6-chloro-3-ethyl-[1,2,4]triazolo[3,4-a]phthalazine | 678193-49-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 6-chloro-3-ethyl-[1,2,4]triazolo[3,4-a]phthalazine
• 英文别名: 6-Chloro-3-ethyl[1,2,4]triazolo[3,4-a]phthalazine
• CAS: 678193-49-2
• 化学式: C₁₁H₉ClN₄
• mdl: MFCD06618964
• 分子量: 232.672
• InChiKey: XJIMFWNSKGDPIS-UHFFFAOYSA-N

物化性质

• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  43.1
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-chloro-3-ethyl-[1,2,4]triazolo[3,4-a]phthalazine 在 一水合肼 、 potassium hydroxide 作用下， 以 乙醇 为溶剂， 反应 2.5h， 生成 6-ethyl-bis([1,2,4]triazolo)[3,4-a:4′,3′-c]phthalazine-3-thiol
  参考文献：
  名称：

  设计，合成，分子建模，体内研究和评估新型酞嗪衍生物作为潜在的DNA嵌入剂和拓扑异构酶II抑制剂的抗癌活​​性。

  摘要：

  在本文中，我们报告了作为Topo II抑制剂和DNA嵌入剂的一系列新的酞嗪衍生物的设计和合成。体外评价合成的化合物对HepG-2，MCF-7和HCT-116细胞系的细胞毒性活性。此外，还对Topo II抑制活性和DNA嵌入亲和力进行了研究，发现它们具有最强的活性，是抗癌活性的潜在机制。化合物15h，23c，32a，32b和33表现出对Topo II的最高活性，IC 50为5.44至8.90 µM，而化合物27和32a被认为是IC 50最有效的DNA结合剂值分别为36.02和48.30 µM。此外，化合物32a诱导HepG-2细胞凋亡，并使细胞周期停滞在G2 / M期。此外，化合物32a在2.5和5μM的浓度下显示Topo II中毒作用，并且在10μM的浓度下显示Topo II催化抑制作用。另外，化合物32b在体内显示出显着的肿瘤生长抑制作用。此外，针对DNA-Topo II复合物和DNA进

  DOI：

  10.1016/j.bioorg.2020.104233
• 作为产物：
  描述：

  1,4-二氯酞嗪 在 一水合肼 作用下， 以 乙醇 为溶剂， 反应 1.5h， 生成 6-chloro-3-ethyl-[1,2,4]triazolo[3,4-a]phthalazine
  参考文献：
  名称：

  设计，合成，分子建模，体内研究和评估新型酞嗪衍生物作为潜在的DNA嵌入剂和拓扑异构酶II抑制剂的抗癌活​​性。

  摘要：

  在本文中，我们报告了作为Topo II抑制剂和DNA嵌入剂的一系列新的酞嗪衍生物的设计和合成。体外评价合成的化合物对HepG-2，MCF-7和HCT-116细胞系的细胞毒性活性。此外，还对Topo II抑制活性和DNA嵌入亲和力进行了研究，发现它们具有最强的活性，是抗癌活性的潜在机制。化合物15h，23c，32a，32b和33表现出对Topo II的最高活性，IC 50为5.44至8.90 µM，而化合物27和32a被认为是IC 50最有效的DNA结合剂值分别为36.02和48.30 µM。此外，化合物32a诱导HepG-2细胞凋亡，并使细胞周期停滞在G2 / M期。此外，化合物32a在2.5和5μM的浓度下显示Topo II中毒作用，并且在10μM的浓度下显示Topo II催化抑制作用。另外，化合物32b在体内显示出显着的肿瘤生长抑制作用。此外，针对DNA-Topo II复合物和DNA进

  DOI：

  10.1016/j.bioorg.2020.104233

文献信息

• [EN] TRIAZOLO-PYRIDAZINE COMPOUNDS AND DERIVATIVES THEREOF USEFUL IN THE TREATMENT OF NEUROPATHIC PAIN<br/>[FR] COMPOSES DE TRIAZOLO-PYRIDAZINE ET LEURS DERIVES, DESTINES AU TRAITEMENT DE LA DOULEUR NEUROPATHIQUE
  申请人：MERCK & CO INC

  公开号：WO2005041971A1

  公开（公告）日：2005-05-12

  The present invention is directed to a method of use of triazolo-pyridazine compounds in the treatment of neuropathic pain. The present invention is also directed to the use of triazolo-pyridazine compounds in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorders, and panic, as well as in the treatment of pain, Parkinson’s disease, cognitive dysfunction, epilepsy, circadian rhythm and sleep disorders - such as shift-work induced sleep disorder and jet-lag, drug addiction, drug abuse, drug withdrawal and other diseases. The present invention is also directed to novel triazolo-pyridazine compounds that selectively bind to α2δ-1 subunit of Ca channels.

  本发明涉及一种在治疗神经病性疼痛中使用三唑吡啶化合物的方法。本发明还涉及在治疗精神和情绪障碍，如精神分裂症、焦虑、抑郁、躁郁症和恐慌，以及在治疗疼痛、帕金森病、认知功能障碍、癫痫、昼夜节律和睡眠障碍（如倒班引起的睡眠障碍和时差反应）、药物成瘾、药物滥用、药物戒断和其他疾病中使用三唑吡啶化合物的方法。本发明还涉及选择性结合到Ca通道α2δ-1亚基的新型三唑吡啶化合物。
• 3-Phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-<i>a</i>]phthalazines and Analogues:  High-Affinity γ-Aminobutyric Acid-A Benzodiazepine Receptor Ligands with α2, α3, and α5-Subtype Binding Selectivity over α1
  作者：Robert W. Carling、Kevin W. Moore、Leslie J. Street、Deborah Wild、Catherine Isted、Paul D. Leeson、Steven Thomas、Desmond O'Connor、Ruth M. McKernan、Katherine Quirk、Susan M. Cook、John R. Atack、Keith A. Wafford、Sally A. Thompson、Gerard R. Dawson、Pushpinder Ferris、José L. Castro

