SYNTHESIS AND CA-2+ ANTAGONISTIC ACTIVITY OF 2-[2-[(AMINOALKYL)OXY]-5-METHOXYPHENYL]-3,4-DIHYDRO-4-METHYL-3-OXO-2H-1,4-BENZO-THIAZINES

As an extension of the previous investigation (J. Med. Chem. 1988, 31, 919), we synthesized a series of 2-[2-[(am-inoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-l,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-[N-methyl-iV-[2-[3,4-(methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2ff-l,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 of 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. © 1990, American Chemical Society. All rights reserved.