cycloalkyl; (h) carboxy; (i) heterocydooxy: 0) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl; (k) mercapto; (I) nitro; (m) cyano; (n) sulfonamido, sulfonamidoalkyl, sulfonamidoaryl or sulfonamidodialkyl; (o) alkylcarbonyloxy; (p) arylcarbonyloxy; (q) arylthio; (r) aryloxy; (s) alkylthb; (t) formyl; (u) carbamoyl; (v) aralkyl; or (w) aryl substituted with alkyl, cydoalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino or halo. The term "heterocyctooxy" denotes a heterocyclic group bonded through an oxygen bridge. The term "heteroaryl" refers to an aromatic heterocyde, for example monocyclic or bicydic aryl, such as pyrrolyl, pyrazolyl, imidazolyt, oxazolyl, tsoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl and the like; optionally substituted by, e.g., lower alkyl, lower alkoxy or halo. The term "heteroarylsulfonyT refers to heteroaryl-S(0)2-. The term "heteroaroyl" refers to heteroaroyl-C(O)-. The term "heteroaralkyl" refer to a heteroaryl group bonded through an alkyl group. Pharmaceutically acceptable salts of any compound of the present invention refer to salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris(hydroxymethyl)-methyl-ammonium salts, and salts with amino acids. Similarly add addition salts, such as those formed with mineral adds, organic carboxylic acids and organic sulfonic acids, e.g., hydrochloric add, maleic add and methanesulfonic acid, are possible provided a basic group, such as pyridyl or oxazolyl, constitutes part of the structure. Prodrug derivatives of any compound of the invention are derivatives of said compounds which following administration release the parent compound in vivo via some chemical or physiological process, e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the parent compound. Exemplary prodrug derivatives are, e.g., esters of free carboxylic acids and S-acyl and O-acyl derivatives of thiols, alcohols or phenols, wherein aryl has a meaning as defined herein. Preferred are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyi esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono or disubstituted tower alkyl esters such as the ©-(amino, mono* or di-lower alkylamino, carboxy, lower alkoxycarbonyf)-lower alkyl esters, the (lower alkanoybxy, tower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester, and the like conventionally used in the art. The compounds of the invention depending on the nature of the substituents, may possess one or more asymmetric centers. The resulting diastereoisomers, optical isomers, i.e., enantiomers, and geometric isomers are encompassed by the instant invention. As described herein above, the present invention provides phenyiacetic acid derivatives of formula (I), pharmaceutical compositions containing them, methods for preparing such compounds and methods of treating conditions mediated by the PPAR activity by administration of a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. R2 is hydrogen, hydroxy, oxo, optionally substituted alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio or aralkytthio; R3 is hydrogen; or R2 and R3 combined are alkylene which together with the carbon atoms to which they are attached form a fused 5- to 7-rnembered ring; or R2 and R3 combined are a bond between the carbon atoms to which they are attached; nis 1; Ya is hydrogen; or Ya and R2 combined are a bond between the carbon atoms to which they are attached; R4a is hydrogen; or R4a, and Ya combined are a bond between the carbon atoms to which they are attached; R" is hydrogen, optionally substituted alkyl, alkoxy or halogen; mis 1; Yb is hydrogen; R4b is hydrogen; or R4b and Yb combined are a bond between the carbon atoms to which they are attached; R and R' are independently hydrogen, halogen, optionally substituted alkyl, alkoxy, aralkyl or heteroaralkyl; or R and R' combined together with the carbon atoms to which they are attached form an optionally substituted fused 5- to 6-membered aromatic or heteroaromatic ring provided that R and Rf are attached to carbon atoms adjacent to each other, or Z is a bond, O or S; p is an integer from 1 to 8; Q is a bond; or Q is -0(CH2)r or -S(CH2)r in which r is zero or an integer from 1 to 8; or Q is -C(0)NR6- in which R6 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or Q is -NRT-, -NR7C(Oh -NR7C(0)NR8- or -NR7C(0)O in which R7 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Ra is hydrogen, alkyl or aralkyl; W is cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; or W and Re taken together with the nitrogen atom to which they are attached form a 8-to 12-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; X2 is -C(R9)r. O , S or -NR10- in which R9 is hydrogen or lower alkyl; Rto is hydrogen or lower alkyl; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutical^ acceptable salt thereof. Preferred are the compounds of formula (IA) wherein R, is hydrogen or optionally substituted alkyl; R2 and R3 are hydrogen; Y8 and Yb are hydrogen; R4a and R4b are hydrogen; R and Rr are independently hydrogen, halogen, optionally substituted C1-6 alkyl or C1-6 alkoxy; p is an integer from 1 to 5; Q is a bond; or Q is -0(CH2)r or -S(CH2)r in which r is zero or 1; or Q is -C(0)NR6- in which R6 is hydrogen or lower alkyl; or Q is -NFV, -NR7C(O) -NR7C(0)NR6- or -NR7C(0)0- in which R7 is hydrogen or optionally substituted alkyl; Re is hydrogen or alkyl; X2 is -C(R9)2-. O , S or -NR10- in which R9 is hydrogen or methyl; R10 is hydrogen; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutical^ acceptable salt thereof. More preferred are the compounds of formula (IA) wherein R, R' and R" are hydrogen; Q is a bond; or Q is -O(CH2)r or -S(CH2)r in which r is zero; or Q is -NR7-, -NR7C(O) -NR7C(0)NR8- or -NR7C(0)0- in which R7 is hydrogen or optionally substituted lower alkyl; W is cycloalkyl, aryl or heterocyclyl; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutical^ acceptable salt thereof. Most preferred are the compounds of formula (IA), wherein the asymmetric center in radical L is in the (R) configuration; or a pharmaceutical^ acceptable salt thereof. Most preferred are also the compounds of formula (IA), wherein X2 is -C(R9)2- in