Patent GB-874588-A (GB)
Title: New benzimidazoles
IPC: C07D235/12
Filed: 1958-10-14
Abstract: The invention comprises compounds of the general formula <FORM:0874588/IV (b)/1> (wherein A represents a C1-5 alkylene radical, R represents a di-(lower alkyl)-amino group or an alkyleneimino group which may be interrupted by a hetero atom, X represents an oxygen or sulphur atom, and R1 and R2 represent lower alkyl groups or one of them may also represent a hydrogen atom, the term "lower alkyl" in all cases denoting a C1-5 alkyl group) and their acid addition salts, and pharmaceutical preparations containing them (see Group VI).  The compounds may be prepared by introducing the group R-A- directly or in stages into the 1-position of a 2-(p-alkoxy- or p-alkylmercapto-benzyl)-5- and/or -6-lower-alkyl-benzimidazole, or by a ring closure of a 2-(R11-NH)-4- and/or -5-lower-alkyl-aniline (wherein R11 represents R-A- or a substituent replaceable and subsequently replaced thereby) by reaction with a p-alkoxy- or p-alkylmercapto-phenylacetic acid or a reactive functional derivative thereof, or with a p-alkoxy- or p-alkylmercapto-phenylacetaldehyde or a functional derivative thereof with subsequent oxidisation, or by reducing a hydroxyalkyl group in the 5- and/or 6-position of a benzimidazole containing the desired substituents in the 1- and 2-positions, or by alkylating a free hydroxy or mercapto group in the p-position of the benzyl group of a 1-(tertiary aminoalkyl)-2-benzyl-5- and/or -6-lower-alkyl-benzimidazole.  Free bases so obtained may be converted into acid addition salts and vice versa.  2-(b -Diethylaminoethylamino)-4- and -5-methylaniline are prepared by condensing 3-chloro-4-nitrotoluene and 3-nitro-4-chlorotoluene respectively with b -diethylaminoethylamine and then reducing the nitro group with hydrogen in the presence of Raney nickel, in alcohol.  p-Methylmercaptobenzyl cyanide is prepared by reacting p-methylmercaptobenzyl chloride with potassium cyamide in boiling acetone in the presence of potassium iodide. 2-(p-Ethoxybenzyl)-5(6)-methyl- and- 5,6-dimethyl-benzimidazole are prepared by refluxing the imino-ether hydrochloride of p-ethoxyphenylacetic acid with 3,4-diaminotoluene and 2-amino-4,5-dimethylaniline respectively in chloroform. 1-(b -Diethylaminoethyl)-2-(p-hydroxybenzyl) -5- methylbenzimidazole is similarly prepared from the iminoether hydrochloride of p-hydroxyphenylacetic acid and 2-(b -diethylaminoethylamino)-5-methylaniline.  1 -(b - Diethylaminoethyl) -2- (p-methoxybenzyl)-5-hydroxymethylbenzimidazole is prepared by condensing 3-nitro-4-chlorobenzoic acid ethyl ester with b -diethylaminoethylamine to form 3-nitro-4-(b -diethylaminoethylamino)-benzoic acid ethyl ester, isolating the hydrochloride thereof and reducing the nitro group therein with hydrogen in the presence of palladium/charcoal, in ethanol, condensing the resulting amino-ester with the iminoether hydrochloride of p-methoxyphenylacetic acid to form 1-(b -diethylaminoethyl)-2-(p-methoxybenzyl) -5- carbethoxybenzimidazole, and finally reducing the carbethoxy group with LiAlH4 in ether.ALSO:Pharmaceutical preparations, useful as analgesics and muscle relaxants, comprise, in admixture with a pharmaceutical carrier suitable for enteral, parenteral or topical administration, a compound of the general formula <FORM:0874588/VI/1> (wherein A represents a C1-5 alkylene radical, R represents a di-(lower alkyl)-amino group or an alkyleneimino group which may be interrupted by a hetero atom, X represents an oxygen or sulphur atom, and R1 and R2 represent lower alkyl groups or one of them may also represent a hydrogen atom, the term "lower alkyl" in all cases denoting a C1-5 alkyl group, or an acid addition salt thereof (e.g. a hydrohalide, sulphate, nitrate, phosphate, thiocyanate, acetate, propionate, oxalate, malonate, succinate, malate, or methane-, ethane-, hydroxyethane-, benzene- or toluene-sulphonate, or a salt with a therapeutically active acid).  They may take the form of tablets, dragees, salves, creams, solutions, suspensions or emulsions, and may be sterilized and/or may contain preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure, buffers, or other therapeutically valuable substances.