8-cyclopentyl-1-propyl-7-pivaloyloxymethylxanthine | 200556-95-2

• 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-cyclopentyl-1-propyl-7-pivaloyloxymethylxanthine
• 英文别名: 1-propyl-8-cyclopentyl-7-pivaloyloxymethylxanthine；(8-cyclopentyl-2,6-dioxo-1-propyl-3H-purin-7-yl)methyl 2,2-dimethylpropanoate
• CAS: 200556-95-2
• 化学式: C₁₉H₂₈N₄O₄
• 分子量: 376.456
• InChiKey: UOOSNTOSOBTPDR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  93.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-cyclopentyl-1-propyl-7-pivaloyloxymethylxanthine 在 sodium hydroxide 作用下， 以 二甲基亚砜 为溶剂， 反应 24.5h， 生成 1-propyl-3-(2-hydroxyethyl)-8-cyclopentyl-7H-purine-2,6-dione
  参考文献：
  名称：

  A₁ Adenosine Receptor Antagonists as Ligands for Positron Emission Tomography (PET) and Single-Photon Emission Tomography (SPET)

  摘要：

  The high affinity of 8-cyclopentyl-1,3-dipropylxanthine (CPX) for the A(1) adenosine receptor (A(1)AR) provides a good lead for developing radioligands suitable for positron emission tomography (PET) and single-photon emission tomography (SPET). This study tested the hypothesis that the kinds of chemical modifications made in the synthesis of CPX analogues containing carbon-ii, fluorine-18, or radioiodine will not alter affinity for the A(1)AR. This report describes the synthesis and radioligand binding assays of unlabeled CPX analogues having methyl, 2-methoxyethyl, 2-fluoropropyl, or 3-fluoropropyl substituents, respectively, at either N-1 (13a-d) or N-3 (8a-d) or an (E)-3-iodoprop-2-en-1-yl substituent at N-3 (8f). Compounds 8d,f and 13b,d antagonized the binding of [H-3]CPX to the A(1)AR of rat brain with affinities similar to those of CPX; compound 8c was twice as potent as CPX. Analogues 8a,b and 13a were less potent than CPX, but for each the K-i of antagonism was greater than or equal to 0.5 nM. Attempts to iodinate the 8-(4-hydroxyphenyl) analogue of CPX failed, probably because the xanthine substituent strongly deactivated the phenol toward electrophilic iodination. In summary, several of the modifications of the propyl groups of CPX needed to produce ligands for imaging by PET and SPET preserve or enhance affinity for the A(1)AR.

  DOI：

  10.1021/jm9705465
• 作为产物：
  描述：

  环戊基甲酰氯 在 palladium on activated charcoal ammonium formate 、 sodium carbonate 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.25h， 生成 8-cyclopentyl-1-propyl-7-pivaloyloxymethylxanthine
  参考文献：
  名称：

  A₁ Adenosine Receptor Antagonists as Ligands for Positron Emission Tomography (PET) and Single-Photon Emission Tomography (SPET)

  摘要：

  The high affinity of 8-cyclopentyl-1,3-dipropylxanthine (CPX) for the A(1) adenosine receptor (A(1)AR) provides a good lead for developing radioligands suitable for positron emission tomography (PET) and single-photon emission tomography (SPET). This study tested the hypothesis that the kinds of chemical modifications made in the synthesis of CPX analogues containing carbon-ii, fluorine-18, or radioiodine will not alter affinity for the A(1)AR. This report describes the synthesis and radioligand binding assays of unlabeled CPX analogues having methyl, 2-methoxyethyl, 2-fluoropropyl, or 3-fluoropropyl substituents, respectively, at either N-1 (13a-d) or N-3 (8a-d) or an (E)-3-iodoprop-2-en-1-yl substituent at N-3 (8f). Compounds 8d,f and 13b,d antagonized the binding of [H-3]CPX to the A(1)AR of rat brain with affinities similar to those of CPX; compound 8c was twice as potent as CPX. Analogues 8a,b and 13a were less potent than CPX, but for each the K-i of antagonism was greater than or equal to 0.5 nM. Attempts to iodinate the 8-(4-hydroxyphenyl) analogue of CPX failed, probably because the xanthine substituent strongly deactivated the phenol toward electrophilic iodination. In summary, several of the modifications of the propyl groups of CPX needed to produce ligands for imaging by PET and SPET preserve or enhance affinity for the A(1)AR.