which Rg is methyl; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutical^ acceptable salt thereof. Most preferred are also the compounds of formula (IA) having the formula wherein R1 is hydrogen or optionally substituted alkyl; Z is a bond, O or S; p is an integer from 1 to 3; Q is a bond, O or S; or Q is -NR7C(0)- in which R7 is hydrogen or optionally substituted lower alkyl; W is aryl or heterocyclyl; X2 is -C(Rfl)2-, O , S or -NH- in which R9 is hydrogen or methyl; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. Preferred are the compounds of formula (IB) wherein Z is O or S; p is an integer of 2 or 3; Q is O or S; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. Preferred are also the compounds of formula (IB), designated as the A group, wherein Z is bond, O or S; p is an integer of 1 or 2; Q is a bond; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. Preferred are the compounds in the A group wherein Z is O; p is 1; X2 Is -C(R9)2- in which R9 is methyl; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. Further preferred are the compounds in the A group wherein the asymmetric center in radical L is in the (R) configuration; or a pharmaceutically acceptable salt thereof. Preferred are also the compounds of formula (IB) wherein Z is O or S; p is 2; Q is a bond; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. Preferred are also the compounds of formula (IB) wherein Z is a bond; pisl; Q is -NR7C(O)- in which R7 is hydrogen or methyl; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. Most preferred are also the compounds of formula (IA) having the formula wherein R1 is hydrogen or optionally substituted alkyl; Z is a bond, O or S; p is an integer from 1 to 3; Q is a bond, O or S; or Q is -NR7C(0)- in which R7 is hydrogen or optionally substituted lower alkyl; W is aryl or heterocyclyl; X2 is -C(R9)2-, O , S or -NH- in which R9 is hydrogen or methyl; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceuticaliy acceptable salt thereof. Preferred are the compounds of formula (IC) wherein Z is O or S; p is an integer of 2 or 3; Q is O or S; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. Preferred are also the compounds of formula (IC), designated as the B group, wherein 2 is bond, O or S; p is an integer of 1 or 2; Q is a bond; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. Preferred are the compounds in the B group wherein Z is O; p is l; X2 is -C(R9)2 in which R9 is methyl; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. Further preferred are the compounds in the B group wherein the asymmetric center in radical L is in the (R) configuration; or a pharmaceutically acceptable salt thereof. Preferred are also the compounds of formula (IC) wherein Z is O or S; p is 2; Q is a bond; W is selected from the group consisting of: Compounds of formula (I) wherein X2 represents -C(R9)2- in which R9 has a meaning as defined herein may be prepared by reacting an activated derivative of a carboxylic acid of the formula wherein R and R' have meanings as defined herein, X1 represents X1 as defined herein, or X1/ is a groups convertible to X1 and X2 represents -C(R9)2 in which R9 has a meaning as defined herein, with an amine of the formula in which R1, R2, R3, R4a Ya, n, R", R4b, Yb and m have meanings as defined herein, to afford compounds of the formula wherein R, R1, X1 and X2 have meanings as defined for formula (IV), and L is a radical selected from the group consisting of: in which Ri R2, R3 R4a. Ya, n, R' R4b, Yb and m have meanings as defined herein above. Amines of formula (II') and (III') may be obtained by methods described herein or modifications thereof, or by methods generally known in the art. In the processes cited herein, activated derivatives of carboxylic acids, e.g., those corresponding to carboxylic acids of formula (IV), include add chlorides, bromides and fluorides, mixed anhydrides, lower alkyl esters and activated esters thereof, and adducts formed with coupling agents, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetramethyluronium tetrafluoroborate and the like. Mixed anhydrides are preferably such from pivalic acid, or lower alkyl hemiesters of carbonic acids, such as ethyl or tsobutyl analogs. Activated esters include, for example, succinirnido, phthalimido or 4-nitrophenyl esters. The reaction of an activated derivative of a carboxylic acid, e.g., those corresponding to carboxylic acids of formula (IV), with an amine, e.g., those of formula (II1) and (III9), may be carried out in the presence of a base, such as triethylamine (TEA), diisopropylethylamine (DIEA) or N-methylmorpholine (NMM) in an inert organic solvent, such as dichloromethane (DCM), N,N-dimethylformamide (DMF) or tetrahydrofuran (THF). Carboxylic acids of formula (IV) can be converted to their activated derivatives using methods described herein or according to methods generally known in the art. Compounds of formula (I) wherein X2 is O, S or -NR10- in which R10 has a meaning as defined herein may be prepared, e.g., by first converting amines of formula (II) or (III) to carbamoyl chlorides of the formula wherein Rl R2, R3, R4a. Ya, n, R", R4b ,Yb and m have meanings as defined herein, by treatment with a reagent such as phosgene, or analogs thereof, in the presence of a base, such as TEA, DIEA or NMM, in an inert solvent such DCM, DMF or THF. Carbamoyl chlorides of formula (V) or (VI) may then be reacted with a compound of the formula wherein R and R' have meanings as defined herein, X1 represents X1 as defined herein, or X1 is a groups convertible to X1 and X2 is O, S or -NR10- in which R10 has a meaning as defined herein, in the presence of a base, such as potassium or cesium carbonate, in an organic solvent, such as THF or DMF, to afford compounds of formula (I*) wherein X2 is O, S or -NR10- in which R10 has a meaning as defined herein. Compounds of formula (I*) wherein X1 represents X1 as defined herein can be obtained from compounds of formula (P) wherein X1 is a group convertible to X1 using methods described herein or modifications thereof, or using methods well known in the art. For example, compounds of the formula wherein R, R', X2 and L