Patent GB-1317379-A (GB)
Title: Benzimidazoles their preparation and pharmaceutical compositions containing them
IPC: C07H19/052
Filed: 1971-04-19
Abstract: 1317379 Benzimidazole derivatives MERCK & CO Inc 19 April 1971 [5 March 1970] 22744/71 Headings C2C and C2P The invention comprises novel benzimidazole derivatives of the formula wherein X is O or S, R 1  is a 5-membered monocyclic heteroaromatic ring containing 1, 2 or 3 hetero atoms selected from O, S and N; R 2  is C 2-8  alkanyloxy, amino-(C 2-6  alkoxy) or an N- alkyl, N,N-dialkyl or trialkyl-ammonium halide derivative thereof, phosphonoalkoxy or an alkyl ester thereof, phosphatoalkoxy or an alkyl ester thereof, alkylthioalkoxy, or a sulphoxide or sulphone thereof, sulphoalkoxy, amidinoalkoxy, or an N 1  and/or N 2  alkyl derivative thereof, (1-iminoalkyl) aminoalkoxy, or an N- alkyl derivative thereof, (1-biguanidino) alkoxy, diaminomethyleneaminoalkoxy or guanidinoalkoxy or an N 1 , N 2  and/or N 3  alkyl derivative thereof, aminoguanidinoalkoxy, or N-aminodiaminomethyleneaminoalkoxy or an N<SP>1</SP>, N 1 , N 2  and/or N 3  derivative thereof, (2-imidazolin-2- yl)aminoalkoxy or a 1-alkyl derivative thereof, 1,4,5,6 - tetrahydropyrimidin - 2 - ylaminoalkoxy or a 1-alkyl derivative thereof, (2-thiazolin - 2 - yl)aminoalkoxy, (2 - thiazin - 2 - yl)- aminoalkoxy, imidazolinylalkoxy or a 1-alkyl derivative thereof, 1,4,5,6-tetrahydropyrimidinyl alkoxy or a 1-alkyl derivative thereof, α-aminocarboxyalkoxy, glycosyloxy, p-alkylphenacyloxy or p-alkoxyphenacyloxy, the alkyl and the alkoxy radicals in the foregoing values of R 2  containing not more than 8 C atoms; R 3  is H, C 1-8  alkyl; and R 4  is H, haloaralkyl, cycloalkyl, C 1-8  alkylamino, di-(C 1-8  alkyl) amino, cycloalkylamino, alkyleneimino or heterointerrupted alkyleneimino, or a radical of the formula R-, RO- or RS- in which R is C 1-8  univalent aliphatic hydrocarbon, C 1-8  univalent aliphatic halohydrocarbon, aryl, heterocyclic, haloaryl, alkaryl or aminoaryl radical and non- toxic alkali, metal alkaline earth metal, magnesium, ammonium and pharmaceutically amine salts and heavy metal complexes thereof when R 2  is sulphoalkoxy, phosphoalkoxy, phosphatoalkoxy; or α-aminocarboxyalkoxy; and salts thereof with pharmaceutically acceptable acids when R 2  is aminoalkoxy, amidinoalkoxy, (1- iminalkyl)aminoalkexy, (1-biguanido)alkoxy, guanidinoalkoxy, aminoguanidinoalkoxy, diaminomethyleneaminoalkoxy, N - aminodiaminomethyleneaminoalkoxy, (2-imidazolin-2- yl)aminoalkoxy, tetrahydropyrimidinylaminoalkoxy, thiazolinylaminoalkoxy, thiazinylaminoalkoxy, imidazolinylalkoxy, tetrahydropyrimidinylalkoxy or α-aminocarboxyalkoxy, and the preparation thereof. Compounds of the above formula in which R 2  is alkenyloxy, phosphonoalkoxy, or an alky ester thereof, alkylthioalkoxy, sulphoalkoxy, guanidinoalkoxy, imidazolinylalkoxy, or 1-alkyl derivatives thereof, 1,4,5,6 - tetrahydropyrimidinylalkoxy or 1-alkyl derivative thereof, α-aminocarboxyalkoxy, glycosyloxy, p-alkylphenacyloxy or palkoxyphenacyloxy are prepared by reacting the appropriate 2-(R 1 )-5-(N-R 3 -CX-R 4 )-1- hydroxybenzimidazoles with the appropriate halides. Compounds of the above formula in which R 2  is amino-(C 2-6  alkoxy) are obtained by reacting the appropriately substituted 1- (phthalimido - (C 2-6  alkyl) benzimidazoles with hydrazine hydrate. Compounds of the above formula in which R 2  is 2-imidazolinylamino- (C 1-8  alkoxy), or 1-alkyl-derivatives thereof, 1,4,5,6 - tetrahydropyrimidinyl - (C 1-8  alkoxy) of 1-alkyl derivatives thereof, thiazolinyl-(C 1-8  alkoxy), thiazinyl - (C 1-8  alkoxy) or guanidino- (C 1-8  