Conformational study of 2-phenylbenzothiazine part of SA2995, a Ca2+ antagonist having a benzothiazine skeleton, and structure-activity relationships

Nuclear magnetic resonance (NMR) studies were carried out for the title compound ((+/-)-3,4-dihydro-2-[5-methoxy-2- [3-[N-methyl-N-[2-(3,4-methylenedioxy)phenoxy]ethyl]amino] propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine) (1a; R = H) and its 2-substituted analogs (1b; R = OCH3, 1c; R = SCH3, 1d; R = CH3, 1e; R = i-C3H7) which had Ca2+ antagonistic activities. Conformational analysis using the model compounds of the 2-phenylbenzothiazine (2-PBT) part of 1 by semiempirical molecular orbital method agreed with the NMR behavior. Two local minimum conformations, having different rotational angles (theta 1) of the 2-phenyl ring, were suggested for biologically active 1a-1d. The molar fractional ratios, including the conformations within a particular theta 1 range that contained each global minimum conformation, were found to correlate well with the activities. In the same theta 1 range, any stable conformation was not indicated for non-active compound 1e. From these results, the active conformation for the 2-PBT part of 1 was suggested to be similar to the global minimum conformation indicated for the most potent 1a.