4-oxo-4-((1-phenethylpiperidin-4-yl)(phenyl)amino)butanoic acid | 52994-23-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-oxo-4-((1-phenethylpiperidin-4-yl)(phenyl)amino)butanoic acid
• 英文别名: N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]-3-carboxypropanamide；ω-carboxy-fentanyl；Carboxyfentanyl；4-oxo-4-(N-[1-(2-phenylethyl)piperidin-4-yl]anilino)butanoic acid
• CAS: 52994-23-7
• 化学式: C₂₃H₂₈N₂O₃
• 分子量: 380.487
• InChiKey: MEVFKTVEGJUHHI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  60.8
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 储存条件：
  -20°C，密闭保存，置于干燥处。

制备方法与用途

butryl fentanyl carboxy metabolite 是一种结构与已知阿片类药物相似的分析标准品。

反应信息

• 作为反应物：
  描述：

  4-oxo-4-((1-phenethylpiperidin-4-yl)(phenyl)amino)butanoic acid 在 乙酸酐 、 高氯酸 作用下， 反应 1.0h， 生成 (5-Oxooxolan-2-ylidene)-phenyl-[1-(2-phenylethyl)piperidin-1-ium-4-yl]azanium;diperchlorate
  参考文献：
  名称：

  混合 μ-阿片类药物和 δ-阿片类激动剂作为可能的二价配体治疗疼痛的合成和研究。

  摘要：

  几项研究表明μ-阿片类药物和δ-阿片类受体之间存在功能关联，并表明μ-活性可以通过δ-配体调节。总体结论是δ-受体激动剂可以增强μ-激动剂的镇痛效力和功效。我们的初步研究表明，由μ-激动剂芬太尼和δ-激动剂脑啡肽样肽构建的新二价配体是创造新的镇痛药的有前景的实体，可减少治疗神经性疼痛的副作用。上述药效团的新叠加产生了新型μ-二价/δ-二价化合物，这些化合物在抗炎和神经性疼痛模型中表现出μ-阿片和δ-阿片受体激动剂活性和高效性，并有可能减少不良副作用。

  DOI：

  10.1002/jhet.2696
• 作为产物：
  描述：

  N-(2-苯乙基)-4-哌啶酮 在 sodium tetrahydroborate 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 4-oxo-4-((1-phenethylpiperidin-4-yl)(phenyl)amino)butanoic acid
  参考文献：
  名称：

  Metabolism of Butyrylfentanyl in Fresh Human Hepatocytes: Chemical Synthesis of Authentic Metabolite Standards for Definitive Identification

  摘要：

  使用从肝人源化小鼠模型中分离的新鲜人肝细胞，研究了一种新型设计药物丁酰芬太尼的代谢情况。在与人肝细胞共培养的介质中，鉴定出了丁酰芬太尼的脱芬太尼代谢物（去甲丁酰芬太尼）、ω-羟基丁酰芬太尼、(ω-1)-羟基丁酰芬太尼、4′-羟基丁酰芬太尼、β-羟基丁酰芬太尼、4′-羟基-3′-甲氧基丁酰芬太尼和ω-羧基芬太尼作为其代谢物。每个代谢物通过与标准品的分析数据比较得到确切鉴定。主要代谢物去甲丁酰芬太尼的量在48小时达到了初始丁酰芬太尼量的37%。由丁酰芬太尼的N-丁酰基团羟化形成的ω-羟基丁酰芬太尼和(ω-1)-羟基丁酰芬太尼分别为第二和第三大代谢物。大多数4′-羟基丁酰芬太尼和4′-羟基-3′-甲氧基丁酰芬太尼被认为是共轭物。使用人肝微粒体和各种抗CYP抗体对丁酰芬太尼进行CYP反应表型分析显示，CYP3A4参与了去甲丁酰芬太尼、(ω-1)-羟基丁酰芬太尼和β-羟基丁酰芬太尼的形成。相比之下，CYP2D6参与了ω-羟基丁酰芬太尼的形成。

