1,3-dipropyl-7-(3-chloropropyl)-8-bromoxanthine | 913555-85-8

• 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-7-(3-chloropropyl)-8-bromoxanthine
• 英文别名: 1,3-Dipropyl-7-(3-chloropropyl)-8-bromoxanthine；8-bromo-7-(3-chloropropyl)-1,3-dipropylpurine-2,6-dione
• CAS: 913555-85-8
• 化学式: C₁₄H₂₀BrClN₄O₂
• 分子量: 391.695
• InChiKey: JGMJZPPLIFEVRU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  58.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1,3-dipropyl-7-(3-chloropropyl)-8-bromoxanthine 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 、 丁酮 为溶剂， 反应 19.0h， 生成 9-(4-(2-morpholinoethoxy)phenylethyl)-1,3-dipropyl-6,7,8,9-tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione
  参考文献：
  名称：

  在人和大鼠腺苷受体上三环嘧啶基和吡嗪并黄嘌呤的亲和力和结合方式的异同。

  摘要：

  获得了一系列新的32个嘧啶基和5个四氢吡嗪并[2,1-f]嘌呤二酮，并对其腺苷受体（ARs）亲和力进行了评估。9-（4-（2-（二甲基氨基）乙氧基）苯基）-1,3-二丁基衍生物-6,7,8,9-四氢嘧啶基[1,2-f]嘌呤-2,4（1H，3H） -dione被发现是本系列中最有效的A1 AR拮抗剂，显示出对其他AR亚型的选择性。建立了获得的嘌呤二酮的结构活性。将研究的文库与人和大鼠A1和A2A AR的同源性模型对接实验，可以比较所选化合物的预期结合模式。

  DOI：

  10.1016/j.bmc.2016.07.028
• 作为产物：
  描述：

  1,3-dipropyl-8-bromo-3,7-dihydropurine-2,6-dione 、 1-溴-3-氯丙烷 在 苄基三乙基氯化铵 、 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 10.0h， 生成 1,3-dipropyl-7-(3-chloropropyl)-8-bromoxanthine
  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

• Tricyclic xanthine derivatives containing a basic substituent: adenosine receptor affinity and drug-related properties
  作者：Michał Załuski、Katarzyna Stanuch、Tadeusz Karcz、Sonja Hinz、Gniewomir Latacz、Ewa Szymańska、Jakub Schabikowski、Agata Doroż-Płonka、Jadwiga Handzlik、Anna Drabczyńska、Christa E. Müller、Katarzyna Kieć-Kononowicz

  DOI：10.1039/c8md00070k

  日期：——

  amino function. Compounds with nanomolar AR affinities and at the same time high water-solubility were obtained (A1 (Ki = 24–605 nM), A2A (Ki = 242–1250 nM), A2B (Ki = 66–911 nM) and A3 (Ki = 155–1000 nM)). 2-(4-(2-(1,3-Dibutyl-2,4-dioxo-1,2,3,4,7,8-hexahydropyrimido[2,1-f]purin-9(6H)-yl)ethyl)phenoxy)-N-(3-(diethylamino)propyl)acetamide (27) and the corresponding N-(2-(pyrrolidin-1-yl)ethyl)acetamide (36)

  设计并合成了 27 种新颖的稠合黄嘌呤酰胺衍生物库。新化合物代表 1,3-二丙基-和 1,3-二丁基-嘧啶并[2,1- f ]嘌呤二酮-9-乙基苯氧基衍生物，包括 (CH 2 ) 2 -氨基和苯氧基之间的 CH 2 CONH 连接基部分。开发了一种涉及无溶剂微波辐射的获得最终产品的合成策略。对新化合物的腺苷受体（AR）亲和力进行了评估。最有效的衍生物含有末端叔氨基官能团。获得了具有纳摩尔 AR 亲和力且同时具有高水溶性的化合物（A 1 ( K = 24–605 nM)、A 2A ( K = 242–1250 nM)、A 2B ( K = 66–911 nM) 和A 3 ( K = 155–1000 nM))。 2-(4-(2-(1,3-二丁基-2,4-二氧代-1,2,3,4,7,8-六氢嘧啶基[2,1 -f ]嘌呤-9(6 H )-基) )乙基)苯氧基) -N- (3-(二乙氨基)丙基)乙酰胺(
• Phenylethyl-substituted pyrimido[2,1-f]purinediones and related compounds: Structure–activity relationships as adenosine A1 and A2A receptor ligands
  作者：Anna Drabczyńska、Christa E. Müller、Anke Schiedel、Britta Schumacher、Janina Karolak-Wojciechowska、Andrzej Fruziński、Weronika Zobnina、Olga Yuzlenko、Katarzyna Kieć-Kononowicz

