Alpha-(trifluoromethyl-substituted aryloxy, arylamino, arylthio or arylmethyl)-trifluoromethyl-substituted phenylacetic acids and derivatives as antidiabetic agents

Abstract

Compounds having a formula: or a pharmaceutically acceptable salt or prodrug thereof, are provided, and are useful for the treatment of metabolic disorders.

1 . A compound having the formula 
     
       
         
         
             
             
         
       
     
     and all pharmaceutically acceptable salts and prodrugs thereof, wherein
 X is a member selected from the group consisting of O, S, SO, SO 2 , CHR and NR, wherein R is H, (C 1 -C 8 )alkyl, COR a , COOR a  and CONR a R b  wherein R a  and R b  are each independently selected from the group consisting of H and (C 1 -C 8 )alkyl; 
 Y is a member selected from the group consisting of CH 2 OR c , CO 2 R c , tetrazole, CHO, CONR c R m , CH(═NR c ) and CH(═NOR c ), wherein R c  is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )cycloalkyl-alkyl, aryl, aryl(C 1 -C 8 )alkyl and (C 1 -C 8 )alkylene-Z, wherein Z is selected from the group consisting of COR d , COOR d , NR d R e , NR d CONR e R f , NR d COR e , NR d COOR e  and CONR d R e  wherein R d , R e  and R f  are each independently selected from the group consisting of H, (C 1 -C 8 )alkyl and phenyl, or optionally two of R d , R e  and R f  when attached to the same nitrogen atom are combined to form a five- or six-membered ring; and wherein R m  is selected from the group consisting of H, (C 1 -C 8 )alkyl, aryl and OH, and R m  and R c  are optionally combined with the nitrogen atom to which each is attached to form a five or six-membered ring; 
 each R 1  and R 3  is a member independently selected from the group consisting of halogen, hydroxy, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )cycloalkyl-alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )heteroalkyl, (C 2 -C 5 )heterocyclyl, heterosubstituted(C 3 -C 7 )cycloalkyl, heteroalkyl substituted (C 3 -C 7 )cycloalkyl, O(C 1 -C 8 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl, S(O) r -phenyl, COR j , COOR j , NR j R k , S(O) r R j , SO 2 NR j R k , NR j CONR k R l , NR j COR k , NR j COOR k  and CONR j R k  wherein the phenyl ring is optionally substituted and R j , R k  and R l  are each independently selected from the group consisting of H and (C 1 -C 8 )alkyl, or optionally two of R j , R k  and R l  when attached to the same nitrogen atom are combined to form a five- or six-membered ring, and the subscript r is an integer of from 0 to 2; 
 R 2  is a member selected from the group consisting of H and (C 1 -C 8 )alkyl; 
 Q is CH or N 
 the subscript m is an integer of from 0 to 3; and 
 the subscript p is an integer of from 0 to 2. 
 
   
   
       2 . A compound of  claim 1 , wherein Q is CH. 
   
   
       3 . A compound of  claim 2 , wherein X is selected from the group consisting of O, S and NR. 
   
   
       4 . A compound of  claim 3 , wherein Y is CO 2 R c . 
   
   
       5 . A compound of  claim 4 , wherein the subscript m is 0 to 2 and the subscript p is 0 to 1. 
   
   
       6 . A compound of  claim 5 , wherein each R 3  is selected from the group consisting of halogen, nitro, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )alkoxy and (C 1 -C 8 )haloalkoxy. 
   
   
       7 . A compound of  claim 5 , wherein each R 1  is selected from the group consisting of halogen, nitro, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )alkoxy and (C 1 -C 8 )haloalkoxy. 
   
   
       8 . A compound of  claim 5 , wherein R c  is selected from the group consisting of H, (C 1 -C 8 )alkyl and (C 1 -C 8 )alkylene-Z. 
   
   
       9 . A compound of  claim 8 , wherein R 2  is H or CH 3 . 
   
