tert-butyl 2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((S)-1-hydroxybutan-2-yl)-3-oxomorpholin-2-yl)acetate | 1432669-96-9

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: tert-butyl 2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((S)-1-hydroxybutan-2-yl)-3-oxomorpholin-2-yl)acetate
• 英文别名: tert-butyl 2-[(2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-[(2S)-1-hydroxybutan-2-yl]-3-oxomorpholin-2-yl]acetate
• CAS: 1432669-96-9
• 化学式: C₂₆H₃₁Cl₂NO₅
• 分子量: 508.442
• InChiKey: JOGCXHCRGUEWIB-ZQRMPTRQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl 2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((S)-1-hydroxybutan-2-yl)-3-oxomorpholin-2-yl)acetate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 4.5h， 以100%的产率得到2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((S)-1-hydroxybutan-2-yl)-3-oxomorpholin-2-yl)acetic acid
  参考文献：
  名称：

  Rational Design and Binding Mode Duality of MDM2–p53 Inhibitors

  摘要：

  Structural analysis of both the MDM2-p53 protein protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 mu M. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 mu M) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAFl) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.

  DOI：

  10.1021/jm400293z
• 作为产物：
  描述：

  tert-butyl 2-((2RS,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((S)-1-((3,4-dimethoxybenzyl)oxy)butan-2-yl)-3-oxomorpholin-2-yl)acetate 在 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 2.0h， 以14%的产率得到tert-butyl 2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((S)-1-hydroxybutan-2-yl)-3-oxomorpholin-2-yl)acetate
  参考文献：
  名称：

  Rational Design and Binding Mode Duality of MDM2–p53 Inhibitors

  摘要：

  Structural analysis of both the MDM2-p53 protein protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 mu M. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 mu M) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAFl) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.

  DOI：

  10.1021/jm400293z

文献信息

• [EN] CIS-MORPHOLINONE AND OTHER COMPOUNDS AS MDM2 INHIBITORS FOR THE TREATMENT OF CANCER<br/>[FR] CIS-MORPHOLINONE ET AUTRES COMPOSÉS SERVANT D'INHIBITEURS DE MDM2 POUR LE TRAITEMENT DU CANCER
  申请人：AMGEN INC

  公开号：WO2014130470A1

  公开（公告）日：2014-08-28

  The present invention provides MDM2 inhibitor compounds of Formula (I), or the pharmaceutically acceptable salts thereof, wherein the variables are defined above, which compounds are useful as therapeutic agents, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor.

  本发明提供了式（I）的MDM2抑制剂化合物，或其药学上可接受的盐，其中变量如上所定义，这些化合物可用作治疗剂，特别用于治疗癌症。本发明还涉及含有MDM2抑制剂的药物组合物。
• CIS-MORPHOLINONE AND OTHER COMPOUNDS AS MDM2 INHIBITORS FOR THE TREATMENT OF CANCER
  申请人：AMGEN INC.

  公开号：US20160002185A1

  公开（公告）日：2016-01-07

  The present invention provides MDM2 inhibitor compounds of Formula (I), or the pharmaceutically acceptable salts thereof, wherein the variables are defined above, which compounds are useful as therapeutic agents, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor.

  本发明提供了公式（I）的MDM2抑制剂化合物或其药学上可接受的盐，其中变量如上所定义，这些化合物可用作治疗剂，特别是用于治疗癌症。本发明还涉及含有MDM2抑制剂的药物组合物。
• CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer
  申请人：AMGEN INC.

  公开号：US11407721B2

  公开（公告）日：2022-08-09

  The present invention provides MDM2 inhibitor compounds of Formula I, or the pharmaceutically acceptable salts thereof, wherein the variables are defined above, which compounds are useful as therapeutic agents, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor.

  本发明提供了式 I 的 MDM2 抑制剂化合物或其药学上可接受的盐类、 其中变量定义如上，这些化合物可用作治疗剂，特别是用于治疗癌症。本发明还涉及含有 MDM2 抑制剂的药物组合物。