8-[2-(3-Hydroxy-phenyl)-vinyl]-3,7-dimethyl-1-prop-2-ynyl-3,7-dihydro-purine-2,6-dione | 261705-77-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 8-[2-(3-Hydroxy-phenyl)-vinyl]-3,7-dimethyl-1-prop-2-ynyl-3,7-dihydro-purine-2,6-dione
• 英文别名: 8-[(E)-2-(3-hydroxyphenyl)ethenyl]-3,7-dimethyl-1-prop-2-ynylpurine-2,6-dione
• CAS: 261705-77-5
• 化学式: C₁₈H₁₆N₄O₃
• 分子量: 336.35
• InChiKey: FJDBEAWFOVMSSI-CMDGGOBGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  78.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-[2-(3-Hydroxy-phenyl)-vinyl]-3,7-dimethyl-1-prop-2-ynyl-3,7-dihydro-purine-2,6-dione 在 四氮唑 、 叔丁基过氧化氢 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 15.0h， 生成 3,7-dimethyl-8-(m-O-phosphatylstyryl)-1-propargylxanthine
  参考文献：
  名称：

  Water-Soluble Phosphate Prodrugs of 1-Propargyl-8-styrylxanthine Derivatives, A_2A-Selective Adenosine Receptor Antagonists

  摘要：

  Water-soluble prodrugs of potent, A(2A)-selective adenosine receptor (AR) antagonists were prepared. 8-(m-Bromostyryl)-3,7-dimethyl-1-propargylxanthine (BS-DMPX, 11) and the analogous 8-(m-methoxystyryl)xanthine derivative (MS-DMPX, 5b) were used as starting points. It was found that polar functional groups suitable for the attachment of a prodrug moiety were tolerated on the styryl ring and even better on the 3-substituent. 8-(m-Hydroxystyryl)-DMPX (7) and 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-1-propargylxanthine (5e, MSX-2) were the most potent and A(2A)-selective compounds and were selected for prodrug formation. For the preparation of 5e a new ring-closure method was applied. Treatment of 6-amino-1-(3-hydroxypropyl)-5-(m-methoxycinnamoylamino) with hexamethyldisilazane at high temperature resulted in higher yields of the target xanthine than the standard ring-closure procedure using sodium hydroxide. Phosphate prodrugs were prepared by classical phosphorylation using phosphorus oxychloride and alternatively by using a phosphoramidite method. Phosphates of the aliphatic alcohol 5e could be obtained by both methods in similar yields. The phenolic compound 7, however, could be phosphorylated only by using the phosphoramidite method. The disodium salts of the phosphate prodrugs exhibited high water solubility (8-(m-methoxystyryl)-7-methyl-3-[3-O-phosphatylpropyl]-1-propargylxanthine disodium salt, 9b: 17 mM, 9 mg/mL). Prodrug 9b was found to be stable in aqueous solution (pH 7) but readily cleaved by phosphatases to liberate 5e (MSX-2). Compound 5e showed high affinity for rat A(2A) AR (K-i = 8 nM), human recombinant A(2A) AR (K-i = 5 nM), and human native A(2A) AR (K-i = 15 nM) and was highly selective versus rat A(1) AR (110-fold), human recombinant A(2A) AR (500-fold), human A(2B) AR (> 2000-fold), and human A(3) AR (>2000-fold).

  DOI：

  10.1021/jm9911480
• 作为产物：
  描述：

  5,6-diamino-3-prop-2-ynyl-1H,3H-pyrimidine-2,4-dione 在 sodium hydroxide 、 三溴化硼 、 potassium carbonate 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.0h， 生成 8-[2-(3-Hydroxy-phenyl)-vinyl]-3,7-dimethyl-1-prop-2-ynyl-3,7-dihydro-purine-2,6-dione
  参考文献：
  名称：

  Water-Soluble Phosphate Prodrugs of 1-Propargyl-8-styrylxanthine Derivatives, A_2A-Selective Adenosine Receptor Antagonists

