Benzimidazolone Compounds Having 5-HT4 Receptor Agonistic Activity

Abstract

This invention provides a compound of the formula (I): or a pharmaceutically acceptable salt thereof, and compositions containing such compounds and the use of such compounds for the manufacture of medicament for gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes and apnea syndrome. These compounds have 5-HT 4 receptor agonistic activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans.

1 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         Het represents a heterocyclic group having one nitrogen atom, to which B binds directly, and from 4 to 7 carbon atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of substituents α 1 ; 
         A represents an alkylene group having from 1 to 4 carbon atoms; 
         B represents a covalent bond or an alkylene group having from 1 to 5 carbon atoms, and said alkylene group being unsubstituted or substituted by an oxo group when R 3  represents a heterocyclic group; 
         R 1  represents an isopropyl group or a cyclopentyl group; 
         R 2  independently represents a halogen atom or an alkyl group having from 1 to 4 carbon atoms; m is 0, 1, 2, 3 or 4; and 
         R 3  represents
 (i) a cycloalkyl group having from 3 to 8 carbon atoms, and said cycloalkyl group being substituted by 1 to 5 substituents independently selected from the group consisting of substituents α 2 , or 
 (ii) a heterocyclic group having from 3 to 8 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 5 substituents independently selected from the group consisting of substituents β, 
 
         said substituents α 1  are independently selected from a hydroxy group and an amino group; 
         said substituents α 2  are independently selected from a hydroxy group, an amino group, a hydroxy-substituted alkyl group having from 1 to 4 carbon atoms, a carboxyl group and an alkoxy group having from 1 to 4 carbon atoms; and 
         said substituents β are independently selected from a hydroxy group, a hydroxy-substituted alkyl group having from 1 to 4 carbon atoms, a carboxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an amino-substituted alkyl group having from 1 to 4 carbon atoms and a carbamoyl group, or a pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The compound or the pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 Het represents a heterocyclic group selected from   
       
         
           
           
               
               
           
         
         said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of substituents α 1 ; and 
         A represents an alkylene group having from 1 to 3 carbon atoms. 
       
     
     
         3 . The compound or the pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 Het represents a group of formula   
       
         
           
           
               
               
           
         
         and this group being unsubstituted or substituted by one substituent selected from the group consisting of substituents α 1 ; 
         A represents an alkylene group having from 1 to 2 carbon atoms; 
         B represents an alkylene group having from 1 to 4 carbon atoms, and said alkylene group being unsubstituted or substituted by an oxo group when R 3  represents a heterocyclic group; 
         R 2  independently represents a halogen atom or an alkyl group having from 1 to 2 carbon atoms; m is 0, 1 or 2; and 
         R 3  represents
 (i) a cycloalkyl group having from 4 to 7 carbon atoms, and said cycloalkyl group being substituted by 1 to 3 substituents independently selected from the group consisting of substituents α 2 , or 
 (ii) a heterocyclic group having from 4 to 7 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of substituents β. 
 
       
     
     
         4 . The compound or the pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 Het represents a group of formula   
       
         
           
           
               
               
           
         
         and this group being unsubstituted or substituted by one substituent selected from the group consisting of substituents α 1 ; 
         A represents a methylene group; 
         B represents an alkylene group having from 1 to 2 carbon atoms; 
         R 1  represents an isopropyl group; 
         R 2  independently represents a fluorine atom, a chlorine atom or a methyl; and 
         R 3  represents
 (i) a cycloalkyl group having from 5 to 7 carbon atoms, and said cycloalkyl group being substituted by 1 to 2 substituents independently selected from the group consisting of substituents α 2 , or 
 (ii) a heterocyclic group having from 5 to 7 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of substituents β, 
 
         said substituents α 2  are independently selected from a hydroxy group, an amino group and an alkoxy group having from 1 to 2 carbon atoms; and 
         said substituents β are independently selected from a hydroxy group, a hydroxy-substituted alkyl group having from 1 to 2 carbon atoms, a carboxyl group, an amino group, an amino-substituted alkyl group having from 1 to 2 carbon atoms and a carbamoyl group. 
       
     
     
         5 . The compound or the pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 Het represents a group of formula   
       
         
           
           
               
               
           
         
         A represents a methylene group; 
         B represents a methylene group; 
         R 1  represents an isopropyl group; 
         R 2  represents a fluorine atom; m is 0 or 1; and 
         R 3  represents
 (i) a cycloalkyl group having from 5 to 6 carbon atoms, and said cycloalkyl group being substituted by 1 to 2 substituents independently selected from the group consisting of substituents α 2 , or 
 (ii) a heterocyclic group having from 5 to 6 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of substituents β, 
 
         said substituents α 2  are independently selected from a hydroxy group and an amino group; and 
         said substituents β are independently selected from a hydroxy group and an amino group. 
       
     
     
         6 . The compound or the pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 Het represents a group of formula   
       
         
           
           
               
               
           
         
         A represents a methylene group; 
         B represents a methylene group; 
         R 1  represents an isopropyl group; 
         R 2  represents a fluorine atom; m is 0; and 
         R 3  represents
 (i) a cyclohexyl group substituted by 1 to 2 substituents independently selected from a hydroxy group or an amino group, or 
 (ii) a heterocyclic group having from 6 atoms, and said heterocyclic group being substituted by a hydroxy group or an amino group. 
 
       
     
     
         7 . The compound or the pharmaceutically acceptable salt, as claimed in  claim 6 , wherein
 R 3  represents
 (i) a cyclohexyl group substituted by 1 or 2 hydroxy group, or 
 (ii) a tetrahydropyran group substituted by 1 or 2 hydroxy group. 
   
