5-amino-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylic acid | 1282449-07-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩哒嗪类
• 英文名称: 5-amino-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylic acid
• 英文别名: 5-amino-3-(4-fluorophenyl)-4-oxothieno[3,4-d]pyridazine-1-carboxylic acid
• CAS: 1282449-07-3
• 化学式: C₁₃H₈FN₃O₃S
• 分子量: 305.289
• InChiKey: LXKJTDVHWVUZAR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  124
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-amino-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylic acid 在 盐酸 、 水 作用下， 以 乙腈 为溶剂， 反应 0.5h， 生成 3-(4-fluorophenyl)-4,5-dioxo-3,4,5,7-tetrahydrothieno[3,4-d]pyridazine-1-carboxylic acid
  参考文献：
  名称：

  Aminothienopyridazine inhibitors of tau aggregation: Evaluation of structure–activity relationship leads to selection of candidates with desirable in vivo properties

  摘要：

  Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50 mg/kg/day. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.05.027
• 作为产物：
  描述：

  ethyl 5-cyano-1-(4-fluorophenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate 在 吗啉 、 lithium hydroxide monohydrate 、 水 、 sulfur 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 18.25h， 生成 5-amino-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylic acid
  参考文献：
  名称：

  开环氨基噻吩并哒嗪类新型tau聚集抑制剂

  摘要：

  氨基噻吩并哒嗪（ATPZs）在体外已证明可作为tau蛋白聚集抑制剂发挥作用。对ATPZ支架进行了修改，以确定某些结构特征对于活性的重要性。更具体地说，合成了在哒嗪的氮-氮键上分离的开环类似物，并对其抑制活性进行了评估。初步数据表明，开环结构保持抑制活性，与tau氧化反应无关。详细的结构代表了解构，重建和修饰研究的开始，目的是鉴定更简单的支架，这些支架保留活性并可以在理化特性方面进行优化。

  DOI：

  10.1039/c6md00306k

文献信息

• AMINOTHIENOPYRIDAZINE INHIBITORS OF TAU ASSEMBLY
  申请人：Ballatore Carlo

  公开号：US20130029983A1

  公开（公告）日：2013-01-31

  The present invention is directed to methods of inhibiting a tauopathy in a patient by administration of a compound of formula I: Novel aminothienopyridazine compounds are also described.

  本发明涉及通过给予I型化合物来抑制患者的tau病变的方法：还描述了新的氨基噻吩吡嗪化合物。
• [EN] AMINOTHIENOPYRIDAZINE INHIBITORS OF TAU ASSEMBLY<br/>[FR] INHIBITEURS AMINOTHIÉNOPYRIDAZINIQUES DE L'ASSEMBLAGE DES MICROTUBULES SOUS L'EFFET DE LA PROTÉINE TAU
  申请人：UNIV PENNSYLVANIA

  公开号：WO2011037985A1

  公开（公告）日：2011-03-31

  The present invention is directed to methods of inhibiting a tauopathy in a patient by administration of a compound of formula (I): Novel aminothienopyridazine compounds are also described.
• Aminothienopyridazine inhibitors of tau aggregation: Evaluation of structure–activity relationship leads to selection of candidates with desirable in vivo properties
  作者：Carlo Ballatore、Alex Crowe、Francesco Piscitelli、Michael James、Kevin Lou、Gabrielle Rossidivito、Yuemang Yao、John Q. Trojanowski、Virginia M.-Y. Lee、Kurt R. Brunden、Amos B. Smith

  DOI：10.1016/j.bmc.2012.05.027

  日期：2012.7

  Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50 mg/kg/day. (C) 2012 Elsevier Ltd. All rights reserved.
• Ring-opened aminothienopyridazines as novel tau aggregation inhibitors
  作者：M. Moir、S. W. Chua、T. Reekie、A. D. Martin、A. Ittner、L. M. Ittner、M. Kassiou

  DOI：10.1039/c6md00306k

  日期：——

  detached at the nitrogen–nitrogen bond of the pyridazine, were synthesized and their inhibitory activity evaluated. Preliminary data suggests that the ring-opened structures retain inhibitory activity, independent of tau oxidation. The structures detailed represent the beginnings of a deconstruction–reconstruction–elaboration study, with the aim of identifying simpler scaffolds, which retain activity and can

  氨基噻吩并哒嗪（ATPZs）在体外已证明可作为tau蛋白聚集抑制剂发挥作用。对ATPZ支架进行了修改，以确定某些结构特征对于活性的重要性。更具体地说，合成了在哒嗪的氮-氮键上分离的开环类似物，并对其抑制活性进行了评估。初步数据表明，开环结构保持抑制活性，与tau氧化反应无关。详细的结构代表了解构，重建和修饰研究的开始，目的是鉴定更简单的支架，这些支架保留活性并可以在理化特性方面进行优化。