6-chloro-7-methoxy-2-methylquinolin-4(1H)-one | 1248347-12-7

• 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: 6-chloro-7-methoxy-2-methylquinolin-4(1H)-one
• 英文别名: 6-chloro-7-methoxy-2-methyl-1H-quinolin-4-one
• CAS: 1248347-12-7
• 化学式: C₁₁H₁₀ClNO₂
• 分子量: 223.659
• InChiKey: YBAFNTKBWYZCNR-UHFFFAOYSA-N

物化性质

• 沸点：
  362.3±42.0 °C(Predicted)
• 密度：
  1.270±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-chloro-7-methoxy-2-methylquinolin-4(1H)-one 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 氢溴酸 、 碘 、 碳酸氢钠 、 potassium carbonate 、 溶剂黄146 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 500.0h， 生成 ELQ-300
  参考文献：
  名称：

  ELQ-300、ELQ-316 和其他抗寄生虫喹诺酮类药物的新可扩展合成路线

  摘要：

  内啡肽样喹诺酮 (ELQ) 化合物类可以为一系列重要的人类和动物疾病提供有效、安全的治疗方法。然而，为了获得该化合物系列的公共卫生潜力，需要设计一种合成路线，该路线将降低成本并适合大规模生产。在这里描述的新合成路线中，通过 Ullmann 反应和随后的酰化形成取代的 β-酮酯，通过 Conrad-Limpach 反应与苯胺反应生成 3-取代的 4( 1H )-喹诺酮类，例如ELQ -300和ELQ-316. 该合成路线首次被描述为真正适合工业规模生产，相对较短（五个反应步骤），不需要钯、色谱分离或保护基化学，并且可以在没有高真空蒸馏的情况下进行。

  DOI：

  10.1021/acs.oprd.1c00099
• 作为产物：
  描述：

  3-甲氧基-4-氯苯胺 在 dowtherm A 、 对甲苯磺酸 作用下， 以 苯 为溶剂， 反应 6.33h， 生成 6-chloro-7-methoxy-2-methylquinolin-4(1H)-one
  参考文献：
  名称：

  Discovery, Synthesis, and Optimization of Antimalarial 4(1H)-Quinolone-3-Diarylethers

  摘要：

  The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.

  DOI：

  10.1021/jm500147k

文献信息

• [EN] NOVEL INTERMEDIATES AND SYNTHESIS FOR ENDOCHIN-LIKE QUINOLONE COMPOUNDS<br/>[FR] NOUVEAUX INTERMÉDIAIRES ET SYNTHÈSE POUR DES COMPOSÉS DE QUINOLONE DE TYPE ENDOCHINE
  申请人：UNIV OREGON HEALTH & SCIENCE

  公开号：WO2021231335A1

  公开（公告）日：2021-11-18

  The present invention provides synthetic methods and novel intermediates in the preparation of 3-aryl Endochin-like quinolone (ELQ) compounds.

  本发明提供了一种合成方法和新型中间体，用于制备3-芳基内奎诺酮（ELQ）化合物。
• COMPOUNDS HAVING ANTIPARASITIC OR ANTI-INFECTIOUS ACTIVITY
  申请人：Riscoe Michael K.

  公开号：US20120115904A1

  公开（公告）日：2012-05-10

  Compounds of formula I: or formula II: or a pharmaceutically acceptable salt of formula I or formula II, wherein: R 1 is H, hydroxyl, alkoxy, acyl, alkyl, cycloalkyl, aryl, or heteroaryl; R 2 is methyl or haloalkyl; R 4 is hydroxyl, carbonyloxy, or carbonyldioxy; and R 3 is aliphatic, aryl, aralkyl, or alkylaryl; and R 5 , R 6 , R 7 and R 8 are each individually H, halogen, alkoxy, alkyl, haloalkyl, aryl, nitro, cyano, amino, amido, acyl, carboxyl, substituted carboxyl, or —SO 2 R 10 , wherein R 10 is H, alkyl, amino or haloalkyl; provided that in formula I, R 5 and R are not both H or R 6 is not H or methoxy; and in formula II that if R 4 is carbonyldioxy then R 7 is not methoxy.

