Heterocyclic compounds and methods of use

Abstract

Compounds of the formula provide pharmacological agents which are potent agonists of 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 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. Preferred are the compounds of the invention which are dual agonists of PPARα and PPARγ receptors.

1 . A compound of the formula  
     
       
         
         
             
             
         
       
     
     wherein 
 L is  
                     
 radical in which R 1  is hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl; 
 R 2  is hydrogen, hydroxy, optionally substituted alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio or aralkylthio;  
 R 3  is hydrogen or aryl; or  
 R 2  and R 3  combined are alkylene which together with the carbon atoms they are attached to form a 5- to 7-membered ring;  
 n is zero or an integer from 1 to 2;  
 Y is hydrogen; or  
 Y and R 2  taken together with the carbon atoms they are attached to form a bond provided that n is 1;  
 R 4  is hydrogen; or  
 R 4  and Y taken together with the carbon atoms they are attached to form a bond provided that n is 1, and R 2  and R 3  taken together with the carbon atoms they are attached to form a bond; or  
 
 L is  
                     
  radical in which R 1  is hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl; 
 R″ is hydrogen, optionally substituted alkyl, alkoxy or halogen;  
 m is an integer from 1 to 2;  
 Y is hydrogen;  
 R 4  is hydrogen; or  
 R 4  and Y taken together with the carbon atoms they are attached to form a bond provided that m is 1;  
 
 R and R′ are independently hydrogen, halogen, optionally substituted alkyl, alkoxy, aralkyl or heteroaralkyl; or  
 R and R′ combined together form a methylenedioxy group provided that R and P′ are attached to carbon atoms adjacent to each other; or  
 R and R′ combined together with the carbon atoms they are attached to form an optionally substituted 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 wherein Z is a bond, O, S, —C(O)— or —C(O)NR 5 — in which 
 R 5  is hydrogen, alkyl or aralkyl;  
 p is an integer from 1 to 8;  
 Q is a bond provided that Z is not a bond when p is 1; 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—, —S(CH 2 ) 1-8 S—, —C(O)— or —C(O)NR 6 — in which R 6  is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or  
 Q is —NR 6 —, —NR 5 C(O)—, —NR 5 C(O)NH— or —NR 5 C(O)O— provided that p is not 1;  
 W is cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; or  
 W and R 6  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;  
 or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.  
 
 
   
   
       2 . A compound according to  claim 1  of the formula  
     
       
         
         
             
             
         
       
     
     wherein 
 L is  
                     
  radical in which R 1  is hydrogen or optionally substituted alkyl; 
 R 2  and R 3  are hydrogen; or  
 R 2  and R 3  combined are alkylene which together with the carbon atoms they are attached to form a 6-membered ring;  
 n is zero or an integer from 1 to 2;  
 Y is hydrogen;  
 R 4  is hydrogen; or  
 
 L is  
                     
  radical in which R 1  is hydrogen or optionally substituted alkyl; 
 R″ is hydrogen, optionally substituted alkyl, alkoxy or halogen;  
 m is an integer from 1 to 2;  
 Y is hydrogen;  
 R 4  is hydrogen;  
 
 R and R′ are independently hydrogen, halogen, optionally substituted C 1-6 alkyl or C 1-6 alkoxy; or  
 R and R′ combined together form a methylenedioxy group provided that R and P′ are attached to carbon atoms adjacent to each other;  
 Z is a bond, O, S or —C(O)NR 5 — in which R 5  is hydrogen, alkyl or aralkyl;  
 p is an integer from 1 to 5;  
 Q is a bond provided that Z is not a bond when p is 1; or  
 Q is —O(CH 2 ) r — or —S(CH 2 ) r  in which r is zero; or  
 Q is —C(O)— or —C(O)NR 6 — in which R 6  is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or  
 Q is —NR 6 —, —NR 5 C(O)—, —NR 5 C(O)NH— or —NR 5 C(O)O— provided that p is not 1;  
 W is cycloalkyl, aryl or heterocyclyl; or  
 W and R 6  taken together with the nitrogen atom to which they are attached form a 9- to 10-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur;  
 or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.  
 
