Synthesis and pharmacological evaluation of pyrroloazepine derivatives as potent antihypertensive agents with antiplatelet aggregation activity

A series of 1-aminoalkyl-pyrrolo[2,3-c]azepin-8-one derivatives was synthes ized and evaluated as alpha(1) adrenergic and serotonin 2 (5-HT2) receptor antagonists, with the aim of finding a novel antihypertensive agent potentl y exhibiting both activities. Some compounds with a 4-[4-(4-fluorobenzoyl)p iperidino]butyl group at the 1-position exhibited both activities, and vari ed significantly in terms of the substituents at the 4-position of the pyrr oloazepine ring. Among the compounds obtained in this study, (E)-1-[4-[4-(4 -fluorobenzoyl)piperidino]-butyl]-4-hydroxyimino-7-methyl-1,4,5,6,7,8-hexah ydropyrrolo[2,3-c]azepin-8-one (15a, SUN9221) displayed potent alpha(1)-adr energic antagonistic activity (pA(2) = 8.89 +/- 0.21) and 5-HT2 antagonisti c activity (pA(2) = 8.74 +/- 0.22) in isolated guinea pig arteries. This co mpound exhibited antihypertensive activity and a duration of action equival ent to orally administered prazosin or doxazosin, 3 mg/kg, in conscious spo ntaneously hypertensive rats, as well as potent antiplatelet aggregation ac tivity.