have meanings as defined herein, Z is O or S, and Pg represents a protecting group, such as benzyl, trialkylsilyl, e.g., f-butyldimethylsilyi, or acyl, may be converted to compounds of the formula wherein R, R', X2, L and Z have meanings as defined for formula (la'), according to methods described herein in the illustrative Examples or using conditions generally known in the art. Compounds of formula (lbr) may then be treated with an alkylating agent of the formula wherein p, Q and W have meanings as defined herein and Lg represents a leaving group, such as iodide, bromide, chloride or trifiuoromethanesulfonate, in the presence of a base, such as potassium or cesium carbonate, in an inert solvent, such as THF or DMF, to form compounds of formula (P) wherein X1' is -Z-(CH2)p-Q-W in which Z is O or S, and p, Q and W have meanings as defined herein. Preferably, the alkylating agent of formula (VIII) is selected from a group wherein p is an integer of 2 or 3, Q is O or S, Lg is chloride or bromide and W is or the alkylating agent of formula (VIII) is selected from a group wherein p is 2, Q is a bond, Lg is chloride or bromide and W is The alkylating agents of formula (VIII) may be prepared using methods described herein or modifications thereof, or using methods known in the art, e.g., 4-chloromethyl-5-methyl-2-phenyloxazole and 4-chloromethyl-5-methyl-2-[4-(trifluoromethyl)-phenyl]-oxa2ole may be prepared using methods described in International PCT Patent Application No. WO 00/64888 or according to J. Med. Chem., Vol. 43, pp. 995-1010 (2000). 1-(3-Bromo-propoxy)-4-phenoxy-2-propyI-benzene may be prepared as described in International PCT Patent Application No. WO 00/78312. wherein p, Q and W have meanings defined herein, under Mitsunobu conditions, e.g., in the presence of triphenylphoshine and diethyl azodicarboxylate in an organic solvent, such as THF, to afford compounds of formula (V) wherein X1 is -Z-(CH2)P-Q-W in which Z is O or S, and p, Q and W have meanings as defined herein. Alcohols of formula (Vlir) may be prepared by methods described herein or modifications thereof, or by methods well known in the art Compounds of formula (I') wherein X1 is -Z-(CH2)P-Q-W in which Z is a bond, p and W have meanings as defined herein, and Q represents O or S, may be obtained, e.g., by treating compounds of the formula wherein R, R,' p, X2 and L have meanings as defined herein, with phenols of formula W-OH or thiols of formula W-SH, e.g., under Mitsunobu conditions, to form compounds of formula (P) wherein R, R\ X2 and L have meanings as defined herein, and X1' represents -Z-(CH2)P-Q-W, in which Z is a bond, p and W have meanings as defined herein, and Q is O or S, respectively. Compounds of formula (IX) may be prepared by methods described herein or modifications thereof, or by methods generally known in the art. Alternatively, alcohols of formula (IX) may be converted to compounds of the formula wherein R, R', p, X2 and L have meanings as defined herein and Lg represents a leaving group, such as iodide, chloride, bromide or trifluorosulfonate, using methods described herein or modifications thereof, or using methods well-known in the art. Subsequent reaction of compounds of formula (X) with a phenol of formula W-OH or a thiol of formula W-SH in the presence of a base, such as potassium or cesium carbonate, in an inert solvent, such as DMF or THF, affords compounds of formula (I') wherein R, R', X2 and L have meanings as defined herein, and X1 represents -Z-(CH2)P-Q-W, in which Z is a bond, p and W have meanings as defined herein, and Q is O or S, respectively. Compounds of formula (P) wherein R, R', X2 and L have meanings as defined herein, and X1 represents -Z-(CH2)P-Q-W in which Z is -C(0)NR5- and R5, p. Q and W have meanings as defined herein, may be prepared by reacting an activated derivative of a carboxyiic acid corresponding to a carboxyiic acid of the formula wherein R, R', X2 and L have meanings as defined herein, with amines, or acid addition salts thereof, of the formula wherein R5, p, Q and W have meanings as defined herein. Carboxyiic acids of formula (XI) and amines of formula (XII) may be prepared using methods described herein or modifications thereof, or using methods generally known in the art Similarly, compounds of formula (P) wherein R, R', X2 and L have meanings as defined herein, and X/ represents -Z-(CH2)p-Q-W wherein Z, p and W have meanings as defined herein, and Q is -C(0)NR6- in which R6 has a meaning as defined herein, may be prepared by reacting an activated derivative of a carboxyiic acid corresponding to a carboxyiic acid of the formula wherein R, R', X2 L, Z and p have meanings as defined herein, with amines, or acid addition salts thereof, of the formula wherein R6 and W have meanings as defined herein above. Carboxyiic acids of formula (XIII) and amines of formula (XIV) may be prepared using methods described herein or modifications thereof, or using methods known in the art. Compounds of formula (P) wherein R, R', X2 and L have meanings as defined herein, and X1 represents -Z-(CH2)P-Q-W wherein Z, p and W have meanings as defined herein, and Q is -NR7C(O) -NR7C(0)NR8- or -NR7C(0)O in which R7 and R6 have meanings as defined herein, may be obtained by reacting amines of the formula wherein R1 R', X2, L, Z, p and R7 have meanings as defined herein, with a N-derivatizing agent, such as an activated derivative of a carboxylic acid, an isocyanate or a chloroformate, respectively, in the presence of a base, such as TEA, DIEA or NMM, in an inert solvent, such as DCM, DMF or THF. Amines of formula (XV) may be prepared using methods described herein or modifications thereof, or using methods generally known in the art. Preferably, the N-derivatizing agent is an activated derivative of a carboxylic acid of the formula Compounds of formula (I') in which R, R', X2 ,L and X1 have meanings as defined herein, and R1 is optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl can be converted to compounds of the formula (V) in which R, is hydrogen using reaction conditions described herein or modifications thereof, or using methods know in the art, e.g., compounds