methyl (1R,20S,23S)-20-tert-butyl-3,18,21-trioxo-2,17-dioxa-4,19,22-triazatetracyclo[20.2.1.1(4,7).0(6,11)]hexacosa-6,8,10-triene-23-carboxylate | 923591-13-3

• 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: methyl (1R,20S,23S)-20-tert-butyl-3,18,21-trioxo-2,17-dioxa-4,19,22-triazatetracyclo[20.2.1.1(4,7).0(6,11)]hexacosa-6,8,10-triene-23-carboxylate
• 英文别名: methyl (5R,7S,10S)-10-tert-butyl-3,9,12-trioxo-1,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-2,22:5,8-dimethano-4,13,2,8,11-benzodioxatriazacycloicosine-7-carboxylate；methyl (1R,20S,23S)-20-tert-butyl-3,18,21-trioxo-2,17-dioxa-4,19,22-triazatetracyclo[20.2.1.14,7.06,11]hexacosa-6(11),7,9-triene-23-carboxylate
• CAS: 923591-13-3
• 化学式: C₂₇H₃₇N₃O₇
• 分子量: 515.607
• InChiKey: RCPKSRXVDVRMIQ-BAGYTPMASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  37
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  115
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl (1R,20S,23S)-20-tert-butyl-3,18,21-trioxo-2,17-dioxa-4,19,22-triazatetracyclo[20.2.1.1(4,7).0(6,11)]hexacosa-6,8,10-triene-23-carboxylate 在 甲醇 、 lithium hydroxide 、 水 、 盐酸 作用下， 以 四氢呋喃 、 水 、 乙酸乙酯 为溶剂， 反应 1.0h， 生成 (1R,20S,23S)-20-tert-butyl-3,18,21-trioxo-2,17-dioxa-4,19,22-triazatetracyclo[20.2.1.14,7.06,11]hexacosa-6(11),7,9-triene-23-carboxylic acid
  参考文献：
  名称：

  HCV NS3 protease inhibitors

  摘要：

  本发明涉及一种公式（I）的大环化合物，该化合物可用作乙型肝炎病毒（HCV）NS3蛋白酶的抑制剂，其合成以及用于治疗或预防HCV感染的用途。

  公开号：

  US20070027071A1
• 作为产物：
  描述：

  methyl (1R,20S,23S)-20-tert-butyl-3,18,21-trioxo-2,17-dioxa-4,19,22-triazatetracyclo[20.2.1.14,7.06,11]hexacosa-6,8,10,12-tetraene-23-carboxylate 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 4.0h， 以83%的产率得到methyl (1R,20S,23S)-20-tert-butyl-3,18,21-trioxo-2,17-dioxa-4,19,22-triazatetracyclo[20.2.1.1(4,7).0(6,11)]hexacosa-6,8,10-triene-23-carboxylate
  参考文献：
  名称：

  Inhibitors of hepatitis C virus NS3/4A: α-Ketoamide based macrocyclic inhibitors

  摘要：

  A novel series of hepatitis C virus (HCV) NS3/4A protease inhibitors bearing a P2-P4 macrocycle and a P1-P1' alpha-ketoamide serine trap is reported. The NS3 protease, which is essential for viral replication, is considered one of the most attractive targets for developing novel anti-HCV therapies. The optimization of both the macrocycle and the warhead portions led to the discovery of compounds 8b and 8g with a good activity both in the enzyme as well as in the cell based (replicon) assays with favorable PK profile in a preclinical species. (c) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.02.079

文献信息

• HCV NS3 protease inhibitors
  申请人：Holloway Katharine M.

  公开号：US20070027071A1

  公开（公告）日：2007-02-01

  The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.

  本发明涉及一种公式（I）的大环化合物，该化合物可用作乙型肝炎病毒（HCV）NS3蛋白酶的抑制剂，其合成以及用于治疗或预防HCV感染的用途。
• HCV NS3 PROTEASE INHIBITORS
  申请人：HOLLOWAY M. Katharine

  公开号：US20090124661A1

  公开（公告）日：2009-05-14

  The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.

  本发明涉及公式（I）的大环化合物，其可用作丙型肝炎病毒（HCV）NS3蛋白酶的抑制剂，其合成以及用于治疗或预防HCV感染的用途。
• US7470664B2
  申请人：——

  公开号：US7470664B2

  公开（公告）日：2008-12-30
• US8216999B2
  申请人：——

  公开号：US8216999B2

  公开（公告）日：2012-07-10
• Discovery of Vaniprevir (MK-7009), a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor
  作者：John A. McCauley、Charles J. McIntyre、Michael T. Rudd、Kevin T. Nguyen、Joseph J. Romano、John W. Butcher、Kevin F. Gilbert、Kimberly J. Bush、M. Katharine Holloway、John Swestock、Bang-Lin Wan、Steven S. Carroll、Jillian M. DiMuzio、Donald J. Graham、Steven W. Ludmerer、Shi-Shan Mao、Mark W. Stahlhut、Christine M. Fandozzi、Nicole Trainor、David B. Olsen、Joseph P. Vacca、Nigel J. Liverton

  DOI：10.1021/jm9015526

  日期：2010.3.25

  A new class of H CV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the PI side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral closing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.