Patent EA-000999-B1 (EA)
Title: Benzimidazole compounds
Inventor: GRIFFIN ROGER JOHN
IPC: C07D235/06
Filed: 1996-07-30
Abstract: 1. Use of a benzimidazole compound, having general structural formula I   or a pharmaceutically acceptable salt and/or pro-drug form thereof as active agent for the manufacture of a medical or veterinary preparation for use in therapy for inhibiting activity of the enzyme poly(ADP-ribose)polymerase or PARP (also known as ADP-ribosyl transferase or DPRT) , moreover such enzyme inhibition constituting an element of a therapeutic treatment, characterised in that said benzimidazole compound provides the active PARP enzyme inhibiting agent and in general structural formula I R is selected from hydrogen, alkyl, hydroxyalkyl (e.g. CH2CH2OH), acyl (e.g. acetyl or benzoyl) or an optionally substituted aryl (e.g. phenyl) or aralkyl (e.g. benzyl or carboxybenzyl) group, and  R' is selected from hydrogen, alkyl, hydroxyalkyl (e.g. CH2CH2OH), acyl (e.g. acetyl or benzoyl) or an optionally substituted aryl (e.g. phenyl) or aralkyl (e.g. benzyl or carboxybenzyl) group. 2. Use of a benzimidazole compound as claimed in claim 1 wherein each presenting alkyl group, either as such or as a moiety in an alkoxy or other group, contains 1-6 carbon atoms. 3. Use of a benzimidazole compound as claimed in claim 1, determined in claims 1 or 2, wherein R represents an optionally substituted phenyl group having the structural formula II   wherein R1, R2 and R9 are each selected independently from H, hydroxy, alkoxy, NO2, N3, NR5R6 (R5 and R6 each being independently hydrogen, alkyl or alkoxy), NHCOR3 (R3 being alkyl or aryl), CO2R4 (R4 being H or alkyl), an amide (e.g. CONH2), tetrazole, alkyl, hydroxyalkyl, CW3 or W (W being halogen), and CN. 4. Use of a benzimidazole compound as claimed in claim 1, determined in claim 3, wherein R1 is a group other than hydrogen and is in the 4'-position, and wherein R2 and R9 are each hydrogen. 5. Use of a benzimidazole compound as claimed in claim 1, determined in any of the preceding claims, wherein R' represents an optionally substituted phenyl group having the structural formula III   wherein R7, R8 and R10 are each selected independently from H, hydroxy, alkoxy, NO2, N3, NR5R6 (R5 and R6 each being independently hydrogen, alkyl or alkoxy), NHCOR3 (R3 being alkyl or aryl), CO2R4 (R4 being H or alkyl), an amide (e.g. CONH2), tetrazole, alkyl, hydroxyalkyl, CW3 or W (W being halogen), and CN. 6. Use of a benzimidazole compound as claimed in claim 1, determined in claim 5, wherein R7 is a group other than hydrogen and is in the 4'-position, and wherein R8 and R10 are each hydrogen. 7. Use of a benzimidazole compound as claimed in claim 1, determined in it, wherein R is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl and cyclohexyl.8. Use of a benzimidazole compound as claimed in claim 1, determined on it,  wherein R' is hydrogen or alkyl and R is phenyl or benzyl, having at least one substituent in the benzene ring, which is selected from hydroxy, alkoxy, NO2, N3, NR5R6 (R5 and R6 each being independently hydrogen, alkyl or alkoxy), NHCOR3 (R3 being alkyl or aryl), CO2R4 (R4 being H or alkyl), an amide (e.g. CONH2), tetrazole, alkyl, hydroxyalkyl, CW3 or W (W being halogen), and CN. 9. Use of a benzimidazole compound as claimed in claim 1, which is one of the following: (a) 2-methylbenzimidazole-4-carboxamide; (b) benzimidazole-4-carboxamide; (c) 2-phenylbenzimidazole-4-carboxamide; (d) 2-(4'-methoxyphenyl)benzimidazole-4-carboxamide; (e) 2-(4'-trifluoromethylphenyl)benzimidazole-4-carboxamide; (f) 2-(4'-hydroxyphenyl)benzimidazole-4-carboxamide; (g) 2-trifluoromethylbenzimidazole-4-carboxamide; (h) 2-(4'-methoxyphenyl)-N-methylbenzimidazole-4-carboxamide; (i) 2-(4'-nitrophenyl)benzimidazole-4-carboxamide; (j) 2-(4'-cyanophenyl)benzimidazole-4-carboxamide; (k) 2-(3'-trifluoromethylphenyl)benzimidazole-4-carboxamide; (1) 2-(3'-methoxyphenyl)benzimidazole-4-carboxamide; (m) 2-(4'-methoxyphenyl)-1-N-benzoylbenzimidazole-4-carboxamide; (n) 2-(4'-aminophenyl)benzimidazole-4-carboxamide; (o) 2-(2'-trifluoromethylphenyl)benzimidazole-4-carboxamide; (p) N-carboxybenzyl-2-(4'-methoxyphenyl)-benzimidazole-4-carboxamide. 10. Use of a benzimidazole compound as claimed in claim 1, determined in any of the preceding claims, wherein said compound is in the form of a pro-drug having a substituent group selected from phosphate, carbamate and amino acid. 11. Use of a benzimidazole compound as claimed in claim 1, which is a phosphate derivative of a compound, having the general structural formula I, and which is the pro-drug form of a benzimidazole compound, determined in any of claims 1-9. 12. Use of a benzimidazole compound as claimed in claim 1, said compound being pro-drug in the form of phosphate derivative, which is a water-soluble ammonium or alkali metal phosphate salt derived from a benzimidazole compound of structure, determined in any of claims 1-9, wherein at least one substituent is a hydroxyl group. 13. Use of a benzimidazole compound as claimed in claim 12, wherein the compound from which the pro-drug in the form of phosphate derivative has a hydroxyl group substituent, which is reacted with a dibenzylphosphonate. 14. The benzimidazole compound having the general structural formula I    or a pharmaceutically acceptable salt and/or pro-drug form thereof, wherein R is selected from hydrogen, alkyl, hydroxyalkyl and an optionally substituted aryl or aralkyl group, with proviso that R is not 4'-methanesulphonyloxy-2'-methoxyphenyl, or 4'-methanesulphonylamino-2'-methoxyphenyl and do not represent phenyl group, having a substituent, which is alkylsulphenyl, alkylsulphinyl, alkanesulphonyl or alkylsulphoxymino group, substituted on nitrogen atom by alkanoyl, alkylsulphonyl or hydroxycarbonylalkylenecarbonyl group, ethoxy or n-propoxy group, each of them is substituted in terminal position with alkylsulphenyl, alkylsulphynyl, alkanesulphonyl or alkylsulphoxymino group, alkoxy-carbonylamino or N-alkylaminocarbonylamino group; and R' is selected from hydrogen, alkyl, hydroxyalkyl, acyl or optionally substituted aryl group, with proviso that R' does not comprise biphenyl or substituted biphenyl group; as an active pharmaceutical agent. 