of formula (V) in which R1 is lower alkyl, such as methyl or ethyl, may be treated with an aqueous base, such as sodium, lithium or potassium hydroxide, in a polar solvent, such as methanol, ethanol, 1,4-dioxane or THF, to afford compounds of formula (V) in which R, R', X2, L and X1' have meanings as defined herein, and R1 is hydrogen. The starting compounds and intermediates which are converted to the compounds of the invention in a manner described herein, functional groups present, such as amino, thiol, carboxyl and hydroxy groups, are optionally protected by conventional protecting groups that are common in preparative organic chemistry. Protected amino, thiol, carboxyl and hydroxy groups are those that can be converted under mild conditions into free amino, thiol, carboxyl and hydroxy groups without the molecular framework being destroyed or other undesired side reactions taking place. The purpose of introducing protecting groups is to protect the functional groups from undesired reactions with reaction components under the conditions used for carrying out a desired chemical transformation. The need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxy! group, amino group, etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions. Well-known protecting groups that meet these conditions and their introduction and removal are described, e.g., in McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, NY (1973); and Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, Inc., NY (1999). The above-mentioned reactions are earned out according to standard methods, in the presence or absence of diluent, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at tow temperatures, RT or elevated temperatures (preferably at or near the boiling point of the solvents used), and at atmospheric or super-atmospheric pressure. The preferred solvents, catalysts and reaction conditions are set forth in the appended illustrative Examples. The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes. Compounds of the invention and intermediates can also be converted into each other according to methods generally known per $e. The invention also relates to any novel starting materials and processes for their manufacture. Depending on the choice of starting materials and methods, the compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, optical isomers (antipodes), racemates or mixtures thereof. The aforesaid possible isomers or mixtures thereof are within the purview of this invention. Any resulting mixtures of isomers can be separated on the basis of the physico-chemical differences of the constituents, into the pure geometric or optical isomers, diastereoisomers, racemates, for example, by chromatography and/or fractional crystallization. Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereoisomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. The carboxylic acid intermediates can thus be resolved into their optical antipodes, e.g., by fractional crystallization of D- or L-(alpha-methy!benzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, brucine or strychnine)-salts. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography using a chiral adsorbent. Finally, compounds of the invention are either obtained in the free form, or as a salt thereof if salt forming groups are present. Acidic compounds of the invention may be converted into salts with pharmaceutically acceptable bases, e.g., an aqueous alkali metal hydroxide, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the solutions of the latter, the salts may be precipitated with ethers, e.g., diethyl ether. Resulting salts may be converted into the free compounds by treatment with acids. These or other salts can also be used for purification of the compounds obtained. Compounds of the invention having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts. These are formed, for example, with inorganic acids, such as mineral acids, for example, sulfuric acid, a phosphoric or hydrohalic acid; or with organic carboxylic acids, such as (C1-C4)-alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, for example, acetic acid, such as saturated or unsaturated dicarboxylic acids, for example, oxalic, succinic, maleic or fumaric acid, such as hydroxy-carboxyfic acids, for example, glycolic, lactic, malic, tartaric or citric acid, such as amino adds, for example, aspartic or glutamic add; or with organic sulfonic adds, such as (C1-C4)-alkyl-sulfonic adds, for example, methanesulfonic acid; or arylsulfonic adds which are unsubstituted or substituted, for example, by halogen. Preferred are salts formed with hydrochloric add, methanesulfonic acid and maleic acid. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the drcumstances. The compounds, induding their salts, can also be obtained in the form of their hydrates, or indude other solvents used for their crystallization. The pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal or parenteral administration to mammals, induding man, for the treatment of conditions mediated by PPAR receptors, in particular, PPARou Such conditions indude dyslipidemia, hyperiipidemia, hypercholesteremia, atherosderosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, IBDs, ulcerative colitis, Crohn's disease, and conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, and Syndrome X. The said pharmaceutical compositions comprise an effective amount of a pharmacologically active compound of the instant invention, alone or in combination with one or more pharmaceutically acceptable carriers. The pharmacologically active compounds of the invention may be employed in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with exdpients or carriers suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glydne; b) lubricants, e.g., silica, talcum, stearic add, its magnesium or caldum salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic add or its sodium salt, or effervescent mixtures; and/or e) absorbants, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, preferably about 1-50%, of the active ingredient. Suitable compositions for transdermal application include a therapeutically effective amount