(E)-(3-{8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl}propyl) dihydrogen phosphate | 261705-79-7

• 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: (E)-(3-{8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl}propyl) dihydrogen phosphate
• 英文别名: 3-(3-O-phosphatylpropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine；phosphoric acid mono-(3-(8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl)propyl) ester；MSX-3；MSX-3 free acid；3-[8-[(E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-2,6-dioxo-1-prop-2-ynylpurin-3-yl]propyl dihydrogen phosphate
• CAS: 261705-79-7
• 化学式: C₂₁H₂₃N₄O₇P
• 分子量: 474.41
• InChiKey: DUCGTTGSVYZHJS-MDZDMXLPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  134
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  在 叔丁基过氧化氢 、 三氟乙酸 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 2.5h， 生成 (E)-(3-{8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl}propyl) dihydrogen phosphate
  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

• Multigram-Scale Syntheses, Stability, and Photoreactions of A_2A Adenosine Receptor Antagonists with 8-Styrylxanthine Structure:  Potential Drugs for Parkinson's Disease
  作者：Jörg Hockemeyer、Joachim C. Burbiel、Christa E. Müller

  DOI：10.1021/jo0358574

  日期：2004.5.1

  configuration exhibited a considerably lower A2A adenosine receptor affinity than their parent compounds. The dimerization product of MSX-2 was a moderately potent nonselective A1 and A2A antagonist (Ki(A1) = 273 nM, Ki (A2A) = 175 nM) while the dimer of the related compound KW-6002 was inactive at A1 and only weakly active at A2A adenosine receptors (Ki = 1.57 μM). The light sensitivity of 8-styrylxanthine

  描述了重要的8-苯乙烯基黄嘌呤A 2A腺苷受体拮抗剂MSX-2 （8），其水溶性前药MXS-3（9）和KW-6002（16）的改进的克级合成。优化了尿嘧啶衍生物不同位置的N-烷基化反应。研究了从6-氨基-5-肉桂酰基氨基尿嘧啶前体形成黄嘌呤的两种不同方法：（a）通过碱催化消除水和（b）六甲基二硅氮烷作为缩合剂；后者被认为是优越的。研究了8-苯乙烯黄嘌呤的光敏性。（E）构型的苯乙烯基黄嘌呤MSX-2（8）在稀释溶液中异构化，得到的（Z分离并表征）-异构体（10a）。此外，我们首次描述了固态8-苯乙烯黄嘌呤在暴露于日光或用紫外线照射时可二聚。得到的具有头尾（syn）构型的环丁烷衍生物显示出比其母体化合物低得多的A 2A腺苷受体亲和力。MSX-2的二聚产物是中等强度的非选择性A 1和A 2A拮抗剂（K i（A 1）= 273 nM，K i（A 2A）= 175 nM），而相关化合物KW-6002的二聚体为在A