6-chloro-7-methoxy-2-methyl-3-(o-tolyl)quinolin-4(1H)-one | 1515856-02-6

• 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: 6-chloro-7-methoxy-2-methyl-3-(o-tolyl)quinolin-4(1H)-one
• 英文别名: P4Q-146；6-chloro-7-methoxy-2-methyl-3-(o-tolyl)-1H-quinolin-4-one；6-chloro-7-methoxy-2-methyl-3-(2-methylphenyl)-1H-quinolin-4-one
• CAS: 1515856-02-6
• 化学式: C₁₈H₁₆ClNO₂
• 分子量: 313.784
• InChiKey: NRGUUPUJRJMUOX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.47
• 重原子数：
  22.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  42.09
• 氢给体数：
  1.0
• 氢受体数：
  2.0

反应信息

• 作为反应物：
  描述：

  6-chloro-7-methoxy-2-methyl-3-(o-tolyl)quinolin-4(1H)-one 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 6-chloro-7-methoxy-2-methyl-3-(o-tolyl)-4-((ethoxycarbonyl)oxy)quinoline
  参考文献：
  名称：

  具有 pH 触发释放机制的氨基烷氧基羰基氧基甲基醚前药：通过单剂量治疗提高抗疟药 4(1H)-喹诺酮类药物的溶解度、生物利用度和功效的案例研究

  摘要：

  许多小分子的临床前和临床开发因其水溶性差、吸收有限和口服生物利用度而受到阻碍。在此，我们公开了一种通用的前药方法，该方法将有前景的先导化合物转化为氨基烷氧基羰基氧基甲基（氨基 AOCOM）醚取代的类似物，显示出显着改善的水溶性和增强的口服生物利用度，恢复了候选药物的典型关键要求。前药完全独立于生物转化和动物独立，因为它通过 pH 触发的分子内环化 - 消除反应成为活性化合物。作为概念验证，这种新型氨基 AOCOM 醚前药方法的效用在代表多种抗疟药 4(1H )-喹诺酮类药物，在过去十年中进入临床前开发并失败。使用氨基 AOCOM 醚前药部分，3-aryl-4(1 H )-喹诺酮类临床前候选药物显示在啮齿动物疟疾模型中以 3 mg/kg 的口服剂量提供单剂量治疗，而无需使用先进的配方技术。

  DOI：

  10.1021/acs.jmedchem.0c01104
• 作为产物：
  描述：

  3-甲氧基-4-氯苯胺 在 2-双环己基膦-2',6'-二甲氧基联苯 、 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 碘 、 sodium carbonate 、 溶剂黄146 作用下， 以 甲醇 、 苯 为溶剂， 反应 18.2h， 生成 6-chloro-7-methoxy-2-methyl-3-(o-tolyl)quinolin-4(1H)-one
  参考文献：
  名称：

  Orally Bioavailable 6-Chloro-7-methoxy-4(1H)-quinolones Efficacious against Multiple Stages of Plasmodium

  摘要：

  The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure-activity and structure-property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99% after 6 days.

  DOI：

  10.1021/jm500942v

文献信息

• [EN] COMPOUNDS AND METHODS FOR THEIR USE IN THE TREATMENT OF MALARIA<br/>[FR] COMPOSÉS ET MÉTHODES À UTILISER DANS LE TRAITEMENT DU PALUDISME
  申请人：UNIV SOUTH FLORIDA

  公开号：WO2017127820A1

  公开（公告）日：2017-07-27

  Disclosed herein, in part, are compounds and methods for their use in the treatment of malaria. In at least one specific embodiment, the compounds or salts thereof can include compounds of Formula (I):

  本文披露了部分化合物及其在治疗疟疾中的应用方法。在至少一个具体实施例中，这些化合物或其盐可以包括式（I）的化合物：
• Metal-Free Arylation of Ethyl Acetoacetate with Hypervalent Diaryliodonium Salts: An Immediate Access to Diverse 3-Aryl-4(1<i>H</i>)-Quinolones
  作者：Andrii Monastyrskyi、Niranjan K. Namelikonda、Roman Manetsch

  DOI：10.1021/jo5023958

  日期：2015.3.6

  A clean arylation protocol of ethyl acetoacetate was developed using hypervalent diaryliodonium salts under mild and metal-free conditions. The scope of the reaction, using symmetric and unsymmetric iodonium salts with varying sterics and electronics, was examined. Further, this method has been applied for the synthesis of antimalarial compound ELQ-300, which is currently in preclinical development.
• COMPOUNDS AND METHODS FOR THEIR USE IN THE TREATMENT OF MALARIA
  申请人：University of South Florida

  公开号：US20190031613A1

  公开（公告）日：2019-01-31

  Disclosed herein, in part, are compounds and methods for their use in the treatment of malaria. In at least one specific embodiment, the compounds or salts thereof can include compounds of Formula (I):
• Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1<i>H</i>)-Quinolones with Single Dose Cures
  作者：Andrii Monastyrskyi、Fabian Brockmeyer、Alexis N. LaCrue、Yingzhao Zhao、Steven P. Maher、Jordany R. Maignan、Vivian Padin-Irizarry、Yana I. Sakhno、Prakash T. Parvatkar、Ami H. Asakawa、Lili Huang、Debora Casandra、Sherwin Mashkouri、Dennis E. Kyle、Roman Manetsch

  DOI：10.1021/acs.jmedchem.0c01104

  日期：2021.5.27

  numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for

  许多小分子的临床前和临床开发因其水溶性差、吸收有限和口服生物利用度而受到阻碍。在此，我们公开了一种通用的前药方法，该方法将有前景的先导化合物转化为氨基烷氧基羰基氧基甲基（氨基 AOCOM）醚取代的类似物，显示出显着改善的水溶性和增强的口服生物利用度，恢复了候选药物的典型关键要求。前药完全独立于生物转化和动物独立，因为它通过 pH 触发的分子内环化 - 消除反应成为活性化合物。作为概念验证，这种新型氨基 AOCOM 醚前药方法的效用在代表多种抗疟药 4(1H )-喹诺酮类药物，在过去十年中进入临床前开发并失败。使用氨基 AOCOM 醚前药部分，3-aryl-4(1 H )-喹诺酮类临床前候选药物显示在啮齿动物疟疾模型中以 3 mg/kg 的口服剂量提供单剂量治疗，而无需使用先进的配方技术。
• Orally Bioavailable 6-Chloro-7-methoxy-4(1<i>H</i>)-quinolones Efficacious against Multiple Stages of <i>Plasmodium</i>
  作者：R. Matthew Cross、David L. Flanigan、Andrii Monastyrskyi、Alexis N. LaCrue、Fabián E. Sáenz、Jordany R. Maignan、Tina S. Mutka、Karen L. White、David M. Shackleford、Ian Bathurst、Frank R Fronczek、Lukasz Wojtas、Wayne C. Guida、Susan A. Charman、Jeremy N. Burrows、Dennis E. Kyle、Roman Manetsch

  DOI：10.1021/jm500942v

  日期：2014.11.13

  The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure-activity and structure-property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99% after 6 days.