Casopitant甲磺酸酯 | 414910-30-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: Casopitant甲磺酸酯
• 英文名称: casopitant mesylate
• 英文别名: (2R,4S)-4-(4-acetyl-1-piperazinyl)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidine-1-carboxamide methanesulfonate；(2R,4S)-4-(4-acetyl-1-piperazinyl)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide methanesulfonate；casopitant；4-(S)-(4-acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid-[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide methanesulphonate；(2R,4S)-4-(4-acetylpiperazin-1-yl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide;methanesulfonic acid
• CAS: 414910-30-8
• 化学式: CH₄O₃S*C₃₀H₃₅F₇N₄O₂
• 分子量: 712.729
• InChiKey: YRFKYVWDPCOSTE-REWBLLDVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.16
• 重原子数：
  48
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  110
• 氢给体数：
  1
• 氢受体数：
  13

制备方法与用途

卡索哌坦甲磺酸盐（GW679769B）是一种有效的、选择性的、具有脑渗透性和口服活性的神经激肽1(NK1)受体拮抗剂，属于第二类止吐药，能对抗物质P引起的呕吐反应。此外，它还是CYP3A4的底物和弱至中度抑制剂，可用于治疗化疗引起的恶心和呕吐（CINV）及术后恶心和呕吐（PONV）。

反应信息

• 作为产物：
  描述：

  N-[1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxopiperidine-1-carboxamide 生成 Casopitant甲磺酸酯
  参考文献：
  名称：

  WO2008046882A2

  摘要：

  公开号：

文献信息

• 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。
• 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。
• 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.
• Development of Drug Substances as Mixture of Polymorphs: Studies to Control Form 3 in Casopitant Mesylate
  作者：Zadeo Cimarosti、Carlo Castagnoli、Marco Rossetti、Mirka Scarati、Caroline Day、Brendan Johnson、Pieter Westerduin

  DOI：10.1021/op100150b

  日期：2010.11.19

  Polymorphism is characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice and this can impact the physical properties of a drug substance. In this paper the studies carried out on casopitant mesylate, a NK(1) antagonist developed in GlaxoSmithKline (GSK), are reported.During process development studies it was discovered that what was initially considered a single crystalline phase, Form 1, was actually a mixture of two different forms, Form 1 and Form 3. A retrospective analysis of all the key drug substance batches clearly indicated that Form 3 was always present as minor component in mixture with Form 1. Furthermore any attempt to generate either pure Form 1 or pure Form 3 failed. As a result of this, the project team explored the opportunity to develop the drug substance as a mixture of polymorphs. The studies performed to assess the ability of the manufacturing process to control the amount of Form 3 in the drug substance, according to the Quality by Design principle and the assessment of the impact of this finding on the drug product performance are reported in this paper. Collectively, the data demonstrated that the level of Form 3 in the drug substance (up to a level of 27% w/w) is not a drug substance critical quality attribute (drug substance-CQA) for casopitant mesylate.