Phenylpyrrole derivative

Abstract

Provided are novel compounds that are useful in the prevention or treatment of such diseases as dementia, Alzheimer's disease, attention-deficient hyperactivity disorder, schizophrenia, epilepsy, central convulsion, obesity, diabetes mellitus, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behaviorally induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorder, parasomnia, sleep related movement disorder, insomnia, and depression, or allergic rhinitis, or pharmaceutically acceptable salts of such compounds. Specifically, there are provided phenylpyrrole compounds represented by the following formula (I) or pharmaceutically acceptable salts thereof: Formula (I) [wherein Q refers to a group represented by the following formula (A) or (B):

1 - 8 . (canceled) 
     
     
         9 . A method for treatment of dementia, Alzheimer's disease, attention-deficient hyperactivity disorder, schizophrenia, epilepsy, central convulsion, obesity, diabetes mellitus, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behaviorally induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorder, parasomnia, sleep related movement disorder, insomnia, depression, or allergic rhinitis, the method comprising administering to a subject in need of said treatment, an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         [wherein 
         Q refers to a group represented by the following formula (A) or (B): 
       
       
         
           
           
               
               
           
         
         R 1  is hydroxyl, C 1 -C 6  alkoxy, or NR 1A  R 1B ; 
         R 1A  and R 1B , which may be the same or different, are each a hydrogen atom, C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, or 
         R 1A  and R 1B  are bonded together with the adjacent nitrogen atom to form a 3- to 7-membered saturated heterocyclic ring (the saturated heterocyclic ring being optionally substituted by one or two C 1 -C 6  alkyls); 
         R 2  is a hydrogen atom, a halogen atom, or C 1 -C 6  alkyl; 
         n is 1 or 2; 
         R 3  is a hydrogen atom, a halogen atom, or C 1 -C 6  alkyl; 
         R 4  is C 1 -C 6  alkyl (the C 1 -C 6  alkyl may be substituted by one or two C 3 -C 7  cycloalkyls) or C 3 -C 7  cycloalkyl (the C 3 -C 7  cycloalkyl may be substituted by one or two C 1 -C 6  alkyls); 
         R 5  and R 6 , which may be the same or different, are each C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, or 
         R 5  and R 6  are bonded together with the adjacent nitrogen atom to form a 3- to 7-membered saturated heterocyclic ring (the saturated heterocyclic ring being optionally substituted by one or two C 1 -C 6  alkyls)]. 
       
     
     
         10 . The method according to  claim 9 , wherein Q is represented by formula (A): 
       
         
           
           
               
               
           
         
         (wherein R 4  is as defined in claim  1 ). 
       
     
     
         11 . The method according to  claim 9 , wherein R 1  is NR 1A R 1B  (wherein R 1A  and R 1B  are as defined in  claim 9 ). 
     
     
         12 . The method according to  claim 9 , wherein R 2  and R 3  are each a hydrogen atom and n is 1. 
     
     
         13 . The method according to  claim 9 , wherein R 4  is C 3 -C 7  cycloalkyl. 
     
     
         14 . The method according to  claim 9 , wherein the compound is selected from the group consisting of the following or a pharmaceutically acceptable salt thereof:
 Methyl 1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxylate,   1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxylic acid,   Azetidin-1-yl(1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)methanone,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)(pyrrolidin-1-yl)methanol,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)(piperidin-1-yl)methanol,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-N,N-dimethyl-1H-pyrrole-3-carboxamide,   1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-N-methyl-1H-pyrrole-3-carboxamide,   1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxamide,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)(morpholin-4-yl)methanone,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)((2R,6S)-2,6-dimethylmorpholin-4-yl)methanone,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)(2-oxa-6-azaspiro[3.3]hepta-6-yl)methanone,   N-tert-butyl-1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxamide,   N-cyclobutyl-1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxamide,   Methyl 1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2,5-dimethyl-1H-pyrrole-3-carboxylate,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2,5-dimethyl-1H-pyrrol-3-yl) (pyrrolidin-1-yl)methanone,   [1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrrol-3-yl](pyrrolidin-1-yl)methanone,   (1-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)(pyrrolidin-1-yl)methanone,   1-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}-N-methyl-1H-pyrrole-3-carboxamide,   (1-{4-[(1-tert-butylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)(pyrrolidin-1-yl)methanone, and   1-{4-[(1-tert-butylpiperidin-4-yl)oxy]phenyl}-N-methyl-1H-pyrrole-3-carboxamide.   
     
