4-[2-[[3-(9H-咔唑-4-基氧基)-2-羟基丙基]氨基]乙氧基]-3-甲氧基-苯酚 | 142227-49-4

• 物质功能分类: 原料药 - 循环系统用药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: 4-[2-[[3-(9H-咔唑-4-基氧基)-2-羟基丙基]氨基]乙氧基]-3-甲氧基-苯酚
• 中文别名: 卡维地洛对羟基代谢物
• 英文名称: 4'-Hydroxyphenylcarvedilol
• 英文别名: (2RS)-1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxy-4-hydroxyphenoxy)ethyl]amino]propan-2-ol；1-[9H-carbazol-4-yloxy]-3-[[2-(4-hydroxy-2-methoxyphenoxy)ethyl]amino]-2-propanol；4'-hydroxycarvedilol；4-Hydroxycarvedilol；4-[2-[[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino]ethoxy]-3-methoxyphenol
• CAS: 142227-49-4
• 化学式: C₂₄H₂₆N₂O₅
• 分子量: 422.481
• InChiKey: ZCJHEORDHXCJNB-UHFFFAOYSA-N

物化性质

• 熔点：
  163-165°C
• 沸点：
  702.0±60.0 °C(Predicted)
• 密度：
  1.305±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于乙腈（少许）、DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  96
• 氢给体数：
  4
• 氢受体数：
  6

安全信息

• 储存条件：
  2-8℃

制备方法与用途

概述

卡维地洛是第3代β受体阻滞剂，由罗氏公司研发并于1991年上市。1995年，美国食品药品监督管理局（FDA）批准该药用于治疗慢性充血性心力衰竭；随后在1996年开始在全球范围内广泛使用。卡维地洛除了具有阻滞肾上腺素β1和β2受体的作用外，还能够阻滞α1受体，并抑制钙、钠、钾通道，从而抑制平滑肌细胞的增殖，具有抗炎、抗氧化以及抑制前列腺素F1a的缩血管作用。其中，针对其心血管作用的研究最为深入；此外，它对肾脏和肝脏的影响以及抗氧化能力也备受关注。

临床研究证明，卡维地洛能显著降低心衰的发病率和死亡率，并能有效防止细胞凋亡的发生。与传统β受体阻滞剂相比，卡维地洛具有无可比拟的优势，最初用于治疗原发性的轻、中度高血压和心绞痛。目前它仍是我国批准用于临床治疗的唯一适应症。由于其良好的降压效果以及较小的副作用，卡维地洛具备安全温和降压的特点，是高血压伴有心绞痛或心肌梗塞患者的首选药物。

生物活性

4-羟基苯卡维定（4-Hydroxyphenyl Carvedilol）是卡维地洛的一种代谢产物。

反应信息

• 作为产物：
  描述：

  4-羟基咔唑 在 lithium bromide 作用下， 以 异丙醇 为溶剂， 反应 12.0h， 生成 4-[2-[[3-(9H-咔唑-4-基氧基)-2-羟基丙基]氨基]乙氧基]-3-甲氧基-苯酚
  参考文献：
  名称：

  Suppression of store overload-induced calcium release by hydroxylated metabolites of carvedilol

  摘要：

  Carvedilol is a drug widely used in the treatment of heart failure and associated cardiac arrhythmias. A unique action of carvedilol is its suppression of store overload-induced calcium release (SOICR) through the cardiac ryanodine receptor (RyR2), which can trigger ventricular arrhythmias. Since the effects of carvedilol metabolites on SOICR have not yet been investigated, three carvedilol metabolites hydroxylated at the 3-, 4' and 5'-positions were synthesized and assayed for SOICR inhibition in mutant HEK 293 cells expressing the RyR2 mutant R4496C. This cell line is especially prone to SOICR and calcium release through the defective RyR2 channel was measured with a calcium-sensitive fluorescent dye. These results revealed that the 3- and 4'-hydroxy derivatives are slightly more effective than carvedilol in suppressing SOICR, while the 5'-analog proved slightly less active. Metabolic deactivation of carvedilol via these hydroxylation pathways is therefore insignificant. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.11.008

文献信息

• Synthesis of Active Metabolites of Carvedilol, an Antihypertensive Drug
  作者：N. Senthilkumar、Y. S. Somannavar、Shankar B. Reddy、Brajesh Kumar Sinha、G. K. A. S. S. Narayan、Ramesh Dandala、Kaga Mukkanti

  DOI：10.1080/00397910903534072

  日期：2010.12.22

  A simple synthetic route for active metabolites of carvedilol is reported. The metabolites 4'-hydroxycarvedilol and 5'-hydroxycarvedilol have exhibited high activity for -blockade. We have disclosed syntheses of 4'-hydroxycarvedilol and 5'-hydroxycarvedilol from commercially available vanillin and isovanillin, respectively.
• Suppression of store overload-induced calcium release by hydroxylated metabolites of carvedilol
  作者：Thomas Malig、Zhichao Xiao、S.R. Wayne Chen、Thomas G. Back

  DOI：10.1016/j.bmcl.2015.11.008

  日期：2016.1

  Carvedilol is a drug widely used in the treatment of heart failure and associated cardiac arrhythmias. A unique action of carvedilol is its suppression of store overload-induced calcium release (SOICR) through the cardiac ryanodine receptor (RyR2), which can trigger ventricular arrhythmias. Since the effects of carvedilol metabolites on SOICR have not yet been investigated, three carvedilol metabolites hydroxylated at the 3-, 4' and 5'-positions were synthesized and assayed for SOICR inhibition in mutant HEK 293 cells expressing the RyR2 mutant R4496C. This cell line is especially prone to SOICR and calcium release through the defective RyR2 channel was measured with a calcium-sensitive fluorescent dye. These results revealed that the 3- and 4'-hydroxy derivatives are slightly more effective than carvedilol in suppressing SOICR, while the 5'-analog proved slightly less active. Metabolic deactivation of carvedilol via these hydroxylation pathways is therefore insignificant. (C) 2015 Elsevier Ltd. All rights reserved.