(4aS,6R,8aS)-11-甲基-5,6,9,10,11,12-六氢-4aH-[1]苯并呋喃并[3a,3,2-ef][2]苯并氮杂卓-3,6-二醇 | 60755-80-8

• 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
• 中文名称: (4aS,6R,8aS)-11-甲基-5,6,9,10,11,12-六氢-4aH-[1]苯并呋喃并[3a,3,2-ef][2]苯并氮杂卓-3,6-二醇
• 中文别名: 加兰他敏杂质
• 英文名称: O-Demethylgalantamine
• 英文别名: sanguinine；(1S,12S,14R)-4-methyl-11-oxa-4-azatetracyclo[8.6.1.01,12.06,17]heptadeca-6(17),7,9,15-tetraene-9,14-diol
• CAS: 60755-80-8
• 化学式: C₁₆H₁₉NO₃
• 分子量: 273.332
• InChiKey: OYSGWKOGUVOGFQ-RBOXIYTFSA-N

物化性质

• 熔点：
  227-230°C (dec.)
• 沸点：
  451.9±45.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  20
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  52.9
• 氢给体数：
  2
• 氢受体数：
  4

ADMET

代谢

O-去甲他克林已知的人体代谢物包括[(1S,12S,14R)-14-羟基-4-甲基-11-氧杂-4-氮杂四环[8.6.1.01,12.06,17]十七烷-6(17),7,9,15-四烯-9-基]氢硫酸盐和(2S,3S,4S,5R)-3,4,5-三羟基-6-[[(1S,12S,14R)-14-羟基-4-甲基-11-氧杂-4-氮杂四环[8.6.1.01,12.06,17]十七烷-6(17),7,9,15-四烯-9-基]氧基]氧杂环己烷-2-羧酸。

O-Desmethylgalantamine has known human metabolites that include [(1S,12S,14R)-14-hydroxy-4-methyl-11-oxa-4-azatetracyclo[8.6.1.01,12.06,17]heptadeca-6(17),7,9,15-tetraen-9-yl] hydrogen sulfate and (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[[(1S,12S,14R)-14-hydroxy-4-methyl-11-oxa-4-azatetracyclo[8.6.1.01,12.06,17]heptadeca-6(17),7,9,15-tetraen-9-yl]oxy]oxane-2-carboxylic acid.

来源:NORMAN Suspect List Exchange

安全信息

• 储存条件：
  存储条件：2-8°C，需密封并保持干燥。

制备方法与用途

去甲基加兰他敏（血根碱）属于加兰他敏类生物碱。它是一种乙酰胆碱酯酶（AChE）抑制剂，其IC50值为1.83μM。

反应信息

• 作为反应物：
  描述：

  (4aS,6R,8aS)-11-甲基-5,6,9,10,11,12-六氢-4aH-[1]苯并呋喃并[3a,3,2-ef][2]苯并氮杂卓-3,6-二醇 生成 (4S,4'R,6'R)-4',6'-dihydroxy-1-methylspiro[2,3-dihydroquinoline-4,3'-cyclohexene]-5,8-dione
  参考文献：
  名称：

  SAA, JOSE M.;CAPOO, MAGDALENA;MARTI, CATALINA;GARCIA-RASO, ANGEL, J. ORG. CHEM., 55,(1990) N, C. 288-292

  摘要：

  DOI：
• 作为产物：
  描述：

  氢溴酸加兰他敏 在 L-Selectride 作用下， 以 四氢呋喃 为溶剂， 反应 24.0h， 以98%的产率得到(4aS,6R,8aS)-11-甲基-5,6,9,10,11,12-六氢-4aH-[1]苯并呋喃并[3a,3,2-ef][2]苯并氮杂卓-3,6-二醇
  参考文献：
  名称：

  Synthesis of deuterium-labelled (−)-galanthamine

  摘要：

  报道了氘标记加兰他敏的合成。通过七步反应，从加兰他敏得到了6-[2H3]甲氧基-N-[2H3]甲基-(-)-加兰他敏。合成过程采用选择性的O-和N-脱甲基化反应完成。[2H3]-N-甲基和[2H3]-O-甲基是通过选择性氨基还原和O-甲基化引入的。版权所有 © 2008 John Wiley & Sons, Ltd.

  DOI：

  10.1002/jlcr.1510

文献信息

• Alkaloid N-oxides from Lycoris sanguinea
  作者：Shigeru Kobayashi、Kimihito Satoh、Atsushi Numata、Tetsuro Shingu、Masaru Kihara

  DOI：10.1016/0031-9422(91)83751-6

  日期：1991.1

  Abstract Three new alkaloids, galanthamine N-oxide, sanguinine N-oxide and lycoramine N-oxide were isolated from Lycoris sanguinea var. Kiushiana Makino.

