c-Met/RON双激酶抑制剂 | 913376-84-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: c-Met/RON双激酶抑制剂
• 英文名称: N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
• 英文别名: AMG-1；N-[3-Fluoro-4-[(7-methoxyquinolin-4-yl)oxy]phenyl]-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide；N-[3-fluoro-4-(7-methoxyquinolin-4-yl)oxyphenyl]-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenylpyrazole-4-carboxamide
• CAS: 913376-84-8
• 化学式: C₃₁H₂₉FN₄O₅
• 分子量: 556.593
• InChiKey: UYMSIPINLJNNOU-UHFFFAOYSA-N

物化性质

• 溶解度：
  DMSO：100 mg/mL（179.67 mM；需要超声波）

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  41
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  8

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

AMG-1（c-Met/RON 双激酶抑制剂，RON-IN-1）是一种有效的人类 c-Met 和 RON 抑制剂。其对应的 IC50 值分别为 4 nM 和 9 nM。

靶点

Target	Value
c-Met (细胞自由体系)	4 nM
RON (细胞自由体系)	9 nM

反应信息

• 作为产物：
  描述：

  3-fluoro-4-((7-methoxyquinolin-4-yl)oxy)aniline 、 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.25h， 以68%的产率得到c-Met/RON双激酶抑制剂
  参考文献：
  名称：

  Discovery of a Potent, Selective, and Orally Bioavailable c-Met Inhibitor: 1-(2-Hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458)

  摘要：

  Deregulation of the receptor tyrosine kinase c-Met has been implicated in human cancers. Pyrazolones with N-1 bearing a pendent hydroxyalkyl side chain showed selective inhibition of c-Met over VEGFR2. However, studies revealed the generation of active, nonselective metabolites. Blocking this metabolic hot spot led to the discovery of 17 (AMG 458). When dosed orally, 17 significantly inhibited tumor growth in the NIH3T3/FPR-Met and U-87 MG xenograft models with no adverse effect on body weight.

  DOI：

  10.1021/jm800401t

文献信息

• [EN] THIENOPYRIDINE DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING SAME<br/>[FR] DÉRIVÉS DE THIÉNOPYRIDINE ET COMPOSITION PHARMACEUTIQUE LE COMPRENANT
  申请人：WELLMARKER BIO CO LTD

  公开号：WO2019182274A1

  公开（公告）日：2019-09-26

  A thienopyridine derivative compound represented by Formula 1 or pharmaceutically acceptable salts thereof have an excellent inhibitory effect on protein kinase activity, and accordingly, pharmaceutical compositions comprising same can be usefully used for the prevention or treatment of a disease associated with the activity of a protein kinase.

  由化学式1表示的噻吩吡啶衍生物化合物或其药用盐在蛋白激酶活性上具有出色的抑制作用，因此，包含该化合物的药物组合物可用于预防或治疗与蛋白激酶活性相关的疾病。
• BIOMARKER-BASED THERAPEUTIC COMPOSITION
  申请人：Wellmarker Bio Co., Ltd.

  公开号：EP3819300A1

  公开（公告）日：2021-05-12

  The present invention provides an anticancer agent for treating a patient who is resistant to a protein kinase inhibitor, the anticancer agent comprising, as an active ingredient, a thienopyridine derivative compound or a pharmaceutically acceptable salt thereof. Here, the patient may be a patient carrying active RON. In addition, the patient may be a patient carrying normal KRAS. In addition, the anticancer agent may be applied to a patient who is resistant to an EGFR inhibitor. In particular, the anticancer agent may be usefully used to treat a patient who is resistant to the therapeutic agent cetuximab.

  本发明提供了一种抗癌药物，用于治疗对蛋白激酶抑制剂产生抗药性的患者，该抗癌药物包括作为活性成分的噻吩吡啶衍生物化合物或其药用可接受的盐。在这里，患者可能是携带活性RON的患者。此外，患者可能是携带正常KRAS的患者。此外，抗癌药物可以应用于对EGFR抑制剂产生抗药性的患者。特别是，该抗癌药物可以有效用于治疗对治疗剂西妥昔单抗产生抗药性的患者。
• [EN] PYRIDO-PYRIMIDINE DERIVATIVES<br/>[FR] DÉRIVÉS DE PYRIDO-PYRIMIDINE
  申请人：MERCK PATENT GMBH

  公开号：WO2013022519A1

  公开（公告）日：2013-02-14

  Compounds of the formula I in which Het, R3 and R4 have the meanings indicated in Claim 1, are inhibitors of RON and can be employed, for the treatment of cancer.

  具有公式I的化合物，其中Het、R3和R4具有权利要求1中指示的含义，是RON的抑制剂，可用于癌症治疗。
• Substituted amide derivatives and methods of use
  申请人：Kim Tae-Seong

  公开号：US20080312232A1

  公开（公告）日：2008-12-18

  Selected compounds are effective for prophylaxis and treatment of diseases, such as HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

  所选化合物对于预防和治疗疾病，如HGF介导的疾病具有有效性。本发明涵盖了新型化合物、类似物、前药及其药学上可接受的盐、药物组合物和用于预防和治疗涉及癌症等疾病和其他疾病或状况的方法。本发明还涉及制备这些化合物的过程，以及在这些过程中有用的中间体。
• METHOD OF TREATING CANCER WITH SUBSTITUTED AMIDE DERIVATIVES
  申请人：KIM Tae-Seong

  公开号：US20120070413A1

  公开（公告）日：2012-03-22

  Selected compounds are effective for prophylaxis and treatment of diseases, such as HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

  选定的化合物对于预防和治疗疾病，如HGF介导的疾病非常有效。本发明包括新颖的化合物、类似物、前药和其药学上可接受的盐、制药组合物以及用于预防和治疗涉及癌症等疾病和其他疾病或情况的方法。本发明还涉及制备这些化合物的过程以及在这些过程中有用的中间体。