Synthesis of hexahydro-1H-pyrido{[}3,2-c]azepines as hypotensive agents of expected calcium-channel blocking activity

Michael addition reaction of 3-(4-fluorophenylamino)-2-cyclohexenone and its 5,5-dimethyl derivative to the acrylonitrile derivatives afforded the novel hexahydroquinolines. The target hexahydro-1H-pyrido{[}3,2-c]azepine derivatives were obtained via ring enlargement of the corresponding hexahydroquinolines under Schmedt conditions. Some novel pyrido{[}3,2-c]azepines showed hypotensive activity in vivo on normotensive anaesthetized male adult albino rats and their effects on the ventricular contraction and auricular rate of isolated rabbit hearts using Langendorff's method and nefidipine as a reference drug were studied. Compounds 29 and 36 which bear some structural similarities to nefidipine exhibited the highest hypotensive activity and negative inotropic as well as chronotropic activities.