1,5-Benzodiazepines IX. A new route to substituted 4 H-[1,2,4]triazolo[4,3- a][1,5]benzodiazepin-5-amines with analgesic and/or anti-inflammatory activities

Abstract

A new two-step synthetic pathway to substituted 4 H-[1,2,4]triazolo[4,3- a][1,5]benzodiazepin-5-amines 2a–p is described. The cyclocondensation of (dimethylamino)benzodiazepinone 1a with hydrazides afforded triazolobenzodiazepinones 5 which in turn reacted with suitable primary or secondary amines, in the presence of titanium tetrachloride, to give the desired 5-amino-derivatives 2a–p. When compounds 5 were treated with the Lawesson's reagent thiolactams 6 were obtained, which then reacted with sodium hydride and proper alkyl halides to yield 5-(alkylthio)derivatives 7a–d. Compounds 2a–h, j–p, and 7a–d were tested for their analgesic and anti-inflammatory activities, as well as for their acute toxicity and gross behavioral effects. The analgesic activity appeared noteworthy in the writhing test, where fifteen compounds were more effective than both the reference drugs acetylsalicyclic acid and dipyrone, but was less evident in the hot plate test. An anti-inflammatory activity, lower than that of indomethacin but reaching the level of statistical significance, was displayed in the carrageenin-induced edema assay by five of the nineteen test compounds.