1,3-dipropyl-8-bromo-3,7-dihydropurine-2,6-dione | 127946-27-4

• 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: 1,3-dipropyl-8-bromo-3,7-dihydropurine-2,6-dione
• 英文别名: 1,3-dipropyl-8-bromoxanthine；8-bromo-1,3-dipropylxanthine；8-bromo-1,3-dipropyl-7H-purine-2,6-dione
• CAS: 127946-27-4
• 化学式: C₁₁H₁₅BrN₄O₂
• 分子量: 315.17
• InChiKey: ZFLKZWJOIPYVKS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  69.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1,3-dipropyl-8-bromo-3,7-dihydropurine-2,6-dione 在 氯化亚砜 作用下， 以 甲醇 为溶剂， 反应 48.25h， 生成 8-[Bis-(2-chloro-ethyl)-amino]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione
  参考文献：
  名称：

  Substituted 1,3-Dipropylxanthines as Irreversible Antagonists of A1 Adenosine Receptors

  摘要：

  This report describes the synthesis of 29 xanthines containing a chemoreactive chloroaryl beta-chloroethylamino, alpha,beta-unsaturated carbonyl bromoacetyl, 3-(fluorosulfonyl)benzoyl, or 4-(fluorosulfonyl)benzoyl group as part of an exocyclic 1-, 3-, or 8-substituent. The xanthines inhibited the binding of [H-3]-8-cyclopentyl-1,3-dipropylxanthine ([H-3]CPX) to the A(1) adenosine receptor (A(1)AR) of DDT1 MF2 cells at IC(50)s in the low-nanomolar to low-micromolar range. Seven of the 29 analogues irreversibly inhibited the binding of [H-3]CPX without changing the K-D of that ligand; five were 1,3-dipropylxantines having the following reactive groups as 8-substituents: (bromoacetamido)methyl (24), (bromoacetamido)ethyl (25), (bromoacetamido)propyl (26), [4-(fluorosulfonyl)benzamido]methyl (33) or 3-[[4-(fluorosulfonyl)benzoyl]oxy]cyclopentyl (42). Both 8-cyclopentyl-3-[3-[[4-(fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxanthine (53) and 8-cyclopentyl-3-bis[3-[[4-(fluorosulfonyl)benzoyl]oxy]propyl]xanthine (55) inhibited [H-3]CPX binding irreversibly. Five of the ligands, including 26, 33 (IC50 = 49 mu M), and 53 (IC50 = 9 mu M), antagonized the binding of [H-3]NECA to the A(2a)AR of PC12 cells, but unlike binding to the A(1)AR, binding to the A(2a)AR was completely reversible. The potency of 33 (IC50 = 2 mu M, 72% loss of CPX binding at 1 mu M) and 53 (IC50 - 0.01 mu M, 74% loss of CPX binding at 0.05 mu M) and their seletivity for the A(1)AR suggest that those two ligands may be useful in studies of the structure and function of that receptor.

  DOI：

  10.1021/jm00043a010
• 作为产物：
  描述：

  3,9-二氢-1,3-二丙基-1H-嘌呤-2,6-二酮 在 sodium chlorate 、 氢溴酸 、 溶剂黄146 作用下， 以 水 为溶剂， 反应 2.0h， 以78%的产率得到1,3-dipropyl-8-bromo-3,7-dihydropurine-2,6-dione
  参考文献：
  名称：

  N9-苄基取代的1,3-二甲基-和1,3-二丙基-嘧啶[2,1-f]嘌呤二酮：在腺苷A1和A2A受体上的合成与构效关系。

  摘要：

  描述了N-苄基嘧啶[2,1-f]嘌呤二酮的合成及其理化性质。这些衍生物是通过将7-氯丙基o-8-溴-1,3-二甲基-或1,3-二丙基黄嘌呤衍生物与相应的（未）取代的苄胺环合而合成的。也可以在微波辐射条件下获得二丙基衍生物。评价获得的化合物（1-20）对腺苷A1和A2A受体的亲和力，另外研究所选化合物对A3受体亚型的亲和力。放射性配体对A1和A2A腺苷受体的结合测定结果表明，大多数1,3-二甲基-9-苄基嘧啶嘌呤二酮在微摩尔或亚微摩尔浓度下均表现出对A2A受体的选择性亲和力（例如，具有邻甲氧基取代基的衍生物9在大鼠A2A受体上的Ki值为0.699 microM，选择性超过36倍。与先前描述的芳基嘧啶并[2,1-f]嘌呤二酮二丙基衍生物（化合物15-20）相反，对两种受体的亲和力均增加，但A1亲和力增加的幅度更大，结果取消了A2A的选择性。最佳的腺苷A1受体配体是间氯苄基衍生物18（Ki = 0

  DOI：

  10.1016/j.bmc.2007.04.018

文献信息

• Structure-activity relationships of 8-cycloalkyl-1,3-dipropylxanthines as antagonists of adenosine receptors
  作者：T. Katsushima、L. Nieves、J. N. Wells

  DOI：10.1021/jm00169a012

  日期：1990.7

  least 1000-fold more potent as an antagonist of A1 than of A2 adenosine receptors. While most substitutions on the 8-cycloalkyl moiety caused decreased potency to inhibit both A1 and A2 adenosine receptors, 8-[trans-4-(acetamidomethyl)cyclohexyl]-1,3-dipropylxanthine was nearly equipotent as an antagonist of the two receptors and appeared to be the most potent antagonist of A2 adenosine receptors reported