  DOI：10.1016/j.bmc.2007.07.051

  日期：2007.11

  distinctly negative effect on the activity. In this series of compounds more frequently the adenosine A(1) activity was observed, also in submicromolar range as for dipropyl derivative 2Ba with K(i) value of 0.62 microM at the rat A(2A) AR. 3D-QSAR models were developed for the compounds presented in this paper as well as in the previous publications showing activity at adenosine A(1) and A(2A) ARs.

  N-（未）取代的苯基烷基嘧啶基[2,1-f]嘌呤二酮的合成从7-（3-氯丙基）-8-溴茶碱和7-（3-氯丙基）-8-溴-1,3开始进行-二丙基黄嘌呤。合成了在芳环上具有未取代或取代的乙烯间隔基的化合物。另外，对包含两个以上原子的连接基的间隔基-延伸，双键或杂原子的引入进行了改变。描述了合成化合物的理化性质。评估了所设想的化合物为8-苯乙烯基黄嘌呤的空间固定和构型稳定的类似物，评估了它们对腺苷A（1）和A（2A）受体（脑中主要的受体亚型）的亲和力。还研究了所选化合物对A（2B）和A（3）受体亚型的亲和力。有人指出，苯乙基嘧啶并[2,1-f]嘌呤二酮及其类似物，带有乙烯间隔基的变化（取代或扩展），对A（2A）ARs（腺苷受体）表现出微摩尔或亚微摩尔的亲和力。例如，具有对羟基取代基的化合物2Ac在大鼠A（2A）受体上的K（i）值为0.23 microM。与先前获得的具有较短间隔基的苯基和苄基嘧啶并[2
• 1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases
  作者：Pierre Koch、Rhalid Akkari、Andreas Brunschweiger、Thomas Borrmann、Miriam Schlenk、Petra Küppers、Meryem Köse、Hamid Radjainia、Jörg Hockemeyer、Anna Drabczyńska、Katarzyna Kieć-Kononowicz、Christa E. Müller

  DOI：10.1016/j.bmc.2013.09.044

  日期：2013.12

  Adenosine receptors and monoamine oxidases are drug targets for neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In the present study we prepared a library of 55 mostly novel tetrahydropyrimido[2,1-f]purinediones with various substituents in the 1- and 3-position (1,3-dimethyl, 1,3-diethyl, 1,3-dipropyl, 1-methyl-3-propargyl) and broad variation in the 9-position. A synthetic strategy to obtain 3-propargyl-substituted tetrahydropyrimido[2,1-f]purinedione derivatives was developed. The new compounds were evaluated for their interaction with all four adenosine receptor subtypes and for their ability to inhibit monoamine oxidases (MAO). Introduction of mono-or di-chloro-substituted phenyl, benzyl or phenethyl residues at N9 of the 1,3-dimethyl series led to the discovery of a novel class of potent MAO-B inhibitors, the most potent compound being 9-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione (21g, IC50 human MAO-B: 0.0629 mu M), which displayed high selectivity versus the other investigated targets. Potent dually active A(1)/A(2A) adenosine receptor antagonists were identified, for example, 9-benzyl-1-methyl-3-propargyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)dione (19f, K-i, human receptors, A(1): 0.249 mu M, A(2A): 0.253 mu M). Several compounds showed triple-target inhibition, the best compound being 9-(2-methoxybenzyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9-tetrahydro pyrimido [1,2-f]purine-2,4(1H,3H)-dione (19g, K-i A(1): 0.605 mu M, K-i A(2A): 0.417 mu M, IC50 MAO-B: 1.80 mu M). Compounds inhibiting several different targets involved in neurodegeneration may exhibit additive or even synergistic effects in vivo. (C) 2013 Elsevier Ltd. All rights reserved.
• Synthesis and biological activity of tricyclic aryloimidazo-, pyrimido-, and diazepinopurinediones
  作者：Anna Drabczyńska、Christa E. Müller、Svenja K. Lacher、Britta Schumacher、Janina Karolak-Wojciechowska、Antony Nasal、Piotr Kawczak、Olga Yuzlenko、Elżbieta Pękala、Katarzyna Kieć-Kononowicz

