Benzimidazole derivatives

Abstract

A benzimidazole derivative or its medically acceptable salt, represented by the following formula (1), that is a human chymase activity inhibitor capable of being applied clinically: wherein, R 1 and R 2 represent a hydrogen atom, an alkyl group or an alkoxy group, etc., A represents an alkylene group or an alkenylene group, E represents —COOR 3 , —SO 3 R 3 , —CONHR 3 or —SO 2 NHR 3 , etc., G represents an alkylene group, M represents a single bond or —S(O) m . J represents a heterocyclic group, and X represents —CH═ or a nitrogen atom.

1 . A benzimidazole derivative or its medically acceptable salt represented by the following formula (1):  
       
         
           
           
               
               
           
         
       
       wherein, R 1  and R 2  may be the same or different and each independently represents a hydrogen atom, halogen atom, trihalomethyl group, cyano group, hydroxyl group, alkyl group having 1-4 carbon atoms, alkoxy group having 1-4 carbon atoms, or R 1  and R 2  together represent —O—CH 2 —O—, —O—CH 2 CH 2 —O— or —CH 2 CH 2 CH 2 — (these groups may be substituted by one or more alkyl groups having 1-4 carbon atoms); 
 A represents a substituted or unsubstituted, linear, cyclic or branched alkylene group or alkenylene group having 1-7 carbon atoms which may be interrupted by one or more of —O—, —S—, —SO 2 — and —NR 3 — (where R 3  represents a hydrogen atom or linear or branched alkyl group having 1-6 carbon atoms); the substituent that can be possessed by these groups is selected from a halogen atom, a hydroxyl group, a nitro group, a cyano group, a linear or branched alkyl group having 1-6 carbon atoms, a linear or branched alkoxy group having 1-6 carbon atoms (including the case in which two adjacent groups form an acetal bond, namely including the case in which the alkyl portions of geminal two alkoxy groups are connected to form a ring), a linear or branched alkylthio group having 1-6 carbon atoms, a linear or branched alkylsulfonyl group having 1-6 carbon atoms, a linear or branched acyl group having 1-6 carbon atoms, a linear or branched acylamino group having 1-6 carbon atoms, a trihalomethyl group, a trihalomethoxy group, a phenyl group, an oxo group, and a phenoxy group that may be substituted by one or more halogen atoms; and, one or more of these substituents may be each independently be bonded to optional positions of the alkylene or alkenylene group;  
 E represents a —COOR 3 , a —SO 3 R 3 , a —CONHR 3 , a —SO 2 NHR 3 , a tetrazole-5-yl group, a 5-oxo-1,2,4-oxadiazole-3-yl group or a 5-oxo-1,2,4-thiadiazole-3-yl group (where R 3  is as defined above);  
 G represents a substituted or unsubstituted, linear or branched alkylene group having 1-6 carbon atoms which may be interrupted by one or more of —O—, —S—, —SO 2 — and —NR 3 — (where, R 3  is as defined above. Where these atoms or atomic groups exist, they are not bonded directly to the benzimidazole ring.); and, the substituent that can be possessed by said alkylene group is selected from a halogen atom, a hydroxyl group, a nitro group, a cyano group, a linear or branched alkyl group having 1-6 carbon atoms, a linear or branched alkoxy group having 1-6 carbon atoms (including the case in which two adjacent groups form an acetal bond), a trihalomethyl group, a trihalomethoxy group, a phenyl group, an oxo group;  
 M represents a single bond or —S(O)—, where m is an integer of 0-2;  
 J represents a substituted or unsubstituted heterocyclic group having 4-10 carbon atoms and containing one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its ring, with the proviso that an imidazole ring is excluded; the substituent that can be possessed by said heteroaryl group is selected from a halogen atom, a hydroxyl group, a nitro group, a cyano group, a linear or branched alkyl group having 1-6 carbon atoms, a linear or branched alkoxy group having 1-6 carbon atoms (including the case in which two adjacent groups form an acetal bond), a linear or branched alkylthio group having 1-6 carbon atoms, a linear or branched alkylsulfonyl group having 1-6 carbon atoms, a linear or branched acyl group having 1-6 carbon atoms, a linear or branched acylamino group having 1-6 carbon atoms, a substituted or non-substituted anilide group, a trihalomethyl group, a trihalomethoxy group, a phenyl group, an oxo group, a COOR 3  group, and a phenoxy group that may be substituted by one or more halogen atoms; and, one or more of these substituents may be substituted at optional positions on the ring; and,  
 X represents a methine group (—CH═) or nitrogen atom.  
 