of a compound of the invention with a carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host Characteristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. The present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with one or more pharmaceutically acceptable carriers. Thus, the present invention provides pharmaceutical compositions as described above for the treatment of conditions mediated by PPARs, preferably, dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, IBDs, ulcerative colitis, Crohn's disease, and conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, and Syndrome X. The pharmaceutical compositions may contain a therapeutically effective amount of a compound of the invention as defined above, either alone or in a combination with another therapeutic agent, e.g., each at an effective therapeutic dose as reported in the art. Such therapeutic agents include insulin, insulin derivatives and mimetics; insulin secretagogues, such as the sulfonylureas, e.g.. Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands, such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizers, such as protein tyrosine phosphatase-1B (PTP-1B) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB-517955. SB-4195052, SB-216763, NN-57-05441, NN-57-05445 or RXR ligands such as GW-0791, AGN-194204; sodium-dependent glucose cotransporter inhibitors, such as T-1095; glycogen phosphorylase A inhibitors, such as BAY R3401; biguanides, such as metformin; alpha-glucosidase inhibitors, such as acarbose; GLP-1 (glucagon Bke peptide-1), GLP-1 analogs, such as Exendin-4, and GLP-1 mimetics; DPPIV (dipeptidyl peptidase IV) inhibitors such as LAF237; hypolipidemic agents, such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, , e.g., iovastatin, pravastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dafvastatin, atorvastatin, rosuvastatin and rivastatin, squalene synthase inhibitors or FXR (farnesoid X receptor) and LXR (liver X receptor) ligands, cholestyramine, fibrates, nicotinic acid and aspirin; anti-obesity agents, such as orlistat; anti-hypertensive agents, e.g., loop diuretics, such as ethacrynic acid, furosemide and torsemide; angiotensin converting enzyme (ACE) inhibitors, such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolaprii; inhibitors of the Na-K-ATPase membrane pump, such as digoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors, such as omapatriiat, sampatrilat and fasidotril; angiotensin II antagonists, such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan; p-adrenergic receptor blockers, such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agents, such as digoxin, dobutamine and milrinone; calcium channel blockers, such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists and aldosterone synthase inhibitors. Other specific antidiabetic compounds are described by Patel Mona in Expert Opin Investig Drugs, 2003,12(4), 623-633, in the figures 1 to 7, which are herein incorporated by reference. A compound of the present invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation. The structure of the active agents identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g., Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Accordingly, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a therapeutically effective amount of another therapeutic agent, preferably selected from antidiabetics, hypolipidemic agents, anti-obesity agents, anti-hypertensive agents or inotropic agents, most preferably from antidiabetics or hypolipidemic agents as described above. The present invention further relates to pharmaceutical compositions as described above for use as a medicament. Thus, the present invention relates to use of pharmaceutical compositions or combinations as described above for the preparation of a medicament for the treatment of conditions mediated by PPARs, preferably, dyslipidemia, hyperliptdemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, IBDs, ulcerative colitis, Crohn's disease, and conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, and Syndrome X. A unit dosage for a mammal of about 50-70 kg may contain between about 1 mg and 1000 mg, advantageously between about 5-500 mg of the active ingredient. The therapeutically effective dosage of active compound is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, on the form of administration, and on the compound involved. The compounds of the present invention bind to PPARs, and thus may be employed for the treatment of conditions mediated by the PPARs. Such compounds may therefore be employed therapeutically for the treatment of dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, IBDs, ulcerative colitis, Crohn's disease, and conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, and Syndrome X. Thus, the present invention also relates to a compound of formula (I) for use as a medicament; to the use of a compound of formula (I) for the preparation of a pharmaceutical composition for the prevention and/or treatment of conditions mediated by PPARs; and to a pharmaceutical composition for use in conditions mediated by PPARs comprising a compound of formula (I) in free form or pharmaceutically acceptable salt form in association with a pharmaceutically acceptable diluent or carrier therefore. Furthermore, the present invention provides a method for the prevention and/or treatment of conditions mediated by PPARs, which comprises administering a therapeutically effective amount of a compound of the present invention. In accordance with the foregoing the present invention also provides a therapeutic combination, e.g., a kit, kit of parts, e.g., for use in any method as defined herein, comprising a compound of formula (I), in free form or in pharmaceutically acceptable salt form, to be used concomitantly or in sequence with at least one pharmaceutical composition comprising at least another therapeutic agent, preferably selected from antidiabetics, hypolipidemic agents, anti-obesity agents, anti-hypertensive agents or inotropic agents. The kit may comprise instructions for its administration. Similarly, the present invention provides a kit of parts comprising: (i) a