benzyl 1-[(2S)-2-hydroxybutyl]-5-methyl-3-oxo-2-phenylpyrazole-4-carboxylate | 1034355-92-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: benzyl 1-[(2S)-2-hydroxybutyl]-5-methyl-3-oxo-2-phenylpyrazole-4-carboxylate
• CAS: 1034355-92-4
• 化学式: C₂₂H₂₄N₂O₄
• 分子量: 380.444
• InChiKey: QQUSFGIIULHXTA-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  70.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  benzyl 1-[(2S)-2-hydroxybutyl]-5-methyl-3-oxo-2-phenylpyrazole-4-carboxylate 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 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 (S)-N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-hydroxybutyl)-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：

  1,2-环氧丁烷 、 benzyl 5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate 在 magnesium(II) perchlorate 作用下， 以 乙腈 为溶剂， 生成 benzyl 1-[(2S)-2-hydroxybutyl]-5-methyl-3-oxo-2-phenylpyrazole-4-carboxylate
  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

文献信息

• Selective β-Hydroxyethylation at the N-1 Position of a Pyrazolone: Synthesis of Benzyl 1-(β-Hydroxyethyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1<i>H</i>-pyrazole-4-carboxylate
  作者：Longbin Liu、Aaron Siegmund、Daniel Retz、Ning Xi、Celia Dominguez、Roland Bürli

  DOI：10.1055/s-2008-1042923

  日期：——

  Selective 2-hydroxyethylation at the N-1 position of benzyl 5-methyl-3-oxo-2-phenyl-2,3-dihydro-1 H-pyrazole-4-carboxylate with epoxides was achieved using either AlMe 3 or Mg(ClO 4 ) 2 under mild conditions. The epoxide ring opening was both regioselective and stereospecific. Moderate to excellent yields were obtained from mono- and disubstituted epoxides with the exception of CIS-dimethyl-2-butene

  使用 AlMe 3 或 Mg(ClO) 在 5-甲基-3-氧代-2-苯基-2,3-二氢-1 H-吡唑-4-羧酸苄基酯的 N-1 位选择性 2-羟乙基化与环氧化物4 ) 2 在温和条件下。环氧化物开环具有区域选择性和立体特异性。除了仅产生痕量产物的 CIS-二甲基-2-丁烯氧化物外，单取代和双取代环氧化物的产率中等至极好。
• 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.