  摘要：

  Water-soluble prodrugs of potent, A(2A)-selective adenosine receptor (AR) antagonists were prepared. 8-(m-Bromostyryl)-3,7-dimethyl-1-propargylxanthine (BS-DMPX, 11) and the analogous 8-(m-methoxystyryl)xanthine derivative (MS-DMPX, 5b) were used as starting points. It was found that polar functional groups suitable for the attachment of a prodrug moiety were tolerated on the styryl ring and even better on the 3-substituent. 8-(m-Hydroxystyryl)-DMPX (7) and 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-1-propargylxanthine (5e, MSX-2) were the most potent and A(2A)-selective compounds and were selected for prodrug formation. For the preparation of 5e a new ring-closure method was applied. Treatment of 6-amino-1-(3-hydroxypropyl)-5-(m-methoxycinnamoylamino) with hexamethyldisilazane at high temperature resulted in higher yields of the target xanthine than the standard ring-closure procedure using sodium hydroxide. Phosphate prodrugs were prepared by classical phosphorylation using phosphorus oxychloride and alternatively by using a phosphoramidite method. Phosphates of the aliphatic alcohol 5e could be obtained by both methods in similar yields. The phenolic compound 7, however, could be phosphorylated only by using the phosphoramidite method. The disodium salts of the phosphate prodrugs exhibited high water solubility (8-(m-methoxystyryl)-7-methyl-3-[3-O-phosphatylpropyl]-1-propargylxanthine disodium salt, 9b: 17 mM, 9 mg/mL). Prodrug 9b was found to be stable in aqueous solution (pH 7) but readily cleaved by phosphatases to liberate 5e (MSX-2). Compound 5e showed high affinity for rat A(2A) AR (K-i = 8 nM), human recombinant A(2A) AR (K-i = 5 nM), and human native A(2A) AR (K-i = 15 nM) and was highly selective versus rat A(1) AR (110-fold), human recombinant A(2A) AR (500-fold), human A(2B) AR (> 2000-fold), and human A(3) AR (>2000-fold).

  DOI：

  10.1021/jm9911480

文献信息

• Water-Soluble Phosphate Prodrugs of 1-Propargyl-8-styrylxanthine Derivatives, A_2A-Selective Adenosine Receptor Antagonists
  作者：Roland Sauer、Juris Maurinsh、Ulrike Reith、Friederike Fülle、Karl-Norbert Klotz、Christa E. Müller

  DOI：10.1021/jm9911480

  日期：2000.2.1

  Water-soluble prodrugs of potent, A(2A)-selective adenosine receptor (AR) antagonists were prepared. 8-(m-Bromostyryl)-3,7-dimethyl-1-propargylxanthine (BS-DMPX, 11) and the analogous 8-(m-methoxystyryl)xanthine derivative (MS-DMPX, 5b) were used as starting points. It was found that polar functional groups suitable for the attachment of a prodrug moiety were tolerated on the styryl ring and even better on the 3-substituent. 8-(m-Hydroxystyryl)-DMPX (7) and 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-1-propargylxanthine (5e, MSX-2) were the most potent and A(2A)-selective compounds and were selected for prodrug formation. For the preparation of 5e a new ring-closure method was applied. Treatment of 6-amino-1-(3-hydroxypropyl)-5-(m-methoxycinnamoylamino) with hexamethyldisilazane at high temperature resulted in higher yields of the target xanthine than the standard ring-closure procedure using sodium hydroxide. Phosphate prodrugs were prepared by classical phosphorylation using phosphorus oxychloride and alternatively by using a phosphoramidite method. Phosphates of the aliphatic alcohol 5e could be obtained by both methods in similar yields. The phenolic compound 7, however, could be phosphorylated only by using the phosphoramidite method. The disodium salts of the phosphate prodrugs exhibited high water solubility (8-(m-methoxystyryl)-7-methyl-3-[3-O-phosphatylpropyl]-1-propargylxanthine disodium salt, 9b: 17 mM, 9 mg/mL). Prodrug 9b was found to be stable in aqueous solution (pH 7) but readily cleaved by phosphatases to liberate 5e (MSX-2). Compound 5e showed high affinity for rat A(2A) AR (K-i = 8 nM), human recombinant A(2A) AR (K-i = 5 nM), and human native A(2A) AR (K-i = 15 nM) and was highly selective versus rat A(1) AR (110-fold), human recombinant A(2A) AR (500-fold), human A(2B) AR (> 2000-fold), and human A(3) AR (>2000-fold).