(6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl 4-[4-(trifluoromethoxy)phenyl]-piperazine-1-carboxylate | 1263417-13-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl 4-[4-(trifluoromethoxy)phenyl]-piperazine-1-carboxylate
• 英文别名: (6S)-2-nitro-6-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl 4-[4-(trifluoromethoxy)phenyI]-1-piperazinecarboxylate；(6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl 4-[4-(trifluoromethoxy)phenyl]-1-piperazinecarboxylate；[(6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl] 4-[4-(trifluoromethoxy)phenyl]piperazine-1-carboxylate
• CAS: 1263417-13-5
• 化学式: C₁₈H₁₈F₃N₅O₆
• 分子量: 457.366
• InChiKey: KLZHZXNGDKJDJB-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  115
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 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 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 3.75h， 生成 (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl 4-[4-(trifluoromethoxy)phenyl]-piperazine-1-carboxylate
  参考文献：
  名称：

  NITROIMIDAZOOXAZINES AND THEIR USES IN ANTI-TUBERCULAR THERAPY

  摘要：

  本发明涉及新型硝基咪唑噁啉类化合物，其制备方法，以及它们作为治疗结核分枝杆菌和其他微生物感染的药物的用途，可以单独使用或与其他抗感染治疗联合使用。

  公开号：

  US20120028973A1

文献信息

• [EN] NITROIMIDAZOOXAZINES AND THEIR USES IN ANTI-TUBERCULAR THERAPY<br/>[FR] NITROIMIDAZOOXAZINES ET LEURS UTILISATIONS EN THÉRAPIE ANTITUBERCULEUSE
  申请人：GLOBAL ALLIANCE FOR TB DRUG DEV

  公开号：WO2011014774A1

  公开（公告）日：2011-02-03

  The present invention relates to novel nitroimidazooxazines, to their preparation, and to their use as drugs for treating Mycobacterium tuberculosis and other microbial infections, either alone or in combination with other anti-infective treatments.

  本发明涉及新型硝基咪唑噁啉类化合物，其制备方法，以及它们作为治疗结核分枝杆菌和其他微生物感染的药物的用途，可以单独使用或与其他抗感染治疗方法结合使用。
• NITROIMIDAZOOXAZINES AND THEIR USES IN ANTI-TUBERCULAR THERAPY
  申请人：Denny William Alexander

  公开号：US20120028973A1

  公开（公告）日：2012-02-02

  The present invention relates to novel nitroimidazooxazines, to their preparation, and to their use as drugs for treating Mycobacterium tuberculosis and other microbial infections, either alone or in combination with other anti-infective treatments.

  本发明涉及新型硝基咪唑噁啉类化合物，其制备方法，以及它们作为治疗结核分枝杆菌和其他微生物感染的药物的用途，可以单独使用或与其他抗感染治疗联合使用。
• US9198913B2
  申请人：——

  公开号：US9198913B2

  公开（公告）日：2015-12-01
• 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.