Benzimidazole derivatives, preparation and therapeutic use thereof

Abstract

The invention relates to benzimidazole derivatives of general formula in which X represents a nitrogen atom or a carbon atom; and when X represents a nitrogen atom: R3 represents a hydrogen atom or a C1-C4 alkyl group, or does not exist, to give the compounds of formula (I) comprising a secondary or tertiary amine; R4 represents a hydrogen atom or a C1-C6 alkyl, C3-C7 cycloalkyl, optionally substituted C3-C7 heterocycloalkyl, —(CH 2 ) p -heteroaryl, heteroaryl-carbonyl, phenylcarbonyl, (C1-C6)alkylcarbonyl, —(CH 2 ) p COOR, optionally substituted phenylsulphonyl or optionally substituted —(CH 2 ) p -phenyl group, and, when X represents a carbon atom: R3 represents a hydrogen atom or a group —NR5R6, —N(R5) 3 + , —NHCOR7, —CONHR5, —COR7, —NHCONH 2 , —OH or —CH 2 OH, R4 represents a hydrogen atom or an optionally substituted —(CH 2 ) p -phenyl, —(CH 2 ) p -heteroaryl or —(CH 2 ) t NR7R8 group. Preparation process and therapeutic application.

1 . A compound corresponding to formula (I)  
       
         
           
           
               
               
           
         
       
       in which: 
 R1 represents a hydrogen atom, a C1-C4 alkyl group, a halogen atom, a nitro group or a C1-C4 alkoxy group,  
 R2 and R2′ represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,  
 X represents a nitrogen atom or a carbon atom,  
 n is equal to 1 or 2,  
 m is equal to 1 or 2,  
 and, when X represents a carbon atom:  
 R3 represents a hydrogen atom, a group —NR5R6, a group —N(R5) 3   + , a group —NHCOR7, a group —CONHR5, a group —COR7, an —NHCONH 2  group, an —OH group or a —CH 2 OH group,  
 R4 represents  
 a —(CH 2 ) p -heteroaryl group, in which p may range from 0 to 4 and in which the heteroaryl group is chosen from an imidazolyl group, optionally substituted with a C1-C4 alkyl group,  
 or a pharmaceutically acceptable acid addition salt thereof,  
 with the proviso that when R1=R2=R2′=R3=H, X=C, n=m=1, R4 is other than 4-imidazolyl or 5-methyl-4-imidazolyl.  
 
     
     
         2 . A compound according to  claim 1 , wherein: 
 R1 represents a hydrogen atom,    R2 and R2′ represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,    X represents a carbon atom,    n is equal to 1 or 2,    m is equal to 1,    R3 represents a hydrogen atom, a group —NR5R6, a group —N(R5) 3   + , a group —NHCOR7, a group —CONHR5, an —NHCONH 2  group, an —OH group or a —CH 2 OH group,    R4 represents    a heteroaryl group chosen from an imidazolyl group, optionally substituted with a C1-C4 alkyl group.    
     
     
         3 . A compound according to  claim 2  wherein: 
 R1 represents a hydrogen atom,    R2 and R2′ represent, independently of each other, a hydrogen atom or a methyl group,    X represents a carbon atom,    n is equal to 1 or 2,    m is equal to 1,    R3 represents a hydrogen atom, a group —NR5R6, an —N(CH 3 ) 3   +  group, a group —NHCOR7, a group —CONHR5, an —NHCONH 2  group, an —OH group or a —CH 2 OH group,    R4 represents    a heteroaryl group chosen from an imidazolyl group, optionally substituted with a methyl group,.    
     
     
         4 . A process for preparing a compound according to  claim 1  wherein a compound of formula (II):  
       
         
           
           
               
               
           
         
         in which R1, R2, R2′ and n are as defined in  claim 1  and A represents a leaving group, is reacted with an amine of formula (III):  
         
           
             
             
                 
                 
             
           
         
         in which X, R3, R4 and m are as defined in  claim 1 , in a solvent.  
       
     
     
         5 - 10 . (Cancelled)  
     
     
         11 . A process according to  claim 4  wherein the solvent is an alcohol, an ether, or a hydrocarbon.  
     
     
         12 . A process according to  claim 11  carried out in the presence of a base.  
     
     
         13 . A process according to  claim 11  carried out in the presence of a palladium-based or nickel-based catalyst.  
     
     
         14 . A process according to  claim 12  carried out in the presence of an alkali metal halide.  
     
     
         15 . A pharmaceutical composition which comprises a compound according to  claim 1  together with a pharmaceutically acceptable excipient.  
     
