Bis-aryl thiazole derivatives
View Patent ↗Compounds, compositions and methods are provided that are useful in the treatment or prevention of a condition or disorder mediated by an uncoupling protein. In particular, the compounds of the invention modulate the expression and/or activity of UCP3. The subject compositions are particularly useful in the treatment of obesity and type II diabetes, and associated diseases
1. A method for treating obesity or diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
X is selected from the group consisting of CO 2 R 1 and C(O)NR 1 R 2 ;
Y is selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl, aryl, heteroaryl, halogen, NR 3 R 4 and CO 2 R 3 ;
Z 1 is selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl and halogen;
Z 2 is selected from the group consisting of aryl and heteroaryl, or Z 1 and Z 2 may be combined to form a fused 6-membered ring; and
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, carboxy(C 1 -C 4 ) alkyl and aryl.
2. The method of claim 1 , wherein said compound has the formula (II):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
X is selected from the group consisting of CO 2 R 1 and C(O)NR 1 R 2 ;
Y is selected from the group consisting of hydrogen, (C 1 -C 4 alkyl, fluoro(C 1 -C 4 )alkyl, aryl, heteroaryl, halogen, NR 3 R 4 and COR 2 R 3 ;
Z 1 is selected from the group consisting of hydrogen, (C 1 -C 4 alkyl and halogen;
Z 2 is selected from the group consisting of aryl and heteroaryl, or Z 1 and Z 2 may be combined to form a fused 6-membered ring; and
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, carboxy(C 1 -C 4 )alkyl and aryl.
3. The method of claim 1 , wherein X is CO 2 H.
4. The method of claim 1 , wherein Y is hydrogen. (C 1 -C 4 ) alkyl or fluoro (C 1 -C 4 )alkyl.
5. The method of claim 1 , wherein Z 1 is hydrogen.
6. The method of claim 1 , wherein Z 2 is phenyl, naphthyl, pyridyl or pyrimidinyl.
7. The method of claim 1 , wherein Z 2 is phenyl and X is CO 2 H.
8. The method of claim 1 , wherein Z 2 is phenyl and Y is (C 1 -C 4 alkyl or fluoro(C 1 -C 4 )alkyl.
9. The method of claim 1 , wherein Z 1 and Z 2 are combined to form a fused benzene ring.
10. The method of claim 2 , wherein said compound has the formula (III):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Y is selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl, aryl, heteroaryl, halogen, NR 3 R 4 and CO 2 R 3 ;
Z 1 is selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl and halogen;
Z 2 is selected from the group consisting of aryl and heteroaryl, or Z 1 and Z 2 may be combined to form a fused 6-membered ring; and
R 1 , R 3 and R 4 are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, carboxy(C 1 -C 4 )alkyl and aryl.
11. The method of claim 10 , wherein R 1 is hydrogen.
12. The method of claim 10 , wherein Z 2 is phenyl.
13. The method of claim 12 , wherein said compound has the formula (IV):
or a pharmaceutically acceptable salt or prodrug thereot wherein
Y is selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 alkyl, aryl, heteroaryl, halogen, NR 3 R 4 and CO 2 R 3 ;
R 1 , R 2 and R 4 are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, carboxy(C 1 -C 4 )alkyl and aryl;
W is (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl, halogen or nitro; and
n is an integer from 1 to 3.
14. The method of claim 13 , wherein Y is (C 1 -C 4 )alkyl.
15. The method of claim 2 , wherein said compound has the formula (VI):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Y is selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl, aryl, heteroaryl, halogen, NR 3 R 4 and CO 2 R 3 ;
Z 1 is selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl and halogen;
Z 2 is selected from the group consisting of atyl and heteroaryl, or Z 1 and Z 2 may be combined to form a fused 6-membered ring; and
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, carboxy(C 1 -C 4 )alkyl and aryl.
16. The method of claim 15 , wherein Z 2 is phenyl.
17. The method of claim 16 , wherein said compound has the formula (VII):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Y is selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl, aryl, heteroaryl, halogen, NR 3 R 4 and CO 2 R 3 ;
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, carboxy(C 1 -C 4 )alkyl and aryl;
W is (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl, halogen or nitro; and
n is an integer from 1 to 3.
18. The method of claim 17 , wherein Y is (C 1 -C 4 )alkyl.
19. The method of claim 1 , wherein said compound is
20. The method of claim 1 , wherein said compound is administered in combination with a therapeutic agent selected from the group consisting of a β 3 adrenergic receptor agonist, a leptin, a lepuin derivative, a neuropeptide Y antagonist insulin and derivatives thereof, a hypoglycemic agent, an antihyperglyeemic agent, an czglucosidase inhibitor, an insulin sensitizer, an RXR agonist, a cholesterol lowering agent, a calcium channel blocker, interferon alpha, interferon beta, a DNA-alkylating agent, an antirnetabolite, a microtubule disruptor, a DNA intercalator, a DNA synthesis inhibitor and a hormone.
21. The method of claim 1 , wherein said administering is oral or parenteral.