Synthesis and Ca2+ Antagonistic Activity of 2--5-methoxyphenyl>-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazines

Article abstract of DOI:10.1021/jm00169a011

As an extension of the previous investigation (J.Med.Chem. 1988, 31, 919), we synthesized a series of 2-<2-<(aminoalkyl)oxy>5-methoxyphenyl>-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazines (3) and evaluated their Ca²⁺ antagonistic activities.Ca²⁺ antagonistic activity was measured with isolated depolarized guinea pig taenia cecum.On the basis of their potent Ca²⁺ antagonistic activity, six benzothiazines were selected and further evaluated for their vasocardioselectivity.Among these six compounds, the key compound 15 <3,4-dihydro-2-<5-methoxy-2-<3-ethyl>amino>propoxy>phenyl>- 4-methyl-3-oxo-2H-1,4-benzothiazine hydrogen fumarate was recognized as having the lowest cardioselectivity.Following optical resolution, the absolute configuration of the compound's optically active enantiomer was determined by means X-ray crystallography of a synthetic precursor (+)-4a.The Ca²⁺ antagonistic activity of 15 was found to reside primarily in (+)-15 (which was about 7 times more potent than (-)-15).The in vitro study showed that (+)-15 had a low cardioselectivity compared to verapamil and diltiazem.This result suggests that (+)-15 would exhibit less adverse effects due to cardiac inhibition than diltiazem and verapamil in therapeutic use.