Compounds that modulate PPAR activity and methods for their preparation

Abstract

This invention discloses compounds that alter PPAR activity. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds of their salts, and methods of using them as therapeutic agents for treating or preventing disipidemia, hypercholesteremia, obesity, eating disorders, hyperglycemia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia and diabetes in a mammal as well as methods of suppressing appetite and modulating leptin levels in a mammal. The present invention also discloses methods for making the disclosed compounds.

1. A compund of formula (I): 
                   
       and pharmaceutically acceptable salts thereof, wherein:
 X 0  and S; X 1  is absent; O, S, —CH 2 —, —CH 2 —CH 2 —, or —CH═CH—;  
 Ar 1  and Ar 2  are each independently unsubstituted or substituted phenyl or pyridinyl; 
                 
 
  is absent;  
 R 1  and R 2  are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , halogen, nitro, cyano, —OH, —SH or —CF 3 ;  
 R 3  and R 4  are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , halogen, nitro, cyano, —OH, —SH or —CF 3 ;  
 provided that at least one of R 1 -R 4  is H, lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , halogen, nitro, cyano, —OH, —SH or —CF 3 ;  
 m is 0 to 5;  
 q is 0 to 1; and  
 r is 0 to 1.  
 
     
     
       2. The compund of  claim 1 , wherein
 X 1  is absent or 0;    Ar 1  and Ar 2  are each independently unsubstituted or substituted phenyl or pyridinyl;    R 1  is hydrogen;    R 2  is lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , halogen, nitro, cyano, —OH, —SH or —CF 3 ;    R 3  is lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , halogen, nitro, cyano, —OH, —SH or —CF 3 ;    R 4  is hydrogen, lower alkyl, lower alkoxy, haloalkyl, —O—CH 2 ) m CF 3 , halogen, nitro, cyano, —OH, —SH or —CF 3 ;    m is 0 to 5;    q is 1; and    r is 0 to 1.    
     
     
       3. The compund of  claim 1 , wherein
 X 1  is absent;    Ar 1  is phenyl;    Ar 2  is substituted phenyl or pyridinyl;    R 1  is hydrogen;    R 2  is lower alkyl, lower alkoxy, haloalkyl, —O—(CH 2 ) m CF 3 , —OH or —SH;    R 3  is lower alkyl or haloalkyl;    R 4  is hydrogen;    m is 0 to 5;    q is 1; and    r is 0.    
     
     
       4. The compund of  claim 1 , wherein
 X 1  is absent or 0;    Ar 1  is phenyl;    Ar 2  is substituted phenyl;    R 1  is hydrogen;    R 2  is lower alkoxy;    R 3  is lower alkyl;    R 4  is hydrogen;    q is 1; and    r is 0 to 1.    
     
     
       5. The compund of  claim 1 , wherein
 X 1  is absent or 0;    Ar 1  is phenyl;    Ar 2  is substituted phenyl;    R 1  is hydrogen;    R 2  is methoxy;    R 3  is methyl;    R 4  is hydrogen;    q is 1; and    r is 0 to 1.    
     
     
       6. The compound of  claim 1 , wherein q is 1. 
     
     
       7. The compound of  claim 1 , wherein Ar 1  is substituted or unsubstituted phenyl. 
     
     
       8. The compound of  claim 1 , wherein Ar 2  is 4-trifluoromethylphenyl. 
     
     
       9. The compound of  claim 1 , wherein:
 R 1 , R 2 , R 3 , and R 4  are selected from hydrogen, alkyl, or alkoxy.    
     
     
       10. The compound of  claim 1 , wherein:
 R 2  and R 3  are hydrogen; and    R 1  and R 4  are alkyl or alkoxy.    
     
     
       11. The compound of  claim 1 , wherein:
 R 1  is alkyl;    R 2  and R 3  are hydrogen; and    R 4  is alkoxy.    
     
     
       12. The compound of  claim 1 , wherein:
 R 1  is methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, or isobutyl;    R 2  and R 3  are hydrogen; and    R 4  is methyoxy, ethoxy, isopropoxy, n-propoxy, t-butoxy, n-butoxy, or isobutoxy.    
     
     
       13. A compound selected from: 
       [4-(Biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methylphenoxy]-acetic acid;  
       [5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid;  
       [4-(2′,4′-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acid;  
       [5-Methoxy-2-methyl-4-(3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid;  
       [4-(4′-Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acid;  
       [5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy]-acetic acid;  
       [5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)-phenoxy]-acetic acid;  
       {{-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-acetic acid;  
       {5-Methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethylsulfanyl]-phenoxy}-acetic acid;  
       [3-Methoxy-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid;  
       (4-{4-[2-(3-Fluoro-phenyl)-vinyl]benzylsulfanyl}-5-methoxy-2-methyl-phenoxy)-acetic acid;  
       [5-Methoxy-2-methyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid;  
       [5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-phenoxy]-acetic acid;  
       and pharmaceutically acceptable salts thereof.  
     
