N-{[5-(2-(4-benzylpiperidin-1-yl)ethoxy)-1-methyl-1H-indol-2-yl]methyl}-N-methylprop-2-yn-1-amine | 1334106-29-4

• 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: N-{[5-(2-(4-benzylpiperidin-1-yl)ethoxy)-1-methyl-1H-indol-2-yl]methyl}-N-methylprop-2-yn-1-amine
• 英文别名: N-[[5-[2-(4-benzylpiperidin-1-yl)ethoxy]-1-methylindol-2-yl]methyl]-N-methylprop-2-yn-1-amine
• CAS: 1334106-29-4
• 化学式: C₂₈H₃₅N₃O
• 分子量: 429.605
• InChiKey: DPUKGNVEMIXJJV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  20.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-{[5-(2-(4-benzylpiperidin-1-yl)ethoxy)-1-methyl-1H-indol-2-yl]methyl}-N-methylprop-2-yn-1-amine 在 盐酸 作用下， 以 乙醚 为溶剂， 生成 N-{(5-[2-(4-benzylpiperidin-1-yl)ethoxy]-1-methyl-1H-indol-2-yl)methyl}-N-methylprop-2-yn-1-amine dihydrochloride
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Molecular Modeling of Donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine Hybrids as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimer’s Disease

  摘要：

  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 (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50 = 5.2 +/- 1.1 nM) and MAO-B (IC50 = 43 +/- 8.0 nM) and is a moderately potent inhibitor of AChE (IC50 = 0.35 +/- 0.01 mu M) and BuChE (IC50 = 0.46 +/- 0.06 mu M). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on A beta aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.

  DOI：

  10.1021/jm200853t
• 作为产物：
  描述：

  1-甲基-2-[(甲基-丙-2-炔基氨基)甲基]吲哚-5-醇 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 、 丁酮 为溶剂， 反应 6.0h， 生成 N-{[5-(2-(4-benzylpiperidin-1-yl)ethoxy)-1-methyl-1H-indol-2-yl]methyl}-N-methylprop-2-yn-1-amine
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Molecular Modeling of Donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine Hybrids as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimer’s Disease

  摘要：

  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 (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50 = 5.2 +/- 1.1 nM) and MAO-B (IC50 = 43 +/- 8.0 nM) and is a moderately potent inhibitor of AChE (IC50 = 0.35 +/- 0.01 mu M) and BuChE (IC50 = 0.46 +/- 0.06 mu M). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on A beta aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.

  DOI：

  10.1021/jm200853t

文献信息

• NEW DERIVATIVES OF PROPARGYLAMINE HAVING NEUROPROTECTIVE CAPACITY FOR THE TREATMENT OF ALZHEIMER'S AND PARKINSON'S DISEASES
  申请人：Samadi Abdelouahid

  公开号：US20130012522A1

  公开（公告）日：2013-01-10

  The present invention relates to a compound of formula (I) wherein: R 1 and R 2 are selected from among H and C1-C10 alkyl; R 3 is selected from among H, —OR 4 , N, —CN, —C(O)R 4 , —C(O)OR 4 , —C(O)N 4 R 5 , —C═NR 4 , —OC(O)R 4 , —NR 4 R 5 , —NR 4 C(O)R 5 , —NO 2 , —N═CR 4 R 5 , halogen and C1-C10 alkyl, wherein R 4 and R 5 are selected from among H, alkyl, alkenyl, cycloalkyl and aryl; X, Y, Z 1 , Z 2 and Z 3 are selected independently from among CH and N; A is selected from among (CH 2 ) n , NH, O and CO, wherein n is an integer between 1 and 6, to the procedure for the obtainment of said compounds, to a pharmaceutical composition comprising said compound, and to the use thereof in the treatment of a neurodegenerative disease, more particularly treatment of Alzheimer's or Parkinson's disease.

  本发明涉及一种化合物，其化学式为（I），其中：R1和R2从H和C1-C10烷基中选择；R3从H，—OR4，N，—CN，—C（O）R4，—C（O）OR4，—C（O）N4R5，—C═NR4，—OC（O）R4，—NR4R5，—NR4C（O）R5，—NO2，—N═CR4R5，卤素和C1-C10烷基中选择，其中R4和R5从H，烷基，烯基，环烷基和芳基中选择；X、Y、Z1、Z2和Z3分别从CH和N中选择；A从（CH2）n，NH，O和CO中选择，其中n是1到6之间的整数；本发明还涉及所述化合物的制备方法，包括所述化合物的制药组合物，并用于治疗神经退行性疾病，特别是治疗阿尔茨海默病或帕金森病。
• US8999994B2
  申请人：——

  公开号：US8999994B2

  公开（公告）日：2015-04-07
• [EN] NEW DERIVATIVES OF PROPARGYLAMINE HAVING NEUROPROTECTIVE CAPACITY FOR THE TREATMENT OF ALZHEIMER'S AND PARKINSON'S DISEASES<br/>[ES] NUEVOS DERIVADOS DE PROPARGILAMINA CON CAPACIDAD NEUROPROTECTORA PARA EL TRATAMIENTO DE LAS ENFERMEDADES DE ALZHEIMER Y PARKINSON<br/>[FR] NOUVEAUX DÉRIVÉS DE PROPARGYLAMINE À POUVOIR NEUROPROTECTEUR POUR LE TRAITEMENT DES MALADIES D'ALZHEIMER ET DE PARKINSON
  申请人：CONSEJO SUPERIOR INVESTIGACION

  公开号：WO2011113988A1

  公开（公告）日：2011-09-22

  La presente invención se refiere a un compuesto de fórmula (I) donde: - R1 y R2 se seleccionan entre H y alquilo C1-C10, - R3 se selecciona entre H, -OR4, N, -CN, -C(0)R4, -C(0)OR4, -- C(0)NR4R5, -C=NR4, -OC(0)R4, -NR4R5, -NR4C(0)R5, -N02, -N=CR4R5, halógeno y alquilo C1-C10, - donde R4 y R5 se seleccionan entre H, alquilo, alquenilo, cicloalquilo y arilo, - X, Y, Z1, Z2 y Z3 se seleccionan independientemente entre CH y N, - A se selecciona entre (CH2)n, NH, O y CO, donde n es un número entero de 1 a 6, al procedimiento de obtención de dichos compuestos, a una composición farmacéutica que comprende dicho compuesto, y al uso de los mismos en el tratamiento de una enfermedad neurodegenerativa, más especialmente, tratamiento de Alzheimer o Parkinson.
• Synthesis, Biological Evaluation, and Molecular Modeling of Donepezil and <i>N</i>-[(5-(Benzyloxy)-1-methyl-1<i>H</i>-indol-2-yl)methyl]-<i>N</i>-methylprop-2-yn-1-amine Hybrids as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimer’s Disease
  作者：Irene Bolea、Jordi Juárez-Jiménez、Cristóbal de los Rı́os、Mourad Chioua、Ramón Pouplana、F. Javier Luque、Mercedes Unzeta、José Marco-Contelles、Abdelouahid Samadi

  DOI：10.1021/jm200853t

  日期：2011.12.22

  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 (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50 = 5.2 +/- 1.1 nM) and MAO-B (IC50 = 43 +/- 8.0 nM) and is a moderately potent inhibitor of AChE (IC50 = 0.35 +/- 0.01 mu M) and BuChE (IC50 = 0.46 +/- 0.06 mu M). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on A beta aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.