1,4-二氯-5-甲基二氮杂萘 | 678193-44-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 1,4-二氯-5-甲基二氮杂萘
• 中文别名: 1,4-二氯-5-甲基酞嗪
• 英文名称: 1,4-dichloro-5-methylphthalazine
• CAS: 678193-44-7
• 化学式: C₉H₆Cl₂N₂
• 分子量: 213.066
• InChiKey: SYLVRLGENAJCHB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  25.8
• 氢给体数：
  0
• 氢受体数：
  2

安全信息

• 海关编码：
  2933990090

反应信息

• 作为反应物：
  描述：

  1,4-二氯-5-甲基二氮杂萘 在 sodium hydride 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 、 xylene 为溶剂， 反应 45.25h， 生成 7-Methyl-3-phenyl-6-(pyridin-2-ylmethoxy)-[1,2,4]triazolo[3,4-a]phthalazine
  参考文献：
  名称：

  3-Phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and Analogues:  High-Affinity γ-Aminobutyric Acid-A Benzodiazepine Receptor Ligands with α2, α3, and α5-Subtype Binding Selectivity over α1

  摘要：

  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.

  DOI：

  10.1021/jm031020p
• 作为产物：
  描述：

  3-甲基邻苯二甲酸酐 在 一水合肼 、 三氯氧磷 作用下， 以 neat (no solvent) 为溶剂， 反应 27.0h， 生成 1,4-二氯-5-甲基二氮杂萘
  参考文献：
  名称：

  通过双环化/开环机制的1,4-二甲氧基邻苯二甲酰氮的N-氯化环收缩

  摘要：

  发现并利用亲电子氯化试剂三氯异氰尿酸（TCICA）对1,2-二嗪进行了前所未有的N-氯化环收缩。通过优化和机理分析，确定了n -Bu 4 NCl作为外源性亲核试剂的辅助作用，并将优化的反应条件应用于一系列1,4-二甲氧基邻苯二甲酰肼衍生物。同样，通过使用不稳定的O证明了整体效率的提高。-硅烷基。提出了一种由Favorskii重排启发的双环化/开环机制，并得到DFT计算的支持。此外，在范围扩大方面的努力以及对其他亲电性启动子的评估表明，新开发的环收缩反应性是1,4-二甲氧基邻苯二甲酰胺骨架和TCICA的独特特征。

  DOI：

  10.1055/s-0040-1706639

文献信息

• N-Chlorination-induced, oxidative ring contraction of 1,4-dimethoxyphthalazines
  作者：Jeong Kyun Im、ByeongDo Yang、Ilju Jeong、Jun-Ho Choi、Won-jin Chung

  DOI：10.1016/j.tetlet.2020.152048

  日期：2020.6

  A rarely explored oxidative ring contraction of electron-rich 1,2-diazine is described. Upon treatment with an electrophilic chlorinating reagent (TCICA), 1,4-dimethoxyphthalazines undergo an N-chlorination-induced ring contraction that is accompanied by the loss of one nitrogen atom. The scope of this unusual reactivity was examined with a range of 1,4-dimethoxyphthalazine derivatives. In addition

  描述了很少探索的富电子的1,2-二嗪的氧化环收缩。用亲电子氯化试剂（TCICA）处理后，1,4-二甲氧基邻苯二甲azine嗪会经历N-氯化诱导的环收缩，并伴有一个氮原子的损失。用一系列的1，4-二甲氧基邻苯二甲醛衍生物检查了这种异常反应性的范围。另外，基于分离的反应中间体和DFT计算，提出了经由双环物质进行的机理。
• [EN] FUSED PYRIDAZINE DERIVATIVES AS NLRP3 INHIBITORS<br/>[FR] DÉRIVÉS DE PYRIDAZINE FUSIONNÉS UTILISÉS COMME INHIBITEURS DE NLRP3
  申请人：[en]TAKEDA PHARMACEUTICAL COMPANY LIMITED

  公开号：WO2023194964A1

  公开（公告）日：2023-10-12

  Disclosed are compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein α, β, m, R5, R6, R7, R9, R10, R11, Ra, Rb, X1, X2, X3, X4and X8are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula (I), to pharmaceutical compositions which contain them, and to their use for treating diseases, disorders, and conditions associated with NLRP3.
• 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.
• N-Chlorinative Ring Contraction of 1,4-Dimethoxyphthalazines via a Bicyclization/Ring-Opening Mechanism
  作者：Jeong Kyun Im、Ilju Jeong、Jun-Ho Choi、Won-jin Chung、ByeongDo Yang、Hyeon Moon

  DOI：10.1055/s-0040-1706639

  日期：2021.5

  Also, an improvement of overall efficiency was demonstrated by the use of a labile O-silyl group. A bicyclization/ring-opening mechanism, inspired by the Favorskii rearrangement, was proposed and supported by the DFT calculations. Furthermore, the efforts on scope expansion as well as the evaluation of other electrophilic promoters revealed that the newly developed ring contraction reactivity is a

  发现并利用亲电子氯化试剂三氯异氰尿酸（TCICA）对1,2-二嗪进行了前所未有的N-氯化环收缩。通过优化和机理分析，确定了n -Bu 4 NCl作为外源性亲核试剂的辅助作用，并将优化的反应条件应用于一系列1,4-二甲氧基邻苯二甲酰肼衍生物。同样，通过使用不稳定的O证明了整体效率的提高。-硅烷基。提出了一种由Favorskii重排启发的双环化/开环机制，并得到DFT计算的支持。此外，在范围扩大方面的努力以及对其他亲电性启动子的评估表明，新开发的环收缩反应性是1,4-二甲氧基邻苯二甲酰胺骨架和TCICA的独特特征。