8-(m-methoxystyryl)-3-methyl-1-propargylxanthine | 261705-87-7

• 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: 8-(m-methoxystyryl)-3-methyl-1-propargylxanthine
• 英文别名: 8-[(E)-2-(3-methoxyphenyl)ethenyl]-3-methyl-1-prop-2-ynyl-7H-purine-2,6-dione
• CAS: 261705-87-7
• 化学式: C₁₈H₁₆N₄O₃
• 分子量: 336.35
• InChiKey: WLJZXLCGIUWADD-CMDGGOBGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  78.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-(m-methoxystyryl)-3-methyl-1-propargylxanthine 在 三溴化硼 、 potassium carbonate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 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
• 作为产物：
  描述：

  5,6-diamino-3-prop-2-ynyl-1H,3H-pyrimidine-2,4-dione 在 sodium hydroxide 、 potassium carbonate 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 生成 8-(m-methoxystyryl)-3-methyl-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

文献信息

• METHODS AND COMPOSITIONS FOR IMPROVING IMMUNE RESPONSES
  申请人：NorthEastern University

  公开号：EP2111231A2

  公开（公告）日：2009-10-28
• [EN] METHODS AND COMPOSITIONS FOR IMPROVING IMMUNE RESPONSES<br/>[FR] PROCÉDÉS ET COMPOSITIONS POUR AMÉLIORER LES RÉPONSES IMMUNITAIRES
  申请人：UNIV NORTHEASTERN

  公开号：WO2008147482A2

  公开（公告）日：2008-12-04

  (EN) The present invention relates to compositions and methods for enhancing an immune response, for example to a vaccine, by combining the administration of oxygen (O2 gas), an adenosine pathway antagonist and/or an HIF- lα antagonist, and/or inhibitors of enzymes that produce or generate adenosine with the administration of the vaccine to the patient. The present invention also relates to methods of inducing or enhancing immune responses, methods of treating subjects having a tumor, methods of ablating or killing tumor cells and methods of disrupting the blood supply to a tumor, comprising administering oxygen alone or in combination with therapeutic agents that prevent inhibition of anti-tumor T cells. Tumor defense-resistant immune cells, anti-viral immune cells, and methods of their production are also disclosed.(FR) La présente invention concerne des compositions et procédés pour amplifier une réponse immunitaire, par exemple à un vaccin, en combinant l'administration d'oxygène (gaz O2), un antagoniste des voies de l'adénosine et/ou antagoniste de HIF-1a et/ou des inhibiteurs d'enzymes qui produisent ou génèrent de l'adénosine avec l'administration du vaccin au patient. La présente invention concerne également des procédés pour induire ou amplifier des réponses immunitaires, des procédés de traitement de sujets ayant une tumeur, des procédés pour pratiquer une ablation de cellules tumorales ou tuer celles-ci et des procédés pour interrompre l'alimentation en sang d'une tumeur, comprenant l'administration d'oxygène seul ou en combinaison avec des agents thérapeutiques qui empêchent l'inhibition de lymphocytes T antitumoraux. Des cellules immunitaires résistant à la défense tumorale, des cellules immunitaires antivirales et des procédés pour leur production sont également révélés.