methyl (1S,2S,5R)-6,6-dichloro-3-[(2S)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate | 394735-35-4

• 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 (1S,2S,5R)-6,6-dichloro-3-[(2S)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate
• CAS: 394735-35-4
• 化学式: C₂₀H₃₀Cl₂N₂O₅
• 分子量: 449.375
• InChiKey: SHOWMHPNFCWWTM-AJNGGQMLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  84.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl (1S,2S,5R)-6,6-dichloro-3-[(2S)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 3-(2-tert-butoxycarbonylamino-2-cyclohexyl-acetyl)-6,6-dichloro-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid
  参考文献：
  名称：

  Potent and selective small molecule NS3 serine protease inhibitors of Hepatitis C virus with dichlorocyclopropylproline as P2 residue

  摘要：

  Starting from a pentapeptide Hepatitis C virus NS3 protease inhibitor, a number of alpha-ketoamide inhibitors based on novel dichlorocyclopropylproline P2 core were synthesized and investigated for their HCV NS3 serine protease activity. The key intermediate 3,4-dichlorocyclopropylproline was obtained through a dichloro carbene insertion to 3,4-dehydroproline. The size of the molecules was reduced significantly through a series of truncations of the initial pentapeptide. By varying P1 side chain in length and size, potency and selectivity were improved. A variety of aliphatic carbamate and urea capping groups were examined. In general, compounds with urea cappings were more potent and selective than their carbamate counterparts. The most potent compound was a tert-butyl urea analog. Variations at P3 position were also investigated. Among the three residues incorporated, tert-leucine was clearly superior, leading to compounds that had excellent enzyme potency and selectivity. The most potent compound achieved cell-based replicon assay EC50 of 40 nM. The most promising compound of all had excellent potency in both enzyme (K-i* = 9 nM) and replicon assays (EC50 = 100 nM). Its bioavailabilities were above 10% in all three animal species (rats, monkeys, and dogs). It has provided a lead for future investigations. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.11.002
• 作为产物：
  描述：

  6,6-dichloro-3-aza-bicyclo[3,1,0]hexane-2-carboxylic acid methyl ester hydrochloride 、 Boc-L-环己基甘氨酸 在 N-甲基吗啉 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 3-羟基-1,2,3-苯并三嗪-4(3H)-酮 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.5h， 生成 methyl (1S,2S,5R)-6,6-dichloro-3-[(2S)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate
  参考文献：
  名称：

  Potent and selective small molecule NS3 serine protease inhibitors of Hepatitis C virus with dichlorocyclopropylproline as P2 residue

  摘要：

  Starting from a pentapeptide Hepatitis C virus NS3 protease inhibitor, a number of alpha-ketoamide inhibitors based on novel dichlorocyclopropylproline P2 core were synthesized and investigated for their HCV NS3 serine protease activity. The key intermediate 3,4-dichlorocyclopropylproline was obtained through a dichloro carbene insertion to 3,4-dehydroproline. The size of the molecules was reduced significantly through a series of truncations of the initial pentapeptide. By varying P1 side chain in length and size, potency and selectivity were improved. A variety of aliphatic carbamate and urea capping groups were examined. In general, compounds with urea cappings were more potent and selective than their carbamate counterparts. The most potent compound was a tert-butyl urea analog. Variations at P3 position were also investigated. Among the three residues incorporated, tert-leucine was clearly superior, leading to compounds that had excellent enzyme potency and selectivity. The most potent compound achieved cell-based replicon assay EC50 of 40 nM. The most promising compound of all had excellent potency in both enzyme (K-i* = 9 nM) and replicon assays (EC50 = 100 nM). Its bioavailabilities were above 10% in all three animal species (rats, monkeys, and dogs). It has provided a lead for future investigations. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.11.002

文献信息

• Novel peptides as NS3-serine protease inhibitors of hepatitis C virus
  申请人：Saksena K. Anil

  公开号：US20070032433A1

  公开（公告）日：2007-02-08

  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.

  本发明揭示了具有HCV蛋白酶抑制活性的新化合物，以及制备这些化合物的方法。在另一种实施方式中，本发明揭示了包含这些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。
• NOVEL PEPTIDES AS NS3-SERINE PROTEASE INHIBITORS OF HEPATITIS C VIRUS
  申请人：Schering Corporation

  公开号：EP1481000B1

  公开（公告）日：2010-06-02
• US7244721B2
  申请人：——

  公开号：US7244721B2

  公开（公告）日：2007-07-17
• US7592316B2
  申请人：——

  公开号：US7592316B2

  公开（公告）日：2009-09-22
• [EN] NOVEL PEPTIDES AS NS3-SERINE PROTEASE INHIBITORS OF HEPATITIS C VIRUS<br/>[FR] NOUVEAUX PEPTIDES UTILES COMME INHIBITEURS DE SERINE PROTEASE NS3 DU VIRUS DE L'HEPATITE C
  申请人：SCHERING CORP

  公开号：WO2003062265A2

  公开（公告）日：2003-07-31

  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.