GB1356763A — Substituted benzimidazole derivatives

USPTO Abstract

1356763 2 - Benzo(heterocyclic)ethyl benzimidazoles and derivatives thereof MERCK & CO Inc 18 April 1972 [21 April 1971] 17917/72 Heading C2C [Also in Division C4] Novel compounds of the Formula I wherein m is 0, 1 or 2, n is 0 or 1, each R is C 1-5 alkyl, alkoxy, haloalkoxy or alkylthio, C 3-6 cycloalkoxy, C 2-6 alkenyl, or halogen or when m is 2 the R groups together form a methylene dioxy group; R 1 is hydrogen or C 1-5 alkyl; each R 2 is hydrogen or hydroxyl; X is carbonyl; A is oxygen, sulphur, nitrogen, imino, methylene or methine; the dotted lines indicate that a double bond is located at one of the two positions available between A and N with a hydrogen atom attached to N if valency considerations require it; with the provisos that when n is 0, A is not hydrogen or imino, and that when n is 0 and A is oxygen or sulphur at least one m is not 0; and acid addition salts thereof are prepared (a) by reacting the compounds and wherein R, R<SP>1</SP>, R 2 and m are as defined above Z is a carboxylic acid group, an aldehyde or Schiff base derivative thereof, or a nitrile, carboxylic ester, carboximidic ester or carboxylic amide group, and Z 1 is a group of the type defined for Z or is a group of the Formula IV wherein R, X, A, m and n and the dotted lines are as defined above and when Z 1 is a group of the type defined for Z reacting the intermediate of the formula wherein A* is oxygen or sulphur, and then closing the ring; and (b) reacting the above compound of Formula IV when Z is cyano with or when Z is other than cyano with to produce Various [2R,3R] - 2,3 - dihydroxy - 3 - (6- substituted - 2 - benzothiazolyl) - propion - [2- amino-4(5)-methoxy]anilides may be prepared by acetylation of the sodium salt of [2R,3R]-2, 3 - dihydroxy - 3 - (6 - substituted - 2 - benzothiazolyl propionic acid to yield the sodium salt of [2R,3R] - 2,3 - diacetoxy - 3 - (6 - substituted- 2-benzothiazolyl propionic acid which on treatment with 4-methoxy-o-phenylene diamine in the presence of acid and a dehydrating agent yields [2R,3R] - 2,3 - diacetoxy - 3 - (6 - substituted - 2 - benzothiazolyl) - propion - [2 - amino- 4(5)-methoxy]-anilide which on treatment with sodium methoxide yields the required compound. The sodium salt of [2R,3R]-2,3-dihydroxy-3- (6 - methoxy - 2 - benzothiazolyl)propionic acid may be prepared by reacting 2-amino-5-methoxythiophenol with L-diacetyl tartaric anhydride to yield [2R,3R]-2,3-diacetoxy-3-(6-methoxy-2-benzothiazolyl) propionic acid which was converted to its ammonium salt and hydrolsyed with sodium methoxide to the required compound. Various substituted 2-(#-cyanoethyl)benzimidazoles may be prepared by reacting the appropriate o-phenylenediamine with methyl-3-cyanopropyl carboximidate hydrochloride. Various ethyl - 3 - benzimidazolyl - (2) - propionimidate dihydrochlorides substituted in the benzimidazole ring may be prepared by reacting the appropriate 2-(#-cyanoethyl)benzimidazole with ethanol and hydrogen chloride in anhydrous conditions. [2R,3R] - 2,3 - Dihydroxy - 3 - [2 - 4(3H)- quinazolinonyl] - propion - [2 - amino - 4(5). methoxy]-anilide and various derivatives substituted in the 7-position of the quinazoline ring may be prepared by reaction of 4-methoxy-ophenylene diamine with the appropriate [2R, 3R] - 2,3 - dihydroxy - 3 - [2 - 4(3H) - quinazolinonyl]propionic acid which in turn is prepared by treatment of a [αR,#R]-diacetyltartar-2-carbamoyl anilide with sodium hydroxide, which anilide is prepared by treatment of an anthranilamide with L-diacetyl tartaric anhydride. Pharmaceutical compositions of the compounds I show antiviral activity when administered orally, parenterally, topically or as an oral or nasal spray with the usual excipients.