苯基哒嗪酮及其GABA衍生物的合成、抗惊活性及构效关系的研究

本文报道了14个6－芳基－4，5－二氢－3（2H）哒嗪酮，15个6－芳基－3（2H）哒嗪酮和17个6－芳基哒嗪的3位GABA衍生物的合成及其抗电惊活性。活性最强的是2′，4′－二氯苯基－3（2H）哒嗪酮（ED50＝10.15mg/kg）。对芳基哒嗪酮类的构效分析表明，苯环上的取代基对化合物的抗惊活性有明显影响，吸电子取代基和疏水性参数值较大的取代基有利于提高化合物的抗惊活性。     

Aminopyridazines attenuate hippocampus-dependent behavioral deficits induced by human β-amyloid in a murine model of neuroinflammation

The importance of glial cell-driven neuroinflammation in the pathogenesis and progression of Alzheimer’s disease (AD) led us to initiate a drug discovery effort targeting the neuroinflammatory cycle that is characteristic of AD. We used our synthetic chemistry platform focused on bioavailable aminopyridazines as a new chemotype for AD drug discovery to develop novel, selective suppressors of key inflammatory and oxidative pathways in glia. We found that MW01-070C, an aminopyridazine that works via mechanisms distinct from NSAIDs and p38 MAPK inhibitors, attenuates β-amyloid (Aβ)-induced neuroinflammation and neuronal dysfunction in a dose-dependent manner, and prevents Aβ-induced behavioral impairment. In vivo data were obtained with a murine model that uses intraventricular infusion of human Aβ1–42 peptide and replicates many of the hallmarks of AD pathology, including neuroinflammation, neuronal and synaptic degeneration, and amyloid deposition. The quantifiable endpoint pathology is robust, reproducible, and rapid in onset. Our results provide a proof of concept that targeting neuroinflammation with aminopyridazines is a viable AD drug discovery approach that has the potential to modulate disease progression and document the utility of this mouse model for preclinical screening of compounds targeting AD-relevant neuroinflammation and neuronal death.     

Synthesis and biological evaluation of pyridazino[4,3-b]indoles and indeno[1,2-c]pyridazines as new ligands of central and peripheral benzodiazepine receptors

A large number of pyridazino[4,3-b]indoles and indeno[1,2-c]pyridazines were synthesised and tested to evaluate their binding affinities at both central (CBR) and peripheral (PBR) benzodiazepine receptors. Relatively good PBR binding affinities were found for ligands belonging to the 3-arylmethyloxy-pyridazinoindole series, whereas only 2-aryl-indenopyridazines 7a, 8a and 10a display a weak binding affinity for CBR. To find out the main structural determinants affecting PBR affinity, a molecular modelling study based on the comparative analysis of the three-dimensional properties of four properly selected derivatives 24a, 3b, 18a and 10d, with those of highly active and selective PBR ligands, taken as reference, was performed.     

双二茂铁丙烷哒嗪酮的合成与电化学性质

目的合成6-双二茂铁丙烷基4,5-二氢哒嗪-3（2H）酮,对其电化学性质进行初步研究。方法双二茂铁丙烷先与丁二酸单乙酯酰氯发生酰化反应,生成的1,4-酮酸酯再与水合肼缩合得到含有双二茂铁丙烷的哒嗪酮衍生物。结果通过两步反应合成了6-双二茂铁丙烷基-4,5-二氢哒嗪-3（2H）-酮。结论用IR、MS、^1NMR对标题化合物的结构进行了表征。电化学研究表明哒嗪酮基团的引入会对双二茂铁的氧化还原可逆性造成一定的影响。     

哒嗪类药物Y－909对凝血酶诱导的人血小板聚集和胞浆游离钙水平的影响

哒嗪类药物Ｙ－９０９对凝血酶诱导的人血小板聚集和胞浆游离钙水平的影响汪钟，于润，张宏，白建平（中国医学科学院基础医学研究所，北京１００００５）６－［对－（４－（４－甲氧基苯基）哌嗪基）－乙酰胺基苯基］－５－甲基－４，５－二氢－３（２氢）哒嗪酮｛６－［...     

Inhibition of fibroblast-like cell proliferation by interleukin-1 blockers, CK-119 and CK-122

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哒嗪酮类化合物的合成及抑制血小板聚集作用

目的:设计合成6-(4-取代乙酰胺基)苯基-4,5-二氢-3(2H)-哒嗪酮和6-(4-取代乙酰胺基)苯基-5-甲基-4,5-二氢-3(2H)-哒嗪酮两类化合物,以寻找作用更强、选择性更好的血小板聚集抑制剂.方法:以乙酰苯胺为原料,经傅-克反应、满尼烯反应、水解及水合肼环合反应、酰化反应、取代反应,合成两类中间体及其衍生物,并进行体外药理实验考察其对血小板聚集的抑制作用.结果:共合成哒嗪酮类化合物16个,其中15个属首次报道,并通过元素分析和1H-NMR确证了它们的结构.其中化合物(4)抑制血小板聚集的活性最强,比对照物MCI-154强10倍;化合物(6)、(7)、(8)、(12)、(13)、(14)的活性也优于MCI-154.结论:合成的哒嗪酮类化合物具有抗血小板聚集活性.     

二氢哒嗪酮类化合物的合成及其抗血小板聚集活性研究

目的：合成新的哒嗪酮类化合物，并研究其抗血小板聚集活性。方法：在6-（4-氯乙酰氨基苯基）-4，5-二氢-3（2H）-哒嗪酮侧链引入不同取代的哌嗪，合成了一系列化合物，采用^1H-NMR、IR及元素分析等方法确证其结构。采用Born比浊法进行体外抗血小板聚集药理实验。结杲：合成的10个化合物都具有一定的抗血小板凝集的活性，其中化合物4的抗血小板聚集活性明显优于先导化合物MCI-154。结论：4-位取代哌嗪环基的引入对哒嗪酮类化合物抗血小板聚集的活性有显著影响。     

咪唑-[1，2-b]哒嗪类mTOR抑制剂的合成及抗肿瘤活性研究

目的设计合成咪唑-[1,2-b]哒嗪类mTOR抑制剂,并对其抗肿瘤活性及构效关系进行初步研究。方法以3-氨基4-溴-6-氯哒嗪、1-（N-Boc-哌啶4-基）溴乙醛等为原料,通过对咪唑[1,2-b]哒嗪环的构建,Suzuki偶联等5步反应得到目标化合物;分别采用SRB染色法、Z′-LYTE（r）法对目标化合物的抗肿瘤活性、mTOR激酶抑制活性进行评价。结果与结论共合成16个未见文献报道的新化合物,其结构经1H-NMR、13C-NMR、HRMS确证;活性测试结果表明,化合物15、16、27等对肿瘤细胞的生长有显著抑制作用。