1-(2-(4-((5-chloro-6-methylpyridin-3-yl)methylamino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one | 1173896-62-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 1-(2-(4-((5-chloro-6-methylpyridin-3-yl)methylamino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one
• 英文别名: 1-[2-(4-{[(5-chloro-6-methyl-3-pyridinyl)methyl]amino}-1-piperidinyl)ethyl]-7-fluoro-1,5-naphthyridin-2(1H)-one；1-[2-[4-[(5-Chloro-6-methylpyridin-3-yl)methylamino]piperidin-1-yl]ethyl]-7-fluoro-1,5-naphthyridin-2-one
• CAS: 1173896-62-2
• 化学式: C₂₂H₂₅ClFN₅O
• 分子量: 429.925
• InChiKey: NXNCVAQPAVCKBK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  61.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-羟基苯磺酰胺 、 1-(2-(4-((5-chloro-6-methylpyridin-3-yl)methylamino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one 在 caesium carbonate 作用下， 以 二甲基亚砜 为溶剂， 反应 0.5h， 生成 4-((5-(2-(4-((5-chloro-6-methylpyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yloxy)benzenesulfonamide
  参考文献：
  名称：

  Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding

  摘要：

  Structure activity relationship (SAR) exploration on the left-hand side (LHS) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement in the selectivity against hERG cardiac channel binding with concomitant potent antimycobacterial activity. Bulky polar substituents at the C-7 position of the naphthyridone ring did not disturb its positioning between two base pairs of DNA. Further optimization of the polar substituents on the LHS of the naphthyridone ring led to potent antimycobacterial activity (Mtb MIC = 0.06 mu M) against Mycobacterium tuberculosis (Mtb). Additionally, this knowledge provided a robust SAR understanding to mitigate the hERG risk. This compound class inhibits Mtb DNA gyrase and retains its antimycobacterial activity against moxifloxacin-resistant strains of Mtb. Finally, we demonstrate in vivo proof of concept in an acute mouse model of TB following oral administration of compound 19.

  DOI：

  10.1021/ml500531p

文献信息

• Compounds
  申请人：GLAXO GROUP LIMITED

  公开号：EP2080761A1

  公开（公告）日：2009-07-22

  Compounds of Formula (I), compositions containing them, their use in therapy, including their use as antibacterials, for example in the treatment of tuberculosis, and methods for the preparation of such compounds, are provided.

  公式（I）的化合物， 包含它们的组合物，它们在治疗中的使用，包括它们作为抗菌剂的使用，例如在结核病治疗中的使用，以及制备这类化合物的方法，均已提供。
• NAPHTHYRIDIN-2(1H) -ONE COMPOUNDS USEFUL AS ANTIBACTERIALS
  申请人：ALEMPARTE-GALLARDO Carlos

  公开号：US20110319424A1

  公开（公告）日：2011-12-29

  Compounds of Formula (I), wherein substituents R 1 , R 2 and R 5 are as defined, and Ar represents substituted phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, furanyl, imidazolyl and thiophenyl; compositions containing them, their use in therapy, including their use as antibacterials, for example in the treatment of tuberculosis, and methods for the preparation of such compounds, are provided.

  本发明提供了化学式(I)的化合物，其中取代基R1、R2和R5如定义所述，Ar代表取代的苯基、吡啶基、吡嗪基、嘧啶基、吡咯嗪基、噻唑基、呋喃基、咪唑基和噻吩基；含有它们的组合物，它们在治疗中的使用，包括它们作为抗菌剂的使用，例如在结核病的治疗中，以及制备这种化合物的方法。
• Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding
  作者：Shahul Hameed P、Praveena Manjrekar、Anandkumar Raichurkar、Vikas Shinde、Jayashree Puttur、Gajanan Shanbhag、Murugan Chinnapattu、Vikas Patil、Suresh Rudrapatana、Sreevalli Sharma、C. N. Naveen Kumar、Radha Nandishaiah、Prashanti Madhavapeddi、D. Sriram、Suresh Solapure、Vasan K. Sambandamurthy

  DOI：10.1021/ml500531p

  日期：2015.7.9

  Structure activity relationship (SAR) exploration on the left-hand side (LHS) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement in the selectivity against hERG cardiac channel binding with concomitant potent antimycobacterial activity. Bulky polar substituents at the C-7 position of the naphthyridone ring did not disturb its positioning between two base pairs of DNA. Further optimization of the polar substituents on the LHS of the naphthyridone ring led to potent antimycobacterial activity (Mtb MIC = 0.06 mu M) against Mycobacterium tuberculosis (Mtb). Additionally, this knowledge provided a robust SAR understanding to mitigate the hERG risk. This compound class inhibits Mtb DNA gyrase and retains its antimycobacterial activity against moxifloxacin-resistant strains of Mtb. Finally, we demonstrate in vivo proof of concept in an acute mouse model of TB following oral administration of compound 19.