pharmaceutical composition of the invention; and (ii) a pharmaceutical composition comprising a compound selected from an antidiabetic, anti-obesity agent, anti-hypertensive agent, inotropic agent or hypolipidemic agent, or a pharmaceutically acceptable salt thereof, in the form of two separate units of the components (i) to (ii). Likewise, the present invention provides a method as defined above comprising coadministration, e.g., concomitantly or in sequence, of a therapeutically effective amount of a compound of formula (I) in free form or in pharmaceutically acceptable salt form, and a second drug substance, said second drug substance being a antidiabetic, anti-obesity agent anti-hypertensive agent, inotropic agent or hypolipidemic agent, e.g., as indicated above. Preferably, a compound of the invention is administered to a mammal in need thereof. Preferably, a compound of the invention is used for the treatment of a disease which responds to modulation of the PPAR activity, particularly, PPARa activity. Preferably, the conditions associated with PPAR activity are selected from dysfipidemia, hyperiipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, IBDs, ulcerative colitis, Crohn's disease, and conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, and Syndrome X. Finally, the present invention provides a method or use which comprises administering a compound of formula (I) in combination with a therapeutically effective amount of an antidiabetic agent, anti-obesity agent, anti-hypertensive agent, inotropic agent or hypolipidemic agent. Ultimately, the present invention provides a method or use which comprises administering a compound of formula (I) in the form of a pharmaceutical composition as described herein. As used throughout the specification and in the claims, the term "treatment* embraces all the different forms or modes of treatment as known to those of the pertinent art and in particular includes preventive, curative, delay of progression and palliative treatment The above-cited properties are demonstrable in vitro and in vivo tests, using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. Said compounds can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enteralty, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about -5 -10 10 molar and 10 molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 1 and 500 mg/kg, preferably between about 5 and 100 mg/kg. The activity of a compound according to the invention can be assessed by the following methods or methods well-described in the art: The in vitro functional binding to the PPARα, PPARδ and PPARγ receptors is determined as follows: The functional binding assays for the PPARα, PPARδ and PPARγ receptors are a variation of the coactivator-dependent receptor ligand assay (CARLA) (see Krey et al., "Fatty Acids, Eicosanoids, and Hypolipidemic Agents Identified as Ligands of Peroxisome Proliferator-Activated Receptors by Coactivator-Dependent Receptor Ligand Assay", Molecular Endocrinology, Vol. 11, pp. 779-791 (1997)). The present CARLA assays use a TR-FRET detection method previously reviewed (see Hemmiia, "LANCE: Homogeneous Assay Platform for HTS"\ J. 8/omo/. Screening, Vol. 4, pp. 303-307 (1999); Mathis, "HTRF Technology", J. Bhmol. Screening, Vol. 4, pp. 309-313 (1999)). All assays included 3 nM of the glutathione-S-transferase (GST) fusion proteins of either the hPPARa ligand binding domain (LBD) (amino acids 167-468) (GST-hPPARa LBD), GST-hPPAR5 LBD (amino acids 139-442) or GST-hPPARy LBD (amino acids 175-476); 3 nM Eu-labeled anti-GST antibody (Wallac); 30 nM biotinylated steroid receptor coacttvator-1 (SRC-1) peptide (an N-terminal biotinylated peptide, CPSSHSSLTERHKILHRLLQEGSPS, derived from amino acids 676-700 of SRC-1); and 10 nM streptavidin-labelled altophycocyanin (APC; Prozyrne). The binding of a ligand to a PPAR LBD alters the conformation of the LBD and permits the biotinylated SRC-1 peptide to bind. This brings the Eu-labeled anti-GST antibody and the strepavidin-labeled APC in dose proximity, thereby facilitating fluorescence energy transfer. The biotinylated SRC-1 peptide is prepared by standard solid-phase peptide synthetic methods. The GST-PPAR LBDs are expressed in pGEX vectors (Amersham Pharmacia) in the E. colt strain BL21(DE3) using standard expression conditions at 18°C. In some cases the GST-PPAR LBDs are co-expressed with groESL. The GST fusion proteins are purified on glutathione sepharose affinity columns (Amersham Pharmacia) using the method described by the manufacturer. The assay buffer contained 50 rnM Tris pH 7.4, 50 mM KCI, 0.1% BSA and 1 mM DTT (dithiothreitol). The assay is earned out in black half area 96-well plates in a final volume of 25 pL. After mixing all components, the reaction mixture stands for 3 hours at RT before reading the TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer) signal on a Wallac Victor 2 plate reader (measuring the ratio of signals at 665 nM and 620 nM). EC50 values are estimated with the Excel add-in program XLFit (ID Business Solutions, Guildford, Surrey, UK) utilizing a 4-parameter logistic equation. The glucose and insulin lowering activity in vivo can be evaluated as follows: Adult male C57BL ob/ob mice (Jackson Lab, Bar Harbor, ME) at the age of 11 weeks are housed six per cage in a reversed light cycle room (light on from 6:00 p.m. to 6:00 a.m.) and given access to Purina rodent chow and water ad libitum. On day 1, tail blood samples are taken at 8:00 am and plasma glucose levels are determined. The animals are randomLy assigned to the control and compound groups. The means of plasma glucose values of the groups were matched. Animals are then orally dosed with vehicle (0.5% carboxymethyl-cellulose with 0.2% Tween-80) or compounds (at 30 mg/kg) in vehicle. The mice are dosed daily for a total of 3 days. On day 4, basal blood samples are taken. The plasma samples are analyzed for glucose concentrations using a YSI2700 Dual Channel Biochemistry Analyzer (Yellow Springs Instrument Co., Yellow Springs, OH) and insulin concentrations using an ELISA assay. illustrative of the invention, the compound of Example 9 demonstrates an