4-[3-(2-furyl)-1H-1,2,4-triazol-5-yl]-1-methyl-1H-pyrazol-3-amine | 159979-89-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 亚胺内酰胺
• 英文名称: 4-[3-(2-furyl)-1H-1,2,4-triazol-5-yl]-1-methyl-1H-pyrazol-3-amine
• 英文别名: 4-[5-(furan-2-yl)-1H-1,2,4-triazol-3-yl]-1-methylpyrazol-3-amine
• CAS: 159979-89-2
• 化学式: C₁₀H₁₀N₆O
• 分子量: 230.229
• InChiKey: OLUDFFLNUJSCKX-UHFFFAOYSA-N

物化性质

• 沸点：
  541.6±60.0 °C(Predicted)
• 密度：
  1?+-.0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  98.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-[3-(2-furyl)-1H-1,2,4-triazol-5-yl]-1-methyl-1H-pyrazol-3-amine 在 吡啶 、 五氯化磷 、 三乙胺 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 27.5h， 生成 (R)-(2-(furan-2-yl)-8-methyl-pyrazolo[4,3-e][1,2,4]triazolo-[1,5-c]pyrimidin-5-yl)-(1-phenyl-ethyl)amine
  参考文献：
  名称：

  Revisiting a Receptor-Based Pharmacophore Hypothesis for Human A_2A Adenosine Receptor Antagonists

  摘要：

  The application of both structure- and ligand-based design approaches represents to date one of the most useful strategies in the discovery of new drug candidates. In the present paper, we investigated how the application of docking-driven conformational analysis can improve the predictive ability of 3D-QSAR statistical models. With the use of the crystallographic structure in complex with the high affinity antagonist ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo [2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol), we revisited a general pharmacophore hypothesis for the human A(2A) adenosine receptor of a set of 751 known antagonists, by applying an integrated ligand- and structure-based approach. Our novel pharmacophore hypothesis has been validated by using an external test set of 29 newly synthesized human adenosine receptor antagonists.

  DOI：

  10.1021/ci300615u
• 作为产物：
  描述：

  1-甲基-3-氨基-4-氰基吡唑 在 盐酸 作用下， 以 二苯醚 、 乙二醇甲醚 、 水 为溶剂， 反应 46.0h， 生成 4-[3-(2-furyl)-1H-1,2,4-triazol-5-yl]-1-methyl-1H-pyrazol-3-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

• 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
• Exploring the Directionality of 5-Substitutions in a New Series of 5-Alkylaminopyrazolo[4,3-<i>e</i>]1,2,4-triazolo[1,5-<i>c</i>]pyrimidine as a Strategy To Design Novel Human A₃ Adenosine Receptor Antagonists.
  作者：Stephanie Federico、Antonella Ciancetta、Davide Sabbadin、Silvia Paoletta、Giorgia Pastorin、Barbara Cacciari、Karl Norbert Klotz、Stefano Moro、Giampiero Spalluto

  DOI：10.1021/jm300899q

  日期：2012.11.26

  The structure-activity relationship (SAR) of new 5-alkylaminopyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as antagonists of the A(3) adenosine receptor (AR) was explored with the principal aim to establish the directionality of 5-substitutions inside the orthosteric binding site of the A(3) AR. All the synthesized compounds showed affinity for the hA(3) AR from nanomolar to subnanomolar range. In particular, the most potent and selective antagonist presents an (S) alpha-phenylethylamino moiety at the 5 position (26, K-i hA(3) = 0.3 nM). Using an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 position of the pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) scaffold, opening the possibility for further derivatizations aimed at directing the N-5 position toward the extracellular environment.
• [EN] ENHANCING TREATMENT OF CANCER AND HIF-1 MEDIATED DISODERS WITH ADENOSINE A3 RECEPTOR ANTAGONISTS<br/>[FR] AMELIORATION DU TRAITEMENT DU CANCER ET DE TROUBLES MEDIES PAR HIF-1 AU MOYEN D'ANTAGONISTES DES RECEPTEURS DE L'ADENOSINE A3
  申请人：KING PHARMACEUTICALS RES & DEV

  公开号：WO2007040565A9

  公开（公告）日：2007-07-05

  [EN] The present invention relates to the use of adenosine receptor antagonists, preferably A₃ receptor antagonists, either alone or in combination with other agents for the treatment, prevention and/or management of diseases or disorders associated with overexpression of HIF-la and/or increased HIF-1 a activity (e.g., cancer, respiratory disease). The methods and compositions of the invention are particularly useful for preventing, treating, or ameliorating symptoms associated with a cancer, disease or disorder associated with hypoxia-inducible factor 1-a (HIF-la) using the A₃ receptor antagonists of the invention. The present invention provides methods to inhibit the growth of tumors, particularly solid tumors and more particularly hypoxic tumors.
  [FR] La présente invention concerne l'utilisation d'antagonistes des récepteurs de l'adénosine, de préférence des antagonistes des récepteurs de l'A₃, de manière isolée ou en combinaison avec d'autres agents pour le traitement, la prévention et/ou la gestion de maladies ou de troubles associés à la surexpression de HIF-1a et/ou à une activité HIF-1a accrue (par ex., cancer, maladie respiratoire). Les méthodes et les compositions de l'invention sont particulièrement utiles pour prévenir, traiter ou atténuer les symptômes associés à un cancer, une maladie ou un trouble liés au facteur inductible par l'hypoxie 1a (HIF-1a) au moyen des antagonistes des récepteurs de l'A₃ susmentionnés. La présente invention concerne des méthodes destinées à inhiber la croissance de tumeurs, notamment de tumeurs solides, et plus particulièrement de tumeurs hypoxiques.
• One-Pot Reaction To Obtain N,N′-Disubstituted Guanidines of Pyrazolo[4,3-<i>e</i>][1,2,4]triazolo[1,5-<i>c</i>]pyrimidine Scaffold as Human A₃ Adenosine Receptor Antagonists
  作者：Pier Giovanni Baraldi、Stefania Baraldi、Giulia Saponaro、Mojgan Aghazadeh Tabrizi、Romeo Romagnoli、Emanuela Ruggiero、Fabrizio Vincenzi、Pier Andrea Borea、Katia Varani

  DOI：10.1021/acs.jmedchem.5b00551

  日期：2015.7.9

  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.
• Revisiting a Receptor-Based Pharmacophore Hypothesis for Human A_2A Adenosine Receptor Antagonists
  作者：Magdalena Bacilieri、Antonella Ciancetta、Silvia Paoletta、Stephanie Federico、Sandro Cosconati、Barbara Cacciari、Sabrina Taliani、Federico Da Settimo、Ettore Novellino、Karl Norbert Klotz、Giampiero Spalluto、Stefano Moro

  DOI：10.1021/ci300615u

  日期：2013.7.22

  The application of both structure- and ligand-based design approaches represents to date one of the most useful strategies in the discovery of new drug candidates. In the present paper, we investigated how the application of docking-driven conformational analysis can improve the predictive ability of 3D-QSAR statistical models. With the use of the crystallographic structure in complex with the high affinity antagonist ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo [2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol), we revisited a general pharmacophore hypothesis for the human A(2A) adenosine receptor of a set of 751 known antagonists, by applying an integrated ligand- and structure-based approach. Our novel pharmacophore hypothesis has been validated by using an external test set of 29 newly synthesized human adenosine receptor antagonists.