Synthesis and Calcium Antagonistic Activity of (+)-(R)- and (-)-(S)-3-Acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5-trimethoxyphenethyl)amino]butoxy]phenyl]benzothiazoline Hydrochloride

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SA2572 ((±)-1), 3-acetyl-2-[5-methoxy-2-[-[N-methyl-N-(3,4,5-trimethoxyphenethyl)amino]butoxy]phenyl]-benzothiazoline hydrocholoride is a newly synthesized Ca^<2+> antagonist having a inhibitory effect on the fast Na^+ inward channel In order to clarify the absolute configurations and the pharmacological properties of both enantiomers, compounds ((+)-1 and (-)-1) were synthesized. The configurations of these compounds were assigned on the basis of an X-ray crystallographic analysis of synthetic precursor (5). The in vitro Ca^<2+> channel blocking activities of (+)-1 and (-)-1 were evaluated in terms of the inhibitory activities on depolarization-induced contraction of guinea pig taenia cecum and rabbit aorta. The in vivo efficacy of the enantiomers was evaluated with their hypotensive effects in spontaneously hypertensive rats. Compound (-)-1 showed more potent Ca^<2+> antagonistic activities on guinea pig taenia cecum and rabbit aorta and the hypotensive effect than those activities of (+)-1. In the electrophysiological study of Langendorff perfused rabbit hearts, compound (+)-1 showed more potent inhibitory effect on the fast Na^+ inward channel than that of compound (-)-1,and an approximately equal potent inhibitory effect on the slow Ca^<2+> inward channel as compared (-)-1. Stereoselectivity of the pharmacological activity was found.
社団法人日本薬学会の論文
1990-04-25