哒嗪酮酸类化合物的合成及其抗惊活性的研究

以ａ－酮戊二酸与水合肼与水合肼为原始原料合成了１５个Ｎ－（３’－磷酸二乙酯丙基）－１，６－二氢－６－氧－３－哒嗪酰胺类化合物，并对它们进行了最大电休克发作（ＭＥＳ）实验，结果表明其中４个化合物表现出中等强度的抗惊活性。     

药物对TNF诱导的牛脑微血管平滑肌细胞增值的拮抗作用

研究表明,肿瘤坏死因子(TNH)在50～5000U·mL^-1范围内呈剂量依赖性地诱导牛脑微血管平滑肌细胞增殖,TNF与该细胞培养24h时,即可明显刺激细胞增殖,48h时达最大刺激效应。欧芹素乙(imperatorin,Imp),异欧芹素乙(iso-imperatorin,Isi)在浓度为10^-6～10^-4mol·L^-1时,均可剂量依赖性地拮抗TNF诱导该细胞增殖。6-(α,α-二苯基乙酰哌嗪基苯基)-4,5-二氢-5-甲基-3(2H)哒嗪酮,6-(α-苯基乙酰哌嗪基苯基)-4,5-二氢-5-甲基-3(2H)哒嗪酮,则只在低浓度(10^-6mol·L^-1)时拮抗TNF诱导该细胞的增殖。     

Some pyrrole substituted aryl pyridazinone and phthalazinone derivatives and their antihypertensive activities

In this work, some 2-nonsubstituted/2-methyl-/2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone, derivatives and 2-nonsubstituted/2-methyl- 4-[4-(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were synthesised by reacting hexan-2,5-dion or 1-aryl-3-carbethoxypent-1,4-diones with corresponding 2-substituted/nonsubstituted 6-(4'-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone or 2-substituted/nonsubstituted-4-(4'-aminophenyl)-(2H)-phthalazinone under Paal-Knorr pyrrole synthesis conditions. The antihypertensive activities of the compounds were examined both in vitro and in vivo. Some pyridazinone derivatives showed appreciable activity.     

药物对TNF诱导的牛脑微血管平滑肌细胞增值的拮抗作用

研究表明，肿瘤坏死因子（ＴＮＨ）在５０～５０００Ｕ·ｍｌ－１范围内呈剂量依赖性地诱导牛脑微血管平滑肌细胞增殖，ＴＮＦ与该细胞培养２４ｈ时，即可明显刺激细胞增殖，４８ｈ时达最大刺激效应。欧芹素乙（ｉｍｐｅｒａｔｏｒｉｎ，Ｉｍｐ），异欧芹素乙（ｉｓｏ－ｉｍｐｅｒａｔｏｒｉｎ，Ｉｓｉ）在浓度为１０－６～１０－４ｍｏｌ·Ｌ－１时，均可剂量依赖性地拮抗ＴＮＦ诱导该细胞增殖。６－（α，α－二苯基乙酰哌嗪基苯基）－４，５－二氢－５－甲基－３（２Ｈ）哒嗪酮，６－（α－苯基乙酰哌嗪基苯基）－４，５－二氢－５－甲基－３（２Ｈ）哒嗪酮，则只在低浓度（１０－６ｍｏｌ·Ｌ－１）时拮抗ＴＮＦ诱导该细胞的增殖。     

Theoretical studies on the glucosidation mechanism of 6-(4-halophenyl)-3(2H)-pyridazinone

The glucosidation of 6-(4-halophenyl)-3(2H)-pyridazinone engenders two isomers, O-glucoside and N-glucoside. In order to find appropriate methods to obtain different glucosides, density functional theory (DFT) calculation at B3LYP/6-31G(d) level was employed to explore the mechanisms of two processes including Koenigs-Knorr reaction and phase-transfer catalysis reaction of 6-(4-halophenyl)-3(2H)-pyridazinone glucosidation. The calculation results reveal that both processes are S_N2 reaction, in which O-glucosides are kinetic products and N-glucosides are thermodynamic products. That O-glucosides were main products in Koenigs-Knorr reaction is due to the assistance of sliver ions, which bond to 2-N of pyridazinone and prevent the transforming from O-glucosides to N-glucosides.     

哒嗪酮类化合物的药用研究近况

简要综述哒嗪酮类化合物近年来的药用研究进展.哒嗪酮类化合物具有多种重要的生物活性,根据作用机制的不同,可分为钙增敏剂、磷酸二酯酶抑制剂、环氧合酶抑制剂等,并可用于相关疾病的治疗.     

Synthesis and in‐vitro Cytotoxic Evaluation of Novel Pyridazin‐4‐one Derivatives

A new series of N‐aryl‐4‐oxo‐1,4‐dihydro‐pyridazine‐3‐carboxylic acids has been synthesized by condensation of aryldiazonium with 4‐hydroxy‐6‐methyl‐2‐pyrone. Some of these compounds exhibited in‐vitro cytotoxic activity with moderate to excellent growth inhibition against the murine P815 mastocytoma cell line. Compound 5b showed an important cytotoxic activity against cell line P815 (IC₅₀ = 0.40 μg/mL).     

Investigations of new pyridazinone derivatives for the synthesis of potent analgesic and anti-inflammatory compounds with cyclooxygenase inhibitory activity

In this study we describe the synthesis of two novel 4-phenyl-and 4-(2-chlorophenyl)-6-(5-chloro-2-oxo-3H-benzoxazol-7-yl)-3(2H)-pyridazinone derivatives (compounds 8a and b) and their testing as inhibitors of cyclooxygenases (COX-1 and COX-2). Both compounds inhibited COX-1 (by 59 % and 61 % for compounds 8a and 8b respectively and COX-2 (by 37 % and 28 % for compounds 8a and 8b respectively) at a concentration of 10 microM. Furthermore, we tested the analgesic and anti-inflammatory activities of the synthesized compounds in vivo by using the p-benzoquinone-induced writhing test and the carrageenan-induced hind paw edema model, respectively. Compounds 8a and 8b showed potent analgesic and anti-inflammatory activities without causing gastric lesions in the tested animals.     

6-(4-取代苯基)哒嗪酮类化合物对血小板聚集的抑制作用

目的观察不同浓度的6-(4-取代苯基)哒嗪酮类化合物对二磷酸腺苷(ADP)诱导血小板聚集的抑制作用。方法将不同浓度的6-(4-取代苯基)哒嗪酮类化合物分别加入人富含血小板血浆(PRP)中,用多功能血小板聚集仪测定 ADP 诱导的血小板聚集作用。结果该哒嗪酮类化合物对 ADP 诱导血小板聚集有剂量依赖性抑制作用,其半数抑制浓度(IC_(50))分别为1.04μmol/L 和2.80μmol/L。结论新的6-(4-取代苯基)哒嗪酮类化合物具有较强的抑制 ADP 诱导的血小板聚集作用。