1-甲基-2-[(甲基-丙-2-炔基氨基)甲基]吲哚-5-醇 | 130081-94-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: 1-甲基-2-[(甲基-丙-2-炔基氨基)甲基]吲哚-5-醇
• 英文名称: 5-hydroxy-N-[(1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine
• 英文别名: 1-methyl-2-{[methyl(prop-2-yn-1-yl)-amino]methyl}-1H-indol-5-ol；1-methyl-2-((methyl(prop-2-yn-1-yl)amino)methyl)-1H-indol-5-ol；1-methyl-2-{[methyl(prop-2-yn-1-yl)amino]methyl}-1H-indol-5-ol；N-Methyl-N-(2-propynyl)-2-(5-hydroxy-1-methylindolyl)methylamine；1-methyl-2-[[methyl(prop-2-ynyl)amino]methyl]indol-5-ol
• CAS: 130081-94-6
• 化学式: C₁₄H₁₆N₂O
• 分子量: 228.294
• InChiKey: HFMZYVHURLNZFT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  28.4
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  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
• 作为产物：
  描述：

  5-benzyloxy-1-methyl-2-(methylaminomethyl)indole 在 palladium on activated charcoal 氢气 、 溶剂黄146 、 叔丁胺 作用下， 以 四氢呋喃 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 5.0h， 生成 1-甲基-2-[(甲基-丙-2-炔基氨基)甲基]吲哚-5-醇
  参考文献：
  名称：

  Acetylenic and allenic derivatives of 2-(5-benzyloxyindolyl) and 2-(5-hydroxyindolyl)methylamines: synthesis and in vitro evaluation as monoamine oxidase inhibitors

  摘要：

  We report the synthesis and in vitro studies as MAO inhibitors of 2 series of new acetylenic and allenic derivatives of 2-(5-benzyloxyindolyl)- and 2-(5-hydroxyindolyl)methylamines and their indolylmethylamine precursors. All compounds were MAO inhibitors and either did not show selectivity (the benzyloxy compounds 5) or were selective for MAO-A (most of the hydroxy compounds 7). Three of the studied compounds, 7d, 7g and 7i, were found to be slightly more selective for MAO-A than clorgyline.

  DOI：

  10.1016/0223-5234(91)90210-e

文献信息

• Multitarget‐Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H ₃ R Antagonism for Neurodegenerative Diseases
  作者：Óscar M. Bautista‐Aguilera、Stefanie Hagenow、Alejandra Palomino‐Antolin、Víctor Farré‐Alins、Lhassane Ismaili、Pierre‐Louis Joffrin、María L. Jimeno、Ondřej Soukup、Jana Janočková、Lena Kalinowsky、Ewgenij Proschak、Isabel Iriepa、Ignacio Moraleda、Johannes S. Schwed、Alejandro Romero Martínez、Francisco López‐Muñoz、Mourad Chioua、Javier Egea、Rona R. Ramsay、José Marco‐Contelles、Holger Stark

  DOI：10.1002/anie.201706072

  日期：2017.10.2

  of multitarget‐directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small‐molecule hits demonstrated balanced activities at the targets, mostly in

  复杂的神经退行性疾病的治疗需要开发多靶标定向药物（MTD）。通过掺入普遍接受的H3R药效基团来优化神经保护剂ASS234，可获得对乙酰基/丁酰胆碱酯酶和单胺氧化酶A / B以及组胺H 3受体（H3R）具有抑制活性的新型吲哚衍生物。这些小分子命中物显示了在靶标上的平衡活性，主要是在纳摩尔浓度范围内。其他体外研究显示抗氧化神经保护作用以及穿透血脑屏障的能力。有了这种有前途的体外研究，辅助剂（1 mg kg -1 ip）可以显着改善脂多糖引起的认知功能障碍。
• 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。
• Derivatives of propargylamine having neuroprotective capacity for the treatment of Alzheimer's and Parkinson's diseases
  申请人：Samadi Abdelouahid

  公开号：US08999994B2

  公开（公告）日：2015-04-07

  The present invention relates to a compound of formula (I): wherein: R1 and R2 are selected from among H and C1-C10 alkyl; R3 is selected from among H, —OR4, N, —CN, —C(O)R4, —C(O)OR4, —C(O)NR4R5, —C═NR4, —OC(O)R4, —NR4R5, —NR4C(O)R5, —NO2, —N═CR4R5, halogen and C1-C10 alkyl, wherein R4 and R5 are selected from among H, alkyl, alkenyl, cycloalkyl and aryl; X, Y, Z1, Z2 and Z3 are selected independently from among CH and N; A is selected from among (CH2)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）NR4R5，—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从CH和N中独立选择；A从（CH2）n、NH、O和CO中选择，其中n为1到6之间的整数，本发明还涉及获得所述化合物的方法，包括该化合物的制药组合物，以及在治疗神经退行性疾病中的使用，更具体地是治疗阿尔茨海默病或帕金森病。
• <i>N</i>-Methyl-<i>N</i>-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1<i>H</i>-indol-2-yl)methyl)prop-2-yn-1-amine, a New Cholinesterase and Monoamine Oxidase Dual Inhibitor
  作者：Oscar M. Bautista-Aguilera、Abdelouahid Samadi、Mourad Chioua、Katarina Nikolic、Slavica Filipic、Danica Agbaba、Elena Soriano、Lucía de Andrés、María Isabel Rodríguez-Franco、Stefano Alcaro、Rona R. Ramsay、Francesco Ortuso、Matilde Yañez、José Marco-Contelles

  DOI：10.1021/jm501501a

  日期：2014.12.26

  On the basis of N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (II, ASS234) and QSAR predictions, in this work we have designed, synthesized, and evaluated a number of new indole derivatives from which we have identified N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine (2, MBA236) as a new cholinesterase and monoamine oxidase dual inhibitor.
• Contilisant, a Tetratarget Small Molecule for Alzheimer’s Disease Therapy Combining Cholinesterase, Monoamine Oxidase Inhibition, and H3R Antagonism with S1R Agonism Profile
  作者：Óscar M. Bautista-Aguilera、Josiane Budni、Francielle Mina、Eduarda Behenck Medeiros、Winnie Deuther-Conrad、José M. Entrena、Ignacio Moraleda、Isabel Iriepa、Francisco López-Muñoz、José Marco-Contelles

  DOI：10.1021/acs.jmedchem.8b00848

  日期：2018.8.9

  Contilisant, a permeable, antioxidant, and neuroprotectant agent, showing high nM affinity at H3R and excellent inhibition of the monoamine oxidases and cholinesterases, is an affine and selective SIR agonist in the nanomolar range, based on the binding affinity and functional experiment, a result confirmed by molecular modeling. In addition, contilisant significantly restores the cognitive deficit induced by A beta(1-42) in the radial maze assay in an in vivo Alzheimer's disease test, comparing very favorably with donepezil.