Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
View Patent ↗Triazole derivatives of structural formula I are selective inhibitors of the 11β-hydroxysteroid dehydrogenase-1. The compounds are useful for the treatment of diabetes, such as noninsulin-dependent diabetes (NIDDM), hyperglycemia, obesity, insulin resistance, dyslipidemia, hyperlipidemia, hypertension, Metabolic Syndrome, and other symptoms associated with NIDDM.
1. A compound represented by formula I:
or a pharmaceutically acceptable salt or solvate thereof wherein:
each R 1 is selected from the group consisting of H, halo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkoxy;
R 2 is hydrogen or is selected from the group consisting of C 1-6 alkyl and haloC 1-6 alkyl;
each R 3 independently represents a member selected from the group consisting of: hydrogen, hydroxyl and oxo;
R 4 is selected from the group consisting of: C 3-6 alkyl or C 2-4 alkenyl, each substituted with a CF 3 group and optionally further substituted with 1-4 halo atoms and 1-2 moieties selected from the group consisting of; OH, C 1-4 alkoxy, haloC 1-4 alkoxy, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , Aryl and HAR, said Aryl and HAR being optionally substituted with 1-3 halo groups, and 1-2 groups selected from C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 2-4 alkenyl, haloC 2-4 alkenyl, C 2-4 alkenyloxy and haloC 2-4 alkenyloxy; and
HAR is oxadiazole.
2. A compound in accordance with claim 1 wherein each R 1 is selected from H, halo, C 1-2 alkyl, haloC 1-2 alkyl, C 1-2 alkoxy and haloC 1-2 alkoxy.
3. A compound in accordance with claim 2 wherein each R 1 , is selected from H, Cl, Br, CH 3 , OCH 3 , CF 3 , OCF 3 , OCF 2 H and OCFH 2 .
4. A compound in accordance with claim 3 wherein R 1 , located at the ortho position relative to the point of attachment of the triazole ring, is selected from Cl, Br, CH 3 , OCH 3 , CF 3 , OCF 3 , OCF 2 H and OCFH 2 and R 1 is otherwise H.
5. A compound in accordance with claim 4 wherein R 1 , located at the ortho position relative to the point of attachment of the triazole ring, represents a CF 3 group and R 1 is otherwise H.
6. A compound in accordance with claim 1 wherein R 2 represents hydrogen or C 1-6 alkyl.
7. A compound in accordance with claim 6 wherein R 2 represents C 1-3 alkyl.
8. A compound in accordance with claim 7 wherein R 2 represents methyl, ethyl or cyclopropyl.
9. A compound in accordance with claim 1 wherein each R 3 represents hydrogen.
10. A compound in accordance with claim 1 wherein R 4 represents C 3-6 alkyl or C 2-4 alkenyl, each substituted with a CF 3 group and optionally further substituted with 1-4 halo atoms and 1-2 moieties selected from the group consisting of; OH, C 1 -4 alkoxy, haloC 1-4 alkoxy, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl) 2 .
11. A compound in accordance with claim 10 wherein R 4 represents C 3-5 alkyl or C 2-4 alkenyl, each substituted with a CF 3 group and optionally further substituted with 1 halo atom selected from Cl, Br and F, and 1 OH group.
12. A compound in accordance with claim 1 , wherein HAR represents 1,2,4-oxadiazole or 1,3,4-oxadiazole.
13. A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
14. A compound in accordance with claim 1 selected from the group consisting of 3-(4-{4-Methyl-5-[2-(trifluoromethyl)phenyl] -4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-5-(4,4,4-trifluorobutyl)-1,2,4-oxadiazole and 2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl }bicyclo [2.2.2]oct-1-yl)-5-(3,3,3-trifluoro-1-methylpropyl)-1,3,4-oxadiazole
or a pharmaceutically acceptable salt thereof.