Novel compounds

Abstract

The present invention relates to novel bicyclic benzamide derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders.

1 . A method of treatment of neurological diseases which comprises administering to a host in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  and R 2  independently represent halogen, hydroxy, cyano, nitro, oxo, haloC 1-6  alkyl, polyhaloC 1-6  alkyl, haloC 1-6  alkoxy, polyhaloC 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkoxy, arylC 1-6  alkoxy, C 1-6  alkylthio, C 1-6  alkoxyC 1-6  alkyl, C 3-7  cycloalkylC 1-6  alkoxy, C 1-6  alkanoyl, C 1-6  alkoxycarbonyl, aryl, heteroaryl, heterocyclyl with 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring containing 1 to 3 heteroatoms selected from oxygen or nitrogen, arylC 1-6  alkyl, heteroarylC 1-6  alkyl, heterocyclylC 1-6  alkyl, C 1-6  alkylsulfonyl, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyloxy, C 1-6  alkylsulfonylC 1-6  alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC 1-6  alkyl, aryloxy, —CO-aryl, —CO-heterocyclyl, —CO-heteroaryl, C 1-6  alkylsulfonamidoC 1-6  alkyl, C 1-6  alkylamidoC 1-6  alkyl, arylsulfonamido, arylaminosulfonyl, arylsulfonamidoC 1-6  alkyl, arylcarboxamidoC 1-6  alkyl, aroylC 1-6  alkyl, arylC 1-6  alkanoyl, or a group NR 15 R 16 , —NR 15 CO-aryl, —NR 15 CO-heterocyclyl, —NR 15 CO-heteroaryl, —CONR 15 R 16 —NR 15 COR 16 , —NR 15 SO 2 R 16  or —SO 2 NR 15 R 16 , wherein R 15  and R 16  independently represent hydrogen or C 1-6  alkyl; 
 wherein said aryl, heteroaryl and heterocyclyl groups of R 1  and R 2  may be optionally substituted by one or more substituents which may be the same or different and which are selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, oxo, CF 3 , OCF 3 , CN, C 1-6  alkanoyl, C 1-6  alkylsulfonyl, C 1-6  alkylsulfonyloxy, C 1-6  alkylamido or C 1-6  alkylsulfonamido; 
 a and b independently represent 0, 1 or 2, such that a and b cannot both represent 0; 
 ═ is a single or double bond; 
 R 3  represents halogen, C 1-6  alkyl, C 1-6  alkoxy, cyano, amino or trifluoromethyl; 
 m and n independently represent 0, 1 or 2; 
 p represents an integer from 0 to 3, such that when p is an integer greater than 1, two R 1  groups may instead be linked to form a heterocyclyl group; 
 R 4  represents —(CH 2 ) q —NR 11 R 12  or a group of formula (i): 
 
     
       
         
         
             
             
         
       
       wherein q is 2, 3 or 4; 
       R 11  and R 12  independently represent C 1-6  alkyl or together with the nitrogen atom to which they are attached represent an N-linked heterocyclic group optionally substituted by one or two R 17  groups; 
       R 13  represents hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl, —C 1-6  alkyl-aryl or heterocyclyl; 
       R 14  and R 17  independently represent halogen, C 1-6  alkyl, haloC 1-6  alkyl, OH, diC 1-6  alkylamino or C 1-6  alkoxy; 
       f and k independently represent 0, 1 or 2; 
       g is 0, 1 or 2 and h is 0, 1, 2 or 3, such that g and h cannot both be 0; 
     
     or solvates thereof; and wherein the neurological disease is selected from the group consisting of Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficit, neuropathic pain, epilepsy, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, and sleep disorder. 
   
   
       2 . The method of  claim 1  wherein R 1  represents halogen, hydroxy, cyano, nitro, —NR 15 R 16 , —NR 15 COR 16 , polyhaloC 1-6  alkyl, heterocyclyl, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylsulfonyl, C 1-6  alkylsulfinyl, C 1-6  alkanoyl, arylsulfonamido, arylaminosulfonyl, —NR 15 SO 2 R 16 , —SO 2 NR 15 R 16 , —CO-heterocyclyl or two R 1  groups are linked to form a heterocyclyl group. 
   
   
       3 . The method of  claim 2  wherein p represents 1 and R 1  represents fluoro or cyano. 
   
   
       4 . The method of  claim 1  wherein m represents 1 and R 2  represents C 1-6  alkyl, arylC 1-6  alkyl, aryl or heteroaryl. 
   
   
       5 . A compound of  claim 1  wherein n represents 1 and R 3  represents halogen or polyhaloC 1-6  alkyl. 
   