     
         16 . A pharmaceutical composition which comprises a compound according to  claim 2  together with a pharmaceutically acceptable excipient.  
     
     
         17 . A pharmaceutical composition which comprises a compound according to  claim 3  together with a pharmaceutically acceptable excipient.  
     
     
         18 . A method for the treatment of disorders in which the enzyme poly (ADP-ribose) polymerase is involved which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having formula (I)  
       
         
           
           
               
               
           
         
         in which:  
         R1 represents a hydrogen atom, a C1-C4 alkyl group, a halogen atom, a nitro group or a C1-C4 alkoxy group,  
         R2 and R2′ represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,  
         X represents a nitrogen atom or a carbon atom,  
         n is equal to 1 or 2,  
         m is equal to 1 or 2,  
         and, when X represents a nitrogen atom:  
         R3 is not present or represents a C1-C4 alkyl group, and  
         R4 represents  
         a hydrogen atom,  
         a C1-C6 alkyl group,  
         a C3-C7 cycloalkyl group,  
         a C3-C7 heterocycloalkyl group optionally substituted with a C1-C4 alkyl group or a group —COOR, in which R represents a C1-C6 alkyl group,  
         a group —(CH 2 ) p -heteroaryl, in which p may range from 0 to 4 and in which the heteroaryl group is chosen from pyridyl, aminopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl and thienyl groups, the said heteroaryl group optionally being substituted with a C1-C4 alkyl group,  
         a heteroarylcarbonyl group, the heteroaryl group being chosen from furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl and imidazolyl groups,  
         a phenylcarbonyl group, the phenyl group optionally being substituted with a halogen atom,  
         a (C1-C6)alkylcarbonyl group,  
         a group —(CH 2 ) p COOR in which p may range from 0 to 4 and in which R represents a C1-C6 alkyl group,  
         a phenylsulphonyl group optionally substituted on the phenyl nucleus with a halogen atom, a trifluoromethyl group, a C1-C4 alkyl group, a nitro group or a C1-C4 alkoxy group, or  
         a —(CH 2 ) p -phenyl group, in which p may range from 0 to 4 and in which the phenyl group is optionally substituted with one to three groups chosen, independently of each other, from: a C1-C4 alkyl group, a nitro group, an amino group, a hydroxyl group, a halogen atom, a trifluoromethyl group, a C1-C4 alkoxy group, a (C1-C4)alkoxyphenyl group, a C1-C4 alkylamino group, a C1-C4 dialkylamino group, an —NHCHO group or a group —NHCOR′, in which R′ represents a C1-C4 alkoxy group or a C1-C4 alkyl group, this C1-C4 alkyl group optionally being substituted with a dimethylamino group,  
         and, when X represents a carbon atom:  
         R3 represents a hydrogen atom, a group —NR5R6, a group —N(R5) 3   + , a group —NHCOR7, a group —CONHR5, a group —COR7, an —NHCONH 2  group, an —OH group or a —CH 2 OH group,  
         R4 represents  
         a hydrogen atom,  
         a —(CH 2 ) p -phenyl group, in which p may range from 0 to 4 and in which the phenyl group is optionally substituted with one to three groups chosen, independently of each other, from: a C1-C4 alkyl group, a nitro group, an amino group, a halogen atom, a trifluoromethyl group or a C1-C4 alkoxy group,  
         a —(CH 2 ) p -heteroaryl group, in which p may range from 0 to 4 and in which the heteroaryl group is chosen from an imidazolyl group, optionally substituted with a C1-C4 alkyl group, a pyridyl group, an aminopyridyl group, a pyrimidinyl group, a pyrazinyl group or a pyridazinyl group, or  
         a group —(CH 2 ) t NR7R8, in which t is equal to 0 or 1,  
         R5 and R6 represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group, and  
         R7 and R8 represent, independently of each other, a C1-C4 alkyl or C1-C4 alkoxy group or together form a saturated 5- to 7-membered ring optionally comprising an additional nitrogen atom, this ring optionally being substituted, on a carbon atom or on a nitrogen atom, including the nitrogen atom to which the groups R7 and R8 are attached, with a C1-C4 alkyl group or a group —COOR″, in which R″ represents a phenyl or (C1-C4)alkylphenyl group,  
         or a pharmaceutically acceptable acid addition salt thereof,  
         with the proviso that when R4 represents a group —NR7R8, R3 is other than —NR5R6, —NHCOR7, —NHCONH 2  or —OH, and when R1=R2=R2′=R3=H, X=C and n=m=1, R4 is other than 4-imidazolyl or 5-methyl-4-imidazolyl.  
       
