5-amino-8-butyl-2-(furan-2-yl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine | 159980-11-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三唑并嘧啶类
• 英文名称: 5-amino-8-butyl-2-(furan-2-yl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
• 英文别名: 5-Amino-8-butyl-2-(2-furyl)-pyrazolo[4,3-e] 1,2,4-triazolo[1,5-c]pyrimidine；5-Amino-8-butyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine；8-Butyl-2-furan-2-yl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine；11-butyl-4-(furan-2-yl)-3,5,6,8,10,11-hexazatricyclo[7.3.0.02,6]dodeca-1(12),2,4,7,9-pentaen-7-amine
• CAS: 159980-11-7
• 化学式: C₁₄H₁₅N₇O
• 分子量: 297.319
• InChiKey: NSGXVWJIQHDYOE-UHFFFAOYSA-N

物化性质

• 密度：
  1.592±0.14 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  100
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-amino-8-butyl-2-(furan-2-yl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine 在 盐酸 、 氯磺酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 24.0h， 生成 4-[3-(8-Butyl-2-furan-2-yl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-ureido]-benzenesulfonic acid
  参考文献：
  名称：

  新型吡唑并[4,3-e] -1,2,4-三唑并[1,5-c]嘧啶衍生物作为人A（3）腺苷受体拮抗剂的合成，生物活性和分子模型研究。

  摘要：

  描述了一个新系列的吡唑并三唑并嘧啶，它们在N5位置的苯基氨基甲酰基部分具有不同的取代基，是高度有效的和选择性的人A（3）腺苷受体拮抗剂。这些化合物代表了我们先前对这类化合物的工作的扩展和改进（J. Med。Chem。1999，42，4473-4478; J. Med。Chem。2000，43，4768-4780）。所有合成的化合物在人A（1），A（2A），A（2B）和A（3）腺苷受体的放射性配体结合测定中均显示出亚纳摩尔范围内的A（3）腺苷受体亲和力和高水平的选择性。特别地，已经研究了取代作用及其在苯环上的位置。根据结合数据，很明显苯环上的未取代衍生物（例如化合物59，hA（3）= 0.16 nM，hA（1）/ hA（3）= 3713，hA（2A）/ hA（3）= 2381，hA（2B）/ hA（3）= 1388）在对人A（3）腺苷受体的亲和力和选择性方面显示出最佳特性。为了设计水溶性衍生

  DOI：

  10.1021/jm0109614
• 作为产物：
  描述：

  2-呋喃甲酰肼 在 N-甲基吡咯烷酮 、 盐酸 、 对甲苯磺酸 作用下， 以 二苯醚 、 乙二醇甲醚 为溶剂， 反应 4.5h， 生成 5-amino-8-butyl-2-(furan-2-yl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
  参考文献：
  名称：

  Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives:  Potent and Selective A_2A Adenosine Antagonists

  摘要：

  A series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives (10a-o,q,r), bearing alkyl and aralkyl chains on positions 7 and 8, were synthesized in the attempt to obtain potent and selective antagonists for the A(2A) adenosine receptor subtype. The compounds were tested in binding and functional assays to evaluate their potency for the A(2A) compared with the A(1) adenosine receptor subtype. In binding studies in rat brain membranes, most of the compounds showed affinity for A(2A) receptors in the low nanomolar range with a different degree of A(2A) versus A(1) selectivity. Comparison of N-7 (10a-d,h-o)- and N-8 (10e-g)-substituted pyrazolo derivatives indicates that N-7 substitution decreases the A(1) affinity with the concomitant increase of A(2A) selectivity. Specifically, the introduction of a 3-phenylpropyl group at pyrazolo nitrogen in position 7 (101) increased significantly the A(2A) selectivity, being 210-fold, while the A(2A) receptor affinity remained high (K-i = 2.4 nM). With regards to the affinity for A(2A) receptors, also the compound 10n, bearing in the 7-position a beta-morpholin-4-ylethyl group, deserves attention (K-i = 5.6 nM) even though the A(2A) selectivity (84-fold) was not as high as that of 101. Conversely, the compound 10m (N-7-4-phenylbutyl derivative) showed a remarkable selectivity (A(1)/A(2A) ratio = 129) associated with lower A(2A) affinity (K-i = 21 nM). In functional studies, most of the compounds examined reversed 5'-(N-ethylcarbamoyl)adenosine-induced inhibition of rabbit platelet aggregation inhibition which is a biological response mediated by the A(2A) receptor subtype. The compounds are potent and selective A(2A) antagonists which can be useful to elucidate the pathophysiological role of this adenosine receptor subtype. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease.

