Polycyclic N‐heterocyclic compounds. XLI. Synthesis of 4‐substituted 6,7‐dihydro‐5H‐pyrimido[5,4‐d][1]benzazepines, 1,2,5,6‐tetrahydro‐4H‐imidazo[1′,2′:1,6]pyrimido[5,4‐d][1]benzazepines and their related compounds as a series of potential blood platelet aggregation inhibitors

Abstract

AbstractAs a series of polyheterocyclic compounds for exploitation as anti‐platelet agents, tricyclic heterocyclic compounds, 4‐substituted 6,7‐dihydro‐5H‐pyrimido[5,4‐d][1]benzazepines 3–6, 9, 12–14, and 16–26, having nitrogen, oxygen, or sulfur containing functional groups at the 4‐position, were prepared. In addition, tetra‐cyclic heterocyclic compounds, 3‐methyl‐1,2,5,6‐tetrahydro‐4H‐imidazo[1′,2′:1,6]pyrimido[5,4‐d][1]benzaze‐pinium chloride (7), 1,2,5,6‐tetrahydro‐4H‐imidazo[1′,2′:1,6]pyrimido[5,4‐d][1]benzazepines 10a‐e, 2,3,6,7‐tetrahydro‐1H 5H‐pyrimido[1′,2′:1,6]pyrimido[5,4‐d][1]benzazepine (11), and 1,2,5,6‐tetrahydro‐4H‐thiazolo‐[3′,2′:1,6]pyrimido[5,4‐d][1]benzazepinium chloride (15) via ring closure of 4‐(hydroxyalkylamino)‐ 6, 9a‐e, and 3c, and 4‐(2‐hydroxyethylthio)‐6,7‐dihydro‐5H‐pyrimido[5,4‐d][1]benzazepine (14) with phosphoryl chloride or thionyl chloride, respectively, were also prepared. Their inhibitory activities against collagen‐induced aggregation of rabbit blood platelets in vitro were investigated. Among them, compound 5 having a morpholino group at the 4‐position on the tricyclic nucleus, which enhanced the activity more than 14‐fold as compared with aspirin, was found to have the most satisfactory in inhibitory activity.