((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)-(4-trifluoromethoxybenzyl)-amine | 1105632-46-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)-(4-trifluoromethoxybenzyl)-amine
• 英文别名: (S)-N-(4-(trifluoromethoxy)benzyl)-6,7-dihydro-2-nitro-5H-imidazo[2,1-b][1,3]oxazin-6-amine；(6S)-2-nitro-N-[[4-(trifluoromethoxy)phenyl]methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-amine
• CAS: 1105632-46-9
• 化学式: C₁₄H₁₃F₃N₄O₄
• 分子量: 358.277
• InChiKey: OWKPAFONRAJFPD-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  94.1
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  ((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)-(4-trifluoromethoxybenzyl)-amine 、 3-氯苯甲酰氯 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 3.17h， 以55%的产率得到(S)-3-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]-oxazin-6-yl)-N-(4-trifluoromethoxybenzyl)-benzamide
  参考文献：
  名称：

  Structure–Activity Relationships of Antitubercular Nitroimidazoles. 3. Exploration of the Linker and Lipophilic Tail of ((S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)-(4-trifluoromethoxybenzyl)amine (6-Amino PA-824).

  摘要：

  The (S)-2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine named PA-824 (1) has demonstrated antitubercular activity in vitro and in animal models and is currently in clinical trials. We synthesized derivatives at three positions of the 4-(trifluoromethoxy)benzylamino tail, and these were tested for whole-cell activity against both replicating and nonreplicating Mycobacterium tuberculosis (Mtb). In addition, we determined their kinetic parameters as substrates of the deazaflavin-dependent nitroreductase (Ddn) from Mtb that reductively activates these pro-drugs. These studies yielded multiple compounds with 40 nM aerobic whole cell activity and 1.6 mu M anaerobic whole cell activity: 10-fold improvements over both characteristics from the parent molecule. Some of these compounds exhibited enhanced solubility with acceptable stability to microsomal and in vivo metabolism. Analysis of the conformational preferences of these analogues using quantum chemistry suggests a preference for a pseudoequatorial orientation of the linker and lipophilic tail.

  DOI：

  10.1021/jm1010644
• 作为产物：
  描述：

  对三氟甲氧基苯甲醛 、 (S)-2-硝基-6,7-二氢-5H-咪唑并[2,1-B][1,3]噁嗪-6-胺 在 溶剂黄146 、 sodium cyanoborohydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 以0.29 g的产率得到((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)-(4-trifluoromethoxybenzyl)-amine
  参考文献：
  名称：

  抗结核硝基咪唑的构效关系。2. 有氧活动的决定因素和数量结构-活动关系

  摘要：

  ( S )-2-硝基-6-取代的6,7-二氢-5 H-咪唑并[2,1- b ][1,3]恶嗪类化合物由于其优异的性能而被广泛探索作为新型抗结核药物的潜在用途。结核分枝杆菌需氧全细胞的杀菌特性. 有氧活性需要咪唑环 2-位上的氧原子。在这里，我们表明用氮或硫取代这种氧会产生等效的类似物。酰化氨基系列、氧化硫醚或用碳取代醚氧显着降低了化合物的效力。用氮替换 6 位的苄氧稍微提高了效力，并促进了对更易溶的 6-氨基系列中 SAR 的探索。通过在 6-( S ) 位置和末端疏水性芳族取代基之间扩展接头区域，实现了效力的显着改进。一个简单的四特征 QSAR 模型被推导出来合理化这一系列双环硝基咪唑的 MIC 结果。

  DOI：

  10.1021/jm801374t

文献信息

• Benzotriazine Oxides as Drugs Targeting Mycobacterium Tuberculosis
  申请人：Madrid Peter

  公开号：US20130150369A1

  公开（公告）日：2013-06-13

  Benzotriazine doxides are disclosed as drugs targeting mycobacterium tuberculosis , including novel compounds of formula I:

  Benzotriazine doxides被披露为针对结核分枝杆菌的药物，包括公式I的新化合物。
• Structure–Activity Relationships for Amide-, Carbamate-, And Urea-Linked Analogues of the Tuberculosis Drug (6<i>S</i>)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5<i>H</i>-imidazo[2,1-<i>b</i>][1,3]oxazine (PA-824)
  作者：Adrian Blaser、Brian D. Palmer、Hamish S. Sutherland、Iveta Kmentova、Scott G. Franzblau、Baojie Wan、Yuehong Wang、Zhenkun Ma、Andrew M. Thompson、William A. Denny

  DOI：10.1021/jm2012276

  日期：2012.1.12

  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.
• BENZOTRIAZINE OXIDES AS DRUGS TARGETING MYCOBACTERIUM TUBERCULOSIS
  申请人：Sri International Inc.

  公开号：EP2800744A1

  公开（公告）日：2014-11-12
• US9663478B2
  申请人：——

  公开号：US9663478B2

  公开（公告）日：2017-05-30
• [EN] ORGANIC COMPOUNDS<br/>[FR] COMPOSÉS ORGANIQUES
  申请人：BARRY CLIFTON

  公开号：WO2011087995A2

  公开（公告）日：2011-07-21

  This invention provides compounds which are useful in the treatment of mycobacterial infections, pharmaceutical compositions containing the compounds, processes for their preparation, and uses of the compounds in various medicinal applications, such as the treatment or prevention of mycobacterial infections, such as those caused by Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium africanum, Mycobacterium avium, Mycobacterium microti, or any mycobacterium that causes multi-drug resistant (MDR) TB or extensively resistant (XDR) TB, or any other mycobacterial species known to cause disease in humans; or the treatment or prevention of parasitic diseases, such as those caused by a parasite of the genus Trypanosoma, e.g. Trypanosoma cruzi or Trypanosoma brucei or a parasite of the genus Leishmania which causes visceral leishmaniasis or kala-azar, e.g., Leishmania donovani.