   
   
       3 . A compound according to  claim 2 , wherein 
 L is                           radical in which R 1  is hydrogen or optionally substituted alkyl; 
 R 2  and R 3  are hydrogen;  
 n is zero or an integer from 1 to 2; or  
   L is                           radical in which R 1  is hydrogen or optionally substituted alkyl; 
 R″ is hydrogen;  
 m is an integer from 1 to 2;  
   R is hydrogen) halogen, optionally substituted C 1-6 alkyl or C 1-6 alkoxy;    R′ is hydrogen;    Z is a bond, O or S;    p is an integer from 1 to 5;    Q is a bond provided that Z is not a bond when p is 1; or    Q is O, S or —C(O)NR 6 — in which R 6  is hydrogen, optionally substituted alkyl or cycloalkyl; or    Q is —NR 6 —, —NR 5 C(O)NH— or —NR 5 C(O)O— in which R 5  is hydrogen, alkyl or aralkyl provided that p is not 1;    W is cycloalkyl, aryl or heterocyclyl; or    W and R 6  taken together with the nitrogen atom to which they are attached form a 9- to 10-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur;    or a pharmaceutically acceptable salt thereof, or an optical isomer thereof; or a mixture of optical isomers thereof.    
   
   
       4 . A compound according to  claim 3  of the formula  
     
       
         
         
             
             
         
       
     
     wherein 
 L is  
                     
  radical in which R 1  is hydrogen or optionally substituted alkyl; 
 n is zero or 1; or  
 
 L is  
                     
  radical in which R 1  is hydrogen or optionally substituted alkyl; 
 m is 1;  
 
 R is hydrogen, halogen, optionally substituted C 1-5 alkyl or C 1-6 alkoxy;  
 Z is a bond, O or S;  
 p is an integer from 1 to 5;  
 Q is a bond provided that Z is not a bond when p is 1; or  
 Q is O, S or —C(O)NR 6 — in which R 6  is hydrogen, optionally substituted alkyl or cycloalkyl; or  
 Q is —NR 6 —, —NR 5 C(O)NH— or —NR 5 C(O)O— in which R 5  is hydrogen, alkyl or aralkyl provided that p is not 1;  
 W is cycloalkyl, aryl or heterocyclyl, or  
 W and R 6  taken together with the nitrogen atom to which they are attached form a 9- to 10-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur;  
 or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.  
 
   
   
       5 . A compound according to  claim 4 , wherein 
 L is                           radical in which R 1  is hydrogen; and n is zero or 1;    R is hydrogen, halogen, optionally substituted C 1-6 alkyl or C 1-6 alkoxy;    Z is a bond, O or S;    p is an integer from 1 to 4;    Q is a bond provided that Z is not a bond when p is 1, or    Q is O or S;    W is aryl or heterocyclyl;    or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.    
   
   
       6 . A compound according to  claim 4 , wherein 
 L is                           radical in which R 1  is hydrogen;    R is hydrogen, halogen, optionally substituted C 1-6 alkyl or C 1-6 alkoxy;    Z is a bond, O or S;    p is an integer from 1 to 4;    Q is a bond provided that Z is not a bond when p is 1; or    Q is O or S;    W is aryl or heterocyclyl;    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 , wherein the asymmetric center in radical L is in the (R) configuration;  
     or a pharmaceutically acceptable salt thereof.  
   
   
       8 . A compound according to  claim 4 , wherein 
 R 1  is hydrogen or optionally substituted alkyl;    R is hydrogen, halogen, optionally substituted C 1-6 alkyl or CO 1-6 alkoxy;    Z is O or S;    p is 2;    Q is a —NR 6 — in which R 6  is lower alkyl;    W is aryl or heterocyclyl;    or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.    
   
   
       9 . A compound according to  claim 8 , wherein 
 R is hydrogen, chloro, n-propyl or methoxy;    or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.    
   
   
       10 . A compound according to  claim 4 , wherein 
 R 1  is hydrogen or optionally substituted alkyl;    R is hydrogen, halogen, optionally substituted C 1-6 -alkyl or C 1-6 alkoxy;    Z is a bond;    p is 2;    Q is a —C(O)NR 6 — in which R 6  is optionally substituted alkyl;    W is aryl or heterocyclyl; or    W and R 6  taken together with the nitrogen atom to which they are attached form a 9- to 10-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur;    or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.    
   
   
       11 . A compound according to  claim 10 , wherein 
 R is hydrogen, chloro, n-propyl or methoxy;    or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers thereof.    
   
   
       12 . A compound according to  claim 4 , wherein 
 R 1  is hydrogen or optionally substituted alkyl;    R is hydrogen, halogen, optionally substituted C 1-6 alkyl or C 1-6 alkoxy;    Z is a bond, O or S;    p is an integer from 2 to 3;    Q is O or S;    W is aryl or heterocyclyl;    or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.    
   
   
       13 . A compound according to  claim 12 , wherein 
 R is hydrogen, chloro, n-propyl or methoxy;    or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.    
   
   
       14 . A compound according to  claim 12 , wherein W is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.  
   
