N'-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide | 1204670-46-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: N'-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide
• 英文别名: N'-hydroxy-4-[2-(methanesulfonamido)ethylamino]-1,2,5-oxadiazole-3-carboximidamide
• CAS: 1204670-46-1
• 化学式: C₆H₁₂N₆O₄S
• 分子量: 264.265
• InChiKey: OXNMGSAIPOICQS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  17
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  164
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N'-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide 在 盐酸 、 三乙胺 、 sodium chloride 、 sodium nitrite 作用下， 以 乙醇 、 水 、 乙酸乙酯 为溶剂， 生成 N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide
  参考文献：
  名称：

  INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology

  摘要：

  A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 41, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.

  DOI：

  10.1021/acsmedchemlett.6b00391
• 作为产物：
  描述：

  4-amino-N'-hydroxy-N-{2-[(methylsulfonyl)amino]ethyl}-1,2,5-oxadiazole-3-carboximidamide 在 potassium hydroxide 作用下， 以 乙二醇 为溶剂， 反应 4.0h， 以96%的产率得到N'-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide
  参考文献：
  名称：

  1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase

  摘要：

  本发明涉及1,2,5-噁二唑衍生物及其组合物，其为吲哚胺2,3-二氧化酶的抑制剂，并且在癌症和其他疾病的治疗中有用，以及用于制备此类1,2,5-噁二唑衍生物的过程和中间体。

  公开号：

  US09320732B2

文献信息

• 1,2,5-OXADIAZOLES AS INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE
  申请人：Combs Andrew P.

  公开号：US20100015178A1

  公开（公告）日：2010-01-21

  The present invention is directed to 1,2,5-oxadiazole derivatives, and compositions of the same, which are inhibitors of indoleamine 2,3-dioxygenase and are useful in the treatment of cancer and other disorders, and to the processes and intermediates for making such 1,2,5-oxadiazole derivatives.

  本发明涉及1,2,5-噁二唑衍生物及其组合物，它们是色胺酸2,3-双氧酶的抑制剂，可用于治疗癌症和其他疾病，并涉及制备此类1,2,5-噁二唑衍生物的过程和中间体。
• [EN] SYNERGISTIC COMBINATION OF IMMUNOLOGIC INHIBITORS FOR THE TREATMENT OF CANCER<br/>[FR] COMBINAISON SYNERGIQUE D'INHIBITEURS IMMUNOLOGIQUES POUR LE TRAITEMENT DU CANCER
  申请人：UNIV CHICAGO

  公开号：WO2014066834A1

  公开（公告）日：2014-05-01

  In some embodiments, the methods involve the use of a combination of at least two of the following: an inhibitor of indoleamine-2,3-dioxygenase (IDO), an inhibitor of the PD-L1/PD-1 pathway, an inhibitor of CTLA-4, an inhibitor of CD25, or IL-7. The inventors particularly observed a major synergistic effect of combining anti-CTLA-4 with either an IDO inhibitor, with anti-PD-L1 mAb, or with CD-25 depletion. Such combinations have been found to demonstrate a synergistic effect in treating cancer and tumors, for example by reducing tumor size, increasing the percentage of antigen-specific T cells, and increasing T cell function.

  在一些实施方式中，这些方法涉及至少两种以下物质的组合使用：缓解吲哚胺-2,3-二氧化酶（IDO）的抑制剂、PD-L1/PD-1通路的抑制剂、CTLA-4的抑制剂、CD25的抑制剂或IL-7。发明者特别观察到将抗CTLA-4与IDO抑制剂、抗PD-L1单抗或CD-25耗尽结合的主要协同作用。这些组合已被发现在治疗癌症和肿瘤中展现出协同作用，例如通过减小肿瘤大小、增加特异性抗原T细胞的百分比以及增强T细胞功能。
• 1,2,5-Oxadiazoles As Inhibitors Of Indoleamine 2,3- Dioxygenase
  申请人：Incyte Corporation

  公开号：US20150190378A1

  公开（公告）日：2015-07-09

  The present invention is directed to 1,2,5-oxadiazole derivatives, and compositions of the same, which are inhibitors of indoleamine 2,3-dioxygenase and are useful in the treatment of cancer and other disorders, and to the processes and intermediates for making such 1,2,5-oxadiazole derivatives.

  本发明涉及1,2,5-噁二唑衍生物及其组合物，其为色胺2,3-二氧化酶抑制剂，可用于治疗癌症和其他疾病，并涉及制备此类1,2,5-噁二唑衍生物的过程和中间体。
• 1,2,5-Oxadiazoles as Inhibitors of Indoleamine 2,3-Dioxygenase
  申请人：Combs Andrew P.

  公开号：US20120058079A1

  公开（公告）日：2012-03-08

  The present invention is directed to 1,2,5-oxadiazole derivatives, and compositions of the same, which are inhibitors of indoleamine 2,3-dioxygenase and are useful in the treatment of cancer and other disorders, and to the processes and intermediates for making such 1,2,5-oxadiazole derivatives.

  本发明涉及1,2,5-噁二唑衍生物及其组合物，它们是吲哚胺2,3-双加氧酶的抑制剂，在癌症和其他疾病的治疗中有用，并涉及制备这种1,2,5-噁二唑衍生物的过程和中间体。
• 1,2,5-Oxadiazoles As Inhibitors Of Indoleamine 2,3-Dioxygenase
  申请人：Combs Andrew P.

  公开号：US20140023663A1

  公开（公告）日：2014-01-23

  The present invention is directed to 1,2,5-oxadiazole derivatives, and compositions of the same, which are inhibitors of indoleamine 2,3-dioxygenase and are useful in the treatment of cancer and other disorders, and to the processes and intermediates for making such 1,2,5-oxadiazole derivatives.

  本发明涉及1,2,5-噁二唑衍生物及其组合物，其是色胺酸2,3-双加氧酶的抑制剂，并可用于治疗癌症和其他疾病，以及制造此类1,2,5-噁二唑衍生物的过程和中间体。