(6S)-6-({2-[4-(difluoromethoxy)phenyl]-5-pyrimidinyl}methoxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine | 1257426-51-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (6S)-6-({2-[4-(difluoromethoxy)phenyl]-5-pyrimidinyl}methoxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
• 英文别名: (6S)-6-({2-[4-(Difluoromethoxy)phenyl]pyrimidin-5-yl}methoxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine；(6S)-6-[[2-[4-(difluoromethoxy)phenyl]pyrimidin-5-yl]methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
• CAS: 1257426-51-9
• 化学式: C₁₈H₁₅F₂N₅O₅
• 分子量: 419.344
• InChiKey: CEKXIJLRIBIJKZ-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  117
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  对二氟甲氧基苯硼酸 、 (6S)-6-{[2-(methylsulfanyl)-5-pyrimidinyl]methoxy}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine 在 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 三(2-呋喃基)膦 、 copper benzothiophene-2-carboxylate 作用下， 以 四氢呋喃 为溶剂， 反应 18.0h， 以37%的产率得到(6S)-6-({2-[4-(difluoromethoxy)phenyl]-5-pyrimidinyl}methoxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of Aza- and Diazabiphenyl Analogues of the Antitubercular Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

  摘要：

  New heterocyclic analogues of the potent biphenyl class derived from antitubercular drug PA-824 were prepared, aiming to improve aqueous solubility but maintain high metabolic stability and efficacy. The strategy involved replacement of one or both phenyl groups by pyridine, pyridazine, pyrazine, or pyrimidine, in order to reduce lipophilicity. For para-linked biaryls, hydrophilicities (ClogP) correlated with measured solubilities, but highly soluble bipyridine analogues displayed weak antitubercular activities. A terminal pyridine or proximal heterocycle allowed retention of potency and provided solubility improvements, particularly at low pH, with examples from the latter classes displaying the better in vivo efficacies, high metabolic stabilities, and excellent pharmacokinetics. Five such compounds were >100-fold better than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection, and two orally bioavailable pyridine analogues (3-4-fold more soluble than the parent at low pH) were superior to antitubercular drug OPC-67683 in a chronic infection model.

  DOI：

  10.1021/jm101288t

文献信息

• Synthesis and Structure−Activity Relationships of Aza- and Diazabiphenyl Analogues of the Antitubercular 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：Iveta Kmentova、Hamish S. Sutherland、Brian D. Palmer、Adrian Blaser、Scott G. Franzblau、Baojie Wan、Yuehong Wang、Zhenkun Ma、William A. Denny、Andrew M. Thompson

  DOI：10.1021/jm101288t

  日期：2010.12.9

  New heterocyclic analogues of the potent biphenyl class derived from antitubercular drug PA-824 were prepared, aiming to improve aqueous solubility but maintain high metabolic stability and efficacy. The strategy involved replacement of one or both phenyl groups by pyridine, pyridazine, pyrazine, or pyrimidine, in order to reduce lipophilicity. For para-linked biaryls, hydrophilicities (ClogP) correlated with measured solubilities, but highly soluble bipyridine analogues displayed weak antitubercular activities. A terminal pyridine or proximal heterocycle allowed retention of potency and provided solubility improvements, particularly at low pH, with examples from the latter classes displaying the better in vivo efficacies, high metabolic stabilities, and excellent pharmacokinetics. Five such compounds were >100-fold better than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection, and two orally bioavailable pyridine analogues (3-4-fold more soluble than the parent at low pH) were superior to antitubercular drug OPC-67683 in a chronic infection model.