1,3-Bis-hydroxymethyl-5-methyl-1H-pyrimidine-2,4-dione | 98609-37-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 1,3-Bis-hydroxymethyl-5-methyl-1H-pyrimidine-2,4-dione
• 英文别名: 1,3-Bis(hydroxymethyl)-5-methylpyrimidine-2,4-dione
• CAS: 98609-37-1
• 化学式: C₇H₁₀N₂O₄
• 分子量: 186.167
• InChiKey: FWCYWMVLJDZGPE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  81.1
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1,3-Bis-hydroxymethyl-5-methyl-1H-pyrimidine-2,4-dione 在 palladium on activated charcoal 4-二甲氨基吡啶 、 氢气 、 N,N'-二环己基碳二亚胺 作用下， 以 乙酸乙酯 为溶剂， 反应 2.0h， 生成 Boc-L-Glu-(thymin-1-yl-methyl ester)-OH
  参考文献：
  名称：

  Pyrimidine and nucleoside γ-esters of l-Glu-Sar: Synthesis, stability and interaction with hPEPT1

  摘要：

  The aim of the present study was to improve the synthetic pathway of bioreversible dipeptide derivatives as well as evaluate the potential of using L-Glu-Sar as a pro-moiety for delivering three newly synthesised nucleoside and pyrimidine L-Glu-Sar derivatives. L-Glu(trans-2-thymine-1-yl-tetrahydrofuran-3-yl ester)-Sar (I), L-Glu(thymine-1-yl-methyl ester)-Sar (II) and L-Glu(acyclothymidine)-Sar (III) were synthesised and in vitro stability was studied in various aqueous and biological media. Affinity to and translocation via hPEPT1 was investigated in mature Caco-2 cell monolayers, grown on permeable supports. Affinity was estimated in a competition assay, using [C-14] labelled Gly-Sar (glycylsarcosine). Translocation was measured as pHi-changes induced by the substrates using the fluorescent probe BCECF and an epifluorescence microscope setup. All dipeptide derivatives released the model drugs quantitatively by specific base-catalysed hydrolysis at pH > 6.0. II was labile in aqueous buffer solution, whereas 1 and III showed appropriate stability for oral administration. In 10% porcine intestinal homogenate, the half-lives of the dipeptide derivatives indicated limited enzyme catalyzed degradation. All compounds showed good affinity to hPEPT1, but the Compounds I and III showed not to be translocated by hPEPT1. The translocation of the L-Glu-Sar derivative of acyclovir, L-Glu(acyclovir)-Sar was also investigated and showed not to take place. Consequently, L-Glu-Sar seems to be a poor pro-moiety for hPEPT1-mediated transport. (c) 2005 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejps.2005.02.007
• 作为产物：
  描述：

  聚合甲醛 、 胸腺嘧啶 生成 1,3-Bis-hydroxymethyl-5-methyl-1H-pyrimidine-2,4-dione
  参考文献：
  名称：

  Pyrimidine and nucleoside γ-esters of l-Glu-Sar: Synthesis, stability and interaction with hPEPT1

  摘要：

  The aim of the present study was to improve the synthetic pathway of bioreversible dipeptide derivatives as well as evaluate the potential of using L-Glu-Sar as a pro-moiety for delivering three newly synthesised nucleoside and pyrimidine L-Glu-Sar derivatives. L-Glu(trans-2-thymine-1-yl-tetrahydrofuran-3-yl ester)-Sar (I), L-Glu(thymine-1-yl-methyl ester)-Sar (II) and L-Glu(acyclothymidine)-Sar (III) were synthesised and in vitro stability was studied in various aqueous and biological media. Affinity to and translocation via hPEPT1 was investigated in mature Caco-2 cell monolayers, grown on permeable supports. Affinity was estimated in a competition assay, using [C-14] labelled Gly-Sar (glycylsarcosine). Translocation was measured as pHi-changes induced by the substrates using the fluorescent probe BCECF and an epifluorescence microscope setup. All dipeptide derivatives released the model drugs quantitatively by specific base-catalysed hydrolysis at pH > 6.0. II was labile in aqueous buffer solution, whereas 1 and III showed appropriate stability for oral administration. In 10% porcine intestinal homogenate, the half-lives of the dipeptide derivatives indicated limited enzyme catalyzed degradation. All compounds showed good affinity to hPEPT1, but the Compounds I and III showed not to be translocated by hPEPT1. The translocation of the L-Glu-Sar derivative of acyclovir, L-Glu(acyclovir)-Sar was also investigated and showed not to take place. Consequently, L-Glu-Sar seems to be a poor pro-moiety for hPEPT1-mediated transport. (c) 2005 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejps.2005.02.007

