4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyric acid methyl ester | 1323407-21-1

• 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-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyric acid methyl ester
• 英文别名: methyl 5-amino-4-(4-(4-(morpholinomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate；methyl 5-amino-4-[7-[[4-(morpholin-4-ylmethyl)phenyl]methoxy]-3-oxo-1H-isoindol-2-yl]-5-oxopentanoate
• CAS: 1323407-21-1
• 化学式: C₂₆H₃₁N₃O₆
• 分子量: 481.549
• InChiKey: ADPHUANLUHYZTI-UHFFFAOYSA-N

物化性质

• 沸点：
  732.8±60.0 °C(Predicted)
• 密度：
  1.287±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  35
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  111
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyric acid methyl ester 在 potassium tert-butylate 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 以72%的产率得到(S)-3-(4-((4-(吗啉基甲基)苄基)氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
  参考文献：
  名称：

  A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos

  摘要：

  The drugs lenalidomide and pomalidomide bind to the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation. Here we describe CC-220 (compound 6), a cereblon modulator in clinical development for systemic lupus erythematosis and relapsed/refractory multiple myeloma. Compound 6 binds cereblon with a higher affinity than lenalidomide or pomalidomide. Consistent with this, the cellular degradation of Ikaros and Aiolos is more potent and the extent of substrate depletion is greater. The crystal structure of cereblon in complex with DDB1 and compound 6 reveals that the increase in potency correlates with increased contacts between compound 6 and cereblon away from the modeled binding site for Ikaros/Aiolos. These results describe a new cereblon modulator which achieves greater substrate degradation via tighter binding to the cereblon E3 ligase and provides an example of the effect of E3 ligase binding affinity with relevance to other drug discovery efforts in targeted protein degradation.

  DOI：

  10.1021/acs.jmedchem.6b01921
• 作为产物：
  描述：

  3-羟基-2-甲基苯甲酸甲酯 在 咪唑 、 N-溴代丁二酰亚胺(NBS) 、 偶氮二甲酸二异丙酯 、 potassium carbonate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙酸甲酯 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 44.83h， 生成 4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyric acid methyl ester
  参考文献：
  名称：

  [EN] METHODS FOR TREATING SYSTEMIC LUPUS ERYTHEMATOSUS AND THE USE OF BIOMARKERS AS A PREDICTOR OF CLINICAL SENSITIVITY TO THERAPIES
  [FR] MÉTHODES DE TRAITEMENT DU LUPUS ÉRYTHÉMATEUX DISSÉMINÉ ET UTILISATION DE BIOMARQUEURS COMME PRÉDICTEUR DE LA SENSIBILITÉ CLINIQUE À DES THÉRAPIES

  摘要：

  一种用于确定治疗系统性红斑狼疮（SLE）患者的治疗化合物剂量的方法，包括从患者获取样本并测量样本中IKZF3基因表达水平和/或IFI27、IFI44、IFI44L和RSAD2基因表达水平。

  公开号：

  WO2022072576A1

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。
• [EN] METHODS FOR THE TREATMENT OF LOCALLY ADVANCED BREAST CANCER<br/>[FR] MÉTHODES POUR LE TRAITEMENT DU CANCER DU SEIN LOCALEMENT AVANCÉ
  申请人：CELGENE CORP

  公开号：WO2014039960A1

  公开（公告）日：2014-03-13

  Provided herein are methods of treating, preventing and/or managing locally advanced breast cancer, including inflammatory breast cancer, which comprise administering to a patient one or more immunomodulatory compounds or enantiomers or mixtures of enantiomers thereof, or pharmaceutically acceptable salts, solvates, hydrates, co-crystals, clathrates, or polymorphs thereof.

  本文提供了治疗、预防和/或管理局部晚期乳腺癌的方法，包括炎性乳腺癌，该方法包括向患者施用一种或多种免疫调节化合物或其对映体或对映体混合物，或其药用可接受的盐、溶剂化合物、水合物、共晶体、包合物或多形体。
• [EN] METHODS FOR TREATING SOLID TUMORS AND THE USE OF BIOMARKERS AS A PREDICTOR OF CLINICAL SENSITIVITY TO IMMUNOMODULATORY THERAPIES<br/>[FR] MÉTHODES DE TRAITEMENT DE TUMEURS SOLIDES ET UTILISATION DE BIOMARQUEURS EN TANT QUE FACTEURS PRÉDICTIFS DE LA SENSIBILITÉ CLINIQUE À DES TRAITEMENTS IMMUNOMODULATEURS
  申请人：CELGENE CORPORATON

  公开号：WO2016060702A1

  公开（公告）日：2016-04-21

  A method of identifying a subject having a solid tumor who is likely to be responsive to a treatment compound, comprising: administering the treatment compound to a subject having the solid tumor; obtaining a sample from the subject; determining the level of a biomarker in the sample from the subject, and diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample of the subject changes as compared to a reference level of the biomarker.

  一种识别可能对治疗化合物产生响应的固体肿瘤患者的方法，包括：向患有固体肿瘤的受试者施用治疗化合物；从受试者获取样本；确定来自受试者样本中生物标志物的水平，并且如果受试者样本中生物标志物的水平与生物标志物的参考水平相比发生变化，则诊断受试者可能对治疗化合物产生响应。
• TREATMENT OF IMMUNE-RELATED AND INFLAMMATORY DISEASES
  申请人：Celgene Corporation

  公开号：US20140045844A1

  公开（公告）日：2014-02-13

  Provided herein are methods of using compounds and compositions for modulating leukocytic activity, including activity of B cells and/or T cells monocytes, macrophages, and other lymphoid or myeloid-derived cell types, in immune-related diseases or inflammatory diseases. Pharmaceutical compositions and dosing regimens for use in the methods are also provided herein.

  本文提供了一种使用化合物和组合物调节白细胞活性的方法，包括调节B细胞和/或T细胞、单核细胞、巨噬细胞以及其他淋巴细胞或髓系细胞类型在免疫相关疾病或炎症性疾病中的活性。同时还提供了用于这些方法的药物组合物和用药方案。
• METHODS FOR MEASURING SMALL MOLECULE AFFINITY TO CEREBLON
  申请人：CELGENE CORPORATION

  公开号：US20180224435A1

  公开（公告）日：2018-08-09

  A complex comprises a CRBN having a europium-anti-his antibody on the N-terminus of the CRBN, and a Cy5-conjugated small molecule, wherein the Cy5-conjugated small molecule binds the CRBN, and uses thereof for identifying therapeutic compounds.

  一个复合物包括具有CRBN的欧洲锗-抗his抗体位于CRBN的N-末端，并且一个Cy5共轭的小分子，其中Cy5共轭的小分子结合CRBN，并用于识别治疗化合物的用途。