11-Beta-Hydroxysteroid Dehydrogenase Type 1 Active Compounds

Abstract

A novel class of compounds of the general formula (I), their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments are described. The present compounds modulate the activity of 11β-hydroxy-steroid dehydrogenase type 1 (11βHSD1) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, e.g. the metabolic syndrome.

1 - 15 . (canceled) 
     
     
         16 . A method of lowering intracellular glucocorticoid levels in a subject, the method comprising administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is hydrogen, C 1 -C 4 alkyl, or cyclopropyl; 
         R 2  is adamantyl optionally substituted with 0 to 1 R 18 ; 
         R 4  is hydrogen, C 1 -C 4 alkyl, trifluoromethyl, halogen, C 1 -C 4 alkyloxy, C 1 -C 4 alkyloxyC 1 -C 4 alkyl, or C 1 -C 4 alkylcarbonyl, wherein the alkyl portion of each is substituted with 0 to 1 R 18 ; 
         X is —O—; 
         R 3  is -1,4-cyclohexyl-R 9 , —CH 2 -1,4-cyclohexyl-R 9 , -4-piperidin-1-yl-R 11 , or —CH 2 -4-piperidin-1-yl-R 11 ; 
         R 9  is hydroxy, cyano, C(O)R 13 , —(CR 14 R 15 ) n C(O)NR 7 R 8 , —(CR 14 R 15 ) n NHC(O)R 16 , —(CR 14 R 15 ) n OR 16 , —(CR 14 R 15 ) n S(O) m R 16 , —(CR 14 R 15 ) n S(O) 2 NR 7 R 8 , —(CR 14 R 15 ) n NR 7 R 8 , —(CR 14 R 15 ) n NR 17 C(O)NR 7 R 8 , —(CR 14 R 15 ) n NR 17 S(O) 2 R 16 , —(CR 14 R 15 ) n C═C—R 16 , —(CR 14 R 15 ) n C≡C—R 16 , —(CR 14 R 15 ) n aryl substituted with 0 to 2 R 20 , or —(CR 14 R 15 ) n hetaryl optionally substituted with 0 to 2 R 19 ; 
         R 11  is —C(O)NR 7 R 8 , —CH 2 C(O)NR 7 R 8 , —C(O)R 17 , —S(O) 2 R 16  or —S(O) 2 NR 7 R 8 ; 
         R 13  is hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, C 1 -C 6 alkyloxy, aryl, aryloxy, arylC 1 -C 6 alkyloxy, hetaryl, hetaryloxy or hetarylC 1 -C 6 alkyloxy, wherein the C 1 -C 6 alkyl, cycloalkyl, aryl and hetaryl groups are optionally substituted with one or more R 19 ; 
         R 14  and R 15  independently are hydrogen, halogen, C 1 -C 6 alkyl or cycloalkyl, wherein each is optionally substituted with 0 to 2 substituents selected independently from the group consisting of halogen, hydroxyl, and oxo; 
         or R 14  and R 15 , together with the carbon atom to which they are attached, form a cycloalkyl ring; 
         R 16  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, hetcycloalkyl, aryl, or hetaryl, wherein the C 1 -C 6 alkyl, cycloalkyl, aryl and hetaryl groups are each optionally substituted with one or more R 19 ; 
         R 17  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylC(O)R 20 , —(CR 14 R 15 ) n NR 17 S(O) 2 R 16 , cycloalkyl, hetcycloalkyl, aryl, or hetaryl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are each optionally are substituted with one or more R 21 ; 
         R 18  is halogen, hydroxy, oxo, —S(O) 2 C 1 -C 4 alkyl, —S(O) 2 NR 7 R 8  or —C(O)R 13 ; 
         R 19  is halogen, hydroxy, oxo, —C(O)R 20 , C 1 -C 6 alkylC(O)R 20 , —S(O) n R 16 , —S(O) n NR 7 R 8 , cyclopropyl, —OR 16 , C 1 -C 6 alkyl, aryl, hetaryl, —NR 22 C(O)NR 7 R 8 , —NR 22 S(O) 2 NR 7 R 8 , or —NC(O)NHS(O) 2 R 16 ; 
         R 20  is hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, C 1 -C 6 alkyloxy, aryl, aryloxy, arylC 1 -C 6 alkyloxy, hetaryl, hetaryloxy or hetarylC 1 -C 6 alkyloxy; 
         R 21  is halogen, cyano or hydroxy; and 
         m and n independently are 0, 1 or 2. 
       
     
     
         17 . The method of  claim 16 , wherein R 3  is -1,4-cyclohexyl-R 9  or —CH 2 -1,4-cyclohexyl-R 9 . 
     