     
     
         8 . The compound or the pharmaceutically acceptable salt, as claimed in  claim 7 , wherein
 R 3  represents hydroxytetrahydropyranyl or dihydroxycyclohexyl.   
     
     
         9 . The compound as claimed in  claim 1 , which is selected from:
 N-({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;   N-({1-[(trans-1,4-dihydroxyhexyl)methyl]piperidin-4-yl}methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;   N-({1-[(cis-1,4-dihydroxyhexyl)methyl]piperidin-4-yl}methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide; and   6-fluoro-N-({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide,   or the pharmaceutically acceptable salt thereof.   
     
     
         10 . The compound or the pharmaceutically acceptable salt, as claimed in any one of  claims 1  to  9 , wherein the pharmaceutically acceptable salt is a hydrochloride or hemiedysilate. 
     
     
         11 . A pharmaceutical composition including the compound or the pharmaceutically acceptable salt thereof, as claimed in any one of  claims 1  to  9 , together with a pharmaceutically acceptable excipient. 
     
     
         12 . A method of the treatment of disease conditions mediated by 5-HT 4  receptor activity, in a mammalian subject, which comprises administering to the said subject in need of such treatment a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof, as claimed in any one of  claims 1  to  9 . 
     
     
         13 . A method of the treatment of diseases selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes and apnea syndrome, which comprises administering to the said subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof, as claimed in any one of  claims 1  to  9 . 
     
     
         14 . Use of the compound or the pharmaceutically acceptable salt thereof, as claimed in any one of  claims 1  to  9  for the manufacture of a medicament for the treatment of disease conditions mediated by 5-HT 4  receptor activity, in a mammalian subject. 
     
     
         15 . Use of a compound as claimed in  claim 14 , wherein said condition is selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes and apnea syndrome. 
     
     
         16 . A compound of the formula (2-A′): 
       
         
           
           
               
               
           
         
         wherein 
         R a  represents a hydrogen atom or a N-protecting group; 
         Het represents a heterocyclic group having one nitrogen atom, to which B binds directly, and from 4 to 7 carbon atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of substituents α 1 ; 
         A represents an alkylene group having from 1 to 4 carbon atoms; 
         B represents a covalent bond or an alkylene group having from 1 to 5 carbon atoms, and said alkylene group being unsubstituted or substituted by an oxo group when R 3  represents a heterocyclic group; 
         R 3  represents
 (i) a cycloalkyl group having from 3 to 8 carbon atoms, and said cycloalkyl group being substituted by 1 to 5 substituents independently selected from the group consisting of substituents α 2 , or 
 (ii) a heterocyclic group having from 3 to 8 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 5 substituents independently selected from the group consisting of substituents β, 
 
         said substituents α 1  are independently selected from a hydroxy group and an amino group; 
         said substituents α 2  are independently selected from a hydroxy group, an amino group, a hydroxy-substituted alkyl group having from 1 to 4 carbon atoms, a carboxyl group and an alkoxy group having from 1 to 4 carbon atoms; and 
         said substituents β are independently selected from a hydroxy group, a hydroxy-substituted alkyl group having from 1 to 4 carbon atoms, a carboxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an amino-substituted alkyl group having from 1 to 4 carbon atoms and a carbamoyl group, 
         or a salt thereof 
       
     
     
         17 . The compound or the salt thereof, as claimed in  claim 16 , wherein
 R a  represents a hydrogen atom or a t-butoxycarbonyl group;   Het represents a group of formula   
       
         
           
           
               
               
           
         
         A represents an methylene group; B represents an methylene group; and 
         R 3  represents hydroxytetrahydropyranyl or dihydroxycyclohexyl. 
       
     
     
         18 . A combination of the compound or the pharmaceutically acceptable salt thereof as claimed in any one of  claims 1  to  9 , and another pharmacologically active agent. 
     
     
         19 . A pharmaceutical composition including the compound or the pharmaceutically acceptable salt thereof as claimed in any one of  claims 1  to  9 , and another pharmacologically active agent. 
     
     
         20 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         Het represents a heterocyclic group having one nitrogen atom, to which B binds directly, and from 4 to 7 carbon atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of substituents α 1 ; 
         A represents an alkylene group having from 1 to 4 carbon atoms; 
         B represents a covalent bond or an alkylene group having from 1 to 5 carbon atoms, and said alkylene group being unsubstituted or substituted by an oxo group when R 3  represents a heterocyclic group; 
         R 1  represents an isopropyl group or a cyclopentyl group; 
         R 2  independently represents a halogen atom or an alkyl group having from 1 to 4 carbon atoms; m is 0, 1, 2, 3 or 4; and 
         R 3  represents
 (i) a cycloalkyl group having from 3 to 8 carbon atoms, and said cycloalkyl group being substituted by 1 to 5 substituents independently selected from the group consisting of substituents α 2 , or 
 (ii) a heterocyclic group having from 3 to 8 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 5 substituents independently selected from the group consisting of substituents β, 
 
         said substituents α 1  are independently selected from a hydroxy group and an amino group; 
         said substituents α 2  are independently selected from a hydroxy group, an amino group, a hydroxy-substituted alkyl group having from 1 to 4 carbon atoms, a carboxyl-substituted alkyl group having 1 to 4 carbon atoms, a carboxyl group and an alkoxy group having from 1 to 4 carbon atoms; and 
         said substituents β are independently selected from a hydroxy group, a hydroxy-substituted alkyl group having from 1 to 4 carbon atoms, a carboxyl-substituted alkyl group having 1 to 4 carbon atoms, a carboxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an amino-substituted alkyl group having from 1 to 4 carbon atoms and a carbamoyl group, 
         or a pharmaceutically acceptable salts thereof.