三唑并酞嗪及其雜環(huán)類(lèi)衍生物的合成與抗驚厥活性的研究
發(fā)布時(shí)間：2018-07-28 15:04
【摘要】：癲癇是中樞神經(jīng)系統(tǒng)常見(jiàn)多發(fā)病,其特點(diǎn)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(yán)重危害人類(lèi)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(zhǎng)期應(yīng)用現(xiàn)有的抗癲癇藥對(duì)中樞、血液等系統(tǒng)產(chǎn)生嚴(yán)重不良反應(yīng)。因此,研究與開(kāi)發(fā)抗癲癇作用強(qiáng)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(lèi)重要的化合物,通常具有多種生物活性。其中,三唑類(lèi)是一類(lèi)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(lái)越多的含三唑類(lèi)的藥物被設(shè)計(jì)出來(lái)。本文旨在尋找抗驚厥活性更強(qiáng)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(jì)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(gè)系列,48個(gè)化合物。另外,為了考查其它雜環(huán)化合物對(duì)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(gè)系列8個(gè)其它相關(guān)的雜環(huán)化合物。所有的化合物,都通過(guò)IR,1H-NMR,13C-NMR和MS等相關(guān)譜圖來(lái)確定其結(jié)構(gòu)。藥理實(shí)驗(yàn)動(dòng)物,采用昆明種小鼠。用最大電驚厥實(shí)驗(yàn)(MES test)來(lái)評(píng)估它們的抗驚厥活性,用旋轉(zhuǎn)棒法(Rotatod Test)來(lái)評(píng)估它們的神經(jīng)毒性。并測(cè)定了由戊四唑和荷包牡丹堿誘發(fā)的驚厥實(shí)驗(yàn)。藥理實(shí)驗(yàn)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(shí),化合物6e的半數(shù)有效量(ED50)為10.2 mg/kg,保護(hù)指數(shù)(PI = TD50/ED50)為7.64,對(duì)照藥卡馬西平的ED50=11.8 mg/kg,PI= 6.4,說(shuō)明腹腔注射給藥時(shí)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(shí),化合物6e的ED50為24.89 mg/kg,PI=TD50/ED5為23.84,對(duì)照藥卡馬西平的ED50為27.3mg/kg,PI=12.0,說(shuō)明口服給藥時(shí)化合物6e同樣優(yōu)于對(duì)照藥卡馬西平�；衔�6e對(duì)抗由戊四唑(PTZ)和荷包牡丹堿(BIC)所引起的驚厥實(shí)驗(yàn)結(jié)果表明,化合物6e能夠有效對(duì)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(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R914;R96
本文編號(hào)：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(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R914;R96
【參考文獻(xiàn)】
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(duì)癲癇患者認(rèn)知功能障礙的影響[J];南方醫(yī)科大學(xué)學(xué)報(bào);2008年08期
2 吳希如;癲遺傳學(xué)的研究進(jìn)展[J];中華兒科雜志;2000年11期
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