Therapeutic uses of di-aryl acid derivatives

Abstract

The use of diaryl acid derivatives of formula (I) or pharmaceutically acceptable salts, N-oxides, hydrates or solvates thereof, wherein the variables shown are defined in the disclosure, and their pharmaceutical compositions as PPAR ligand receptor binders. The PPAR ligand receptor binders of this invention are useful as agonists or antagonists of the PPAR receptor.

1. A compound of formula (I) 
                 
 
       wherein: 
                 
 
       is oxazolyl or quinolinyl, which are optionally substituted by one or more ring system substituents; 
                 
 
       is phenyl, which is optionally substituted by one or more ring system substituents, in addition to being substituted by group Z;
 A is 
                 
 
 B and E are a chemical bond; 
 a is 1;  
 b is 0 or 1;  
 c is 0; 
 d is 0; 
 g is 1-5;  
 R 1 , R 2 , R 3  and R 4  are, independently, hydrogen, halogen or alkyl, wherein alkyl is optionally substituted by one or more alkyl group substituents;  
 Z is R 21 O 2 C—, R 21 OC—, —CN, R 21 O 2 SHNCO—, R 21 O 2 SHN—, (R 21 ) 2 NCO— or R 21 O—;  
 R 21  is independently 
 hydrogen,  
 alkyl, which is optionally substituted by one or more alkyl group substituents,  
 aryl, which is optionally substituted by one or more ring system substituents,  
 cycloalkyl, which is optionally substituted by one or more ring system substituents, or  
 aralkyl, wherein the aryl portion is optionally substituted by one or more ring system substituents and the alkyl portion is optionally substituted by one or more alkyl group substituents;  
 
 R 15 , R 16  are independently 
 hydrogen,  
 alkyl, which is optionally substituted by one or more alkyl group substituents,  
 aralkyl, wherein the aryl portion is optionally substituted by one or more ring system substituents and the alkyl portion is optionally substituted by one or more alkyl group substituents, or  
 alkoxycarbonyl, wherein the alkyl portion is optionally substituted by one or more alkyl group substituents;  
 
 
       or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, a hydrate thereof or a solvate thereof, 
       wherein
 alkyl is an aliphatic hydrocarbon group which is straight or branched having 1 to about 20 carbon atoms;  
 aryl is an aromatic monocyclic or multicyclic ring system of about 6 to about 14 carbon atoms;  
 a ring system substituent is halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aryloxy, unsubstituted aralkyloxy or unsubstituted cycloalkylalkyloxy; and  
 an alkyl group substituent is unsubstituted acyl, carboxyl, unsubstituted carboxymethyl, unsubstituted methoxycarbonylethyl, unsubstituted benzyloxycarbonylmethyl, unsubstituted pyridylmethyloxycarbonylmethyl or unsubstituted alkoxycarbonyl.  
 
     
     
       2. A compound according to  claim 1  wherein a=0;  R 15  and R 16  are hydrogen; g is 1, 2, 3 or 4; and b=0. 
     
     
       3. A compound according to  claim 1  wherein Z is R 21 O 2 SHNCO—, and R 21  is phenyl, wherein phenyl is optionally substituted by one or more ring system substituents. 
     
     
       4. A compound according to  claim 1  wherein Z is —CO 2 H or —CN. 
     
     
       5. A compound according to  claim 1  wherein 
                 
 
       is unsubstituted quinolin-2-yl, 3-substituted quinolin-2-yl, 4-substituted quinolin-2-yl, 6-substituted quinolin-2-yl or 7 substituted quinolin-2-yl; or 2-substituted-oxazol4-yl or 2,5 disubstituted-oxazol4-yl; 4-substituted oxazol-2-yl or 4,5-disubstituted-oxazol-2-yl; wherein an indicated substituent is a ring system substituent. 
     
     
       6. A compound as claimed in  claim 1 , wherein the compound is 2-methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoic acid. 
     
     
       7. A compound as claimed in  claim 1 , which is of formula 
                 
 
       wherein
 b=0;  
 R 1 , R 2 , R 3 , R 4  are hydrogen  
 R 15 , R 16  are hydrogen;  
 g=2, 3, 4 or 5;  
 Z is R 21 O 2 C—, R 21 OC—, or R 21 O—;  
 R′ is hydrogen, halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aryloxy or unsubstituted aralkyloxy; and  
 R″ is hydrogen, halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aralkyloxy or unsubstituted cycloalkylalkyloxy, or  
 
       a pharmaceutically acceptable salt thereof, or an N-oxide thereof, a hydrate thereof or a solvate thereof . 
     
