Organic Compounds

Abstract

Compounds of the formula provide pharmacological agents which bind to Peroxisome Proliferator-Activated Receptors (PPARs). Accordingly, the compounds of the present 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 (IBDs), ulcerative colitis and Crohn's disease. The compounds of the present invention are particularly useful in mammals as hypoglycemic agents for the treatment and prevention of conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, and Syndrome X.

1 . A method for the activation of a Peroxisome Proliferator-Activated Receptor which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl; 
 R 2  and R 3  are independently hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethyl, optionally substituted alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, aryloxy, aralkoxy or heteroaralkoxy; or 
 R 2  and R 3  combined together with the carbon atoms they are attached to form an optionally substituted fused 5- to 6-membered aromatic or heteroaromatic ring provided that R 2  and R 3  are attached to carbon atoms adjacent to each other; 
 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 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—(CH 2 ) p -Q-W in which
 Z is a bond, O, S, S(O), S(O) 2 , —C(O)— or —NHC(O)—; or 
 Z is —C(O)NR 4 — in which
 R 4  is hydrogen, alkyl or aralkyl; 
 
 p is an integer from 1 to 8; 
 Q is a bond or —C(O)—; or 
 Q is —O(CH 2 ) r — or —S(CH 2 ) r — in which
 r is zero or an integer from 1 to 8; or 
 
 Q is —O(CH 2 ) 1-8 O—, —S(CH 2 ) 1-8 O— or —S(CH 2 ) 1-8 S—; or 
 Q is —C(O)NR 5 — in which
 R 5  is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or 
 
 Q is —NR 6 —, —NR 6 C(O)—, —NR 6 C(O)NH— or —NR 6 C(O)O— in which
 R 6  is hydrogen, lower alkyl or aralkyl; 
 
 W is cycloalkyl, aryl or heterocyclyl; or 
 W and R 5  taken together with the nitrogen atom to which they are attached form a fused 8- to 12-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or 
 W is —[C(R 7 ) 2 ] S -L in which
 R 7  is hydrogen or lower alkyl; 
 s is an integer from 1 to 3; 
 L is aryl or heteroaryl; 
 
 
 A-B is —NH—S(O) 2 —; or 
 A-B is —Y—C(R 8 ) 2 — in which
 Y is O or S; 
 R 8  is hydrogen or lower alkyl; 
 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       2 . A method for the treatment of a condition mediated by a Peroxisome Proliferator-Activated Receptor which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl; 
 R 2  and R 3  are independently hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethyl, optionally substituted alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, aryloxy, aralkoxy or heteroaralkoxy; or 
 R 2  and R 3  combined together with the carbon atoms they are attached to form an optionally substituted fused 5- to 6-membered aromatic or heteroaromatic ring provided that R 2  and R 3  are attached to carbon atoms adjacent to each other; 
 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 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—(CH 2 ) p -Q-W in which
 Z is a bond, O, S, S(O), S(O) 2 , —C(O)— or —NHC(O)—; or 
 Z is —C(O)NR 4 — in which
 R 4  is hydrogen, alkyl or aralkyl; 
 
 p is an integer from 1 to 8; 
 Q is a bond or —C(O)—; or 
 Q is —O(CH 2 ) r — or —S(CH 2 ) r — in which
 r is zero or an integer from 1 to 8; or 
 
 Q is —O(CH 2 ) 1-8 O—, —S(CH 2 ) 1-8 O— or —S(CH 2 ) 1-8 S—; or 
 Q is —C(O)NR 5 — in which
 R 5  is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or 
 
 Q is —NR 6 —, —NR 6 C(O)—, —NR 6 C(O)NH— or —NR 6 C(O)O— in which
 R 6  is hydrogen, lower alkyl or aralkyl; 
 
 W is cycloalkyl, aryl or heterocyclyl; or 
 W and R 5  taken together with the nitrogen atom to which they are attached form a fused 8- to 12-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or 
 W is —[C(R 7 ) 2 ] 5 -L in which
 R 7  is hydrogen or lower alkyl; 
 s is an integer from 1 to 3; 
 L is aryl or heteroaryl; 
 
 
 A-B is —NH—S(O) 2 —; or 
 A-B is —Y—C(R 8 ) 2 — in which
 Y is O or S; 
 R 8  is hydrogen or lower alkyl; 
 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       3 . The method according to  claim 2 , which method comprises administering said compound in combination with a therapeutically effective amount of an anti-diabetic agents, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent. 
   
