4-amino-3-[6-(4-methylpiperazinyl)benzimidazol-2-yl]-2-oxohydroquinoline-6-carboxylic acid | 668431-36-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 4-amino-3-[6-(4-methylpiperazinyl)benzimidazol-2-yl]-2-oxohydroquinoline-6-carboxylic acid
• 英文别名: 4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-2-oxo-1H-quinoline-6-carboxylic acid
• CAS: 668431-36-5
• 化学式: C₂₂H₂₂N₆O₃
• 分子量: 418.455
• InChiKey: LECUVYDKVOBYCR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.2
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  128
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-amino-3-[6-(4-methylpiperazinyl)benzimidazol-2-yl]-2-oxohydroquinoline-6-carboxylic acid 、 苄胺 在 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 以45%的产率得到{4-amino-3-[5-(4-methylpiperazinyl)benzimidazol-2-yl]-2-oxo(6-hydroquinolyl)}-N-benzylcarboxamide
  参考文献：
  名称：

  Design, Structure−Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors

  摘要：

  The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TK1258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFR beta with IC50 values <0.1 mu M. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.

  DOI：

  10.1021/jm800790t
• 作为产物：
  描述：

  4-amino-3-[5-(4-methylpiperazinyl)benzimidazol-2-yl]-2-oxohydroquinoline-6-carbonitrile 在 sodium hydroxide 、 水 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以100%的产率得到4-amino-3-[6-(4-methylpiperazinyl)benzimidazol-2-yl]-2-oxohydroquinoline-6-carboxylic acid
  参考文献：
  名称：

  Design, Structure−Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors

  摘要：

  The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TK1258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFR beta with IC50 values <0.1 mu M. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.

  DOI：

  10.1021/jm800790t

文献信息

• Combination therapy with CHK1 inhibitors
  申请人：Gesner G. Thomas

  公开号：US20050256157A1

  公开（公告）日：2005-11-17

  Compounds of Structure I, and salts, tautomers, stereoisomers, and mixtures thereof may be used in methods of inhibiting checkpoint kinase 1 in subjects, in methods for inducing cell cycle progression, and in methods for increasing apoptosis in cells. Such compounds may be used to prepare pharmaceutical compositions and may be used in conjunction with DNA damaging agents.

  结构I的化合物及其盐类、互变异构体、立体异构体和混合物可用于抑制受试者中的检查点激酶1，用于诱导细胞周期进展的方法，以及用于增加细胞凋亡的方法。这些化合物可用于制备药物组合物，并且可以与DNA损伤剂联合使用。
• Inhibition of FGFR3 and treatment of multiple myeloma
  申请人：Cai Shaopei

  公开号：US20050261307A1

  公开（公告）日：2005-11-24

  Methods of inhibiting fibroblast growth factor receptor 3 and treating various conditions mediated by fibroblast growth factor receptor 3 are provided that include administering to a subject a compound of Structure I, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer. Compounds having the Structure I have the following structure where and have the variables described herein. Such compounds may be used to prepare medicaments for use in inhibiting fibroblast growth factor receptor 3 and for use in treating conditions mediated by fibroblast growth factor receptor 3 such as multiple myeloma.

  提供了抑制成纤维母细胞生长因子受体3并治疗由纤维母细胞生长因子受体3介导的各种疾病的方法，包括向受试者施用结构I的化合物，其药学上可接受的盐，其互变异构体，或其互变异构体的药学上可接受的盐。具有结构I的化合物具有以下结构，其中具有本文描述的变量。这些化合物可用于制备用于抑制纤维母细胞生长因子受体3和用于治疗由纤维母细胞生长因子受体3介导的疾病，如多发性骨髓瘤的药物。
• Benzimidazole quinolinones and uses thereof
  申请人：Chiron Corporation

  公开号：US20040092535A1

  公开（公告）日：2004-05-13

  Methods of inhibiting various enzymes and treating various conditions are provided that include administering to a subject a compound of Structure I or IB, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer. Compounds having the Structure I and IB have the following structures and have the variables described herein. Such compounds may be used to prepare medicaments for use in inhibiting various enzymes and for use in treating conditions mediated by such enzymes. 1

  提供了抑制各种酶和治疗各种疾病的方法，包括向受试者给予结构式I或IB的化合物、其药学上可接受的盐、其互变异构体或其药学上可接受的互变异构体盐。具有结构式I和IB的化合物具有以下结构，并具有此处描述的变量。这些化合物可用于制备药物，用于抑制各种酶的使用和用于治疗由这些酶介导的疾病。
• Pharmaceutically acceptable salts of quinolinone compounds and their medical use
  申请人：Novartis Vaccines and Diagnostics, Inc.

  公开号：EP2762475A1

  公开（公告）日：2014-08-06

  A salt of a compound of Formula I or a tautomer of the compound, wherein Formula I has the following structure and R1-R9 and R12-R14 are as defined herein

  式 I 化合物的盐或该化合物的同系物，其中式 I 具有如下结构，R1-R9 和 R12-R14 如本文所定义
• BENZIMIDAZOLE QUINOLINONES AND USES THEREOF
  申请人：Chiron Corporation

  公开号：EP1539754A2

  公开（公告）日：2005-06-15