Benzazepinone calcium channel blockers. 3. Synthesis and structure-activity studies of 3-alkylbenzazepinones.
As part of a program aimed at identifying novel analogues of diltiazem, we developed several synthetic routes for 3-alkylbenzazepinones, both in racemic and nonracemic form. Structure-activity relationship studies in this series have led to identification of several analogues as potent calcium channel blocking agents, both in vitro and in vivo. Analogues containing a 6-trifluoromethyl substituent (17a and 17b) are the most potent vasorelaxants in vitro. The oral antihypertensive activity of these compounds is comparable to its 3-acetoxy derivative 1 (X = 6-CF3) and 8-chlorodiltiazem (2b). The 3-allyl analogue 17c is a more potent antihypertensive agent than 17a, 17b, or 8-chlorodiltiazem (2b), and has a longer duration of action in vivo.
Das
J
J
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Floyd
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Kimball
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Duff
K J
KJ
Vu
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Lago
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Moquin
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Lee
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Gougoutas
J Z
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Malley
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D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001552:Benzazepines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D009132:Muscles / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects; D014961:X-Ray Diffraction
D000959:Antihypertensive Agents; D001552:Benzazepines; D002121:Calcium Channel Blockers