6-chloro-9-(9-aminononylamino)-1,2,3,4-tetrahydroacridine | 827601-90-1

• 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: 6-chloro-9-(9-aminononylamino)-1,2,3,4-tetrahydroacridine
• 英文别名: N¹-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)nonane-1,9-diamine；9-[(9-aminononyl)amino]-6-chloro-1,2,3,4-tetrahydroacridine；N~1~-(6-Chloro-1,2,3,4-tetrahydroacridin-9-yl)nonane-1,9-diamine；N'-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)nonane-1,9-diamine
• CAS: 827601-90-1
• 化学式: C₂₂H₃₂ClN₃
• 分子量: 373.969
• InChiKey: LKSHTRXNBWUALR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  26
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  50.9
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-chloro-9-(9-aminononylamino)-1,2,3,4-tetrahydroacridine 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 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 乙醚 、 乙醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.25h， 生成 N-{9-[(1,2,3,4-tetrahydroacridin-9-yl)amino]nonyl}-2-(6-hydroxy-7-methoxy-2-methylchroman-2-yl)acetamide hydrochloride
  参考文献：
  名称：

  Centrally Active Multitarget Anti-Alzheimer Agents Derived from the Antioxidant Lead CR-6

  摘要：

  Oxidative stress is a major pathogenic factor in Alzheimer's disease, but it should not be tackled alone rather together with other key targets to derive effective treatments. The combination of the scaffold of the polar antioxidant lead 7-methoxy-2,2-dimethylchroman-6-ol (CR-6) with that of the lipophilic cholinesterase inhibitor 6-chlorotacrine results in compounds with favorable brain permeability and multiple activities in vitro (acetylcholinesterase, butyrylcholinesterase, beta-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1), and A beta 42 and tau aggregation inhibition). In in vivo studies on wild-type and APP/presenilin 1 (PS1) mice, two selected compounds were well tolerated and led to positive trends, albeit statistically nonsignificant in some cases, on memory performance, amyloid pathology (reduced amyloid burden and potentiated non-amyloidogenic APP processing), and oxidative stress (reduced cortical oxidized proteins and increased antioxidant enzymes superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1 (GPX1), and heme oxygenase 1 (Hmox1) and transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2)). These compounds emerge as interesting brain-permeable multitarget compounds, with a potential as anti-Alzheimer agents beyond that of the original lead CR-6.

  DOI：

  10.1021/acs.jmedchem.0c00528
• 作为产物：
  描述：

  2-氨基-4-氯苯甲酸 在 potassium iodide 、 三氯氧磷 作用下， 以 戊醇 为溶剂， 生成 6-chloro-9-(9-aminononylamino)-1,2,3,4-tetrahydroacridine
  参考文献：
  名称：

  O-Hydroxyl- or o-amino benzylamine-tacrine hybrids: Multifunctional biometals chelators, antioxidants, and inhibitors of cholinesterase activity and amyloid-β aggregation

  摘要：

  In an effort to identify novel multifunctional drug candidates for the treatment of Alzheimer's disease (AD), a series of hybrid molecules were synthesised by reacting N-(aminoalkyl)tacrine with salicylic aldehyde or derivatives of 2-aminobenzaldehyde. These compounds were then evaluated as multifunctional anti-Alzheimer's disease agents. All of the hybrids are potential biometal chelators, and in addition, most of them were better antioxidants and inhibitors of cholinesterases and amyloid-beta (A beta) aggregation than the lead compound tacrine. Compound 7c has the potential to be a candidate for AD therapy: it is a much better inhibitor of acetylcholinesterase (AChE) than tacrine (IC50: 0.55 nM vs 109 nM), has good biometal chelation ability, is able to inhibit A beta aggregation and has moderate antioxidant activity (1.22 Trolox equivalents). (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.07.045

文献信息

• [EN] TACRINE DERIVATIVES AS INHIBITORS OF ACETYLCHOLINESTERASE<br/>[FR] DERIVES DE TACRINE UTILISES EN TANT QU'INHIBITEURS DE L'ACETYLCHOLINESTERASE
  申请人：NEUROPHARMA SA

  公开号：WO2005005413A1

  公开（公告）日：2005-01-20

  The invention provides compounds of formula: (I) which have a tacrine moiety connected to an heterocyclic moiety through a linker. Through careful selection of the substituents and the linker, the activity and selectivity towards acetylcholinesterase can be modulated. The compounds show potent AChE inhibition activities together with modifications in the beta-amyloid aggregation properties by binding simultaneously to the catalytic and peripheral AChE sites. They are useful in the treatment of AChE mediated diseases, such as the Alzheimer's disease.

