5-[[(phenyl)amino]carbonyl]amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine | 361484-62-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-[[(phenyl)amino]carbonyl]amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine
• 英文别名: MRE 3048F20；1-(8-Ethyl-2-furan-2-yl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-3-phenyl-urea；1-[11-ethyl-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-yl]-3-phenylurea
• CAS: 361484-62-0
• 化学式: C₁₉H₁₆N₈O₂
• 分子量: 388.388
• InChiKey: ZFWFVVFEJZLCTO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  115
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-[[(phenyl)amino]carbonyl]amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine 在 氟磺酸 作用下， 反应 2.0h， 以72%的产率得到4-[3-(8-Ethyl-2-furan-2-yl-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：

  异氰酸苯酯 、 5-Amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine 以 四氢呋喃 为溶剂， 反应 18.0h， 以94%的产率得到5-[[(phenyl)amino]carbonyl]amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine
  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

文献信息

• 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
• 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.