(±)-5-[(3-chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]pentanenitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (±)-5-[(3-chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]pentanenitrile
• 英文别名: 5-[[(1S,13S)-7-chloro-15-methyl-10-azatetracyclo[11.3.1.02,11.04,9]heptadeca-2,4(9),5,7,10,14-hexaen-3-yl]amino]pentanenitrile
• 化学式: C₂₂H₂₄ClN₃
• 分子量: 365.906
• InChiKey: KPTRIEXMOQLDNE-JKSUJKDBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  48.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (±)-5-[(3-chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]pentanenitrile 在 氯甲酸乙酯 、 三乙胺 、 potassium hydroxide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 75.5h， 生成 5-[(3-chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]-N-(4-hydroxy-3-methoxybenzyl)pentanamide
  参考文献：
  名称：

  Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

  摘要：

  DOI：

  10.1021/acs.jmedchem.0c01775
• 作为产物：
  描述：

  5-溴戊腈 、 (±)-huprine Y 在 potassium hydroxide 作用下， 以 二甲基亚砜 为溶剂， 反应 2.0h， 以54%的产率得到(±)-5-[(3-chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]pentanenitrile
  参考文献：
  名称：

  [EN] MULTITARGET COMPOUNDS FOR THE TREATMENT OF ALZHEIMER'S DISEASE
  [FR] COMPOSÉS À CIBLES MULTIPLES POUR LE TRAITEMENT DE LA MALADIE D'ALZHEIMER

  摘要：

  该发明提供了以下结构的化合物，其中：m为0、1或2；n为2、3、4或5；R0和R1均为H，或它们形成一个桥 -CH2-C(R4)=CH-，其中R4为CH3或CH2CH3；R2和R3独立地为H、F、Cl或(C1-C4)-烷基；R5为H、F、Cl、Br、I、OCH3、OCF3、SF5、SO2F、SO2CH3、NO2、CF3或(C1-C4)-烷基；R6和R7独立地为H、F、Cl、CH3或CF3；并且可选地R5和R6形成一个桥 -O-CH2 -O-，其中R7为H，在体外实验表明化合物I同时是乙酰胆碱酯酶抑制剂和可溶性环氧化酶抑制剂，并且它们具有良好的血脑屏障透过性。因此，化合物I是治疗人类阿尔茨海默病的多靶活性药用成分。

  公开号：

  WO2020193448A1

文献信息

• [EN] MULTITARGET COMPOUNDS FOR THE TREATMENT OF ALZHEIMER'S DISEASE<br/>[FR] COMPOSÉS À CIBLES MULTIPLES POUR LE TRAITEMENT DE LA MALADIE D'ALZHEIMER
  申请人：UNIV BARCELONA

  公开号：WO2020193448A1

  公开（公告）日：2020-10-01

  The invention provides compounds of formula I wherein: m is 0, 1 or 2; n is 2, 3, 4 or 5; R0 and R1 are both H, or they form a bridge -CH2-C(R4 )=CH-, R4 being CH3 or CH2CH3; R2 and R3 independently are H, F, Cl or (C1-C4)-alkyl; R5 is H, F, Cl, Br, I, OCH3, OCF3, SF5, SO2F, SO2CH3, NO2, CF3 or (C1-C4)-alkyl; R6 and R7 independently are H, F, Cl, CH3 or CF3; and optionally R5 and R6 form a bridge -O-CH2 -O-, R7 being H, in vitro assays show that compounds I are simultaneously inhibitors of acetylcholinesterase and inhibitors of soluble epoxide hydrolase, and that they have a good blood-brain barrier permeability. Thus, compounds I are multitarget active pharmaceutical ingredients for the treatment of Alzheimer's disease in humans.

  该发明提供了以下结构的化合物，其中：m为0、1或2；n为2、3、4或5；R0和R1均为H，或它们形成一个桥 -CH2-C(R4)=CH-，其中R4为CH3或CH2CH3；R2和R3独立地为H、F、Cl或(C1-C4)-烷基；R5为H、F、Cl、Br、I、OCH3、OCF3、SF5、SO2F、SO2CH3、NO2、CF3或(C1-C4)-烷基；R6和R7独立地为H、F、Cl、CH3或CF3；并且可选地R5和R6形成一个桥 -O-CH2 -O-，其中R7为H，在体外实验表明化合物I同时是乙酰胆碱酯酶抑制剂和可溶性环氧化酶抑制剂，并且它们具有良好的血脑屏障透过性。因此，化合物I是治疗人类阿尔茨海默病的多靶活性药用成分。
• Synthesis and Multitarget Biological Profiling of a Novel Family of Rhein Derivatives As Disease-Modifying Anti-Alzheimer Agents
  作者：Elisabet Viayna、Irene Sola、Manuela Bartolini、Angela De Simone、Cheril Tapia-Rojas、Felipe G. Serrano、Raimon Sabaté、Jordi Juárez-Jiménez、Belén Pérez、F. Javier Luque、Vincenza Andrisano、M. Victòria Clos、Nibaldo C. Inestrosa、Diego Muñoz-Torrero

  DOI：10.1021/jm401824w

  日期：2014.3.27

  We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer's disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase, butyrylcholinesterase, and BACE-1, dual Aβ42 and tau antiaggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction, preventing the loss of synaptic proteins and/or have a positive effect on the induction of long-term potentiation. In vivo studies in APP-PS1 transgenic mice treated ip for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.
• Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice
  作者：Elisabet Viayna、Nicolas Coquelle、Monika Cieslikiewicz-Bouet、Pedro Cisternas、Carolina A. Oliva、Elena Sánchez-López、Miren Ettcheto、Manuela Bartolini、Angela De Simone、Mattia Ricchini、Marisa Rendina、Mégane Pons、Omidreza Firuzi、Belén Pérez、Luciano Saso、Vincenza Andrisano、Florian Nachon、Xavier Brazzolotto、Maria Luisa García、Antoni Camins、Israel Silman、Ludovic Jean、Nibaldo C. Inestrosa、Jacques-Philippe Colletier、Pierre-Yves Renard、Diego Muñoz-Torrero

  DOI：10.1021/acs.jmedchem.0c01775

  日期：2021.1.14
• Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease
  作者：Sandra Codony、Caterina Pont、Christian Griñán-Ferré、Ania Di Pede-Mattatelli、Carla Calvó-Tusell、Ferran Feixas、Sílvia Osuna、Júlia Jarné-Ferrer、Marina Naldi、Manuela Bartolini、María Isabel Loza、José Brea、Belén Pérez、Clara Bartra、Coral Sanfeliu、Jordi Juárez-Jiménez、Christophe Morisseau、Bruce D. Hammock、Mercè Pallàs、Santiago Vázquez、Diego Muñoz-Torrero

  DOI：10.1021/acs.jmedchem.1c02150

  日期：2022.3.24