     
     
         19 . A method according to  claim 18  wherein: 
 X is a nitrogen atom and R3 is not present,    R1 represents a hydrogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group,    R2 represents a hydrogen atom or a C1-C4 alkyl group,    R2′ represents a hydrogen atom,    n is equal to 1 or 2,    m is equal to 1 or 2, and    R4 represents    a hydrogen atom,    a C1-C6 alkyl group,    a C3-C7 cycloalkyl group,    a pyridyl, pyrimidinyl or pyrazinyl group, optionally substituted with a C1-C4 alkyl group,    a heteroarylcarbonyl group, the heteroaryl group being chosen from a furyl group and a pyridyl group,    a phenylcarbonyl group, the phenyl group optionally being substituted with a halogen atom,    a (C1-C6)alkylcarbonyl group,    a group —(CH 2 ) p COOR in which p can range from 0 to 4 and in which R represents a C1-C6 alkyl group,    a phenylsulphonyl group,    a phenyl group substituted with one to three groups chosen, independently of each other, from: a C1-C4 alkyl group, a nitro group, an amino group, a hydroxyl group, a halogen atom, a trifluoromethyl group, a C1-C4 alkoxy group, a (C1-C4)alkoxyphenyl group, a (C1-C4)- dialkylamino group, an —NHCHO group or a group —NHCOR′, in which R′ represents a C1-C4 alkoxy group or a C1-C4 alkyl group, this C1-C4 alkyl group optionally being substituted with a dimethylamino group,    a —(CH 2 ) p -phenyl group, in which p can range from 0 to 4,    a —(CH 2 ) p -pyridyl group, in which p can range from 0 to 4,    a —(CH 2 ) p -thienyl group, in which p can range from 0 to 4, or    a (C3-C7)heterocycloalkyl group optionally substituted with a C1-C4 alkyl group or a group —COOR, in which R represents a C1-C6 alkyl group, or    X is a carbon atom and R3 is a hydrogen atom, a group —NR5R6, a group —N(R5) 3   + , a group —NHCOR7, a group —CONHR5, an —NHCONH 2  group, an —OH group or a —CH 2 OH group,    R1 represents a hydrogen atom,    R2 and R2′ represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,    n is equal to 1 or 2,    m is equal to 1,    R4 represents    a hydrogen atom,    a benzyl group,    a phenyl group optionally substituted with one to three groups chosen, independently of each other, from: a C1-C4 alkyl group, a nitro group, an amino group, a halogen atom, a trifluoromethyl group or a C1-C4 alkoxy group,    a heteroaryl group chosen from an imidazolyl group, optionally substituted with a C1-C4 alkyl group, or a pyridyl group, or    a group —NR7R8,    R5 and R6 represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group, and    R7 and R8 represent, independently of each other, a C1-C4 alkyl or C1-C4 alkoxy group, or together form a saturated 5- to 7-membered ring optionally comprising an additional nitrogen atom, this ring optionally being substituted, on a carbon atom or a nitrogen atom, including the nitrogen atom to which the groups R7 and R8 are attached to form a quaternary ammonium, with a C1-C4 alkyl group or a group —COOR″, in which R″ represents a phenyl or (C1-C4)alkylphenyl group.    
     
