1-(6-carboxymethyl-3-chloro-2-fluoro-phenyl)-5-(3-chloro-4-fluoro-phenyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid ethyl ester | 1268680-63-2

• 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-(6-carboxymethyl-3-chloro-2-fluoro-phenyl)-5-(3-chloro-4-fluoro-phenyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid ethyl ester
• 英文别名: 2-[4-Chloro-2-[5-(3-chloro-4-fluorophenyl)-2-cyclohexyl-4-ethoxycarbonylimidazol-1-yl]-3-fluorophenyl]acetic acid
• CAS: 1268680-63-2
• 化学式: C₂₆H₂₄Cl₂F₂N₂O₄
• 分子量: 537.39
• InChiKey: RLOLJKPWVDBLQV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  81.4
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-(6-carboxymethyl-3-chloro-2-fluoro-phenyl)-5-(3-chloro-4-fluoro-phenyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid ethyl ester 在 N-甲基吗啉 、 盐酸 、 4-二甲氨基吡啶 、 2-( 1H-7-azabenzotniazol-1-yl)-1,1,3,3-tetrarmethyluroniumhexafluorophosphate methanaminium 、 三氟化硼乙醚 、 碳酸氢钠 、 三乙胺 、 lithium hydroxide 、 肼 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 环己烯 为溶剂， 反应 88.0h， 生成 2-[2-[4-(5-amino-1,3,4-oxadiazol-2-yl)-5-(3-chloro-4-fluorophenyl)-2-cyclohexylimidazol-1-yl]-4-chloro-3-fluorophenyl]-N-phenylacetamide
  参考文献：
  名称：

  Tetra-substituted imidazoles as a new class of inhibitors of the p53–MDM2 interaction

  摘要：

  Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.03.039
• 作为产物：
  描述：

  3-氯-2-氟苯胺 在 potassium phosphate 、 N-溴代丁二酰亚胺(NBS) 、 N-碘代丁二酰亚胺 、 四(三苯基膦)钯 、 dimethyl sulfide borane 、 三甲基铝 、 palladium diacetate 、 碳酸氢钠 、 三乙胺 、 三苯基膦 、 环己烯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 甲苯 、 乙腈 为溶剂， 反应 52.0h， 生成 1-(6-carboxymethyl-3-chloro-2-fluoro-phenyl)-5-(3-chloro-4-fluoro-phenyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid ethyl ester
  参考文献：
  名称：

  Tetra-substituted imidazoles as a new class of inhibitors of the p53–MDM2 interaction

  摘要：

  Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.03.039

文献信息

• [EN] TETRA-SUBSTITUTED HETEROARYL COMPOUNDS AND THEIR USE AS MDM2 AND/OR MDM4 MODULATORS<br/>[FR] COMPOSÉS HÉTÉROARYLIQUES TÉTRASUBSTITUÉS ET LEUR UTILISATION COMME MODULATEURS DE MDM2 ET/OU MDM4
  申请人：NOVARTIS AG

  公开号：WO2011023677A1

  公开（公告）日：2011-03-03

  The invention relates to tetra-substituted heteroarylic compounds of the formula (I) wherein X1, X3 and X4 are independently C or N, Y is C-H, N-H or N, wherein the total number of nitrogen atoms represented by X1, X3, X4 and Y is 1 or 2; rings A and B are independently selected from phenyl or pyridyl; R1, R4, R', R", n and m are as defined herein. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of MDM2 and/or MDM4, or variants thereof.

  该发明涉及公式（I）的四取代杂芳基化合物，其中X1、X3和X4独立地为C或N，Y为C-H、N-H或N，其中由X1、X3、X4和Y表示的氮原子的总数为1或2；环A和环B独立地选自苯基或吡啶基；R1、R4、R'、R"、n和m如本文所定义。这些化合物适用于治疗由MDM2和/或MDM4的活性或其变体介导的疾病或疾病。
• TETRA-SUBSTITUTED HETEROARYL COMPOUNDS AND THEIR USE AS MDM2 AND/OR MDM4 MODULATORS
  申请人：Bold Guido

  公开号：US20120149661A1

  公开（公告）日：2012-06-14

  The invention relates to tetra-substituted heteroarylic compounds of the formula (I) wherein X 1 , X 3 and X 4 are independently C or N, Y is C—H, N—H or N, wherein the total number of nitrogen atoms represented by X 1 , X 3 , X 4 and Y is 1 or 2; rings A and B are independently selected from phenyl or pyridyl; R1, R4, R′, R″, n and m are as defined herein. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of MDM2 and/or MDM4, or variants thereof.

  本发明涉及公式（I）的四取代杂芳基化合物，其中X1、X3和X4独立地为C或N，Y为C-H、N-H或N，其中由X1、X3、X4和Y所代表的氮原子的总数为1或2；环A和环B独立地选自苯基或吡啶基；R1、R4、R'、R"、n和m如本文所定义。这些化合物适用于治疗由MDM2和/或MDM4或其变异体的活性介导的疾病或疾患。
• Tetra-substituted imidazoles as a new class of inhibitors of the p53–MDM2 interaction
  作者：Andrea Vaupel、Guido Bold、Alain De Pover、Thérèse Stachyra-Valat、Joanna Hergovich Lisztwan、Joerg Kallen、Keiichi Masuya、Pascal Furet

  DOI：10.1016/j.bmcl.2014.03.039

  日期：2014.5

  Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line. (C) 2014 Elsevier Ltd. All rights reserved.