   
       10 . A compound of  claim 1 , wherein Q is CH—X is selected from the group consisting of O and NR; Y is selected from the group consisting of CH-10R c  and CO 2 R c ; the subscript m is 0 to 2 and the subscript p is 0 to 1; each R 1  is selected from the group consisting of halogen, nitro, (C 1 -C 8 )alkyl and (C 1 -C 8 )alkoxy; each R 3  is selected from the group consisting of halogen, nitro, (C 1 -C 8 ) alkyl and (C 1 -C 8 ) alkoxy; and R 2  is H or CH 3 . 
   
   
       11 . A compound of  claim 10 , wherein X is O and Y is COR c . 
   
   
       12 . A compound of  claim 10 , wherein X is O and Y is CH 2 OR c . 
   
   
       13 . A compound of  claim 10 , wherein X is NH and Y is CO 2 R c . 
   
   
       14 . A compound of  claim 10 , wherein X is NH and Y is CH 2 OR c . 
   
   
       15 . A composition comprising a pharmaceutically acceptable excipient and a compound having a formula: 
     
       
         
         
             
             
         
       
       and all pharmaceutically acceptable salts and prodrugs thereof, wherein 
       X is a member selected from the group consisting of O, S, SO, SO 2 , CHR and NR, wherein R is H, (C 1 -C 8 )alkyl, COR a , COOR a  and CONR a R b  wherein R a  and R b  are each independently selected from the group consisting of H and (C 1 -C 8 )alkyl; 
       Y is a member selected from the group consisting of CH 2 OR c , CO 2 R c , tetrazole, CHO, CONR c R m , CH(═NR c ) and CH(═NOR c ), wherein R c  is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )cycloalkyl-alkyl, aryl, aryl(C 1 -C 8 )alkyl and (C 1 -C 8 )alkylene-Z, wherein Z is selected from the group consisting of COR d , COOR d , NR d R e , NR d CONR e R f , NR d COR e , NR d COOR e  and CONR d R e  wherein R d , R e  and R f  are each independently selected from the group consisting of H, (C 1 -C 8 )alkyl and phenyl, or optionally two of R d , R e  and R f  when attached to the same nitrogen atom are combined to form a five- or six-membered ring; and wherein R m  is selected from the group consisting of H, (C 1 -C 8 )alkyl, aryl and OH, and R m  and R c  are optionally combined with the nitrogen atom to which each is attached to form a five or six-membered ring; 
       each R 1  and R 3  is a member independently selected from the group consisting of halogen, hydroxy, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )cycloalkyl-alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )heteroalkyl, (C 2 -C 5 )heterocyclyl, heterosubstituted(C 3 -C 7 )cycloalkyl, heteroalkyl substituted (C 3 -C 7 )cycloalkyl, O(C 1 -C 8 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl, S(O) r -phenyl, COR j , COOR j , NR j R k , S(O) r R j , SO 2 NR j R k , NR j CONR k R l , NR j COR k , NR j COOR k  and CONR j R k  wherein the phenyl ring is optionally substituted and R j , R k  and R l  are each independently selected from the group consisting of H and (C 1 -C 8 )alkyl, or optionally two of R j , R k  and R l  when attached to the same nitrogen atom are combined to form a five- or six-membered ring, and the subscript r is an integer of from 0 to 2; 
       R 2  is a member selected from the group consisting of H and (C 1 -C 8 )alkyl; 
       Q is CH or N 
       the subscript m is an integer of from 0 to 3; and 
       the subscript p is an integer of from 0 to 2. 
     
   
   
       16 . A method for treating inflammation or a metabolic disorder selected from the group consisting of type II diabetes, hyperlipidemia, hyperuricemia and diseases associated with insulin resistance, said method comprising administering to a subject in need of such treatment, a compound of  claim 1 . 
   
   
       17 . A method in accordance with  claim 16 , wherein said metabolic disorder is type II diabetes. 
   
   
       18 . A method in accordance with  claim 16 , wherein said metabolic disorder is hyperlipidemia. 
   
   
       19 . A method in accordance with  claim 16 , wherein said metabolic disorder is a disease associated with insulin resistance. 
   
   
       20 . A method in accordance with  claim 16 , wherein said compound is administered in combination with a second agent useful for treating metabolic disorders. 
   
   
       21 . A method in accordance with  claim 16 , wherein said compound is administered to a patient having an inflammatory condition.