2-(2-hydroxyphenyl)benzimidazoles useful for treating obesity and diabetes
View Patent ↗The present invention relates to novel compounds that act as chemical uncouplers. Compounds of the invention are useful, inter alia, in the treatment, including prevention, of obesity, diabetes and a number of diseases or conditions associated therewith.
1. A compound according to formula I or a pharmaceutically acceptable salt thereof:
wherein
m is 0;
R 1 is tert-butyl;
R 2 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 -cycloalkyl, C 4-8 cycloalkenyl or C 1-6 alkoxy;
R 4 is methyl;
R 5 , R 6 and R 7 independently are hydrogen, nitro, cyano, halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, C 1-6- haloalkyl, —OR 10 , —NR 10 R 11 , —C(O)OR 10 , —COR 10 , —C(O)NR 10 R 11 , —SH, —S(O) 2 NR 10 R 11 , —S(O)R 11 , aryl or heteroaryl, wherein the latter aryl or heteroaryl groups are optionally substituted with one or more substituents selected independently from the group consisting of C 1-6 alkyl, halogen, hydroxy and phenyl;
R 10 and R 11 independently are hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 -cycloalkyl, C 4-8 cycloalkenyl or C 1-6 haloalkyl; or R 10 and R 11 , together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic 3-8-membered ring, optionally substituted with one or more C 1-6 alkyl substituents; and
R 3 is —SCH 3 , —S(O)CH 3 , —S(O) 2 CH 3 , fluoro, or chloro;
or a hydrate of any of the foregoing.
2. The compound according to claim 1 , wherein one substituent from among R 5 , R 6 and R 7 is —SR 11 , —S(O)R 11 or —S(O) 2 R 11 , wherein R 11 is C 1-6 -fluoroalkyl.
3. The compound according to claim 2 , wherein one substituent from among R 5 , R 6 and R 7 is —S(O) 2 CF 3 .
4. A compound, which is a compound selected from the group consisting of:
6-tert-Butyl-3-methyl-2-(5-trifluoromethyl-1H-benzimidazol-2-yl)-phenol;
2-(3-tert-Butyl-2-hydroxy-6-methyl-phenyl)-1H-benzimidazole-5-carbonitrile;
4-Bromo-6-tert-butyl-3-methyl-2-(5-trifluoromethyl-1H-benzimidazol-2-yl)-phenol;
2-(3-tert-Butyl-5-chloro-2-hydroxy-6-methyl-phenyl)-1H-benzimidazole-5-carbonitrile;
2-(3-tert-Butyl-5-chloro-2-hydroxy-6-methyl-phenyl)-1H-benzimidazole-5-sulfonic acid diethylamide;
6-tert-Butyl-4-chloro-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-3-methoxy-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-4-chloro-2-(5,6-difluoro-1H-benzimidazol-2-yl)-3-methyl-phenol;
6-tert-Butyl-4-chloro-3-methyl-2-(5-trifluoromethoxy-1H-benzimidazol-2-yl)-phenol;
4-Bromo-6-tert-butyl-3-methyl-2-(5-trifluoromethoxy-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-3-methyl-4-methylsulfanyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-4-methanesulfinyl-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-4-fluoro-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-4-bromo-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
N-[5-tert-Butyl-4-hydroxy-2-methyl-3-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenyl]-methanesulfonamide;
5-tert-Butyl-4-hydroxy-2-methyl-3-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-benzonitrile;
6-tert-Butyl-4-methanesulfonyl-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-4-trifluoromethylsulfanyl-phenol;
6-tert-Butyl-4-chloro-3-ethyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-3-ethyl-4-methanesulfinyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
(R)-6-tert-Butyl-4-methanesulfinyl-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
(S)-6-tert-Butyl-4-methanesulfinyl-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
4-Bromo-6-tert-butyl-3-isopropyl-2-(5-methanesulfonyl-1H-benzimidazol-2-yl)-phenol;
N-[5-tert-Butyl-4-hydroxy-3-(5-methanesulfonyl-1H-benzimidazol-2-yl)-2-methyl-phenyl]-methanesulfonamide;
6-tert-Butyl-4-fluoro-2-(5-methanesulfonyl-1H-benzimidazol-2-yl)-3-methyl-phenol;
6-tert-Butyl-3-isopropyl-2-(5-methanesulfonyl-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-2-(5-methanesulfonyl-1H-benzimidazol-2-yl)-3-methyl-phenol; and
6-tert-Butyl-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
or a pharmaceutically acceptable salt thereof, or a hydrate of any of the foregoing.
5. A compound, which is a compound selected from the group consisting of:
6-tert-Butyl-3-methyl-2-(5-trifluoromethyl-1H-benzimidazol-2-yl)-phenol;
2-(3-tert-Butyl-2-hydroxy-6-methyl-phenyl)-1H-benzimidazole-5-carbonitrile;
2-(3-tert-Butyl-5-chloro-2-hydroxy-6-methyl-phenyl)-1H-benzimidazole-5-carbonitrile;
2-(3-tert-Butyl-5-chloro-2-hydroxy-6-methyl-phenyl)-1H-benzimidazole-5-sulfonic acid diethylamide;
6-tert-Butyl-4-chloro-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-3-methoxy-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-4-chloro-3-methyl-2-(5-trifluoromethoxy-1H-benzimidazol-2-yl)-phenol;
4-Bromo-6-tert-butyl-3-methyl-2-(5-trifluoromethoxy-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-3-methyl-4-methylsulfanyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-4-methanesulfinyl-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
6-tert-Butyl-4-fluoro-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol; and
6-tert-Butyl-3-methyl-2-(5-trifluoromethanesulfonyl-1H-benzimidazol-2-yl)-phenol;
or a pharmaceutically acceptable salt thereof, or a hydrate of any of the foregoing.
6. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
7. A pharmaceutical composition comprising a compound according to claim 4 and a pharmaceutically acceptable carrier or diluent.
8. A pharmaceutical composition comprising a compound according to claim 5 and a pharmaceutically acceptable carrier or diluent.