Cyano-[5-fluoro-1-(4-methyl-benzyl)-2-oxo-1,2-dihydro-indol-(3E)-ylidene]-acetic acid | 522612-31-3

• 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: Cyano-[5-fluoro-1-(4-methyl-benzyl)-2-oxo-1,2-dihydro-indol-(3E)-ylidene]-acetic acid
• 英文别名: 2-cyano-2-[5-fluoro-1-[(4-methylphenyl)methyl]-2-oxoindol-3-ylidene]acetic acid
• CAS: 522612-31-3
• 化学式: C₁₉H₁₃FN₂O₃
• 分子量: 336.322
• InChiKey: SCHCVAFKKHLFIL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.04
• 重原子数：
  25.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  81.4
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  Cyano-[5-fluoro-1-(4-methyl-benzyl)-2-oxo-1,2-dihydro-indol-(3E)-ylidene]-acetic acid 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 为溶剂， 以45%的产率得到Cyano-[5-fluoro-1-(4-methyl-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-acetic acid
  参考文献：
  名称：

  Novel, Highly Potent Aldose Reductase Inhibitors:  Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic Acid Derivatives

  摘要：

  Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives were synthesized and tested as a novel class of aldose reductase (ALR2) inhibitors. Each compound was evaluated as a diastereomeric mixture, due to tautomeric equilibria in solution. The parent compound 39 exhibited a good inhibitory activity with an IC50 value of 0.85 muM, similar to that of the well-known ARI sorbinil (IC50 0.50 muM). The concurrent introduction of a halogen and a lipophilic group in the 5- and in the 1-positions, respectively, of the indole nucleus of 39, gave compound 55, cyano[5-fluoro-1-(4-methylbenzyl)-2-oxo-2,3-dihydroindol-3-yl] acetic acid, which displayed the highest activity (IC50 0.075 muM, very close to that of tolrestat IC50 0.046 muM), with a good selectivity toward ALR2 compared with aldehyde reductase (ALR1) (16.4-fold), and no appreciable inhibitory properties against sorbitol dehydrogenase (SD), or glutathione reductase (GR). The isopropyl ester 59, a prodrug of 55, was found to be almost as effective as tolrestat in preventing cataract development in severely galactosemic rats when administered as an eye drop solution. Docking simulation of 55 into a three-dimensional model of human ALR2 made it possible to formulate the hypothesis that the 2-hydroxy tautomer was the active species binding into the catalytic site of the enzyme. This was fully consistent with the structure-activity relationships within this series of cyanooxoindolylacetic acid derivatives.

  DOI：

  10.1021/jm030762f
• 作为产物：
  描述：

  5-氟靛红 在 sodium hydride 、 三乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成 Cyano-[5-fluoro-1-(4-methyl-benzyl)-2-oxo-1,2-dihydro-indol-(3E)-ylidene]-acetic acid
  参考文献：
  名称：

  Novel, Highly Potent Aldose Reductase Inhibitors:  Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic Acid Derivatives

  摘要：

  Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives were synthesized and tested as a novel class of aldose reductase (ALR2) inhibitors. Each compound was evaluated as a diastereomeric mixture, due to tautomeric equilibria in solution. The parent compound 39 exhibited a good inhibitory activity with an IC50 value of 0.85 muM, similar to that of the well-known ARI sorbinil (IC50 0.50 muM). The concurrent introduction of a halogen and a lipophilic group in the 5- and in the 1-positions, respectively, of the indole nucleus of 39, gave compound 55, cyano[5-fluoro-1-(4-methylbenzyl)-2-oxo-2,3-dihydroindol-3-yl] acetic acid, which displayed the highest activity (IC50 0.075 muM, very close to that of tolrestat IC50 0.046 muM), with a good selectivity toward ALR2 compared with aldehyde reductase (ALR1) (16.4-fold), and no appreciable inhibitory properties against sorbitol dehydrogenase (SD), or glutathione reductase (GR). The isopropyl ester 59, a prodrug of 55, was found to be almost as effective as tolrestat in preventing cataract development in severely galactosemic rats when administered as an eye drop solution. Docking simulation of 55 into a three-dimensional model of human ALR2 made it possible to formulate the hypothesis that the 2-hydroxy tautomer was the active species binding into the catalytic site of the enzyme. This was fully consistent with the structure-activity relationships within this series of cyanooxoindolylacetic acid derivatives.

  DOI：

  10.1021/jm030762f