alkoxy) are made by reacting the appropriately substituted 1-(amino-C 1-8  alkoxy) benzimidazoles with compounds of the formula CH 3 -S-R 7  in which R 7  is 2-imidazolinyl; 1-alkyl- 2 - imidazolinyl, 2 - (1,4,5,6 - tetrahydropyrimidinyl), 1 - alkyl - 2 - (1,4,5,6 - tetrahydropyrimidinyl), 2-thiazolinyl, 2-thiazinyl or amidino. Compounds of the above formula in which R 2  is (1-biguanidino)-(C 1-8  alkoxy) or aminoguanidino-(C 1-8  alkoxy) are prepared by reacting the appropriately substituted 1-(amino- C 1-8  alkoxy)-benzimidazoles with dicyandiamide and nitroguanidine and reducing the resulting 1 - nitroguanidino - C 1-8  alkoxy respectively. Compounds of the formula  wherein R 6  is C 1-8  alkylene and R 12  and R 13  each are H or C 1-8  alkyl are obtained by reacting the appropriately substituted 1-(amino (or alkylamino) - C 1-8  alkoxy) benzimidazole with compounds of the formula R 13 .C(=NH).OR 14 .HCl, in which R 14  is C 1-8  alkyl. Compounds of the invention in which R 2  is amidino-C 1-8  alkoxy or N-alkyl or N,N-dialkyl derivatives thereof are made by reacting compounds of the formula with amines of the formula HN(R 15 )R 16 , wherein R 15  and R 16  are H or C 1-8  alkyl. Compounds of the invention in which R 2  is (1-iminoalkyl) aminoalkoxy are obtained by reacting the appropriate 1-aminoalkoxybenzimidazoles with alkyl or the esters in the presence of a catalytic quantity of HCl and reacting the intermediate thus formed with ammonia, or mono- or dialkylamines. Compounds of the invention in which R 2  is diaminomethyleneaminoalkoxy or N - aminodiaminomethyleneaminoalkoxy or the N 1 , N 2  and/or N 3  alkyl derivatives thereof are prepared by reacting the appropriate 1-aminoalkoxybenzimidazoles or N-alkyl derivatives thereof with alkyl isocyanates or dialkylthiocarbamoyl halides, alkylating the resulting 1 - (alkylthiouredioalkoxy) benzimidazoles, and treating the thus obtained S-alkylisothiouronium salts with ammonia, alkylamines, hydrazines or alkylhydrazines. The sulphones and sulphoxides of thz compounds of the invention in which R 2  is alkylthioalkoxy are made by oxidizing the corresponding 1-(alkylthioalkoxy) benzimidazoles. Compounds of the inventions in which R 2  is phosphatoalkoxy are obtained by reacting the corresponding 1-hydroxyalkoxybenzimidazoles with mixtures of phosphoric acid anhydride and orthophosphoric acid, the alkyl ester of such compound being obtained by reacting the 1-hydroxyalkoxybenzimidazoles with mono- or di-alkyl phosphoryl halides. The compounds of the invention in which the substituent at the 5-position is of the formulµ ROCONH- or RSCONH- may be obtained by treating the appropriate 5-aminobenzimidazoles with the corresponding R-haloformates or R-halothioformates. 5 - Amino - 2 - R 1  - benzimidazoles are obtained by reducing 5-nitro-2-R 1 -benzimidazoles, resulting from the nitration of 2-R 1 -benzimidazoles or reacting aldehydes of the formula R 1 CHO and o-amino-p-nitroaniline. The following intermediates or starting materials are also prepared:- 5 - Isopropoxycarbonylamino - 1 - hydroxy-2- (4 - thiazolyl) benzimidazole, 5 - amino - 1 - hydroxy - 2 - (4 - thiazolyl) benzimidazole hydrochloride, 1 - hydroxy - 5 - nitro - 2 - (4 - thiazolyl) benzimidazole 3 - chloro - 4 - nitroaniline, 4- [N - (2 - nitro - 5 - aminophenyl) aminomethyl] thiazole, 4 - [N - (2 - nitro - 5 - isopropoxycarbonylaminophenyl) aminomethyl] thiazole and 1 - (2 - methylaminoethoxy) - 2 - (4 - thiazolyl) benzimidazole. Anthelmintic compositions, suitable for oral or parenteral administration, contain the above novel compounds or salts thereof and suitable carriers or diluents.