文献信息

• N-hydroxymethyl Derivatives of Nitrogen Heterocycles as Possible Prodrugs I: N-hydroxymethylation of Uracils
  作者：Padam C. Bansal、Ian H. Pitman、Josiah N.S. Tam、Mathias Mertes、James J. Kaminski

  DOI：10.1002/jps.2600700803

  日期：1981.8

  constants for formation of N-1-hydroxymethyl derivatives were approximately twice those for formation of N-3-hydroxymethyl derivatives, and they were formed more rapidly throughout the pH 3--8 range. Substituents at C-5 of uracil had little effect on the thermodynamics of N-hydroxymethylation. The potential usefulness of N-hydroxymethyl compounds as prodrugs is discussed.

  制备了1，3-二羟甲基尿嘧啶，3-羟甲基-1-甲基尿嘧啶和1-羟甲基-3-甲基尿嘧啶的固体样品，并通过光谱分析确认了它们的结构。还研究了在甲醛水溶液中形成N-羟甲基化尿嘧啶的热力学和动力学。用于形成N-1-羟甲基衍生物的平衡常数大约是用于形成N-3-羟甲基衍生物的平衡常数的两倍，并且它们在整个pH 3--8范围内的形成速度更快。尿嘧啶C-5处的取代基对N-羟甲基化的热力学影响很小。讨论了N-羟甲基化合物作为前药的潜在用途。
• Pyrimidine and nucleoside γ-esters of l-Glu-Sar: Synthesis, stability and interaction with hPEPT1
  作者：André H. Eriksson、Peter L. Elm、Mikael Begtrup、Birger Brodin、Robert Nielsen、Bente Steffansen

  DOI：10.1016/j.ejps.2005.02.007

  日期：2005.5

  The aim of the present study was to improve the synthetic pathway of bioreversible dipeptide derivatives as well as evaluate the potential of using L-Glu-Sar as a pro-moiety for delivering three newly synthesised nucleoside and pyrimidine L-Glu-Sar derivatives. L-Glu(trans-2-thymine-1-yl-tetrahydrofuran-3-yl ester)-Sar (I), L-Glu(thymine-1-yl-methyl ester)-Sar (II) and L-Glu(acyclothymidine)-Sar (III) were synthesised and in vitro stability was studied in various aqueous and biological media. Affinity to and translocation via hPEPT1 was investigated in mature Caco-2 cell monolayers, grown on permeable supports. Affinity was estimated in a competition assay, using [C-14] labelled Gly-Sar (glycylsarcosine). Translocation was measured as pHi-changes induced by the substrates using the fluorescent probe BCECF and an epifluorescence microscope setup. All dipeptide derivatives released the model drugs quantitatively by specific base-catalysed hydrolysis at pH > 6.0. II was labile in aqueous buffer solution, whereas 1 and III showed appropriate stability for oral administration. In 10% porcine intestinal homogenate, the half-lives of the dipeptide derivatives indicated limited enzyme catalyzed degradation. All compounds showed good affinity to hPEPT1, but the Compounds I and III showed not to be translocated by hPEPT1. The translocation of the L-Glu-Sar derivative of acyclovir, L-Glu(acyclovir)-Sar was also investigated and showed not to take place. Consequently, L-Glu-Sar seems to be a poor pro-moiety for hPEPT1-mediated transport. (c) 2005 Elsevier B.V. All rights reserved.