(Z)-3-[(1-methyl-piperidin-4-ylamino)phenylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid n-methyl-ethylamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (Z)-3-[(1-methyl-piperidin-4-ylamino)phenylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid n-methyl-ethylamide
• 英文别名: 3-Z-[1-(1-methyl-piperidin-4-yl)-amino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone；(3Z)-N-ethyl-N-methyl-3-[[(1-methylpiperidin-4-yl)amino]-phenylmethylidene]-2-oxo-1H-indole-6-carboxamide
• 化学式: C₂₅H₃₀N₄O₂
• 分子量: 418.539
• InChiKey: DVCSUGRKKGJBHN-FCQUAONHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.28
• 重原子数：
  31.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  64.68
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  N-乙基甲基胺 、 (Z)-3-[(1-methyl-piperidin-4-ylamino)phenylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid 在 二乙基异丙基胺 、 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.5h， 以61%的产率得到(Z)-3-[(1-methyl-piperidin-4-ylamino)phenylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid n-methyl-ethylamide
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Indolinones as Inhibitors of the Transforming Growth Factor β Receptor I (TGFβRI)

  摘要：

  Inhibition of transforming growth factor β (TGFβ) type I receptor (Alk5) offers a novel approach for the treatment of fibrotic diseases and cancer. Indolinones substituted in position 6 were identified as a new chemotype inhibiting TGFβRI concomitant with a low cross-reactivity among the human kinome. A subset of compounds showed additional inhibition of platelet-derived growth factor receptor alpha (PDGFRα), contributing to an interesting pharmacological profile. In contrast, p38 kinase, which is often inhibited by TGFβRI inhibitors, was not targeted by derivatives based on the indolinone chemotype. Guided by an X-ray structure of lead compound 5 (BIBF0775) soaked into the kinase domain of TGFβRI, optimization furnished potent and selective inhibitors of TGFβRI. Potent inhibition translated well into good inhibition of TGFβRI-mediated phosphorylation of Smad2/3, demonstrating efficacy in a cellular setting. Optimized compounds were extensively profiled on a 232-kinase panel and showed low cross-reactivities within the human kinome.

  DOI：

  10.1021/jm100812a