(3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-aminium hydrochloride | 1375470-88-4

• 物质功能分类: 有机原料 - 有机氟化合物
• 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: (3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-aminium hydrochloride
• 英文别名: (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride；(3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one；(3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one;hydrochloride
• CAS: 1375470-88-4
• 化学式: C₁₄H₁₇F₃N₂O*ClH
• 分子量: 322.758
• InChiKey: IXWPEFGFFDTWQC-GWFKABJVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  46.3
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-aminium hydrochloride 、 2’-oxo-1,1‘,2’,3-tetrahydrospiro[indene-2,4’-pyrido[2,3-d][1,3]oxazine]-5-carboxylic acid 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2’-oxo-1,1‘,2’,3-tetrahydrospiro[indene-2,4’-pyrido[2,3-d][1,3]oxazine]-5-carboxamide
  参考文献：
  名称：

  [EN] HETEROCYCLIC CGRP RECEPTOR ANTAGONISTS
  [FR] ANTAGONISTES DE RÉCEPTEUR DE CGRP HÉTÉROCYCLIQUES

  摘要：

  本发明涉及杂环化合物，其为CGRP受体拮抗剂，并可用于治疗或预防涉及CGRP的疾病，如偏头痛。该发明还涉及包含这些化合物的药物组合物，以及在预防或治疗涉及CGRP的疾病中使用这些化合物和组合物。

  公开号：

  WO2013169565A1
• 作为产物：
  描述：

  4-溴苯基丙酮 在 盐酸 、 palladium on activated charcoal 、 磷酸吡哆醛 、 transaminase ATA-426 、 potassium formate 、 potassium carbonate 、 caesium carbonate 、 对甲基苯甲酸 、 异丙胺 、 lithium tert-butoxide 作用下， 以 四氢呋喃 、 甲醇 、 甲基叔丁基醚 、 醋酸异丙酯 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 生成 (3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-aminium hydrochloride
  参考文献：
  名称：

  Ubrogepant. Calcitonin gene-related peptide (CGRP) receptor antagonist, Treatment of migraine

  摘要：

  Migraineis ranked as the sixth cause of years lost due to disability, with around 1.04 billion migraine sufferers globally. Triptans are considered the standard for acute migraine treatment, but an important number of migraineurs do not respond to them and these drugs are contraindicated in patients with cardiovascular disease. Migraine therapy is currently undergoing tremendous development, i.e., 5-HT1F receptor agonists (ditans), anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies, and small-molecule CGRP receptor antagonists (gepants). Ubrogepant (MK-1620) is a small-molecule, potent and selective CGRP receptor antagonist. In two phase III clinical trials (ACHIEVE I and II), ubrogepant showed, at 2 hours, significant percentages of pain freedom, and absence of the most bothersome symptoms in migraine patients. In a phase III study to assess the long-term (52-week) safety and tolerability, ubrogepant displayed good tolerability, and no signs of hepatic toxicity. In March 2019, the U.S. Food and Drug Administration accepted the new drug application (NDA) for ubrogepant for the acute treatment of migraine.

  DOI：

  10.1358/dof.2019.44.11.3035581

文献信息

• [EN] SPIROLACTAM CGRP RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DE RÉCEPTEUR DE CGRP À BASE DE SPIROLACTAME
  申请人：MERCK SHARP & DOHME

  公开号：WO2013169567A1

  公开（公告）日：2013-11-14

  The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

  本发明涉及螺内酰胺类似物，其为CGRP受体拮抗剂，可用于治疗或预防涉及CGRP的疾病，如偏头痛。该发明还涉及包含这些化合物的药物组合物，以及在预防或治疗涉及CGRP的这类疾病中使用这些化合物和组合物。
• PIPERIDINONE CARBOXAMIDE AZAINDANE CGRP RECEPTOR ANTAGONISTS
  申请人：Bell Ian M.

  公开号：US20120122899A1

  公开（公告）日：2012-05-17

  The present invention is directed to piperidinone carboxamide azaindane derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

  本发明涉及哌啶酮羧酰胺吖啶衍生物，它们是CGRP受体拮抗剂，可用于治疗或预防CGRP参与的疾病，如偏头痛。该发明还涉及包含这些化合物的药物组合物，以及在预防或治疗CGRP参与的这类疾病中使用这些化合物和组合物。
• Practical Asymmetric Synthesis of a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist Ubrogepant
  作者：Nobuyoshi Yasuda、Ed Cleator、Birgit Kosjek、Jianguo Yin、Bangping Xiang、Frank Chen、Shen-Chun Kuo、Kevin Belyk、Peter R. Mullens、Adrian Goodyear、John S. Edwards、Brian Bishop、Scott Ceglia、Justin Belardi、Lushi Tan、Zhiguo J. Song、Lisa DiMichele、Robert Reamer、Fabien L. Cabirol、Weng Lin Tang、Guiquan Liu

  DOI：10.1021/acs.oprd.7b00293

  日期：2017.11.17

  The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an

  描述了一种新的降钙素基因相关肽（CGRP）受体拮抗剂的可扩展的不对称路线的发展。重新定义了两个关键片段的合成，并通过新型化学方法访问了中间体。手性内酰胺2是通过同时介导两个立体中心的酶介导的动态动力学氨基转移反应制备的。酶的进化产生了优化的转氨酶，提供了大于60：1的syn / anti所需的构型。最终的手性中心是通过结晶诱导的非对映异构转变而设定的。不对称螺环化形成第二个片段，手性螺酸中间体3，由一种新型的双季铵化的相转移催化剂催化，并在分离时提供了光学纯的材料。有了这两个片段，描述了通过酰胺键形成以及随后的直接分离来发展其最终结合的过程。所描述的化学物质已用于递送超过100公斤的所需目标物，泛素。
• [EN] PIPERIDINE CARBOXAMIDE SPIROHYDANTOIN CGRP RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES SPIROHYDANTOÏNES DES RÉCEPTEURS CGRP DE TYPE CARBOXAMIDE DE PIPÉRIDINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2012129014A1

  公开（公告）日：2012-09-27

  The present invention is directed to piperidinone carboxamide spirohydantoin derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

  本发明涉及吡啶酮羧酰胺螺内酰脲衍生物，这些衍生物是CGRP受体拮抗剂，并且在治疗或预防涉及CGRP的疾病，如偏头痛等方面具有用途。该发明还涉及包含这些化合物的药物组合物，以及在预防或治疗涉及CGRP的这类疾病中使用这些化合物和组合物。
• SPIROLACTAM CGRP RECEPTOR ANTAGONISTS
  申请人：Merck Sharp & Dohme Corp.

  公开号：US20150111914A1

  公开（公告）日：2015-04-23

  The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

  本发明涉及螺内酰胺类似物，其为CGRP受体拮抗剂，可用于治疗或预防CGRP参与的疾病，如偏头痛。本发明还涉及包含这些化合物的药物组合物以及在预防或治疗CGRP参与的这些疾病中使用这些化合物和组合物的用途。