三唑并酞嗪及其雜環(huán)類衍生物的合成與抗驚厥活性的研究
發(fā)布時間：2018-07-28 15:04
【摘要】：癲癇是中樞神經(jīng)系統(tǒng)常見多發(fā)病,其特點為突然而反復(fù)發(fā)作的難治性疾病,其意外死亡率較高,是嚴重危害人類健康的中樞神經(jīng)系統(tǒng)疾病。應(yīng)用現(xiàn)有的抗癲癇藥物,僅有70%患者得到控制發(fā)作,其余30%的患者難以得到控制發(fā)作。且長期應(yīng)用現(xiàn)有的抗癲癇藥對中樞、血液等系統(tǒng)產(chǎn)生嚴重不良反應(yīng)。因此,研究與開發(fā)抗癲癇作用強而毒性小的新抗癲癇藥具有重要意義。雜環(huán)化合物是一類重要的化合物,通常具有多種生物活性。其中,三唑類是一類具有代表性的化合物。而且,由于其具有良好的脂水分配系數(shù)和較好的受體結(jié)合體,越來越多的含三唑類的藥物被設(shè)計出來。本文旨在尋找抗驚厥活性更強且毒副作用更小的化合物。本論文中,以雙酮酞嗪為先導(dǎo)化合物,經(jīng)氯代、水解、肼代、三唑的環(huán)合、三唑的取代和烷基化等反應(yīng),設(shè)計合成了 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)兩個系列,48個化合物。另外,為了考查其它雜環(huán)化合物對雙酮酞嗪母環(huán)的影響,又合成了(9a-b,10a-b,12a-b和14a-b)等四個系列8個其它相關(guān)的雜環(huán)化合物。所有的化合物,都通過IR,1H-NMR,13C-NMR和MS等相關(guān)譜圖來確定其結(jié)構(gòu)。藥理實驗動物,采用昆明種小鼠。用最大電驚厥實驗(MES test)來評估它們的抗驚厥活性,用旋轉(zhuǎn)棒法(Rotatod Test)來評估它們的神經(jīng)毒性。并測定了由戊四唑和荷包牡丹堿誘發(fā)的驚厥實驗。藥理實驗結(jié)果表明,化合物5-庚基-[1,2,4]三唑并[3,4-a]酞嗪-6(5H)-酮(6e)抗驚厥活性最好。腹腔注射給藥時,化合物6e的半數(shù)有效量(ED50)為10.2 mg/kg,保護指數(shù)(PI = TD50/ED50)為7.64,對照藥卡馬西平的ED50=11.8 mg/kg,PI= 6.4,說明腹腔注射給藥時化合物6e具有比卡馬西平較好的抗驚厥活性和較高的安全性�？诜o藥時,化合物6e的ED50為24.89 mg/kg,PI=TD50/ED5為23.84,對照藥卡馬西平的ED50為27.3mg/kg,PI=12.0,說明口服給藥時化合物6e同樣優(yōu)于對照藥卡馬西平�；衔�6e對抗由戊四唑(PTZ)和荷包牡丹堿(BIC)所引起的驚厥實驗結(jié)果表明,化合物6e能夠有效對抗由戊四唑(PTZ)和荷包牡丹堿(BIC)所引起的驚厥。
[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).
【學(xué)位授予單位】：延邊大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914;R96
本文編號：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).
【學(xué)位授予單位】：延邊大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914;R96
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相關(guān)期刊論文 前2條
1 陳湛a;陸兵勛;劉中華;林海峰;陳逢儉;王志海;陳文榮;;不同抗癲癇藥物對癲癇患者認知功能障礙的影響[J];南方醫(yī)科大學(xué)學(xué)報;2008年08期
2 吳希如;癲遺傳學(xué)的研究進展[J];中華兒科雜志;2000年11期
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