Shimokawa N, Nakamura H, Shimakawa K, Minami H, Nishimura H
J Med Chem. 1979 Jan;22(1):58-63. doi: 10.1021/jm00187a014.
The preparation and analgesic activity of a series of the title compounds (8-55 and 57) are described. The intermediates, 2-phenyl-2-(1-piperazinyl)acetophenones 5 and 6, were prepared from benzyl phenyl ketones 3 via their bromides 4. On reduction, compounds 5 afforded the titled compounds 8-12, 16, and 26-48. Compounds 13-15 and 17-25 were obtained by alkylation or benzylation of 1.2-diphenyl-2-(1-piperazinyl)ethanols 7 derived from 6 by reduction. The reduction of 5 and 6 with metal hydrides predominantly gave the erythro isomers. The erythro isomers were remarkably more active than their threo isomers. The more active members in this series of compounds were 16 and derivatives 35 and 37-44 of dl-erythro-1-phenyl-2-(substituted phenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl]ethanol. Compounds 16, 43, and 44 were the most active with a potency of about two to three times that of codeine. Racemates 16 and 38 were resolved into their optical isomers and it was found that (-)-16 and (+)-38 were more potent than their antipodes. Structure-activity relationship are discussed.
描述了一系列标题化合物（8 - 55和57）的制备及其镇痛活性。中间体2 - 苯基 - 2 -（1 - 哌嗪基）苯乙酮5和6由苄基苯基酮3通过其溴化物4制备。经还原后，化合物5得到标题化合物8 - 12、16以及26 - 48。化合物13 - 15和17 - 25是通过对由6经还原得到的1,2 - 二苯基 - 2 -（1 - 哌嗪基）乙醇7进行烷基化或苄基化反应得到的。用金属氢化物还原5和6主要得到赤型异构体。赤型异构体的活性明显高于其苏型异构体。该系列化合物中活性较高的成员是16以及dl - 赤型 - 1 - 苯基 - 2 -（取代苯基）- 2 - [4 -（对甲氧基苄基）- 1 - 哌嗪基]乙醇的衍生物35和37 - 44。化合物16、43和44活性最强，效力约为可待因的两到三倍。外消旋体16和38被拆分为其旋光异构体，发现（-）- 16和（+）- 38比其对映体更有效。讨论了构效关系。
