(2S,5R,6R)-6-(2,4-difluorophenyl)-5-methyl-2-hydroxy-4-<4-(trifluoromethyl)benzoyl>-6-<(1H-1,2,4-triazol-1-yl)methyl>morpholine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: (2S,5R,6R)-6-(2,4-difluorophenyl)-5-methyl-2-hydroxy-4-<4-(trifluoromethyl)benzoyl>-6-<(1H-1,2,4-triazol-1-yl)methyl>morpholine
• 英文别名: [(2R,3R,6S)-2-(2,4-difluorophenyl)-6-hydroxy-3-methyl-2-(1,2,4-triazol-1-ylmethyl)morpholin-4-yl]-[4-(trifluoromethyl)phenyl]methanone
• 化学式: C₂₂H₁₉F₅N₄O₃
• 分子量: 482.41
• InChiKey: QJHNXGWLYVMQTP-YIILKADPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  80.5
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  (2R,3R)-2-(2,4-difluorophenyl)-3--N-(2-hydroxyethyl)amino>-1-(1H-1,2,4-triazol-1-yl)-2-butanol 在 二甲基亚砜 、 三乙胺 、 三氟乙酸酐 作用下， 生成 (2S,5R,6R)-6-(2,4-difluorophenyl)-5-methyl-2-hydroxy-4-<4-(trifluoromethyl)benzoyl>-6-<(1H-1,2,4-triazol-1-yl)methyl>morpholine
  参考文献：
  名称：

  Synthesis and Antifungal Activity of New Azole Derivatives Containing an N-Acylmorpholine Ring

  摘要：

  A series of azole derivatives carrying an N-acylmorpholine ring are described. The compounds were chemically designed to simulate the lanosterol D ring, taking advantage of the conformational preferences of 2-alkyl-1-acylmorpholines. Three structural variables, the nature of the N-benzoyl group, the phenyl substituents, and the degree of oxidation at carbon 2 of the morpholine, were optimized for maximum activity. Only the (5R,6R) isomers showed antifungal activity. Cyclic hemiacetal(-)-39a (UR-9746) and cyclic ether (-)-41 (UR-9751) were selected for further development. In vitro, (-)-41 was clearly more active than (-)-39a and somewhat less active than the acyclic counterpart (-)-7. lit vivo activity was assessed by a systemic (mouse) and a vaginal (rat) candidosis model. In the former, (-)-39a, (-)-41, and (-)-7 at 1 mg/kg given 1, 4, and 24 h postinfection displayed 90-100% protection from mortality on day 9. Compound (-)-39a was slightly more potent than (-)-41 and similar in potency to (-)-7. The three compounds were superior in potency to fluconazole and similar in potency to SCH-42427 in this test. In the vaginal model, (-)-39a and (-)-41 given daily during 3 days after infection at 0.5 mg/kg showed high levels of protection on days 10 and 15. At 0.25 mg/kg, (-)-39a was slightly more potent than SCH-42427 and (-)-7 and superior in potency to (-)-41 and fluconazole in this model. Preliminary 28-day toxicity tests at 100 mg/kg/day po in rats indicated no or very mild adverse effects for the two UR compounds.

  DOI：

  10.1021/jm00020a005

文献信息

• Synthesis and Antifungal Activity of New Azole Derivatives Containing an N-Acylmorpholine Ring
  作者：Javier Bartroli、Enric Turmo、Monica Alguero、Eulalia Boncompte、Maria L. Vericat、Julian Garcia-Rafanell、Javier Forn

  DOI：10.1021/jm00020a005

  日期：1995.9

  A series of azole derivatives carrying an N-acylmorpholine ring are described. The compounds were chemically designed to simulate the lanosterol D ring, taking advantage of the conformational preferences of 2-alkyl-1-acylmorpholines. Three structural variables, the nature of the N-benzoyl group, the phenyl substituents, and the degree of oxidation at carbon 2 of the morpholine, were optimized for maximum activity. Only the (5R,6R) isomers showed antifungal activity. Cyclic hemiacetal(-)-39a (UR-9746) and cyclic ether (-)-41 (UR-9751) were selected for further development. In vitro, (-)-41 was clearly more active than (-)-39a and somewhat less active than the acyclic counterpart (-)-7. lit vivo activity was assessed by a systemic (mouse) and a vaginal (rat) candidosis model. In the former, (-)-39a, (-)-41, and (-)-7 at 1 mg/kg given 1, 4, and 24 h postinfection displayed 90-100% protection from mortality on day 9. Compound (-)-39a was slightly more potent than (-)-41 and similar in potency to (-)-7. The three compounds were superior in potency to fluconazole and similar in potency to SCH-42427 in this test. In the vaginal model, (-)-39a and (-)-41 given daily during 3 days after infection at 0.5 mg/kg showed high levels of protection on days 10 and 15. At 0.25 mg/kg, (-)-39a was slightly more potent than SCH-42427 and (-)-7 and superior in potency to (-)-41 and fluconazole in this model. Preliminary 28-day toxicity tests at 100 mg/kg/day po in rats indicated no or very mild adverse effects for the two UR compounds.