Direct high-performance liquid chromatographic resolution of a novel benzothiazine Ca 2+ antagonist and related compounds

Abstract

Enantiomers of 3,4-dihydro-2-{;5-methoxy-2-[3-(N-methyl-N-{;2-[(3,4-methylenedioxy)phenoxy]ethyl};amino)propoxy]phneyl};-4-methyl-3-oxo-2H-1,4- benzothiazine hydorgen fumarate (I), a novel and potent Ca 2+ antagonist, and its synthetic pecursors, phenol (II) and bromide (III), were directly resolved by high-performance liquid chromatography on a chiral column, with a stationary phase of cellulose carbamate-coated silica gel. Further, the resolution of some 2-(substituted-phenyl)benzothiazines (IVa–IVl) was investigated to study the effects of 2-phenyl ring substituents on chial recognition. As an index of the characteristics of substituents, substituent constants for quantitative structure-activity relationship studies were used. The correlations between the resolution efficiency ( R s ) and the substituent constants for these benzothiazines were investigated by regression analysis. As a result, for 2-(4-substituted-phenyl)-benzothiazines, R s showed good correlation with E s , Taft's steric parameter [correlation coefficient ( r) = 0.99]. It was also shown that R s correlated with R, an electronic constant for the resonance effect, for 2-(2-hydroxy-5-substituted-phenyl)benzothiazines ( r=0.92). These findings suggest that the 2-phenyl ring plays an important role in chiral recognition in the resolution of these benzothiazines.