1-ethyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid | 5677-69-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-ethyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid
• 英文别名: 1-Aethyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-carbonsaeure；1-Ethyl-2,3-dihydro-5-methyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxylic acid；1-ethyl-5-methyl-3-oxo-2-phenylpyrazole-4-carboxylic acid
• CAS: 5677-69-0
• 化学式: C₁₃H₁₄N₂O₃
• 分子量: 246.266
• InChiKey: DMNGKQNGKCSHBK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  60.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-fluoro-4-((7-methoxyquinolin-4-yl)oxy)aniline 、 1-ethyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid 在 三乙胺 、 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 24.0h， 以80%的产率得到1-ethyl-N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
  参考文献：
  名称：

  Structure-Based Design of Novel Class II c-Met Inhibitors: 2. SAR and Kinase Selectivity Profiles of the Pyrazolone Series

  摘要：

  As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of 1. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound 59e (AMG 458) was ultimately advanced into preclinical safety studies.

  DOI：

  10.1021/jm201331s
• 作为产物：
  描述：

  1-ethyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde 在 sodium chlorite 、 磷酸 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 0.5h， 以49.5%的产率得到1-ethyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid
  参考文献：
  名称：

  [EN] SUBSTITUTED QUINOLINE COMPOUNDS AND METHODS OF USE
  [FR] COMPOSÉS DE QUINOLINE SUBSTITUÉS ET PROCÉDÉS D'UTILISATION

  摘要：

  本发明提供了新颖的取代喹啉类化合物，其药用盐及制剂，用于调节蛋白酪氨酸激酶活性，以及调节细胞活动，如增殖、分化、凋亡、迁移和侵袭。该发明还提供了包括这些化合物的药用组合物，以及在哺乳动物，尤其是人类的高增殖性疾病治疗中使用这些组合物的方法。

  公开号：

  WO2013180949A1

文献信息

• [EN] SUBSTITUTED QUINOLINE COMPOUNDS AND METHODS OF USE<br/>[FR] COMPOSÉS DE QUINOLINE SUBSTITUÉS ET PROCÉDÉS D'UTILISATION
  申请人：XI NING

  公开号：WO2013180949A1

  公开（公告）日：2013-12-05

  The present invention provides novel substituted quinoline compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.

  本发明提供了新颖的取代喹啉类化合物，其药用盐及制剂，用于调节蛋白酪氨酸激酶活性，以及调节细胞活动，如增殖、分化、凋亡、迁移和侵袭。该发明还提供了包括这些化合物的药用组合物，以及在哺乳动物，尤其是人类的高增殖性疾病治疗中使用这些组合物的方法。
• Kaufmann; Huang, Chemische Berichte, 1942, vol. 75, p. 1214,1222
  作者：Kaufmann、Huang

  DOI：——

  日期：——
• Structure-Based Design of Novel Class II c-Met Inhibitors: 2. SAR and Kinase Selectivity Profiles of the Pyrazolone Series
  作者：Longbin Liu、Mark H. Norman、Matthew Lee、Ning Xi、Aaron Siegmund、Alessandro A. Boezio、Shon Booker、Debbie Choquette、Noel D. D’Angelo、Julie Germain、Kevin Yang、Yajing Yang、Yihong Zhang、Steven F. Bellon、Douglas A. Whittington、Jean-Christophe Harmange、Celia Dominguez、Tae-Seong Kim、Isabelle Dussault

  DOI：10.1021/jm201331s

  日期：2012.3.8

  As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of 1. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound 59e (AMG 458) was ultimately advanced into preclinical safety studies.