4-取代芬太尼类化合物的晶体结构和构效关系

以芬太尼为典型代表物的4-苯胺哌啶类化合物是一类具有独特结构类型、强度高、作用迅速的高效麻醉镇痛剂。该类化合物哌啶环的3位或4位引入适当取代基团能提高镇痛活性,其活性强度已达微克水平。芬太尼类化合物的构效关系研究表明:分子构象与生物活性之间关系密切。虽Peeters和Koch等人分别对芬太尼(R 4263)和4-甲氧甲基芬太尼类代表物(R 30490,R 30730)     

4-甲氧甲基芬太尼类似物的合成及其镇痛作用

本文报道了某些N-[1-(2-苯乙基)-4-甲氧甲基-4-哌啶基]-N-丙酰苯胺(4-甲氧甲基芬太尼)类似物的合成及其镇痛活性。小白鼠热板试验的结果表明,该类化合物有很强的吗啡样镇痛活性,但活性弱于相应的4-甲氧羰基芬太尼类化合物;4-N-酰基上羰基的存在对产生强效镇痛活性有重要作用。     

4-甲氧羰基芬太尼的4-N-丙酰基结构类似物的合成与镇痛活性

本文报道了4-甲氧羰基芬太尼4-N-丙酰基结构改变衍生物的合成及其镇痛活性。试验结果表明,该类衍生物均具有典型吗啡样作用的性质。多数化合物具有很强的镇痛活性。其中1379,1385和1387的镇痛活性强于先导物4-甲氧羰基芬太尼。     

芬太尼类似物结构修饰中高活性基团研究

芬太尼是Janssen于20世纪60年代早期报道的一类高效镇痛剂,本文针对芬太尼类化合物结构修饰中,对化合物镇痛作用具有重要贡献的高活性取代基团进行了归纳和总结,特别是3-甲基芬太尼和4-甲氧羰基芬太尼类化合物。本文着重总结了芬太尼类化合物1-位取代基对化合物活性的重要影响,同时提出了保持或提高现有高效麻醉镇痛药活性的基本结构要求,以期为该类化合物的新药开发研究人员提供参考。     

4-甲氧羰基芬太尼1-位衍生物的合成及生物活性

合成了5个4-甲氧羰基芬太尼1-位衍生物,有4个化合物的分子中带有可与阿片受体发生烷化反应的官能团。镇痛试验结果表明,它们都有典型的吗啡样镇痛活性。离体组织试验结果表明,这些新化合物均作用于阿片受体,其中化合物2,4和5为新型的阿片受体不可逆配体。     

新型镇痛药——3-(1-吲哚基)苄胺类

3-(1-吲哚基)苄胺类是一类新型镇痛药。其中吲哚环无取代基的Ⅱ(X=H)在苯醌引起的小鼠扭体试验[ED_(50)=4.2mg/kg(皮下注射),活性与右丙氧芬相当,而稍弱于喷他佐辛]、大鼠甩尾试验中均有活性。在转棒试验中给药8mg/kg仍未见运动缺陷。也     

4-甲氧羰基芬太尼非芳基类似物的合成及镇痛作用

报道了某些4-N-苯基或4-N-苯基与1-β苯基同时被某些非芳香基团替代的4-甲氧羰基芬太尼衍生物的合成及其镇痛活性。结果表明,4-N-苯基和1-β-苯基被某些适宜非芳香基团替代可保持强效镇痛活性。分子中不含苯(或芳)基的化合物4和6的镇痛活性分别是吗啡活性的695倍和818倍。讨论了结构与镇痛活性之间的关系。     

2-(1-取代哌啶-4-氨基)喹唑啉类化合物的合成及抗肿瘤活性研究(英文)

本文合成了一系列新结构的2-(1-取代哌啶-4-氨基)喹唑啉衍生物,采用MTT法评价了化合物对5种肿瘤细胞系的抑制活性。研究结果表明:在哌啶环上引入小体积的疏水性烷基取代基,得到的化合物4j～4l、5a、5b和5d具有较强的细胞毒活性,IC50值在微摩尔水平。在小鼠移植瘤模型实验中,化合物4l表现出了较强的体内抗肿瘤活性,在200 mg.kg1的剂量下,对H22肿瘤生长抑制率为72.9%,对Lewis肺癌的抑制率达到了80%。     

1-取代-5-苯基-3-吡唑烷酮化合物的合成及抗惊厥活性的研究

用Fibonaeci寻找法及Topliss方法设计并合成了14个1-取代-5-苯基-3-吡唑烷酮化合物。药理实聆表明,11个化合物具有抗惊厥活性,其中以1-正丙基-5苯基-3-吡唑烷酮最佳。抗最大电休克(MES)ED_(50)=27mg/kg。以取代基的f值、I×10~3及Vander Waals体积与log 1/c进行QSAR研究发现,抗惊厥活性与取代基的诱导效应及体积均呈抛物线关系,在合适的体积范围内,给电效应有利于抗惊厥活性的提高。     

强效镇痛剂研究——Ⅰ.芬太尼类衍生物的合成及其镇痛作用

本文报道了芬太尼类衍生物的化学结构与镇痛活性之间的关系。分别改变了芬太尼中的哌啶环1位氮原子的取代基,N-酰芳胺基及哌啶环等部分结构。药理试验结果表明,大部分化合物均具有吗啡样镇痛活性,其镇痛强度分别为吗啡的2～150倍左右。     

N-4-Substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin.

