[(Z)-(1R,4R,6S,15R,17R)-4-cyclopropanesulfonylaminocarbonyl-17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0^4,6]octadec-7-en-13-yl]-carbamic acid tert-butyl ester | 959434-78-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: [(Z)-(1R,4R,6S,15R,17R)-4-cyclopropanesulfonylaminocarbonyl-17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0^4,6]octadec-7-en-13-yl]-carbamic acid tert-butyl ester
• 英文别名: [4-cyclopropanesulphonylaminocarbonyl-17-(7-methoxy-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4,6*]octadec-7-en-13-yl]-carbamic acid tert.butyl ester；tert-butyl N-[(1R,4R,6S,7Z,15R,17R)-4-(cyclopropylsulfonylcarbamoyl)-17-(7-methoxy-2-phenylquinolin-4-yl)oxy-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-en-13-yl]carbamate
• CAS: 959434-78-7
• 化学式: C₄₁H₄₉N₅O₉S
• 分子量: 787.934
• InChiKey: YUGQTUXWJYXLLJ-KMCVGVHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  56
• 可旋转键数：
  9
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  191
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  [(Z)-(1R,4R,6S,15R,17R)-4-cyclopropanesulfonylaminocarbonyl-17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0^4,6]octadec-7-en-13-yl]-carbamic acid tert-butyl ester 在 三乙基硅烷 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以95%的产率得到cyclopropanesulfonic acid [(Z)-(1R,4R,6S,15R,17R)-13-amino-17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0^4,6]octadec-7-ene-4-carbonyl]amide
  参考文献：
  名称：

  Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: Use of cyclopentane and cyclopentene P2-motifs

  摘要：

  Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding PI acylsulfonamides had superior potencies over the corresponding PI carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K-i value of 0.41 nM and an EC50 value of 9 nM in the subgenomic HCV replicon cell model on genotype lb. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assav and lacking the P4 substituent, a finding which Should facilitate the development of orally active small molecule inhibitors against the HCV protease. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.07.027
• 作为产物：
  描述：

  环丙磺酰胺 在 N,N-二异丙基乙胺 、 4-二甲氨基吡啶 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 DMF (N,N-dimethyl-formamide) 为溶剂， 反应 121.02h， 生成 [(Z)-(1R,4R,6S,15R,17R)-4-cyclopropanesulfonylaminocarbonyl-17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0^4,6]octadec-7-en-13-yl]-carbamic acid tert-butyl ester
  参考文献：
  名称：

  [EN] HCV NS-3 SERINE PROTEASE INHIBITORS
  [FR] INHIBITEURS DE LA NS-3 SERINE PROTEASE DU VHC

  摘要：

  公开号：

  WO2005073195A3

文献信息

• Hcv Ns-3 Serine Protease Inhibitors
  申请人：Rosenquist Asa

  公开号：US20070203072A1

  公开（公告）日：2007-08-30

  Peptidomimetic compounds are described which inhibit the NS3 protease of the hepatitis C virus (HCV). The compounds have the formula where the variable definitions are as provided in the specification. The compounds comprise a carbocyclic P2 unit in conjunction with a novel linkage to those portions of the inhibitor more distal to the nominal cleavage site of the native substrate, which linkage reverses the orientation of peptidic bonds on the distal side relative to those proximal to the cleavage site.

  本文描述了一种抑制丙型肝炎病毒（HCV）的NS3蛋白酶的肽类类似物化合物。该化合物的化学式中，变量定义如规范中所提供。该化合物包括一个碳环P2单元，与抑制剂更远离天然底物的名义剪切位点的那些部分的新型连接结合，该连接将远侧的肽键方向相对于靠近剪切位点的肽键反转。
• HCV NS-3 SERINE PROTEASE INHIBITORS
  申请人：Rosenquist Asa

  公开号：US20100166706A1

  公开（公告）日：2010-07-01

  Methods drawn to peptidomimetic compounds which inhibit the NS3 protease of the hepatitis C virus (HCV), are described. The compounds have the formula (VI) where the variable definitions are as provided in the specification. The compounds comprise a carbocyclic P2 unit in conjunction with a novel linkage to those portions of the inhibitor more distal to the nominal cleavage site of the native substrate, which linkage reverses the orientation of peptidic bonds on the distal side relative to those proximal to the cleavage site.

  本文描述了用于抑制丙型肝炎病毒（HCV）NS3蛋白酶的肽类类似物化合物的方法。这些化合物的公式为（VI），其中变量定义如规范所述。这些化合物包括一个碳环P2单元，与抑制剂更远离原生底物的部分具有新颖的连接，该连接将远离切割位点的肽键的方向与靠近切割位点的肽键的方向相反。
• HCV NS-3 serine protease inhibitors
  申请人：Medivir AB

  公开号：US10172846B2

  公开（公告）日：2019-01-08

  Methods drawn to peptidomimetic compounds which inhibit the NS3 protease of the hepatitis C virus (HCV), are described. The compounds have the formula (VI) where the variable definitions are as provided in the specification. The compounds comprise a carbocyclic P2 unit in conjunction with a novel linkage to those portions of the inhibitor more distal to the nominal cleavage site of the native substrate, which linkage reverses the orientation of peptidic bonds on the distal side relative to those proximal to the cleavage site.

  本文介绍了抑制丙型肝炎病毒（HCV）NS3蛋白酶的拟肽化合物的制备方法。这些化合物具有式 (VI)，其中变量定义如说明书所提供。这些化合物包括一个碳环 P2 单元，该单元与抑制剂中离原生底物名义裂解位点较远的部分有一种新的连接，这种连接使远端肽键的方向与裂解位点近端的肽键方向相反。
• US7671032B2
  申请人：——

  公开号：US7671032B2

  公开（公告）日：2010-03-02
• Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: Use of cyclopentane and cyclopentene P2-motifs
  作者：Marcus Bäck、Per-Ola Johansson、Fredrik Wångsell、Fredrik Thorstensson、Ingemar Kvarnström、Susana Ayesa、Horst Wähling、Mikael Pelcman、Katarina Jansson、Stefan Lindström、Hans Wallberg、Björn Classon、Christina Rydergård、Lotta Vrang、Elizabeth Hamelink、Anders Hallberg、Åsa Rosenquist、Bertil Samuelsson

  DOI：10.1016/j.bmc.2007.07.027

  日期：2007.11

  Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding PI acylsulfonamides had superior potencies over the corresponding PI carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K-i value of 0.41 nM and an EC50 value of 9 nM in the subgenomic HCV replicon cell model on genotype lb. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assav and lacking the P4 substituent, a finding which Should facilitate the development of orally active small molecule inhibitors against the HCV protease. (C) 2007 Elsevier Ltd. All rights reserved.