ethyl 1,6-dihydro-1-(m-chlorophenyl)-5-cyano-4-methyl-6-oxopyridazine-3-carboxylate | 123534-18-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: ethyl 1,6-dihydro-1-(m-chlorophenyl)-5-cyano-4-methyl-6-oxopyridazine-3-carboxylate
• 英文别名: ethyl 1-(3-chlorophenyl)-5-cyano-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate；Ethyl 1-(3-chlorophenyl)-5-cyano-4-methyl-6-oxopyridazine-3-carboxylate
• CAS: 123534-18-9
• 化学式: C₁₅H₁₂ClN₃O₃
• 分子量: 317.732
• InChiKey: YHMVCNSYMJECMC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  82.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 1,6-dihydro-1-(m-chlorophenyl)-5-cyano-4-methyl-6-oxopyridazine-3-carboxylate 在 吗啉 、 1,2,3,4,5,6,7,8-八硫杂环辛烷 、 lithium hydroxide monohydrate 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 水 、 二甲基亚砜 为溶剂， 反应 20.25h， 生成 5-amino-3-(3-chlorophenyl)-N-isopropyl-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide
  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：

  氰乙酸乙酯 、 3-chlorophenyl-hydrazono-ethyl-2,3-dioxobutyrate 在 4-氨基丁酸 作用下， 反应 2.5h， 以90%的产率得到ethyl 1,6-dihydro-1-(m-chlorophenyl)-5-cyano-4-methyl-6-oxopyridazine-3-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

• Green and efficient synthesis of polyfunctionally substituted cinnolines under controlled microwave irradiation
  作者：Afaf Abdel Hameed、Essam Khalaf Ahmed、Asmaa A. Abdel Fattah、Carlos Kleber Z. Andrade、Kamal Usef Sadek

  DOI：10.1007/s11164-017-2944-1

  日期：2017.10

  Abstract A convenient, simple and efficient synthesis of polyfunctionally substituted cinnolines has been developed that involves the reaction of ethyl 5-cyano-4-methyl-1-aryl-6-oxo-1,6-dihydropyridazine-3-carboxylate with nitroolefins in dioxane/piperidine under controlled microwave irradiation. The obtained heterocycles are a privileged scaffold in a few natural compounds and in many drugs with a

  摘要 已经开发了一种方便，简单且有效的多官能取代肉桂酸合成方法，该方法涉及在氰基/二恶烷中使5-氰基-4-甲基-1-甲基-1-芳基-6-氧代-1,6-二氢哒嗪-3-羧酸乙酯与硝基烯烃反应。哌啶在受控微波辐射下。所获得的杂环是一些天然化合物和具有广泛生物活性的许多药物中的特权支架。 图形概要
• Studies on alkylheteroaromatic compounds. The reactivity of alkyl polyfunctionally substituted azines towards electrophilic reagents
  作者：Mohamed Hilmy Elnagdi、Fathy Mohamed Abdelrazek、Nadia Sobhy Ibrahim、Ayman Wahba Erian

  DOI：10.1016/s0040-4020(01)81038-3

  日期：1989.1

  Several new alkylpyridine, pyridazine and pyrimidine derivatives are synthesized from acyclic intermediates. The reactivity of these alkylazines towards aromatic aldehydes and arylidenemalononitrile is reported. New synthesis for substituted phthalazines cinnolines and quinazolines could be achieved.

  从无环中间体合成了几种新的烷基吡啶，哒嗪和嘧啶衍生物。据报道这些烷基嗪对芳族醛和芳基丙二腈的反应性。可以实现取代邻苯二氮杂萘酚和喹唑啉的新合成。
• 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.
• Elnagdi, Mohamed Hilmy; Aal, Fatma Abdel Maksoud Abdel; Hafez, Ebtisam Abdel Aziz, Zeitschrift fur Naturforschung, B: Chemical Sciences, 1989, vol. 44, # 6, p. 683 - 689
  作者：Elnagdi, Mohamed Hilmy、Aal, Fatma Abdel Maksoud Abdel、Hafez, Ebtisam Abdel Aziz、Yassin, Youssef Mahfouz

  DOI：——

  日期：——
• Densely functionalized cinnolines: Controlled microwave-assisted facile one-pot multi-component synthesis and in vitro anticancer activity via apoptosis induction
  作者：Maiiada Hassan Nazmy、Ramadan Ahmed Mekheimer、Mai E. Shoman、Mohamed Abo-Elsebaa、Mohamed Abd-Elmonem、Kamal Usef Sadek

  DOI：10.1016/j.bioorg.2020.103932

  日期：2020.8

  There is an urging continuous need for novel anti-cancer agents due to persistent chemoresistance. Herein, newly synthesized cinnolines are evaluated for their possible anticancer activities and suggested mechanisms. In the current study, a simple and efficient synthesis of densely functionalized cinnolines has been developed that relied on multi-component reaction of ethyl 5-cyano-4-methyl-1-aryl-6-oxo-1,6-dihydropyridazine-3-carbox-ylates with aromatic aldehydes and nitromethane in dioxane/pipridine under controlled microwave heating. Selected cinnolines (4a-c, e, h, j-n, q-v) were tested for possible anticancer activity using in vitro one dose assay at National Cancer institute, USA. Only cinnoline 4b stood out as the most potent cinnoline derivative (mean GI %=26.33) with broad-spectrum antitumor activity against the most tested cancer cell lines from all subpanels. The target cinnoline 4b emerged as the most active derivative against both leukemia RPMI-8226 and melanoma LOX IMVI cell lines (GI% = 106.06 and 82.1) respectively, with IC50 values equal to 17.12 +/- 1.31 and 12.32 +/- 0.75 mu g/mL, which are comparable to those of staurosporin; 24.97 +/- 1.47 and 8.45 +/- 0.42 mu g/mL, respectively. Cinnoline 4b influenced cell cycle distribution causing pre-G1 apoptosis and cell growth arrest at G2/M phase. It also induced apoptosis in both cell lines as manifested by significant increase in the percent of annexin V-FITC positive apoptotic cells in leukemia RPMI-8226 cells (from 1.09% to 12.47%) and melanoma LOX IMVI (from 1.32% to 19.05%). In addition, it showed lower expression levels of anti-apoptotic Bcl-2 protein, and higher expression levels of pro-apoptotic proteins; Bax, p53, cytochrome c, caspases 3 and 9. Conclusion: Induction of mitochondrial intrinsic pathway of apoptosis is a possible mechanism by which cin-noline 4b may confer its anticancer activity.