[Stereoisomers of 3-methylfentanyl: synthesis, absolute configuration and analgesic activity].
Fractional crystallization of fumarate salt and oxalate salt of the mixture of cis- and trans-N-(3-methyl-4-piperidyl)-aniline (6) gave pure cis-6 x fumarate salt and trans-6 x oxalate salt respectively. Four optically pure 6 were obtained via resolution of cis-6 and trans-6 with D- and L-tartaric acid. Respective reaction of the optically pure 6 with phenylethyl bromide following propionylation gave optically active 3-methylfentanyl (2). The absolute configuration was confirmed: cis-(+)-2 as (3R,4S), cis-(-)-2 as (3S,4R), trans-(+)-2 as (3S,4S), trans-(-)-2 as (3R,4R). Pharmacological results showed that the configuration of two chiral centers in 2 was very important for analgesic potency. The median effective dose (ED50) of cis-(+)-2, which is the most potent among the four isomers, was found to be 0.00767 mg/kg (in mice, ip., hot plate) with 2600 times as potent as morphine while 119 and 1.5 times as potent as cis-(-)-2 and cis-(+/-)-2 respectively. The potency ratio between trans-(+)-2 and morphine was calculated as 450:1, while that between trans-(+)-2 and trans-(-)-2 as 4:1.
Wang
Z X
ZX
Shanghai Institute of Materia Medica, Academia Sinica.
Zhu
Y C
YC
Chen
X J
XJ
Ji
R Y
RY
D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D005260:Female; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; C030592:3-methylfentanyl; D005283:Fentanyl