Pyrroloquinoline derivatives as 5-ht6 antagonists, preparation method and use thereof

Abstract

This invention concerns pyrroloquinoline derivatives as antagonists of 5-HT6 receptors, to methods for the preparation of these compounds and to novel intermediates useful for their synthesis. The invention also relates to the uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in schizophrenia, anxiety, depression, maniac depression, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, panic attacks, attention deficit hyperactivity disorder, attention deficit disorder, Parkinson's disease, Huntington's disease, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, obesity and type-2 diabetes, functional bowel disorder, Irritable Bowel Syndrome. The compounds have the general formula (XIV), wherein the symbols have the meanings given in the description.

What is claimed is: 
     
         1 . A method of treating cognitive disorders/deficits in a subject in need thereof, said method comprising administering to said subject a compound of the general formula (XIV): 
       
         
           
           
               
               
           
         
         or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or a pharmacologically acceptable salt, hydrate or solvate thereof, wherein: 
         R 1  and R 2  are independently selected from the group consisting of hydrogen, an unsubstituted alkyl(C 1 -C 3 ) group, an alkyl(C 1 -C 3 ) group substituted with one or more halogen atoms, an alkoxyl(C 1 -C 3 ) group, cyano, nitro, amino, and hydroxyl; 
         T is CO, CH 2 , substituted alkyl(C 1 -C 2 ) group, SO, or SO 2 ; 
         Ar is an unsubstituted aryl (5-6 membered), biaryl (8-10 membered), heteroaryl (5-6 membered), or heteroaryl (8-10 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O, S, optionally substituted with one or more substituents selected from the group consisting of alkyl(C 1 -C 3 ) group, an alkyl(C 1 -C 3 ) group substituted with one or more halogen atoms, alkoxy(C 1 -C 3 ) group, alkenyl(C 2 -C 4 ), halogen, nitro, hydroxyl, cyano, amino, alkylamino, and carboxamide; 
         R 3  is a substituent selected from the group consisting of cyclic or linear substituted or unsubstituted groups of structures XV-XVIII: 
       
       
         
           
           
               
               
           
         
         wherein:
 A is NH, O, CH 2 , or NR 5 ; 
 B—R 4  is NH, O, or NR 7 ; 
 R 7  is a hydrogen atom or an alkyl(C 1 -C 3 ) group; 
 R 5  is an alkyl(C 1 -C 3 ) group or benzyl; 
 R 6  is an alkyl(C 1 -C 3 ) group; 
 n is 0, 1, or 2; 
 m is 0, 1, or 2; 
 l is 1 or 2. 
 
       
     
     
         2 . The method of  claim 1 , wherein, in the compound of formula (XIV),
 R 1  and R 2  are independently selected from the group consisting of hydrogen, a methyl group optionally substituted with one or more halogen atoms, an ethyl group optionally substituted with one or more halogen atoms, cyano, nitro, amino, hydroxyl, and methoxyl;   T is CO, CH 2 , substituted alkyl(C 1 -C 2 ) group, or SO 2 ;   Ar is unsubstituted aryl (5-6 membered), biaryl (8-10 membered), heteroaryl (8-10 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O, S, optionally substituted with one or more substituents selected from alkyl(C 1 -C 3 ) group, an alkyl(C 1 -C 3 ) group substituted with one or more halogen atoms, methoxy, ethoxy, halogen, nitro, hydroxyl, cyano, amino, alkylamino, carboxamide; and   B—R 4  is NH or O.   
     
