4-[(2S)-2-amino-3,3-dimethylbutyl]morpholine-3,5-dione | 1132107-70-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: 4-[(2S)-2-amino-3,3-dimethylbutyl]morpholine-3,5-dione
• CAS: 1132107-70-0
• 化学式: C₁₀H₁₈N₂O₃
• 分子量: 214.265
• InChiKey: DSAYKANOFDVAEM-SSDOTTSWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  72.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  光气 、 4-[(2S)-2-amino-3,3-dimethylbutyl]morpholine-3,5-dione 在 碳酸氢钠 作用下， 以 二氯甲烷 、 水 为溶剂， 生成
  参考文献：
  名称：

  Second-Generation Highly Potent and Selective Inhibitors of the Hepatitis C Virus NS3 Serine Protease

  摘要：

  The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC90 by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K-i* = 4 nM, EC90 = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K-i* = 4 nM, EC90 = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.

  DOI：

  10.1021/jm801238q
• 作为产物：
  描述：

  在 盐酸 、 水 作用下， 以 1,4-二氧六环 为溶剂， 生成 4-[(2S)-2-amino-3,3-dimethylbutyl]morpholine-3,5-dione
  参考文献：
  名称：

  Second-Generation Highly Potent and Selective Inhibitors of the Hepatitis C Virus NS3 Serine Protease

  摘要：

  The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC90 by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K-i* = 4 nM, EC90 = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K-i* = 4 nM, EC90 = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.

  DOI：

  10.1021/jm801238q

文献信息

• [EN] NOVEL KETOAMIDES WITH CYCLIC P4'S AS INHIBITORS OF NS3 SERINE PROTEASE OF HEPATITIS C VIRUS<br/>[FR] NOUVEAUX CETOAMIDES A P4 CYCLIQUES EN TANT QU'INHIBITEURS DE LA NS3 SERINE PROTEASE DU VIRUS DE L'HEPATITE C
  申请人：SCHERING CORP

  公开号：WO2005085242A1

  公开（公告）日：2005-09-15

  The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.

  本发明公开了具有HCV蛋白酶抑制活性的新化合物，以及制备这种化合物的方法。在另一实施方式中，该发明公开了包含这种化合物的药物组合物，以及使用它们治疗与HCV蛋白酶相关的疾病的方法。
• EP1730142B1
  申请人：——

  公开号：EP1730142B1

  公开（公告）日：2011-06-29
• Novel ketoamides with cyclic P4's as inhibitors of NS3 serine protease of hepatitis C virus
  申请人：Chen X. Kevin

  公开号：US20070093430A1

  公开（公告）日：2007-04-26

  The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.
• US7173057B2
  申请人：——

  公开号：US7173057B2

  公开（公告）日：2007-02-06
• US7619094B2
  申请人：——

  公开号：US7619094B2

  公开（公告）日：2009-11-17