(Z)-3-[(1-methylpiperidin-4-ylamino)-phenyl-methylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester | 334950-66-2

• 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-[(1-methylpiperidin-4-ylamino)-phenyl-methylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester
• 英文别名: (Z)-2-oxo-3-((1-methyl-piperidin-4-ylamino)phenylmethylene)-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester；methyl (3Z)-3-[[(1-methylpiperidin-4-yl)amino]-phenylmethylidene]-2-oxo-1H-indole-6-carboxylate
• CAS: 334950-66-2
• 化学式: C₂₃H₂₅N₃O₃
• 分子量: 391.47
• InChiKey: NELGLGILOKCALP-MRCUWXFGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.98
• 重原子数：
  29.0
• 可旋转键数：
  4.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  70.67
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  (Z)-3-[(1-methylpiperidin-4-ylamino)-phenyl-methylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 在 水 、 sodium hydroxide 、 盐酸 作用下， 以 甲醇 、 水 为溶剂， 反应 5.0h， 以79%的产率得到(Z)-3-[(1-methyl-piperidin-4-ylamino)phenylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid
  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
• 作为产物：
  描述：

  4-氨基-1-甲基哌啶 、 (E)-1-乙酰基-3-(甲氧基(苯基)亚甲基)-2-氧代吲哚-6-羧酸酯甲酯 在 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 (Z)-3-[(1-methylpiperidin-4-ylamino)-phenyl-methylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester
  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

• 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。
• [DE] IN 6-STELLUNG SUBSTITUIERTE INDOLINONE, IHRE HERSTELLUNG UND IHRE VERWENDUNG ALS ARZNEIMITTEL<br/>[EN] 6-POSITION SUBSTITUTED INDOLINE, PRODUCTION AND USE THEREOF AS A MEDICAMENT<br/>[FR] INDOLINONES SUBSTITUEES EN POSITION 6, LEUR PREPARATION ET LEUR UTILISATION EN TANT QUE MEDICAMENTS
  申请人：BOEHRINGER INGELHEIM PHARMA

  公开号：WO2001027081A1

  公开（公告）日：2001-04-19

  Die vorliegende Erfindung betrifft in 6-Stellung 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 Rezeptor-Tyrosinkinasen und Cyclin/CDK-Komplexe sowie auf die Proliferation von Endothelzellen und verschiedener Tumorzellen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung.

  本发明涉及一般式（I）中R1至R5和X如权利要求1所定义的6-位取代的吲哚酮及其异构体和盐，特别是其生理上可接受的盐，具有有价值的药理学特性，特别是对各种受体酪氨酸激酶和环/ CDK复合物以及内皮细胞和各种肿瘤细胞的增殖具有抑制作用，含有这些化合物的药物，其使用和制备方法。
• 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。
• In 6-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
  申请人：Boehringer Ingelheim Pharma GmbH & Co. KG

  公开号：EP2157081A1

  公开（公告）日：2010-02-24

  Die vorliegende Erfindung betrifft in 6-Stellung substituierte Indolinone der allgemeinen Formel 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 Rezeptor-Tyrosinkinasen und Cyclin/CDK-Komplexe sowie auf die Proliferation von Endothelzellen und verschiedener Tumorzellen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung.

  本发明涉及通式中 6 位被取代的吲哚啉酮类化合物 其中 R1至R5和X如权利要求1所定义，它们的异构体和它们的盐，特别是它们的生理耐受盐，它们具有宝贵的药理特性，特别是对各种受体酪氨酸激酶和细胞周期蛋白/CDK复合物以及对内皮细胞和各种肿瘤细胞增殖的抑制作用，含有这些化合物的药物，它们的用途和制备过程。
• 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。