     
       8. A compound according to  claim 7 , wherein Z is —CO 2 H. 
     
     
       9. A compound according to  claim 7 , wherein R′ is hydrogen; and R″ is lower alkyl of 1 to about 4 carbon atoms. 
     
     
       10. A compound according to  claim 7 , wherein 
                 
 
       is 2-substituted-oxazol-4-yl, wherein the substituent is a ring system substituent. 
     
     
       11. A compound according to  claim 1 , wherein the compound is 
                 
                 
 
     
     
       12. A compound according to  claim 1 , wherein the compound is 
                 
 
     
     
       13. A compound according to  claim 1  , wherein the compound is 
                 
 
     
     
       14. A pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       15. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to  claim 1  having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound wherein the disorder is associated with a physiological detrimental blood level of insulin, glucose, free fatty acids, or triglycerides. 
     
     
       16. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to  claim 1  having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hyperglycemia. 
     
     
       17. The method according to  claim 16 , wherein the hyperglycemia is diabetes. 
     
     
       18. The method according to  claim 16 , wherein the hyperglycemia is  A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to  claim 1  having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the disorder is Type II diabetes. 
     
     
       19. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to  claim 1  having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hyperinsulinism. 
     
     
       20. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to  claim 1  having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is insulin resistance. 
     
     
       21. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to  claim 1  having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is a cardiovascular condition. 
     
     
       22. The method according to  claim 21 , wherein the cardiovascular condition is atherosclerosis. 
     
     
       23. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to  claim 1  having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hyperlipidemia. 
     
     
       24. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to  claim 1  having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hypertension. 
     
     
       25. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to  claim 1  having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is an eating disorder. 
     
     
       26. A compound of formula ( I ) 
                   
       
         wherein: 
         
           
           
               
               
           
         
         
           is a oxazolyl or quinolinyl, which are optionally substituted by one or more substituents selected from  
           
             phenyl optionally substituted by one or more ring system substituents,  
           
           
             thienyl optionally substituted by one or more ring system substituents,  
           
           
             cycloalkyl optionally substituted by one or more ring system substituents,  
           
           
             lower alkyl optionally substituted by one or more alkyl group substituents,  
           
           
             branched alkyl optionally substituted by one or more alkyl group substituents,  
           
           
             fluoro,  
           
           
             chloro,  
           
           
             alkoxy wherein the alkyl portion is optionally substituted by one or more alkyl group substituents,  
           
           
             aralkyloxy wherein the aryl portion is optionally substituted with one or more ring system substituents and the alkyl portion is optionally substituted with one or more alkyl group substituents,  
           
           
             trifluoromethyl, and  
           
           
             trifluoromethyloxy; 
             
               
               
                   
                   
               
             
           
         
         
           is phenyl, which is optionally substituted by one or more ring system substituents, in addition to being substituted by group Z; 
           
             
             
                 
                 
             
           
         
         
           a is  1 ;  
         
         
           b is  0  or  1 ;  
         
           g is  1   -   5 ;    
         
           R 
           1 
           , R 
           2 
           , R 
           3  
           and R 
           4  
           are, independently, hydrogen, halogen or alkyl, wherein alkyl is optionally substituted by one or more alkyl group substituents;  
         
           Z is R   21   O   2   C—, R   21   OC—, —CN, R   21   O   2   SHNCO—, R   21   O   2   SHN—,  ( R   21 ) 2   NCO— or R   21   O—;    
         
           R 
           21  
           is independently  
           
             hydrogen,  
           
           
             alkyl, which is optionally substituted by one or more alkyl group substituents,  
           
           
             aryl, which is optionally substituted by one or more ring system substituents,  
           
           
             cycloalkyl, which is optionally substituted by one or more ring system substituents, or  
           
           
             aralkyl, wherein the aryl portion is optionally substituted by one or more ring system substituents and the alkyl portion is optionally substituted by one or more alkyl group substituents;  
           
         
         
           R 
           15 
           , R 
           16  
           are independently  
           
             hydrogen,  
           
           
             alkyl, which is optionally substituted by one or more alkyl group substituents,  
           
           
             aralkyl, wherein the aryl portion is optionally substituted by one or more ring system substituents and the alkyl portion is optionally substituted by one or more alkyl group substituents, or  
           
           
             alkoxycarbonyl, wherein the alkyl portion is optionally substituted by one or more alkyl group substituents;  
           
