三唑并酞嗪及其杂环类衍生物的合成与抗惊厥活性的研究
发布时间：2018-07-28 15:04
【摘要】：癫痫是中枢神经系统常见多发病,其特点为突然而反复发作的难治性疾病,其意外死亡率较高,是严重危害人类健康的中枢神经系统疾病。应用现有的抗癫痫药物,仅有70%患者得到控制发作,其余30%的患者难以得到控制发作。且长期应用现有的抗癫痫药对中枢、血液等系统产生严重不良反应。因此,研究与开发抗癫痫作用强而毒性小的新抗癫痫药具有重要意义。杂环化合物是一类重要的化合物,通常具有多种生物活性。其中,三唑类是一类具有代表性的化合物。而且,由于其具有良好的脂水分配系数和较好的受体结合体,越来越多的含三唑类的药物被设计出来。本文旨在寻找抗惊厥活性更强且毒副作用更小的化合物。本论文中,以双酮酞嗪为先导化合物,经氯代、水解、肼代、三唑的环合、三唑的取代和烷基化等反应,设计合成了 5-取代-[1,2,4]三唑并[3,4-a]酞嗪-6(5H)-酮(6a-y)和2-取代-4-(1H-1,2,4-三唑)酞嗪-1(2H)-酮(8a-w)两个系列,48个化合物。另外,为了考查其它杂环化合物对双酮酞嗪母环的影响,又合成了(9a-b,10a-b,12a-b和14a-b)等四个系列8个其它相关的杂环化合物。所有的化合物,都通过IR,1H-NMR,13C-NMR和MS等相关谱图来确定其结构。药理实验动物,采用昆明种小鼠。用最大电惊厥实验(MES test)来评估它们的抗惊厥活性,用旋转棒法(Rotatod Test)来评估它们的神经毒性。并测定了由戊四唑和荷包牡丹碱诱发的惊厥实验。药理实验结果表明,化合物5-庚基-[1,2,4]三唑并[3,4-a]酞嗪-6(5H)-酮(6e)抗惊厥活性最好。腹腔注射给药时,化合物6e的半数有效量(ED50)为10.2 mg/kg,保护指数(PI = TD50/ED50)为7.64,对照药卡马西平的ED50=11.8 mg/kg,PI= 6.4,说明腹腔注射给药时化合物6e具有比卡马西平较好的抗惊厥活性和较高的安全性。口服给药时,化合物6e的ED50为24.89 mg/kg,PI=TD50/ED5为23.84,对照药卡马西平的ED50为27.3mg/kg,PI=12.0,说明口服给药时化合物6e同样优于对照药卡马西平。化合物6e对抗由戊四唑(PTZ)和荷包牡丹碱(BIC)所引起的惊厥实验结果表明,化合物6e能够有效对抗由戊四唑(PTZ)和荷包牡丹碱(BIC)所引起的惊厥。
[Abstract]:Epilepsy is a common and frequent disease in the central nervous system, which is characterized by sudden and recurrent refractory diseases, and its accidental mortality is high. Epilepsy is a serious disease of the central nervous system which is harmful to human health. With existing antiepileptic drugs, only 70% of the patients were controlled, while the remaining 30% were difficult to control. And long-term use of existing antiepileptic drugs on the central, blood and other systems of serious adverse reactions. Therefore, it is of great significance to study and develop new antiepileptic drugs with strong antiepileptic effect and low toxicity. Heterocyclic compounds are an important class of compounds, which usually have a variety of biological activities. Among them, triazole is a kind of representative compound. Moreover, more and more triazole-containing drugs have been designed because of their good lipopolysaccharide partition coefficient and better receptor binding. The aim of this study was to search for compounds with higher anticonvulsant activity and less toxic side effects. In this paper, diketophthalazine was used as the leading compound, which was synthesized by chlorination, hydrolysis, hydrazine, triazole cyclization, substitution and alkylation of triazole. Two series of 5- substituted-[1H2H4] triazolazo [3H4a] phthalazine -6 (5H) -ketone (6a-y) and 2-substituted -4- (1H-1- (1H-1-) -triazole) phthalazine -1 (2H) -one (8a-w) were designed and synthesized. In addition, in order to investigate the effect of other heterocyclic compounds on the parent ring of diketophthalazine, eight other related heterocyclic compounds (9a-b ~ (10) a-b ~ (12) a-b and 14a-b) were synthesized. The structures of all compounds were determined by IR 1H-NMRN 13C-NMR and MS spectra. Kunming mice were used as pharmacological laboratory animals. Their anticonvulsant activity was evaluated by maximum electric convulsion test (MES test) and their neurotoxicity was evaluated by rotating rod method (Rotatod Test). The convulsion induced by pentylenetetrazole and bicuculline was determined. The pharmacological results showed that the anticonvulsant activity of compound 5- heptyl-[1 H2H4] triazolazo [3H4-a] phthalazine -6 (5H)-ketone (6e) was the best. When the drug was injected intraperitoneally, The half effective dose (ED50) of compound 6e was 10. 2 mg / kg, the protection index (Pi = TD50/ED50) was 7. 64, and the ED50=11.8 mg / kg PI of carbamazepine was 6. 4, which indicated that compound 6e had better anticonvulsant activity and higher safety than carbamazepine. The ED50 of compound 6e was 24.89 mg 路kg ~ (-1) 路kg ~ (-1) P ~ (-1) D _ (50) = 23.84, and the ED50 of control drug carbamazepine was 27.3 mg / kg ~ (-1) (12.0), which indicated that compound 6e was also superior to carbamazepine in oral administration. Compound 6e antagonizes convulsion induced by pentylenetetrazole (PTZ) and bicuculline (BIC). The results show that compound 6e can effectively antagonize the convulsion induced by pentylenetetrazole (PTZ) and bicuculline (BIC).