     
         20 . A method according to  claim 19  wherein: 
 X is a nitrogen atom and R3 is not present,    R1 represents a hydrogen atom, a methyl group or a methoxy group,    R2 represents a hydrogen atom or a methyl group,    R2′ represents a hydrogen atom,    n is equal to 1 or 2,    m is equal to 1 or 2, and    R4 represents    a hydrogen atom,    a C1-C4 alkyl group,    a C6-C7 cycloalkyl group,    a pyridyl, pyrimidinyl or pyrazinyl group, optionally substituted with a C1-C4 alkyl group,    a heteroarylcarbonyl group, the heteroaryl group being chosen from a furyl group and a pyridyl group,    a phenylcarbonyl group, the phenyl group optionally being substituted with a halogen atom,    a (C3-C5)alkylcarbonyl group,    a group —(CH 2 ) p COOR in which p is equal to 0 or 1 and in which R represents a C1-C4 alkyl group,    a phenylsulphonyl group,    a phenyl group substituted with one to three groups chosen, independently of each other, from: a methyl group, a nitro group, an amino group, a hydroxyl group, a halogen atom, a trifluoromethyl group, a methoxy group, a (C1-C4)alkoxyphenyl group, a dimethylamino group, an —NHCHO group or a group —NHCOR′, in which R′ represents a C1-C4 alkoxy group or a C1-C4 alkyl group, this C1-C4 alkyl group optionally being substituted with a dimethylamino group,    a —(CH 2 ) p -phenyl group, in which p is equal to 1, 2, 3 or 4,    a —(CH 2 ) p -pyridyl group, in which p can range from 1 to 3,    a —(CH 2 ) p -thienyl group, in which p is equal to 2, or    a C6-C7 heterocycloalkyl group optionally substituted with a methyl group or a group —COOR, in which R represents a C1-C4 alkyl group, or    X is a carbon atom R3 is a hydrogen atom, a group —NR5R6, an —N(CH 3 ) 3   +  group, a group —NHCOR7, a group —CONHR5, an —NHCONH 2  group, an —OH group or a —CH 2 OH group,    R1 represents a hydrogen atom,    R2 and R2′ represent, independently of each other, a hydrogen atom or a methyl group,    n is equal to 1 or 2,    m is equal to 1,    R4 represents    a hydrogen atom,    a benzyl group,    a phenyl group optionally substituted with one to three groups chosen, independently of each other, from a halogen atom and a trifluoromethyl group,    a heteroaryl group chosen from an imidazolyl group, optionally substituted with a methyl group, or a pyridyl group, or    a group —NR7R8,    R5 and R6 represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group, and    R7 and R8 represent, independently of each other, a C1-C4 alkyl group or together form a saturated 5- to 7-membered ring optionally comprising an additional nitrogen atom, this ring optionally being substituted, on a carbon atom or on a nitrogen atom, including the nitrogen atom to which the groups R7 and R8 are attached to form a quaternary ammonium, with a methyl group or a group —COOR″, in which R″ represents a (C1-C4)alkylphenyl group.    
     
     
         21 . A method according to  claim 18  wherein the disorders are selected from myocardial infarction, cardiac ischemia, cardiac insufficiency, atherosclerosis, restenosis after PTCA or bypass, cerebral ischemia and cerebral infarction, caused by an ischemia, a trauma or a thromboembolic accident, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and Huntington's chorea, acute renal insufficiency, in particular that of ischemic origin or appearing after kidney transplant, heart transplant: treatment of graft rejection and accelerated atherosclerosis of grafts, inflammatory pathologies, immunological disorders, rheumatoid diseases, diabetes and pancreatitis, septic shock, acute respiratory distress syndrome, tumours and metastases, autoimmune diseases, AIDS, hepatitis, psoriasis, vasculitis, ulcerative colitis, multiple sclerosis or myasthenia.  
     
     
         22 . A method according to  claim 19  wherein the disorders are selected from myocardial infarction, cardiac ischemia, cardiac insufficiency, atherosclerosis, restenosis after PTCA or bypass, cerebral ischemia and cerebral infarction, caused by an ischemia, a trauma or a thromboembolic accident, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and Huntington's chorea, acute renal insufficiency, in particular that of ischemic origin or appearing after kidney transplant, heart transplant: treatment of graft rejection and accelerated atherosclerosis of grafts, inflammatory pathologies, immunological disorders, rheumatoid diseases, diabetes and pancreatitis, septic shock, acute respiratory distress syndrome, tumours and metastases, autoimmune diseases, AIDS, hepatitis, psoriasis, vasculitis, ulcerative colitis, multiple sclerosis or myasthenia.  
     
     
         23 . A method according to  claim 20  wherein the disorders are selected from myocardial infarction, cardiac ischemia, cardiac insufficiency, atherosclerosis, restenosis after PTCA or bypass, cerebral ischemia and cerebral infarction, caused by an ischemia, a trauma or a throboembolic accident, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and Huntington's chorea, acute renal insufficiency, in particular that of ischemic origin or appearing after kidney transplant, heart transplant: treatment of graft rejection and accelerated atherosclerosis of grafts, inflammatory pathologies, immunological disorders, rheumatoid diseases, diabetes and pancreatitis, septic shock, acute respiratory distress syndrome, tumours and metastases, autoimmune diseases, AIDS, hepatitis, psoriasis, vasculitis, ulcerative colitis, multiple sclerosis or myasthenia.  
     
     
         24 . A method for the treatment of disorders in which the enzyme poly(ADP-ribose) polymerase is involved which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula  
       
         
           
           
               
               
           
         
       
       in which R4 is 4-imidazolyl or 5-methyl-4imidazolyl.