Molecular geometries of dibenzothiazepinone and dibenzoxazepinone calcium antagonists.

A number of dibenzothiazepinones and dibenzoxazepinones have been designed, synthesized and evaluated as calcium antagonists. Molecular geometries of these dibenzotricyclic calcium antagonists have been studied using X-ray crystallography, molecular modeling and two-dimensional NMR spectroscopy. X-Ray diffraction reveals dibenzothiazepinone 1 and dibenzoxazepinone 2 to have, respectively, flexure angles of 108 degrees and 116.9 degrees between the two benzene rings. The molecular mechanics-optimized geometry of dibenzothiazepinone 1 shows a 7 degrees smaller flexure angle than the X-ray crystallographic result, while that of dibenzoxazepinone 2 has an angle only 2 degrees smaller than the X-ray result. AM1 and ab initio calculations show that the side chains can affect the geometry of the tricyclic nucleus and both 1 and 2 have negative electrostatic potentials around the bridged portion of the tricyclics. Two-dimensional NOESY NMR spectroscopy supports the extended geometry of the 6 carbon spacer as obtained from X-ray crystallography and molecular mechanics calculations. Vasorelaxation properties among these compounds appear to be relatively insensitive to the flexure angle and to chain length. Vasorelaxation is profoundly influenced by the nature of the basic terminal moiety.