(2R,6S,13aS,14aR,16aS,Z)-6-(((tert-butoxy)carbonyl)amino)-14a-((cyclopropylsulfonyl)carbamoyl)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate | 1439898-52-8

• 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: (2R,6S,13aS,14aR,16aS,Z)-6-(((tert-butoxy)carbonyl)amino)-14a-((cyclopropylsulfonyl)carbamoyl)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate
• 英文别名: (2R, 6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,8,9,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate；[(1S,4R,6S,7Z,14S,18R)-4-(cyclopropylsulfonylcarbamoyl)-14-[(2-methylpropan-2-yl)oxycarbonylamino]-2,15-dioxo-10-oxa-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-18-yl] 4-fluoro-1,3-dihydroisoindole-2-carboxylate
• CAS: 1439898-52-8
• 化学式: C₃₄H₄₄FN₅O₁₀S
• 分子量: 733.815
• InChiKey: XSVCIQZTRLZSFH-SAMQGORBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  51
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  198
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  (2R,6S,13aS,14aR,16aS,Z)-6-(((tert-butoxy)carbonyl)amino)-14a-((cyclopropylsulfonyl)carbamoyl)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate 在 氢气 作用下， 以 乙酸乙酯 为溶剂， 反应 16.0h， 以50%的产率得到(2R,6S,13aR,14aR,16aS)-6-(((tert-butoxy)carbonyl)amino)-14a-((cyclopropylsulfonyl)carbamoyl)-5,16-dioxohexadecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate
  参考文献：
  名称：

  Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease

  摘要：

  HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a Pl/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.

  DOI：

  10.1021/jm400164c
• 作为产物：
  描述：

  (S)-5-(allyloxy)-2-(((tert-butoxy)carbonyl)amino)pentanoic acid 在 詹氏钌催化剂-1 、 水 、 N,N-二异丙基乙胺 、 N,N'-羰基二咪唑 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲苯 、 乙腈 为溶剂， 反应 57.0h， 生成 (2R,6S,13aS,14aR,16aS,Z)-6-(((tert-butoxy)carbonyl)amino)-14a-((cyclopropylsulfonyl)carbamoyl)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate
  参考文献：
  名称：

  Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease

  摘要：

  HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a Pl/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.

  DOI：

  10.1021/jm400164c

文献信息

• Novel macrocyclic inhibitors of hepatitis C virus replication
  申请人：Blatt M. Lawrence

  公开号：US20070054842A1

  公开（公告）日：2007-03-08

  The embodiments provide compounds of the general Formulae I through general Formula VIII, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

  本实施例提供一般式I至一般式VIII的化合物，以及包括药物组合物在内的组合物，其中包括一种主体化合物。本实施例还提供治疗方法，包括治疗丙型肝炎病毒感染和治疗肝纤维化的方法，这些方法通常涉及向需要治疗的个体施用一种主体化合物或组合物的有效量。
• NOVEL MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS REPLICATION
  申请人：Blatt Lawrence M.

  公开号：US20120208995A1

  公开（公告）日：2012-08-16

  The embodiments provide compounds of the general Formulae I through general Formula VIII, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

  本实施例提供了一般式I至一般式VIII的化合物，以及包括药物组合物在内的组合物。实施例还提供了治疗方法，包括治疗丙型肝炎病毒感染和治疗肝纤维化的方法，通常涉及向需要的个体施用所述化合物或组合物的有效量。
• Macrocyclic inhibitors of hepatitis C virus replication
  申请人：InterMune, Inc.

  公开号：US07829665B2

  公开（公告）日：2010-11-09

  The embodiments provide compounds of the general Formulae I through general Formula VIII, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

  本实施例提供一般式I至一般式VIII的化合物，以及包括药物组合物在内的组合物，其中包括一种主体化合物。本实施例还提供治疗方法，包括治疗丙型肝炎病毒感染和治疗肝纤维化的方法，一般涉及向需要治疗的个体施用所述主体化合物或组合物的有效量。
• Novel Macrocyclic Inhibitors of Hepatitis C Virus Replication
  申请人：Blatt Lawrence M.

  公开号：US20090148407A1

  公开（公告）日：2009-06-11

  The embodiments provide compounds of the general Formulae (I) through general Formula (VIII), as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

  本实施例提供通式（I）到通式（VIII）的化合物，以及包括制药组合物在内的组合物，其中包括主体化合物。本实施例还提供治疗方法，包括治疗丙型肝炎病毒感染和治疗肝纤维化的方法，通常涉及向需要治疗的个体施用所述主体化合物或组合物的有效量。
• Novel macrocyclic inhibitors of Hepatitis C virus replication
  申请人：Intermune, Inc.

  公开号：EP2103623A2

  公开（公告）日：2009-09-23

  The embodiments provide compounds of the general Formulae (I) through general Formula (VIII), as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

  本发明的实施方案提供了通式(I)至通式(VIII)的化合物，以及包含主题化合物的组合物，包括药物组合物。本发明的实施方案进一步提供了治疗方法，包括治疗丙型肝炎病毒感染的方法和治疗肝纤维化的方法，这些方法一般涉及向有需要的个体施用有效量的主题化合物或组合物。