2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid chloride | 1584731-91-8

• 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: 2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid chloride
• 英文别名: 2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetyl chloride
• CAS: 1584731-91-8
• 化学式: C₂₉H₃₄Cl₃NO₄S
• 分子量: 599.018
• InChiKey: LXRFSBKTHFKNKO-HIJQLYNKSA-N

物化性质

• 沸点：
  718.8±60.0 °C(predicted)
• 密度：
  1.304±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  38.0
• 可旋转键数：
  8.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  71.52
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid chloride 在 劳森试剂 、 四丁基氟化铵 、 sodium t-butanolate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 15.25h， 生成
  参考文献：
  名称：

  Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Acid Isosteres

  摘要：

  We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.

  DOI：

  10.1021/jm401911v
• 作为产物：
  描述：

  5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one 在 2,6-二甲基吡啶 、 sodium periodate 、 草酰氯 、 rhodium(III) chloride hydrate 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 乙酸乙酯 、 乙腈 为溶剂， 反应 68.75h， 生成 2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid chloride
  参考文献：
  名称：

  BENZOIC ACID DERIVATIVE MDM2 INHIBITOR FOR THE TREATMENT OF CANCER

  摘要：

  本发明提供了一种MDM2抑制剂化合物，或其药用可接受的盐，该化合物可作为治疗剂，特别是用于癌症治疗。本发明还涉及含有MDM2抑制剂的药物组合物。

  公开号：

  US20140243372A1

文献信息

• Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2–p53 Interaction
  作者：Yosup Rew、Daqing Sun、Xuelei Yan、Hilary P. Beck、Jude Canon、Ada Chen、Jason Duquette、John Eksterowicz、Brian M. Fox、Jiasheng Fu、Ana Z. Gonzalez、Jonathan Houze、Xin Huang、Min Jiang、Lixia Jin、Yihong Li、Zhihong Li、Yun Ling、Mei-Chu Lo、Alexander M. Long、Lawrence R. McGee、Joel McIntosh、Jonathan D. Oliner、Tao Osgood、Anne Y. Saiki、Paul Shaffer、Yu Chung Wang、Sarah Wortman、Peter Yakowec、Qiuping Ye、Dongyin Yu、Xiaoning Zhao、Jing Zhou、Julio C. Medina、Steven H. Olson

  DOI：10.1021/jm501550p

  日期：2014.12.26

  Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (K-D from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.
• [EN] COMBINATION THERAPY INCLUDING AN MDM2 INHIBITOR AND ONE OR MORE ADDITIONAL PHARMACEUTICALLY ACTIVE AGENTS FOR THE TREATMENT OF CANCERS<br/>[FR] POLYTHÉRAPIE COMPRENANT UN INHIBITEUR DE MDM2 ET UN OU PLUSIEURS PRINCIPES PHARMACEUTIQUEMENT ACTIFS SUPPLÉMENTAIRES POUR LE TRAITEMENT DE CANCERS
  申请人：AMGEN INC

  公开号：WO2015070224A3

  公开（公告）日：2015-08-13