     
     
         2 . A benzimidazole derivative or its medically acceptable salt according to  claim 1  wherein, in said formula (1), A represents a substituted or unsubstituted, linear, cyclic or branched alkylene group having 1-7 carbon atoms (and may be interrupted by one or more of —O—, —S—, —SO 2 — and —NR 3 —).  
     
     
         3 . A benzimidazole derivative or its medically acceptable salt according to  claim 1  or  2  wherein, in said formula (1), M represents S.  
     
     
         4 . A benzimidazole derivative or its medically acceptable salt according to  claim 1  or  2  wherein, in said formula (1), M represents SO 2 .  
     
     
         5 . A benzimidazole derivative or its medically acceptable salt according to  claim 1  or  2  wherein, in said formula (1), M represents SO.  
     
     
         6 . A benzimidazole derivative or its medically acceptable salt according to  claim 1  or  2  wherein, in said formula (1), M represents a single bond.  
     
     
         7 . A benzimidazole derivative or its medically acceptable salt according to any one of  claims 1  to  6 , wherein, in said formula (1), J represents a substituted or unsubstituted heterocyclic group having 7-10 carbon atoms and containing one or more hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its ring.  
     
     
         8 . A benzimidazole derivative or its medically acceptable salt according to any one of  claims 1  to  7 , wherein, in said formula (1), G represents —CH 2 —, —CH 2 CH 2 —, —CH 2 CO—, —CH 2 CH 2 O—, —CH 2 CONH—, —CO—, —SO 2 —, —CH 2 SO 2 —, —CH 2 S— or —CH 2 CH 2 S— (and these divalent groups are bonded on the left hand side to position 1 of the benzimidazole ring while on the right hand side to J).  
     
     
         9 . A benzimidazole derivative or its medically acceptable salt according to any one of  claim 1  to  8 , wherein, in said formula (1), R 1  and R 2  may be the same or different and each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1-4 carbon atoms, an alkoxy group having 1-4 carbon atoms, a trihalomethyl group, a cyano group or a hydroxyl group.  
     
     
         10 . A benzimidazole derivative or its medically acceptable salt according to any one of  claims 1  to  9 , wherein, in said formula (1), E represents —COOH or a tetrazole-5-yl group.  
     
     
         11 . A benzimidazole derivative or its medically acceptable salt according to any one of  claims 1  to  10 , wherein, in said formula (1), X represents —CH═.  
     
     
         12 . A human chymase inhibitor containing as its active ingredient at least one benzimidazole derivative or its medically acceptable salt according to  claim 1 .  
     
     
         13 . A therapeutic agent, for diseases primarily caused by the appearance of human chymase activity, containing as its active ingredient at least one benzimidazole derivative or its medically acceptable salt according to  claim 1 .  
     
     
         14 . A pharmaceutical composition comprising at least one benzimidazole or its medically acceptable salt according to  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         15 . A pharmaceutical composition according to  claim 14 , which is a preventive agent and/or therapeutic agent for a disease.  
     
     
         16 . A pharmaceutical composition according to  claim 15 , wherein said disease is an inflammatory disease, an allergic disease, a respiratory disease, a cardiovascular disease or a bone or cartilage metabolic disease.