(6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-amine hydrochloride | 187235-71-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-amine hydrochloride
• 英文别名: 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-6-amine hydrochloride
• CAS: 187235-71-8
• 化学式: C₆H₈N₄O₃*ClH
• 分子量: 220.615
• InChiKey: DHQRQJCOPNFZAY-WCCKRBBISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.07
• 重原子数：
  14.0
• 可旋转键数：
  1.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  96.21
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-amine hydrochloride 在 potassium carbonate 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 4.08h， 生成 N-[(6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl]-2-[4'-(trifluoromethyl)biphenyl-4-yl]acetamide
  参考文献：
  名称：

  Structure–Activity Relationships for Amide-, Carbamate-, And Urea-Linked Analogues of the Tuberculosis Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

  摘要：

  Analogues of clinical tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), in which the OCH2 linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metabolism, reduce lipophilicity, and improve aqueous solubility. Several soluble monoaryl examples displayed moderately improved (similar to 2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivatives mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly soluble. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a soluble, orally bioavailable carbamate analogue providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.

  DOI：

  10.1021/jm2012276
• 作为产物：
  描述：

  (S)-2-硝基-6,7-二氢-5H-咪唑并[2,1-B][1,3]噁嗪-6-胺 在 盐酸 作用下， 以 乙醇 、 乙酸乙酯 为溶剂， 以90%的产率得到(6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-amine hydrochloride
  参考文献：
  名称：

  硝基咪唑类化合物中间体及其盐的制备方法

  摘要：

  本发明公开了一种硝基咪唑类化合物中间体及其盐的制备方法。所述方法包括步骤：(1)将结构如式1所示的化合物与结构如式2所示的化合物混合，得到结构如式A所示的化合物；(2)式A化合物经酯还原制得式B化合物；(3)使式B化合物下经环合反应得到结构如式C所示的化合物；(4)结构如式C所示的化合物脱去氨基保护基，得到结构如式D所示的化合物；和(5)结构如式D所示的化合物与酸形成结构如式E所述的化合物。

  公开号：

  CN109553580B

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.