     
         3 . The method of  claim 1 , wherein the compound of formula (XIV) is selected from the group consisting of:
 N1,N1-dimethyl-N2-(1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]quinolin-4-yl) ethane-1,2-diamine;   1-((3-chlorophenyl) sulfonyl)-N-(azetidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-(naphthalen-1-ylsulfonyl)-N-(azetidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-(phenylsulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-((3-chlorophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   (S)-1-((3-chlorophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   (R)-1-((3-chlorophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-((3-fluorophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   (S)-1-((3-fluorophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   (R)-1-((3-fluorophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-((4-fluorophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-((2,5-difluorophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-((3-methoxyphenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-((3-(trifluoromethyl)phenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   (S)-1-((3-(trifluoromethyl)phenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   (R)-1-((3-(trifluoromethyl)phenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-((4-(tert-butyl)phenyl)sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-((4-aminophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   (S)-1-((4-aminophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   (R)-1-((4-aminophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-(naphthalen-1-ylsulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-(quinolin-8-ylsulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   1-((5-methylbenzo[b]thiophen-2-yl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   7-fluoro-1-((3-chlorophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   8-chloro-1-((3-chlorophenyl) sulfonyl)-N-(pyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine;   N-methyl-1-(1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)pyrrolidin-3-amine;   1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((2-bromophenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3-chlorophenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3-fluorophenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((4-fluorophenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((2,5-difluorophenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3,4-difluorophenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3,4-dichlorophenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3-(trifluoromethyl)phenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((4-(trifluoromethyl)phenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3-methoxyphenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3-cyanophenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3-methylphenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((4-isopropylphenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((4-(tert-butyl)phenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-(4-(aminophenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-(naphthalen-1-ylsulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-(naphthalen-2-ylsulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-(quinolin-8-ylsulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((5-chlorothiophen-2-yl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((5-methylbenzo[b]thiophen-2-yl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((5-chloro-3-methylbenzo[b]thiophen-2-yl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-(3-chlorobenzyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-(3-fluorobenzyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   (3-chlorophenyl)-(4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)methanone;   (3-methylphenyl)-(4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)methanone;   1-(phenylsulfonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3-chlorophenyl) sulfonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3-fluorophenyl) sulfonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((4-fluorophenyl) sulfonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((4-aminophenyl) sulfonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-(naphthalen-1-ylsulfonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-(quinolin-8-ylsulfonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[3,2-c]quinolone;   1-(phenylsulfonyl)-4-(4-benzylpiperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((5-chlorothiophen-2-yl) sulfonyl)-4-(4-benzylpiperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline 41-1-(quinolin-8-ylsulfonyl)-4-(4-benzylpiperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   8-nitro-1-((4-isopropylphenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   8-nitro-1-((3-(trifluoromethyl)phenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   8-amino-1-((3,4-dichlorophenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   8-carbonitrile-1-(3-methylphenyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   8-carbonitrile-1-(naphthalen-1-ylsulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   8-methoxy-1-((3-(trifluoromethyl)phenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   8-methoxy-1-((3-fluorophenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   8-chloro-1-((3-chlorophenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   8-chloro-1-(naphthalen-1-ylsulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   7-fluoro-1-((3-methylphenyl) sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   7-fluoro-1-((3-chlorophenyl)sulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3,4-difluorophenyl) sulfonyl)-4-(1,4-diazepan-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3-chlorophenyl) sulfonyl)-4-(1,4-diazepan-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3-chlorophenyl) sulfonyl)-4-(piperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-(quinolin-8-ylsulfonyl)-4-(piperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3-chlorophenyl) sulfonyl)-4-(morpholine-4-yl)-1H-pyrrolo[3,2-c]quinoline;   1-(quinolin-8-ylsulfonyl)-4-(morpholine-4-yl)-1H-pyrrolo[3,2-c]quinoline;   1-((3-methylphenyl) sulfonyl)-4-(pyrrolidin-3-yloxy)-1H-pyrrolo[3,2-c]quinoline;   1-((2,5-difluorophenyl) sulfonyl)-4-(pyrrolidin-3-yloxy)-1H-pyrrolo[3,2-c]quinoline;   salts thereof; and   mixtures thereof.   
     
     
         4 . The method of  claim 1 , wherein the compound of formula (XIV) is an optically active enantiomer. 
     
     
         5 . The method of  claim 1 , wherein the subject in need thereof is affected by at least one disorder selected from the group consisting of schizophrenia, Alzheimer's disease, attention deficit disorder, age related cognitive decline, mild cognitive impairment, and Parkinson's disease. 
     
     
         6 . The method of  claim 5 , wherein the subject in need thereof is affected by schizophrenia. 
     
     
         7 . The method of  claim 5 , wherein the subject in need thereof is affected by Alzheimer's disease. 
     
     
         8 . The method of  claim 5 , wherein the subject in need thereof is affected by attention deficit disorder. 
     
     
         9 . The method of  claim 5 , wherein the subject in need thereof is affected by Parkinson's disease. 
     
     
         10 . The method of  claim 5 , wherein the subject in need thereof is affected by age related cognitive decline. 
     
     
         11 . The method of  claim 5 , wherein the subject in need thereof is affected by mild cognitive impairment. 
     
     
         12 . The method of  claim 2 , wherein the subject in need thereof is affected by at least one disorder selected from the group consisting of schizophrenia, Alzheimer's disease, attention deficit disorder, age related cognitive decline, mild cognitive impairment and Parkinson's disease. 
     
     
         13 . The method of  claim 3 , wherein the subject in need thereof is affected by at least one disorder selected from the group consisting of schizophrenia, Alzheimer's disease, attention deficit disorder, age related cognitive decline, mild cognitive impairment, and Parkinson's disease. 
     
     
         14 . The method of  claim 13 , wherein the subject in need thereof is affected by attention deficit disorder. 
     
     
         15 . The method of  claim 13 , wherein the subject in need thereof is affected by Parkinson's disease. 
     
     
         16 . The method of  claim 13 , wherein the subject in need thereof is affected by schizophrenia. 
     
     
         17 . The method of  claim 13 , wherein the subject in need thereof is affected by Alzheimer's disease. 
     
     
         18 . The method of  claim 4 , wherein the subject in need thereof is affected by at least one disorder selected from the group consisting of schizophrenia, Alzheimer's disease, attention deficit disorder, age related cognitive decline, mild cognitive impairment, and Parkinson's disease. 
     
     
         19 . The method of  claim 1 , wherein:
 the compound of formula XIV is administered in combination with a second medicament;   said compound of formula XIV and said second medicament being administered simultaneously or sequentially to said patient.