Pharmaceutical use of substituted amides

Abstract

The use of substituted amides for modulating the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and the use of these compounds as pharmaceutical compositions, are described. Also a novel class of substituted amides, their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments are described. The present compounds are modulators and more specifically inhibitors of the activity of 11βHSD1 and may be useful in the treatment, prevention and/or prophylaxis of a range of medical disorders where a decreased intracellular concentration of active glucocorticoid is desirable.

1 . A compound of Formula IA or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —(CH 2 ) 1-2 —R 6 ; 
         R 2  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and —C(═O)R 13 ; 
         the ring 
       
       
         
           
           
               
               
           
         
         R 6  is selected from the group consisting of cyano, aryl, hetaryl, -oxoC 1 -C 6 alkyl-S(═O) n R 13 , —C(═O)R 13 , —S(═O) n R 13 , —S(═O) n NR 18 R 19 , —N(R 18 )S(═O) n R 13 , —N(R 23 )C(═O)NR 18 R 19 , —C(═NR 15 )NR 15 , —N(R 18 )C(═O)R 13 , —N(R 18 )C(═O)—C 3 -C 6 cycloalkyl, and —N(R 18 )C(═O)— (3-6 membered hetcycloalkyl), wherein the cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are substituted with 0-3 R 16 ; 
         R 13  is selected from the group consisting of —OH, C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, C 1 -C 4 alkyloxyC 1 -C 4 alkylene, aryl, hetaryl, aryloxy, hetaryloxy, and NR 18 R 19 ; 
         R 15  and R 16  are independently selected from the group consisting of H, C 1 -C 4 alkyl, 3-6-membered cycloalkyl, halo, OH, cyano, —C(═O)R 13 , —S(═O) n R 13 , —S(═O) n NR 18 R 19 , —N(R 18 )S(═O) n R 13 , aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are substituted with 0-1 R 20 ; 
         R 18  and R 19  are independently selected from the group consisting of H, C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, aryl, hetaryl, arylC 1 -C 4 alkylene, and hetarylC 1 -C 4 alkylene, wherein the alkyl, alkylene, aryl, and hetaryl groups are independently substituted with 0-1 R 20 ; 
         alternatively, R 18  and R 19 , together with the nitrogen atom to which they are attached, form a saturated or partially saturated monocyclic, bicyclic, or tricyclic ring consisting of the shown nitrogen, 4-5 carbon atoms, and 0-1 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein this ring is substituted 0-1 times with substituents selected from the group consisting of C 1 -C 4 alkyl, aryl, hetaryl, arylC 1 -C 4 alkylene, hetarylC 1 -C 4 alkylene, hydroxy, and C 1 -C 4 alkyloxy; 
         R 20  is selected from the group consisting of H, OH, oxo, halo, cyano, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, NR 21 R 22 , trihalomethyl, and trihalomethyloxy; 
         R 21  and R 22  are independently selected from the group consisting of H, C 1 -C 4 alkyl, and arylC 1 -C 4 alkyl; 
         R 23  is selected from the group consisting of H and C 1 -C 6 alkyl; and 
         n is 2. 
       
     
     
         2 . The compound of  claim 1 , wherein R 2  is H. 
     
     
         3 . The compound of  claim 2 , wherein R 1  is —(CH 2 ) 2 —R 6 . 
     
     
         4 . A compound, which is a compound selected from the group consisting of:
 Furan-2-carboxylic acid {2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide;   1-Acetyl-piperidine-4-carboxylic acid {2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide;   2-Methoxy-N-{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidazol-1-yl]-ethyl}-acetamide;   N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidazol-1-yl]-ethyl}-isonicotinamide;   N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidazol-1-yl]-ethyl}-acetamide;   {2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidazol-1-yl]-ethyl}-carbamic acid tert-butyl ester;   Isoxazole-5-carboxylic acid {2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide;   N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidazol-1-yl]-ethyl}-benzamide;   3-[2-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzimidazol-1-yl]-propionic acid ethyl ester;   3-[2-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzimidazol-1-yl]-propionic acid;   3-[2-Methyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzimidazol-1-yl]-propionic acid ethyl ester;   2-[1-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]octane-6-carbonyl)-1H-benzimidazol-2-yl]-cyclopropanecarboxylic acid ethyl ester;   3-[2-Methyl-5-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]octane-6-carbonyl)-benzimidazol-1-yl]-propionic acid;   2-[1-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]octane-6-carbonyl)-1H-benzimidazol-2-yl]-cyclopropanecarboxylic acid;   3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid ethyl ester;   3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid;   [5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-acetic acid tert-butyl ester;   [5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-acetic acid;   1-Morpholin-4-yl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propan-1-one;   1-Morpholin-4-yl-2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-ethanone;   2,2-Dimethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid ethyl ester;   2,2-Dimethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid;   2-Methyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid methyl ester;   3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-butyric acid methyl ester;   3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-butyric acid;   2-Methyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid;   3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylmethyl]-benzoic acid;   4-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylmethyl]-benzoic acid methyl ester; and   4-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylmethyl]-benzoic acid; or a pharmaceutically acceptable salt thereof.   
     
     
         5 . 3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid ethyl ester or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of  claim 5 , where the compound is 3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid ethyl ester. 
     
     
         7 . 3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound of  claim 7 , where the compound is 3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid. 
     
     
         9 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         10 . A pharmaceutical composition comprising a compound of  claim 4  and a pharmaceutically acceptable carrier. 
     
     
         11 . A pharmaceutical composition comprising a compound of  claim 5  and a pharmaceutically acceptable carrier. 
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 6  and a pharmaceutically acceptable carrier. 
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 7  and a pharmaceutically acceptable carrier. 
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 8  and a pharmaceutically acceptable carrier.