(R)-trans-6-((4-(1-amino-2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)cyclohexylamino)methyl)-2Hpyrido[3,2-b][1,4]oxazin-3(4H)-one | 1227303-03-8

• 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: (R)-trans-6-((4-(1-amino-2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)cyclohexylamino)methyl)-2Hpyrido[3,2-b][1,4]oxazin-3(4H)-one
• 英文别名: NBTI 5463
• CAS: 1227303-03-8
• 化学式: C₂₅H₃₀N₆O₄
• 分子量: 478.551
• InChiKey: HXCSDXBLCTUKEB-BXWFABGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.81
• 重原子数：
  35.0
• 可旋转键数：
  7.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  133.39
• 氢给体数：
  3.0
• 氢受体数：
  9.0

反应信息

• 作为产物：
  描述：

  tert-butyl N-(4-ethenylcyclohexyl)carbamate 在 Cu(OTf)₂ 、 sodium hydride 、 potassium carbonate 、 苯硫酚 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 10.75h， 生成 (R)-trans-6-((4-(1-amino-2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)cyclohexylamino)methyl)-2Hpyrido[3,2-b][1,4]oxazin-3(4H)-one
  参考文献：
  名称：

  Optimization of physicochemical properties and safety profile of novel bacterial topoisomerase type II inhibitors (NBTIs) with activity against Pseudomonas aeruginosa

  摘要：

  Type II bacterial topoisomerases are well validated targets for antimicrobial chemotherapy. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. We now disclose the optimization of a class of NBTIs towards Gram-negative pathogens, especially against drug-resistant Pseudomonas aeruginosa. Physicochemical properties (pKa and logD) were optimized for activity against P. aeruginosa and for reduced inhibition of the hERG channel. The optimized analogs 9g and 9i displayed potent antibacterial activity against P. aeruginosa, and a significantly improved hERG profile over previously reported analogs. Compound 9g showed an improved QT profile in in vivo models and lower clearance in rat over earlier compounds. The compounds show promise for the development of new antimicrobial agents against drug-resistant Pseudomonas aeruginosa.

  DOI：

  10.1016/j.bmc.2014.07.040

文献信息

• [4-( 1-AMINO-ETHYL) - CYCLOHEXYL ] - METHYL - AMINES AS ANTIBACTERIALS
  申请人：Cronin Mark

  公开号：US20110288084A1

  公开（公告）日：2011-11-24

  The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, to their use in the treatment of bacterial infections, and to their methods of preparation.

  本发明涉及式(I)化合物及其药学上可接受的盐，以及它们在治疗细菌感染方面的应用和制备方法。
• Optimization of physicochemical properties and safety profile of novel bacterial topoisomerase type II inhibitors (NBTIs) with activity against Pseudomonas aeruginosa
  作者：Folkert Reck、David E. Ehmann、Thomas J. Dougherty、Joseph V. Newman、Sussie Hopkins、Gregory Stone、Nikunj Agrawal、Paul Ciaccio、John McNulty、Herbert Barthlow、Jennifer O’Donnell、Kosalaram Goteti、John Breen、Janelle Comita-Prevoir、Mark Cornebise、Mark Cronin、Charles J. Eyermann、Bolin Geng、Greg R. Carr、Lakshmipathi Pandarinathan、Xuejun Tang、Andrew Cottone、Liang Zhao、Natascha Bezdenejnih-Snyder

  DOI：10.1016/j.bmc.2014.07.040

  日期：2014.10

  Type II bacterial topoisomerases are well validated targets for antimicrobial chemotherapy. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. We now disclose the optimization of a class of NBTIs towards Gram-negative pathogens, especially against drug-resistant Pseudomonas aeruginosa. Physicochemical properties (pKa and logD) were optimized for activity against P. aeruginosa and for reduced inhibition of the hERG channel. The optimized analogs 9g and 9i displayed potent antibacterial activity against P. aeruginosa, and a significantly improved hERG profile over previously reported analogs. Compound 9g showed an improved QT profile in in vivo models and lower clearance in rat over earlier compounds. The compounds show promise for the development of new antimicrobial agents against drug-resistant Pseudomonas aeruginosa.