     
         18 . The method of  claim 17 , wherein R 9  is C(O)R 13 . 
     
     
         19 . The method of  claim 18 , wherein R 13  is hydroxy. 
     
     
         20 . The method of  claim 17 , wherein R 9  is selected from —CH 2 —O-aryl, —CH 2 —O-hetaryl, —O-aryl, —O-hetaryl, —CH 2 —O—C 1-6 alkyl, or —NHC(O)R 16 , wherein the aryl, hetaryl, and alkyl groups are each optionally substituted with one or more R 19 . 
     
     
         21 . The method of  claim 17 , wherein R 9  is —NH—S(O) 2 -aryl, —NH—S(O) 2 -hetaryl, —NH-aryl, —NH-hetaryl, —S(O) 2 -aryl, or —S(O) 2 -hetaryl, where the aryl and hetaryl groups are each optionally substituted with one or more R 19 . 
     
     
         22 . The method of  claim 16 , wherein R 3  is -4-piperidin-1-yl-R 11 , or —CH 2 -4-piperidin-1-yl-R 11 . 
     
     
         23 . A method of lowering intracellular glucocorticoid levels in a subject, the method comprising administering to a subject a compound, which is a compound selected from the group consisting of:
 4-(1-Cyclopropanecarbonyl-piperidin-4-yloxy)-N-adamantan-2-yl-benzamide;   4-[1-(3-Methyl-butyryl)-piperidin-4-yloxy]-N-adamantan-2-yl-benzamide;   4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-adamantan-1-yl-benzamide;   4-[4-(Cyclopropane-carbonyl-amino)-cyclo-hexyloxy]-N-adamantan-2-yl-benzamide;   N-Adamantan-2-yl-4-(4-hydroxy-cyclohexyloxy)-benzamide;   4-[4-adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid;   N-Adamantan-2-yl-4-[4-(4-methyl-1H-imidazol-2-ylsulfanylmethyl)-cyclohexyloxy]-benzamide;   4-[4-(Pyridin-2-yloxy)-cyclohexyloxy]-N-adamantan-2-yl-benzamide;   4-[4-(Pyrazol-1-yloxy)-cyclohexyloxy]-N-adamantan-2-yl-benzamide;   4-[4-(Pyrazol-1-yl-oxymethyl)-cyclohexyloxy]-N-adamantan-2-yl-benzamide;   4-[4-(Pyridin-2-yloxymethyl)-cyclohexyloxy]-N-adamantan-2-yl-benzamide;   4-(4-Hydroxy-cyclohexyl-methoxy)-N-adamantan-2-yl-benzamide;   4-{4-[4-(Adamantan-2-yl-carbamoyl)-phenoxy]-cyclo-hexylmethoxy}-benzoic acid;   4-{4-[4-(Adamantan-2-yl-carbamoyl)-phenoxy]-cyclo-hexylmethoxy}-benzoic acid allyl ester;   Cis-N-Adamantan-2-yl-4-[4-(pyridine-2-sulfonylamino)-cyclohexyloxy]-benzamide;   Cis-Pyridine-2-sulfonic acid {4-[4-(octahydro-quinoline-1-carbonyl)-phenoxy]-cyclohexyl}-amide;   Cis-N-Adamantan-2-yl-4-[4-(cyclopropanecarbonyl-amino)-cyclohexyloxy]-benzamide;   N-(5-Hydroxy-adamantan-2-yl)-4-(4-hydroxy-cyclohexyl-oxy)-N-methyl-benzamide;   N-(5-Hydroxy-adamantan-2-yl)-4-(4-hydroxy-cyclohexyl-oxy)-N-methyl-benzamide;   N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[4-(pyridine-2-sulfonylamino)-cyclohexyloxy]-benzamide;   4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide;   4-[4-(3-Hydroxy-adamantan-1-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid;   4-{4-[(5-Hydroxy-adamantan-2-yl)-methyl-carbamoyl]-phen-oxy}-cyclohexanecarboxylic acid;   4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N—(Z)-(5-hydroxy-adamantan-2-yl)-benzamide;   4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(E)-(5-hydroxy-adamantan-2-yl)-benzamide;   N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[1-(pyridine-2-sulfonyl)-piperidin-4-yl-methoxy]-benzamide;   4-{4-[(5-Hydroxy-adamantan-2-yl)-methyl-carbamoyl]-phenoxy-methyl}-piperidine-1-carboxylic acid isopropylamide;   N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-ylmethoxy]-benzamide; and   4-(1-Ethanesulfonyl-piperidin-4-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide;   or a pharmaceutically acceptable salt thereof.