Novel PPAR-gamma agonists as agents for the treatment of type II diabetes

Abstract

Disclosed are compounds of the formula: or the pharmaceutically acceptable non-toxic salts thereof wherein: Z is aryl or heteroaryl; n and m are 0, 1 or 2; A is a carboxylic acid or ester; or A is where D, F and G are hydrogen, (un)substituted amino, (un)substituted alkoxy, methylene or an (un)substituted sulfide; X is N, O, CH 2 , S, SO or SO 2 ; R 4 is oxo, hydrogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyl, keto, acyl, or sulfonyl; Y is hydrogen, (un)substituted amino, (un)substituted alkoxy, methylene, an (un)substituted sulfide, (un)substituted sulfonyl or an (un)substituted sulfoxide; and R 5 , R 6 and R 8 are hydrogen, lower alkyl, lower alkoxy, cycloalkyl, keto, acyl, or sulfonyl; or R 5 and R 6 together form a ring. These [N-(substituted)carbamoylaryl- and heteroaryl aminopropanoic and butanoic acid compounds are highly selective agonists for the PPAR-γ receptor or prodrugs of agonists for the PPAR-γ receptor. Thus these compounds are useful in the treatment of Type II diabetes (NIDDM).

What is claimed is:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable non-toxic salts thereof wherein: 
 Z is a 5 or 6 membered aryl or heteroaryl ring optionally substituted with up to three groups selected from lower alkyl, halogen or lower alkoxy;  
 n and m independently represent 0, 1 or 2;  
 A is C0 2 R 9 ; or  
 A is  
                     
 D, F and G are the same or different and represent hydrogen, NR 1 R 12 , OR 1 , CH 2 R 1  or SR 1 ;  
 R 1  and R 12  are the same or different and represent hydrogen, lower alkyl, R 10 C═O, R 10 SO 2 , or 
 cycloalkyl optionally substituted with one, two, three or four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl, or  
 aryl, heteroaryl, arylalkyl, or heteroarylalkyl, where the ring portion of each is optionally substituted with one, two, three or four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl;  
 
 R 10  is hydrogen or lower alkyl, or aryl, heteroaryl, arylalkyl or heteroarylalkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl;  
 R 9  is H or lower alkyl;  
 X is N, O, CH 2 , S, SO or SO 2 ;  
 R 4  is O, hydrogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyl, R 10 C═O or R 10 SO 2 ;  
 Y is hydrogen, NR 1 R 12 , OR 1 , CH 2 R 1 , SR 1 , SOR 1  or SO 2 R 1 ; and  
 R 5 , R 6  and R 8 , are the same or different and represent hydrogen, lower alkyl, R 10 C═O, R 10 SO 2 , or 
 cycloalkyl optionally substituted with one, two, three or four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl, or  
 aryl, heteroaryl, arylalkyl, or heteroarylalkyl, where the ring portion of each is optionally substituted with one, two, three or four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl; or  
 
 R 5  and R 6  together with the carbon atom to which they are attached form a 5, 6, or 7 membered carbocyclic ring up to two of which members are optionally hetero atoms selected from oxygen, sulfur and nitrogen.  
 
     
     
         2 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable non-toxic salts thereof wherein: 
 n and m independently represent 0, 1 or 2;  
 A is CO 2 R 9 ; or  
 A is  
                     
 D, F and G are the same or different and represent hydrogen, NR 1 R 12 , OR 1 , CH 2 R 1  or SR 1 ;  
 R 1  and R 12  are the same or different and represent hydrogen, lower alkyl, R 10 C═O, R 10 SO 2 , or 
 cycloalkyl optionally substituted with one, two, three or four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl, or  
 aryl, heteroaryl, arylalkyl, or heteroarylalkyl, where the ring portion of each is optionally substituted with one, two, three or four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl;  
 
 R 10  is hydrogen or lower alkyl, or aryl, heteroaryl, arylalkyl or heteroarylalkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl;  
 R 9  is H or lower alkyl;  
 X is N, O, CH 2 , S, SO or SO 2 ;  
 R 4  is O, hydrogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyl, R 10 C═O or R 10 SO 2 ;  
 Y is hydrogen, NR 1 R 12 , OR 1 , CH 2 R 1 , SR 1 , SOR 1  or SO 2 R 1 ; and  
 R 5 , R 6  and R 8 , are the same or different and represent hydrogen, lower alkyl, R 10 C═O, R 10 SO 2 , or 
 cycloalkyl optionally substituted with one, two, three or four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl, or  
 aryl, heteroaryl, arylalkyl, or heteroarylalkyl, where the ring portion of each is optionally substituted with one, two, three or four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl; or  
 
 R 5  and R 6  together with the carbon atom to which they are attached form a 5, 6, or 7 membered carbocyclic ring up to two of which members are optionally hetero atoms selected from oxygen, sulfur and nitrogen.  
 
     
     
         3 . A compound according to  claim 1  which is 
 (2S)-2-[benzylamino]-3-{4-[N-(3-phenylpropyl)carbamoyl]phenyl} propanoic acid;  
 (2S)-3-{4-[N-methyl-N(2-phenylthiocyclopentyl)carbamoyl]phenyl}-2-[benzylamino]propanoic acid;  
 (2S)-2-{[(4-methoxyphenyl)methyl]amino}-3-{4-[N-(3-phenylpropyl) carbamoyl]phenyl}propanoic acid;  
 (2S)-3-{4-[N-methyl-N-(2-phenylthiocyclopentyl)carbamoyl]phenyl}-2-({[4-(trifluoromethoxy)phenyl]methyl}amino)propanoic acid;  
 (2S)-2-{[(4-fluorophenyl)methyl]amino}-3-{4-[N-methyl-N-(2-phenylthiocyclopentyl)carbamoyl]phenyl}propanoic acid;  
 (2S)-3-{4-[N-methyl-N-(2-phenoxycyclopentyl)carbamoyl]phenyl}-2-[benzylamino]propanoic acid;  
 (2S)-3-{4-[N-methyl-N-(2-phenylthiocyclohexyl)carbamoyl]phenyl}-2-({[4-(trifluoromethoxy)phenyl]methyl}amino)propanoic acid; and  
 (2S)-2-{ [(4-fluorophenyl)methyl] amino}-3-{4-[N-methyl-N-(2-phenylthiocyclohexyl)carbamoyl]phenyl}propanoic acid.  
 
     
     
         4 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         5 . A method of treating Type II diabetes in a mammal comprising administering to said mammal a compound according to  claim 1.