Patent GB-862175-A (GB)
Title: New benzimidazoles
IPC: C07D235/14
Filed: 1957-09-27
Abstract: The invention comprises benzimidazoles of the general formula <FORM:0862175/IV (b)/1> (wherein A represents a lower alkylene residue, R represents a tertiary amino group which is either a saturated heterocyclic nitrogen-containing ring attached to A through the nitrogen atom or, preferably, a di-lower alkyl-amino group, and R1 represents a phenyl radical which is unsubstituted or substituted by halogen atoms or lower alkyl, lower alkoxy, lower alkanoyloxy, amino or nitro groups, the term "lower" indicating groups having at most 6 carbon atoms) and salts thereof.  These compounds, which are useful as analgesic agents (see Group VI), may be prepared by the following methods: (a) reacting a 5-nitro-2-benzyl-benzimidazole with a reactive ester of an alcohol of the formula HO-A-R1 (wherein R1 represents R or a residue convertible thereto or replaceable thereby and subsequently so converted or replaced); (b) cyclizing a 2-(R11-NH)-5-nitroaniline or a correspondingly N-substituted derivative thereof (wherein R11 represents R-A- or a residue convertible thereto and subsequently so converted).  Substituents in R1 may thereafter be interconverted, e.g. a hydroxy group may be etherified or esterified, whilst a lower alkoxy or nitro group may be replaced by or converted into an amino group and the latter replaced by a lower alkoxy group or a halogen atom.  In Examples: ( (1) 2-(b -diethylamino-ethylamino) - 5 - nitro - aniline is reacted with an imino-ether hydrochloride solution prepared from benzyl cyanide, ethanol and hydrochloric acid to give 1-(b -diethylamino-ethyl) - 2 - benzyl - 5 - nitro - benzimidazole; (2) the product of (1) is prepared from b -diethylaminoethylamine and 2-chloro-5-nitrophenylacetyl-aniline, itself prepared from 2-chloro-5-nitraniline and phenyl-acetyl chloride; (3) to (5) the p-chlorobenzyl, m-methoxybenzyl and 3 : 4-dimethoxy-benzyl analogues of the product of (1) are prepared by the method of (1); (6) 2-amino-4-nitro-aniline is reacted with the iminoether of (1) to give 2-benzyl-5-nitro-benzimidazole hydrochloride and thence the free base, and the sodium salt of this is reacted with b -diethylamino-ethyl chloride to give a mixture of 1-(b -diethylamino-ethyl)-2-benzyl-5-and -6-nitro-benzimidazoles, separated by crystallization and salt formation; (7) 2-(p-chlorobenzyl)-5-nitro-benzimidazole is similarly prepared and is similarly converted to a mixture of 1 - (b  - diethylamino - ethyl) - 2 - (p - chlorobenzyl)-5- and -6-nitro-benzimidazoles, which are similarly separated; (8) to (11) and (17) products wherein R1 is variously p-methoxy-, p-butoxy-, p-propoxy-, p-iso-propoxy-, p-methyl-, p-ethoxy-, p-tert-butyl-, p-fluoro-, p-hydroxy-, o-chloro-, 2 : 4-dichloro-, o-methyl-, 2 : 5-dimethyl- and p-nitro-benzyl and R-A-is variously b -diethylamino-ethyl, b -piperidino - ethyl, b  - morpholino - ethyl, b  - (41-methyl - piperazino) - ethyl, b  - dimethylaminoethyl and gamma-diethylamino-propyl are prepared by the method of (1); (12) 1-(b -diethylamino - ethyl) - 2 - (p - hydroxy - benzyl) - 5 - nitro-benzimidazole is heated with dimethyl sulphate to give the p-methoxy compound, and the p - (o  - methoxy - nona - ethylene - oxy), p - (o  - methoxy - tri - ethylene - oxy) and p-ethoxy-ethylene-oxy) compounds are similarly prepared; (13) the p-hydroxy compound is acetylated to give the p-acetoxy compound; and (14) 1 - (b  - diethylamino - ethyl) - 2 - (p-nitro - benzyl) - 5 - nitro - benzimidazole is reduced to the p-amino compound. Hydrochlorides and methane sulphonates of some of the products are described and a list of further salt-forming organic and inorganic acids is also provided.  Further starting materials.  2-b -(41-Methyl-piperazino) - ethylamino - 5 - nitro - aniline is prepared by condensing methyl - di - (b  - chloro-ethyl)-amine with ethylene diamine to give 1 - methyl - 4 - (b  - amino - ethyl) - piperazine, condensing this with 2 : 4-dinitro-chlorobenzene to give N - [b  - (4 - methyl - piperazino) - ethyl] 2 : 4-dinitro-aniline and partially reducing this. 2 - (b  - Dimethylamino - ethylamino)-, 2 - (b -piperidino - ethylamino)-, 2 - (b  - morpholino ethylamino)- and 2 - (gamma - diethylamino-propylamino) - 5 - nitro - anilines and the 2 : 4-nitro intermediates therefor are similarly prepared. p-Butoxy-, p-propoxy- and p-isopropoxy-benzyl cyanides are prepared from the p-hydroxy compound and the appropriate alkyl iodides.ALSO:Pharmaceutical preparations contain a benzimidazole of the formula <FORM:0862175/VI/1> (wherein A is a lower alkylene radical, R is a saturated nitrogen containing heterocyclic ring attached to A through the nitrogen atom or a di-(lower alkyl)-amino group and R1 is a phenyl radical which may contain halogen atoms or lower alkyl, lower alkoxy, lower alkanoyloxy, amino or nitro groups, the term "lower" indicating groups having at most 6 carbon atoms) or a salt thereof with an inorganic or organic acids in admixture with an organic or inorganic solid or liquid carrier.  They may take the form of tablets, dragees, salves, creams, solutions, suspensions or emulsions and may contain auxiliary substances, such as preserving, emulsifying or wetting agents, salts for regulating osmotic pressure, buffers, or other therapeutically useful substances.  Examples describe tablets containing 1-(b -diethylaminoethyl) - 2 - (p - chloro - benzyl) - 5 - nitro - benzimidazole methane sulphonate and various fillers, and aqueous injection solutions made up in ampoules containing the same active ingredient.