阿巴康唑 | 187949-02-6

• 物质功能分类: 原料药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 阿巴康唑
• 中文别名: 7-氯-3-[(2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1,2,4-三唑-1-基)丁-2-基]喹唑啉-4-酮
• 英文名称: albaconazole
• 英文别名: 7-chloro-3-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]quinazolin-4-one
• CAS: 187949-02-6
• 化学式: C₂₀H₁₆ClF₂N₅O₂
• 分子量: 431.829
• InChiKey: UHIXWHUVLCAJQL-MPBGBICISA-N

物化性质

• 熔点：
  124-126°C
• 沸点：
  658.9±65.0 °C(Predicted)
• 密度：
  1.48±0.1 g/cm3(Predicted)
• 溶解度：
  氯仿（微溶）、甲醇（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  83.6
• 氢给体数：
  1
• 氢受体数：
  7

安全信息

• 储存条件：
  -20°C 冰箱

制备方法与用途

阿巴康唑是一种用于医药的原料药。

反应信息

• 作为反应物：
  描述：

  阿巴康唑 在 sodium hydroxide 、 聚合甲醛 作用下， 生成 7-Chloro-3-[(1R,2R)-2-(2,4-difluoro-phenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]-2,3-dihydro-1H-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：

  2-氨基-4-氯苯甲酸 在 盐酸 、 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.0h， 生成 阿巴康唑
  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

文献信息

• <i>anti</i>-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients
  作者：Tomoya Karasawa、Raphaël Oriez、Naoya Kumagai、Masakatsu Shibasaki

  DOI：10.1021/jacs.8b08236

  日期：2018.9.26

  nitroalkanes and α-keto esters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized

  稀土金属/碱金属双金属催化剂被证明对于以反选择性方式对映选择性偶联硝基烷烃和 α-酮酯特别有效，以提供合成通用、密集功能化和光学活性的 α-硝基叔醇。手性二酰胺配体捕获两种不同的金属阳离子，通过自组装的简单混合产生具有催化能力的固相异双金属催化剂。通过在连续流动平台中成功应用于对映和非对映选择性反应，实现了固相不对称催化剂的优势。使用在结构和极性参数方面密切相关的溶剂，THF 及其甲基化同源物 2-Me-​​THF，对反应速率和立体选择性都有出乎意料的大溶剂影响。
• Method for preparing pyrimidone derivatives with antifungal activity
  申请人：——

  公开号：US20030064986A1

  公开（公告）日：2003-04-03

  Process for the preparation of pyrimidone derivatives of formula I, which comprises reacting a compound of formula II with a compound of formula III in the presence of a base. The pyrimidone derivatives of formula I are useful as antifungal agents. 1

  制备式I嘧啶酮衍生物的过程包括在碱存在下将式II化合物与式III化合物反应。式I的嘧啶酮衍生物可用作抗真菌剂。
• [EN] NEW PYRIMIDONE DERIVATIVES WITH ANTIFUNGAL ACTIVITY<br/>[FR] NOUVEAUX DERIVES PYRIMIDONE A ACTIVITE ANTIFONGIQUE
  申请人：J. URIACH & CIA. S.A.

  公开号：WO1997005130A1

  公开（公告）日：1997-02-13

  (EN) Compounds of general formula (I) and their salts and solvates are antifungal agents and as such are useful in the treatment of various fungal infections. Pharmaceutical compositions including these compounds and processes for their preparation are also provided.(FR) Les composés de la formule générale (I) et leurs sels et solvates sont des agents antifongiques. Il sont utiles pour le traitement de différentes infections fongiques. L'invention concerne également des compositions pharmaceutiques comprenant ces composés et des procédés permettant leur préparation.

  化合物的一般式（I）及其盐和溶剂物是抗真菌剂，因此可用于治疗各种真菌感染。还提供了包括这些化合物的制药组合物和其制备方法。
• Pyrimidone derivatives with antifungal activity
  申请人：J. Uriah & Cia. S.A.

  公开号：US05807854A1

  公开（公告）日：1998-09-15

  Compounds of general formula I and their salts and solvates are antifungal agents and as such are useful in the treatment of various fungal infections. Pharmaceutical compositions including these compounds and processes for their preparation are also provided.

  通式I的化合物及其盐和溶剂化物是抗真菌剂，因此在治疗各种真菌感染方面非常有用。还提供包括这些化合物的制药组合物和其制备过程。
• Crystalline forms of (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
  申请人：Palau Pharma, S.A.

  公开号：EP1887004A1

  公开（公告）日：2008-02-13

  Novel crystalline forms of (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, pharmaceutical compositions containing these crystalline forms, methods of using these crystalline forms for treating and/or preventing various microbial and/or fungal infections or disorders, and processes for obtaining these crystalline forms. In particular, the present subject matter relates to the specific crystalline Forms I, II, III, IV, and V of (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.

  (1R,2R)-7-氯-3-[2-(2,4-二氟苯基)-2-羟基-1-甲基-3-(1H-1,2,4-三唑-1-基)丙基]喹唑啉-4(3H)-酮的新型结晶形式、含有这些结晶形式的药物组合物、使用这些结晶形式治疗和/或预防各种微生物和/或真菌感染或疾病的方法以及获得这些结晶形式的工艺。特别是，本主题涉及(1R,2R)-7-氯-3-[2-(2,4-二氟苯基)-2-羟基-1-甲基-3-(1H-1,2,4-三唑-1-基)丙基]喹唑啉-4(3H)-酮的特定结晶形式 I、II、III、IV 和 V。