(2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(2-(ethoxycarbonyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)butan-2-ol | 1575607-74-7

• 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: (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(2-(ethoxycarbonyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)butan-2-ol
• 英文别名: (2R,3R)-3-(2-ethoxyformyl-5,6-dihydroimidazo[1,2-a]piperazine-7(8H)-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol；ethyl 7-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-2-carboxylate
• CAS: 1575607-74-7
• 化学式: C₂₁H₂₄F₂N₆O₃
• 分子量: 446.457
• InChiKey: BYSOBSZDGOYDED-SPLOXXLWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  98.3
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  咪唑并[1,2-A]吡嗪-2-甲酸乙酯 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 、 乙腈 为溶剂， 20.0~80.0 ℃ 、101.33 kPa 条件下， 反应 24.0h， 生成 (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(2-(ethoxycarbonyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)butan-2-ol
  参考文献：
  名称：

  Design, Synthesis, and Structure–Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility

  摘要：

  Triazoles with fused-heterocycle nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SAR of antifungal triazoles. Tetrahydro-[1,2,4]-triazolo[1,5-a]pyrazine and tetrahydro-thiazolo[5,4-c]pyridine nuclei were preferable to the other four fused-heterocycle nuclei investigated. Potent in vitro activity, broad spectrum and better water solubility were attained when triazoles containing nitrogen aromatic heterocycles were attached to these two nuclei. The most potent compounds 27aa and 45x, with low hERG inhibition and hepatocyte toxicity, both exhibited excellent activity against Candida, Cryptococcus, and Aspergillus spp., as well as selected fluconazole-resistant strains. A high water-soluble compound 58 (the disulfate salt of 45x) displayed unsatisfactory in vivo activity because of its poor PK profiles. Mice infected with C.alb. SC5314 and C.alb. 103 (fluconazole-resistant strain) and administered with 27aa displayed significantly improved survival rates. 27aa also showed favorable pharmacokinetic (PK) profiles.

  DOI：

  10.1021/jm4016284

文献信息

• [EN] NOVEL TRIAZOLE ANTIFUNGAL COMPOUNDS, AND PHARMACEUTICAL COMPOSITION, PREPARATION METHOD, AND APPLICATION THEREOF<br/>[FR] NOUVEAUX COMPOSÉS ANTIFONGIQUES À BASE DE TRIAZOLES, COMPOSITION PHARMACEUTIQUE LES CONTENANT, PROCÉDÉ DE PRÉPARATION ET APPLICATION ASSOCIÉS
  申请人：SHANGHAI INST MATERIA MEDICA

  公开号：WO2014117318A1

  公开（公告）日：2014-08-07

  本发明提供了一类通式（I）表示的三氮唑类化合物、其光学异构体、或其药学上可接受的盐；以及所述化合物、其光学异构体或其药学上可接受的盐在制备抗真菌，特别是抗白假丝酵母菌、近平滑假丝酵母菌、光滑假丝酵母菌、新生隐球菌、石膏状小孢子菌、红色毛癣菌和/或烟曲霉菌的药物中的用途。本发明还提供了一种药物组合物，其包含治疗有效量的选自通式（I）表示的化合物、其光学异构体和其药学上可接受的盐中的一种或多种以及可药用辅料。
• Design, Synthesis, and Structure–Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility
  作者：Xufeng Cao、Zhaoshuan Sun、Yongbing Cao、Ruilian Wang、Tongkai Cai、Wenjing Chu、Wenhao Hu、Yushe Yang

  DOI：10.1021/jm4016284

  日期：2014.5.8

  Triazoles with fused-heterocycle nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SAR of antifungal triazoles. Tetrahydro-[1,2,4]-triazolo[1,5-a]pyrazine and tetrahydro-thiazolo[5,4-c]pyridine nuclei were preferable to the other four fused-heterocycle nuclei investigated. Potent in vitro activity, broad spectrum and better water solubility were attained when triazoles containing nitrogen aromatic heterocycles were attached to these two nuclei. The most potent compounds 27aa and 45x, with low hERG inhibition and hepatocyte toxicity, both exhibited excellent activity against Candida, Cryptococcus, and Aspergillus spp., as well as selected fluconazole-resistant strains. A high water-soluble compound 58 (the disulfate salt of 45x) displayed unsatisfactory in vivo activity because of its poor PK profiles. Mice infected with C.alb. SC5314 and C.alb. 103 (fluconazole-resistant strain) and administered with 27aa displayed significantly improved survival rates. 27aa also showed favorable pharmacokinetic (PK) profiles.