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。     

6-取代苯基哒嗪的3位γ-氨基丁酸衍生物的合成及抗惊活性

GABA的合成类似物是开发新型抗惊剂和抗癫痫药物的新领域。由芳香醛与吗啉、氰化钾反应形成的α-芳基-α-(4-吗啉)乙腈,可对α,β-不饱和腈或酯进行1,4-加成,生成1,4-酮酸型化合物。此物与肼缩合,再经芳构化即得6-芳基-3(2H)哒嗪酮。后者再经氯化后。与GABA缩合,制备3-(N-GABA)-6-芳基哒嗪类及其分子内脱水产物3-(N-丁内酰胺)-6-芳基哒嗪类化合物。本文应用此法合成了17个上述苯代哒嗪的GABA衍生物,并初步测验了它们的抗惊(MES)活性。活性最强的是3-(N-GABA)-6-(2′,4′-二氯苯基)哒嗪(ED₅₀=21.05mg/kg)。     

Derivatives of pyrrolo[3,4-d]pyridazinone, a new class of analgesic agents

A series of N2-{2-[4-aryl(benzyl)-1-piperazinyl(piperidinyl)]ethyl}pyrrolo[3,4-d]pyridazinones 4 and related derivatives 5 were synthesized as potential analgesic agents. The structures of the new compounds were elucidated by micro, spectral and X-ray analysis. Analgesic activity of the compounds was investigated in the phenylbenzoquinone induced ‘writhing’ and ‘hot plate’ test in mice and at radioligand binding assay. At ‘writhing’ test all compounds, without exception, were more active than acetylsalicylic acid (ASA) with ED₅₀ values ranging from 0.04 to 11 mg/kg (i.p.) (ED₅₀ for ASA - 39.15 mg/kg). Analgesic effect at the ‘hot plate’ test was observed for three compounds 4c,e,f at the dose 3-5 times higher then that of morphine (ED₅₀-3.39 mg/kg). At radioligand binding assay of 4c,e,f only compound 4f exhibited affinity for the μ-opioid receptors similar to that of Tramadol. The acute toxicity of the pyrrolopyridazinones 4, 5 were also studied and non toxic effect was observed at the 2000 mg/kg (5a 1420 mg/kg) i.p. dose level. On the basis of the available pharmacological data S-A relationship is discussed. The preferred conformational characteristic of 4, taken 4c as an example, was also described.     

New derivatives of pyrrolo[3,4-d]pyridazinone and their anticancer effects

Eighteen new derivatives of pyrrolo[3,4-d]pyridazinone modified at the pyrrole and pyridazine rings were synthesized and 12 of them were evaluated in vitro through anticancer screenings. The structures of new compounds were confirmed by elemental analysis and spectral data (IR, 1H NMR). None of the eight compounds assayed blocked the cell cycle regulating CDK1/cyclin B kinase, whereas two of the six compounds tested were active in anticancer screening at the cell experiments at a concentration of > or = 10(-5) M/l.     

6-取代苯基-3(2H)哒嗪酮的合成、抗惊活性及其构效关系的研究

本文报道了14个6-取代苯基-4,5-二氢-3(2H)哒嗪酮和15个6-取代苯基-3(2H)哒嚎酮的合成及其抗电惊活性。其ED₅₀值表明,以2′,4′-二氯苯基-3(2H)哒嗪酮的抗惊作用为最强。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。     

6-[4-(取代胺基乙酰胺基苯基)]-4,5-二氢-3(2H)哒嗪酮类化合物的合成及其抗血小板聚集活性研究

目的:合成新的含有胺基的哒嗪酮类化合物,并研究其对抗血小板聚集活性的影响.方法:以乙酰基为连接片段,引入不同的取代胺基,设计合成未见报道的目标化合物8个,所有化合物均经过1H-NMR谱等确证;体外药理实验参考Born方法进行.结果:所有化合物都具有体外抑制血小板聚集的活性,其中化合物(1),(3)和(8)的活性较强,化合物(3)的活性是MCI-154的6倍.结论:引入不同的取代胺基,对化合物抑制血小板聚集的活性有影响.     

6-取代乙酰哌嗪苯基二氢哒嗪酮类化合物的合成及其抑制血小板聚集的作用

目的：设计合成6-[4-(4-取代乙酰胺基哌嗪基)苯基]-4，5-二氢-3(2H)-哒嗪酮和6-[4-(4-取代酰胺基哌嗪基)苯基]-5-甲基-4，5-二氢-3(2H)-哒嗪酮两类化合物，寻找作用更强的血小板聚集抑制剂。方法：以乙酰苯胺为原料，经傅克反应、满尼希反应、环合反应、酰化反应合成两类中间体(M)和(N)，再经缩合和取代反应得到两类目标化合物，参考Bonn方法进行体外抑制血小板聚集实验。结果：共合成目标化合物12个，其中10个属首次报道，通过元素分析，^1H-NMR确证结构。其中化合物(9)抑制血小板聚集作用的活性最强，为对照物CCI-17810的60多倍；化合物(6)、(7)、(10)、(11)、(12)的活性也优于CCI-17810．结论：目标化合物具有较强的抑制血小板聚集活性。     

Structure-Activity Relationships in a Series of 8-Substituted Xanthines as Bronchodilator and A1-Adenosine Receptor Antagonists

Four new derivatives of 8-piperazine ethyl xanthine were synthesized and their bronchospasmolytic activity and A₁-adenosine affinity were studied. Their relaxant action in the tracheal muscle was lower than that of theophylline and that of theophylline derivatives substituted at the 7-position. Only compound 9 , where the methyl group in the 1-position of the theophylline was substituted by an isobutyl group, shows a good affinity towards the A₁-adenosine receptor.