  DOI：10.1021/jm031020p

  日期：2004.3.1

  Studies with our screening lead 5 and the literature compound 6 led to the identification of 6-benzyloxy-3-(4-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazine 8 as a ligand with binding selectivity for the gamma-aminobutyric acid-A (GABA-A) alpha3- and alpha5-containing receptor subtypes over the GABA-A alpha1 subtype (K-i: alpha2 = 850 nM, alpha3 = 170 nM, alpha5 = 72 nM, alpha1 = 1400 nM). Early optimization studies identified the close analogue 10 (Ki: alpha2 = 16 nM, alpha3 = 41 nM, alpha5 = 38 nM, alpha1 = 280 nM) as a suitable lead for further study. High-affinity ligands were identified by replacing the 6-benzyloxy group of compound 10 with 2-pyridylmethoxy (compound 29), but binding selectivity was not enhanced (K-i: alpha2 = 1.7 nM, alpha3 = 0.71 nM, alpha5 = 0.33 nM, alpha1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes,(22) 29 was discovered to be a weak to moderate inverse agonist at all four receptor subtypes (alpha1, -7%; alpha2, -5%; alpha3, -16%; alpha5, -5%). Replacement of the 3-phenyl group of 29 with alternatives led to reduced affinity, and smaller 3-substituents led to reduced efficacy. Methyl substitution of the benzo-fused ring of 29 at the 7-, 8-, and 10-positions resulted in increased efficacy although selectivity was abolished. Increased efficacy and retention of selectivity for alpha3 over alpha1 was achieved with the 7,8,9,10-tetrahydro-(7,10-ethano)-phthalazine 62. Compound 62 is currently one of the most binding selective GABA-A alpha3-benzodiazepine-site partial agonists known, and although its selectivity is limited, its good pharmacokinetic profile in the rat (33% oral bioavailability after a 3 mg/kg dose, reaching a peak plasma concentration of 179 ng/mL; half-life of I h) made it a useful pharmacological tool to explore the effect of a GABA-A alpha2/alpha3 agonist in vivo.
• Identification and synthesis of [1,2,4]triazolo[3,4-a]phthalazine derivatives as high-affinity ligands to the α2δ-1 subunit of voltage gated calcium channel
  作者：Alec D. Lebsack、Janet Gunzner、Bowei Wang、Richard Pracitto、Hervé Schaffhauser、Angelina Santini、Jayashree Aiyar、Robert Bezverkov、Benito Munoz、Wensheng Liu、Shankar Venkatraman

  DOI：10.1016/j.bmcl.2004.03.008

  日期：2004.5

  We have identified and synthesized a series of [1,2,4]triazolo[3,4-a]phthalazine derivatives as high-affinity ligands to alpha(2)delta-1 subunit of voltage gated calcium channels. Structure-activity relationship studies directed toward improving the potency and physical properties of 2 lead to the discovery of 20 (IC50 = 15 nM) and (S)-22 (IC50 = 30 nM). A potent and selective radioligand, [H-3]-(S)-22 was also synthesized to demonstrate that this ligand binds to the same site as gabapentin. (C) 2004 Elsevier Ltd. All rights reserved.
• [1,2,4]Triazolo[4,3-<i>a</i>]phthalazines: Inhibitors of Diverse Bromodomains
  作者：Oleg Fedorov、Hannah Lingard、Chris Wells、Octovia P. Monteiro、Sarah Picaud、Tracy Keates、Clarence Yapp、Martin Philpott、Sarah J. Martin、Ildiko Felletar、Brian D. Marsden、Panagis Filippakopoulos、Susanne Müller、Stefan Knapp、Paul E. Brennan

  DOI：10.1021/jm401568s

  日期：2014.1.23

  Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9, CECR2, and CREBBP. This new series of compounds. is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology.
• Design, synthesis, molecular modeling, in vivo studies and anticancer activity evaluation of new phthalazine derivatives as potential DNA intercalators and topoisomerase II inhibitors
  作者：Abdel-Ghany A. El-Helby、Helmy Sakr、Rezk R. Ayyad、Hazem A. Mahdy、Mohamed M. Khalifa、Amany Belal、Mahmoud Rashed、Abdou El-Sharkawy、Ahmed M. Metwaly、Mostafa A. Elhendawy、Mohamed M. Radwan、Mahmoud A. ElSohly、Ibrahim H. Eissa

  DOI：10.1016/j.bioorg.2020.104233

  日期：2020.10

  Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism

  在本文中，我们报告了作为Topo II抑制剂和DNA嵌入剂的一系列新的酞嗪衍生物的设计和合成。体外评价合成的化合物对HepG-2，MCF-7和HCT-116细胞系的细胞毒性活性。此外，还对Topo II抑制活性和DNA嵌入亲和力进行了研究，发现它们具有最强的活性，是抗癌活性的潜在机制。化合物15h，23c，32a，32b和33表现出对Topo II的最高活性，IC 50为5.44至8.90 µM，而化合物27和32a被认为是IC 50最有效的DNA结合剂值分别为36.02和48.30 µM。此外，化合物32a诱导HepG-2细胞凋亡，并使细胞周期停滞在G2 / M期。此外，化合物32a在2.5和5μM的浓度下显示Topo II中毒作用，并且在10μM的浓度下显示Topo II催化抑制作用。另外，化合物32b在体内显示出显着的肿瘤生长抑制作用。此外，针对DNA-Topo II复合物和DNA进