(Z)-3-[phenyl-(4-(piperidin-1-ylmethyl)phenylamino)methylene]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide | 247083-35-8

• 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)-3-[phenyl-(4-(piperidin-1-ylmethyl)phenylamino)methylene]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide
• 英文别名: (3Z)-N,N-dimethyl-2-oxo-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1H-indole-5-carboxamide
• CAS: 247083-35-8
• 化学式: C₃₀H₃₂N₄O₂
• 分子量: 480.61
• InChiKey: ZSYCMROIKWLLQN-DQSJHHFOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  64.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (3Z)-2-oxo-3-(phenyl{[4-(piperidin-1-ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid 、 盐酸二甲胺 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 20.5h， 以89%的产率得到(Z)-3-[phenyl-(4-(piperidin-1-ylmethyl)phenylamino)methylene]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide
  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

文献信息

• Three hybrid assay system
  申请人：GPC Biotech AG

  公开号：EP1975620A2

  公开（公告）日：2008-10-01

  The invention provides compositions and methods for isolating ligand binding polypeptides for a user-specified ligand, and for isolating small molecule ligands for a user-specified target polypeptide using an improved class of hypbrid ligand compounds.

  本发明提供了用于分离用户指定配体的配体结合多肽的组合物和方法，以及使用改良的低杂合配体化合物分离用户指定目标多肽的小分子配体的组合物和方法。
• [DE] SUBSTITUIERTE INDOLINONE MIT INHIBIERENDER WIRKUNG AUF KINASEN UND CYCLIN/CDK-KOMPLEXE<br/>[EN] SUBSTITUTED INDOLINONES HAVING AN INHIBITING EFFECT ON KINASES AND CYCLINE/CDK COMPLEXES<br/>[FR] INDOLINONES SUBSTITUEES A EFFET INHIBITEUR SUR DES KINASES ET DES COMPLEXES CYCLINE/CDK
  申请人：BOEHRINGER INGELHEIM PHARMA KG

  公开号：WO1999052869A1

  公开（公告）日：1999-10-21

  (DE) Die vorliegende Erfindung betrifft substituierte Indolinone der allgemeinen Formel (I), in der R1 bis R5 und X wie im Anspruch 1 definiert sind, deren Isomere und deren Salze, insbesondere deren physiologisch verträgliche Salze, welche wertvolle pharmakologische Eigenschaften aufweisen, insbesondere eine inhibierende Wirkung auf verschiedene Kinasen und Cyclin/CDK-Komplexe sowie auf die Proliferation verschiedener Tumorzellen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung.(EN) The invention relates to substituted indolinones of general formula (I), wherein R1 to R5 and X have the meanings given in claim 1, to their isomers and to their salts, especially their physiologically compatible salts. The inventive compounds have valuable pharmacological properties, especially an inhibitory effect on various kinases and cycline/CDK complexes, and on the proliferation of various tumour cells. The invention also relates to medicaments containing these compounds, to their use and to methods for producing them.(FR) L'invention concerne des indolinones substituées de la formule générale (I) ou R1 à R5 et X sont définis comme décrit dans le revendication 1. L'invention concerne également leurs isomères et leurs sels, notamment leurs sels physiologiquement admissibles, ayant de précieuses propriétés pharmacologiques, notamment un effet inhibiteur sur différentes kinases, sur différents complexes Cycline/CDK et sur la prolifération de différentes cellules tumorales. L'invention concerne enfin des médicaments contenant ces composés, leur utilisation et leur procédé de production.

  (DE) Die vorliegende Erfindung betrifft substituierte Indolinone der allgemeinen Formel (I), in der R1 bis R5 und X wie im Anspruch 1 definiert sind, deren Isomere und deren Salze, insbesondere deren physiologisch verträgliche Salze, welche wertvolle pharmakologische Eigenschaften aufweisen, insbesondere eine inhibierende Wirkung auf verschiedene Kinasen und Cyclin/CDK-Komplexe sowie auf die Proliferation verschiedener Tumorzellen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung. (EN) The invention relates to substituted indolinones of general formula (I), wherein R1 to R5 and X have the meanings given in claim 1, to their isomers and to their salts, especially their physiologically compatible salts. The inventive compounds have valuable pharmacological properties, especially an inhibitory effect on various kinases and cycline/CDK complexes, and on the proliferation of various tumour cells. The invention also relates to medicaments containing these compounds, to their use and to methods for producing them. (FR) L'invention concerne des indolinones substitués de la formule générale (I) ou R1 à R5 et X sont définis comme décrit dans le revendication 1. L'invention concerne également leurs isomères et leurs sels, notamment leurs sels physiologiquement admissibles, ayant de précieuses propriétés pharmacologiques, notamment un effet inhibiteur sur différentes kinases, sur différents complexes Cycline/CDK et sur la prolifération de différentes cellules tumorales. L'invention concerne enfin des médicaments contenant ces composés, leur utilisation et leur procédé de production.
• SUBSTITUIERTE INDOLINONE MIT INHIBIERENDE WIRKUNG AUF KINASEN UND CYCLIN/CDK-KOMPLEXE
  申请人：Boehringer Ingelheim Pharma KG

  公开号：EP1071665A1

  公开（公告）日：2001-01-31
• US6169106B1
  申请人：——

  公开号：US6169106B1

  公开（公告）日：2001-01-02
• Design, Synthesis, and Evaluation of Indolinones as Inhibitors of the Transforming Growth Factor β Receptor I (TGFβRI)
  作者：Gerald J. Roth、Armin Heckel、Trixi Brandl、Matthias Grauert、Stefan Hoerer、Joerg T. Kley、Gisela Schnapp、Patrick Baum、Detlev Mennerich、Andreas Schnapp、John E. Park

  DOI：10.1021/jm100812a

  日期：2010.10.28

  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.