   
       4 . A method 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, type-1 and type-2 diabetes, or Syndrome-X which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl; 
 R 2  and R 3  are independently hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethyl, optionally substituted alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, aryloxy, aralkoxy or heteroaralkoxy; or 
 R 2  and R 3  combined together with the carbon atoms they are attached to form an optionally substituted fused 5- to 6-membered aromatic or heteroaromatic ring provided that R 2  and R 3  are attached to carbon atoms adjacent to each other; 
 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 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—(CH 2 ) p -Q-W in which
 Z is a bond, O, S, S(O), S(O) 2 , —C(O)— or —NHC(O)—; or 
 Z is —C(O)NR 4 — in which
 R 4  is hydrogen, alkyl or aralkyl; 
 
 p is an integer from 1 to 8; 
 Q is a bond or —C(O)—; or 
 Q is —O(CH 2 ) r — or —S(CH 2 ) r — in which
 r is zero or an integer from 1 to 8; or 
 
 Q is —O(CH 2 ) 1-8 O—, —S(CH 2 ) 1-8 O— or —S(CH 2 ) 1-8 S—; or 
 Q is —C(O)NR 5 — in which
 R 5  is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or 
 
 Q is —NR 6 —, —NR 6 C(O)—, —NR 6 C(O)NH— or —NR 6 C(O)O— in which
 R 6  is hydrogen, lower alkyl or aralkyl; 
 
 W is cycloalkyl, aryl or heterocyclyl; or 
 W and R 5  taken together with the nitrogen atom to which they are attached form a fused 8- to 12-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or 
 W is —[C(R 7 ) 2 ] 5 -L in which
 R 7  is hydrogen or lower alkyl; 
 s is an integer from 1 to 3; 
 L is aryl or heteroaryl; 
 
 
 A-B is —NH—S(O) 2 —; or 
 A-B is —Y—C(R 8 ) 2 — in which
 Y is O or S; 
 R 8  is hydrogen or lower alkyl; 
 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       5 . The method according to  claim 2 , wherein the compound is represented by formula (IC): 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen or optionally substituted lower alkyl; 
 R 2  and R 3  are independently hydrogen, halogen, lower alkyl or lower alkoxy; 
 R is hydrogen; 
 Z is a bond, O or S; 
 p is an integer from 1 to 4; 
 Q is a bond, O or S; or 
 Q is —NR 6 C(O)— in which
 R 6  is hydrogen or lower alkyl; 
 
 W is cycloalkyl, aryl or heterocyclyl; or 
 W is —[C(R 7 ) 2 ] s -L in which
 R 7  is hydrogen or methyl; 
 s is 1; 
 L is aryl; 
 
 A-B is —NH—S(O) 2 —; or 
 A-B is —Y—C(R 8 ) 2 — in which
 Y is O or S; 
 R 8  is hydrogen or methyl; 
 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       6 . The method according to  claim 5 , wherein
 R 1  is hydrogen;   R 2  is hydrogen, fluoro, chloro, C 1-3  alkyl or C 1-3  alkoxy; and   R 3  is fluoro, chloro, C 1-3  alkyl, C 1-3  alkoxy or phenyl;   
     or a pharmaceutically acceptable salt thereof. 
   
   
       7 . The method according to  claim 5 , wherein
 R 1  is hydrogen or optionally substituted lower alkyl;   R 2  and R 3  are independently hydrogen, halogen, lower alkyl or lower alkoxy;   Z is O or S;   p is an integer of 1 or 2;   Q is a bond;   W is aryl, heterocyclyl or heteroaralkyl;   A-B is —NH—S(O) 2 —; or   A-B is —Y—C(R 8 ) 2 — in which
 Y is O or S; 
 R 8  is hydrogen or methyl; 
   
     or a pharmaceutically acceptable salt thereof. 
   
   
       8 . The method according to  claim 7  wherein
 A-B is —NH—S(O) 2 —;   
     or a pharmaceutically acceptable salt thereof. 
   
   
       9 . The method according to  claim 8  wherein
 W is selected from the group consisting of:   
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       10 . The method according to  claim 9  wherein
 W is selected from the group consisting of:   
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       11 . The method according to  claim 7  wherein
 A-B is —Y—C(R 8 ) 2 — in which
 Y is O; 
 R 8  is hydrogen; 
   
     or a pharmaceutically acceptable salt thereof. 
   
