Novel 2-Amino-1,4-dihydropyridine Calcium Antagonists. II. Synthesis and Antihypertensive Effects of 2-Amino-1,4-dihydropyridine Derivatives Having N,N-Dialkylaminoalkoxycarbonyl Groups at 3- and/or 5-Position.
Takashi Kobayashi, Teruhiko Inoue, Shigeyoshí Nishino, Yoshimi Fujihara, Kiyoshi Oizumi, Tomio Kimura · Chemical and Pharmaceutical Bulletin · 1995
Novel 2-amino-1, 4-dihydropyridine derivatives I, which contain N, N-dialkylaminoalkoxycarbonyl groups at the 3- and/or 5-position, were synthesized and their antihypertensive effects were evaluated in spontaneously hypertensive rats. Remarkably prolonged duration of antihypertensive action was observed when a tertiary amino group was introduced into either the 3- or 5-ester side-chain of the 1, 4-dihydropyridine ring. In particular, the compounds containing cyclic amino moieties at the 3-position showed greater potency than those with acyclic amino moieties. Chemical modification studies indicated that the two ester side-chains of 1, 4-dihydropyridine at the 3- and 5-position might function in a different manner in relation to the antihypertensive activities. 3-(1-Benzhydrylazetidin-3-yl) 5-isopropyl 2-amino-1, 4-dihydro-6-methyl-4-(3-nitrophenyl)-3, 5-pyridine-dicarboxylate, I-43 (CS-905), exhibited potent and long-lasting antihypertensive effects with gradual onset of action, and is a promising candidate as an antihypertensive drug.