(2R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxo-1-piperidinecarboxamide | 414910-03-5

• 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)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxo-1-piperidinecarboxamide
• 英文别名: (2R)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methylamino-carbonyl]-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine；(2R)-1-{N-(1-(R)-3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine；2-(R)-(4-fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methylamide；(R)-N-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxopiperidine-1-carboxamide；(2R)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxopiperidine-1-carboxamide
• CAS: 414910-03-5
• 化学式: C₂₄H₂₃F₇N₂O₂
• 分子量: 504.448
• InChiKey: GMZGGIIEDNOWCW-SPLOXXLWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  35
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxo-1-piperidinecarboxamide 在 titanium(IV) tetraethanolate 、 锌 作用下， 以 四氢呋喃 为溶剂， 生成 (2R,4R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-4-{[(1,1-dimethylethyl)sulfinyl]amino}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-(2-propen-1-yl)-1-piperidinecarboxamide
  参考文献：
  名称：

  [EN] SPIRO (PIPERIDINE-4, 2 ' -PYRROLIDINE) -1- (3, 5- TRIFLUOROMETHYL PHENYL) METHYLCARBOXAMIDES AS NK1 TACHIKYNIN RECEPTOR ANTAGONISTS
  [FR] SPIRO (PIPÉRIDINE-4, 2 ' -PYRROLIDINE) -1- (3, 5- TRI FLUOROMÉTHYL PHÉNYLE) MÉTHYLCARBOXAMIDES EN TANT QU'ANTAGONISTES DU RÉCEPTEUR NKL TACHIKYNINE.

  摘要：

  化合物的结构式（I）或其药用盐，其中R为氢或C 1-4 烷基；R1为氢、C 1-4 烷基、C(O)OH、C(O)NH2或(C 1-4 烷基)R10；R2和R3分别为氢、C 1-4 烷基，或者R2与R3一起以及与它们连接的碳原子形成一个C3-8环烷基基团；R4为C 1-4 烷基、C 1-4 烷氧基或卤素；R5和R7分别为氢、羟基、卤素、C(O)NH2、C(O)OH或(C 1-4 烷基)R10；R6和R8分别为氢或卤素；R9为氢、(C 1-4 烷基)R10、C(O)NH2、C(O)OH或R9与R一起形成一个6元杂环环，可选择地含有氧、硫或氮等进一步的杂原子；R10为氢、卤素、羟基、C(O)NH2、C(O)NH(C 1-4 烷基)、C(O)N(C 1-4 烷基)2或C(O)OH；n为O、1或2。它们的制备方法，含有它们的组合物，以及它们在治疗需要NK1拮抗作用的疾病和症状中的用途。

  公开号：

  WO2009133135A1
• 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 、 碳酸氢钠 、 sodium carbonate 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 、 异丙醇 为溶剂， 10.0~20.0 ℃ 、400.01 kPa 条件下， 反应 11.25h， 生成 (2R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxo-1-piperidinecarboxamide
  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

• [EN] NOVEL PIPERIDINE COMPOUND<br/>[FR] NOUVEAU COMPOSE DE PIPERIDINE
  申请人：TANABE SEIYAKU CO

  公开号：WO2003099787A1

  公开（公告）日：2003-12-04

  The present invention provides a novel piperidine compound of the formula [I]: wherein Ring A represents an optionally substituted benzene ring, Ring B represents an optionally substituted benzene ring, R1 represents an optionally substituted alkyl group, an optionally substituted hydroxyl group, etc., or a group of the formula: (a) wherein R11 and R12 are the same or different, and each represents hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group, etc., R2 represents hydrogen atom, etc., Z represents oxygen atom or a group represented by -N(R3)-, R3 represents hydrogen atom or an alkyl group, etc., R4 represents hydrogen atom or an alkyl group, etc.,or a pharmaceutically acceptable salt thereof.

