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.
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.
Kurokawa
M
M
Research Laboratory, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Sato
F
F
Hatano
N
N
Honda
Y
Y
Uno
H
H
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D003988:Dibenzothiepins / Q000138:chemical synthesis* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D003988:Dibenzothiepins