N-methoxy-N-methyl-4-(trifluoromethyl)nicotinamide | 323180-94-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: N-methoxy-N-methyl-4-(trifluoromethyl)nicotinamide
• 英文别名: 4-trifluoromethylnicotinic acid-N-methyl-N-methoxy-amide；N-methoxy-N-methyl-4-(trifluoromethyl)pyridine-3-carboxamide
• CAS: 323180-94-5
• 化学式: C₉H₉F₃N₂O₂
• 分子量: 234.178
• InChiKey: FSWDISCZHTVENR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  42.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-methoxy-N-methyl-4-(trifluoromethyl)nicotinamide 在 diisopropyl aluminum hydride 、 copper(II) sulfate 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 70.0h， 生成 (R)-2-methyl-N-((4-(trifluoromethyl)pyridin-3-yl)methylene)propane-2-sulfinamide
  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
• 作为产物：
  描述：

  二甲羟胺盐酸盐 、 4-三氟甲基烟酸 在 HATU 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 生成 N-methoxy-N-methyl-4-(trifluoromethyl)nicotinamide
  参考文献：
  名称：

  [EN] TRPM8 ANTAGONISTS AND THEIR USE IN TREATMENTS
  [FR] ANTAGONISTES DE TRPM8 ET LEUR UTILISATION DANS DES TRAITEMENTS

  摘要：

  公开号：

  WO2012177893A3

文献信息

• Asymmetric Defluoroallylation of 4‐Trifluoromethylpyridines Enabled by Umpolung C−F Bond Activation**
  作者：Fei‐Yu Zhou、Lei Jiao

  DOI：10.1002/anie.202201102

  日期：2022.5.16

  trifluoromethyl group represents a formidable challenge. An asymmetric defluoroallylation reaction of 4-trifluoromethylpyridines and -pyrimidines is reported, which features an umpolung C−F bond activation, a broad substrate scope and excellent enantioselectivities.

  三氟甲基的对映选择性脱氟转化是一项艰巨的挑战。报道了 4-三氟甲基吡啶和 -嘧啶的不对称脱氟烯丙基化反应，其特点是具有超大的 C-F 键活化、广泛的底物范围和优异的对映选择性。
• TRPM8 ANTAGONISTS AND THEIR USE IN TREATMENTS
  申请人：Biswas Kaustav

  公开号：US20130157996A1

  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.

  公式I的化合物可用作TRPM8的拮抗剂。这些化合物在治疗许多TRPM8介导的疾病和病症方面非常有用，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。
• TRPM8 antagonists and their use in treatments
  申请人：Chen Jian J.

  公开号：US08710043B2

  公开（公告）日：2014-04-29

  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的化合物可作为TRPM8拮抗剂使用。这些化合物可用于治疗多种TRPM8介导的疾病和症状，并可用于制备治疗此类疾病和症状的药物和制剂。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的化合物具有以下结构：其中变量的定义在此提供。
• [EN] TRPM8 ANTAGONISTS AND THEIR USE IN TREATMENTS<br/>[FR] ANTAGONISTES DE TRPM8 ET LEUR UTILISATION DANS DES TRAITEMENTS
  申请人：AMGEN INC

  公开号：WO2012177893A3

  公开（公告）日：2013-06-13
• TRIFLUOROMETHYLPYRI(MI)DINE CARBOXAMIDES
  申请人：Syngenta Participations AG

  公开号：EP1200413A1

  公开（公告）日：2002-05-02