(2R,4S)-4-(azetidin-1-yl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide | 1265855-27-3

• 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: (2R,4S)-4-(azetidin-1-yl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide
• CAS: 1265855-27-3
• 化学式: C₂₇H₃₀F₇N₃O
• 分子量: 545.544
• InChiKey: DEVSGOOMIYSMNC-OUPRXKBMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  38
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  26.8
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  1-benzyloxycarbonyl-2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one 在 5% Pd(II)/C(eggshell) 、 氢气 、 三乙酰氧基硼氢化钠 、 碳酸氢钠 、 sodium carbonate 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 、 异丙醇 、 乙腈 为溶剂， 10.0~20.0 ℃ 、400.01 kPa 条件下， 反应 35.25h， 生成 (2R,4R)-4-(azetidin-1-yl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide 、 (2R,4S)-4-(azetidin-1-yl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide
  参考文献：
  名称：

  Discovery and Biological Characterization of (2R,4S)-1′-Acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4′-bipiperidine-1-carboxamide as a New Potent and Selective Neurokinin 1 (NK₁) Receptor Antagonist Clinical Candidate

  摘要：

  A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK1 receptor antagonists elicited clinical efficacy in major depression disorders. In addition, aprepitant (Merck) was launched as a new drug able to prevent chemotherapy-induced nausea and vomiting (CINV). After the discovery by GlaxoSmithKline of vestipitant, a wide drug discovery program was launched aimed at identifying additional clinical candidates. New compounds were designed to maximize affinity at the NK1 receptor binding site while retaining suitable physicochemical characteristics to ensure excellent pharmacokinetic and pharmacodynamic properties in vivo. Herein we describe the discovery process of a new NK1 receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.

  DOI：

  10.1021/jm1013264

文献信息

• Discovery and Biological Characterization of (2<i>R</i>,4<i>S</i>)-1′-Acetyl-<i>N</i>-{(1<i>R</i>)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-<i>N</i>-methyl-4,4′-bipiperidine-1-carboxamide as a New Potent and Selective Neurokinin 1 (NK₁) Receptor Antagonist Clinical Candidate
  作者：Romano Di Fabio、Giuseppe Alvaro、Cristiana Griffante、Domenica A. Pizzi、Daniele Donati、Mario Mattioli、Zadeo Cimarosti、Giuseppe Guercio、Carla Marchioro、Stefano Provera、Laura Zonzini、Dino Montanari、Sergio Melotto、Philip A. Gerrard、David G. Trist、Emiliangelo Ratti、Mauro Corsi

  DOI：10.1021/jm1013264

  日期：2011.2.24

  A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK1 receptor antagonists elicited clinical efficacy in major depression disorders. In addition, aprepitant (Merck) was launched as a new drug able to prevent chemotherapy-induced nausea and vomiting (CINV). After the discovery by GlaxoSmithKline of vestipitant, a wide drug discovery program was launched aimed at identifying additional clinical candidates. New compounds were designed to maximize affinity at the NK1 receptor binding site while retaining suitable physicochemical characteristics to ensure excellent pharmacokinetic and pharmacodynamic properties in vivo. Herein we describe the discovery process of a new NK1 receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.