Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
View Patent ↗The present invention provides compounds useful, for example, for modulating insulin levels in a subject and that have the general formula Q-L 1 -P-L 2 -M-X-L 3 -A wherein the definitions of the variables Q, L 1 , P, L 2 , M, X, L 3 and A are provided herein. The present invention also provides compositions and methods for use of the compounds, for instance, for treatment of type II diabetes.
1. A compound having the formula (I):
or a pharmaceutically acceptable salt, or ester thereof, wherein
Q is heteroaryl
L 1 is a bond;
P is an aromatic ring;
L 2 is oxymethylene or thiomethylene;
M is an aromatic ring;
X is CR 3 R 4 ;
L 3 is (C 1 -C 5 )alkylene;
A is —CO 2 H;
R 1 is (C 1 -C 6 )alkyl, aryl(C 1 -C 3 ) alkyl or (C 2 -C 6 )heteroalkyl;
R 3 is cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )alkynyl, —NR 8 R 9 , —C(O)NR 10 R 11 , —NR 12 C(O)R 13 or —NR 12 S(O) p R 13 ;
R 4 is hydrogen, cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl or (C 2 -C 8 )alkynyl;
R 8 and R 9 are independently hydrogen, (C 1 -C 5 )alkyl, oxy(C 1 -C 5 )alkyl or carboxy(C 1 -C 5 )alkyl;
optionally, R 8 and R 9 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S;
R 10 , R 11 and R 12 are independently selected from hydrogen, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl and (C 3 -C 8 )heterocycloalkyl;
optionally, R 10 and R 11 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S;
R 13 is aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )heterocycloalkyl;
the subscript p is 1 or 2; and
wherein the aromatic rings, aryl groups, and heteroaryl groups set forth above are optionally substituted with substituents selected from -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO 2 , —CO 2 R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O) 2 R′, —NR′—C(O)NR″R″′, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —N 3 , —CH(Ph) 2 , perfluoro(C 1 -C 4 )alkoxy, and perfluoro(C 1 -C 4 )alkyl, in a number ranging from zero to the total number of open valences on the aromatic, aryl, or heteroaryl ring; and further wherein R′, R″ and R″′ are independently selected from hydrogen, (C 1 -C 8 )alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C 1 -C 4 )alkyl, and (unsubstituted aryl)oxy-(C 1 -C 4 )alkyl.
2. The compound of claim 1 , wherein P and M are benzene.
3. The compound of claim 1 , wherein the compound has the following structure:
or is a salt thereof.
4. The compound of claim 1 , wherein R 3 is cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or —NR 8 R 9 .
5. The compound of claim 4 , wherein R 4 is hydrogen.
6. The compound of claim 1 , wherein M is benzene.
7. The compound of claim 6 , wherein R 3 is cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or —NR 8 R 9 .
8. The compound of claim 7 , wherein P is benzene.
9. The compound of claim 1 , wherein P is benzene.
10. The compound of claim 9 , wherein R 3 is cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or —NR 8 R 9 .
11. The compound of claim 10 , wherein R 4 is hydrogen.
12. The compound of claim 11 , wherein M is benzene.
13. The compound of claim 9 , wherein M is benzene and X is para to L 2 .
14. The compound of claim 13 , wherein L 3 is methylene.
15. The compound of claim 14 , wherein R 3 is cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or —NR 8 R 9 .
16. The compound of claim 15 , wherein L 2 is oxymethylene.
17. The compound of claim 15 , wherein R 4 is hydrogen.
18. The compound of claim 1 , wherein L 2 is oxymethylene.
19. The compound of claim 17 , wherein L 2 is oxymethylene.
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient and the compound of claim 1 .
21. A method for treating a disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 , wherein the disease or condition is type II diabetes.
22. The method of claim 21 , wherein said compound is administered orally, parentally or topically.
23. The method of claim 21 wherein said compound is administered in combination with a second therapeutic agent.
24. The method of claim 23 wherein said second therapeutic agent is a metformin or a thiazolidinedione.
25. A method for increasing circulating insulin concentration in a subject, comprising administering the compound of claim 1 to the subject.