Studies on Antihypertensive Agents with Antithrombotic Activity.2.Syntheses and Pharmacological Evaluation of Pyrrolo[2, 3-c]azepine Derivatives

Abstract

As an extension of our previous investigation, a series of 7-aminoalkylpyrrolo[2, 3-c]azepine derivatives was synthesized and evaluated as α₁-adrenergic- and serotonin 2(5-HT₂)-receptor antagonists, with the aim of finding a novel potent antihypertensive agent with both activities. Among the compounds obtained in this study, (E)-1-ethyl-7-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-4-hydroxyimino-1, 4, 5, 6, 7, 8-hexahydropyrrolo[2, 3-c]azepin-8-one (16d) displayed potent α₁-adrenoceptor blocking activity (pA₂=7.83±0.20) and 5-HT₂-receptor blocking activity (pA₂=9.47±0.17) in isolated guinea pig arteries. At 3 mg/kg oral administration, compound 16d exhibited antihypertensive activity more potent than that of doxazosin in deoxycorticosterone acetate (DOCA)-salt hypertensive dogs. Furthermore, this compound reduced the rate of mouse acute pulmonary thromboembolitic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or more, and its effect lasted for at least 6 h at 3 mg/kg.