   
       6 . The method of  claim 1  wherein R 4  represents —(CH 2 ) q —NR 11 R 12  q represents 3 and NR 11 R 12  represents unsubstituted piperidine. 
   
   
       7 . The method of  claim 1  which is selected from the group consisting of: 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]indoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-3,4-dihydro-1H-isoquinoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-5-bromoindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]indole; 
     5-Fluoro-2-methyl-N-[4-(3-piperidin-1-ylpropoxy)benzoyl]-indole; 
     5-Methoxy-2-methyl-N-[4-(3-piperidin-1-ylpropoxy)benzoyl]-indole; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-5-fluoroindoline; 
     (±)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-2-methylindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-1,2,3,4-tetrahydroquinoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)-benzoyl]-5-nitroisoindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)-benzoyl]-5-aminoisoindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)-benzoyl]-5-(1-succinimido)-isoindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)-benzoyl]-5-(2-oxo-pyrrolidin-1-yl)-isoindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)-2-trifluoromethyl-benzoyl]isoindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-6-cyano-1,2,3,4-tetrahydroisoquinoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-7-cyano-1,2,3,4-tetrahydroisoquinoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-3,3-dimethylindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-5-methoxy-6-trifluoromethyl-indoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-5-(dimethylaminosulfonyl)-indoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-5-(methylsulfinyl)-indoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-5-(methylsulfonyl)-indoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-5-acetyl-indoline; 
     (±)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-2-methyl-1,2,3,4-tetrahydroquinoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-6-methyl-1,2,3,4-tetrahydroquinoline; 
     (±)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-1-benzyl-1,2,3,4-tetrahydroisoquinoline; 
     (±)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-1-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-5-(phenylsulfonamido)-1,2,3,4-tetrahydroisoquinoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-7-(phenylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline;
 (±)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-1-phenyl-1,2,3,4-tetrahydroisoquinoline; 
 
     N-[4-(3-Piperidin-1-ylpropoxy)-benzoyl]-5-methoxyisoindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)-benzoyl]-5-trifluoromethylisoindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-7-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-7-acetylamino-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-7-methylsulfonamido-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-6,7,8,9-tetrahydro-5H-[1,3]dioxolo[4,5-h][3]benzazepine; 
     (±)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-1-phenyl-6,7-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     (±)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-1-phenyl-8,9-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     (±)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-1-phenyl-7,9-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     (±)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-1-phenyl-7-hydroxy-8-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     (±)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-1-(4-methoxyphenyl)-6,9-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     (±)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-1-thienyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-6-bromo-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     (±)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-1-(4-i-propylsulfonyl)-6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-7-fluoro-1,2,3,4-tetrahydroisoquinoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-6-chloro-1,2,3,4-tetrahydroisoquinoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-7,8-dichloro-1,2,3,4-tetrahydroisoquinoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-8-chloro-1,2,3,4-tetrahydroisoquinoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine; N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-4-fluoroisoindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-5-cyanoisoindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-5-[(pyrrolidin-1-yl)carbonyl]isoindoline; 
     N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-5-[(morpholin-4-yl)carbonyl]isoindoline; 
     N-[2-Chloro-4-(3-Piperidin-1-ylpropoxy)benzoyl]isoindoline; 
     N-{2-Chloro-4-[(1-isopropyl-4-piperidinyl)oxy]benzoyl}isoindoline; 
     N-{2-Chloro-4-[(1-isopropyl-4-piperidinyl)oxy]benzoyl}-5-fluoro-isoindoline; 
     N-{2-Chloro-4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl}isoindoline; or 
     N-{2-Chloro-4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl}-5-fluoro-isoindoline or a pharmaceutically acceptable salt thereof. 
   
   
       8 . The method of  claim 1  wherein said compound is selected from the group consisting of: 
     N-[4-(3-Piperidin-1-ylpropoxy)-benzoyl]-5-fluoroisoindoline; 
     N-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoyl}isoindoline; or 
     N-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoyl}-5-fluoro-isoindoline 
     or a pharmaceutically acceptable salt thereof. 
   
   
       9 . The method of  claim 1  which is N-[4-(3-piperidin-1-ylpropoxy)benzoyl]isoindoline or a pharmaceutically acceptable salt thereof. 
   
   
       10 . The method of  claim 1  wherein the neurological disorder is selected from the group consisting of wherein the neurological disease is selected from the group consisting of Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, and cognitive deficit. 
   
   
       11 . The method of  claim 1  wherein the neurological disorder is Alzheimer's disease. 
   
   
       12 . The method of  claim 1  wherein said host is a human.