EC50 of about 3 nM in the PPARa receptor binding assay and an EC50 of about 1800 nM in the PPARy receptor binding assay. The following Examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centrigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 10 and 100 mmHg. The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR and NMR. Abbreviations used are those conventional in the art. Example 1 (R)-1-2-[3-(5-Methyl-2-phenyl-oxazo-4-ylmethoxy)-phenyl]-acetyl}-pyrrolidine-2-carboxylic acid A. (R)-1-[2-(3-Hydroxy-phenyl)-acetyl]-pyrrolidine-2-carboxyiic acid ethyl ester To a suspension of 3-hydroxy phenylacetic acid (1.52 g, 10.0 mmol) in 10 mL of DCM is added L-proline methyl ester hydrochloride (1.80 g, 10.0 mmol) followed by the addition of TEA (1.67 mL, 12 mmol), 1-hydroxybenzotriazole (HOBt, 1.17 g, 10 mmol), and EDCI (1.92 g, 10 mmol). The mixture is stirred at RT for 4 days. Ethyl acetate and water is added, and the organic layer is separated and washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude mixture is purified by flash chromatography (silica gel) eluting with hexanerethyl acetate (1:2) to give (R)-1-[2-(3-hydroxy-phenyl)-acetyl]-pyrrolidine-2-carboxylic acid ethyl ester as an oil. What is claimed is: Rn is hydrogen, optionally substituted alky!, aryl, heteroaryl, aralkyl or cycloalkyl; R2 is hydrogen, hydroxy, oxo, optionally substituted alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, aikylthio, arylthio or aralkylthio; R3 is hydrogen; or R2 and R3 combined are alkylene which together with the carbon atoms to which they are attached form a fused 5- to 7-membered ring; or R2 and R3 combined are a bond between the carbon atoms to which they are attached; n is zero or an integer of 1 or 2; Ya is hydrogen; or Ya and R2 combined are a bond between the carbon atoms to which they are attached; R4a is hydrogen; or R4a and Ya combined are a bond between the carbon atoms to which they are attached; R" is hydrogen, optionally substituted alkyl, alkoxy or halogen; m is an integer of 1 or 2; Yb is hydrogen; R4b is hydrogen; or R4b and Yb combined are a bond between the carbon atoms to which they are attached; R and R' are independently hydrogen, halogen, optionally substituted alkyl, aikoxy, aralkyf or heteroaralkyl; or R and R' combined together with the carbon atoms to which they are attached form an optionally substituted fused 5- to 6-membered aromatic or heteroaromatic ring provided that R and R' are attached to carbon atoms adjacent to each other, or R-C and R-C may independently be replaced by nitrogen; X, is -Z-(CH2)P-Q-W wherein Z is a bond, O, S, S(O) or S(O)2; or Z is -C(0)NR5- in which Rs is hydrogen, alkyl or aralkyl; p is an integer from 1 to 8; Q is a bond; or Q is -0(CH2)r or -S(CH2)r- in which r is zero or an integer from 1 to 8; or Q is -0(CH2)1-8 O-, -S(CH2),1-8 O-, -S(CH2)1-8S- or -C(O)-; or Q is -C(0)NR6- in which R6 is hydrogen, optionally substituted alkyl, cydpalkyl, aryl, heieroaryl, aralkyl or heteroaralkyl; or Q is -NR7-, -NR7C(Oh -NR7C(0)NR6- or -NR7C(O)O- in which R7 is hydrogen, optionally substituted alkyl, cycfoalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R6 is hydrogen, alkyl or aralkyl; W is cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; or W and R6 taken together with the nitrogen atom to which they are attached form a 8- to 12-membered bicyclic ring, which may be optional!/ substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; X2 is -C(R9)2, O , S or -NR10- in which R9 is hydrogen or lower alkyl; R10 is hydrogen, alkyl or aralkyl; provided that W is not 2-methylquinolin-4-yl when Z is O, p is 1, Q is a bond, X2 is -C(R9)2- in which R9 is hydrogen, and Xt is located at the 4-position; or W is not 2-butyl-4-chloro-5-hydroxymethylimidazoM-yl when Z is a bond, p is 1, Q is a bond, X2 is -NR10- in wNch R10 is hydrogen, and X* is located at the 4-position; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. in which Ri is hydrogen, optionally substituted alkyl, aryl, heteroaryt, aralkyl or cycloalkyl; R2 is hydrogen, hydroxy, oxo, optionally substituted alkyl, aryl, aralkyl, alkoxy, aryloxy aralkoxy, alkylthio, arylthio or aralkylthio; R3 is hydrogen; or R2 and R3 combined are alkylene which together with the carbon atoms to which they are attached form a fused 5- to 7-membered ring; or R2 and R3 combined are a bond between the carbon atoms to which they are attached; n is 1; Ya is hydrogen; or Ya and R2 combined are a bond between the carbon atoms to which they are attached; R4a is hydrogen; or R4a and Ya combined are a bond between the carbon atoms to which they are attached; R" is hydrogen, optionally substituted alkyl, alkoxy or halogen; m is 1; Yb is hydrogen; R4b is hydrogen; or R4b and Yb combined are a bond between the carbon atoms to which they are attached; R and R' are independently hydrogen, halogen, optionally substituted alkyl, alkoxy, aralkyl or heteroaralkyl; or R and R' combined together with the carbon atoms to which they are attached form an optionally substituted fused 5- to 6-membered aromatic or heteroaromattc ring provided that R and R' are attached to carbon atoms adjacent to each other; or Z is a bond, O or S; p is an integer from 1 to 8; Q is a bond; or Q is -0(CH2)r or -S(CH2)r in which r is zero or an integer from 1 to 8; or Q is -C(0)NR6- in which R6 is hydrogen, optionally substituted alkyl, cydoalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or Q is -NRT-, -NR7C(Oh -NR7C(0)NR,r or -NR7C(0)0- in which R7 is hydrogen, optionally substituted alkyl, cydoalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Re is hydrogen, alkyl or aralkyl; W is cydoalkyl, aryl, heterocydyl, aralkyl or heteroaralkyl; or W and R6 taken together with the nitrogen atom to which they are attached form a 8-to 12-membered bicydic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; X2 is -C(R9)r, O , S or -NR10- in which R9 is hydrogen or lower alkyl; R10 is hydrogen or lower alkyl; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 2, wherein R1 is hydrogen or optionally substituted alkyl; R2 and R3 are hydrogen; Ya and Yb are hydrogen; R4a and R4b are hydrogen; R and R' are independently hydrogen, halogen, optionally substituted C1-4 alkyl or C1-6 alkoxy; p is an integer from 1 to 5; Q is a bond; or Q is -0(CH2)r~ or -S(CH2)r- in which r is zero or 1;or Q is -C(0)NRe- in which Re is hydrogen or lower alkyl; or Q is -NR7-f -NR7C(Oh "NR7C(0)NRe- or -NR7C(0)0- in which R7 is hydrogen or optionally substituted alkyl; R6 is hydrogen or alkyl; X2 is -C(R9)2, OtSor -NR10- in which R9 is hydrogen or methyl; R10 is hydrogen; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutical^ acceptable salt thereof. 