tert-butyl 2-(2-(2-(2-(3-(hydroxymethyl)-5-methoxy-2-methyl-4,7-dioxo-4,7-dihydro-1H-indol-1-yl)acetamido)ethoxy)ethoxy)ethylcarbamate | 1190931-02-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: tert-butyl 2-(2-(2-(2-(3-(hydroxymethyl)-5-methoxy-2-methyl-4,7-dioxo-4,7-dihydro-1H-indol-1-yl)acetamido)ethoxy)ethoxy)ethylcarbamate
• CAS: 1190931-02-2
• 化学式: C₂₄H₃₅N₃O₉
• 分子量: 509.557
• InChiKey: AXOHQBMWQPFRON-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.87
• 重原子数：
  36.0
• 可旋转键数：
  13.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  154.42
• 氢给体数：
  3.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  tert-butyl 2-(2-(2-(2-(3-(hydroxymethyl)-5-methoxy-2-methyl-4,7-dioxo-4,7-dihydro-1H-indol-1-yl)acetamido)ethoxy)ethoxy)ethylcarbamate 、 对硝基苯基氯甲酸酯 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 以89%的产率得到tert-butyl (2-(2-(2-(2-(5-methoxy-2-methyl-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)-4,7-dioxo-4,7-dihydro-1H-indol-1-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate
  参考文献：
  名称：

  Human plasma-mediated hypoxic activation of indolequinone-based naloxone pro-drugs

  摘要：

  Hypoxia is known to occur in tissues in response to narcotic analgesic therapy using as a result of respiratory depression. The aim of this study was to synthesize a narcotic antagonist pro-drug that can be activated by tissue hypoxia to prevent the damage associated with respiratory depression. We synthesized three different pro-drugs of the narcotic antagonist naloxone utilizing indolequinone as the hypoxia-sensitive moiety. The indolequinone structure in the pro-drugs was designed to have an open reactive point at the N-1 position offering the possibility of further conjugation with macromolecules to modify the bio-availability of these pro-drugs in vivo. A pro-drug (labeled 1) where naloxone and the indolequinone moiety were linked through a carbonate bond was rapidly hydrolyzed in phosphate buffered saline. However, two additional pro-drugs (labeled 2 and 3) having carbamate linkers were stable in phosphate buffered saline for 24 h. The reductive release of naloxone from the pro-drugs was achieved in the presence of the bio-reductive enzyme DT-Diaphorase, with about 80% release occurring from the two pro-drugs in 24 h. More than 99% of naloxone was released from pro-drug 2 in 30% human plasma, however the release only occurred under hypoxic conditions. This system provides a potential means for feedback control to counter critical respiratory depression induced by narcotic analgesics. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.07.061
• 作为产物：
  描述：

  2-(3-(hydroxymethyl)-5-methoxy-2-methyl-4,7-dioxo-4,7-dihydro-1H-indol-1-yl)acetic acid 、 2-(2-(2-氨基乙氧基)乙氧基)乙基氨基甲酸叔丁酯 在 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以72%的产率得到tert-butyl 2-(2-(2-(2-(3-(hydroxymethyl)-5-methoxy-2-methyl-4,7-dioxo-4,7-dihydro-1H-indol-1-yl)acetamido)ethoxy)ethoxy)ethylcarbamate
  参考文献：
  名称：

  Human plasma-mediated hypoxic activation of indolequinone-based naloxone pro-drugs

  摘要：

  Hypoxia is known to occur in tissues in response to narcotic analgesic therapy using as a result of respiratory depression. The aim of this study was to synthesize a narcotic antagonist pro-drug that can be activated by tissue hypoxia to prevent the damage associated with respiratory depression. We synthesized three different pro-drugs of the narcotic antagonist naloxone utilizing indolequinone as the hypoxia-sensitive moiety. The indolequinone structure in the pro-drugs was designed to have an open reactive point at the N-1 position offering the possibility of further conjugation with macromolecules to modify the bio-availability of these pro-drugs in vivo. A pro-drug (labeled 1) where naloxone and the indolequinone moiety were linked through a carbonate bond was rapidly hydrolyzed in phosphate buffered saline. However, two additional pro-drugs (labeled 2 and 3) having carbamate linkers were stable in phosphate buffered saline for 24 h. The reductive release of naloxone from the pro-drugs was achieved in the presence of the bio-reductive enzyme DT-Diaphorase, with about 80% release occurring from the two pro-drugs in 24 h. More than 99% of naloxone was released from pro-drug 2 in 30% human plasma, however the release only occurred under hypoxic conditions. This system provides a potential means for feedback control to counter critical respiratory depression induced by narcotic analgesics. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.07.061