  DOI：10.1016/j.bmc.2006.06.052

  日期：2006.11

  Syntheses and physicochemical properties of N-aryl-substituted imidazo-, pyrimido-, and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-haloalkyl-8-bromo-1,3-dimethyl- or 1,3-dipropyl-xanthine derivatives with corresponding arylamines. The obtained compounds (1-40), which can be envisaged as sterically fixed and configurationally stable analogs of 8-styrylxanthines, were evaluated for their affinity to adenosine A(1) and A(2A) receptors, the receptor subtypes that are predominant in the brain. Selected compounds were additionally investigated for affinity to the A(2B) and A(3) receptor subtypes. Many of the compounds showed adenosine A(2A) receptor affinity at micromolar or submicromolar concentrations and were A(2A)-selective, for example, compound 23 with p-fluoro substituent displayed K-i value of 0.147 mu M at the rat A2A receptor and more than 170-fold-A(2A) selectivity, compound 17 with naphthyl substituent had K-i value of 0.219 mu M and a more than 114-fold-A2A selectivity. The compounds were-somewhat weaker and less selective at the human receptor subtypes. Elongation of the dimethyl substituent to dipropyl in xanthine moiety improved affinity but reduced selectivity. 1,3-Dimethylimidazo-, pyrimido-, and diazepinopurinediones were evaluated in vivo as anticonvulsants in MES, ScMet, TTE tests and examined for neurotoxicity in mice (ip). Substances with pyrimido ring displayed protective activity in ScMet or in MES and ScMet tests, showing also neurotoxicity. The pyrimidine annelated ring is beneficial for both receptor affinity and anticonvulsant activity. (c) 2006 Elsevier Ltd. All rights reserved.
• Similarities and differences in affinity and binding modes of tricyclic pyrimido- and pyrazinoxanthines at human and rat adenosine receptors
  作者：Ewa Szymańska、Anna Drabczyńska、Tadeusz Karcz、Christa E. Müller、Meryem Köse、Janina Karolak-Wojciechowska、Andrzej Fruziński、Jakub Schabikowski、Agata Doroz-Płonka、Jadwiga Handzlik、Katarzyna Kieć-Kononowicz

  DOI：10.1016/j.bmc.2016.07.028

  日期：2016.9

  tetrahydropyrazino[2,1-f]purinediones was obtained and evaluated for their adenosine receptors (ARs) affinities. The 1,3-dibutyl derivative of 9-(4-(2-(dimethylamino)ethoxy)phenyl)-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione was found to be the most potent A1 AR antagonist of the present series, showing selectivity over the other AR subtypes. The structure-activity for the obtained purinediones

  获得了一系列新的32个嘧啶基和5个四氢吡嗪并[2,1-f]嘌呤二酮，并对其腺苷受体（ARs）亲和力进行了评估。9-（4-（2-（二甲基氨基）乙氧基）苯基）-1,3-二丁基衍生物-6,7,8,9-四氢嘧啶基[1,2-f]嘌呤-2,4（1H，3H） -dione被发现是本系列中最有效的A1 AR拮抗剂，显示出对其他AR亚型的选择性。建立了获得的嘌呤二酮的结构活性。将研究的文库与人和大鼠A1和A2A AR的同源性模型对接实验，可以比较所选化合物的预期结合模式。