Kudzma L V, Severnak S A, Benvenga M J, Ezell E F, Ossipov M H, Knight V V, Rudo F G, Spencer H K, Spaulding T C
Anaquest and The BOC Group, Inc., BOC Group Technical Center, Murray Hill, New Jersey 07974.
J Med Chem. 1989 Dec;32(12):2534-42. doi: 10.1021/jm00132a007.
The incorporation of the 4-phenylpiperidine pharmacophore found in morphine into 4-anilidopiperidines related to fentanyl (1) led to a novel class of potent opioid analgesic and anesthetic agents with a favorable pharmacological profile. The synthesis, analgesic activity, and anesthetic properties of a series of 4-phenyl-4-anilidopiperidines (13-29) are discussed. Isosteric replacement of the phenyl by various heteroaryl substituents extended the series to include 4-heteroaryl-4-anilidopiperidines (30-53). Within this group, 1-[2-(1H-pyrazol-1-yl)ethyl]-4-(4-methylthiazol-2-yl)-4-(N- phenylpropionamido)piperidine (48), exhibited high analgesic potency, short duration of action, rapid recovery of motor coordination following anesthetic doses, and greater cardiovascular and respiratory safety during anesthesia as compared with opioids fentanyl (1) and alfentanil (2) currently in clinical use. Such analgesics could be of great utility to clinicians in the expanding outpatient surgical arena and for patient-controlled analgesia and computer assisted continuous infusion pain control techniques.
将吗啡中发现的4-苯基哌啶药效基团引入与芬太尼相关的4-苯胺基哌啶（1）中，产生了一类新型的强效阿片类镇痛和麻醉剂，其药理学特性良好。讨论了一系列4-苯基-4-苯胺基哌啶（13 - 29）的合成、镇痛活性和麻醉特性。用各种杂芳基取代基对等排体苯基进行取代，将该系列扩展到包括4-杂芳基-4-苯胺基哌啶（30 - 53）。在该组化合物中，1-[2-(1H-吡唑-1-基)乙基]-4-(4-甲基噻唑-2-基)-4-(N-苯基丙酰胺基)哌啶（48）与目前临床使用的阿片类药物芬太尼（1）和阿芬太尼（2）相比，表现出高镇痛效力、短作用持续时间、麻醉剂量后运动协调性快速恢复以及麻醉期间更大的心血管和呼吸安全性。这类镇痛药对于不断扩大的门诊手术领域的临床医生以及患者自控镇痛和计算机辅助持续输注疼痛控制技术可能具有很大的实用价值。
