强效镇痛剂研究 Ⅶ.1-β-羟基-3-甲基芬太尼(7302)及有关化合物非对映异构体的合成及镇痛活性

本文报道N-1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(简称1-β-羟基-3-甲基芬太尼,编号7302)及N-1-苯甲酰基甲基-3-甲基-4-哌啶基]-N-丙酰苯胺(7303)非对映异构体的合成及镇痛活性。初步结果表明(小鼠,ip,热板法),7302分子中三个手性中心的构型对镇痛活性影响都至关重要。顺-A-7302的强度为顺-B-7302的5.3倍,反-A-7302为反-B-7302的2倍左右。顺-A-7302为四个非对映异构体中作用最强者,为吗啡的6000多倍,为依托芬的3倍左右。

Studies on potent analgesics. VII. Synthesis and analgesic activity of diastereoisomers of 1-beta-hydroxy-3-methylfentanyl (7302) and related compounds

After systematic structural modification of 3-methylfentanyl derivatives; N-1-(β-hydroxy-β-phenylethyl)-3-methyl-4-piperidyl]-N-phenyl propanamide (7302) was found to be the most potent analgesic agent in this series. There are three chiral centers in the 7302 molecule, so there are four diastereoisomeric pairs. In view of the high stereoselective recognition of opiate receptor to its ligands, we had separated the diastereoisomers of 7302 and of related compounds, cis-7303 and trans-7303, all as racemic pairs,by fractional crystallization. Pharmacological results showed that the configuration of the three chiralities in 7302 was very important for analgesic potency. The activity ratio for cis-A-7302/cis-B-7302 was 5.3; trans-A-7302/trans-B-7302 was about 2. Among the four diastereoisomers of, 7302, cis-A-7302 was the most potent compound with a potency 6000 times of morphine and 3 times of etorphine. Compound 7302 in our previous report⁽²⁾ was actually the purified form which we now designate as cis-A-7302.