4. A compound according to claim 3, wherein R, R' and R" are hydrogen; Q is a bond; or Q is -0(CH2)r or -S(CH2)r in which r is zero; or Q is -NFV, -NRTC(O)-, -NR7C(O)NR8- or -NR7C(O)O- in which R7 is hydrogen or optionally substituted lower alkyl; W is cydoalkyl, aryl or heterocyclyl; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutical^ acceptable salt thereof. 5. A compound according to claim 4, wherein the asymmetric center in radical L is in the (R) configuration; or a pharmaceutical^ acceptable salt thereof. 6. A compound according to claim 4, wherein X2 is -C(R9)2- in which R9 is methyl; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof. 7. A compound according to claim 4 of the formula wherein R1 is hydrogen or optionally substituted alkyl; Z is a bond, O or S; p is an integer from 1 to 3; Q is a bond, O or S; or Q is -NR7C(0)- in which R7 is hydrogen or optionally substituted lower alkyl; W is aryl or heterocyclyl; X2 is -C(R9)2, O , S or -NH- in which R9 is hydrogen or methyl; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutical^ acceptable salt thereof. 8. A compound according to claim 7, wherein Z is O or S; p is an integer of 2 or 3; Q is O or S; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutical^ acceptable salt thereof. 9. A compound according to claim 7, wherein Z is bond, O or S; p is an integer of 1 or 2; Q is a bond; W is selected from the group consisting of: 11. A compound according to claim 10, wherein the asymmetric center in radical L is in the (R) configuration; or a pharmaceutically acceptable salt thereof. 12. A compound according to claim 7, wherein 2 is O or S; p is 2; Q is a bond; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. 13. A compound according to claim 7, wherein Z is a bond; p is l ; Q is -NR7C(0)- in which R7 is hydrogen or methyl; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutical^ acceptable salt thereof. 14. A compound according to claim 4 of the formula wherein R1 is hydrogen or optionally substituted alkyl; Z is a bond, O or S; p is an integer from 1 to 3; Q is a bond, O or S; or Q is -NR7C(O)- in which R7 is hydrogen or optionally substituted lower alkyl; W is aryl or heterocyclyl; X2 is -C(R9)2, O . S or -NH- in which R9 is hydrogen or methyl; or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. 15. A compound according to claim 14, wherein Z is O or S; P is an integer of 2 or 3; Q is O or S; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. 16. A compound according to claim 14, wherein Z is bond, O or S; p is an integer of 1 or 2; Q is a bond; W is selected from the group consisting of: 18. A compound according to claim 17, wherein the asymmetric center in radical L is in the (R) configuration; or a pharmaceutically acceptable salt thereof. 19. A compound according to claim 14, wherein Z is O or S; pis 2; Q is a bond; W is selected from the group consisting of: or an optical isomer thereof; or a mixture of optical isomers thereof; or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 14, wherein Z is a bond; p is 1; Q is -NR7C(0)- in which R7 is hydrogen or methyl; inhibitor, HMG-CoA reductase inhibitor; squalene synthase inhibitor; FXR or LXR ligand; cholestyramine; fibrates; nicotinic acid or aspirin. 25. A method for the treatment of dyslipidemia, hyperlipemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, ulcerative colitis and Crohn's disease, Syndrome-X, and type-1 and type-2 diabetes which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1. 26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable earners. 27. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a therapeutically effective amount of insulin, insulin derivative or mimetic; insulin secretagogue; insulinotropic sulfonylurea receptor ligand; insulin sensitizer; biguanide; alpha-glucosidase inhibitors; GLP-1, GLP-1 analog or mimetic; DPPIV inhibitor; HMG-CoA reductase inhibitor, squalene synthase inhibitor; FXR or LXR ligand; cholestyramine; fibrates; nicotinic acid; or aspirin. 28. A pharmaceutical composition according to claim 26 or 27, for the treatment of dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, ulcerative colitis and Crohn's disease, Syndrome-X, and type-1 and type-2 diabetes. 29. A pharmaceutical composition according to claim 26 or 27, for use as medicament. 30. Use of a pharmaceutical composition according to claim 26 or 27, for the preparation of a medicament for the treatment of conditions associated with PPAR activity. 31. Use of a compound according to claim 1, for the preparation of a pharmaceutical composition for the treatment of conditions associated with PPAR activity. 32. Use according to claim 30 or 31, wherein the condition associated with PPAR activity is selected from dyslipidemia, hyperlipemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, ulcerative colitis and Crohn's disease, Syndrome-X, and type-1 and type-2 diabetes. 33. A compound according to claim 1, for use as a medicament.

Documents:

3050-CHENP-2005 ABSTRACT.pdf

3050-CHENP-2005 CLAIMS.pdf

3050-CHENP-2005 CORRESPONDENCE OTHERS.pdf

3050-CHENP-2005 CORRESPONDENCE PO.pdf

3050-CHENP-2005 FORM-3.pdf

3050-CHENP-2005 PETITIONS.pdf

3050-chenp-2005 abstract-duplicate.pdf

3050-chenp-2005 claims-duplicate.pdf

3050-chenp-2005 description (complete)-duplicate.pdf

3050-chenp-2005-abstract.pdf

3050-chenp-2005-assignement.pdf

3050-chenp-2005-claims.pdf

3050-chenp-2005-correspondnece-others.pdf

3050-chenp-2005-description(complete).pdf

3050-chenp-2005-form 1.pdf

3050-chenp-2005-form 18.pdf

3050-chenp-2005-form 26.pdf

3050-chenp-2005-form 3.pdf

3050-chenp-2005-form 5.pdf

3050-chenp-2005-pct.pdf