methyl 2-(3-(1-(2,6-difluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-methyl-1H-indol-1-yl)acetate | 1558049-98-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: methyl 2-(3-(1-(2,6-difluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-methyl-1H-indol-1-yl)acetate
• CAS: 1558049-98-1
• 化学式: C₂₄H₁₉F₃N₂O₃
• 分子量: 440.422
• InChiKey: KZPKIMSPHDMNSA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.42
• 重原子数：
  32.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  53.23
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  methyl 2-(3-(1-(2,6-difluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-methyl-1H-indol-1-yl)acetate 在 lithium hydroxide monohydrate 作用下， 以 四氢呋喃 为溶剂， 反应 0.92h， 以78%的产率得到2-(3-(1-(2,6-difluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-methyl-1H-indol-1-yl)acetic acid
  参考文献：
  名称：

  Discovery of Isoquinolinone Indole Acetic Acids as Antagonists of Chemoattractant Receptor Homologous Molecule Expressed on Th2 Cells (CRTH2) for the Treatment of Allergic Inflammatory Diseases

  摘要：

  Previously we reported the discovery of CRA-898 (1), a diazine indole acetic acid containing CRTH2 antagonist. This compound had good in vitro and in vivo potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. However, it showed low oral exposure in nonrodent safety species (dogs and monkeys). In the current paper, we wish to report our efforts to understand and improve the poor PK in nonrodents and development of a new isoquinolinone subseries that led to identification of a new development candidate, CRA-680 (44). This compound was efficacious in both a house dust mouse model of allergic lung inflammation (40 mg/kg qd) as well as a guinea pig allergen challenge model of lung inflammation (20 mg/kg bid).

  DOI：

  10.1021/jm401509e
• 作为产物：
  描述：

  3-bromo-5-fluoro-2-methyl-1H-indole 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium carbonate 、 caesium carbonate 、 sodium iodide 作用下， 以 乙二醇二甲醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 18.33h， 生成 methyl 2-(3-(1-(2,6-difluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-methyl-1H-indol-1-yl)acetate
  参考文献：
  名称：

  Discovery of Isoquinolinone Indole Acetic Acids as Antagonists of Chemoattractant Receptor Homologous Molecule Expressed on Th2 Cells (CRTH2) for the Treatment of Allergic Inflammatory Diseases

  摘要：

  Previously we reported the discovery of CRA-898 (1), a diazine indole acetic acid containing CRTH2 antagonist. This compound had good in vitro and in vivo potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. However, it showed low oral exposure in nonrodent safety species (dogs and monkeys). In the current paper, we wish to report our efforts to understand and improve the poor PK in nonrodents and development of a new isoquinolinone subseries that led to identification of a new development candidate, CRA-680 (44). This compound was efficacious in both a house dust mouse model of allergic lung inflammation (40 mg/kg qd) as well as a guinea pig allergen challenge model of lung inflammation (20 mg/kg bid).

  DOI：

  10.1021/jm401509e