Substituted phenylacetic acids
Substituted phenylacetic acids, phenylethanols and related compounds are provided that are useful in treating or controlling a number of diseases associated with glucose metabolism, lipid metabolism and insulin secretion.
1. A compound having a formula selected from the group consisting of:
wherein
X is a member selected from the group consisting of O, S, SO, SO 2 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 , CHO, CONR c R m , CH(═NR c ), CH(═NOR c ), C(O)NHSO 2 R n ,sulfonic acids, sulfinic acids, phosphonic acids, phosphinic acids, activated carboxamides, hydroxamic acids, tetrazole, triazole, hydroxypyrazole, hydroxyoxazole, acidic alcohols and SO 2 NHX 1 , wherein X 1 is an electron withdrawing group relative to an alkyl group, 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, OH and SO 2 R n , wherein R n is selected from the group consisting of (C 1 –C 8 )alkyl, (C 1 –C 8 )haloalkyl, aryl(C 1 –C 8 )alkyl, (C 1 –C 8 )heteroalkyl, aryl, heteroaryl, (C 1 –C 8 )alkoxy, aryloxy, alkylamino, dialkylamino, arylamino, diarylamino, haloalkylamino and di(haloalkyl)amino, 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;
HAr is benzo-1,2,3-triazole, optionally substituted with from one to three substituents independently selected from the group consisting of halogen, hydroxy, (C 1 –C 8 )alkyl, aryl(C 1 –C 8 )alkyl, (C 1 –C 8 )alkoxy, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, (C 3 –C 7 )cycloalkyl, (C 4 –C 8 )cycloalkyl-alkyl, (C 1 –C 8 )heteroalkyl, (C 2 –C 5 )heterocyclyl, aryl, aryloxy, heterosubstituted(C 3 –C 7 )cycloalkyl, heteroalkyl substituted (C 3 –C 7 )cycloalkyl, (C 1 –C 8 )haloalkyl, O(C 1 –C 8 )haloalkyl, nitro, cyano, CO 2 R g , COR g , NR g R h , S(O) q R g , SO 2 NR g R h , NR g CONR h R i , NR g COR h , NR g COOR h and CONR g R h , wherein R g , R h and R i are each independently selected from the group consisting of H and (C 1 –C 8 )alkyl, or optionally two of R g , R h and R i when attached to the same nitrogen atom are combined to form a five- or six-membered ring, and the subscript q is an integer of from 0 to 2;
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, (C 1 –C 8 )alkyl and (C 1 –C 8 )haloalkyl, 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, (C 1 –C 8 )alkyl, (C 1 –C 8 )haloalkyl, aryl(C 1 –C 8 )alkyl and (C 1 –C 4 )alkylene-Z, wherein Z is as defined above;
the subscript m is an integer of from 0 to 4;
the subscript p is an integer of from 0 to 3; and
pharmaceutically acceptable salts thereof.
2. A compound of claim 1 , wherein Y is selected from the group consisting of CH 2 OR c , CO 2 R c , tetrazole-5-yl, CONHSO 2 R n and CHO.
3. A compound of claim 1 , wherein Y is selected from the group consisting of CH 2 OR c , tetrazole-5-yl, CONHSO 2 R n and CO 2 R c .
4. A compound of claim 3 , wherein HAr is optionally substituted with from one to three substituents independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, aryl, aryloxy, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, CO 2 R g , COR g and CONR g R h .
5. A compound of claim 4 , wherein X is selected from the group consisting of O, S and NH.
6. A compound of claim 5 , wherein R 2 is selected from the group consisting of H, CH 3 and CF 3 .
7. A compound of claim 6 , wherein HAr is attached to the 2- or 3-position of the ring bearing X and
is optionally substituted with from one to three substituents independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, CO 2 R g , COR g and CONR g R h .
8. A compound of claim 7 , wherein the subscript m is 0 to 2 and each R 3 when present is independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl and S(O) r -phenyl.
9. A compound of claim 8 , wherein p is an integer of from 0 to 2 and each R 1 when present is independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl and S(O) r -phenyl.
10. A compound of claim 1 , wherein m is an integer of from 0 to 2; each R 3 when present is independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl and S(O) r -phenyl; p is an integer of from 0 to 2; and each R 1 is independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl and S(O) r -phenyl.
