4-chloro-6-(3,4-dichloro-phenyl)-5-methyl-pyrimidine | 1426320-75-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-chloro-6-(3,4-dichloro-phenyl)-5-methyl-pyrimidine
• 英文别名: 4-chloro-6-(3,4-dichlorophenyl)-5-methylpyrimidine
• CAS: 1426320-75-3
• 化学式: C₁₁H₇Cl₃N₂
• 分子量: 273.549
• InChiKey: FMPAJFPUZKBALP-UHFFFAOYSA-N

物化性质

• 沸点：
  380.4±37.0 °C(Predicted)
• 密度：
  1.415±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  25.8
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-chloro-6-(3,4-dichloro-phenyl)-5-methyl-pyrimidine 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 20.0~50.0 ℃ 、500.01 kPa 条件下， 反应 34.0h， 生成 6-(3,4-dichlorophenyl)-5-methylpyrimidine-4-carboxylic acid
  参考文献：
  名称：

  Development of a Series of Aryl Pyrimidine Kynurenine Monooxygenase Inhibitors as Potential Therapeutic Agents for the Treatment of Huntington’s Disease

  摘要：

  We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.

  DOI：

  10.1021/jm501350y
• 作为产物：
  描述：

  4,6-二氯-5-甲基嘧啶 、 3,4-二氯苯硼酸 在 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 1,4-二氧六环 为溶剂， 反应 16.0h， 以42%的产率得到4-chloro-6-(3,4-dichloro-phenyl)-5-methyl-pyrimidine
  参考文献：
  名称：

  [EN] KYNURENINE-3-MONOOXYGENASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
  [FR] INHIBITEURS DE KYNURÉNINE-3-MONOOXYGÉNASE, COMPOSITIONS PHARMACEUTIQUES ET PROCÉDÉS D'UTILISATION DE CES COMPOSITIONS

  摘要：

  本文提供了某些化学实体。还提供了包括至少一种化学实体和一种或多种药用可接受载体的药物组合物。描述了治疗对KMO活性抑制敏感的某些疾病和疾病的方法，包括向这些患者施用至少一种化学实体的有效量以减少疾病或疾病的体征或症状。这些疾病包括亨廷顿病等神经退行性疾病。还描述了治疗方法，包括将至少一种化学实体作为单一活性剂或将至少一种化学实体与一种或多种其他治疗剂结合使用。还提供了筛选能够抑制KMO活性的化合物的方法。

  公开号：

  WO2013033068A1

文献信息

• [EN] KYNURENINE-3-MONOOXYGENASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF<br/>[FR] INHIBITEURS DE KYNURÉNINE-3-MONOOXYGÉNASE, COMPOSITIONS PHARMACEUTIQUES ET PROCÉDÉS D'UTILISATION DE CES COMPOSITIONS
  申请人：COURTNEY STEPHEN MARTIN

  公开号：WO2013033068A1

  公开（公告）日：2013-03-07

  Certain chemical entities are provided herein. Also provided are pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of KMO activity are described, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one chemical entity as a single active agent or administering at least one chemical entity in combination with one or more other therapeutic agents. Also provided are methods for screening compounds capable of inhibiting KMO activity.

  本文提供了某些化学实体。还提供了包括至少一种化学实体和一种或多种药用可接受载体的药物组合物。描述了治疗对KMO活性抑制敏感的某些疾病和疾病的方法，包括向这些患者施用至少一种化学实体的有效量以减少疾病或疾病的体征或症状。这些疾病包括亨廷顿病等神经退行性疾病。还描述了治疗方法，包括将至少一种化学实体作为单一活性剂或将至少一种化学实体与一种或多种其他治疗剂结合使用。还提供了筛选能够抑制KMO活性的化合物的方法。
• KYNURENINE-3-MONOOXYGENASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
  申请人：Courtney Stephen Martin

  公开号：US20160251318A1

  公开（公告）日：2016-09-01

  Certain chemical entities are provided herein. Also provided are pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of KMO activity are described, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one chemical entity as a single active agent or administering at least one chemical entity in combination with one or more other therapeutic agents. Also provided are methods for screening compounds capable of inhibiting KMO activity.

  本文提供了某些化学实体。还提供了包含至少一种化学实体和一个或多个药用载体的制药组合物。描述了治疗对KMO活性抑制有反应的某些疾病和障碍的患者的方法，其中包括向这些患者施用至少一种化学实体的有效量，以减轻疾病或障碍的症状。这些疾病包括神经退行性疾病，如亨廷顿病。还描述了治疗方法，包括单独使用至少一种化学实体作为活性药剂或与一个或多个其他治疗剂联合使用至少一种化学实体。此外，还提供了筛选能够抑制KMO活性的化合物的方法。
• US9428464B2
  申请人：——

  公开号：US9428464B2

  公开（公告）日：2016-08-30
• US9981918B2
  申请人：——

  公开号：US9981918B2

  公开（公告）日：2018-05-29
• Development of a Series of Aryl Pyrimidine Kynurenine Monooxygenase Inhibitors as Potential Therapeutic Agents for the Treatment of Huntington’s Disease
  作者：Leticia M. Toledo-Sherman、Michael E. Prime、Ladislav Mrzljak、Maria G. Beconi、Alan Beresford、Frederick A. Brookfield、Christopher J. Brown、Isabell Cardaun、Stephen M. Courtney、Ulrike Dijkman、Estelle Hamelin-Flegg、Peter D. Johnson、Valerie Kempf、Kathy Lyons、Kimberly Matthews、William L. Mitchell、Catherine O’Connell、Paula Pena、Kendall Powell、Arash Rassoulpour、Laura Reed、Wolfgang Reindl、Suganathan Selvaratnam、Weslyn Ward Friley、Derek A. Weddell、Naomi E. Went、Patricia Wheelan、Christin Winkler、Dirk Winkler、John Wityak、Christopher J. Yarnold、Dawn Yates、Ignacio Munoz-Sanjuan、Celia Dominguez

  DOI：10.1021/jm501350y

  日期：2015.2.12

  We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.