7-{[4-(6-fluoropyridin-3-yl)phenoxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 7-{[4-(6-fluoropyridin-3-yl)phenoxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
• 英文别名: 7-[[4-(6-Fluoropyridin-3-yl)phenoxy]methyl]-7-methyl-2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine；7-[[4-(6-fluoropyridin-3-yl)phenoxy]methyl]-7-methyl-2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine
• 化学式: C₁₉H₁₇FN₄O₄
• 分子量: 384.367
• InChiKey: QZLYEICOLMOYGW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  95
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-碘-2-甲基丁-1-烯 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 disodium hydrogenphosphate 、 sodium hydride 、 potassium carbonate 、 potassium hydrogencarbonate 、 间氯过氧苯甲酸 作用下， 以 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 丁酮 为溶剂， 反应 44.5h， 生成 7-{[4-(6-fluoropyridin-3-yl)phenoxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
  参考文献：
  名称：

  7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis

  摘要：

  Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7 substituted 2-nitro-5,6-dihydroimidazo [2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.

  DOI：

  10.1021/acs.jmedchem.7b00034