Muto K, Kuroda T, Kawato H, Karasawa A, Kubo K, Nakamizo N
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Arzneimittelforschung. 1988 Nov;38(11A):1662-5.
1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic++ + acid methyl 1-(phenylmethyl)-3-piperidinyl ester 1, a highly potent calcium antagonist, was separated into stereo- and optical isomers to investigate the differences of antihypertensive activities between them. Fractional crystallization of the hydrochlorides of 1 gave alpha- and beta-diastereoisomers. The alpha-isomer (benidipine hydrochloride, KW-3049) showed very strong hypotensive effect, but little activity was observed in the beta-isomer. From optically resolved 1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-3- pyridinecarboxylic acids 2, and 1-benzyl-3-piperidinols 3, four optical isomers of 1 were synthesized, and their absolute configurations were deduced. The hypotensive activity of (+)-alpha, namely (S)-(S)-1, was 30 to 100 times stronger than that of (-)-alpha in intravenously administered spontaneously hypertensive rats.
1,4 - 二氢 - 2,6 - 二甲基 - 4 -（3 - 硝基苯基）- 3,5 - 吡啶二甲酸1 -（苄基）- 3 - 哌啶酯1是一种高效钙拮抗剂，被分离为立体异构体和旋光异构体以研究它们之间抗高血压活性的差异。1的盐酸盐分步结晶得到α - 和β - 非对映异构体。α - 异构体（盐酸贝尼地平，KW - 3049）显示出非常强的降压作用，而β - 异构体几乎没有活性。由旋光拆分得到的1,4 - 二氢 - 5 - 甲氧基羰基 - 2,6 - 二甲基 - 4 -（3 - 硝基苯基）- 3 - 吡啶羧酸2和1 - 苄基 - 3 - 哌啶醇3合成了1的四种旋光异构体，并推导了它们的绝对构型。在静脉注射的自发性高血压大鼠中，（+）-α即（S）-（S）-1的降压活性比（-）-α强30至100倍。
