Benzimidazolone Carboxylic Acid Derivatives

Abstract

This invention relates to compounds of the formula (I): wherein R 1 , R 2 , R 3 , A and m are each as described herein or a pharmaceutically acceptable salt or solvate thereof, and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by 5-HT 4 receptor activity such as, but not limited to, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 A is an alkylene group having 1 to 4 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 4 substituents independently selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms, or an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S;  
 R 1  is an isopropyl group or a cyclopentyl group;  
 R 2  is a hydrogen atom, a halogen atom, or a hydroxy group;  
 R 3  is a carboxy group, a tetrazolyl group, a 5-oxo-1,2,4-oxadiazole-3-yl group, or a 5-oxo-1,2,4-thiadiazole-3-yl group; and  
 m is the integer 1 or 2.  
 
     
     
         2 . The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 , wherein 
 R 1  is an isopropyl group;    R 2  is a hydrogen atom, a fluorine atom, or a hydroxy group;    R 3  is a carboxy group or a tetrazolyl group;    A is an alkylene group having 1 to 2 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 2 substituents independently selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms, or an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S; and    m is the integer 2.    
     
     
         3 . The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 2 , wherein 
 R 3  is a carboxy group;    A is an alkylene group having 1 to 2 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 2 substituents independently selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms, or an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any two non-halogen geminal substituents can be taken together with the carbon atom to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S; and    m is the integer 2.    
     
     
         4 . The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 , wherein 
 R 1  is an isopropyl group;    R 2  is a hydrogen atom;    R 3  is a carboxy group or a tetrazolyl group;    A is an alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 geminal substituents independently selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms, or an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein two non-halogen geminal substituents can be taken together with the carbon atom to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S; and    m is the integer 2.    
     
     
         5 . The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 , wherein 
 R 1  is an isopropyl group;    R 2  is a hydrogen atom;    R 3  is a carboxy group or a tetrazolyl group;    A is                          and    m is the integer 2.    
     
     
         6 . The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 , wherein 
 R 1  is an isopropyl group;    R 2  is a hydrogen atom, a fluorine atom or a hydroxy group;    R 3  is a carboxy group;    A is                          and    m is the integer 2.    
     
     
         7 . A compound selected from: 
 1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylic acid; and    1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid;    or a pharmaceutically acceptable salt or solvate thereof.    
     
     
         8 . A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 , with or without at least one pharmaceutically acceptable carrier.  
     
     
         9 . A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 7 , with or without at least one pharmaceutically acceptable carrier.  
     
     
         10 . A pharmaceutical composition as claimed in  claim 1 , further comprising at least one pharmacologically active agent in addition to the compound.  
     
     
         11 . A pharmaceutical composition as claimed in  claim 7 , further comprising at least one pharmacologically active agent in addition to the compound.  
     
     
         12 . A method for the treatment of a condition mediated by 5-HT 4  receptor activity, in a mammalian subject, including a human, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 .  
     
     
         13 . A method for the treatment of a condition mediated by 5-HT 4  receptor activity, in a mammalian subject, including a human, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 7 .  
     
     
         14 . The method as claimed in  claim 12 , wherein said condition is gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes, or apnea syndrome.  
     
     
         15 . The method as claimed in  claim 13 , wherein said condition is gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes, or apnea syndrome.  
     
     
         16 . A method for treating gastroesophageal reflux disease comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 .  
     
     
         17 . A method for treating gastroesophageal reflux disease comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 7 .  
     
     
         18 . A compound of formula  
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein independently: 
 R 2  is a hydrogen atom, a hydroxy group or a halogen atom;  
 R 4  is a hydroxy group or a carboxy-protecting group;  
 R 6  is a hydrogen atom or an amino-protecting group;  
 Y is an alkoxy group having 1 to 4 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an imidazolyl group, a phtalimidyl group, succinimidyl group, or sulfonyl group; and  
 A is an alkylene group having 1 to 4 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 4 substituents independently selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms, or an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S; and  
 m is 1 or 2.