methyl 5-((dimethylcarbamoyl)oxy)quinoline-3-carboxylate | 911108-92-4

• 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: methyl 5-((dimethylcarbamoyl)oxy)quinoline-3-carboxylate
• 英文别名: methyl 5-(N,N-dimethylcarbamate)-quinoline-3-carboxylate；Methyl 5-(dimethylcarbamoyloxy)quinoline-3-carboxylate
• CAS: 911108-92-4
• 化学式: C₁₄H₁₄N₂O₄
• 分子量: 274.276
• InChiKey: VDGBMSCTEVHDBS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  68.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl 5-((dimethylcarbamoyl)oxy)quinoline-3-carboxylate 、 三氟甲烷磺酸甲酯 以 二氯甲烷 为溶剂， 反应 2.0h， 以100%的产率得到methyl 5-(N,N-dimethylcarbamate)-1-methylquinolinium-3-carboxylate triflate
  参考文献：
  名称：

  通过“生物可氧化前药”策略合理设计中枢选择性乙酰胆碱酯酶抑制剂†

  摘要：

  这项工作涉及开发新的中央选择性乙酰胆碱酯酶抑制剂的“生物可氧化前药”策略的设计。预期该前药方法会降低外周抗胆碱酯酶活性，从而导致目前市售的各种副作用疼痛抑制剂。这些新的设计疼痛 抑制剂 喹啉 系列大致基于的循环类似物 利凡斯的明。前药的关键活化步骤涉及N-烷基-1，4-二氢喹啉1氧化为相应的喹啉鎓盐2，从而掩盖了与酶的催化阴离子位点结合所需的正电荷。介绍了一组1,4-二氢喹啉1及其相应的喹啉鎓盐2的合成。的体外生物学评价显示，虽然所有的还原形式1无法表现出任何抗胆碱酯酶活性（IC 50 > 10 6 nm）时，大部分的喹啉盐的2显示高疼痛抑制活性（IC 50为6μM至7 nM）。这些初步的体外试验验证了这些环状类似物的使用。利凡斯的明喹啉系列的药物作为进一步在体内开发这种“生物可氧化前药”方法的诱人化学工具。

  DOI：

  10.1039/b903041g
• 作为产物：
  描述：

  二甲氨基甲酰氯 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以85%的产率得到methyl 5-((dimethylcarbamoyl)oxy)quinoline-3-carboxylate
  参考文献：
  名称：

  WO2006/103120

  摘要：

  公开号：

文献信息

• Palladium-Catalyzed Carbonylation of (Hetero)Aryl, Alkenyl and Allyl Halides by Means of <i>N-</i>Hydroxysuccinimidyl Formate as CO Surrogate
  作者：Anaïs Barré、Mihaela-Liliana Ţînţaş、Florent Alix、Vincent Gembus、Cyril Papamicaël、Vincent Levacher

  DOI：10.1021/acs.joc.5b01119

  日期：2015.7.2

  An efficient Pd-catalyzed carbonylation protocol is described for the coupling of a large panel of aryl, heteroaryl, benzyl, vinyl and allyl halides 2 with the unusual N-hydroxysuccinimidyl (NHS) formate 1 as a CO surrogate to afford the corresponding valuable NHS esters 3. High conversion to the coupling products was achieved with up to 98% yield by means of Pd(OAc)(2)/Xantphos catalyst system.
• Dihydroquinoline Carbamate Derivatives as “Bio-oxidizable” Prodrugs for Brain Delivery of Acetylcholinesterase Inhibitors: [¹¹C] Radiosynthesis and Biological Evaluation
  作者：Pierre Bohn、Fabienne Gourand、Cyril Papamicaël、Méziane Ibazizène、Martine Dhilly、Vincent Gembus、Florent Alix、Mihaela-Liliana Ţînţaş、Francis Marsais、Louisa Barré、Vincent Levacher

  DOI：10.1021/cn5003539

  日期：2015.5.20

  With the aim of improving the efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer's disease, plagued by adverse effects arising from peripheral cholinergic activation, this work reports a biological evaluation of new central AChE inhibitors based on an original "bio-oxidizable" prodrug strategy. After peripheral injection of the prodrug la [IC50 > 1 mM (hAChE)] in mice, monitoring markers of central and peripheral cholinergic activation provided in vivo proof-of-concept for brain delivery of the drug 2a [IC50 = 20 nM (hAChE)] through central redox activation of la. Interestingly, peripheral cholinergic activation has been shown to be limited in time, likely due to the presence of a permanent positive charge in 2a promoting rapid elimination of the AChE inhibitor from the circulation of mice. To support these assumptions, the radiosynthesis with carbon-11 of prodrug la was developed for additional ex vivo studies in rats. Whole-body biodistribution of radioactivity revealed high accumulation in excretory organs along with moderate but rapid brain uptake. Radio-HPLC analyses of brain samples confirm rapid CNS penetration of [C-11] la, while identification of [C-11]2a and [C-11]3a both accounts for central redox activation of la and pseudoirreversible inhibition of AChE, respectively. Finally, Caco-2 permeability assays predicted metabolite 3a as a substrate for efflux transporters (P-gp inter alia), suggesting that metabolite 3a might possibly be actively transported out of the brain. Overall, a large body of evidence from in vivo and ex vivo studies on small animals has been collected to validate this "bio-oxidizable" prodrug approach, emerging as a very promising strategy in the rational design of selective central AChE inhibitors.
• WO2006/103120
  申请人：——

  公开号：——

  公开（公告）日：——
• Rational design of central selective acetylcholinesterase inhibitors by means of a “bio-oxidisable prodrug” strategy
  作者：Pierre Bohn、Nicolas Le Fur、Guillaume Hagues、Jean Costentin、Nicolas Torquet、Cyril Papamicaël、Francis Marsais、Vincent Levacher

  DOI：10.1039/b903041g

  日期：——

  oxidation of an N-alkyl-1,4-dihydroquinoline 1 to the corresponding quinolinium salt 2 unmasking the positive charge required for binding to the catalytic anionic site of the enzyme. The synthesis of a set of 1,4-dihydroquinolines 1 and their corresponding quinolinium salts 2 is presented. An in vitro biological evaluation revealed that while all reduced forms 1 were unable to exhibit any anticholinesterase

  这项工作涉及开发新的中央选择性乙酰胆碱酯酶抑制剂的“生物可氧化前药”策略的设计。预期该前药方法会降低外周抗胆碱酯酶活性，从而导致目前市售的各种副作用疼痛抑制剂。这些新的设计疼痛 抑制剂 喹啉 系列大致基于的循环类似物 利凡斯的明。前药的关键活化步骤涉及N-烷基-1，4-二氢喹啉1氧化为相应的喹啉鎓盐2，从而掩盖了与酶的催化阴离子位点结合所需的正电荷。介绍了一组1,4-二氢喹啉1及其相应的喹啉鎓盐2的合成。的体外生物学评价显示，虽然所有的还原形式1无法表现出任何抗胆碱酯酶活性（IC 50 > 10 6 nm）时，大部分的喹啉盐的2显示高疼痛抑制活性（IC 50为6μM至7 nM）。这些初步的体外试验验证了这些环状类似物的使用。利凡斯的明喹啉系列的药物作为进一步在体内开发这种“生物可氧化前药”方法的诱人化学工具。