4-carbamoyl-4-[4-(4-chloromethylbenzyloxy)-1-oxo-1,3-dihydroisoindol-2-yl]butyric acid methyl ester | 1323407-39-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 4-carbamoyl-4-[4-(4-chloromethylbenzyloxy)-1-oxo-1,3-dihydroisoindol-2-yl]butyric acid methyl ester
• 英文别名: methyl 5-amino-4-[7-[[4-(chloromethyl)phenyl]methoxy]-3-oxo-1H-isoindol-2-yl]-5-oxopentanoate
• CAS: 1323407-39-1
• 化学式: C₂₂H₂₃ClN₂O₅
• 分子量: 430.888
• InChiKey: CXUPSFMQHZZVCW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  30
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  98.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-carbamoyl-4-[4-(4-chloromethylbenzyloxy)-1-oxo-1,3-dihydroisoindol-2-yl]butyric acid methyl ester 在 potassium tert-butylate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 0.17h， 生成 3-(4-((4-((4,4-dimethylpiperidin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  参考文献：
  名称：

  Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma

  摘要：

  Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.

  DOI：

  10.1021/acs.jmedchem.9b01928
• 作为产物：
  描述：

  DL-谷氨酸 在 吡啶 、 盐酸 、 三甲基氯硅烷 、 二碳酸二叔丁酯 、 偶氮二甲酸二异丙酯 、 potassium carbonate 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 63.67h， 生成 4-carbamoyl-4-[4-(4-chloromethylbenzyloxy)-1-oxo-1,3-dihydroisoindol-2-yl]butyric acid methyl ester
  参考文献：
  名称：

  Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma

  摘要：

  Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.

  DOI：

  10.1021/acs.jmedchem.9b01928

文献信息

• Arylmethoxy Isoindoline Derivatives and Compositions Comprising and Methods of Using the Same
  申请人：Man Hon-Wah

  公开号：US20110196150A1

  公开（公告）日：2011-08-11

  Provided are 4′-arylmethoxy isoindoline compounds, and pharmaceutically acceptable salts, solvates, clathrates, stereoisomers, and prodrugs thereof. Methods of use, and pharmaceutical compositions of these compounds are disclosed.

  提供了4'-芳基甲氧基异吲哚啉化合物，以及其药用盐、溶剂合物、包合物、立体异构体和前药。公开了这些化合物的使用方法和药物组合物。
• ARYLMETHOXY ISOINDOLINE DERIVATIVES AND COMPOSITIONS COMPRISING AND METHODS OF USING THE SAME
  申请人：Celgene Corporation

  公开号：US20180037567A1

  公开（公告）日：2018-02-08

  Provided are 4′-arylmethoxy isoindoline compounds, and pharmaceutically acceptable salts, solvates, clathrates, stereoisomers, and prodrugs thereof. Methods of use, and pharmaceutical compositions of these compounds are disclosed.

  提供了4'-芳基甲氧基异吲哚啉化合物及其药学上可接受的盐、溶剂合物、笼合物、立体异构体和前药。公开了这些化合物的使用方法和药物组合物。
• Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
  申请人：Celgene Corporation

  公开号：US10189814B2

  公开（公告）日：2019-01-29

  Provided are 4′-arylmethoxy isoindoline compounds, and pharmaceutically acceptable salts, solvates, clathrates, stereoisomers, and prodrugs thereof. Methods of use, and pharmaceutical compositions of these compounds are disclosed.

  本发明提供了 4′-芳基甲氧基异吲哚啉化合物及其药学上可接受的盐、溶液剂、凝胶体、立体异构体和原药。还公开了这些化合物的使用方法和药物组合物。
• US8518972B2
  申请人：——

  公开号：US8518972B2

  公开（公告）日：2013-08-27
• US9309219B2
  申请人：——

  公开号：US9309219B2

  公开（公告）日：2016-04-12