2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine | 261629-20-3

• 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: 2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine
• 英文别名: 5-Amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine；2-Furan-2-yl-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine；4-(furan-2-yl)-11-methyl-3,5,6,8,10,11-hexazatricyclo[7.3.0.02,6]dodeca-1(12),2,4,7,9-pentaen-7-amine
• CAS: 261629-20-3
• 化学式: C₁₁H₉N₇O
• 分子量: 255.239
• InChiKey: PKVBGKUACUZPER-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 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：

  2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine 在 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 5.08h， 生成 4-[({[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]amino}carbonyl)amino]-N-pyridin-4-ylpiperidine-1-carboxamide trifluoroacetate
  参考文献：
  名称：

  Water-Soluble Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines as Human A₃ Adenosine Receptor Antagonists

  摘要：

  A relevant problem of the pyrazolo[4,3-e]-[1,2,4]triazolo[1,5-c]pyrimidine nucleus, an attractive scaffold for the preparation of adenosine receptor antagonists, is the low water solubility. We originally functionalized the C-5 position with a salifiable 4-pyridylcarbamoyl moiety that conferred good water solubility at low pH (<4.0) but poor solubility at physiologic pH, indicative of the dissociation of the pyridinium species. Here we replaced the pyridin-4-yl moiety with a 1-(substituted)piperidin-4-yl ring to exploit the higher basicity of this nucleus and for the the possibility to generate stable, water-soluble salts. The hydrochloride salt of the 1-(cyclohexylmethyl)piperidin-4-yl derivative (10, K-i(hA(3)) = 9.7 nM, IC50(hA(3)) = 30 nM, K-i(hA(1)/hA(3)) = 351, K-i(hA(2A)/hA(3)) > 515, IC50(HA(2B)) > 5 mu M) showed a solubility of 8 mg/mL at physiological pH and gave a stable aqueous system suitable for, intravenous infusion. Molecular modeling studies were helpful in rationalizing the available structure-activity relationships and the selectivity profile of the new ligands.

  DOI：

  10.1021/jm300323t
• 作为产物：
  描述：

  1-甲基-3-氨基-4-氰基吡唑 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 、 水 为溶剂， 反应 52.0h， 生成 2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine
  参考文献：
  名称：

  One-Pot Reaction To Obtain N,N′-Disubstituted Guanidines of Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine Scaffold as Human A₃ Adenosine Receptor Antagonists

  摘要：

  In this paper we describe an extension SAR study of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus as A(3)AR antagonist. Our initial aim was to replace the phenylcarbamoyl moiety at the 5 position of PTP nucleus with a thiourea functionality to evaluate the contribution of new structural modification against the A(3)AR. The synthesized 12-25 were not characterized by the predicted side chain but by a 1,3-disubstituted guanidine and are shown to be interesting A(3)AR antagonists.

  DOI：

  10.1021/acs.jmedchem.5b00551

文献信息

• [EN] PYRAZOLOTRIAZOLOPYRIMIDINE DERIVATIVES AS A2A RECEPTOR ANTAGONIST<br/>[FR] DÉRIVÉS DE PYRAZOLOTRIAZOLOPYRIMIDINE EN TANT QU'ANTAGONISTE DU RÉCEPTEUR A2A
  申请人：BEIGENE LTD

  公开号：WO2020020097A1

  公开（公告）日：2020-01-30

  Disclosed herein is a pyrazolotriazolopyrimidine derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof useful as A2A receptor antagonist, and a pharmaceutical composition comprising the same. Also disclosed herein is a method of treating cancer using the pyrazolotriazolopyrimidine derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as A2A receptor antagonist.

  本文揭示了一种吡唑三唑吡嘧啶衍生物或其立体异构体，或其药学上可接受的盐，可用作A2A受体拮抗剂，以及包含该物质的药物组合物。本文还揭示了一种使用该吡唑三唑吡嘧啶衍生物或其立体异构体，或其药学上可接受的盐作为A2A受体拮抗剂治疗癌症的方法。
• FLUORESCENT ANTAGONISTS OF THE A3 ADENOSINE RECEPTOR
  申请人：e Department of Health and Human Services The United State of America, as represented by th

  公开号：US20130190335A1

  公开（公告）日：2013-07-25

  Disclosed are compounds of the formula (I) which are fluorescently labeled antagonists of the A 3 adenosine receptor: wherein A, R 1 , R 2 , and Y are as described herein. Also disclosed are diagnostic compositions and a method of diagnosis of a patient for a possible treatment by an antagonist of the A 3 adenosine receptor, involving the use of one or more of these compounds as diagnostic agents.

  公开了化合物(I)的结构，它们是A3腺苷受体的荧光标记拮抗剂：其中A、R1、R2和Y如本文所述。还公开了诊断组合物和一种诊断患者是否可能通过A3腺苷受体拮抗剂治疗的方法，涉及使用这些化合物中的一个或多个作为诊断试剂。
• 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。
• Conjugable A3 adenosine receptor antagonists for the development of functionalized ligands and their use in fluorescent probes
  作者：Stephanie Federico、Enrico Margiotta、Stefano Moro、Eszter Kozma、Zhan-Guo Gao、Kenneth A. Jacobson、Giampiero Spalluto

  DOI：10.1016/j.ejmech.2019.111886

  日期：2020.1

  promising research target. In this work, two series of conjugable hA3AR antagonists, based on the pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine nucleus, were developed. The introduction of an aromatic ring at the 5 position of the scaffold, before (phenylacetamido moiety) or after (1,2,3-triazole obtained by click chemistry) the conjugation is aimed to increase affinity and selectivity towards the hA3AR

  能够同时结合生物学靶标并与第二特定部分缀合的化合物是用于开发多用途配体的有吸引力的工具，所述多用途配体可用作多靶标配体，受体探针或药物递送系统，具有治疗和诊断应用。人A3腺苷受体是一种涉及许多生理病理状况（例如癌症和炎症）的G蛋白偶联受体，因此代表了有希望的研究目标。在这项工作中，基于吡唑并[4,3-e] -1,2,4-三唑并[1,5-c]嘧啶核，开发了两个系列的hA3AR拮抗剂。在（苯乙酰胺基部分）之前或之后（1,2，通过点击化学获得的3-三唑）缀合旨在增加对hA3AR受体的亲和力和选择性。如所预期的，可缀合的化合物对hA3AR表现出良好的亲和力。为了证明其在开发用于不同目的的hA3AR配体方面的潜力，还使用了荧光探针对化合物进行了功能化。不幸的是，与hA2AAR相比，缀合降低了对靶标的亲和力和选择性。计算研究确定了细胞外环的特定非保守残基，这些残基构成了能够区分配体的结构屏障，从而为新