The intravenous analgesic activity and toxicity of a novel series of N-[4-substituted 1-(2-arylethyl)-4-piperidinyl]-N-phenylpropanamides was studied in rats. Onset, potency and duration of analgesic action were assessed in the tail withdrawal test and compared with the activity of fentanyl, (+)-cis-3-methylfentanyl (R 26 800), morphine, and pethidine. All compounds studied were found to be extremely potent analgesics characterized by an unusually high safety margin. Methyl 4-[N-(1-oxopropyl)-N-phenyl-amino]-1-(2-phenylethyl)-4-piperidinecarboxylate (R 31 833; lowest ED50 = 0.00032 mg/kg) is the most potent compound (10 031 times morphine). cis-Methyl 3-methyl-4-[N-(1-oxopropyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidine carboxylate (R 32 792) is the longest acting compound (more than 8 h at 4 times the lowest ED50) and N-[4-(1-oxopropyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide (R 33 352) is the shortest acting compound (0.74 h at 4 times the lowest ED50) of the 4-substituted fentanyl derivatives. N-[4-(Methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide (R 30 730) was selected for further investigation. R 30 730 has a rapid onset of action and is 4521 times more potent than morphine at the time of peak effect; it has a relatively short duration of action comparable to that of fentanyl and its safety margin (LD50/lowest ED50 = 25 211) is unusually high.     

强效镇痛剂研究——Ⅱ.3-甲基芬太尼类衍生物的合成及镇痛活性

本文报道了N-[1-(β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(7209)和N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(7302)等一系列3-甲基芬太尼类衍生物的合成及镇痛活性。绝大部分该类衍生物均具有典型的吗啡样镇痛活性,是一类结构较简单、易于合成、镇痛作用极强的麻醉镇痛剂。化合物7302的ED₅₀为0.0022mg/kg(ip,小鼠,热板法),比芬太尼强28倍,竟达吗啡的6318倍,为我们至今合成该类衍生物中作用最强者。     

Synthetic analgesics: N-(1-[2-arylethyl]-4-substituted 4-piperidinyl) N-arylalkanamides.

The synthesis of several 4-arylamino-4-piperdinecarboxylic acids is reported. These acids were starting materials for the preparation of alpha-amino esthers, ethers and ketones. Different synthetic approaches are described. Suitable substitution on both nitrogen atoms afforded extremely potent analgesics. Thus, methyl 4-[N-(1-oxopropyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylate (22),N-(4-(methoxymethyl)-2-[2-(2-thienyl)ethyl]-4-piperidinyl)-N-phenylpropranamide (67) and N-[4-acetyl-1-(2-phenylethyl)-4-piperidinyl]-N-phenylpropanamide (82) were found to be respectively 7682, 3987 and 4921 times as potent as morfine. Both cis- and trans-3-methyl homologs of 22 have been prepared. As expected, analgesic activity resides mainly in the cis-isomer.     

4-Phenyl- and 4-heteroaryl-4-anilidopiperidines. A novel class of analgesic and anesthetic agents

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.     

The major metabolite of fentanyl in the horse

Fentanyl, a potent, synthetic narcotic analgesic, has reportedly been used to "dope" racehorses. Urine was collected from a horse dosed with 70 mg of [3H]fentanyl, and the primary metabolite, a water-soluble, amphoteric compound, was isolated by high-pressure liquid chromatography and identified by spectroscopic analysis. This metabolite was found to be N-[1-(2-phenethyl-4-piperidinyl)] malonanilinic acid.     

New 4-(heteroanilido)piperidines, structurally related to the pure opioid agonist fentanyl, with agonist and/or antagonist properties

A research program based on certain heterocyclic modifications (12-50) of the fentanyl (1) molecule has generated a novel class of opioids. In the mouse hot-plate test, these compounds were weaker analgesics than 1. Two types of antagonists were observed in morphine-treated rabbits: those (e.g., 28) that reversed both respiratory depression and analgesia and those (e.g. 32) that selectively reversed respiratory depression. Evaluation of in vitro binding affinities to rat brain opioid receptors was inconclusive for a common locus of action for the agonist as well as the antagonist component. Further pharmacological evaluation of 32, N-(2-pyrazinyl)-N-(1-phenethyl-4-piperidinyl)-2-furamide, in the rat showed it to be a potent analgesic (ED50 = 0.07 mg/kg, tail-flick test) with little cardiovascular and respiratory depression when compared to fentanyl.     

顺-3-甲基芬太尼的4-N-丙酰基结构类似物的合成与镇痛活性及构效关系的研究

以不同电性的基团取代顺-3-甲基芬太尼中4-N-丙酰基上的乙基,合成某些顺-3-甲基芬太尼的结构类似物。药理试验结果表明,所合成的化合物均有典型的吗啡样作用。化合物3的镇痛活性略强于顺-3-甲基芬太尼。应用半经验的INDO方法对4个代表化合物进行了量子化学计算,讨论了电子结构与镇痛活性间的关系,化合物3由于氯乙烯基的引入具有与顺-3-甲基芬太尼不同的电子结构特征,氯乙烯基可能作为电子接受体参与了与受体的作用。