Diacylglycerol acyltransferase inhibitors
Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.
1. A compound of the formula (I):
wherein:
Y is (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkyl substituted with aryl;
R 1 is substituted or unsubstituted aryl or
R 2 is (C 1 -C 6 ) alkyl;
R 3 is unsubstituted aryl, substituted aryl with a group independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, and —O(CH 2 ) m OCH 3 , unsubstituted saturated, unsaturated or partially saturated heterocycyl which is a 5- or 6-membered heteroaromatic ring connected by a ring carbon atom which has from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, substituted saturated, unsaturated or partially saturated heterocycyl substituted with (C 1 -C 6 ) alkyl, or substituted or unsubstituted 5-10-membered cycloalkyl ring; and
m is 0, 1, 2 or 3,
and pharmaceutically acceptable salts thereof.
2. The compound according to claim 1 , wherein:
Y is CH═CH, (CH 2 ) n , or —CH(Ar)CH 2 ; and
n is 1 or 2.
3. The compound according to claim 1 , wherein:
R 1 is
R 4 is H, (C 1 -C 6 ) alkyl, unsubstituted aryl, aryl which is mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, —O(CH)(CH 3 ) 2 , —CF 3 , —O(CH 2 ) m CH 3 , —OCF 3 , —SCH 3 , —CH(CH 3 ) 2 , —CN, —SO 2 CH 3 , —NO 2 , and —(CH) 2 Ar, O-phenyl, —O(CH 2 ) m CH 3 , or unsubstituted or substituted 4-10 membered cycloalkyl ring attached to the aryl ring by oxygen;
R 5 , R 6 , R 7 independently of each other are H, halogen, phenyl or (C 1 -C 6 ) alkyl; and
m is 0, 1, 2 or 3,
and pharmaceutically acceptable salts thereof.
4. The compound according to claim 1 , wherein R 2 is a cyclomethoxy or cyclobutylmethoxy group.
5. The compound according to claim 1 , wherein R 1 and R 3 , independently of each other, are phenyl.
6. The compound according to claim 1 , wherein the compound is benzoic acid N′-isopropyl-N′-[3-(3′-methoxy-biphenyl-2-yl)-propionyl]-hydrazide.
7. The compound according to claim 1 , wherein the compound is benzoic acid N′-[3-(2-cyclopentyloxy-5-fluoro-phenyl)-propionyl]-N′-isopropyl-hydrazide.
8. The compound according to claim 1 , wherein the compound is benzoic acid N′-[3-(3′-chloro-4′-fluoro-biphenyl-2-yl)-propionyl]-N′-isopropyl-hydrazide.
9. The compound according to claim 1 , wherein the compound is benzoic acid N′-[3-(2′-chloro-biphenyl-2-yl)-propionyl]-N′-isopropyl-hydrazide.
10. The compound according to claim 1 , wherein the compound is benzoic acid N′-[3-(2′,5′-dimethyl-biphenyl-2-yl)-propionyl]-N′-isopropyl-hydrazide.
11. The compound according to claim 1 , wherein the compound is benzoic acid N′-[3-(2-butoxy-5-fluoro-phenyl)-propionyl]-N′-isopropyl-hydrazide.
12. The compound according to claim 1 , wherein the compound is benzoic acid N′-[3-(5′-isopropyl-2′-methoxy-biphenyl-2-yl)-propionyl]-N′-isopropyl-hydrazide.
13. The compound according to claim 1 , wherein the compound is benzoic acid N′-[3-(2′,3′-dimethyl-biphenyl-2-yl)-acryloyl]-N′-isopropyl-hydrazide.
14. The compound according to claim 1 , wherein the compound is benzoic acid N′-[3-(2′,3′-dimethyl-biphenyl-2-yl)-propionyl]-N′-isopropyl-hydrazide.
15. The compound according to claim 1 , wherein the compound is benzoic acid N′-[3-(2-cyclobutylmethoxy-5-fluoro-phenyl)-propionyl]-N′-isopropyl-hydrazide.
16. A method for the treatment of obesity, type II diabetes or metabolic syndrome in a patient in need thereof, which comprises administering to said patient a therapeutically effective amount of a compound of the formula (I):
wherein:
Y is (C 1 -C 6 ) alkylene or (C 1 -C 6 ) alkylene substituted with aryl;
R 1 is substituted or unsubstituted aryl or
R 2 is (C 1 -C 6 ) alkyl;
R 3 is unsubstituted aryl, substituted aryl with a group independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, and —O(CH 2 ) m OCH 3 , unsubstituted saturated, unsaturated or partially saturated heterocycyl which is a 5- or 6-membered heteroaromatic ring connected by a ring carbon atom which has from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, substituted saturated, unsaturated or partially saturated heterocycyl substituted with (C 1 -C 6 ) alkyl, or substituted or unsubstituted 5-10-membered cycloalkyl ring; and
m is 0, 1, 2 or 3, and pharmaceutically acceptable salts thereof.
17. The method according to claim 16 , wherein
R 1 is
R 4 is H, (C 1 -C 6 ) alkyl, unsubstituted aryl, aryl which is mono-, di- or tri-substituted with a group independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, —O(CH)(CH 3 ) 2 , —CF 3 , —O(CH 2 ) m CH 3 , —OCF 3 , —SCH 3 , —CH(CH 3 ) 2 , —CN, —SO 2 CH 3 , —NO 2 , and —(CH) 2 Ar, O-phenyl, —O(CH 2 ) m CH 3 , or unsubstituted or substituted 4-10 membered cycloalkyl ring attached to the aryl ring by oxygen;
R 5 , R 6 , R 7 independently of each other are H, halogen, phenyl or (C 1 -C 6 ) alkyl; and
m is 0, 1, 2 or 3,
and pharmaceutically acceptable salts thereof.
18. The method according to claim 14 , wherein said therapeutically effective amount of said compound is from about 10 mg to about 1000 mg per day.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or ester thereof according to claim 1 , and a pharmaceutically acceptable carrier.