(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-carboxylic acid | 959434-71-0

• 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)-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-carboxylic acid
• 英文别名: (1R,4R,6S,7Z,15R,17R)-13-amino-17-(7-methoxy-2-phenylquinolin-4-yl)oxy-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid
• CAS: 959434-71-0
• 化学式: C₃₃H₃₆N₄O₆
• 分子量: 584.672
• InChiKey: ZPPIGWGXPXVKIT-UEKQPMLNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  43
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  144
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (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-carboxylic acid ethyl ester 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 5.0h， 以52%的产率得到(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-carboxylic acid
  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