A new class of calcium antagonists. 2. Synthesis and biological activity of 11-[[4-[4-(4-fluorophenyl)-1-piperazinyl]butyryl]amino]-6,11- dihydrodibenzo[b,e]-thiepin maleate and related compounds.
A series of [(epsilon-aminoalkanoyl)amino]-6,11- dihydrodibenzo[b,e]thiepins and -5H-dibenzo[a,d]cycloheptenes and related compounds were synthesized and evaluated for calcium antagonistic activity by calcium-induced constriction of potassium-depolarized rat aorta. Semiempirical molecular orbital calculations of the dibenzotricyclic systems indicated that calcium antagonistic activity increased with a decrease of the angle between the planes of the two phenyl rings. AM1 net charge calculations showed that a neutral or positive charge distribution in the bridge portion was necessary for activity. 11-[[4-[4-(4-Fluorophenyl)-1- piperazinyl]butyryl]amino]-6,11-dihydrodibenzo[b,e]thiepin maleate (16, AJ-2615) showed a more gradual and longer lasting antihypertensive effect than diltiazem and nifedipine in spontaneously hypertensive rats (SHR) administered orally. Compound 16 also possessed antianginal effects in methacholine-induced ST elevation and vasopressin-induced ST depression tests in rats. The alteration of the dibenzotricyclic system of 16 to 5H-dibenzo[a,d]cycloheptene (19, 5-[[4-[4-(4-fluorophenyl)-1-piperazinyl]-butyryl]amino]-5H- dibenzo[a,d]cycloheptene) resulted in selectivity for cardiac tissue over vascular tissue, thereby conferring antianginal activity without an effect on blood pressure. Antianginal potencies of 16 and 19 were equal to or somewhat more potent than those of diltiazem.
Kurokawa
M
M
Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Sato
F
F
Fujiwara
I
I
Hatano
N
N
Honda
Y
Y
Yoshida
T
T
Naruto
S
S
Mastumoto
J
J
Uno
H
H
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D003988:Dibenzothiepins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D011188:Potassium; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D014661:Vasoconstriction / Q000187:drug effects
D002121:Calcium Channel Blockers; D003988:Dibenzothiepins; D010879:Piperazines; D016210:Methacholine Chloride; C067818:monatepil; D011188:Potassium; D002118:Calcium