  化合物的化学式为I式：或II式：或I式或II式的药学上可接受的盐，其中：R1为氢、羟基、烷氧基、酰基、烷基、环烷基、芳基或杂环芳基；R2为甲基或卤代烷基；R4为羟基、羰酸酯基或羰基二氧基；R3为脂肪基、芳基、芳基烷基或烷基芳基；以及R5、R6、R7和R8分别为氢、卤素、烷氧基、烷基、卤代烷基、芳基、硝基、氰基、氨基、酰基、羧基、取代羧基或-SO2R10，其中R10为氢、烷基、氨基或卤代烷基；但在I式中，R5和R6不能同时为氢或R6不为氢或甲氧基；在II式中，如果R4为羰基二氧基，则R7不为甲氧基。
• Compounds having antiparasitic or anti-infectious activity
  申请人：Riscoe Michael K.

  公开号：US08598354B2

  公开（公告）日：2013-12-03

  Compounds of formula I: or formula II: or a pharmaceutically acceptable salt of formula I or formula II, wherein: R1 is H, hydroxyl, alkoxy, acyl, alkyl, cycloalkyl, aryl, or heteroaryl; R2 is methyl or haloalkyl; R4 is hydroxyl, carbonyloxy, or carbonyldioxy; and R3 is aliphatic, aryl, aralkyl, or alkylaryl; and R5, R6, R7 and R8 are each individually H, halogen, alkoxy, alkyl, haloalkyl, aryl, nitro, cyano, amino, amido, acyl, carboxyl, substituted carboxyl, or —SO2R10, wherein R10 is H, alkyl, amino or haloalkyl; provided that in formula I, R5 and R7 are not both H or R6 is not H or methoxy; and in formula II that if R4 is carbonyldioxy then R7 is not methoxy.

  式I的化合物：或式II的化合物：或式I或式II的药学上可接受的盐，其中：R1为氢、羟基、烷氧基、酰基、烷基、环烷基、芳基或杂环芳基；R2为甲基或卤代烷基；R4为羟基、羰氧基或羰基二氧基；R3为脂肪基、芳基、芳基烷基或烷基芳基；R5、R6、R7和R8各自独立地为氢、卤素、烷氧基、烷基、卤代烷基、芳基、硝基、氰基、氨基、酰基、羧基、取代羧基或-SO2R10，其中R10为氢、烷基、氨基或卤代烷基；但在式I中，R5和R7不能同时为氢，或者R6不是氢或甲氧基；在式II中，如果R4为羰基二氧基，则R7不是甲氧基。
• Endochin Optimization: Structure−Activity and Structure−Property Relationship Studies of 3-Substituted 2-Methyl-4(1<i>H</i>)-quinolones with Antimalarial Activity
  作者：R. Matthew Cross、Andrii Monastyrskyi、Tina S. Mutka、Jeremy N. Burrows、Dennis E. Kyle、Roman Manetsch

  DOI：10.1021/jm1007903

  日期：2010.10.14

  Since the 1940s endochin and analogues thereof were known to be causal prophylactic and potent erythrocytic stage agents in avian models. Preliminary screening in a current in vitro assay identified several 4(1H)-quinolones with nanomolar EC(50) against erythrocytic stages of mullidrug resistant W2 and TM90-C2B isolates of Plasmodium folciparum. Follow-up structure activity relationship (SAR) studies on 4(1H)-quinolone analogues identified several key features for biological activity. Nevertheless, structure property relationship (SPR) studies conducted in parallel revealed that 4(1H)-quinolone analogues are limited by poor solubilities and rapid microsomal degradations. To improve the overall efficacy, multiple 4(1H)-quinolone series with varying substituents on the benzenoid quinolone ring and/or the 3-position were synthesized and tested for in vitro antimalarial activity. Several structurally diverse 6-chloro-2-methyl-7-methoxy-4(1H)-quinolones with EC(50) in the low nanomolar range against the clinically relevant isolates W2 and TM90-C2B were identified with improved physicochemical properties while maintaining little to no cross-resistance with atovaquone.
• 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.