  该发明提供了具有以下公式的化合物：（I），其中通过连接剂将一种他环境基团连接到一种杂环基团。通过精心选择取代基和连接剂，可以调节对乙酰胆碱酯酶的活性和选择性。这些化合物显示出强大的AChE抑制活性，同时通过同时结合催化和外周AChE位点，改变了β-淀粉样蛋白聚集特性。它们在治疗AChE介导的疾病，如阿尔茨海默病中非常有用。
• Acetylcholinesterase dual inhibitors
  申请人：Gil Martinez Ana

  公开号：US20050148621A1

  公开（公告）日：2005-07-07

  The invention provides compounds of formula: which have a tacrine moiety connected to an heterocyclic moiety through a linker. Through careful selection of the substituents and the linker, the activity and selectivity towards acetylcholinesterase can be modulated. The compounds show potent AChE inhibition activities together with modifications in the β-amyloid aggregation properties by binding simultaneously to the catalytic and peripheral AChE sites. They are useful in the treatment of AChE mediated diseases, such as the Alzheimer's disease.

  该发明提供了公式的化合物：其中通过连接剂连接了一种Tacrine基团和一个杂环基团。通过精心选择取代基和连接剂，可以调节对乙酰胆碱酯酶的活性和选择性。这些化合物显示出强大的AChE抑制活性，同时通过同时结合催化和周围AChE位点，修改β淀粉样聚集物的聚集特性。它们在治疗AChE介导的疾病，如阿尔茨海默病中很有用。
• ACETYLCHOLINESTERASE DUAL INHIBITORS
  申请人：Gil Ana Martinez

  公开号：US20110144148A1

  公开（公告）日：2011-06-16

  The invention provides compounds of formula: which have a tacrine moiety connected to an heterocyclic moiety through a linker. Through careful selection of the substituents and the linker, the activity and selectivity towards acetylcholinesterase can be modulated. The compounds show potent AChE inhibition activities together with modifications in the β-amyloid aggregation properties by binding simultaneously to the catalytic and peripheral AChE sites. They are useful in the treatment of AChE mediated diseases, such as the Alzheimer's disease.

  本发明提供了公式如下的化合物: 通过连接剂将Tacrine基团连接到杂环基团上。通过对取代基和连接剂的精心选择，可以调节其对乙酰胆碱酯酶的活性和选择性。这些化合物表现出强效的AChE抑制活性，并通过同时结合催化和周边AChE位点来改变β-淀粉样聚集物的聚集特性。它们在治疗AChE介导的疾病，如阿尔茨海默病方面非常有用。
• Investigation of the role of linker moieties in bifunctional tacrine hybrids
  作者：Todd J. Eckroat、Keith D. Green、Rebecca A. Reed、Joshua J. Bornstein、Sylvie Garneau-Tsodikova

  DOI：10.1016/j.bmc.2013.02.047

  日期：2013.6

  Alzheimer's disease (AD) is a complex neurological disorder with multiple inter-connected factors playing roles in the onset and progression of the disease. One strategy currently being explored for the development of new therapeutics for AD involves linking tacrine, a known acetylcholinesterase (AChE) inhibitor, to another drug to create bifunctional hybrids. The role and influence on activity of the linker moiety in these hybrids remains ill-defined. In this study, three series of 6-chlorotacrine with linkers varying in terminal functional group and length were synthesized, evaluated for AChE inhibition, and compared to tacrine and 6-chlorotacrine-mefenamic acid hybrids. Out of the compounds with terminal amine, methyl, and hydroxyl moieties tested, several highly potent molecules (low nanomolar IC50 values) comprised of linkers with terminal amines were identified. These 6-chlorotacrine with linkers were significantly more potent than tacrine alone and were often more potent than similar 6-chlorotacrine-mefenamic acid hybrids. (C) 2013 Elsevier Ltd. All rights reserved.
• A tacrine-tetrahydroquinoline heterodimer potently inhibits acetylcholinesterase activity and enhances neurotransmission in mice
  作者：Fanny C.F. Ip、Guangmiao Fu、Fengzhi Yang、Fangyuan Kang、Peiran Sun、Choi Ying Ling、Kit Cheung、Fangzhou Xie、Yueqing Hu、Lei Fu、Nancy Y. Ip

  DOI：10.1016/j.ejmech.2021.113827

  日期：2021.12