3-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]propyl methanesulfonate | 955993-02-9

• 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: 3-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]propyl methanesulfonate
• 英文别名: 6-chloro-9-[(3-methanesulfonyloxypropyl)amino]-1,2,3,4-tetrahydroacridine；3-[(6-Chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]propyl methanesulfonate
• CAS: 955993-02-9
• 化学式: C₁₇H₂₁ClN₂O₃S
• 分子量: 368.884
• InChiKey: NQBHGTFXJIHLEO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  76.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]propyl methanesulfonate 在 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 49.25h， 生成 4-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]-N-(9-fluoro-7H-5,6,8,9,10,11-hexahydro-5,9:7,11-dimethanobenzo[9]annulen-7-yl)butanamide
  参考文献：
  名称：

  A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors

  摘要：

  The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 mu M in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.07.051
• 作为产物：
  描述：

  6,9-二氯-1,2,3,4-四氢吖啶 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 24.5h， 生成 3-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]propyl methanesulfonate
  参考文献：
  名称：

  A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors

  摘要：

  The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 mu M in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.07.051

文献信息

• Novel Donepezil-Based Inhibitors of Acetyl- and Butyrylcholinesterase and Acetylcholinesterase-Induced β-Amyloid Aggregation
  作者：Pelayo Camps、Xavier Formosa、Carles Galdeano、Tània Gómez、Diego Muñoz-Torrero、Michele Scarpellini、Elisabet Viayna、Albert Badia、M. Victòria Clos、Antoni Camins、Mercè Pallàs、Manuela Bartolini、Francesca Mancini、Vincenza Andrisano、Joan Estelrich、Mònica Lizondo、Axel Bidon-Chanal、F. Javier Luque

  DOI：10.1021/jm8001313

  日期：2008.6.1

  A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.
• 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
• [EN] ACETYLCHOLINESTERASE-INHIBITING COMPOUNDS FOR TREATING ALZHEIMER'S DISEASE<br/>[ES] COMPUESTOS INHIBIDORES DE ACETILCOLINESTERASA PARA EL TRATAMIENTO DE LA ENFERMEDAD DE ALZHEIMER<br/>[FR] COMPOSÉS INHIBITEURS D'ACÉTYLCHOLINESTÉRASE UTILISÉS DANS LE TRAITEMENT DE LA MALADIE D'ALZHEIMER
  申请人：UNIV BARCELONA

  公开号：WO2007122274A1

  公开（公告）日：2007-11-01

  [EN] Compounds of formula (I) and the pharmaceutically acceptable salts or solvates thereof, including any stereoisomer or mixture of stereoisomers, in which R₁, R₂, R₃ and R₄ are radicals selected independently from the group consisting of H, Cl, F, Br, CF₃, (C₁-C₄)alkyl, (C₁-C₄)alkoxyl and nitro; R₅, R₆, R₇ and R₈ are radicals selected independently from the group consisting of H and (C₁-C₆)alkoxyl; n is an integer from 3 to 5; r is an integer from 2 to 5; s is an integer from 1 to 5 and X is a biradical selected from CO and CH₂. They behave as acetylcholinesterase inhibitors with two bonding sites and are useful as active principles against Alzheimer's disease.
  [FR] L'invention concerne des composés représentés par la formule (I), ainsi que leurs sels ou leurs solvates acceptables d'un point de vue pharmaceutique, y compris n'importe quel stéréoisomère ou mélange de stéréoisomères, formule dans laquelle R₁, R₂, R₃ et R₄ sont des radicaux sélectionnés indépendamment du groupe composé de H, Cl, F, Br, CF₃, alkyle (C₁-C₄), alcoxyle (C₁-C₄) et nitro; R₅, R₆, R₇ et R₈ sont des radicaux sélectionnés indépendamment du groupe composé de H et alkoxyle (C₁-C₆); n est un entier de 3 à 5; r est un entier de 2 à 5; s est un entier de 1 à 5; et X est un biradical sélectionné parmi CO et CH₂. Lesdits composés sont des inhibiteurs d'acétylcholinestérase à double site de liaison et sont utilisés comme principes actifs contre la maladie d'Alzheimer.
  [ES] Compuestos de fórmula (I) y sus sales o solvatos farmacéuticamente aceptables, incluyendo cualquier estereoisómero o mezcla de estereoisómeros, donde R₁, R₂, R₃ y R₄ son radicales seleccionados independientemente del grupo que consiste en H, Cl, F, Br, CF₃, (C₁-C₄)-alquilo, (C₁ C₄) alcoxilo y nitro; R₅, R₆, R₇ y R₈ son radicales seleccionados independientemente del grupo que consiste en H y (C₁-C₆) alcoxilo, n es un entero de 3 a 5; r es un entero de 2 a 5; s es un entero de 1 a 5 y X es un birradical seleccionado entre CO y CH₂, se comportan como inhibidores de acetilcolinesterasa de sitio de unión dual y son útiles como principios activos contra la enfermedad de Alzheimer.
• A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors
  作者：F. Javier Pérez-Areales、Andreea L. Turcu、Marta Barniol-Xicota、Caterina Pont、Deborah Pivetta、Alba Espargaró、Manuela Bartolini、Angela De Simone、Vincenza Andrisano、Belén Pérez、Raimon Sabate、Francesc X. Sureda、Santiago Vázquez、Diego Muñoz-Torrero

  DOI：10.1016/j.ejmech.2019.07.051

  日期：2019.10

  The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 mu M in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development. (C) 2019 Elsevier Masson SAS. All rights reserved.