A new class of calcium antagonists. Synthesis and biological activity of 11-[(.omega.-aminoalkanoyl)amino]-6,6a,7,8,9,10,10a,11-octahydrodibenzo[b,e]thiepin derivatives

• Published in: Journal of medicinal chemistry Vol. 34; no. 2; pp. 593 - 599
• Main Authors: Kurokawa, Mikio, Sato, Fuminori, Hatano, Naonobu, Honda, Yayoi, Uno, Hitoshi
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.02.1991
• Subjects: Animals; Blood Pressure - drug effects; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - pharmacology; Chemical Phenomena; Chemistry; Dibenzothiepins - chemical synthesis; Dibenzothiepins - pharmacology; Heart Rate - drug effects; Male; Rats; Rats, Inbred Strains; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00106a019

A series of 11-[(omega-aminoalkanoyl)amino]-6,6a,7,8,9,10,10a,11- octahydrodibenzo[b,e]thiepin derivatives were prepared and found to be a structurally new class of calcium antagonists. The structure-activity relationship studies indicated that the optimum was (6aR*,10aR*,11R*)-11-[[4-[4-(4-fluorophenyl)-1- piperazinyl]butyryl] amino]-6,6a,7,8,9,10,10a,11-octahydrodibenzo[b,e]thiepin (31,pA2 8.16), which was superior to diltiazem (pA2 7.42) in calcium antagonistic activity. Compound 31 showed antihypertensive activity in anesthetized rats, without a significant effect on the heart rate. It had also antianginal effects in vasopressin-induced ST-depression and methacholine-induced ST-elevation testings in rats. These potencies of 31 were essentially equal to those of diltiazem.