     
       14. A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof admixed with a carrier, diluent, or excipient. 
     
     
       15. A method of treating or controlling non-insulin dependent diabetes mellitus in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of  claim 1   formula ( I ): 
                 
 
       
         or a pharmaceutically acceptable salt thereof wherein:  
         
           X 
           0  
           is S; X 
           1  
           is absent, O, S, —CH 
           2 
           —, —CH 
           2 
           —CH 
           2 
           —, or —CH═CH;  
         
         
           Ar 
           1  
           and Ar 
           2  
           are each independently unsubstituted or substituted phenyl or pyridinyl;  
           
             
             
                 
                 
             
           
         
           is absent; R   1    and R   2    are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,—O— ( CH   2 ) m   CF   3   , halogen, nitro, cyano, —OH, —SH or —CF   3 ;  
           R   3    and R   4    are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,—O— ( CH   2 ) m   CF   3   , halogen, nitro, cyano, —OH, —SH or —CF   3   , provided that at least one of R   1 - R   4    is H, lower alkyl, lower alkoxy, haloalkyl,—O— ( CH   2 ) m   CF   3   , halogen, nitro, cyano, —OH, —SH or —CF   3   ; m is  0  to  5 ;    
         
           q is  0  to  1 ; and  
         
           r is  0  to  1   .  
       
     
     
       16. A method of treating or controlling obesity in a mammal comprising adminsitering to the mammal in need thereof a therapeutically effective amount of a compound of  claim 1   formula ( I ): 
                 
 
       
         or a pharmaceutically acceptable salt thereof, wherein:  
         
           X 
           0  
           is S; X 
           1  
           is absent, O, S, —CH 
           2 
           —, —CH 
           2 
           —CH 
           2 
           —, or —CH═CH;  
         
         
           Ar 
           1  
           and Ar 
           2  
           are each independently unsubstituted or substituted phenyl or pyridinyl;  
           
             
             
                 
                 
             
           
         
           is absent; R   1    and R   2    are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,—O— ( CH   2 ) m   CF   3   , halogen, nitro, cyano, —OH, —SH or —CF   3 ;  
           R   3    and R   4    are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,—O— ( CH   2 ) m   CF   3   , halogen, nitro, cyano, —OH, —SH or —CF   3   , provided that at least one of R   1 - R   4    is H, lower alkyl, lower alkoxy, haloalkyl,—O— ( CH   2 ) m   CF   3   , halogen, nitro, cyano, —OH, —SH or —CF   3   ; m is  0  to  5 ;    
         
           q is  0  to  1 ; and  
         
           r is  0  to  1   .  
       
     
     
       17. A method of treating or controlling eating disorders in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
       18. A method of supressing appetite in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
       19. A method of modulating leptin levels in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
       20. A method of treating or controlling hyperglycemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
       21. A method of treating or controlling hyperinsulinemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
       22. A method of treating a patient exhibiting glucose disorders associated with circulating glucocorticoids, growth hormone, catecholamines, glucagon, or parathyroid hormone, comprising administering to the patient a therapeutically effective amount of a compound of  claim 1 . 
     
     
       23. A method of treating non-insuline dependent diabetes mellitus in a patient comprising administering to the patient in need of treatment a composition according to  claim 14 . 
     
     
       24. A method of treating metabolic syndrome in a patient comprising administering to the patient in need of treatment a composition according to  claim 14   comprising a compound of formula ( I ): 
                 
 
       
         or a pharmaceutically acceptable salt thereof, wherein:  
         
           X 
           0  
           is S; X 
           1  
           is absent, O, S, —CH 
           2 
           —, —CH 
           2 
           —CH 
           2 
           —, or —CH═CH;  
         
         
           Ar 
           1  
           and Ar 
           2  
           are each independently unsubstituted or substituted phenyl or pyridinyl;  
           
             
             
                 
                 
             
           
         
           is absent; R   1    and R   2    are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,—O— ( CH   2 ) m   CF   3   , halogen, nitro, cyano, —OH, —SH or —CF   3 ;  
           R   3    and R   4    are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,—O— ( CH   2 ) m   CF   3   , halogen, nitro, cyano, —OH, —SH or —CF   3   , provided that at least one of R   1 - R   4    is H, lower alkyl, lower alkoxy, haloalkyl,—O— ( CH   2 ) m   CF   3   , halogen, nitro, cyano, —OH, —SH or —CF   3   ; m is  0  to  5 ;    
         
           q is  0  to  1 ; and  
         
         
           r is  0  to  1 ;  
         
       
         and a pharmacuetically acceptable carrier, diluent or vehicle .