6-(2,4-difluorophenyl)pyrimidine-4-carboxylic acid methyl ester | 1207723-92-9

• 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: 6-(2,4-difluorophenyl)pyrimidine-4-carboxylic acid methyl ester
• 英文别名: Methyl 6-(2,4-difluorophenyl)pyrimidine-4-carboxylate
• CAS: 1207723-92-9
• 化学式: C₁₂H₈F₂N₂O₂
• 分子量: 250.205
• InChiKey: SNDHTSJDNIKVPE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  52.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-(2,4-difluorophenyl)pyrimidine-4-carboxylic acid methyl ester 在 lithium hydroxide monohydrate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 0.75h， 以97%的产率得到6-(2,4-difluorophenyl)pyrimidine-4-carboxylic acid
  参考文献：
  名称：

  发现有效的，选择性的，口服的CXCR7拮抗剂ACT-1004-1239

  摘要：

  趋化因子受体CXCR7，也称为ACKR3，是七种跨膜G蛋白偶联受体（GPCR），涉及多种病理，例如神经系统疾病，自身免疫性疾病和癌症。通过结合和清除趋化因子CXCL11和CXCL12，CXCR7调节它们的细胞外水平。在最初的高通量筛选活动中，出现了热门3。一触即发的优化导致发现了一种新型的化学型系列，例如反式外消旋化合物11i。该系列提供了可阻断CXCL11和CXCL12诱导的β-arrestin募集的CXCR7拮抗剂。11i的三取代哌啶骨架的进一步结构修饰产生具有高CXCR7拮抗活性和平衡ADMET性质的化合物。本文所述的努力最终导致了ACT-1004-1239（28f）的发现。ACT-1004-1239的生物学特性表明它是一种有效的，不可逾越的拮抗剂。在小鼠中口服ACT-1004-1239的剂量高达100 mg / kg导致血浆CXCL12浓度呈剂量依赖性增加。

  DOI：

  10.1021/acs.jmedchem.0c01588
• 作为产物：
  描述：

  2,4-二氟苯硼酸 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 四(三苯基膦)钯 、 potassium carbonate 、 三乙胺 作用下， 50.0~90.0 ℃ 、500.01 kPa 条件下， 反应 20.0h， 生成 6-(2,4-difluorophenyl)pyrimidine-4-carboxylic acid methyl ester
  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

文献信息

• CERTAIN KYNURENINE-3-MONOOXYGENASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
  申请人：CHDI, Inc.

  公开号：EP2331095A1

  公开（公告）日：2011-06-15
• KYNURENINE-3-MONOOXYGENASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
  申请人：Courtney Stephen Martin

  公开号：US20140329795A1

  公开（公告）日：2014-11-06

  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.
• US8536186B2
  申请人：——

  公开号：US8536186B2

  公开（公告）日：2013-09-17
• US9145373B2
  申请人：——

  公开号：US9145373B2

  公开（公告）日：2015-09-29
• US9428464B2
  申请人：——

  公开号：US9428464B2

  公开（公告）日：2016-08-30