N-[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]-N'-piperidin-4-ylurea | 1376982-30-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三唑并嘧啶类
• 英文名称: N-[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]-N'-piperidin-4-ylurea
• 英文别名: 1-[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]-3-piperidin-4-ylurea
• CAS: 1376982-30-7
• 化学式: C₁₇H₁₉N₉O₂
• 分子量: 381.397
• InChiKey: QLHXAPRRXSENQQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  127
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]-N'-piperidin-4-ylurea 、 alkaline earth salt of/the/ methylsulfuric acid 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以50%的产率得到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
• 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 三氟乙酸 作用下， 以 水 、 乙腈 为溶剂， 反应 2.0h， 以91%的产率得到N-[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]-N'-piperidin-4-ylurea
  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.