  DOI：

  10.1248/bpb.b18-00765

文献信息

• Designing and Synthesis of Novel Amidated Fentanyl Analogs
  作者：Yaghoub Haghighatnia、Saeed Balalaie、Hamid Reza Bijanzadeh

  DOI：10.1002/hlca.201100392

  日期：2012.5

  Some new amidated fentanyl (=N‐[1‐(2‐phenylethyl)piperidin‐4‐yl]‐N‐phenylpropanamide) analogs with a 4‐(N‐phenylamido)piperidine scaffold and additional amide bonds have been designed and synthesized through Ugi four‐component reaction (Ugi‐4CR). Good‐to‐high yields, diversity‐oriented synthesis, and possible applications in drug discovery are advantages of this approach.

  通过Ugi设计并合成了一些带有4-（N-苯基酰胺基）哌啶骨架的新型酰胺化芬太尼（= N- [1-（2-苯基乙基）哌啶-4-基] -N-苯基丙酰胺）类似物和其他酰胺键。四组分反应（Ugi - 4CR）。从高产量到高产量，面向多样性的合成以及在药物发现中的可能应用是该方法的优势。
• Method and kit for detecting, or determining the quantity of, metabolites of fentanyl and metabolites of fentanyl analogs
  申请人：Randox Laboratories Ltd.

  公开号：EP1312923A2

  公开（公告）日：2003-05-21

  The invention describes haptens which are derivatised using a crosslinker at positions schematically illustrated as R1, R2, R3 and R4 on accompanying Figure 1a, with the proviso that R1 is not carboxyl. In addition, the invention claims an immunogen comprising certain of the aforementioned haptens coupled to an antigenicity-conferring carrier material; a conjugate comprising certain of the aforementioned haptens coupled to a detectable labelling agent; as well as, antibodies raised against the aforementioned immunogen and capable of binding with at least one structural epitope of metabolites of fentanyl and of metabolites of fentanyl analogs. The invention further provides a method and a kit for detecting, or determining the quantity of, metabolites of fentanyl and metabolites of fentanyl analogs, as well as, use of the aforementioned conjugate with the aforementioned antibodies for detecting, or determining the quantity of, metabolites of fentanyl and metabolites of fentanyl analogs. The present invention has broad specificity across various metabolites of fentanyl and various metabolites of fentanyl analogs.

  本发明描述了使用交联剂在附图 1a 中示意性说明为 R1、R2、R3 和 R4 的位置进行衍生的触价，但 R1 不是羧基。此外，本发明还要求获得一种免疫原，该免疫原包括与抗原性增强载体材料偶联的上述某些触价；一种共轭物，该共轭物包括与可检测标记剂偶联的上述某些触价；以及针对上述免疫原培养的抗体，该抗体能够与芬太尼代谢物和芬太尼类似物代谢物的至少一个结构表位结合。 本发明进一步提供了一种检测或确定芬太尼代谢物和芬太尼类似物代谢物数量的方法和试剂盒，以及使用上述共轭物和上述抗体检测或确定芬太尼代谢物和芬太尼类似物代谢物数量的方法和试剂盒。 本发明对芬太尼的各种代谢物和芬太尼类似物的各种代谢物具有广泛的特异性。
• Development of Novel Enkephalin Analogues that Have Enhanced Opioid Activities at Both μ and δ Opioid Receptors
  作者：Yeon Sun Lee、Ravil Petrov、Chad K. Park、Shou-wu Ma、Peg Davis、Josephine Lai、Frank Porreca、Ruben Vardanyan、Victor J. Hruby

  DOI：10.1021/jm061465o

  日期：2007.11.1

  Enkephalin analogues with a 4-anilidopiperidine scaffold have been designed and synthesized to achieve therapeutic benefit for the treatment of pain due to mixed mu and delta opioid agonist activities. Ligand 16, in which a Dmt-substituted enkephalin-like structure was linked to the N-phenyl-N-piperidin-4-yl propionamide moiety, showed very high binding affinities (0.4 nM) at mu and delta receptors with an increased hydrophobicity (aLogP = 2.96). This novel lead compound was found to have very potent agonist activities in MVD (1.8 nM) and GPI (8.5 nM) assays.
• Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands
  作者：Ruben Vardanyan、Vlad K. Kumirov、Gary S. Nichol、Peg Davis、Erika Liktor-Busa、David Rankin、Eva Varga、Todd Vanderah、Frank Porreca、Josephine Lai、Victor J. Hruby