     
         15 . The method according to  claim 9 , wherein the compound is 1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-N-methyl-1H-pyrrole-3-carboxamide represented by the following formula or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
     
     
         16 . A method of antagonizing histamine H3 receptor, the method comprising administering to a subject in need thereof, an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound or salt thereof is a histamine H3 receptor antagonist or inverse agonist 
       
         
           
           
               
               
           
         
         [wherein 
         Q refers to a group represented by the following formula (A) or (B): 
       
       
         
           
           
               
               
           
         
         R 1  is hydroxyl, C 1 -C 6  alkoxy, or NR 1A  R 1B ; 
         R 1A  and R 1B , which may be the same or different, are each a hydrogen atom, C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, or 
         R 1A  and R 1B  are bonded together with the adjacent nitrogen atom to form a 3- to 7-membered saturated heterocyclic ring (the saturated heterocyclic ring being optionally substituted by one or two C 1 -C 6  alkyls); 
         R 2  is a hydrogen atom, a halogen atom, or C 1 -C 6  alkyl; 
         n is 1 or 2; 
         R 3  is a hydrogen atom, a halogen atom, or C 1 -C 6  alkyl; 
         R 4  is C 1 -C 6  alkyl (the C 1 -C 6  alkyl may be substituted by one or two C 3 -C 7  cycloalkyls) or C 3 -C 7  cycloalkyl (the C 3 -C 7  cycloalkyl may be substituted by one or two C 1 -C 6  alkyls); 
         R 5  and R 6 , which may be the same or different, are each C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, or 
         R 5  and R 6  are bonded together with the adjacent nitrogen atom to form a 3- to 7-membered saturated heterocyclic ring (the saturated heterocyclic ring being optionally substituted by one or two C 1 -C 6  alkyls)]. 
       
     
     
         17 . The method according to  claim 16 , wherein Q is represented by formula (A): 
       
         
           
           
               
               
           
         
         (wherein R 4  is as defined in  claim 16 ). 
       
     
     
         18 . The method according to  claim 16 , wherein R 1  is NR 1A R 1B  (wherein R 1A  and R 1B  are as defined in  claim 16 ). 
     
     
         19 . The method according to  claim 16 , wherein R 2  and R 3  are each a hydrogen atom and n is 1. 
     
     
         20 . The method according to  claim 16 , wherein R 4  is C 3 -C 7  cycloalkyl. 
     
     
         21 . The method according to  claim 16 , wherein the compound is selected from the group consisting of the following or a pharmaceutically acceptable salt thereof:
 Methyl 1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxylate,   1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxylic acid,   Azetidin-1-yl(1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)methanone,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)(pyrrolidin-1-yl)methanol,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)(piperidin-1-yl)methanol,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-N,N-dimethyl-1H-pyrrole-3-carboxamide,   1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-N-methyl-1H-pyrrole-3-carboxamide,   1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxamide,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)(morpholin-4-yl)methanone,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)((2R,6S)-2,6-dimethylmorpholin-4-yl)methanone,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)(2-oxa-6-azaspiro[3.3]hepta-6-yl)methanone,   N-tert-butyl-1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxamide,   N-cyclobutyl-1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxamide,   Methyl 1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2,5-dimethyl-1H-pyrrole-3-carboxylate,   (1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2,5-dimethyl-1H-pyrrol-3-yl) (pyrrolidin-1-yl)methanone,   [1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrrol-3-yl](pyrrolidin-1-yl)methanone,   (1-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)(pyrrolidin-1-yl)methanone,   1-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}-N-methyl-1H-pyrrole-3-carboxamide,   (1-{4-[(1-tert-butylpiperidin-4-yl)oxy]phenyl}-1H-pyrrol-3-yl)(pyrrolidin-1-yl)methanone, and   1-{4-[(1-tert-butylpiperidin-4-yl)oxy]phenyl}-N-methyl-1H-pyrrole-3-carboxamide.   
     
     
         22 . The method according to  claim 16 , wherein the compound is 1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-N-methyl-1H-pyrrole-3-carboxamide represented by the following formula or a pharmaceutically acceptable salt thereof