11. A compound of claim 7 , having a formula selected from the group consisting of:
wherein the subscript m is an integer of from 0 to 2, the subscript p is an integer of from 0 to 2, and R 1 and R 3 are each independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl and S(O) r -phenyl; and R n is selected from the group consisting of (C 1 –C 8 )alkyl, (C 1 –C 8 )haloalkyl, aryl(C 1 –C 8 )alkyl, (C 1 –C 8 )heteroalkyl, aryl, heteroaryl, (C 1 –C 8 )alkoxy, aryloxy, alkylamino, dialkylamino, arylamino, diarylamino, haloalkylamino and di(haloalkyl)amino.
12. A compound of claim 11 , wherein HAr is
and is optionally substituted with from one to three substituents independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, CO 2 R g , COR g and CONR g R h .
13. A compound of claim 12 , wherein R 2 is H or CH 3 ; the subscript m is 0 or 1, and p is 1 or 2; and R 1 and R 3 are each independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro and cyano.
14. A composition comprising a pharmaceutically acceptable excipient and a compound having the formula:
wherein
X is a member selected from the group consisting of O, S, SO, SO 2 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 , CHO, CONR c R m , CH(═NR c ), CH(═NOR c ), C(O)NHSO 2 R n ), sulfonic acids, sulfinic acids, phosphonic acids, phosphinic acids, activated carboxamides, hydroxamic acids, tetrazole, triazole, hydroxypyrazole, hydroxyoxazole, acidic alcohols and SO 2 NHX 1 , wherein X 1 is an electron withdrawing group relative to an alkyl group, 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, OH and SO 2 R n , wherein R n is selected from the group consisting of (C 1 –C 8 )alkyl (C 1 –C 8 )haloalkyl, (C 1 –C 8 )aralkyl, (C 1 –C 8 )heteroalkyl, aryl, heteroaryl, (C 1 –C 8 )alkoxyl, aryloxyl, alkylamino, dialkylamino, arylamino, diarylamino, haloalkylamino and di(haloalkyl)amino; 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;
HAr is benzo-1,2,3-triazole, optionally substituted with from one to three substituents independently selected from the group consisting of halogen, hydroxy, (C 1 –C 8 )alkyl, aryl(C 1 –C 8 )alkyl, (C 1 –C 8 )alkoxy, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, (C 3 –C 7 )cycloalkyl, (C 4 –C 8 )cycloalkyl-alkyl, (C 1 –C 8 )heteroalkyl, (C 2 –C 5 )heterocyclyl, aryl, aryloxy, heterosubstituted(C 3 –C 7 )cycloalkyl, heteroalkyl substituted (C 3 –C 7 )cycloalkyl, (C 1 –C 8 )haloalkyl, O(C 1 –C 8 )haloalkyl, nitro, cyano, CO 2 R g , COR g , NR g R h , S(O) q R g , SO 2 NR g R h , NR g CONR h R i , NR g COR h , NR g COOR h and CONR g R h , wherein R g , R h and R i are each independently selected from the group consisting of H and (C 1 –C 8 )alkyl, or optionally two of R g , R h and R i when attached to the same nitrogen atom are combined to form a five- or six-membered ring, and the subscript q is an integer of from 0 to 2;
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, (C 1 –C 8 )alkyl and (C 1 –C 8 )haloalkyl, 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, (C 1 –C 8 )alkyl, (C 1 –C 8 )haloalkyl, aryl(C 1 –C 8 )alkyl and (C 1 –C 4 )alkylene-Z, wherein Z is as defined above;
the subscript m is an integer of from 0 to 4;
the subscript p is an integer of from 0 to 3; and
pharmaceutically acceptable salts thereof.
15. A composition in accordance with claim 14 , wherein Y is selected from the group consisting of CH 2 OR c , CO 2 R c , tetrazole-5-yl, CONHSO 2 R n and CHO.
16. A composition in accordance with claim 15 , wherein Y is selected from the group consisting of CH 2 OR c , tetrazole-5-yl, CONHSO 2 R n and CO 2 R c .
17. A composition in accordance with claim 16 , wherein HAr is optionally substituted with from one to three substituents independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, aryl, aryloxy, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, CO 2 R g , COR g and CONR g R h .
18. A composition in accordance with claim 17 , wherein X is selected from the group consisting of O, S and NH.
19. A composition in accordance with claim 18 , wherein R 2 is selected from the group consisting of H, CH 3 and CF 3 .
20. A composition in accordance with claim 19 , wherein HAr is attached to the 2- or 3-position of the ring bearing X and is
optionally substituted with from one to three substituents independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, CO 2 R g , COR g and CONR g R h .