  DOI：

  10.1021/jm950746l

文献信息

• Pyrazolo[4,3-<i>e</i>]1,2,4-triazolo[1,5-<i>c</i>]pyrimidine Derivatives as Highly Potent and Selective Human A₃ Adenosine Receptor Antagonists:  Influence of the Chain at the N⁸ Pyrazole Nitrogen
  作者：Pier Giovanni Baraldi、Barbara Cacciari、Romeo Romagnoli、Giampiero Spalluto、Stefano Moro、Karl-Norbert Klotz、Edward Leung、Katia Varani、Stefania Gessi、Stefania Merighi、Pier Andrea Borea

  DOI：10.1021/jm001047y

  日期：2000.12.1

  IB-MECA was measured in membranes of CHO cells stably transfected with the human A(3) receptor. The new compounds are among the most potent and selective A(3) antagonists so far described. The derivatives with higher affinity at human A(3) adenosine receptors proved to be antagonists, in the cAMP assay, capable of inhibiting the effect of IB-MECA with IC(50) values in the nanomolar range, with a trend strictly

  先前已经报道了以初步形式（Baraldi等人，J.Med.Chem.1999，42，4473-4478）作为高效和选择性的人A（3）腺苷受体拮抗剂的一系列吡唑并三唑并嘧啶类化合物。合成的化合物显示在亚纳摩尔范围内的A（3）腺苷受体亲和力和在人类A（1），A（2A），A（2B）和A（3）腺苷的放射性配体结合测定中评估的高水平选择性受体。特别是，分析了该链在N（8）吡唑氮上的作用。这项研究使我们能够鉴定出在N（8）吡唑具有甲基的衍生物与在N（5）位置具有4-甲氧基苯基氨基甲酰基部分的衍生物是在亲和力和选择性（hA）方面均具有最佳结合特性的化合物（3）= 0.2 nM，hA（1）/ hA（3）= 5485，hA（2A）/ hA（3）= 6950，hA（2B）/ hA（3）= 1305）。在特定功能模型中，所有化合物均被证明是完全拮抗剂，其中在稳定转染了人A（3）受体的CHO细胞膜中测量了IB-M
• Adenosine A3 receptor modulators
  申请人：——

  公开号：US20030144266A1

  公开（公告）日：2003-07-31

  The compounds of the following formula: 1 wherein R, R 2 , R 3 and A have the meanings given in the specification, are endowed with selective A 3 adenosine receptor antagonist activity. These compounds can be used in a pharmaceutical composition to treat disorders caused by excessive activation of the A 3 receptor, or can be used in a diagnostic application to determine the relative binding of other compounds to the A 3 receptor. The compounds can be labeled, for example with fluorescent or radiolabels, and the labels used in vivo or in vitro to determine the presence of tumor cells which possess a high concentration of adenosine A 3 receptors.

  具有以下公式的化合物：其中R、R2、R3和A具有规范中给定的含义，具有选择性A3腺苷受体拮抗活性。这些化合物可以用于制备药物组合物，用于治疗由A3受体过度激活引起的疾病，也可以用于诊断应用，以确定其他化合物与A3受体的相对结合。这些化合物可以被标记，例如用荧光标记或放射性标记，并且这些标记可以在体内或体外用于确定具有高浓度腺苷A3受体的肿瘤细胞的存在。
• ADENOSINE A3 RECEPTOR MODULATORS
  申请人：Baraldi Giovanni Pier

  公开号：US20070249641A1

  公开（公告）日：2007-10-25

  The compounds of the following formula: wherein R, R 2 , R 3 and A have the meanings given in the specification, are endowed with selective A 3 adenosine receptor antagonist activity. These compounds can be used in a pharmaceutical composition to treat disorders caused by excessive activation of the A 3 receptor, or can be used in a diagnostic application to determine the relative binding of other compounds to the A 3 receptor. The compounds can be labeled, for example with fluorescent or radiolabels, and the labels used in vivo or in vitro to determine the presence of tumor cells which possess a high concentration of adenosine A 3 receptors.

