4a,5,9,10,11,12-hexahydro-1-fluoro-3-methoxy-11-formyl-6H-benzofuro[3a,3,2-ef]benzazepin-6-one | 909134-32-3

• 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: 4a,5,9,10,11,12-hexahydro-1-fluoro-3-methoxy-11-formyl-6H-benzofuro[3a,3,2-ef]benzazepin-6-one
• 英文别名: 7-Fluoro-9-methoxy-14-oxo-11-oxa-4-azatetracyclo[8.6.1.01,12.06,17]heptadeca-6,8,10(17),15-tetraene-4-carbaldehyde
• CAS: 909134-32-3
• 化学式: C₁₇H₁₆FNO₄
• 分子量: 317.317
• InChiKey: POTRMCHZGJNOQZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4a,5,9,10,11,12-hexahydro-1-fluoro-3-methoxy-11-formyl-6H-benzofuro[3a,3,2-ef]benzazepin-6-one 在 lithium aluminium tetrahydride 、 对甲苯磺酸 作用下， 以 甲苯 为溶剂， 生成 8-fluoronarwedine
  参考文献：
  名称：

  Synthesis of (−)- and (+)-8-fluoro-galanthamine

  摘要：

  The synthesis of racemic 8-fluorogalanthamine and its separation into (-)- and (+)-8-fluorogalanthamine (= (4aS,6R, 8aS)- and(4aR,6S,8aR)-1-fluoro-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol) is described. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2006.06.010
• 作为产物：
  描述：

  N-[(2-fluoro-5-hydroxy-4-methoxyphenyl)methyl]-N-[2-(4-hydroxyphenyl)ethyl]-formamide 在 potassium hexacyanoperferrate 、 potassium carbonate 作用下， 以 水 、 甲苯 为溶剂， 反应 1.0h， 以19%的产率得到4a,5,9,10,11,12-hexahydro-1-fluoro-3-methoxy-11-formyl-6H-benzofuro[3a,3,2-ef]benzazepin-6-one
  参考文献：
  名称：

  Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment

  摘要：

  本发明涉及化合物，除了增强神经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/或神经保护剂之外，与其原始化合物相比具有增强的血脑屏障渗透性。这些化合物来源于属于石蒜科生物碱类的天然化合物，例如迎春碱、纳尔韦丁和莱奥拉明，或者来源于这些化合物的代谢物（无论是从化学结构上还是直接通过化学合成）。本发明的化合物可以直接与其靶分子相互作用，或者它们可以作为“前药”，意味着在到达体内的靶区域后，它们通过水解或酶攻击转化为原始的母体化合物，并且与其靶分子相互作用，或者两者兼而有之。本发明的化合物可用作治疗与胆碱缺乏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。

  公开号：

  EP1777222A1

文献信息

• 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）。
• US9763953B2
  申请人：——

  公开号：US9763953B2

  公开（公告）日：2017-09-19
• [EN] CHOLINERGIC ENHANCERS WITH IMPROVED BLOOD-BRAIN BARRIER PERMEABILITY FOR THE TREATMENT OF DISEASES ACCOMPANIED BY COGNITIVE IMPAIRMENT<br/>[FR] AMPLIFICATEURS CHOLINERGIQUES DE PERMÉABILITÉ DE LA BARRIÈRE SANG-CERVEAU AMÉLIORÉE POUR LE TRAITEMENT DE MALADIES ACCOMPAGNÉES D'UNE DÉFICIENCE COGNITIVE
  申请人：GALANTOS PHARMA GMBH

  公开号：WO2007039138A1

  公开（公告）日：2007-04-12

  [EN] 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. 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. Compounds of this invention may be used as medicaments.
  [FR] La présente invention concerne des composés qui, en plus d'amplifier la sensibilité des récepteurs neuronaux cholinergiques à l'acétylcholine et à la choline, ainsi qu'à leurs agonistes exogènes, et/ou d'agir en tant qu'inhibiteurs de cholinestérase et/ou en tant qu'agents neuroprotecteurs, présentent une perméabilité améliorée vis-à-vis de la barrière sang-cerveau par comparaison avec leurs composés parents. Les composés sont dérivés (soit formellement du fait de leur structure chimique, soit directement par synthèse chimique) de composés naturels appartenant à la classe des alcaloïdes d'amaryllidaceae, par exemple la galanthamine, la narwedine et la lycoramine, ou de métabolites desdits composés. Les composés selon la présente invention peuvent soit interagir en tant que tels avec leurs molécules cibles, soit agir en tant que « pro-médicaments », c'est-à-dire être convertis par hydrolyse ou attaque enzymatique en les composés parents originels après avoir atteint leurs régions cible dans l'organisme, et réagir en tant que tels avec leurs molécules cibles, ou les deux. Les composés selon l'invention peuvent être employés en tant que médicaments.
• Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment
  申请人：Galantos Pharma GmbH

  公开号：EP1777222A1

  公开（公告）日：2007-04-25

  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 chvlinesterase 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 lyeoramine, 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 "prodrugs", 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/或神经保护剂之外，与其原始化合物相比具有增强的血脑屏障渗透性。这些化合物来源于属于石蒜科生物碱类的天然化合物，例如迎春碱、纳尔韦丁和莱奥拉明，或者来源于这些化合物的代谢物（无论是从化学结构上还是直接通过化学合成）。本发明的化合物可以直接与其靶分子相互作用，或者它们可以作为“前药”，意味着在到达体内的靶区域后，它们通过水解或酶攻击转化为原始的母体化合物，并且与其靶分子相互作用，或者两者兼而有之。本发明的化合物可用作治疗与胆碱缺乏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。