3-甲基芬太尼立体异构体的合成、绝对构型和镇痛活性

STEREOISOMERS OF 3-METHYLFENTANYL:SYNTHESIS,ABSOLUTE CONFIGURATION AND ANALGESIC ACTIVITY

报道3-甲基芬太尼(2)四个光学异构体的合成及其绝对构型的确定,并测定了各异构体的镇痛活性(小鼠,ip,热板法)。结果表明,cis-(+)-(3R,4S)-2的镇痛作用最强,ED_(50)0.00767 mg/kg,镇痛效能是吗啡的2600倍,比其对映体cis-(-)-(3S,4R)-2以及混旋的cis-(±)-2分别强119和1.5倍;trans-(+)-(3S,4S)-2的镇痛效能是吗啡的450倍、trans-(-)-(3R,4R)-2的4倍。

Fractional crystallization of fumarate salt and oxalate salt of the mixture of cisand trans-N-(3-methyl-4-piperidyl)-aniline (6) gave pure cis-6 fumarate salt and trans-6·oxalate salt respectively, four optically pure 6 were obtained via resolution of cis-6 and trans-6 with D-and Ltartaric 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, 4R), 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 (ED_(50)) 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.