Compounds that modulate PPAR activity and methods of 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 or their salts, and methods of using them as therapeutic agents for treating or preventing hyperlipidemia and hypercholesteremia in a mammal. The present invention also discloses method for making the disclosed compounds.

1 . A compound having formula 1:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein: 
 V 1  is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain having from 3 to 6 atoms wherein the carbon atom of position 1 is connected to the carbon atom of position 2 to form a five to eight member r ing wherein the  
                     
 is attached to a substitutionally available position of said ring;  
 X 0  and X 1  are independently O or S;  
 X 2  is absent, O, S, or NR 4 ;  
 Ar 1  is substituted or unsubstituted aryl or heteroaryl;  
 R 1 , R 2 , and R 3  are independently hydrogen, lower alkyl, lower alkoxy, lower thioalkoxy, —O(CH 2 ) p CF 3 , halogen, nitro, cyano, —OH, —SH, —CF 3 , S(O) p Alkyl, S(O) p Aryl, —(CH 2 ) m OR 4 , or —(CH 2 ) m NR 5 R 6 , COR 4 , —CO 2 H, —CO 2 R 4 , or —NR 5 R 6  or R 1  and R 2  are joined together to form a substituted or unsubstituted, saturated or unsaturated cyloalkyl or heterocycloalkyl ring;  
 R 4  is hydrogen, alkyl, alkenyl, alkynyl, or aryl;  
 R 5  and R 6  are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, SO 2 Alkyl or, SO 2 Aryl, or joined together to form a 4 to 7 member ring having 0 to 3 heteroatoms;  
 m is 0 to 5;  
 n is 0 to 5; and  
 p is 0 to 2.  
 
     
     
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         15 . A method of treating, preventing 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 .  
     
     
         16 . A method of treating, preventing or controlling obesity in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         17 . A method of treating, preventing or controlling hyperglycemia 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 treating, preventing or controlling hyperlipidemia 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 treating, preventing or controlling hypercholesteremia 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, preventing or controlling atherosclerosis 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, preventing or controlling hypertriglyceridemia 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, preventing or controlling hyperinsulinemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         23 . 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 .  
     
     
         24 . A method of making the compound having Formula 1:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, the method comprising reacting:  
       
         
           
           
               
               
           
         
       
       in a solvent in the presence of a base with:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 10  is a lower alkyl  
 V 1  is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain having from 3 to 6 atoms wherein the carbon atom of position 1 is connected to the carbon atom of position 2 to form a five to eight member ring wherein the  
                     
 is attached to a substitutionally available position of said ring;  
 X 0  and X 1  are independently O or S;  
 X 2  is absent, O, S, or NR 4 ;  
 X is a halogen;  
 Ar 1  is substituted or unsubstituted aryl or heteroaryl;  
 R 1 , R 2 , and R 3  are independently hydrogen, lower alkyl, lower alkoxy, lower thioalkoxy, —O(CH 2 ) p CF 3 , halogen, nitro, cyano, —OH, —SH, —CF 3 , S(O) p Alkyl, S(O) p Aryl, —(CH 2 ) m OR 4 , or —(CH 2 ) m NR 5 R 6 , COR 4 , —CO 2 H, —CO 2 R 4 , —NR 5 R 6 ; or —NR 5 R 6  or R 1  and R2 are joined together to form a substituted or unsubstituted, saturated or unsaturated cyloalkyl or heterocycloalkyl ring;  
 R 4  is hydrogen, alkyl, alkenyl, alkynyl, or aryl;  
 R 5 and R 6  are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, SO 2 Alkyl or, SO 2 Aryl, or joined together to form a 4 to 7 member ring having 1 to 3 heteroatoms;  
 m is 0 to 5;  
 n is 0 to 5; and  
 p is 0 to 2.  
 
     
     
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