2-amino-N-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]-4-fluorobenzamide | 1026929-28-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-amino-N-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]-4-fluorobenzamide
• CAS: 1026929-28-1
• 化学式: C₁₉H₁₈F₃N₅O₂
• 分子量: 405.379
• InChiKey: LVMRNJMNQRCZLC-NSPYISDASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-amino-N-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]-4-fluorobenzamide 在 palladium on activated charcoal 盐酸 、 ammonium formate 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 138.0h， 生成 7-amino-3-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]quinazolin-4-one
  参考文献：
  名称：

  New Azole Antifungals. 3. Synthesis and Antifungal Activity of 3-Substituted-4(3H)-quinazolinones

  摘要：

  A series of azole antifungal agents featuring a quinazolinone nucleus have been subjected to studies of structure-activity relationships. In general, these compounds displayed higher in vitro activities against filamentous fungi and shorter half-lives than the structures described in our preceding paper. The most potent products in vitro carried a halogen (or an isostere) at the 7-position of the quinazolinone ring. Using a murine model of systemic candidosis, oral activity was found to be dependent on hydrophobicity, which, in turn, modulated the compound's half-life. The 7-Cl derivative, (1R,2R)-7-chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one (20, UR-9825), was selected for further testing due to its high in vitro activity, low toxicity, good pharmacokinetic profile, and ease of obtention. Compound 20 is the (1R,2R) isomer of four possible stereoisomers. The other three isomers were also prepared and tested. The enantiomer (1S,2S) and the (LR,BS) epimer were inactive, whereas the (1S,2R) epimer retained some activity. In vitro 20 was superior to fluconazole, itraconazole, SCH-42427, and TAK-187 and roughly similar to voriconazole and ER-30346. In vivo, 20 was only moderately active in a mouse model of systemic candidosis when administration was limited to the first day. This was attributed to its short half-life in that species (t(1/2) = 1 h po). Protection levels comparable to or higher than those of fluconazole, however, were observed in systemic candidosis models in rat and rabbit, where the half-life of the compound was found to be 6 and 9 h, respectively. Finally, 20 showed excellent protection levels in an immunocompromised rat model of disseminated aspergillosis. The compound showed low toxicity signs when administered to rats at 250 mg/kg qd or at 100 mg/kg bid during 28 days.

  DOI：

  10.1021/jm9707277
• 作为产物：
  描述：

  (2R,3R)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁烷-2,3-二醇 在 sodium azide 、 palladium on activated charcoal 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢气 、 氯化铵 、 甲基磺酰氯 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.5h， 生成 2-amino-N-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]-4-fluorobenzamide
  参考文献：
  名称：

  对烟曲霉具有较强抗真菌活性的新型三唑试剂的设计，合成和构效关系研究。

  摘要：

  几十年来，侵袭性真菌感染的发生率急剧上升。为了发现具有广谱和抗曲霉功效的新型抗真菌剂，设计并合成了一系列含有1,2,3-苯并三嗪-4-酮的新型三唑衍生物。与氟康唑相比，大多数化合物对被测真菌表现出更强的体外抗真菌活性。此外，6m对伏立康唑和阿尔巴康唑的7种致病菌株，尤其是对烟曲霉（MIC = 0.25μg/ ml）表现出可比的抗真菌活性，对耐氟康唑的白色念珠菌菌株具有中等的抗真菌活性。一项清晰的SAR研究表明，在7位上带有基团的化合物可产生新型抗真菌三唑，具有更高的效力和更广的光谱范围。

  DOI：

  10.1016/j.bmcl.2020.126951