galanthamine α-naphtylcarbamate | 121326-59-8

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 石蒜科生物碱
• 英文名称: galanthamine α-naphtylcarbamate
• 英文别名: [(1S,12S,14R)-9-methoxy-4-methyl-11-oxa-4-azatetracyclo[8.6.1.01,12.06,17]heptadeca-6(17),7,9,15-tetraen-14-yl] N-naphthalen-1-ylcarbamate
• CAS: 121326-59-8
• 化学式: C₂₈H₂₈N₂O₄
• 分子量: 456.541
• InChiKey: VIKYFDSRGROHRQ-IDOVBLGQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  60
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-Alapha-萘异氰酸酯 、 加兰他敏 以 四氢呋喃 为溶剂， 反应 24.0h， 以60%的产率得到galanthamine α-naphtylcarbamate
  参考文献：
  名称：

  Chemical and pharmacological characterization of galanthamine, an acetylcholinesterase inhibitor, and its derivatives. A potential application in Alzheimer's disease?

  摘要：

  We conducted structural and pharmacological studies of galanthamine, a cortical acetylcholinesterase (AChE) inhibitor, and 19 structural analogs. Systematic derivatization of galanthamine at the cyclohexene ring, tertiary amino, hydroxyl and methoxyl functions indicated that these structural features are essential for biological activity. Molecular modeling studies suggested that the low energy conformations of the analogs are similar to that of the parent. One derivative, galanthamine n-butyl carbamate, had an LD50 of over 100 mg/kg (ip) in mice. In a passive avoidance paradigm, this analog improved performance in a dose-dependent fashion with a peak effect at 0.1 mg/kg in control and 0.5 mg/kg in basal forebrain lesioned mice. In the same paradigm, the peak effect of the parent compound is a 6-fold higher dose. With this surprinsingly high therapeutic ratio, this compound may be of interest in treating cholinergic deficits of the central nervous system such as Alzheimer's disease.

  DOI：

  10.1016/0223-5234(92)90087-h

文献信息

• PROCESS FOR MANUFACTURING EXTREMELY PURE BENZAZEPINE DERIVATIVES
  申请人：GERDES Klaus

  公开号：US20090326219A1

  公开（公告）日：2009-12-31

  A process for the production of extremely pure galanthamine or extremely pure galanthamine derivatives, a start is made from racemic bromine narwedine, which is debrominated under palladium catalysis. In this case, the working-up of the reaction mixture, which is carried out in the presence of oxygen or peroxides so that the palladium catalyst in an insoluble form is converted into an easily separable form, is essential. The further reaction is carried out by reduction of enantiomer-pure narwedine to form enantiomer-pure galanthamine, whereby it is then alkylated or dealkylated so that a corresponding substitution on the ring-nitrogen atom is achieved. By further purification, such as recrystallization, residual portions of palladium of below 5 ppm are achieved, so that direct use as a pharmaceutical raw material is made possible.

  一种生产极纯的风信子碱或其衍生物的方法，首先从外消旋溴化纳尔维丁开始，通过钯催化去溴化。在这种情况下，反应混合物的处理必须在氧气或过氧化物的存在下进行，以便将钯催化剂转化为易于分离的不溶形式。进一步的反应是将对映纯的纳尔维丁还原成对映纯的风信子碱，然后通过烷基化或去烷基化使环氮原子上发生相应的取代。通过进一步的纯化，如重结晶，可以实现钯的残留量低于5 ppm，从而使其可以直接用作药用原料。
• Chemical and pharmacological characterization of galanthamine, an acetylcholinesterase inhibitor, and its derivatives. A potential application in Alzheimer's disease?
  作者：SY Han、JE Sweeney、ES Bachman、EJ Schweiger、G Forloni、JT Coyle、BM Davis、MM Joullié

  DOI：10.1016/0223-5234(92)90087-h

  日期：1992.10

  We conducted structural and pharmacological studies of galanthamine, a cortical acetylcholinesterase (AChE) inhibitor, and 19 structural analogs. Systematic derivatization of galanthamine at the cyclohexene ring, tertiary amino, hydroxyl and methoxyl functions indicated that these structural features are essential for biological activity. Molecular modeling studies suggested that the low energy conformations of the analogs are similar to that of the parent. One derivative, galanthamine n-butyl carbamate, had an LD50 of over 100 mg/kg (ip) in mice. In a passive avoidance paradigm, this analog improved performance in a dose-dependent fashion with a peak effect at 0.1 mg/kg in control and 0.5 mg/kg in basal forebrain lesioned mice. In the same paradigm, the peak effect of the parent compound is a 6-fold higher dose. With this surprinsingly high therapeutic ratio, this compound may be of interest in treating cholinergic deficits of the central nervous system such as Alzheimer's disease.