  DOI：10.1016/j.bmc.2011.08.027

  日期：2011.10

  Newly designed bivalent ligands-opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials-carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds-amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited mu-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds. Published by Elsevier Ltd.
• Metabolism of Butyrylfentanyl in Fresh Human Hepatocytes: Chemical Synthesis of Authentic Metabolite Standards for Definitive Identification
  作者：Tatsuyuki Kanamori、Yuko Togawa Iwata、Hiroki Segawa、Tadashi Yamamuro、Kenji Kuwayama、Kenji Tsujikawa、Hiroyuki Inoue

  DOI：10.1248/bpb.b18-00765

  日期：2019.4.1

  The metabolism of butyrylfentanyl, a new designer drug, was investigated using fresh human hepatocytes isolated from a liver-humanized mouse model. In the culture medium of hepatocytes incubated with butyrylfentanyl, the desphenethylated metabolite (nor-butyrylfentanyl), ω-hydroxy-butyrylfentanyl, (ω-1)-hydroxy-butyrylfentanyl, 4′-hydroxy-butyrylfentanyl, β-hydroxy-butyrylfentanyl, 4′-hydroxy-3′-methoxy-butyrylfentanyl, and ω-carboxy-fentanyl were identified as the metabolites of butyrylfentanyl. Each metabolite was definitively identified by comparing the analytical data with those of authentic standards. The amount of the main metabolite, nor-butyrylfentanyl, reached 37% of the initial amount of butyrylfentanyl at 48 h. ω-Hydroxy-butyrylfentanyl and (ω-1)-hydroxy-butyrylfentanyl, formed by hydroxylation at the N-butyryl group of butyrylfentanyl, were the second and third largest metabolites, respectively. The majority of 4′-hydroxy-butyrylfentanyl and 4′-hydroxy-3′-methoxy-butyrylfentanyl was considered to be conjugated. CYP reaction phenotyping for butyrylfentanyl using human liver microsomes and various anti-CYP antibodies revealed that CYP3A4 was involved in the formation of nor-butyrylfentanyl, (ω-1)-hydroxy-butyrylfentanyl, and β-hydroxy-butyrylfentanyl. In contrast, CYP2D6 was involved in the formation of ω-hydroxy-butyrylfentanyl.

  使用从肝人源化小鼠模型中分离的新鲜人肝细胞，研究了一种新型设计药物丁酰芬太尼的代谢情况。在与人肝细胞共培养的介质中，鉴定出了丁酰芬太尼的脱芬太尼代谢物（去甲丁酰芬太尼）、ω-羟基丁酰芬太尼、(ω-1)-羟基丁酰芬太尼、4′-羟基丁酰芬太尼、β-羟基丁酰芬太尼、4′-羟基-3′-甲氧基丁酰芬太尼和ω-羧基芬太尼作为其代谢物。每个代谢物通过与标准品的分析数据比较得到确切鉴定。主要代谢物去甲丁酰芬太尼的量在48小时达到了初始丁酰芬太尼量的37%。由丁酰芬太尼的N-丁酰基团羟化形成的ω-羟基丁酰芬太尼和(ω-1)-羟基丁酰芬太尼分别为第二和第三大代谢物。大多数4′-羟基丁酰芬太尼和4′-羟基-3′-甲氧基丁酰芬太尼被认为是共轭物。使用人肝微粒体和各种抗CYP抗体对丁酰芬太尼进行CYP反应表型分析显示，CYP3A4参与了去甲丁酰芬太尼、(ω-1)-羟基丁酰芬太尼和β-羟基丁酰芬太尼的形成。相比之下，CYP2D6参与了ω-羟基丁酰芬太尼的形成。