  8-取代的黄嘌呤目前代表最有效的腺苷-受体拮抗剂。制备了一系列8-取代的1，3-二丙基黄嘌呤，并确定了它们分别作为人血小板和大鼠脂肪细胞的A1和A2腺苷受体拮抗剂的效力。没有研究药物能像A1腺苷受体拮抗剂那样与8-环戊基-1,3-二丙基黄嘌呤一样有效，但是8-（2-甲基环丙基）-1,3-二丙基黄嘌呤比A1腺苷受体的效力至少强1000倍。 A1比A2的腺苷受体高。虽然8-环烷基部分上的大多数取代都导致抑制A1和A2腺苷受体，8- [反式-4-（乙酰氨基甲基）环己基] -1的效力降低，
• Xanthine–Dopamine Hybrid Molecules as Multitarget Drugs with Potential for the Treatment of Neurodegenerative Diseases
  作者：Michał Załuski、Tadeusz Karcz、Anna Drabczyńska、Christin Vielmuth、Agnieszka Olejarz-Maciej、Monika Głuch-Lutwin、Barbara Mordyl、Agata Siwek、Grzegorz Satała、Christa E. Müller、Katarzyna Kieć-Kononowicz

  DOI：10.3390/biom13071079

  日期：——

  Multitarget drugs based on a hybrid dopamine–xanthine core were designed as potential drug candidates for the treatment of neurodegenerative diseases. Monoamine oxidase B (MAO-B) inhibitors with significant ancillary A2A adenosine receptor (A2AAR) antagonistic properties were further developed to exhibit additional phosphodiesterase-4 and -10 (PDE4/10) inhibition and/or dopamine D2 receptor (D2R) agonistic activity. While all of the designed compounds showed MAO-B inhibition in the nanomolar range mostly combined with submicromolar A2AAR affinity, significant enhancement of PDE-inhibitory and D2R-agonistic activity was additionally reached for some compounds through various structural modifications. The final multitarget drugs also showed promising antioxidant properties in vitro. In order to evaluate their potential neuroprotective effect, representative ligands were tested in a cellular model of toxin-induced neurotoxicity. As a result, protective effects against oxidative stress in neuroblastoma cells were observed, confirming the utility of the applied strategy. Further evaluation of the newly developed multitarget ligands in preclinical models of Alzheimer’s and Parkinson’s diseases is warranted.

  基于多巴胺-黄嘌呤混合核心的多靶点药物被设计为治疗神经退行性疾病的潜在候选药物。进一步开发的单胺氧化酶 B（MAO-B）抑制剂具有显著的辅助 A2A 腺苷受体（A2AAR）拮抗特性，可表现出额外的磷酸二酯酶-4 和-10（PDE4/10）抑制和/或多巴胺 D2 受体（D2R）激动活性。虽然所有设计的化合物都显示出纳摩尔范围内的 MAO-B 抑制作用，而且大多结合了亚摩尔级 A2AAR 亲和力，但通过各种结构修饰，一些化合物的 PDE 抑制和 D2R 激动活性得到了显著增强。最终的多靶点药物还在体外显示出良好的抗氧化特性。为了评估其潜在的神经保护作用，代表性配体在毒素诱导的神经毒性细胞模型中进行了测试。结果发现，这些药物对神经母细胞瘤细胞的氧化应激具有保护作用，从而证实了这种应用策略的实用性。有必要在阿尔茨海默氏症和帕金森氏症的临床前模型中进一步评估新开发的多靶点配体。
• Structure–activity relationship studies of a new series of imidazo[2,1-f]purinones as potent and selective A3 adenosine receptor antagonists
  作者：Pier Giovanni Baraldi、Delia Preti、Mojgan Aghazadeh Tabrizi、Romeo Romagnoli、Giulia Saponaro、Stefania Baraldi、Maurizio Botta、Cesare Bernardini、Andrea Tafi、Tiziano Tuccinardi

  DOI：10.1016/j.bmc.2008.10.049

  日期：2008.12.15

  We recently described the synthesis of 1-benzyl-3-propyl-1H,8H-imidazo[2,1-f]purine-2,4-diones, new potent and selective A(3) adenosine receptor antagonists containing a xanthine core. The present work can be considered an extension of our SAR studies on related structures in which the effect of different kind of substitutions at the 1-, 3- and 8-positions has been evaluated in order to improve both the potency and the hydrophilicity of the originally synthesised molecules. The A(3) binding disposition of these compounds was also investigated through docking and 3D-QSAR studies. (C) 2008 Elsevier Ltd. All rights reserved.
• KATSUSHIMA, T.;NIEVES, L.;WELLS, J. N., J. MED. CHEM., 33,(1990) N, C. 1906-1910
  作者：KATSUSHIMA, T.、NIEVES, L.、WELLS, J. N.

  DOI：——

  日期：——
• Scammells Peter J., Baker Stephen P., Belardinelli Luiz, Olsson Ray A., J. Med. Chem, 37 (1994) N 17, S 2704-2712
  作者：Scammells Peter J., Baker Stephen P., Belardinelli Luiz, Olsson Ray A.

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  日期：——