Benzazepine Compound

Abstract

[Problem] Provided is a compound which is useful as an agent for treating or preventing 5-HT 2C receptor-related diseases, particularly incontinence such as stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, and the like, sexual dysfunction such as erectile dysfunction syndrome and the like, obesity, and the like. [Means for Solution] The present inventors have investigated compounds having a 5-HT 2C receptor agonist activity, which is promising as an active ingredient of a pharmaceutical composition for treating or preventing incontinence such as stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, and the like, sexual dysfunction such as erectile dysfunction syndrome and the like, obesity, and the like, and have found that the benzazepine compounds of the present invention have an excellent 5-HT 2C receptor agonist activity, thereby completing the present invention. That is, the benzazepine compounds of the present invention have a 5-HT 2C receptor agonist activity and can be used as an agent for treating or preventing 5-HT 2C receptor-related diseases, particularly incontinence such as stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, and the like, sexual dysfunction such as erectile dysfunction syndrome and the like, obesity, and the like.

1 . A pharmaceutical composition comprising a compound of the formula (I) or a salt thereof and a pharmaceutically acceptable excipient: 
       
         
           
           
               
               
           
         
         (wherein 
         R 1a  and R 1b  are the same or different and each represents —H or C 1-6  alkyl, or are combined to form oxo, 
         R 2a  and R 2b  are the same or different and each represents —H or C 1-6  alkyl which may be substituted with —O—C 1-6  alkyl, 
         R 3  represents —H, C 1-6  alkyl which may be substituted, C 3-8  cycloalkyl, aryl which may be substituted, —SO 2 —C 1-6  alkyl, or a hetero ring which may be substituted, 
         R 4  represents —H, halogen, cyano, C 1-6  alkyl which may be substituted, C 2-6  alkenyl, aryl which may be substituted, C 3-8  cycloalkyl which may be substituted, an aromatic hetero ring, or an oxygen-containing hetero ring, 
         R 5  represents —H, halogen, C 1-6  alkyl, C 3-8  cycloalkyl, aryl, or an aromatic hetero ring, 
         R 6  and R 7  are the same or different and each represents —H or C 1-6  alkyl, 
         X represents —C(R A )(R B )— or —O—, and 
         R A  and R B  are the same or different and each represents —H or C 1-6  alkyl). 
       
     
     
         2 . A pharmaceutical composition as described in  claim 1 , wherein R 1a  and R 1b  are respectively —H or are combined to form oxo,
 R 2a  is —H or C 1-6  alkyl, 
 R 2b  is —H, 
 R 3  is —H, C 1-6  alkyl, halogeno-C 1-6  alkyl, C 1-6  alkylene-OH, (C 1-6  alkylene which may be substituted)-O—C 1-6  alkyl, C 1-6  alkylene-cycloalkyl which may be substituted, C 1-6  alkylene-aryl which may be substituted, C 1-6  alkylene-hetero ring group which may be substituted, —CO—C 1-6  alkyl, —CO—C 1-6  alkylene-O—C 1-6  alkyl, —CO-cycloalkyl which may be substituted, —CO-aryl which may be substituted, —CO—NR 8 R 9 , —CO—O—C 1-6  alkyl, —CO—O—C 1-6  alkylene-aryl which may be substituted, —SO 2 —C 1-6  alkyl, aryl which may be substituted, or a hetero ring which may be substituted, 
 R 8  and R 9  are the same or different and each is —H or C 1-6  alkyl, 
 R 4  is —H, C 1-6  alkyl, halogen, halogeno-C 1-6  alkyl, cycloalkyl which may be substituted, or aryl which may be substituted, and 
 R 5  is —H or C 1-6  alkyl. 
 
     
     
         3 . A pharmaceutical composition as described in  claim 1 , wherein R 3  is —H, C 1-6  alkyl which may be substituted, C 3-8  cycloalkyl, aryl which may be substituted, —SO 2 —C 1-6  alkyl, or an oxygen-containing hetero ring, and
 R 4  is —H, halogen, cyano, C 1-6  alkyl which may be substituted, C 2-6  alkenyl, aryl which may be substituted, C 3-8  cycloalkyl, an aromatic hetero ring, or an oxygen-containing hetero ring. 
 
     
     
         4 . A compound of the formula (II) or a salt thereof: 
       
         
           
           
               
               
           
         
         (wherein 
         R 11a  and R 11b  are respectively the same or different and each represents —H or C 1-6  alkyl, or are combined to form oxo, 
         R 21a  and R 21b  are respectively the same or different and each represents —H or C 1-6  alkyl which may be substituted with —O—C 1-6  alkyl, 
         R 31  represents —H, C 1-6  alkyl which may be substituted, C 3-8  cycloalkyl, aryl which may be substituted, —SO 2 —C 1-6  alkyl, or a hetero ring which may be substituted, 
         R 41  represents —H, halogen, cyano, C 1-6  alkyl which may be substituted, C 2-6  alkenyl, aryl which may be substituted, C 3-8  cycloalkyl which may be substituted, an aromatic hetero ring, or an oxygen-containing hetero ring, 
         R 51  represents —H, halogen, C 1-6  alkyl, C 3-8  cycloalkyl, aryl, or an aromatic hetero ring, 
         R 61  and R 71  are the same or different and each represents —H or C 1-6  alkyl, 
         X 1  represents —C(R A1 )(R B1 )— or —O—, and 
         R A1  and R B1  are the same or different and each represents —H or C 1-6  alkyl, 
         provided that 
         (i) in the case where R 11a , R 11b , R 21a , R 21b , R 41 , R 51 , R 61 , and R 71  are respectively —H and X 1  is —O—, R 31  is a group other than —H, —CO-methyl, or —SO 2 -methyl, and 
         (ii) in the case where R 11a  and R 11b  are combined to form oxo, R 21a , R 21b , R 41 , R 51 , R 61 , and R 71  are respectively —H, and X 1  is —O—, R 31  is a group other than —H or methyl). 
       
