[14C]-Casopitant | 414910-27-3

• 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: [14C]-Casopitant
• 英文别名: Casopitant；(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；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；GW679769；(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
• CAS: 414910-27-3
• 化学式: C₃₀H₃₅F₇N₄O₂
• 分子量: 616.622
• InChiKey: XGGTZCKQRWXCHW-WMTVXVAQSA-N

物化性质

• 沸点：
  615.6±55.0 °C(Predicted)
• 密度：
  1.296±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  43
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  47.1
• 氢给体数：
  0
• 氢受体数：
  10

制备方法与用途

casopitant（GW679769）是一种强效的中枢性神经激肽1（NK1）受体拮抗剂，其亲和力为pKi=9.48，具有抗抑郁和止吐作用。

反应信息

• 作为反应物：
  描述：

  [14C]-Casopitant 在 盐酸 作用下， 以 乙醚 为溶剂， 生成 Casopitant hydrochloride
  参考文献：
  名称：

  硅路易斯酸与酰基hydr和Danishefsky二烯的高度对映选择性形式的Aza-Diels-Alder反应

  摘要：

  硅路易斯酸3可有效促进酰基hydr与Danishefsky的二烯的高度对映选择性环加成反应（正式的aza-Diels-Alder反应）。反应在环境温度下进行15分钟，并以高收率和高对映选择性生产产物。在绝对立体化学诱导的意义上，已经观察到显着的溶剂依赖性逆转。该方法已应用于神经激肽1受体拮抗剂casopitant的高效和立体选择性合成。

  DOI：

  10.1016/j.tet.2010.03.036
• 作为产物：
  描述：

  (2R)-2-(4-fluoro-2-methylphenyl)-4-piperidinone L-(+)-mandelate 在 sodium tetrahydroborate 、 甲酸 、 sodium carbonate 、 三乙胺 作用下， 以 水 、 乙酸乙酯 、 乙腈 为溶剂， 反应 16.0h， 生成 [14C]-Casopitant 、 (2R)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-4-hydroxy-N-methylpiperidine-1-carboxamide
  参考文献：
  名称：

  QbD原理在甲磺酸Casopitant甲磺酸盐制造工艺开发中的应用。定义2a，2b和2c阶段某些药物CQA控制策略的过程研究

  摘要：

  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。

  DOI：

  10.1021/op1000622

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。
• Compositions for treating centrally mediated nausea and vomiting
  申请人：Helsinn Healthcare SA

  公开号：EP2722045A2

  公开（公告）日：2014-04-23

  Provided are compositions comprising netupitant for treating nausea and vomiting.

  本发明提供了包含治疗恶心和呕吐的奈普坦的组合物。
• Compositions and methods for treating centrally mediated nausea and vomiting
  申请人：Helsinn Healthcare SA

  公开号：US10828297B2

  公开（公告）日：2020-11-10

  Provided are compositions and methods for treating or preventing nausea and vomiting in patients undergoing chemotherapy, radiotherapy, or surgery.

  本文提供了用于治疗或预防化疗、放疗或手术患者恶心和呕吐的组合物和方法。
• Combinations of paroxetine and 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 for treatment of depression and / or anxiety
  申请人：Carletti Renzo

  公开号：US20060217395A1

  公开（公告）日：2006-09-28

  The present invention relates to therapeutic combinations comprising paroxetine or physiologically acceptable salts or solvates thereof and 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 or pharmaceutically acceptable salts or solvates thereof, to pharmaceutical compositions containing said combinations and their use in the treatment of depression and/or anxiety.

  本发明涉及包含帕罗西汀或其生理学上可接受的盐或溶液和 4-(S)-(4-乙酰基-哌嗪-1-基)-2-(R)-(4-氟-2-甲基-苯基)-哌啶-1-羧酸[1-(R)-(3、5-双三氟甲基-苯基）-乙基]-甲酰胺或其药学上可接受的盐或溶剂，以及含有上述组合物的药物组合物和它们在治疗抑郁症和/或焦虑症中的用途。
• 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.