4-chloro-7-[(2,5-dioxopyrrolidin-1-yl)methyl]quinoline-2-carbonitrile | 1432731-20-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 4-chloro-7-[(2,5-dioxopyrrolidin-1-yl)methyl]quinoline-2-carbonitrile
• 英文别名: 4-Chloro-7-((2,5-dioxopyrrolidin-1-yl)methyl)quinoline-2-carbonitrile
• CAS: 1432731-20-8
• 化学式: C₁₅H₁₀ClN₃O₂
• 分子量: 299.716
• InChiKey: GPXZCPLCHZULJA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  74.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-chloro-7-[(2,5-dioxopyrrolidin-1-yl)methyl]quinoline-2-carbonitrile 在 sodium percarbonate 、 四(三苯基膦)钯 、 sodium carbonate 、 caesium carbonate 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 20.0h， 生成 7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-(2-fluoroethoxy)phenyl)quinoline-2-carboxamide
  参考文献：
  名称：

  Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[¹¹C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2

  摘要：

  Metabotropic glutamate 2 receptors (mGlu(2)) are involved in the pathogenesis of several CNS disorders and neurodegenerative diseases. Pharmacological modulation of this target represents a potential disease modifying approach for the treatment of substance abuse, depression, schizophrenia, and dementias. While quantification of mGlu(2) receptors in the living brain by positron emission tomography (PET) would help us better understand signaling pathways relevant to these conditions, few successful examples have been demonstrated to image mGlu(2) in vivo, and a suitable PET tracer is yet to be identified. Herein we report the design and synthesis of a radiolabeled negative allosteric modulator (NAM) for mGlu(2) PET tracer development based on a quinoline 2-carboxamide scaffold. The most promising candidate, 74(2,5-dioxopyrrolidin-l-yOmethyl)-4-(2-fluoro-4-[C-11]methoxyphenyl) quinoline-2-carboxamide ([C-11]QCA) was prepared in 13% radiochemical yield (non-decay-corrected at the end of synthesis) with >99% radiochemical purity and >74 GBq/pmol (2 Ci/mu mol) specific activity. While the tracer showed limited brain uptake (0.3 SUV), probably attributable to effects on PgP/Bcrp efflux pump, in vitro autoradiography studies demonstrated heterogeneous brain distribution and specific binding. Thus, [C-11]QCA is a chemical probe that provides the basis for the development of a new generation mGlu(2) PET tracers.

  DOI：

  10.1021/acschemneuro.7b00098
• 作为产物：
  描述：

  7-甲基喹啉 在 N-溴代丁二酰亚胺(NBS) 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 二甲氨基甲酰氯 、 三氯氧磷 、 过氧化苯甲酰 作用下， 以 二氯甲烷 、 氯仿 、 乙腈 为溶剂， 反应 17.0h， 生成 4-chloro-7-[(2,5-dioxopyrrolidin-1-yl)methyl]quinoline-2-carbonitrile
  参考文献：
  名称：

  发现4-芳基喹啉-2-羧酰胺，高效和选择性的mGluR2负变构调节剂：从高温超导到动物模型中的活性

  摘要：

  mGluR2受体的拮抗作用可能通过提高突触谷氨酸（大脑中主要的兴奋性神经递质）为认知障碍提供治疗益处。但是，鉴于该受体与mGluR3的同源性非常高，尤其是在正构结合位点，迄今为止，对它的选择性拮抗作用一直难以捉摸。鉴于对mGluR3的抑制与不希望的作用有关，我们寻求鉴定选择性的mGluR2负变构调节剂。在本文中，我们描述了在成功的HTS运动和药物化学优化之后，mGluR2负变构调节剂4-芳基喹啉-2-羧酰胺的高度有效和选择性类别的发现，表明其在啮齿动物中具有有效的体内功效。

  DOI：

  10.1016/j.bmcl.2020.127066

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