   
       12 . The method according to  claim 11  wherein
 W is selected from the group consisting of:   
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       13 . The method according to  claim 12  wherein
 W is selected from the group consisting of:   
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       14 . The method according to  claim 2 , wherein the compound is selected from the group consisting of:
 6-Methyl-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   6-Chloro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   3-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-biphenyl-4-carboxylic acid;   4-Chloro-2-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzene-sulfonylamino}-benzoic acid;   6-Fluoro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   4-Chloro-2-{4-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl methoxy]-benzenesulfonylamino}-benzoic acid;   2-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-6-trifluoromethyl-benzoic acid;   4-Chloro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   3,5-Dim ethyl-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   2-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonylamino}-benzoic acid;   2-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-benzoic acid;   2-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonylamino]-benzoic acid;   4-Fluoro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   2-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   4-Methyl-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   4,5-Difluoro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   6-Methoxy-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   5-Fluoro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   5-Chloro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   3-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-naphthalene-2-carboxylic acid;   5-Methoxy-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   5-Methyl-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   5-Acetylamino-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   4,5-Dimethoxy-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;   4-Chloro-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonylamino}-benzoic acid;   3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonylamino}-biphenyl-4-carboxylic acid;   2,3-Dimethoxy-6-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl-amino}-benzoic acid;   2-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonylamino}-benzoic acid;   2-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylsulfanyl]-benzenesulfonylamino}-benzoic acid;   2-[4-(4-Trifluoromethyl-benzylcarbamoyl)-benzenesulfonylamino]-benzoic acid;   2-Methyl-6-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyloxy]-4-propoxy-benzoic acid methyl ester;   4-Chloro-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-benzoic acid ethyl ester;   4-Methoxy-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-benzoic acid;   3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-naphthalene-2-carboxylic acid;   2-Methyl-6-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-4-propoxy-benzoic acid methyl ester;   2-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-4-propoxy-benzoic acid;   4-Methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-benzoic acid;   4-Chloro-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyloxy]-benzoic acid;   4-Chloro-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxymethyl)-benzyloxy]-benzoic acid;   2,4-Dimethoxy-6-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-benzoic acid;   2-Methyl-6-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-4-propoxy-benzoic acid;   4-Isopropoxy-2-methyl-6-{3-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-benzoic acid;   2,4-Dimethoxy-6-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyloxy]-benzoic acid;   2-Methyl-6-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyloxy]-4-propoxy-benzoic acid;   2-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-4,6-bis-trifluoromethyl-benzoic acid;   2-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyloxy]-4,6-bis-trifluoromethyl-benzoic acid;   2-Fluoro-6-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyloxy]-benzoic acid;   4-Isopropoxy-2-methyl-6-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-benzoic acid;   2-Fluoro-6-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-benzoic acid;   2-Methoxy-6-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyloxy]-benzoic acid;   2-Methoxy-6-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-benzoic acid;   4-Chloro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyloxy]-benzoic acid;   4-Chloro-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-benzoic acid;   4-sec-Butoxy-2-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzyloxy)-6-methyl-benzoic acid;   4-Fluoro-2-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzyloxy)-6-isopropoxy-benzoic acid;   4-Fluoro-2-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzyloxy)-6-propoxy-benzoic acid;   2-(4-{2-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzyloxy)-4-isopropoxy-6-methyl-benzoic acid;   4-Isopropoxy-2-methyl-6-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-benzyloxy)-benzoic acid;   2-(4-{2-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzyloxy)-6-methyl-4-(tetrahydro-furan-3-yloxy)-benzoic acid;   4-Chloro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxymethyl)-benzyloxy]-benzoic acid;   4-Chloro-2-(3-{[(4-methyl-2-phenyl-thiazole-5-carbonyl)-amino]-methyl}-benzyloxy)-benzoic acid;   4-Isopropoxy-2-methyl-6-[3-({methyl-[2-(4-trifluoromethyl-phenyl)-acetyl]-amino}-methyl)-benzyloxy]-benzoic acid;   2-[3-({Ethyl-[2-(4-trifluoromethyl-phenyl)-acetyl]-amino}-methyl)-benzyloxy]-4-isopropoxy-6-methyl-benzoic acid;   2-[3-({[2-(4-Chloro-phenyl)-acetyl]-methyl-amino}-methyl)-benzyloxy]-4-isopropoxy-6-methyl-benzoic acid;   4-Isopropoxy-2-methyl-6-(3-{[methyl-(2-p-tolyl-acetyl)-amino]-methyl}-benzyloxy)-benzoic acid;   2-(3-{[(2-Benzo[1,3]dioxol-5-yl-acetyl)-methyl-amino]-methyl}-benzyloxy)-4-isopropoxy-6-methyl-benzoic acid; and   4-Isopropoxy-2-methyl-6-{3-[(methyl-phenylacetyl-amino)-methyl]-benzyloxy}-benzoic acid;   
     or a pharmaceutically acceptable salt thereof.