(2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one | 1432731-30-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: (2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one
• 英文别名: (2R,6R)-4-Benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one
• CAS: 1432731-30-0
• 化学式: C₁₃H₁₄F₃NO₂
• 分子量: 273.255
• InChiKey: BJFIRJXUIGGEHJ-MWLCHTKSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one 在 盐酸 、 lithium aluminium tetrahydride 、 palladium 10% on activated carbon 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 1.0h， 生成 (2R,6R)-2-methyl-6-(trifluoromethyl)morpholine hydrochloride
  参考文献：
  名称：

  发现 MK-8768，一种有效的选择性 mGluR2 负变构调节剂

  摘要：

  谷氨酸在认知和情绪中起着关键作用，研究表明，抑制离子型谷氨酸受体会破坏认知，而增强离子型受体活性则有利于认知。提高谷氨酸能张力的一种方法是拮抗突触前代谢型谷氨酸受体 2 (mGluR2)。对很大程度上同源的 mGluR3 的选择性的渴望激发了通过鉴定 mGluR2 负变构调节剂 (NAM) 来实现选择性的策略。经过广泛的筛选和优化工作，鉴定出了一系列新型 4-芳基喹啉-2-甲酰胺。该系列针对 mGluR2 NAM 效力、干净的脱靶活性和理想的物理性质进行了优化，从而鉴定出改进的 C4 和 C7 取代基。该系列的最初先导化合物在具有代谢激活的单一菌株中呈艾姆斯阳性，表明反应性代谢物可能导致遗传毒性。多个类似物的代谢分析和 Ames 评估确定了与 Ames 阳性相关的关键结构-活性关系。进一步优化产生了 Ames 阴性 mGluR2 负变构调节剂 MK-8768。

  DOI：

  10.1021/acsmedchemlett.3c00210
• 作为产物：
  描述：

  (S)-N-benzyl-2-hydroxy-N-((R)-3,3,3-trifluoro-2-hydroxypropyl)propanamide 在 sodium hydride 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 生成 (2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one
  参考文献：
  名称：

  发现 MK-8768，一种有效的选择性 mGluR2 负变构调节剂

  摘要：

  谷氨酸在认知和情绪中起着关键作用，研究表明，抑制离子型谷氨酸受体会破坏认知，而增强离子型受体活性则有利于认知。提高谷氨酸能张力的一种方法是拮抗突触前代谢型谷氨酸受体 2 (mGluR2)。对很大程度上同源的 mGluR3 的选择性的渴望激发了通过鉴定 mGluR2 负变构调节剂 (NAM) 来实现选择性的策略。经过广泛的筛选和优化工作，鉴定出了一系列新型 4-芳基喹啉-2-甲酰胺。该系列针对 mGluR2 NAM 效力、干净的脱靶活性和理想的物理性质进行了优化，从而鉴定出改进的 C4 和 C7 取代基。该系列的最初先导化合物在具有代谢激活的单一菌株中呈艾姆斯阳性，表明反应性代谢物可能导致遗传毒性。多个类似物的代谢分析和 Ames 评估确定了与 Ames 阳性相关的关键结构-活性关系。进一步优化产生了 Ames 阴性 mGluR2 负变构调节剂 MK-8768。

  DOI：

  10.1021/acsmedchemlett.3c00210

文献信息

• [EN] QUINOLINE CARBOXAMIDE AND QUINOLINE CARBONITRILE DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE<br/>[FR] DÉRIVÉS QUINOLÉINE CARBOXAMIDES ET QUINOLÉINE CARBONITRILES EN TANT QUE MODULATEURS ALLOSTÉRIQUES NÉGATIFS DE MGLUR2, COMPOSITIONS ET LEUR UTILISATION
  申请人：MERCK SHARP & DOHME

  公开号：WO2013066736A1

  公开（公告）日：2013-05-10

  The present invention provides quinoline carboxamide and quinoline carbonitrile compounds of formula (I) wherein ring A, RQ, -L-, R1, n, R2, and R3 are as defined herein. The compounds of the invention are useful as non-competitive mGluR2 antagonists, or mGluR2 negative allosteric modulators (NAMs), and in methods of treating a patient (preferably a human) for diseases or disorders in which the mGluR2-NAM receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, (optionally in combination with one or more additional active ingredients), and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.

  本发明提供了式(I)喹啉甲酰胺和喹啉腈化合物，其中环A，RQ，-L-，R1，n，R2和R3的定义如本文所述。本发明的化合物可用作非竞争性mGluR2拮抗剂或mGluR2负变构调节剂(NAMs)，并且用于治疗患者(最好是人类)的疾病或失调的方法，其中涉及mGluR2-NAM受体，如阿尔茨海默病，认知障碍，精神分裂症和其他情绪障碍，疼痛障碍和睡眠障碍，通过向患者投给治疗有效量的本发明化合物或其药用可接受的盐。本发明还涉及包含本发明化合物或其药用可接受的盐(可选地与一个或多个其他活性成分组合)和药用可接受载体的药物组合物，以及使用本发明的化合物和药物组合物治疗这些疾病。
• QUINOLINE CARBOXAMIDE AND QUINOLINE CARBONITRILE DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE
  申请人：MERCK SHARP & DOHME CORP.

