6-bromo-3-(3-fluoro-4-methoxybenzyl)-2-methoxyquinoline

• 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-bromo-3-(3-fluoro-4-methoxybenzyl)-2-methoxyquinoline
• 英文别名: 6-Bromo-3-[(3-fluoro-4-methoxyphenyl)methyl]-2-methoxyquinoline
• 化学式: C₁₈H₁₅BrFNO₂
• 分子量: 376.225
• InChiKey: WKIWLTXPTPXXEK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  31.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-bromo-3-(3-fluoro-4-methoxybenzyl)-2-methoxyquinoline 、 1-(2,6-dimethoxypyridin-4-yl)-3-(dimethylamino)propan-1-one 在 正丁基锂 、 二异丙胺 、 溶剂黄146 作用下， 以 四氢呋喃 、 环己烷 为溶剂， 反应 5.5h， 生成
  参考文献：
  名称：

  3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel

  摘要：

  Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drugresistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5dialkoxy- 4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.

  DOI：

  10.1016/j.bmc.2019.02.026
• 作为产物：
  描述：

  6-溴-2-甲氧基喹啉 在 2,2,6,6-四甲基哌啶 、 四(三苯基膦)钯 、 正丁基锂 、 caesium carbonate 作用下， 以 四氢呋喃 、 正己烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 8.0h， 生成 6-bromo-3-(3-fluoro-4-methoxybenzyl)-2-methoxyquinoline
  参考文献：
  名称：

  [EN] ANTIBACTERIAL COMPOUNDS AND USES THEREOF
  [FR] COMPOSÉS ANTIBACTÉRIENS ET UTILISATIONS DE CEUX-CI

  摘要：

  本发明涉及式(I)的化合物，包括其任何立体化异构体或其药学上可接受的盐，用于治疗结核病。

  公开号：

  WO2017155909A1

文献信息

• Antibacterial compounds and uses thereof
  申请人：The Global Alliance for TB Drug Development, Inc.

  公开号：US10508097B2

  公开（公告）日：2019-12-17

  The present invention relates to compounds of formula (I) including any stereochemically isomeric form thereof, or pharmaceutically acceptable salts thereof, for the treatment of tuberculosis.

  本发明涉及用于治疗结核病的式 (I) 化合物，包括其任何立体化学异构体形式，或其药学上可接受的盐类。
• ANTIBACTERIAL COMPOUNDS AND USES THEREOF
  申请人：The Global Alliance for TB Drug Development, Inc.

  公开号：EP3426255A1

  公开（公告）日：2019-01-16
• 3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel
  作者：Hamish S. Sutherland、Amy S.T. Tong、Peter J. Choi、Adrian Blaser、Daniel Conole、Scott G. Franzblau、Manisha U. Lotlikar、Christopher B. Cooper、Anna M. Upton、William A. Denny、Brian D. Palmer

  DOI：10.1016/j.bmc.2019.02.026

  日期：2019.4

  Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drugresistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5dialkoxy- 4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.
• [EN] ANTIBACTERIAL COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS ANTIBACTÉRIENS ET UTILISATIONS DE CEUX-CI
  申请人：THE GLOBAL ALLIANCE FOR TB DRUG DEV INC

  公开号：WO2017155909A1

  公开（公告）日：2017-09-14

  The present invention relates to compounds of formula (I) including any stereochemically isomeric form thereof, or pharmaceutically acceptable salts thereof, for the treatment of tuberculosis.

  本发明涉及式(I)的化合物，包括其任何立体化异构体或其药学上可接受的盐，用于治疗结核病。