ethyl 5-amino-3-(3-chlorophenyl)-4-oxo-3,4-dihydrothieno-[3,4-d]pyridazine-1-carboxylate | 1062292-52-7

• 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: ethyl 5-amino-3-(3-chlorophenyl)-4-oxo-3,4-dihydrothieno-[3,4-d]pyridazine-1-carboxylate
• 英文别名: ethyl 5-amino-3-(3-chlorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylate；ethyl 5-amino-3-(3-chlorophenyl)-4-oxothieno[3,4-d]pyridazine-1-carboxylate
• CAS: 1062292-52-7
• 化学式: C₁₅H₁₂ClN₃O₃S
• 分子量: 349.798
• InChiKey: XXOVWLRNSMIVHV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  113
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 5-amino-3-(3-chlorophenyl)-4-oxo-3,4-dihydrothieno-[3,4-d]pyridazine-1-carboxylate 在 四丁基碘化铵 、 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 ethyl 3-(3-chlorophenyl)-5-(N-methylacetamido)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylate
  参考文献：
  名称：

  New methodology for the N-alkylation of 2-amino-3-acylthiophenes

  摘要：

  2-氨基-3-酰基噻吩已知能变构性调节A1腺苷受体，并且也被用作合成治疗药物和药效团的中间体，如噻唑衍生物和噻唑嘧啶。2-氨基噻吩的N-烷基化在温和条件下 notoriously 难以实现，文献中关于N-烷基化的2-氨基噻吩的例子非常少，且所有这些都采用强迫条件来进行烷基化。在此，我们描述了在温和条件下合成此类化合物的方法，使用2-氨基酰氨和2-酰基氨基-3-酰基噻吩与碳酸铯及四丁基氨盐碘化物在DMF中反应。

  DOI：

  10.1039/c0ob01156h
• 作为产物：
  描述：

  3-chlorophenyl-hydrazono-ethyl-2,3-dioxobutyrate 在 吗啉 、 1,2,3,4,5,6,7,8-八硫杂环辛烷 、 4-氨基丁酸 作用下， 以 乙醇 为溶剂， 反应 2.75h， 生成 ethyl 5-amino-3-(3-chlorophenyl)-4-oxo-3,4-dihydrothieno-[3,4-d]pyridazine-1-carboxylate
  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

文献信息

• 2-Aminothienopyridazines as Novel Adenosine A₁ Receptor Allosteric Modulators and Antagonists
  作者：Gemma N. Ferguson、Celine Valant、James Horne、Heidi Figler、Bernard L. Flynn、Joel Linden、David K. Chalmers、Patrick M. Sexton、Arthur Christopoulos、Peter J. Scammells

  DOI：10.1021/jm800557d

  日期：2008.10.9

  A pharmacophore-based screen identified 32 compounds including ethyl 5-amino-3-(4-tert-butylphenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylate (8) as a new allosteric modulator of the adenosine A(1) receptor (A(1)AR). On the basis of this lead, various derivatives were prepared and evaluated for activity at the human A(1)AR. A number of the test compounds allosterically stabilized agonist-receptor-G protein ternary complexes in dissociation kinetic assays, but were found to be more potent as antagonists in subsequent functional assays of ERK1/2 phosphorylation. Additional experiments on the most potent antagonist, 13b, investigating A(1)AR-mediated [S-35]GTP gamma S binding and [H-3]CCPA equilibrium binding confirmed its antagonistic mode of action and also identified inverse agonism. This study has thus identified a new class of A(1)AR antagonists that can also recognize the receptor's allosteric site with lower potency.
• 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.
• New methodology for the N-alkylation of 2-amino-3-acylthiophenes
  作者：Luigi Aurelio、Bernard L. Flynn、Peter J. Scammells

  DOI：10.1039/c0ob01156h

  日期：——

  2-Amino-3-acylthiophenes are known to allosterically modulate the A1adenosine receptor and are also used as intermediates in the synthesis of therapeutic agents and pharmacophores such as thienoazepines and thienopyrimidines. The N-alkylation of 2-aminothiophenes has been notoriously difficult to accomplish under mild conditions and there are very few examples of N-alkylated 2-aminothiophenes in the literature, all of which use forcing conditions to effect the alkylation. Here we describe the synthesis of such compounds under mild conditions utilising 2-carbamoylamino and 2-acylamino-3-acylthiophenes with caesium carbonate, and tetrabutylammonium iodide in DMF.

  2-氨基-3-酰基噻吩已知能变构性调节A1腺苷受体，并且也被用作合成治疗药物和药效团的中间体，如噻唑衍生物和噻唑嘧啶。2-氨基噻吩的N-烷基化在温和条件下 notoriously 难以实现，文献中关于N-烷基化的2-氨基噻吩的例子非常少，且所有这些都采用强迫条件来进行烷基化。在此，我们描述了在温和条件下合成此类化合物的方法，使用2-氨基酰氨和2-酰基氨基-3-酰基噻吩与碳酸铯及四丁基氨盐碘化物在DMF中反应。