  DOI：

  10.1021/jm9705465

文献信息

• Synthesis and Pharmacological Evaluation of Identified and Putative Metabolites of the A₁ Adenosine Receptor Antagonist 8-Cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX)
  作者：Marcus H. Holschbach、Dirk Bier、Wiebke Sihver、Annette Schulze、Bernd Neumaier

  DOI：10.1002/cmdc.201600592

  日期：2017.5.22

  The A1 adenosine receptor (A1 AR) antagonist [18 F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([18 F]CPFPX), used in imaging human brain A1 ARs by positron emission tomography (PET), is stable in the brain, but rapidly undergoes transformation into one major (3-(3-fluoropropyl)-8-(3-oxocyclopenten-1-yl)-1-propylxanthine, M1) and several minor metabolites in blood. This report describes the synthesis

  A1腺苷受体（A1 AR）拮抗剂[18 F] 8-环戊基-3-（3-氟丙基）-1-丙基黄嘌呤（[18 F] CPFPX），用于通过正电子发射断层扫描（PET）对人脑A1 AR成像，在大脑中是稳定的，但迅速转变为血液中的一种主要的（3-（3-氟丙基）-8-（3-氧代环戊烯-1-基）-1-丙基黄嘌呤，M1）和几种次要的代谢物。该报告描述了CPFPX假定代谢产物的合成，作为鉴定这些代谢产物的标准。（放射）HPLC分析显示，未添加载体的（nca）[18 F] CPFPX孵育的人肝微粒体提取物含有主要代谢物M1，以及与在环戊基部分官能化的衍生物相对应的放射性代谢物，但没有因N3-氟丙基链功能化而产生的N1-去丙基物质或代谢产物。发现推定的代谢物在1.9和380 nm之间的Ki值处取代了[3 H] CPFPX与猪脑皮质中A1 AR的结合，并在Ki值处取代了猪纹状体中[3 H] ZM241385与A2A
• [EN] ADENOSINE RECEPTOR ANTAGONISTS WITH IMPROVED BIOACTIVITY<br/>[FR] ANTAGONISTES DU RECEPTEUR DE L'ADENOSINE PRESENTANT UNE BIOACTIVITE AMELIOREE
  申请人：UNIVERSITY OF SOUTH FLORIDA

  公开号：WO1999031101A1

  公开（公告）日：1999-06-24

  (EN) Xanthine A1AR antagonist having halogenated N-1 and/or N-3 side chains are provided. The methods for the syntheses of such antagonists are also provided. The methods for using such antagonist labeled with carbon-11, fluorine-18 or isotopes of iodine such as iodine-123 for medical diagnostic imaging of the A1AR in patients are provided. Methods for improving the potency and duration of action of xanthine A1AR antagonist by halogenation of N-1 and N-3 propyl substituents is provided.(FR) L'invention concerne une xanthine, antagoniste du récepteur de l'adénosine A1, et/ou des chaînes latérales de N-3. L'invention traite également de procédés permettant d'effectuer la synthèse de ces antagonistes. L'invention a aussi pour objet des procédés permettant d'utiliser cet antagoniste marqué au carbone-11, au fluor-18 ou des isotopes d'iode tel que l'iode-123 pour l'imagerie diagnostique médicale du récepteur de l'adénosine A1 chez les patients. L'invention traite aussi de procédés permettant d'améliorer la puissance et la durée d'action de la xanthine, antagoniste du récepteur de l'adénosine A1 par halogénation de substituants de propyle N-1 et N-3.