(2R)-2-(4-fluoro-2-methylphenyl)-4-piperidinone L-(+)-mandelate | 414910-13-7

• 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: (2R)-2-(4-fluoro-2-methylphenyl)-4-piperidinone L-(+)-mandelate
• 英文别名: (2R)-2-(4-fluoro-2-methylphenyl)-4-piperidinone (2S)-hydroxy(phenyl)ethanoic acid；2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-one mandelic acid；2-(4-Fluoro-2-methylphenyl)piperidin-4-one 2-hydroxy-2-phenylacetate；(2R)-2-(4-fluoro-2-methylphenyl)piperidin-4-one;(2S)-2-hydroxy-2-phenylacetic acid
• CAS: 414910-13-7
• 化学式: C₈H₈O₃*C₁₂H₁₄FNO
• 分子量: 359.397
• InChiKey: HQSMDORBTCGVLS-OLBMHGAYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.93
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  86.6
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2R)-2-(4-fluoro-2-methylphenyl)-4-piperidinone L-(+)-mandelate 以 乙酸乙酯 为溶剂， 反应 45.0h， 以30%的产率得到
  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
• 作为产物：
  描述：

  2-溴-5-氟甲苯 在 Wilkinson's catalyst 、 5% Pd(II)/C(eggshell) 、 氢气 、 碘 、 碳酸氢钠 、 magnesium 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 异丙醇 为溶剂， -20.0~70.0 ℃ 、500.01 kPa 条件下， 反应 10.5h， 生成 (2R)-2-(4-fluoro-2-methylphenyl)-4-piperidinone L-(+)-mandelate
  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

• 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。
• Spiro (Piperidine-4,2'-Pyrrolidine)-1-(3,5-Trifluoromethyl Phenyl) Methylcarboxamides As NK1 Tachikynin Receptor Antagonists
  申请人：Alvaro Giuseppe

  公开号：US20110053922A1

  公开（公告）日：2011-03-03

  Compounds of formula (I) or a pharmaceutically acceptable salt thereof wherein R is hydrogen or C 1-4 alkyl; R 1 is hydrogen, C 1-4 alkyl, C(O)OH, C(O)NH 2 or (C 1-4 alkylene)R 10 ; R 2 and R 3 are independently hydrogen, C 1-4 alkyl or R 2 together with R 3 and together with the carbon atom to which they are attached form a C 3-8 cycloalkyl group; R 4 is C 1-4 alkyl, C 1-4 alkoxy or halogen; R 5 and R 7 are independently hydrogen, hydroxy, halogen, C(O)NH 2 , C(O)OH or (C 1-4 alkylene) R 10 ; R 6 and R 8 are independently hydrogen or halogen; R 9 is hydrogen, (C 1-4 alkylene)R 10 , C(O)NH 2 , C(O)OH or R 9 together with R form a 6 membered heterocyclic ring optionally containing a further heteroatom selected from oxygen, sulphur or nitrogen; R 10 is hydrogen, halogen, hydroxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(C 1-4 alkyl) 2 or C(O)OH; n is 0, 1 or 2. processes for their preparation, to compositions containing them and to their use in the treatment of diseases and conditions for which antagonism of NK1 is beneficial.

  化合物式（I）或其药学上可接受的盐，其中： R为氢或C1-4烷基； R1为氢，C1-4烷基，C（O）OH，C（O）NH2或（C1-4烷基）R10； R2和R3分别为氢，C1-4烷基或R2与R3以及它们连接到的碳原子一起形成C3-8环烷基； R4为C1-4烷基，C1-4烷氧基或卤素； R5和R7分别为氢，羟基，卤素，C（O）NH2，C（O）OH或（C1-4烷基）R10； R6和R8分别为氢或卤素； R9为氢，（C1-4烷基）R10，C（O）NH2，C（O）OH或R9与R一起形成一个6元杂环环，可选地含有进一步的杂原子，选择自氧、硫或氮； R10为氢，卤素，羟基，C（O）NH2，C（O）NH（C1-4烷基），C（O）N（C1-4烷基）2或C（O）OH； n为0、1或2。 本发明还涉及它们的制备方法、含有它们的组合物以及它们在治疗需要抗NK1的疾病和症状中的用途。
• Anhydrous Crystal Form Of Ovrepitant Maleate
  申请人：Beato Stefania

  公开号：US20110166150A1

  公开（公告）日：2011-07-07

  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.

  本发明涉及无水结晶的orvepitant maleate（Form 1），包括该物质的制药配方，其在治疗中的应用以及其制备过程。
• Spiro (piperidine-4,2′-pyrrolidine)-1-(3,5-trifluoromethyl phenyl) methylcarboxamides as NK1 tachikynin receptor antagonists
  申请人：Alvaro Giuseppe

  公开号：US08367692B2

  公开（公告）日：2013-02-05

  Compounds of formula (I) or a pharmaceutically acceptable salt thereof. wherein R is hydrogen or C1-4 alkyl; R1 is hydrogen, C1-4 alkyl, C(O)OH, C(O)NH2 or (C1-4 alkylene)R10; R2 and R3 are independently hydrogen, C1-4 alkyl or R2 together with R3 and together with the carbon atom to which they are attached form a C3-8 cycloalkyl group; R4 is C1-4 alkyl, C1-4 alkoxy or halogen; R5 and R7 are independently hydrogen, hydroxy, halogen, C(O)NH2, C(O)OH or (C1-4 alkylene)R10; R6 and R8 are independently hydrogen or halogen; R9 is hydrogen, (C1-4 alkylene)R10, C(O)NH2, C(O)OH or R9 together with R form a 6 membered heterocyclic ring optionally containing a further heteroatom selected from oxygen, sulphur or nitrogen; R10 is hydrogen, halogen, hydroxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2 or C(O)OH; n is 0, 1 or 2. processes for their preparation, to compositions containing them and to their use in the treatment of diseases and conditions for which antagonism of NK1 is beneficial.

  化合物的结构式(I)或其药学上可接受的盐。其中，R代表氢或C1-4烷基；R1代表氢、C1-4烷基、C（O）OH、C（O）NH2或（C1-4烷基）R10；R2和R3分别代表氢、C1-4烷基或R2与R3一起并与它们所连接的碳原子形成C3-8环烷基；R4代表C1-4烷基、C1-4烷氧基或卤素；R5和R7分别代表氢、羟基、卤素、C（O）NH2、C（O）OH或（C1-4烷基）R10；R6和R8分别代表氢或卤素；R9代表氢、（C1-4烷基）R10、C（O）NH2、C（O）OH或R9与R一起形成一个6元杂环环，该环可选地含有进一步从氧、硫或氮中选择的杂原子；R10代表氢、卤素、羟基、C（O）NH2、C（O）NH（C1-4烷基）、C（O）N（C1-4烷基）2或C（O）OH；n代表0、1或2。其制备方法、含有它们的组合物以及它们在治疗需要抗NK1的疾病和病况中的用途。