(6R)-2-nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine | 2222660-40-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (6R)-2-nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
• 英文别名: 3YN4655Vvy
• CAS: 2222660-40-2
• 化学式: C₁₃H₁₀F₃N₃O₅
• 分子量: 345.235
• InChiKey: IXUWKDINJWESQG-SNVBAGLBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  91.3
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  triisopropyl{(2S)-3-[(4-methoxybenzyl)oxy]-2-[4-(trifluoromethoxy)phenoxy]propoxy}silane 在 咪唑 、 四丁基氟化铵 、 碘 、 sodium hydride 、 potassium carbonate 、 三苯基膦 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 374.0h， 生成 (6R)-2-nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
  参考文献：
  名称：

  Development of (6R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis

  摘要：

  Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo [2,1-1)] [1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads (R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds (R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.

  DOI：

  10.1021/acs.jmedchem.7b01581