   
       15 . A compound according to  claim 4 , wherein 
 R 1  is hydrogen or optionally substituted alkyl;    R is hydrogen, halogen, optionally substituted C 1-6 -alkyl or C 1-6 -alkoxy;    Z is O or S;    p is an integer from 1 to 2;    Q is a bond;    W is aryl or heterocyclyl;    or a pharmaceutically acceptable salt thereof; or an optical isomer or a mixture of optical isomers thereof.    
   
   
       16 . A compound according to  claim 15 , wherein 
 R is hydrogen, chloro, n-propyl or methoxy;    or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.    
   
   
       17 . A compound according to  claim 15 , wherein W is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.  
   
   
       18 . A compound according to  claim 15 , wherein 
 R 1  is hydrogen or optionally substituted alkyl;    R is hydrogen, halogen, optionally substituted C 1-6  alkyl or C 1-6 alkoxy;    Z is O or S;    p is 2;    Q is a bond;    W is selected from the group consisting of:                                            or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.    
   
   
       19 . A compound according to  claim 1 , which is selected from the group consisting of: 
 (R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-azetidine-2-carboxylic acid;    (R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-azetidine-2-carboxylic acid;    (R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-azetidine-2-carboxylic acid;    (R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}-azetidine-2-carboxylic acid;    (R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-azetidine-2-carboxylic acid;    (R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene-sulfonyl}-azetidine-2-carboxylic acid;    (R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-azetidine-2-carboxylic acid;    (R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-(4-{3-[2-Propyl-4-(4-trifluoromethyl-phenoxy)-phenoxy]-propoxy}-benzenesulfonyl)-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-(4-{2-[2-Propyl-4-(4-trifluoromethyl-phenoxy)-phenoxy]-ethoxy}-benzenesulfonyl)-pyrrolidine-2-carboxylic acid;    (R)-1-{3-Methoxy-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{3-Chloro-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-3-propyl-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propyl]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]pyrrolidine-2-carboxylic acid;    (R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene-sulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-[4-(2-Biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid;    (R)-1-[3-Methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid;    (R)-1-[3-Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid;    (R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-3-propyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid;    (R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{3-Methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{3-Chloro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-(4-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-benzenesulfonyl)-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-{3-Methoxy-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-{3-Chloro-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene-sulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-[3-Methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-[3-Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-3-propyl-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-{4-[2-(4-Fluorophenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;    (R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid; and    (R)-1-{3-Chloro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid; (R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzene-sulfonyl}-pyrrolidine-2-carboxylic acid;    (R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzene-sulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;    or a pharmaceutically acceptable salt thereof; or an enantiomer thereof; or a mixture of enantiomers thereof.    
   
   
       20 . A method for the activation of Peroxisome Proliferator-Activated Receptors (PPAR) which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of  claim 1 .  
   
   
       21 . A method for the treatment of conditions mediated by PPARs which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of  claim 1 .  
   
   
       22 . The method according to  claim 21 , which method comprises administering said compound 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.  
   
   
       23 . A method for the treatment of dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, Syndrome-X, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, ulcerative colitis and Crohn's disease, 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 .  
   
   
       24 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with one or more pharmaceutically acceptable carriers.  
   
   
       25 . 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.  
   
   
       26 . A pharmaceutical composition according to any one of claims  24  or  25  for the treatment of dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, Syndrome-X, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, ulcerative colitis and Crohn's disease, impaired glucose tolerance, hyperglycemia, insulin resistance, type-1 and type-2 diabetes.  
   
   
       27 . A method for the preparation of alkylating agents of the formula  
     
       
         
         
             
             
         
       
     
     wherein R a  and R b  are independently hydrogen, halogen, alkyl, alkoxy, trifluoromethyl or aryl; wherein the method comprises treating a compound of the formula  
     
       
         
         
             
             
         
       
     
     wherein R a  and R b  have meanings as defined for formula VIIa; with a chlorinating agent in acetonitrile.  
   
   
       28 . The method according to  claim 27 , wherein the chlorinating agent is phosphorus oxychloride.  
   
   
       29 . The method according to  claim 27 , wherein the alkylating agent of formula VIIa is 4-chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]-oxazole.  
   
   
       30 . The method according to  claim 27 , wherein a compound of formula VIIb is prepared by condensing an aldehyde of the formula  
     
       
         
         
             
             
         
       
     
     wherein R a  and R b  have meanings as defined in said claim; with 2,3-butadione monooxime of the formula  
     
       
         
         
             
             
         
       
     
     in the presence of an acid catalyst and an organic solvent; to afford compounds of formula VIIb.  
   
   
       31 . The method according to  claim 30 , wherein the acid catalyst is gaseous hydrochloric acid and the organic solvent is glacial acetic acid.