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.