Synthesis and pharmacological activity of stereoisomers of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester.
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.
Muto
K
K
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Kuroda
T
T
Kawato
H
H
Karasawa
A
A
Kubo
K
K
Nakamizo
N
N
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D055598:Chemical Phenomena; D002621:Chemistry; D003460:Crystallization; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007536:Isomerism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D011918:Rats, Inbred SHR
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; C050883:benidipine hydrochloride; D009543:Nifedipine