(Z)-3-(hydroxymethylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid ethylamide | 1253769-02-6

• 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-(hydroxymethylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid ethylamide
• 英文别名: (3Z)-N-ethyl-3-(hydroxymethylidene)-2-oxo-1H-indole-6-carboxamide
• CAS: 1253769-02-6
• 化学式: C₁₂H₁₂N₂O₃
• 分子量: 232.239
• InChiKey: MWGPUQLPAJROOB-TWGQIWQCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  78.4
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  (Z)-3-(hydroxymethylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid 、 乙胺 在 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 、 四氢呋喃 为溶剂， 反应 24.5h， 以38%的产率得到(Z)-3-(hydroxymethylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid 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

文献信息

• Medicaments for the Treatment or Prevention of Fibrotic Diseases
  申请人：Park Edward John

  公开号：US20060142373A1

  公开（公告）日：2006-06-29

  The present invention relates to the use of indolinones of general formula substituted in the 6 position, wherein R 1 to R 5 and X are defined as in claim 1, the isomers and the salts thereof, particularly the physiologically acceptable salts thereof, as a medicament for the prevention or treatment of specific fibrotic diseases.

  本发明涉及使用一般公式中6位取代的吲哚酮，其中R1至R5和X的定义如权利要求1中所述，其异构体和盐，特别是其生理上可接受的盐，作为预防或治疗特定纤维化疾病的药物。
• MEDICAMENTS FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES
  申请人：PARK John Edward

  公开号：US20100204211A1

  公开（公告）日：2010-08-12

  The present invention relates to the use of indolinones of general formula substituted in the 6 position, wherein R 1 to R 5 and X are defined as in claim 1 , the isomers and the salts thereof, particularly the physiologically acceptable salts thereof, as a medicament for the prevention or treatment of specific fibrotic diseases.

  本发明涉及使用通式中6位取代的吲哚酮，其中R1至R5和X如权利要求1所定义，其异构体和盐，特别是其生理上可接受的盐，作为预防或治疗特定纤维化疾病的药物。
• Medicaments for the treatment or prevention of fibrotic diseases
  申请人：BOEHRINGER INGELHEIM INTERNATIONAL GMBH

  公开号：EP2384751A1

  公开（公告）日：2011-11-09

  The present invention relates to the use of indolinones of general formula substituted in the 6 position, wherein R1 to R5 and X are defined as in claim 1, the isomers and the salts thereof, particularly the physiologically acceptable salts thereof, as a medicament for the prevention or treatment of specific fibrotic diseases.

  本发明涉及通式如下的吲哚啉酮的用途 其中 R1至R5和X的定义如权利要求1，其异构体及其盐类，特别是其生理上可接受的盐类，作为预防或治疗特定纤维化疾病的药物。
• MEDICAMENTS FOR THE TREATMENT OR PREVENTION OF FIBROTIC DEISEASES
  申请人：Boehringer Ingelheim International GmbH

  公开号：US20190038600A1

  公开（公告）日：2019-02-07

  The present invention relates to the use of indolinones of general formula substituted in the 6 position, wherein R 1 to R 5 and X are defined as in claim 1 , the isomers and the salts thereof, particularly the physiologically acceptable salts thereof, as a medicament for the prevention or treatment of specific fibrotic diseases.
• 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.