(6R)-2-nitro-6-({2-[4-(trifluoromethoxy)phenyl]pyridin-3-yl}methoxy)-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: (6R)-2-nitro-6-({2-[4-(trifluoromethoxy)phenyl]pyridin-3-yl}methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
• 英文别名: (6R)-2-nitro-6-[[2-[4-(trifluoromethoxy)phenyl]pyridin-3-yl]methoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
• 化学式: C₁₉H₁₅F₃N₄O₅
• 分子量: 436.347
• InChiKey: AIJKWDCJBLVTGU-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  104
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  (6R)-6-[(2-bromopyridin-3-yl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine 、 4-三氟甲氧基苯硼酸 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 sodium carbonate 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 3.17h， 以84%的产率得到(6R)-2-nitro-6-({2-[4-(trifluoromethoxy)phenyl]pyridin-3-yl}methoxy)-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

文献信息

• Development of (6<i>R</i>)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5<i>H</i>-imidazo[2,1-<i>b</i>][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis
  作者：Andrew M. Thompson、Patrick D. O’Connor、Andrew J. Marshall、Adrian Blaser、Vanessa Yardley、Louis Maes、Suman Gupta、Delphine Launay、Stephanie Braillard、Eric Chatelain、Baojie Wan、Scott G. Franzblau、Zhenkun Ma、Christopher B. Cooper、William A. Denny

  DOI：10.1021/acs.jmedchem.7b01581

  日期：2018.3.22

  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.