【学位授予单位】：延边大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96
本文编号：2150624
[Abstract]:Epilepsy is a common and frequent disease in the central nervous system, which is characterized by sudden and recurrent refractory diseases, and its accidental mortality is high. Epilepsy is a serious disease of the central nervous system which is harmful to human health. With existing antiepileptic drugs, only 70% of the patients were controlled, while the remaining 30% were difficult to control. And long-term use of existing antiepileptic drugs on the central, blood and other systems of serious adverse reactions. Therefore, it is of great significance to study and develop new antiepileptic drugs with strong antiepileptic effect and low toxicity. Heterocyclic compounds are an important class of compounds, which usually have a variety of biological activities. Among them, triazole is a kind of representative compound. Moreover, more and more triazole-containing drugs have been designed because of their good lipopolysaccharide partition coefficient and better receptor binding. The aim of this study was to search for compounds with higher anticonvulsant activity and less toxic side effects. In this paper, diketophthalazine was used as the leading compound, which was synthesized by chlorination, hydrolysis, hydrazine, triazole cyclization, substitution and alkylation of triazole. Two series of 5- substituted-[1H2H4] triazolazo [3H4a] phthalazine -6 (5H) -ketone (6a-y) and 2-substituted -4- (1H-1- (1H-1-) -triazole) phthalazine -1 (2H) -one (8a-w) were designed and synthesized. In addition, in order to investigate the effect of other heterocyclic compounds on the parent ring of diketophthalazine, eight other related heterocyclic compounds (9a-b ~ (10) a-b ~ (12) a-b and 14a-b) were synthesized. The structures of all compounds were determined by IR 1H-NMRN 13C-NMR and MS spectra. Kunming mice were used as pharmacological laboratory animals. Their anticonvulsant activity was evaluated by maximum electric convulsion test (MES test) and their neurotoxicity was evaluated by rotating rod method (Rotatod Test). The convulsion induced by pentylenetetrazole and bicuculline was determined. The pharmacological results showed that the anticonvulsant activity of compound 5- heptyl-[1 H2H4] triazolazo [3H4-a] phthalazine -6 (5H)-ketone (6e) was the best. When the drug was injected intraperitoneally, The half effective dose (ED50) of compound 6e was 10. 2 mg / kg, the protection index (Pi = TD50/ED50) was 7. 64, and the ED50=11.8 mg / kg PI of carbamazepine was 6. 4, which indicated that compound 6e had better anticonvulsant activity and higher safety than carbamazepine. The ED50 of compound 6e was 24.89 mg 路kg ~ (-1) 路kg ~ (-1) P ~ (-1) D _ (50) = 23.84, and the ED50 of control drug carbamazepine was 27.3 mg / kg ~ (-1) (12.0), which indicated that compound 6e was also superior to carbamazepine in oral administration. Compound 6e antagonizes convulsion induced by pentylenetetrazole (PTZ) and bicuculline (BIC). The results show that compound 6e can effectively antagonize the convulsion induced by pentylenetetrazole (PTZ) and bicuculline (BIC).
【学位授予单位】：延边大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96
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2 吴希如;癫遗传学的研究进展[J];中华儿科杂志;2000年11期
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