15. A benzimidazole compound having the general structural formula I   or a pharmaceutically acceptable salt thereof, wherein R is selected from hydrogen, hydroxyalkyl and substituted aryl group with the provoso that R is not 4'-methanesulphonyloxy-2'-methoxyphenyl, or 4'-methanesulphonylamino-2'-methoxyphenyl and do not represent phenyl group, having a substituent, which is alkylsulphenyl, alkylsulphinyl, alkanesulphonyl or alkylsulphoxymino group, substituted on nitrogen atom by alkanoyl, alkylsulphonyl or hydroxycarbonylalkylenecarbonyl group, ethoxy or n-propoxy group, each of them is substituted in terminal position with alkylsulphenyl, alkylsulphynyl, alkanesulphonyl or alkylsulphoxymino group, alkoxy-carbonylamino or N-alkylaminocarbonylamino group; and R' is selected from hydrogen, alkyl, hydroxyalkyl, acyl or optionally substituted aryl group, with proviso that R' does not comprise biphenyl or substituted biphenyl group. 16. A compound as claimed in claim 10 or 11 wherein the or each alkyl group present, either as such or as a moiety in an alkoxy or other group, contains 1-6 carbon atoms. 17. A compound as claimed in claim 14, 15 or 16 wherein R represents an optionally substituted phenyl group having the structural formula II   wherein R1, R2 and R9 are each selected independently from H, hydroxy, alkoxy, NO2, N3, NR5R6 (R5 and R6 each being independently hydrogen, alkyl or alkoxy), NHCOR3 (R3 being alkyl or aryl), CO2R4 (R4 being H or alkyl), an amide (e.g. CONH2), tetrazole, alkyl, hydroxyalkyl, CW3 or W (W being halogen), and CN. 18. A compound as claimed in claim 17 wherein R1 is a group other than hydrogen and is in the 4'-position, and wherein R2 and R9 are each hydrogen. 19. A compound as claimed in any of claims 14 to 18 wherein R' represents an optionally substituted phenyl group having the structural formula III   wherein R7, R8 and R10 are each selected independently from H, hydroxy, alkoxy, NO2, N3, NR5R6 (R5 and R6 each being independently hydrogen, alkyl or alkoxy), NHCOR3 (R3 being alkyl or aryl), CO2R4 (R4 being H or alkyl), an amide (e.g. CONH2), tetrazole, alkyl, hydroxyalkyl, CW3 or W (W being halogen), and CN. 20. A compound as claimed in claim 19 wherein R7 is a group other than hydrogen and is in the 4'-position, and wherein R8 and R10 are each hydrogen. 21. A compound as claimed in claim 14 or 15 wherein R is selected from methyl, ethyl, n-propyl, i-propyl, nbutyl, t-butyl and cyclohexyl. 22. A compound as claimed in claim 14 or 15 wherein R' is hydrogen and R is either a phenyl or a benzyl group having at least one substituent in the benzene ring which is selected from hydroxy, alkoxy, NO2, N3, NR5R6 (R5 and R6 each being independently hydrogen, alkyl or alkoxy), NHCOR3 (R3 being alkyl or aryl),' CO2R4 (R4 being H or alkyl), an amide (e.g. CONH2), tetrazole, alkyl, hydroxyalkyl, CW3 or W (W being halogen), and CN. 23. A compound as claimed in claim 14 or 15 which is one of the following: (a) benzimidazole-4-carboxamide; (b) 2-(4'-methoxyphenyl)benzimidazole-4-carboxamide; (c 2-(4'-trifluoromethylphenyl)benzimidazole-4-carboxamide; (d) 2-(4' -hydroxyphenyl) benzimidazole-4-carboxamide; (e) 2-(4'-methoxyphenyl)-N-methylbenzimidazole-4-carboxamide; (f) 2-(4'-nitrophenyl)benzimidazole-4-carboxamide; (g) 2-(4'-cyanophenyl) benzimidazole-4-carboxamide; (h) 2-(3'-trifluoromethylphenyl)benzimidazole-4-carboxamide; (i) 2-(3'-methoxyphenyl) benzimidazole-4-carboxamide; (j) 2- (4'-methoxyphenyl)-1-N-benzoylbenzimidazole-4-carboxamide, (k) 2-(4'-aminophenyl)benzimidazole-4-carboxamide; (l) 2-(2'-trifluoromethylphenyl)benzimidazole-4- carboxamide, or (m) N-carboxybenzyl-2-(4'-methoxyphenyl)-benzimidazole-4-carboxamide. 24. A compound as claimed in any of claims 14 to 23 wherein the compound is suitable for oral or intravenous therapeutic ad