  本发明提供了一种新型哌啶化合物，其化学式为[I]：其中环A代表可选择取代的苯环，环B代表可选择取代的苯环，R1代表可选择取代的烷基团，可选择取代的羟基团等，或者化学式的一个基团：(a)其中R11和R12相同或不同，每个代表氢原子，取代的羰基团，取代的磺酰基团，可选择取代的烷基团等，R2代表氢原子等，Z代表氧原子或由-N(R3)-表示的基团，R3代表氢原子或烷基团等，R4代表氢原子或烷基团等，或其药学上可接受的盐。
• Chemical compounds
  申请人：——

  公开号：US20040014770A1

  公开（公告）日：2004-01-22

  Formula (1) wherein R represents a halogen atom or a C 1-4 alkyl group; R 1 represents a C 1-4 alkyl group; R 2 represents hydrogen or a C 1-4 alkyl group; R 3 represents hydrogen, or a C 1-4 alkyl group; R 4 represents a trifluorometyl group; R 5 represents hydrogen, a C 1-4 alkyl group or C(0)R 6 ; R 6? represents C 1-4 alkyl, C 3-7 cycloalkyl, NH(C 1-4 alkyl) or N(C1-4alkyl) 2 ; m is zero or an integer from 1 to 3; n is an integer from 1 to 3 and pharmaceutically acceptable salts and solvates thereof; to processes for their preparation and their use in the treatment of conditions mediated bytachykinins.

  公式（1）中，R代表卤原子或C1-4烷基；R1代表C1-4烷基；R2代表氢或C1-4烷基；R3代表氢或C1-4烷基；R4代表三氟甲基基团；R5代表氢、C1-4烷基或C(0)R6；R6代表C1-4烷基、C3-7环烷基、NH(C1-4烷基)或N(C1-4烷基)2；m为零或1至3的整数；n为1至3的整数及其药学上可接受的盐和溶剂化合物；以及它们的制备过程和在通过tachykinins介导的疾病治疗中的用途。
• [EN] ANHYDROUS CRYSTAL FORM OF ORVEPITANT MALEATE<br/>[FR] FORME DE CRISTAL ANHYDRE DE MALÉATE D'ORVÉPITANT
  申请人：GLAXO GROUP LTD

  公开号：WO2009124996A1

  公开（公告）日：2009-10-15

  The invention relates to anhydrous crystalline orvepitant maleate (Form 1), pharmaceutical formulations comprising the same, its use in therapy and processes for preparing the same.

  该发明涉及无水结晶梅酸奥维匹坦（Form 1），包括该物质的药物配方，其在治疗中的应用以及制备该物质的过程。
• [EN] PIPERIDINE BASED UREAS AS NK1 ANTAGONISTS<br/>[FR] URÉES À BASE DE PIPÉRIDINE EN TANT QU'ANTAGONISTES DU NK1
  申请人：GLAXO WELLCOME MFG PTE LTD

  公开号：WO2010007032A1

  公开（公告）日：2010-01-21

  The invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2; useful in the treatment of conditions for which antagonism of NK1 receptor is beneficial.

  该发明提供了化合物的结构式(I)或其药用可接受的盐，其中n为1或2；用于治疗对NK1受体拮抗有益的疾病。
• Application of the QbD Principles in the Development of the Casopitant Mesylate Manufacturing Process. Process Research Studies for the Definition of the Control Strategy of some Drug Substance-CQAs for Stages 2a, 2b, and 2c
  作者：Zadeo Cimarosti、Fernando Bravo、Damiano Castoldi、Francesco Tinazzi、Stefano Provera、Alcide Perboni、Damiano Papini、Pieter Westerduin

  DOI：10.1021/op1000622

  日期：2010.7.16

  casopitant mesylate was developed and optimised by following a Quality by Design approach, whereby a control strategy was developed, underpinned by process understanding and risk analysis, for an enhanced level of quality assurance. Quality process parameters and specifications levels for the Stages 2a, 2b, and 2c are the elements of the control strategy of the manufacturing process discussed in detail in

  Casopitant被鉴定为强效NK 1葛兰素史克（GSK）的抗性药物。它被选为GSK​​广泛药物发现计划的一部分，因为它在许多治疗靶标上具有潜在的活性，例如炎症性肠病，膀胱过度活动症，中枢神经系统疾病等。选择casopitant的甲磺酸盐以使其充分发育。甲磺酸甲磺酸盐的生产工艺是通过遵循“按质量设计”方法开发和优化的，从而开发了以过程理解和风险分析为基础的控制策略，以提高质量保证水平。阶段2a，2b和2c的质量过程参数和规范级别是本文详细讨论的制造过程控制策略的要素。实验设计方法已被广泛用于支持该过程的公认可接受范围的定义。目的是显示为确保最终原料药的质量控制而进行的过程开发研究。