[3H]-MSX 2 | 261717-18-4

• 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: [3H]-MSX 2
• 英文别名: MSX 2；[³H](E)-3-(3-hydroxypropyl)-8-(2-(3-methoxyphenyl)vinyl)-7-methyl-1-prop-2-ynyl-3,7-dihydropurine-2,6-dione；(E)-3-(3-hydroxypropyl)-8-(2-(3-methoxyphenyl)vinyl)-7-methyl-1-prop-2-ynyl-3,7-dihydropurine-2,6-dione；(E)-3-(3-hydroxypropyl)-8-[2-(3-methoxyphenyl)vinyl]-7-methyl-1-prop-2-ynyl-3,7-dihydropurine-2,6-dione；[3H]3-(3-hydroxypropyl)-7-methyl-8-(m-methoxystyryl)-1-propargylxanthine；3-(3-hydroxypropyl)-7-methyl-8-(m-methoxystyryl)-1-propargyl xanthine；3-(3-hydroxypropyl)-8-[(E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-1-prop-2-ynylpurine-2,6-dione
• CAS: 261717-18-4
• 化学式: C₂₁H₂₂N₄O₄
• 分子量: 394.43
• InChiKey: FWLDDFYHEQMIGG-MDZDMXLPSA-N

物化性质

• 溶解度：
  二甲基亚砜：~14 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  87.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [3H]-MSX 2 以 二氯甲烷 为溶剂， 反应 1.5h， 生成 (Z)-3-(3-hydroxypropyl)-8-[2-(3-methoxyphenyl)vinyl]-7-methyl-1-prop-2-ynyl-3,7-dihydropurine-2,6-dione
  参考文献：
  名称：

  具有8-苯乙烯黄嘌呤结构的2A腺苷受体拮抗剂的多克级合成，稳定性和光反应性：帕金森氏病的潜在药物

  摘要：

  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

  DOI：

  10.1021/jo0358574
• 作为产物：
  描述：

  5,6-diamino-3-prop-2-ynyl-1H,3H-pyrimidine-2,4-dione 在 吡啶 、 硫酸氢铵 、 氢氧化钾 、 potassium carbonate 、 六甲基二硅氮烷 作用下， 以 甲醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 61.5h， 生成 [3H]-MSX 2
  参考文献：
  名称：

  具有8-苯乙烯黄嘌呤结构的2A腺苷受体拮抗剂的多克级合成，稳定性和光反应性：帕金森氏病的潜在药物

  摘要：

  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

  DOI：

  10.1021/jo0358574

文献信息

• A2A ADENOSINE RECEPTOR ANTAGONISTS
  申请人：Elzein Elfatih

  公开号：US20070208040A1

  公开（公告）日：2007-09-06

  The present invention relates to novel compounds that are A 2A adenosine receptor antagonists, and to their use in treating mammals for various disease states, such as obesity, CNS disorders, including the “movement disorders” (Parkinson's disease, Huntington's Chorea, and catelepsy), and cerebral ischemia, excitotoxicity, cognitive and physiological disorders, depression, ADHD, and drug addiction (alcohol, amphetamine, cannabinoids, cocaine, nicotine, and opioids) and to their use in the enhancement of immune response. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.

  本发明涉及一种新型化合物，它们是A2A腺苷受体拮抗剂，并且用于治疗哺乳动物的各种疾病状态，如肥胖、中枢神经系统紊乱，包括“运动障碍”（帕金森病、亨廷顿舞蹈症和猫病）、脑缺血、兴奋毒性、认知和生理紊乱、抑郁症、注意力缺陷多动障碍（ADHD）以及药物成瘾（酒精、安非他明、大麻素、可卡因、尼古丁和阿片类药物），以及用于增强免疫应答。该发明还涉及制备这类化合物的方法，以及含有它们的药物组合物。
• Synthesis and Properties of a New Water-Soluble Prodrug of the Adenosine A2A Receptor Antagonist MSX-2
  作者：Karl Vollmann、Ramatullah Qurishi、Jörg Hockemeyer、Christa Müller

  DOI：10.3390/molecules13020348

  日期：——

  The compound L-valine-3-8-[(E)-2-[3-methoxyphenyl)ethenyl]-7-methyl-1-propargylxanthine-3-yl}propyl ester hydrochloride (MSX-4) was synthesized as an aminoacid ester prodrug of the adenosine A2A receptor antagonist MSX-2. It was found to bestable in artificial gastric acid, but readily cleaved by pig liver esterase.

  作为腺苷 A2A 受体拮抗剂 MSX-2 的氨基酸酯原药，合成了化合物 L-缬氨酸-3-8-[(E)-2-[3-甲氧基苯基]乙烯基]-7-甲基-1-丙炔基黄嘌呤-3-基}丙酯盐酸盐（MSX-4）。研究发现，它在人工胃酸中的稳定性最好，但很容易被猪肝酯酶裂解。
• COMPOUNDS FOR THE TREATMENT OF AURICULAR FIBRILLATION
  申请人：Proyecto de Biomedicina Cima, S.L.

  公开号：EP1949903A2

  公开（公告）日：2008-07-30

  Adenosine A2A receptor antagonists are useful for the preparation of medicaments against atrial fibrillation in mammals, including humans. It has been found that the adenosine A2A receptor is present in human atrial cardiomyocytes and participates in the pathological mechanisms underlying atrial fibrillation. An advantage of using A2A antagonists over other agents known in the art is that the A2A antagonists specifically target patients with atrial fibrillation.

  腺苷 A2A 受体拮抗剂可用于制备防治哺乳动物（包括人类）心房颤动的药物。研究发现，腺苷 A2A 受体存在于人类心房心肌细胞中，并参与心房颤动的病理机制。与本领域已知的其他药物相比，使用 A2A 拮抗剂的优势在于 A2A 拮抗剂专门针对心房颤动患者。
• Antagonizing an adenosine A2A receptor to ameliorate one or more components of addictive behavior
  申请人：Diamond F. Ivan

  公开号：US20060128708A1

  公开（公告）日：2006-06-15

  This invention provides a method of mitigating/ameliorating one or more components of addictive behavior associated with chronic consumption of a substance of abuse, or withdrawal therefrom. The method typically involves administering to a subject in need thereof an adenosine A2A receptor antagonist in an amount sufficient to ameliorate said one or more components of addictive behavior.

  本发明提供了一种减轻/改善与长期服用或戒断滥用物质相关的一种或多种成瘾行为的方法。该方法通常包括向有需要的受试者施用腺苷 A2A 受体拮抗剂，其用量足以改善所述一种或多种成瘾行为。
• 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).