21. A composition in accordance with claim 20 , wherein m is from 0 to 2; and each R 3 when present is independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl and S(O) r -phenyl.
22. A composition in accordance with claim 21 , wherein p is from 0 to 2; and each R 1 when present is independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl and S(O) r -phenyl.
23. A composition in accordance with claim 14 , wherein m is an integer of from 0 to 2; each R 3 is independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl and S(O) r -phenyl; p is an integer of from 0 to 2; and each R 1 is independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl and S(O) r -phenyl.
24. A composition in accordance with claim 20 , having a formula selected from the group consisting of:
wherein the subscript m is an integer of from 0 to 2; the subscript p is an integer of from 0 to 2; R 1 and R 3 are each independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl and S(O) r -phenyl; and R n is selected from the group consisting of (C 1 –C 8 )alkyl, (C 1 –C 8 )haloalkyl, aryl(C 1 –C 8 )alkyl, (C 1 –C 8 )heteroalkyl, aryl, heteroaryl, (C 1 –C 8 )alkoxy, aryloxy, alkylamino, dialkylamino, arylamino, diarylamino, haloalkylamino and di(haloalkyl)amino.
25. A composition in accordance with claim 24 , wherein HAr is
and is optionally substituted with from one to three substituents independently selected from the group consisting of halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )haloalkyl, O(C 1 –C 4 )haloalkyl, nitro, cyano, CO 2 R g , COR g and CONR g R h .
26. A prodrug agent having a formula selected from the group consisting of:
wherein
X is a member selected from the group consisting of O, S, SO, SO 2 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 CO 2 R″, wherein R″ is selected from the group consisting of alkyl, heteroalkyl, aryl, heteroaryl, phenyl-lower alkyl, benzamido-lower alkyl, di-lower alkylamino-lower alkyl, ureido-lower alkyl, N′-lower alkyl-ureido-lower alkyl, carbamoyl-lower alkyl, halophenoxy substituted lower alkyl and carbamoyl substituted phenyl;
HAr is benzo-1,2,3-trizole, optionally substituted with from one to three substituents independently selected from the group consisting of halogen, hydroxy, (C 1 –C 8 )alkyl, aryl(C 1 –C 8 )alkyl, (C 1 –C 8 )alkoxy, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, (C 3 –C 7 )cycloalkyl, (C 4 –C 8 )cycloalkyl-alkyl, (C 1 –C 8 )heteroalkyl, (C 2 –C 5 )heterocyclyl, aryl, aryloxy, heterosubstituted(C 3 –C 7 )cycloalkyl, heteroalkyl substituted (C 3 –C 7 )cycloalkyl, (C 1 –C 8 )haloalkyl, O(C 1 –C 8 )haloalkyl, nitro, cyano, CO 2 R g , COR g , NR g R h , S(O) q R g , SO 2 NR g R h , NR g CONR h R i , NR g COR h , NR g COOR h and CONR g R h , wherein R g , R h and R i are each independently selected from the group consisting of H and (C 1 –C 8 )alkyl, or optionally two of R g , R h and R i when attached to the same nitrogen atom are combined to form a five- or six-membered ring, and the subscript q is an integer of from 0 to 2;
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, (C 1 –C 8 )alkyl and (C 1 –C 8 )haloalkyl, 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, (C 1 –C 8 )alkyl, (C 1 –C 8 )haloalkyl, aryl(C 1 –C 8 )alkyl and (C 1 –C 4 )alkylene-Z, wherein Z is as defined above;
the subscript m is an integer of from 0 to 4;
the subscript p is an integer of from 0 to 3; and
pharmaceutically acceptable salts thereof.
27. A compound of claim 1 , having the structure
and pharmaceutically acceptable salts thereof.
28. A compound of claim 1 , having the structure
29. A compound of claim 1 , selected from the group consisting of (+)-(2-Benzotriazol-2-yl-4-chloro-phenoxy)-phenylacetic acid, (−)-(2-Benzotriazol-2-yl-4-chloro-phenoxy)-phenylacetic acid, and pharmaceutically acceptable salts thereof.
30. A compound of claim 29 , which is (+)-(2-Benzotriazol-2-yl-4-chloro-phenoxy)-phenylacetic acid.
31. A compound of claim 29 , which is (−)-(2-Benzotriazol-2-yl-4-chloro-phenoxy)-phenylacetic acid.