(Z)-6-chloro-3-{phenyl[(4-(piperidin-1-ylmethyl)phenyl)-amino]methylidene}-1,3-dihydro-2H-indolin-2-one | 1168152-08-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (Z)-6-chloro-3-{phenyl[(4-(piperidin-1-ylmethyl)phenyl)-amino]methylidene}-1,3-dihydro-2H-indolin-2-one
• 英文别名: (Z)-6-chloro-3-[phenyl-(4-piperidin-1-ylmethyl-phenylamino)-methylene]-indolin-2-one；(3Z)-6-chloro-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1H-indol-2-one
• CAS: 1168152-08-6
• 化学式: C₂₇H₂₆ClN₃O
• 分子量: 443.976
• InChiKey: VQUBRJKCPJZARY-QPLCGJKRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.26
• 重原子数：
  32.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  44.37
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为产物：
  描述：

  4-(1-哌啶基甲基)苯胺 在 盐酸 、 P4S10-pyridine complex 、 三乙胺 作用下， 以 吡啶 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.67h， 生成 (Z)-6-chloro-3-{phenyl[(4-(piperidin-1-ylmethyl)phenyl)-amino]methylidene}-1,3-dihydro-2H-indolin-2-one
  参考文献：
  名称：

  使用 Eschenmoser 偶联反应合成激酶抑制剂尼达尼布、橙皮苷及其类似物

  摘要：

  一种新的合成方法，包括取代的 3-溴代吲哚（H, 6-Cl, 6-COOMe, 5-NO 2）与两个取代的硫代苯甲酰胺在二甲基甲酰胺或乙腈中的 Eschenmoser 偶联反应，用于合成八种激酶抑制剂，包括尼达尼布和橙皮苷的产率超过 76%。用于合成的起始化合物也很容易以良好的收率获得。3-溴吲哚是通过三步合成法从相应的靛红制备的，平均总产率为 65%，或者通过羟吲哚的直接溴化（产率为 65-86%）。起始N- (4-哌啶-1-基甲基-苯基)-硫代苯甲酰胺通过相应的苯甲酰苯胺以 86% 的收率和N-甲基-N-(4-硫代苯甲酰氨基苯基)-2-(4-甲基哌嗪-1-基)乙酰胺通过相应苯胺与二硫代苯甲酸甲酯的硫代酰化以86%的产率制备。

  DOI：

  10.1021/acs.joc.1c01269

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。
• Novel substituted indolines with an inhibitory effect on various kinases and complexes of CDKs
  申请人：Boehringer Ingelheim Pharma KG

  公开号：US20040058978A1

  公开（公告）日：2004-03-25

  The present invention relates to new substituted indolinones of general formula 1 wherein X and R 1 to R 5 are defined as in claim 1, the isomers and the salts thereof which have valuable properties. The above compounds of general formula I wherein R 1 denotes a hydrogen atom, a C 1-3 -alkyl group or a prodrug group have valuable pharmacological properties, particularly an inhibiting effect on various kinases, on viral cyclin and on receptor tyrosine kinases, and the other compounds of the above general formula I wherein R 1 does not represent a hydrogen atom, a C 1-3 -alkyl group or a prodrug group are valuable intermediate products for the preparation of the abovementioned compounds.

  本发明涉及一种新的通式1的取代吲哚酮，其中X和R1至R5的定义如权利要求书1中所述，其异构体和盐具有有价值的性质。通式I中的上述化合物，其中R1表示氢原子，C1-3-烷基或前药基，具有有价值的药理学性质，特别是对多种激酶、病毒细胞周期蛋白和受体酪氨酸激酶具有抑制作用，上述通式I中R1不表示氢原子、C1-3-烷基或前药基的其他化合物是制备上述化合物的有价值中间体。
• 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.
• NEUE SUBSTITUIERTE INDOLINONE MIT EINER INHIBIERENDEN WIRKUNG AUF VERSCHIEDENE KINASEN UND CYCLIN/CDK-KOMPLEXE
  申请人：Boehringer Ingelheim Pharma KG

  公开号：EP1115704A1

  公开（公告）日：2001-07-18
• 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