5-Amino-8-propyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine | 252979-39-8

• 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-propyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine
• 英文别名: Amino-8-propyl-2-(2-furyl) pyrazolo (4,3-e)-1,2,4-triazolo (1,5-c)pyrimidine；4-(furan-2-yl)-11-propyl-3,5,6,8,10,11-hexazatricyclo[7.3.0.02,6]dodeca-1(12),2,4,7,9-pentaen-7-amine
• CAS: 252979-39-8
• 化学式: C₁₃H₁₃N₇O
• 分子量: 283.293
• InChiKey: SJZFDIQTLVHZRM-UHFFFAOYSA-N

物化性质

• 密度：
  1.65±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 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-propyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine 在 氟磺酸 作用下， 以 四氢呋喃 为溶剂， 反应 20.0h， 生成 4-[3-(2-Furan-2-yl-8-propyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-ureido]-benzenesulfonyl fluoride
  参考文献：
  名称：

  Fluorosulfonyl- and Bis-(β-chloroethyl)amino-phenylamino Functionalized Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine Derivatives:  Irreversible Antagonists at the Human A₃ Adenosine Receptor and Molecular Modeling Studies

  摘要：

  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.

  DOI：

  10.1021/jm010818a
• 作为产物：
  描述：

  8-propyl-2-(2-furyl)pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine 在 对甲苯磺酸 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 7.0h， 生成 5-Amino-8-propyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine
  参考文献：
  名称：

  吡唑并[4,3-e] 1,2,4-三唑并[1,5-c]嘧啶衍生物作为高效和选择性的人A（3）腺苷受体拮抗剂：在N（8）吡唑氮上链的影响。

  摘要：

  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

  DOI：

  10.1021/jm001047y

文献信息

• 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。
• Synthesis, Biological Activity, and Molecular Modeling Investigation of New Pyrazolo[4,3-<i>e</i>]-1,2,4-triazolo[1,5-<i>c</i>]pyrimidine Derivatives as Human A₃ Adenosine Receptor Antagonists
  作者：Pier Giovanni Baraldi、Barbara Cacciari、Stefano Moro、Giampiero Spalluto、Giorgia Pastorin、Tatiana Da Ros、Karl-Norbert Klotz、Katia Varani、Stefania Gessi、Pier Andrea Borea

  DOI：10.1021/jm0109614

  日期：2002.2.1

  unsubstituted derivatives on the phenyl ring (e.g., compound 59, hA(3) = 0.16 nM, hA(1)/hA(3) = 3713, hA(2A)/hA(3) = 2381, hA(2B)/hA(3) = 1388) showed the best profile in terms of affinity and selectivity at the human A(3) adenosine receptors. The introduction of a sulfonic acid moiety at the para position on the phenyl ring was attempted in order to design water soluble derivatives. However, this

  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
• 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。
• The application of a 3D-QSAR (autoMEP/PLS) approach as an efficient pharmacodynamic-driven filtering method for small-sized virtual library: Application to a lead optimization of a human A3 adenosine receptor antagonist
  作者：Stefano Moro、Magdalena Bacilieri、Barbara Cacciari、Chiara Bolcato、Claudia Cusan、Giorgia Pastorin、Karl-Norbert Klotz、Giampiero Spalluto

  DOI：10.1016/j.bmc.2006.03.010

  日期：2006.7.15

  We have recently reported that the combination of molecular electrostatic potential (MEP) surface properties (autocorrelation vectors) with the conventional partial least squares (PLS) analysis can be used to produce a robust ligand-based 3D structure-activity relationship (autoMEP/PLS) for the prediction of the human A(3) receptor antagonist activities. Here, we present the application of the 3D-QSAR (autoMEP/PLS) approach as an efficient and alternative pharmacodynamic filtering method for small-sized virtual library. For this purpose, a small-sized combinatorial library (841 compounds) was derived from the scaffold of the known human A(3) antagonist pyrazolo-triazolo-pyrimidines. The most interesting analogues were further prioritized for synthesis and pharmacological characterization. Remarkably, we have found that all the newly synthetized compounds are correctly predicted as potent human A(3) antagonists, In particular, two of them are correctly predicted as sub-nanomolar inhibitors of the human A3 receptor. (c) 2006 Elsevier Ltd. All rights reserved.
• 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
  作者：Pier Giovanni Baraldi、Barbara Cacciari、Romeo Romagnoli、Giampiero Spalluto、Karl-Norbert Klotz、Edward Leung、Katia Varani、Stefania Gessi、Stefania Merighi、Pier Andrea Borea

  DOI：10.1021/jm991114s

  日期：1999.11.1