(E)-1-acetyl-6-cyano-3-(ethoxy-phenyl-methylene)-indolin-2-one | 1168152-02-0

• 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: (E)-1-acetyl-6-cyano-3-(ethoxy-phenyl-methylene)-indolin-2-one
• 英文别名: (3E)-1-acetyl-3-[ethoxy(phenyl)methylidene]-2-oxoindole-6-carbonitrile
• CAS: 1168152-02-0
• 化学式: C₂₀H₁₆N₂O₃
• 分子量: 332.359
• InChiKey: LCWXCNOETJUMPV-VHEBQXMUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  70.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(1-哌啶基甲基)苯胺 、 (E)-1-acetyl-6-cyano-3-(ethoxy-phenyl-methylene)-indolin-2-one 在 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.5h， 生成 (Z)-6-cyano-3-[phenyl-(4-piperidin-1-ylmethyl-phenylamino)methylene]indolin-2-one
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Indolinones as Triple Angiokinase Inhibitors and the Discovery of a Highly Specific 6-Methoxycarbonyl-Substituted Indolinone (BIBF 1120)

  摘要：

  Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a new treatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as Fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.

  DOI：

  10.1021/jm900431g
• 作为产物：
  描述：

  6-氰基吲哚酮 、 乙酸酐 、 原苯甲酸三乙酯 反应 3.5h， 生成 (E)-1-acetyl-6-cyano-3-(ethoxy-phenyl-methylene)-indolin-2-one
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Indolinones as Triple Angiokinase Inhibitors and the Discovery of a Highly Specific 6-Methoxycarbonyl-Substituted Indolinone (BIBF 1120)

  摘要：

  Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a new treatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as Fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.

  DOI：

  10.1021/jm900431g

文献信息

• Indolinone derivatives substituted in the 6 position, the preparation thereof and their use as pharmaceutical compositions
  申请人：Heckel Armin

  公开号：US20060194813A1

  公开（公告）日：2006-08-31

  The present invention relates to indolinone derivatives substituted in the 6 position of general formula wherein R 1 to R 6 and X are defined as in claim 1 , the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof, which have valuable pharmacological properties, in particular an inhibiting effect on various receptor tyrosine kinases and on the proliferation of endothelial cells and various tumour cells, pharmaceutical compositions containing these compounds, their use and processes for preparing them.

  本发明涉及一种在通式中6位取代的吲哚酮衍生物，其中R1至R6和X如权利要求1所定义，其互变异构体、对映异构体、顺反异构体、混合物及其盐，特别是其生理上可接受的盐，具有有价值的药理特性，特别是对各种受体酪氨酸激酶和内皮细胞以及各种肿瘤细胞的增殖具有抑制作用，包含这些化合物的制药组合物，它们的用途和制备过程。
• IN 6-STELLUNG SUBSTITUIERTE INDOLINONDERIVATE, IHRE HERSTELLUNG UND IHRE VERWENDUNG ALS ARZNEIMITTEL
  申请人：BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG

  公开号：EP1527046A1

  公开（公告）日：2005-05-04
• US7514468B2
  申请人：——

  公开号：US7514468B2

  公开（公告）日：2009-04-07
• [DE] IN 6-STELLUNG SUBSTITUIERTE INDOLINONDERIVATE, IHRE HERSTELLUNG UND IHRE VERWENDUNG ALS ARZNEIMITTEL<br/>[EN] INDOLINE DERIVATIVES SUBSTITUTED IN POSITION 6, PRODUCTION AND USE THEREOF AS MEDICAMENTS<br/>[FR] DERIVES D'INDOLINONE SUBSTITUES EN POSITION 6, LEUR PREPARATION ET LEUR UTILISATION COMME MEDICAMENTS
  申请人：BOEHRINGER INGELHEIM PHARMA

  公开号：WO2004009546A1

  公开（公告）日：2004-01-29

  Die vorliegende Erfindung betrifft in 6-Stellung substituierte Indolinonderivate der allgemeinen Formel (I), in der R1, bis R6 und X wie im Anspruch (1) definiert sind, deren Tautomere, Enantiomere, Diastereomere, deren Gemische und deren Salze, insbesondere deren physiologisch verträgliche Salze, welche wertvolle pharmakologische Eigenschaften aufweisen, insbesondere eine inhibierende Wirkung auf verschiedene Rezeptor-Tyrosinkinasen sowie auf die Proliferation von Endothelzellen und verschiedener Tumorzellen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung.
• Design, Synthesis, and Evaluation of Indolinones as Triple Angiokinase Inhibitors and the Discovery of a Highly Specific 6-Methoxycarbonyl-Substituted Indolinone (BIBF 1120)
  作者：Gerald J. Roth、Armin Heckel、Florian Colbatzky、Sandra Handschuh、Jörg Kley、Thorsten Lehmann-Lintz、Ralf Lotz、Ulrike Tontsch-Grunt、Rainer Walter、Frank Hilberg

  DOI：10.1021/jm900431g

  日期：2009.7.23

  Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a new treatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as Fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.