(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride
• 英文别名: (S)-(3-fluoropyridin-2-yl)-[3-fluoro-4-(trifluoromethoxy)phenyl]methanamine;hydrochloride
• 化学式: C₁₃H₉F₅N₂O*(x)ClH
• 分子量: 340.67
• InChiKey: ZTQQGAQEPTUGBN-MERQFXBCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.73
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  48.1
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride 在 sodium hydroxide 作用下， 以 2-甲基四氢呋喃 为溶剂， 反应 1.0h， 以99%的产率得到(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine
  参考文献：
  名称：

  二芳基甲胺的结晶诱导动态拆分对强效TRPM8抑制剂的合成

  摘要：

  描述了制备手性二芳基甲胺的结晶诱导的动态拆分（CIDR）的开发和演示，该手性二芳基甲胺是合成有效TRPM8抑制剂的关键中间体。开发该方法的关键是发现（1）通过高通量筛选方法获得有效的经典拆分条件，（2）基于一级反应速率常数的比较，将甲醛作为最佳外消旋剂，以及（3）机械研磨是改善固液传质并促进反应进程的一种方法。外消旋过程的动力学分析和外消旋所需的底物官能团的鉴定为机理建议提供了基础。

  DOI：

  10.1021/acs.oprd.6b00162
• 作为产物：
  描述：

  3-氟吡啶 在 三乙烯二胺 、 盐酸 、 正丁基锂 、 copper(II) sulfate 、 magnesium 作用下， 以 四氢呋喃 、 乙醚 、 正己烷 、 二氯甲烷 为溶剂， 反应 8.5h， 生成 (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride
  参考文献：
  名称：

  Discovery of TRPM8 Antagonist (S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine

  摘要：

  Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a non-selective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.

  DOI：

  10.1021/acs.jmedchem.8b00518

文献信息

• [EN] TRPM8 ANTAGONISTS AND THEIR USE IN TREATMENTS<br/>[FR] ANTAGONISTES DE TRPM8 ET LEUR UTILISATION DANS LE CADRE THÉRAPEUTIQUE
  申请人：AMGEN INC

  公开号：WO2012177896A1

  公开（公告）日：2012-12-27

  Compounds of Formula (I) are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula (I) have the above structure, where the definitions of the variables are provided herein.

  式（I）的化合物可用作TRPM8的拮抗剂。这些化合物在治疗许多TRPM8介导的疾病和症状方面具有用处，并可用于制备用于治疗这些疾病和症状的药物和药物组合物。这些疾病的例子包括但不限于偏头痛和神经病性疼痛。式（I）的化合物具有上述结构，其中变量的定义在此提供。
• TRPM8 ANTAGONISTS AND THEIR USE IN TREATMENTS
  申请人：BROWN James

  公开号：US20130158034A1

  公开（公告）日：2013-06-20

  Compounds of Formula I are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.

  式I的化合物是TRPM8拮抗剂，对于治疗许多TRPM8介导的疾病和症状有用，并可用于制备治疗此类疾病和症状的药物和制剂。此类疾病的例子包括但不限于偏头痛和神经病性疼痛。式I的化合物具有以下结构：其中变量的定义在此提供。
• TRPM8 antagonists and their use in treatments
  申请人：Brown James

  公开号：US08778941B2

  公开（公告）日：2014-07-15

  Compounds of Formula I are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.

  公式I的化合物可用作TRPM8的拮抗剂。这些化合物可用于治疗多种TRPM8介导的疾病和病症，并可用于制备用于治疗此类疾病和病症的药物和制剂。此类疾病的示例包括但不限于偏头痛和神经病性疼痛。公式I的化合物具有以下结构：其中变量的定义在此提供。
• US8710043B2
  申请人：——

  公开号：US8710043B2

  公开（公告）日：2014-04-29
• US8778941B2
  申请人：——

  公开号：US8778941B2

  公开（公告）日：2014-07-15