  以下化学式的化合物：其中R、R2、R3和A在说明书中给出的含义，具有选择性A3腺苷受体拮抗活性。这些化合物可以用于制备药物组合物，用于治疗由A3受体过度激活引起的疾病，或者可以用于诊断应用，以确定其他化合物与A3受体的相对结合。这些化合物可以被标记，例如用荧光或放射性标记，并在体内或体外用于确定具有高浓度腺苷A3受体的肿瘤细胞的存在。
• Combining selectivity and affinity predictions using an integrated Support Vector Machine (SVM) approach: An alternative tool to discriminate between the human adenosine A2A and A3 receptor pyrazolo-triazolo-pyrimidine antagonists binding sites
  作者：Lisa Michielan、Chiara Bolcato、Stephanie Federico、Barbara Cacciari、Magdalena Bacilieri、Karl-Norbert Klotz、Sonja Kachler、Giorgia Pastorin、Riccardo Cardin、Alessandro Sperduti、Giampiero Spalluto、Stefano Moro

  DOI：10.1016/j.bmc.2009.05.038

  日期：2009.7

  G Protein-coupled receptors (GPCRs) selectivity is an important aspect of drug discovery process, and distinguishing between related receptor subtypes is often the key to therapeutic success. Nowadays, very few valuable computational tools are available for the prediction of receptor subtypes selectivity.In the present study, we present an alternative application of the Support Vector Machine (SVM) and Support Vector Regression (SVR) methodologies to simultaneously describe both A(2A)R versus A(3)R subtypes selectivity pro. le and the corresponding receptor binding affinities. We have implemented an integrated application of SVM-SVR approach, based on the use of our recently reported autocorrelated molecular descriptors encoding for the Molecular Electrostatic Potential (autoMEP), to simultaneously discriminate A(2A)R versus A(3)R antagonists and to predict their binding affinity to the corresponding receptor subtype of a large dataset of known pyrazolo-triazolo-pyrimidine analogs. To validate our approach, we have synthetized 51 new pyrazolo-triazolo-pyrimidine derivatives anticipating both A(2A)R/A(3)R subtypes selectivity and receptor binding affinity profiles. (C) 2009 Published by Elsevier Ltd.
• Fluorosulfonyl- and Bis-(β-chloroethyl)amino-phenylamino Functionalized Pyrazolo[4,3-<i>e</i>]1,2,4-triazolo[1,5-<i>c</i>]pyrimidine Derivatives:  Irreversible Antagonists at the Human A₃ Adenosine Receptor and Molecular Modeling Studies
  作者：Pier Giovanni Baraldi、Barbara Cacciari、Stefano Moro、Romeo Romagnoli、Xiao-duo Ji、Kenneth A. Jacobson、Stefania Gessi、Pier Andrea Borea、Giampiero Spalluto

  DOI：10.1021/jm010818a

  日期：2001.8.1

  A series of pyrazolotriazolopyrimidines was previously reported to be highly potent and selective human A(3) adenosine receptor antagonists (Baraldi et al. J. Med. Chem. 2000, 43, 4768-4780). A derivative having a methyl group at the N-8 pyrazole combined with a 4-methoxyphenylcarbamoyl moiety at N-5 position, displayed a K-i value at the hA(3) receptor of 0.2 nM. We now describe chemically reactive derivatives which act as irreversible inhibitors of this receptor. Electrophilic groups, specifically sulfonyl fluoride and nitrogen mustard (bis-(beta -chloroethyl)amino) moieties, have been incorporated at the 4-position of the aryl urea group. Membranes containing the recombinant hA3 receptor were preincubated with the compounds and washed exhaustively. The loss of ability to bind radioligand following this treatment indicated irreversible binding. The most potent compound in irreversibly binding to the receptor was 14, which contained a sulfonyl fluoride moiety and a propyl group at the N-8 pyrazole nitrogen. The bis-(beta -chloroethyl)amino derivatives displayed a much smaller degree of irreversible binding than the sulfonyl fluoride derivatives. A computer-generated model of the human A(3) receptor was built and analyzed to help interpret these results. The model of the A(3) transmembrane region was derived using primary sequence comparison, secondary structure predictions, and three-dimensional homology building, using the recently published crystal structure of rhodopsin as a template. According to our model, sulfonyl fluoride derivatives could dock within the hypothetical TM binding domain, adopting two different energetically favorable conformations. We have identified two amino acids, Ser247 and Cys251, both in TM6, as potential nucleophilic partners of the irreversible binding to the receptor.