  公开号：US20140309227A1

  公开（公告）日：2014-10-16

  The present invention provides quinoline carboxamide and quinoline carbonitrile compounds of formula (I) wherein ring A, R Q , -L-, R 1 , n, R 2 , and R 3 are as defined herein. The compounds of the invention are useful as non-competitive mGluR2 antagonists, or mGluR2 negative allosteric modulators (NAMs), and in methods of treating a patient (preferably a human) for diseases or disorders in which the mGluR2-NAM receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, (optionally in combination with one or more additional active ingredients), and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.

  本发明提供了公式（I）中环A、RQ、-L-、R1、n、R2和R3所定义的喹啉羧酰胺和喹啉羰基化合物。本发明的化合物可用作非竞争性mGluR2拮抗剂或mGluR2负向变构调节剂（NAMs），并且用于治疗患有mGluR2-NAM受体参与的疾病或障碍的患者（优选为人类），例如阿尔茨海默病、认知障碍、精神分裂症和其他情绪障碍、疼痛障碍和睡眠障碍，通过向患者投予本发明化合物或其药学上可接受的盐的治疗有效剂量。本发明还涉及包含本发明化合物或其药学上可接受的盐（可选与一种或多种其他活性成分组合）和药学上可接受的载体的制药组合物，以及本发明化合物和制药组合物在治疗此类疾病中的应用。
• Quinoline carboxamide and quinoline carbonitrile derivatives as mGluR2-negative allosteric modulators, compositions, and their use
  申请人：Merck Sharp & Dohme Corp.

  公开号：US09278960B2

  公开（公告）日：2016-03-08

  The present invention provides quinoline carboxamide and quinoline carbonitrile compounds of formula (I) wherein ring A, RQ, -L-, R1, n, R2, and R3 are as defined herein. The compounds of the invention are useful as non-competitive mGluR2 antagonists, or mGluR2 negative allosteric modulators (NAMs), and in methods of treating a patient (preferably a human) for diseases or disorders in which the mGluR2-NAM receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, (optionally in combination with one or more additional active ingredients), and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.

  本发明提供了式（I）中的喹啉羧酰胺和喹啉羰基化合物，其中环A，RQ，-L-，R1，n，R2和R3如本文所定义。本发明的化合物可用作非竞争性mGluR2拮抗剂，或mGluR2负向变构调节剂（NAMs），并用于治疗患有mGluR2-NAM受体参与的疾病或疾病的患者（首选为人类），如阿尔茨海默病，认知障碍，精神分裂症和其他情绪障碍，疼痛障碍和睡眠障碍，通过向患者给予本发明化合物或其药学上可接受的盐的治疗有效量。本发明还涉及包含本发明化合物或其药学上可接受的盐（可选地与一种或多种其他活性成分结合）和药学上可接受的载体的制药组合物，以及本发明化合物和制药组合物在治疗此类疾病中的用途。
• Quinoline Carboxamide and Quinoline Carbonitrile Derivatives as mGluR2-Negative Allosteric Modulators, Compositions, and Their Use
  申请人：Merck Sharp & Dohme Corp

  公开号：US20160158217A1

  公开（公告）日：2016-06-09

  The present invention provides quinoline carboxamide and quinoline carbonitrile compounds of formula (I) wherein ring A, R Q , -L-, R 1 , n, R 2 , and R 3 are as defined herein. The compounds of the invention are useful as non-competitive mGluR2 antagonists, or mGluR2 negative allosteric modulators (NAMs), and in methods of treating a patient (preferably a human) for diseases or disorders in which the mGluR2-NAM receptor is involved, including potentially Alzheimer's disease, cognitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, (optionally in combination with one or more additional active ingredients), and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.

  本发明提供了式（I）的喹啉羧酰胺和喹啉羰基化合物，其中环A、RQ、-L-、R1、n、R2和R3的定义如本文所述。本发明的化合物可用作非竞争性mGluR2拮抗剂，或mGluR2负向变构调节剂（NAMs），并用于治疗患有mGluR2-NAM受体参与的疾病或障碍的患者（优选为人类），包括潜在的阿尔茨海默病，认知障碍，精神分裂症和其他情绪障碍，疼痛障碍和睡眠障碍，通过向患者施用本发明化合物或其药学上可接受的盐的治疗有效量。本发明还涉及包含本发明化合物或其药学上可接受的盐（可选与一种或多种其他活性成分组合）和药学上可接受的载体的制药组合物，以及在治疗这些疾病中使用本发明的化合物和制药组合物。
• US9278960B2
  申请人：——

  公开号：US9278960B2

  公开（公告）日：2016-03-08