9-(3-bromophenyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9-tetrahydropyrimido[1,2-f] purine-2,4(1H,3H)-dione

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 9-(3-bromophenyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9-tetrahydropyrimido[1,2-f] purine-2,4(1H,3H)-dione
• 英文别名: 9-(3-bromophenyl)-1-methyl-3-prop-2-ynyl-7,8-dihydro-6H-purino[7,8-a]pyrimidine-2,4-dione
• 化学式: C₁₈H₁₆BrN₅O₂
• 分子量: 414.261
• InChiKey: QCNBBPGRAQMBJB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  61.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  8-溴-3-甲基-3,7-二氢-嘌呤-2,6-二酮 在 potassium carbonate 、 三乙胺 作用下， 以 乙二醇二甲醚 、 N,N-二甲基甲酰胺 为溶剂， 20.0~90.0 ℃ 、1.0 MPa 条件下， 反应 1.0h， 生成 9-(3-bromophenyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9-tetrahydropyrimido[1,2-f] purine-2,4(1H,3H)-dione
  参考文献：
  名称：

  1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases

  摘要：

  Adenosine receptors and monoamine oxidases are drug targets for neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In the present study we prepared a library of 55 mostly novel tetrahydropyrimido[2,1-f]purinediones with various substituents in the 1- and 3-position (1,3-dimethyl, 1,3-diethyl, 1,3-dipropyl, 1-methyl-3-propargyl) and broad variation in the 9-position. A synthetic strategy to obtain 3-propargyl-substituted tetrahydropyrimido[2,1-f]purinedione derivatives was developed. The new compounds were evaluated for their interaction with all four adenosine receptor subtypes and for their ability to inhibit monoamine oxidases (MAO). Introduction of mono-or di-chloro-substituted phenyl, benzyl or phenethyl residues at N9 of the 1,3-dimethyl series led to the discovery of a novel class of potent MAO-B inhibitors, the most potent compound being 9-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione (21g, IC50 human MAO-B: 0.0629 mu M), which displayed high selectivity versus the other investigated targets. Potent dually active A(1)/A(2A) adenosine receptor antagonists were identified, for example, 9-benzyl-1-methyl-3-propargyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)dione (19f, K-i, human receptors, A(1): 0.249 mu M, A(2A): 0.253 mu M). Several compounds showed triple-target inhibition, the best compound being 9-(2-methoxybenzyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9-tetrahydro pyrimido [1,2-f]purine-2,4(1H,3H)-dione (19g, K-i A(1): 0.605 mu M, K-i A(2A): 0.417 mu M, IC50 MAO-B: 1.80 mu M). Compounds inhibiting several different targets involved in neurodegeneration may exhibit additive or even synergistic effects in vivo. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.09.044

文献信息

• 1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases
  作者：Pierre Koch、Rhalid Akkari、Andreas Brunschweiger、Thomas Borrmann、Miriam Schlenk、Petra Küppers、Meryem Köse、Hamid Radjainia、Jörg Hockemeyer、Anna Drabczyńska、Katarzyna Kieć-Kononowicz、Christa E. Müller

  DOI：10.1016/j.bmc.2013.09.044

  日期：2013.12

  Adenosine receptors and monoamine oxidases are drug targets for neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In the present study we prepared a library of 55 mostly novel tetrahydropyrimido[2,1-f]purinediones with various substituents in the 1- and 3-position (1,3-dimethyl, 1,3-diethyl, 1,3-dipropyl, 1-methyl-3-propargyl) and broad variation in the 9-position. A synthetic strategy to obtain 3-propargyl-substituted tetrahydropyrimido[2,1-f]purinedione derivatives was developed. The new compounds were evaluated for their interaction with all four adenosine receptor subtypes and for their ability to inhibit monoamine oxidases (MAO). Introduction of mono-or di-chloro-substituted phenyl, benzyl or phenethyl residues at N9 of the 1,3-dimethyl series led to the discovery of a novel class of potent MAO-B inhibitors, the most potent compound being 9-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione (21g, IC50 human MAO-B: 0.0629 mu M), which displayed high selectivity versus the other investigated targets. Potent dually active A(1)/A(2A) adenosine receptor antagonists were identified, for example, 9-benzyl-1-methyl-3-propargyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)dione (19f, K-i, human receptors, A(1): 0.249 mu M, A(2A): 0.253 mu M). Several compounds showed triple-target inhibition, the best compound being 9-(2-methoxybenzyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9-tetrahydro pyrimido [1,2-f]purine-2,4(1H,3H)-dione (19g, K-i A(1): 0.605 mu M, K-i A(2A): 0.417 mu M, IC50 MAO-B: 1.80 mu M). Compounds inhibiting several different targets involved in neurodegeneration may exhibit additive or even synergistic effects in vivo. (C) 2013 Elsevier Ltd. All rights reserved.