     
     
         5 . A compound or a salt thereof as described in  claim 4 , wherein R 11a  and R 11b  are respectively —H or are combined to form oxo,
 R 21a  is —H or C 1-6  alkyl, 
 R 21b  is —H, 
 R 31  is —H, C 1-6  alkyl, halogeno-C 1-6  alkyl, C 1-6  alkylene-OH, (C 1-6  alkylene which may be substituted)-O—C 1-6  alkyl, C 1-6  alkylene-cycloalkyl which may be substituted, C 1-6  alkylene-aryl which may be substituted, C 1-6  alkylene-hetero ring group which may be substituted, —CO—C 1-6  alkyl, —CO—C 1-6  alkylene-O—C 1-6  alkyl, —CO-cycloalkyl which may be substituted, —CO-aryl which may be substituted, —CO—NR 81 R 91 , —CO—O—C 1-6  alkyl, —CO—O—C 1-6  alkylene-aryl which may be substituted, —SO 2 —C 1-6  alkyl, aryl which may be substituted, or a hetero ring which may be substituted, 
 R 81  and R 91  are the same or different and each is —H or C 1-6  alkyl, 
 R 41  is —H, C 1-6  alkyl, halogen, halogeno-C 1-6  alkyl, cycloalkyl which may be substituted, or aryl which may be substituted, and 
 R 51  is —H or C 1-6  alkyl. 
 
     
     
         6 . A compound or a salt thereof as described in  claim 4 , wherein R 31  is —H, C 1-6  alkyl which may be substituted, C 3-8  cycloalkyl, aryl which may be substituted, —SO 2 —C 1-6  alkyl, or an oxygen-containing hetero ring, and
 R 41  is —H, halogen, cyano, C 1-6  alkyl which may be substituted, C 2-6  alkenyl, aryl which may be substituted, C 3-8  cycloalkyl, an aromatic hetero ring, or an oxygen-containing hetero ring. 
 
     
     
         7 . A compound or a salt thereof as described in  claim 6 , wherein R 31  is a group other than —H, methyl, —CO-methyl, or —SO 2 -methyl. 
     
     
         8 . A compound or a salt thereof as described in  claim 7 , wherein R 11a  is —H or methyl, and R 11b , R 21a , R 21b , R 51 , R 61 , and R 71  are respectively —H. 
     
     
         9 . A compound or a salt thereof as described in  claim 8 , wherein R 41  is —H, halogen, or C 3-8  cycloalkyl. 
     
     
         10 . A compound or a salt thereof as described in  claim 9 , wherein R 41  is cyclopropyl. 
     
     
         11 . A compound or a salt thereof as described in  claim 10 , wherein R 31  is C 1-6  alkyl which may be substituted with one or more groups selected from the group consisting of (a) halogen, (b) —O—C 1-6  alkyl, (c) phenoxy which may be substituted with one or more groups selected from the group consisting of halogen and cyano, (d) an oxygen-containing hetero ring, and (e) phenyl which may be substituted with one or more groups selected from the group consisting of C 1-6  alkyl which may be substituted with —O—C 1-6  alkyl, halogen, and —O—C 1-6  alkyl. 
     
     
         12 . A compound or a salt thereof as described in  claim 4 , which is
 11-cyclopropyl-1-(2-methoxyethyl)-2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinoline,   4-(3-methoxypropyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(2-methoxyethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(2-ethoxyethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(3-methoxypropyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(3-fluoropropyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   1-isobutyl-2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinoline,   5-bromo-4-(2-methoxyethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-[(2S)-tetrahydrofuran-2-ylmethyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-[(2R)-2-methoxypropyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(2-fluorobenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-[(2S)-3-fluoro-2-methoxypropyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   4-(3-chlorobenzyl)-5-cyclopropyl-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(tetrahydro-2H-pyran-3-ylmethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(2-phenoxyethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(2-methylbenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(3-methylbenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(2,5-difluorobenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-[3-(methoxymethyl)benzyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   4-(5-chloro-2-fluorobenzyl)-5-cyclopropyl-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   (3S)-5-cyclopropyl-4-(2-methoxyethyl)-3-methyl-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   4-[2-(5-cyclopropyl-2,3,7,8,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepin-4(6H)-yl)ethoxy]-3,5-difluorobenzonitrile,   5-cyclopropyl-4-(3-methoxybenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,   5-cyclopropyl-4-(3,5-difluorobenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine, or   5-cyclopropyl-4-[(2R)-2-ethoxypropyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine or a salt thereof.   
     
     
         13 . A pharmaceutical composition comprising a compound or a salt thereof as described in  claim 4  and a pharmaceutically acceptable excipient. 
     
     
         14 . A pharmaceutical composition for preventing or treating 5-HT 2C  receptor-related diseases, comprising a compound or a salt thereof as described in  claim 4 . 
     
     
         15 . A pharmaceutical composition as described in  claim 14 , which is a pharmaceutical composition for preventing or treating incontinence. 
     
     
         16 . Use of a compound or a salt thereof as described in  claim 4  for preparation of a pharmaceutical composition for preventing or treating incontinence. 
     
     
         17 . A compound or a salt thereof as described in  claim 4  for use in the prevention or treatment of incontinence. 
     
     
         18 . A method for preventing or treating incontinence, comprising administering to a subject an effective amount of a compound or a salt thereof as described in  claim 4 .