(2E)-3-(1-benzylpiperidin-4-yl)prop-2-enenitrile | 151097-69-7

• 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: (2E)-3-(1-benzylpiperidin-4-yl)prop-2-enenitrile
• 英文别名: (E)-3-(1-benzylpiperidin-4-yl)-2-propenenitrile；(E)-3-(1-benzylpiperidin-4-yl)prop-2-enenitrile
• CAS: 151097-69-7
• 化学式: C₁₅H₁₈N₂
• 分子量: 226.321
• InChiKey: NPDKEFLLCQFTMK-QPJJXVBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  27
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (2E)-3-(1-benzylpiperidin-4-yl)prop-2-enenitrile 在 碘 、 二异丁基氢化铝 、 magnesium 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 1.17h， 生成 4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-ynyl)amino)butanenitrile
  参考文献：
  名称：

  Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease

  摘要：

  The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 μM; MAO B (IC50 = 10.2 ± 0.9 μM); AChE (IC50 = 1.8 ± 0.1 μM); BuChE (IC50 = 1.6 ± 0.25 μM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice.

  DOI：

  10.1016/j.ejmech.2014.04.078
• 作为产物：
  描述：

  1-苄基-4-哌啶甲醛 、 氰基甲基二乙基磷酸酯 在 potassium carbonate 作用下， 以 四氢呋喃 为溶剂， 反应 12.5h， 以83%的产率得到(2E)-3-(1-benzylpiperidin-4-yl)prop-2-enenitrile
  参考文献：
  名称：

  3,4-亚甲二氧基苯基取代四氢-β-咔啉哌嗪二 酮类衍生物及其用途

  摘要：

  本发明涉及一种3,4‑亚甲二氧基苯基取代四氢‑β‑咔啉哌嗪二酮类衍生物及其用途。具体地，本发明公开了式I所示的化合物或其立体异构体，或其药学上可接受的盐，各基团的定义详见说明书。本发明的化合物具有乙酰胆碱酯酶和磷酸二酯酶5的双重抑制活性，具有良好的血脑屏障透过率。因此，本发明化合物可用于制备治疗和/或预防阿尔茨海默病药物。

  公开号：

  CN108409738B

文献信息

• Neuroprotective multi-target directed drugs
  申请人：Universitat Autònoma de Barcelona

  公开号：EP2727916A1

  公开（公告）日：2014-05-07

  A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil, connected through an oligomethylene linker, to a central nitrogen atom substituted with the propargyl moiety responsible for the MAO inhibition, and a 8-hydroxy-5-methylaminoquinoline functional group, the biometal pro-chelator motif. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potencial impact for AD therapy.

  一种新的多靶分子家族已经合成，能够与乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）以及单胺氧化酶（MAO）A和B相互作用。新颖的化合物是使用联合方法设计的，该方法将AChE抑制剂多奈哌齐的苄哌啶基团与经过寡亚甲基连接的中央氮原子相连接，该中央氮原子上取代了负责MAO抑制的丙炔基团，以及8-羟基-5-甲基氨基喹啉功能基团，生物金属前螯合物基序。总体而言，结果表明这些新化合物是有潜力对阿尔茨海默病治疗产生影响的多靶药物候选物。
• Oxadiazole derivatives having acetylcholinesterase-inhibitory and
  申请人：Fujisawa Pharmaceutical Co., Ltd.

  公开号：US05622976A1

  公开（公告）日：1997-04-22

  Heterocyclic compounds of the formula: R.sup.1 --Q--Z--X--A--M wherein R.sup.1 is lower alkyl, a heterocyclic group which may have suitable substituent(s), etc; Q is oxadiazolediyl, Z is bond or vinyl, X is bond, a group of the formula: ##STR1## (in which R.sup.4 is hydrogen or lower alkyl), a group of the formula: ##STR2## (in which R.sup.8 is hydroxy or protected hydroxy), etc; A is bond, lower alkylene or lower alkynylene and M is a heterocyclic group containing at least one nitrogen atom which may have one substituent selected from the group consisting of lower alkyl, an imino protective group and ar(lower)alkyl which may have suitable substituent(s), and a pharmaceutically acceptable salt thereof which are useful as a medicament.

  式子为R.sup.1 --Q--Z--X--A--M的杂环化合物，其中R.sup.1是低碳基，是一种可能具有适当取代基的杂环基团等；Q是氧杂二唑基，Z是键或乙烯基，X是键，是一种公式为：##STR1##（其中R.sup.4是氢或低碳基），一种公式为：##STR2##（其中R.sup.8是羟基或保护羟基）等；A是键，低碳基亚烷基或低碳基炔亚烷基，M是含有至少一个氮原子的杂环基团，可能具有来自以下取代基组的一种取代基，包括低碳基，亚氨基保护基和ar（低碳基）烷基，可能具有适当的取代基，以及其药学上可接受的盐，用作药物。
• JP6004894
  申请人：——

  公开号：——

  公开（公告）日：——
• OXADIAZOLE DERIVATIVES HAVING ACETYLCHOLINESTERASE-INHIBITORY AND MUSCARINIC AGONIST ACTIVITY
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：EP0619814A1

  公开（公告）日：1994-10-19
• US5622976A
  申请人：——

  公开号：US5622976A

  公开（公告）日：1997-04-22