4-(1-benzylpiperidin-4-yl)butan-1-amine | 1415570-70-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-(1-benzylpiperidin-4-yl)butan-1-amine
• CAS: 1415570-70-5
• 化学式: C₁₆H₂₆N₂
• 分子量: 246.396
• InChiKey: HJJCUHPWJKGKDS-UHFFFAOYSA-N

物化性质

• 沸点：
  350.9±15.0 °C(Predicted)
• 密度：
  0.985±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  29.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-(1-benzylpiperidin-4-yl)butan-1-amine 、 2-氨基-6-氯-4-苯基-吡啶-3,5-二甲腈 在 三乙胺 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 7.0h， 以70%的产率得到2-Amino-6-[4-(1-benzylpiperidin-4-yl)butylamino]-4-phenylpyridine-3,5-dicarbonitrile
  参考文献：
  名称：

  Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease: Synthesis, biological assessment, and molecular modeling

  摘要：

  The synthesis, biological assessment and molecular modeling of new pyridonepezils 1-8, able to inhibit human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBuChE), are described. The new compounds have been designed as hybrids resulting from a conjunctive approach that combines the N-benzylpiperidine moiety, present in donepezil, and the 2-amino-6-chloropyridine heterocyclic ring system, connected by an appropriate polymethylene linker. Compounds 1-8 were prepared by reaction of 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2-amino-6-chloropyridine-3,5-dicarbonitrile (14)] with 2-(1-benzylpiperidin-4-yl)alkylamines (9-12). The biological evaluation of molecules 1-8 showed that compounds 1-6 are potent AChE inhibitors, in the submicromolar, while compounds 7 and 8 are on the nanomolar range, the most potent, 2-amino-6-((3-(1-benzylpiperidin-4-yl)propyl)amino)pyridine-3,5-dicarbonitrile (7), showing a IC50 (hAChE) = 9.4 +/- 0.4 nM. Inhibitors 2-8 are permeable as determined in the PAMPA assay. Compared to donepezil, compound 7 is in the same range of inhibitory activity for hAChE, and 703-fold more selective for hAChE than for hBuChE. Molecular modeling investigation on pyridonepezil 7 supports its dual AChE inhibitory profile, binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The theoretical ADME analysis of pyridonepezils 1-8 has been carried out. Overall, compound 7, a potent and selective dual AChEI, can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.09.030
• 作为产物：
  描述：

  4-(1-苄基哌啶-4-基)丁-1-醇 在 叠氮磷酸二苯酯 、 水 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三苯基膦 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 4-(1-benzylpiperidin-4-yl)butan-1-amine
  参考文献：
  名称：

  Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease: Synthesis, biological assessment, and molecular modeling

  摘要：

  The synthesis, biological assessment and molecular modeling of new pyridonepezils 1-8, able to inhibit human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBuChE), are described. The new compounds have been designed as hybrids resulting from a conjunctive approach that combines the N-benzylpiperidine moiety, present in donepezil, and the 2-amino-6-chloropyridine heterocyclic ring system, connected by an appropriate polymethylene linker. Compounds 1-8 were prepared by reaction of 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2-amino-6-chloropyridine-3,5-dicarbonitrile (14)] with 2-(1-benzylpiperidin-4-yl)alkylamines (9-12). The biological evaluation of molecules 1-8 showed that compounds 1-6 are potent AChE inhibitors, in the submicromolar, while compounds 7 and 8 are on the nanomolar range, the most potent, 2-amino-6-((3-(1-benzylpiperidin-4-yl)propyl)amino)pyridine-3,5-dicarbonitrile (7), showing a IC50 (hAChE) = 9.4 +/- 0.4 nM. Inhibitors 2-8 are permeable as determined in the PAMPA assay. Compared to donepezil, compound 7 is in the same range of inhibitory activity for hAChE, and 703-fold more selective for hAChE than for hBuChE. Molecular modeling investigation on pyridonepezil 7 supports its dual AChE inhibitory profile, binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The theoretical ADME analysis of pyridonepezils 1-8 has been carried out. Overall, compound 7, a potent and selective dual AChEI, can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.09.030

文献信息

• Synthesis and Evaluation of Multi-Target-Directed Ligands against Alzheimer’s Disease Based on the Fusion of Donepezil and Ebselen
  作者：Zonghua Luo、Jianfei Sheng、Yang Sun、Chuanjun Lu、Jun Yan、Anqiu Liu、Hai-bin Luo、Ling Huang、Xingshu Li

  DOI：10.1021/jm401047q

  日期：2013.11.27

  series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer’s disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one

