2,3,6,7,8,9-hexahydro-5H-cyclohepta[d]pyridazine-1,4-dione | 678193-50-5

• 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: 2,3,6,7,8,9-hexahydro-5H-cyclohepta[d]pyridazine-1,4-dione
• 英文别名: 2,3,6,7,8,9-hexahydro-1H-cyclohepta[d]pyridazine-1,4(5H)-dione；3,5,6,7,8,9-hexahydro-2H-cyclohepta[d]pyridazine-1,4-dione
• CAS: 678193-50-5
• 化学式: C₉H₁₂N₂O₂
• 分子量: 180.206
• InChiKey: CEANKMUPYZTHAK-UHFFFAOYSA-N

物化性质

• 密度：
  1.26±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.33
• 重原子数：
  13.0
• 可旋转键数：
  0.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  65.72
• 氢给体数：
  2.0
• 氢受体数：
  2.0

反应信息

• 作为反应物：
  描述：

  2,3,6,7,8,9-hexahydro-5H-cyclohepta[d]pyridazine-1,4-dione 在 tris-(dibenzylideneacetone)dipalladium(0) 、 四(三苯基膦)钯 、 potassium carbonate 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 8.67h， 生成 tert-butyl (R)-3-((4-(2-methoxy-4-methylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyridazin-1-yl)amino)piperidine-1-carboxylate
  参考文献：
  名称：

  [EN] NLRP3 INFLAMMASOME INHIBITOR AND APPLICATION THEREOF
  [FR] INHIBITEUR DE L'INFLAMMASOME NLRP3 ET SON UTILISATION
  [ZH] NLRP3炎症小体抑制剂及其应用

  摘要：

  本发明属于医药技术领域，涉及NLRP3炎症小体抑制剂及其应用。具体涉及通式(I)表示的化合物或其药学上可接受的盐、立体异构体、互变异构体，各基团的定义如说明书中所定义。研究表明，通式(I)表示的化合物或其药学上可接受的盐、立体异构体、互变异构体，对NLRP3炎症小体具有较高的生物活性，对于治疗NLRP3相关疾病具有重要的临床开发价值。

  公开号：

  WO2022253326A1
• 作为产物：
  描述：

  Cycloheptene-1,2-dicarboxylic anhydride 在 sodium acetate 、 一水合肼 、 溶剂黄146 作用下， 以 水 为溶剂， 生成 2,3,6,7,8,9-hexahydro-5H-cyclohepta[d]pyridazine-1,4-dione
  参考文献：
  名称：

  [EN] NLRP3 INFLAMMASOME INHIBITOR AND APPLICATION THEREOF
  [FR] INHIBITEUR DE L'INFLAMMASOME NLRP3 ET SON UTILISATION
  [ZH] NLRP3炎症小体抑制剂及其应用

  摘要：

  本发明属于医药技术领域，涉及NLRP3炎症小体抑制剂及其应用。具体涉及通式(I)表示的化合物或其药学上可接受的盐、立体异构体、互变异构体，各基团的定义如说明书中所定义。研究表明，通式(I)表示的化合物或其药学上可接受的盐、立体异构体、互变异构体，对NLRP3炎症小体具有较高的生物活性，对于治疗NLRP3相关疾病具有重要的临床开发价值。

  公开号：

  WO2022253326A1

文献信息

• 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.