ethyl {4-[({[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]amino}carbonyl)amino]piperidin-1-yl}acetate | 1376982-75-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl {4-[({[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]amino}carbonyl)amino]piperidin-1-yl}acetate
• 英文别名: Ethyl 2-[4-[[4-(furan-2-yl)-11-methyl-3,5,6,8,10,11-hexazatricyclo[7.3.0.02,6]dodeca-1(12),2,4,7,9-pentaen-7-yl]carbamoylamino]piperidin-1-yl]acetate
• CAS: 1376982-75-0
• 化学式: C₂₁H₂₅N₉O₄
• 分子量: 467.487
• InChiKey: HOZPVJIARMMPMI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  145
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4-[({[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]amino}carbonyl)amino]piperidine-1-carbonyl chloride 在 potassium carbonate 、 三氟乙酸 作用下， 以 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 4.0h， 生成 ethyl {4-[({[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]amino}carbonyl)amino]piperidin-1-yl}acetate
  参考文献：
  名称：

  Water-Soluble Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines as Human A₃ Adenosine Receptor Antagonists

  摘要：

  A relevant problem of the pyrazolo[4,3-e]-[1,2,4]triazolo[1,5-c]pyrimidine nucleus, an attractive scaffold for the preparation of adenosine receptor antagonists, is the low water solubility. We originally functionalized the C-5 position with a salifiable 4-pyridylcarbamoyl moiety that conferred good water solubility at low pH (<4.0) but poor solubility at physiologic pH, indicative of the dissociation of the pyridinium species. Here we replaced the pyridin-4-yl moiety with a 1-(substituted)piperidin-4-yl ring to exploit the higher basicity of this nucleus and for the the possibility to generate stable, water-soluble salts. The hydrochloride salt of the 1-(cyclohexylmethyl)piperidin-4-yl derivative (10, K-i(hA(3)) = 9.7 nM, IC50(hA(3)) = 30 nM, K-i(hA(1)/hA(3)) = 351, K-i(hA(2A)/hA(3)) > 515, IC50(HA(2B)) > 5 mu M) showed a solubility of 8 mg/mL at physiological pH and gave a stable aqueous system suitable for, intravenous infusion. Molecular modeling studies were helpful in rationalizing the available structure-activity relationships and the selectivity profile of the new ligands.

  DOI：

  10.1021/jm300323t

文献信息

• Water-Soluble Pyrazolo[4,3-<i>e</i>][1,2,4]triazolo[1,5-<i>c</i>]pyrimidines as Human A₃ Adenosine Receptor Antagonists
  作者：Pier Giovanni Baraldi、Giulia Saponaro、Romeo Romagnoli、Mojgan Aghazadeh Tabrizi、Stefania Baraldi、Allan R. Moorman、Sandro Cosconati、Salvatore Di Maro、Luciana Marinelli、Stefania Gessi、Stefania Merighi、Katia Varani、Pier Andrea Borea、Delia Preti

  DOI：10.1021/jm300323t

  日期：2012.6.14

  A relevant problem of the pyrazolo[4,3-e]-[1,2,4]triazolo[1,5-c]pyrimidine nucleus, an attractive scaffold for the preparation of adenosine receptor antagonists, is the low water solubility. We originally functionalized the C-5 position with a salifiable 4-pyridylcarbamoyl moiety that conferred good water solubility at low pH (<4.0) but poor solubility at physiologic pH, indicative of the dissociation of the pyridinium species. Here we replaced the pyridin-4-yl moiety with a 1-(substituted)piperidin-4-yl ring to exploit the higher basicity of this nucleus and for the the possibility to generate stable, water-soluble salts. The hydrochloride salt of the 1-(cyclohexylmethyl)piperidin-4-yl derivative (10, K-i(hA(3)) = 9.7 nM, IC50(hA(3)) = 30 nM, K-i(hA(1)/hA(3)) = 351, K-i(hA(2A)/hA(3)) > 515, IC50(HA(2B)) > 5 mu M) showed a solubility of 8 mg/mL at physiological pH and gave a stable aqueous system suitable for, intravenous infusion. Molecular modeling studies were helpful in rationalizing the available structure-activity relationships and the selectivity profile of the new ligands.