ALPHA-(TRIFLUOROMETHYL-SUBSTITUTED ARYLOXY, ARYLAMINO, ARYLTHIO OR ARYLMETHYL)-TRIFLUOROMETHYL-SUBSTITUTED PHENYLACETIC ACIDS AND DERIVATIVES AS ANTIDIABETIC AGENTS
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.