2-[(2S)-2-isocyanato-3,3-dimethylbutyl]isoindole-1,3-dione | 848777-14-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2-[(2S)-2-isocyanato-3,3-dimethylbutyl]isoindole-1,3-dione
• CAS: 848777-14-0
• 化学式: C₁₅H₁₆N₂O₃
• 分子量: 272.304
• InChiKey: MINDURRISKIVOD-GFCCVEGCSA-N

物化性质

• 沸点：
  386.8±25.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  66.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 、 2-[(2S)-2-isocyanato-3,3-dimethylbutyl]isoindole-1,3-dione 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 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：

  光气 、 2-[(2S)-2-amino-3,3-dimethylbutyl]isoindole-1,3-dione;hydrochloride 在 碳酸氢钠 作用下， 以 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 2.0h， 生成 2-[(2S)-2-isocyanato-3,3-dimethylbutyl]isoindole-1,3-dione
  参考文献：
  名称：

  3,4-(cyclopentyl)-fused proline compounds as inhibitors of hepatitis C virus NS3 serine protease

  摘要：

  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，本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。

  公开号：

  US20050197301A1

文献信息

• Methods for treating hepatitis C
  申请人：Albrecht K. Janice

  公开号：US20060276405A1

  公开（公告）日：2006-12-07

  Methods of treating hepatitis C are provided comprising using a therapeutically effective amount of at least one novel hepatitis C (“HCV”) protease inhibitor or, alternatively, at least one antiviral or immuno-modulating HCV agent, which is not an HCV protease inhibitor, for a first treatment period. Subsequently, a combination of the at least one novel hepatitis C (“HCV”) protease inhibitor and the at least one antiviral or immuno-modulating HCV agent are administered in a therapeutically effective amount for a second treatment period. The methods are provided for treating a wide variety of diseases, disorders and symptoms associated with hepatitis C virus by modulating the activity of HCV protease (for example HCV NS3/NS4a serine protease) in a subject.

  提供了治疗丙型肝炎的方法，包括使用至少一种新型丙型肝炎（“HCV”）蛋白酶抑制剂的治疗有效量，或者选择至少一种不是HCV蛋白酶抑制剂的抗病毒或免疫调节HCV药物，用于第一治疗期。随后，在第二治疗期内以治疗有效量给予至少一种新型丙型肝炎（“HCV”）蛋白酶抑制剂和至少一种抗病毒或免疫调节HCV药物的组合。这些方法用于通过调节受试者中HCV蛋白酶（例如HCV NS3/NS4a丝氨酸蛋白酶）的活性来治疗与丙型肝炎病毒相关的各种疾病、疾病和症状。
• Controlled-release formulation
  申请人：Malcolm A. Bruce

  公开号：US20060275366A1

  公开（公告）日：2006-12-07

  Controlled-release dosage formulations including at least one compound of Formulae I to XXVI herein and a controlled-release carrier and methods of treatment using the same are provided.

  提供了包括本文中的至少一种I到XXVI式化合物和控释载体的控释剂量制剂，以及使用它们的治疗方法。
• Methods of treating hepatitis C virus
  申请人：Albrecht K. Janice

  公开号：US20060276407A1

  公开（公告）日：2006-12-07

  Compositions and therapeutic combinations are provided including at least one compound selected from the group consisting of compounds of Formulae I to XXVI as defined herein as well as methods of treatment, prevention or amelioration of one or more symptoms of hepatitis C, treating disorders associated with HCV virus, modulating activity of HCV protease, or inhibiting cathepsin activity in a subject using the same, in which the mean volume of distribution/bioavailability (Vd/F) of the compound as measured in the plasma of the subject is greater than about 1000 L.

  提供了包括至少一种从本文中定义的I到XXVI式化合物组成的组合物和治疗组合物，以及治疗、预防或改善丙型肝炎的一个或多个症状的方法，治疗与HCV病毒相关的疾病，调节HCV蛋白酶活性，或在受试者中抑制蛋白酶活性的方法，其中所述化合物在受试者血浆中测量的平均分布体积/生物利用度（Vd/F）大约大于1000升。
• Administration of HCV protease inhibitors in combination with food to improve bioavailability
  申请人：Zhang Jenny

  公开号：US20060281688A1

  公开（公告）日：2006-12-14

  Methods of treating, preventing or ameliorating one or more symptoms of hepatitis C in a subject comprising the step of administering at least one HCV protease inhibitor in combination with food are provided. Also provided are methods of increasing bioavailability of an HCV protease inhibitor and methods of increasing serum levels of an HCV protease inhibitor in a subject. All methods comprise adminstering at least one HCV protease inhibitor in combination with food, the at least one HCV protease inhibitor selected from the group consisting of compounds of Formulae I-XXVI, described herein. Administration of compounds of the present invention in combination with food provides improved bioavailability and increased peak serum levels of the compounds as compared to administration without food.

  提供了一种治疗、预防或改善乙型肝炎患者一种或多种症状的方法，包括在给予患者至少一种HCV蛋白酶抑制剂的步骤中与食物结合。还提供了一种增加HCV蛋白酶抑制剂生物利用度的方法和增加患者血清中HCV蛋白酶抑制剂水平的方法。所有方法包括在与食物结合的情况下给予患者至少一种HCV蛋白酶抑制剂，所述至少一种HCV蛋白酶抑制剂选自本文所述的化合物I-XXVI的组。与不与食物一起给药相比，本发明化合物与食物结合给药提供了改善的生物利用度和增加的化合物峰值血清水平。
• Pharmaceutical formulations and methods of treatment using the same
  申请人：Malcolm A. Bruce

  公开号：US20070010431A1

  公开（公告）日：2007-01-11

  Pharmaceutical formulations containing at least one compound of Formulae I-XXVI herein and at least one surfactant. Pharmaceutically acceptable carriers and excipients may also be included in the formulations. The formulations of the present invention are suited for use in single unit dosages.

  含有本文中的至少一种I-XXVI式化合物和至少一种表面活性剂的制药配方。 制剂中还可以包括药用可接受的载体和辅料。 本发明的制剂适用于单剂量使用。