  通过将胆碱酯酶抑制剂多奈哌齐和抗氧化剂依布硒啉融合获得的一系列新化合物被设计为针对阿尔茨海默氏病的多靶标配体。体外测定表明，这些分子中的某些分子没有表现出强效的胆碱酯酶抑制活性，但确实具有与依布硒仑相关的各种其他药理作用。在这些分子中，发现化合物7d是最有效的乙酰胆碱酯酶抑制剂之一（电泳电乙酰胆碱酯酶的IC 50值为0.042μM，人乙酰胆碱酯酶的IC 50值为0.097μM），是一种强丁酰胆碱酯酶抑制剂（IC 50值为1.586μM），拥有快速的H 2 O 2和过氧亚硝酸盐清除活性，谷胱甘肽过氧化物酶样活性（ν 0 = 123.5μM分钟-1），并且是哺乳动物的TrxR的基板。小鼠毒性试验显示，剂量高达2000 mg / kg时无急性毒性。根据体外血脑屏障模型，7d能够穿透中枢神经系统。
• Donepezil + chromone + melatonin hybrids as promising agents for Alzheimer’s disease therapy
  作者：Irene Pachón-Angona、Bernard Refouvelet、Rudolf Andrýs、Helène Martin、Vincent Luzet、Isabel Iriepa、Ignacio Moraleda、Daniel Diez-Iriepa、María-Jesús Oset-Gasque、José Marco-Contelles、Kamil Musilek、Lhassane Ismaili

  DOI：10.1080/14756366.2018.1545766

  日期：2019.1.1

  Abstract We describe herein the design, multicomponent synthesis and biological studies of new donepezil + chromone + melatonin hybrids as potential agents for Alzheimer’s disease (AD) therapy. We have identified compound 14n as promising multitarget small molecule showing strong BuChE inhibition (IC50 = 11.90 ± 0.05 nM), moderate hAChE (IC50 = 1.73 ± 0.34 μM), hMAO A (IC50 = 2.78 ± 0.12 μM), and MAO

  摘要 我们在此描述了新型多奈哌齐+色酮+褪黑素杂合体的设计、多组分合成和生物学研究，作为阿尔茨海默病（AD）治疗的潜在药物。我们已确定化合物14n是有前景的多靶点小分子，具有强 BuChE 抑制作用 (IC 50  = 11.90 ± 0.05 nM)、中等 hAChE (IC 50  = 1.73 ± 0.34 μM)、hMAO A (IC 50  = 2.78 ± 0.12 μM) 和 MAO B (IC 50  = 21.29 ± 3.85 μM) 抑制，同时保持强大的抗氧化能力（3.04 TE，ORAC 测试）。因此，本文报告的结果支持开发新的多靶点多奈哌齐+色酮+褪黑激素混合物，例如化合物14n，作为治疗 AD 患者的潜在药物。
• [EN] BENZISOSELENAZOLONE-CONTAINING DONEPEZIL ANALOG<br/>[FR] ANALOGUE DE DONÉPÉZIL CONTENANT DE LA BENZISOSÉLÉNAZOLONE
  申请人：UNIV SUN YAT SEN

  公开号：WO2014117669A1

  公开（公告）日：2014-08-07

  本发明公开了游离形式、盐形式或溶剂化物形式的式I所示的含苯并异硒唑酮结构的多奈哌齐类似物，并公开了包含式I的药物组合物及式I化合物在制备治疗、改善和/或预防阿尔茨海默病药物中的应用。式I的结构如图所示，其中R1-R9，X，Y，n的定义如说明书所述。
• Synthesis, pharmacological assessment, and molecular modeling of 6-chloro-pyridonepezils: New dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease
  作者：Abdelouahid Samadi、Mario de la Fuente Revenga、Concepción Pérez、Isabel Iriepa、Ignacio Moraleda、María Isabel Rodríguez-Franco、José Marco-Contelles

  DOI：10.1016/j.ejmech.2013.06.021

  日期：2013.9

  6-Chloro-pyridonepezils are chloropyridine donepezil hybrids designed by combining the N-benzylpiperidine moiety present in donepezil with the 2-chloropyridine-3,5-dicarbonitrile heterocyclic ring system, both connected by an appropriate polymethylene linker. 6-Chloro-pyridonepezils 1-8 were prepared by reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2,6-dichloropyridine3,5-dicarbonitrile (14)1 with suitable 2-(1-benzylpiperidin-4-yDalkylamines (9-12). The biological evaluation showed that these new compounds are cholinesterase inhibitors, in the submicromolar range, one of them (6) being a potent hBuChE inhibitor (IC50 = 0.47 +/- 0.08 mu M). 6-Chloro-pyridonepezils 4, 7 and 8 are potent hAChE inhibitors showing IC50 in the 0.013-0.054 mu M range. Particularly, 6-chloro-pyridonepezil 8 is 625-fold more selective for hAChE than for hBuChE and compared to donepezil is equipotent for the inhibition of hAChE. Molecular modeling investigation on 6-chloro-pyridonepezils 4, 6-8 supports its dual AChE inhibitory profile, by binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The in vitro Blood Brain Barrier (BBB) and theoretical ADME analysis of 6-chloro-pyridonepezils 1-8 have been carried out. Overall, compound 8, is a permeable potent and selective dual AChEI that can be considered as a good candidate with potential impact for further pharmacological development in Alzheimer's therapy. (C) 2013 Elsevier Masson SAS. All rights reserved.
• Quinoline derivatives
  申请人：SS PHARMACEUTICAL CO., LTD.

  公开号：EP0481429B1

  公开（公告）日：2001-01-24