  摘要 从血石蒜变种中分离到了三种新的生物碱，加兰他敏N-氧化物、血根碱N-氧化物和石蒜胺N-氧化物。牧野纪夏奈。
• Synthesis of13C3,15N4-labeled factor Xa inhibitor
  作者：William J. Guilford、Jerry Dallas、Damian Arnaiz

  DOI：10.1002/jlcr.452

  日期：2001.3.30

  The synthesis of an isotopically-labeled, diphenoxypyridine factor Xa inhibitor, 3-[[6-[3-(4,5-dihydro-1-( 13 C)-methyl-1H-(4- 13 C, 15 N 2 -imidazol-2-yl)phenoxy)-3,5-difluoro-4-(4-morpholinyl)-2-pyridinyl]oxy]-4-hydroxybenzene- 13 C-carbox- 15 N-imid- 15 N-amide, is reported for use in factor Xa binding studies using REDOR NMR. N-benzyl protected tetralabeled N-methylethylene diamine was an intermediate

  同位素标记的二苯氧基吡啶因子 Xa 抑制剂的合成，3-[[6-[3-(4,5-dihydro-1-( 13 C)-methyl-1H-(4- 13 C, 15 N 2 -)咪唑-2-基)苯氧基)-3,5-二氟-4-(4-吗啉基)-2-吡啶基]氧基]-4-羟基苯- 13 C-羧基- 15 N-酰亚胺- 15 N-酰胺，是报告用于使用 REDOR NMR 进行因子 Xa 结合研究。N-苄基保护的四标记 N-甲基乙二胺是制备 3-[4,5-1-( 13 C)-甲基-1H-(4- 13 C, 15 N 2 -咪唑-2-基) 的中间体]苯酚。
• Efficient Synthesis Of Morphine And Codeine
  申请人：Magnus Philip D.

  公开号：US20100292475A1

  公开（公告）日：2010-11-18

  The present invention relates to methods for the synthesis of morphine, intermediates, salts and derivatives thereof. In preferred embodiments, the invention relates to methods for improving the efficiency and overall yield of said morphine, morphine related derivatives and intermediates thereof. In further embodiments, the invention relates to methods for improving the efficiency and overall yield of galanthamine and intermediates thereof.

  本发明涉及吗啡、中间体、盐和衍生物的合成方法。在优选实施例中，本发明涉及改善吗啡、吗啡相关衍生物和中间体的效率和总产量的方法。在进一步实施例中，本发明涉及改善迷迭香碱及其中间体的效率和总产量的方法。
• CHOLINERGIC ENHANCERS WITH IMPROVED BLOOD-BRAIN BARRIER PERMEABILITY FOR THE TREATMENT OF DISEASES ACCOMPANIED BY COGNITIVE IMPAIRMENT
  申请人：Maelicke Alfred

  公开号：US20070213318A1

  公开（公告）日：2007-09-13

  The present invention refers to compounds that, in addition to enhancing the sensitivity to acetylcholine and choline of neuronal cholinergic receptors and/or acting as cholinesterase inhibitors and/or neuroprotective agents, have enhanced blood-brain barrier permeability in comparison to their parent compounds. The compounds are derived (either formally by their chemical structure or directly by chemical synthesis) from natural compounds belonging to the class of amaryllidaceae alkaloids e.g. galanthamine, narwedine and lycoramine, or from metabolites of said compounds. The compounds of the present invention can either interact as such with their target molecules, or they can act as “pro-drugs”, in the sense that after reaching their target regions in the body they are converted by hydrolysis or enzymatic attack to the original parent compound and react as such with their target molecules, or both. The compounds of this invention may be used as medicaments for the treatment of human brain diseases associated with a cholinergic deficit, including the neurodegenerative diseases Alzheimer's and Parkinson's disease and the psychiatric diseases vascular dementia, schizophrenia and epilepsy.

  本发明涉及化合物，除了增强神经元胆碱能受体对乙酰胆碱和胆碱的敏感性，或者作为胆碱酯酶抑制剂和/或神经保护剂外，与其母化合物相比，具有增强的血脑屏障渗透性。这些化合物是从天仙子科生物碱类天仙子碱，如无心菜碱、纳尔韦丁和百合碱，或其代谢物中派生的（通过其化学结构或直接通过化学合成）。本发明的化合物可以直接与其目标分子相互作用，也可以作为“前药”，在到达体内目标区域后，通过水解或酶攻击转化为原始母化合物，并像母化合物一样与其目标分子反应，或两者兼而有之。本发明的化合物可用作治疗与胆碱能缺陷相关的人类脑疾病的药物，包括神经退行性疾病阿尔茨海默病和帕金森病以及精神疾病血管性痴呆、精神分裂症和癫痫。
• Cholinergic Enhancers with Improved Blood-Brain Barrier permeability for the Treatment of Diseases Accompanied by Cognitive Impairment
  申请人：Maelicke Alfred

  公开号：US20080261954A1

  公开（公告）日：2008-10-23

  The present invention refers to compounds that, in addition to enhancing the sensitivity to acetylcholine and choline, and their exogenous agonists, of neuronal cholinergic receptors and/or acting as cholinesterase inhibitors and/or neuroprotective agents, have enhanced blood-brain barrier permeability in comparison to their parent compounds. The compounds are derived (either formally by their chemical structure or directly by chemical synthesis) from natural compounds belonging to the class of amaryllidaceae alkaloids e.g. Galanthamine, narwedine and lycoramine, or from metabolites of said compounds.

  本发明涉及一种化合物，除了增强神经元胆碱能受体及外源性激动剂对乙酰胆碱和胆碱的敏感性，以及作为胆碱酯酶抑制剂和/或神经保护剂外，还具有比其母体化合物更强的血脑屏障通透性。这些化合物是从天仙子科生物碱（例如迎春花碱，纳威丁和莲花碱）或其代谢物中衍生出来的（可以通过其化学结构或直接通过化学合成来实现）。