Patent GB-868864-A (GB)
Title: New benzimidazoles
Filed: 1958-09-15
Abstract: The invention comprises benzimidazoles of the formula: <FORM:0868864/IV (b)/1> (wherein A is alkylene of 1 to 5 carbon atoms, R is dialkyl-amino each alkyl group of which contains 1 to 5 carbon atoms, R1 is halogen and R2 is hydrogen or halogen) and acid-addition salts thereof.  They may be prepared by (1) introducing a dialkyl-amino-alkyl radical directly or in stages into the 1-position of a 2 2-(p-alkyl-benzyl)-5-halogeno-or - 5:6-dihalogenobenezimidazole, for example by reaction of the benzimidazole or a metal salt thereof with a reactive ester, such as a hydrohalide or an organic sulphonate, of an alcohol HO-A-R1 (wherein R1 is the dialkyl-amino group or a group convertible thereo) and, where necessary, converting R1 into the dialkyl-amino group e.g. in the case of a hydroxyl group, by chlorination followed by reaction with a dialkylamine; (2) subjecting to ring closure, for example by condensing, directly or in stages, with a p-alkyl-phenyl-acetic acid or a reactive functional derivative thereof such as an ester or an imino ether or with a p-alkyl-phenyl-acetaldehyde or a functional derivative thereof and oxidising the product, a 2-(R11-NH)-5-halogeno- or 4:5-dihalogeno-aniline (wherein R11 is the group A-A- or a substituent, convertible thereto, such as a hydroxy-alkyl group) or an appropriate N-substitution product thereof, and, where necessary, converting R11 into the group R-A- e.g. in the case of a hydroxyalkyl group, by chlorination followed by reaction with a dialkylamine; (3) introducing halogen into the 5- or 5- and 6-position of a 1-(dialkylamino-alkyl)- 2-(p-alkyl benzyl)-benzimidazole, for example by exchanging an amino group for a halogen atom; or (4) introducing an alkyl group into the p-position of the benzyl radical of a 1-(dialkylamino-alkyl)-2-benzyl-5-halogen- or 5:6-dihalogeno-benzimidazole, for example by reducing an acetyl group.  Examples are given, and a list of saltforming organic and inorganic acids is provided. 1-(Beta-diethylamino-ethyl)-2-(p-methyl-benzyl) -5-amino-benzimidazole is prepared by reduction of the 5-nitro compound.  2-(p-Methyl-benzyl)-5-chloro-benzimidazole is prepared from the imino-ether hydrochloride of p-methyl-phenylacetic acid and 2-amino-5-chloro-aniline 1-(Betadiethylamino-ethyl)-2-[p-(alpha-hydroxy-ethyl-benzyl) ]-5-chloro-benzimidazole is prepared by reacting 2-(beta-diethylamino-ethylamino)-5-chloro -aniline with the iminoether hydrochloride of p-acetyl-phenylacetic acid to give 1-(beta-diethylamino-ethyl)-2-(p-acetyl-benzyl) -5-chloro-benzimidazole hydrochloride and then reducing this.ALSO:A pharmaceutical preparation contains a benzimidazole of the formula <FORM:0868864/VI/1> (wherein A is alkylene of 1 to 5 carbon atoms, R is dialkylamino, each alkyl group of which contains 1 to 5 carbon atoms, R1 is halogen and R2 is hydrogen or halogen) or an acid-addition salt thereof, in admixture with a pharmaceutical carrier suitable for enteral, topical or parenteral administration. The carrier may be solid or liquid and the compositions may take the form of tablets, dragees, salves, creams, solutions, suspensions or emulsions and may contain preserving, stabilizing, wetting or emulsifying agents, salts for regulating osmotic pressure, buffers and other therapeutically-valuable substances.  A list of salt-forming organic and inorganic acids is provided.