Indolin-2-one deriv. 4h

• 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: Indolin-2-one deriv. 4h
• 英文别名: (3Z)-6-(2-methoxyphenyl)-3-(4,5,6,7-tetrahydro-1H-indol-2-ylmethylidene)-1H-indol-2-one
• 化学式: C₂₄H₂₂N₂O₂
• 分子量: 370.451
• InChiKey: PFORQVNUDXKNNV-ZHZULCJRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  54.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  4,5,6,7-四氢吲哚 在 哌啶 、 三氯氧磷 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 Indolin-2-one deriv. 4h
  参考文献：
  名称：

  Identification of Substituted 3-[(4,5,6,7-Tetrahydro-1H-indol-2-yl)methylene]- 1,3-dihydroindol-2-ones as Growth Factor Receptor Inhibitors for VEGF-R2 (Flk-1/KDR), FGF-R1, and PDGF-Rβ Tyrosine Kinases

  摘要：

  A series of new 3-substituted indolin-2-ones containing a tetrahydroindole moiety was developed as specific inhibitors of receptor tyrosine kinases associated with VEGF-R, FGF-R, and PDGF-R growth factor receptors. These compounds were evaluated for their inhibitory properties toward VEGF-R2 (Flk-1/KDR), FGF-R1, PDGF-R beta, p60(c-Src), and EGF-R tyrosine kinases and their ability to inhibit growth factor-dependent cell proliferation. Structure-activity relationships of this new pharmacophore have been determined at the level of kinase inhibition. Compounds containing a propionic acid moiety at the C-3' position of the tetrahydroindole ring represented the most potent indolin-2-ones to inactivate the VEGF, FGF, and PDGF receptor kinases. The inhibitory activities of 9d against VEGF-R2 (Flk-1), 9h against FGF-R1, and 9b against PDGF-R beta were 4, 80, and 4 nM, respectively. However, all of these compounds were inactive when tested against the EGF-R tyrosine kinase. Compounds 9a and 9b represented the most potent inhibitors of these classes to inhibit both biochemical kinase and growth factor-dependent cell proliferation for these three targets. In addition, compound 9a was cocrystallized with the catalytic domain of FGF-R1 providing evidence to explain the structure-activity relationship results. This study has provided evidence to support the potential of these new tyrosine kinase inhibitors for the treatment of angiogenesis and other growth factor-related diseases including human cancers.

  DOI：

  10.1021/jm9906116

文献信息

• HETEROCYLIC CLASSES OF COMPOUNDS FOR THE MODULATING TYROSINE PROTEIN KINASE
  申请人：Sugen, Inc.

  公开号：EP1066257A2

  公开（公告）日：2001-01-10
• [EN] HETEROCYCLIC CLASSES OF COMPOUNDS FOR THE MODULATING TYROSINE PROTEIN KINASE<br/>[FR] FAMILLES HETEROCYCLIQUES DE COMPOSES DESTINEES A LA MODULATION DE LA TYROSINE-KINASE
  申请人：——

  公开号：WO1999048868A9

  公开（公告）日：2000-04-20

  [EN] The invention relates to certain indolinone-based and pyrazolylamide-based compounds, their method of synthesis, and combinatorial libraries consisting of the compounds. The invention also relates to methods of modulating the function of protein kinases using these compounds and methods of treating diseases by modulating the function of protein kinases and related signal transduction pathways.
  [FR] L'invention concerne certains composés à base d'indolinone et de pyrazolylamide, leur méthode de synthèse, et des banques combinatoires constituées de ces composés. L'invention concerne également des méthodes utilisant ces composés qui permettent de moduler la fonction de protéines kinases, ainsi que des méthodes de traitement de maladies consistant à moduler la fonction des protéines kinases et les voies de transduction du signal associées.
• [EN] HETEROCYCLIC FAMILIES OF COMPOUNDS FOR THE MODULATION OF TYROSINE PROTEIN KINASE<br/>[FR] FAMILLES HETEROCYCLIQUES DE COMPOSES DESTINEES A LA MODULATION DE LA TYROSINE-KINASE
  申请人：SUGEN, INC.

  公开号：WO1999048868A2

  公开（公告）日：1999-09-30

  (EN) The invention relates to certain indolinone-based and pyrazolylamide-based compounds, their method of synthesis, and combinatorial libraries consisting of the compounds. The invention also relates to methods of modulating the function of protein kinases using these compounds and methods of treating diseases by modulating the function of protein kinases and related signal transduction pathways.(FR) L'invention concerne certains composés à base d'indolinone et de pyrazolylamide, leur méthode de synthèse, et des banques combinatoires constituées de ces composés. L'invention concerne également des méthodes utilisant ces composés qui permettent de moduler la fonction de protéines kinases, ainsi que des méthodes de traitement de maladies consistant à moduler la fonction des protéines kinases et les voies de transduction du signal associées.
• Identification of Substituted 3-[(4,5,6,7-Tetrahydro-1<i>H</i>-indol-2-yl)methylene]- 1,3-dihydroindol-2-ones as Growth Factor Receptor Inhibitors for VEGF-R2 (Flk-1/KDR), FGF-R1, and PDGF-Rβ Tyrosine Kinases
  作者：Li Sun、Ngoc Tran、Congxing Liang、Steve Hubbard、Flora Tang、Kenneth Lipson、Randall Schreck、Yong Zhou、Gerald McMahon、Cho Tang

  DOI：10.1021/jm9906116

  日期：2000.7.1

  A series of new 3-substituted indolin-2-ones containing a tetrahydroindole moiety was developed as specific inhibitors of receptor tyrosine kinases associated with VEGF-R, FGF-R, and PDGF-R growth factor receptors. These compounds were evaluated for their inhibitory properties toward VEGF-R2 (Flk-1/KDR), FGF-R1, PDGF-R beta, p60(c-Src), and EGF-R tyrosine kinases and their ability to inhibit growth factor-dependent cell proliferation. Structure-activity relationships of this new pharmacophore have been determined at the level of kinase inhibition. Compounds containing a propionic acid moiety at the C-3' position of the tetrahydroindole ring represented the most potent indolin-2-ones to inactivate the VEGF, FGF, and PDGF receptor kinases. The inhibitory activities of 9d against VEGF-R2 (Flk-1), 9h against FGF-R1, and 9b against PDGF-R beta were 4, 80, and 4 nM, respectively. However, all of these compounds were inactive when tested against the EGF-R tyrosine kinase. Compounds 9a and 9b represented the most potent inhibitors of these classes to inhibit both biochemical kinase and growth factor-dependent cell proliferation for these three targets. In addition, compound 9a was cocrystallized with the catalytic domain of FGF-R1 providing evidence to explain the structure-activity relationship results. This study has provided evidence to support the potential of these new tyrosine kinase inhibitors for the treatment of angiogenesis and other growth factor-related diseases including human cancers.