         
       
         or a pharmaceutically acceptable salt thereof, or an N - oxide thereof,    
       
         wherein  
         
           alkyl is an aliphatic hydrocarbon group which is straight or branched having  1  to about  20  carbon atoms;  
         
         
           aryl is an aromatic monocyclic or multicyclic ring system of about  6  to about  14  carbon atoms;  
         
         
           a ring system substituent is halo, unsubstituted lower alkyl of  1  to about  4  carbon atoms, unsubstituted alkoxy, unsubstituted aryloxy, unsubstituted aralkyloxy or unsubstituted cycloalkylalkyloxy; and  
         
         
           an alkyl group substituent is unsubstituted acyl, carboxyl, unsubstituted carboxymethyl, unsubstituted methoxycarbonylethyl, unsubstituted benzyloxycarbonylmethyl, unsubstituted pyridylmethyloxycarbonylmethyl or unsubstituted alkoxycarbonyl. 
         
       
     
     
       27. A compound according to  claim 26  wherein R 15    and R   16    are hydrogen; and g is  1 ,  2 ,  3  or  4 .   
     
     
       28. A compound according to  claim 26  wherein Z is R 21   O   2   SHNCO—, and R   21    is phenyl, wherein phenyl is optionally substituted by one or more ring system substituents.   
     
     
       29. A compound according to  claim 26  wherein Z is —CO 2   H or —CN.   
     
     
       30. A compound according to  claim 26  wherein 
                   
         is unsubstituted quinolin -   2   - yl,  3   - substituted quinolin -   2   - yl,  4   - substituted quinolin -   2   - yl,  6   - substituted quinolin -   2   - yl or  7  substituted quinolin -   2   - yl; or  2   - substituted - oxazol -   4   - yl or  2 , 5  disubstituted - oxazol -   4   - yl;  4   - substituted oxazol -   2   - yl or  4 , 5   - disubstituted - oxazol -   2   - yl; wherein an indicated substituent is selected from phenyl optionally substituted by one or more ring system substituents, thienyl optionally substituted by one or more ring system substituents, cycloalkyl optionally substituted by one or more ring system substituents, lower alkyl optionally substituted by one or more alkyl group substituents, branched alkyl optionally substituted by one or more alkyl group substituents, fluoro, chloro, alkoxy wherein the alkyl portion is optionally substituted by one or more alkyl group substituents, aralkyloxy wherein the aryl portion is optionally substituted with one or more ring system substituents and the alkyl portion is optionally substituted with one or more alkyl group substituents, trifluoromethyl and trifluoromethyloxy.   
     
     
       31. A compound as claimed in  claim 26 , which is of formula 
                   
       
         wherein  
         
           R 
           1 
           , R 
           2 
           , R 
           3 
           , R 
           4  
           are hydrogen  
         
         
           R 
           15 
           , R 
           16  
           are hydrogen;  
         
         
           g= 2 ,  3 ,  4  or  5 ;  
         
         
           Z is R 
           21 
           O 
           2 
           C—, R 
           21 
           OC—, or R 
           21 
           O—;  
         
         
           R′ and R″ are independently hydrogen or ring system substituents or  
         
           a pharmaceutically acceptable salt thereof, or an N - oxide thereof.   
       
     
     
       32. A compound according to  claim 31 , wherein Z is —CO 2   H.   
     
     
       33. A compound according to  claim 31 , wherein R′ is hydrogen; and R″ is lower alkyl of  1  to about  4  carbon atoms. 
     
     
       34. A compound according to  claim 31 , wherein 
                   
         is  2   - substituted - oxazol -   4   - yl, wherein the substituent is unsubstituted phenyl.   
     
     
       35. A compound according to  claim 26 , wherein 
                   
       
         is oxazolyl, which is substituted by unsubstituted phenyl. 
       
     
     
       36. A compound, wherein the compound is 
                                     
         or a pharmaceutically acceptable salt thereof, or an N - oxide thereof.   
     
     
       37. A compound according to  claim 26 , wherein the compound is 
                   
         or a pharmaceutically acceptable salt thereof, or an N - oxide thereof.   
     
     
       38. A compound, wherein the compound is 
                   
         or a pharmaceutically acceptable salt thereof, or an N - oxide thereof.   
     
     
       39. A pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound according to  claim 26  and a pharmaceutically acceptable carrier. 
     
     
       40. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to  claim 26  having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the disorder is Type II diabetes. 
     
     
       41. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to  claim 26  having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hypertension. 
     
     
       42. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to  claim 26  having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is an eating disorder.