Dibenzothiazepinones as potential calcium channel antagonists. I.
Certain dibenzo[a,d]cycloheptenes and dibenzo[b,e]thiepins (e.g., 1 and 2) substituted in the 5 and 11-positions, respectively, are potent calcium channel antagonists. It has previously been shown that potency increases with a decrease in the angle between the planes of the flanking aromatic rings, as computed by semi-empirical AM1 calculations with geometry minimization. In the present study, we evaluated a series of dibenzo[b,f]-1,4-thiazepinones (10-14) as potential bioisosteres of these compounds having a slightly more acute angle of flexure. X-Ray diffraction reveals the crystal structure of the parent dibenzo[b,f]-1,4-thiazepinone 4 to have a flexure angle of 108.4 degrees. Due to electron delocalization, the amide moiety in the seven-membered ring adopts a planar conformation. The synthesis of a series of 10-[omega-[4-(4-fluorophenyl)piperazin-1-yl]alkyl]dibenzo[b,f]-1,4 - thiazepin-11(10H)-ones (10-14), and results of their evaluation for calcium channel antagonistic activity on hamster aorta, are presented.
Li
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College of Pharmacy, Dalhousie University, Halifax, Nova Scotia, Canada.
Farmer
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Quillam
M A
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Howlett
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SE
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004110:Diltiazem / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008647:Mesocricetus; D008958:Models, Molecular; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D013841:Thiazepines; D004110:Diltiazem