7-({[5-(4-fluorophenyl)pyrimidin-2-yl]oxy}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-({[5-(4-fluorophenyl)pyrimidin-2-yl]oxy}methyl)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
• 英文别名: 7-[[5-(4-Fluorophenyl)pyrimidin-2-yl]oxymethyl]-7-methyl-2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine；7-[[5-(4-fluorophenyl)pyrimidin-2-yl]oxymethyl]-7-methyl-2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine
• 化学式: C₁₈H₁₆FN₅O₄
• 分子量: 385.355
• InChiKey: DRPGNSGFTZIHNS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  108
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-碘-2-甲基丁-1-烯 在 咪唑 、 盐酸 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 四氧化锇 、 sodium hydride 、 sodium carbonate 、 potassium carbonate 、 N-甲基吗啉氧化物 作用下， 以 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 241.5h， 生成 7-({[5-(4-fluorophenyl)pyrimidin-2-yl]oxy}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

文献信息

• 7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-<i>b</i>][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis
  作者：Andrew M. Thompson、Patrick D. O’Connor、Andrew J. Marshall、Vanessa Yardley、Louis Maes、Suman Gupta、Delphine Launay、Stephanie Braillard、Eric Chatelain、Scott G. Franzblau、Baojie Wan、Yuehong Wang、Zhenkun Ma、Christopher B. Cooper、William A. Denny

  DOI：10.1021/acs.jmedchem.7b00034

  日期：2017.5.25

  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.