(R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ylamine | 1188393-88-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ylamine
• 英文别名: (6R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-amine
• CAS: 1188393-88-5
• 化学式: C₆H₈N₄O₃
• 分子量: 184.155
• InChiKey: SIMHJZHCZNNNEV-SCSAIBSYSA-N

物化性质

• 沸点：
  405.1±55.0 °C(Predicted)
• 密度：
  1.91±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  98.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ylamine 在 盐酸 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.25h， 生成 (6R)-2-nitro-N-[4-(trifluoromethoxy)benzyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-amine
  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
• 作为产物：
  描述：

  (S)-2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]恶嗪-6-醇 在 吡啶 、 1,3-丙二硫醇 、 sodium azide 、 三乙胺 作用下， 以 甲醇 、 二甲基亚砜 为溶剂， 反应 101.5h， 生成 (R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ylamine
  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

• [EN] BICYCLIC NITROIMIDAZOLES COVALENTLY LINKED TO SUBSTITUTED PHENYL OXAZOLIDINONES<br/>[FR] NITROIMIDAZOLES BICYCLIQUES LIÉS PAR COVALENCE À DES PHÉNYLOXAZOLIDINONES SUBSTITUÉES
  申请人：GLOBAL ALLIANCE FOR TB DRUG DE

  公开号：WO2009120789A8

  公开（公告）日：2010-10-28