三唑类化合物的设计与合成及抗癫痫作用研究
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摘要
本文分别以7-烷氧基-4,5-二氢-1,2,4-三唑[4,3-α]喹啉酮(L3)和7-烷氧基-4,5-二氢-1,2,4-三唑[4,3-α]喹啉(L4)为先导化合物,应用局部修饰、生物电子等排原理等设计并合成了66个化合物。首先以6-羟基-3,4-二氢-2(1H)-喹啉酮为起始原料,设计合成了16个2-取代-7-烷氧基-4,5-二氢-[1,2,4]三唑[4,3-α]喹啉-1-酮类化合物(Tla-p)、14个(另有14个中间体也是新化合物)7-烷氧基-[1,2,4]三唑[3,4-α]喹啉-甲酰胺化合物(T2a'-n)。然后又以2-氨基-5-硝基苯酚为起始原料设计合成了19个2-取代-6-[1,2,4]三唑基苯并恶唑化合物(T3a-s)和17个2-苯基-6-(3-取代[1,2,4]三唑)基苯并恶唑(T4a-q),共66个化合物。
所有化合物的结构经1H-NMR、IR和MS等方法确证。药理实验采用小鼠腹腔注射和口服灌胃两种不同的给药途径。抗惊厥实验采用2种模型,即最大电休克发作实验法和皮下戊四唑诱导的惊厥实验法,来评价所合成化合物的抗惊厥活性。以旋转法测化合物的神经毒性,评价所合成化合物的神经毒性作用。
药理实验结果显示：
1.在Tla-p(2-取代-7-烷氧基-4,5-二氢-[1,2,4]三唑[4,3-α]喹啉-1-酮)系列中,化合物2-乙酰基-7-正庚氧基-4,5-二氢-2H-[1,2,4]-三唑[4,3-a]并喹啉-1-酮(T1a)的抗惊厥活性最好,其最大抗惊厥活性ED50是7.23 mg/kg,神经毒性TD50是88mg/kg,相比之下化合物2-丙酰基-7-正庚氧基-4,5-二氢-2HH-[1,2,4]-三唑[4,3-a]并喹啉-1-酮(T1b)的抗惊厥活性与其相近,其最大抗惊厥活性ED50是8.18 mg/kg,但是神经毒性尤为优良,TD50是318mg/kg, PI值为39,总体比较,远远优于对照药卡马西平；但是口服给药后活性不如卡马西平。
2.在T2a'-n(7-烷氧基-4,5-二氢-[1,2，4]三唑[4,3-a]喹啉-1-甲酰胺和1-甲酸乙酯)系列中,所有化合物的神经毒性都很低,同时,抗惊厥活性也很低,并未发现有活性好与对照药的化合物。
3.由于化合物T3a-s和T4a-q同属于一类,所以放在一起综合看：所有的化合物抗惊厥活性都很差。
总之,通过对先导化合物的结构改造,得到66个新化合物,并对所合成的化合物进行抗惊厥活性的筛选,得到化合物2-丙酰基-7-正庚氧基-4,5-二氢-2H-[1,2,4]-三唑[4,3-a]并喹啉-1-酮的抗惊厥活性很好,神经毒性也很低,但是口服给药后活性不如卡马西平,揭示可能这类化合物口服吸收较差。深入的研究仍在进行中。
In this study, a new series of 2-substituted-7-heptyloxy-4,5-dihydro[1,2,4]triazolo [4,3-a]quinolin-1(2H)-ones (Tla-p), 1-Formamide-triazolo[4,3-a]quinoline derivatives (T2a-n),2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles (T3a-s) and 6-(3-substituted-4H-1,2,4-triazol-4-yl)-2-phenylbenzo[d]oxazoles (T4a-q) were designed and synthesized using 7-alkoxy-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one (L3) and 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (L4) as leading compound, starting form 6-hydroxyl-3,4-dihydro-2(1H)-quinoline and 2-amino-5-nitrophenol, respectively.
All the structures of the synthesized compounds were characterized by 1H-NMR, IR and MS. The pharmacological experiments were carried out using (KunMing) mice in two different methods, the intraperitoneal injection and oral gavage administration. The maximal electroshock seizure test (MES) and convulsions caused by PTZ were used as anticonvulsant model experiments to evaluate the anti-epileptic activity of these new compounds. Their neurotoxicity was measured by the rotarod test (Tox).
The pharmacological results showed:
1. Among series T1a-p, compound Tla (with the 2acetyl-substituted group) being the most active compound. It exhibited more potent anticonvulsant activity than referenced drug carbamazepine and leading compound L3 with ED50 values of 7.2 mg/kg in anti-MES activity. But it had high neurotoxicity with TD50= 88.0 mg/kg and PI= 12.2. So, compare with T1a, T1b (with the 2-propionyl-substituted group) could be the potentially most usefuland safe therapeutic compound with ED50= 8.2 mg/kg, TD50= 318 mg/kg and PI= 39.0. Its neurotoxicity was much lower than carbamazipine.
2. Among the series T2a'-n, compound 7-(hexyloxy)-4,5-dihydro-[1,2,4]triazolo [4,3-a] quinoline-1-carboxamide was the most active one. In the anti-MES test, it showed ED50=30.1 mg/kg, TD5o= 286 mg/kg, the PI value 9.5 was better than the reference drug carbamazepine with Pivalue of 6.0.
3. Among the series T3a-s and T4a-q, all the synthesized compounds, compound 2-phenyl-6-(4H-1,2,4-triazol-4-yl) benzo[d]oxazole(T3a) could be the most useful and safe therapeutic compound, with ED50= 29.5 mg/kg, TD50= 285 mg/kg,and PI= 9.7, its neurotoxicity was lower than the reference drug of carbamazepine with PI value of 6.0.
In a word, a process screening novel potential anti-epilepsy drugs was stated in the paper.66 New compounds were abtained and evaluated for anticonvulsant activity, compound 7-Heptyloxy-2-propionyl-4,5-dihydro-2H-[1,2,4]triazolo[4,3-a]quinolin-l-one (Tla) was considered for the potentially most usefuland safe therapeutic compound with ED50= 8.2 mg/kg, TD5o= 318 mg/kg and PI= 39.0. Its neurotoxicity was much lower than carbamazipine. But it was lower anticonvulsant activity when oral in mice. Other work was cointinuring.
所有化合物的结构经1H-NMR、IR和MS等方法确证。药理实验采用小鼠腹腔注射和口服灌胃两种不同的给药途径。抗惊厥实验采用2种模型,即最大电休克发作实验法和皮下戊四唑诱导的惊厥实验法,来评价所合成化合物的抗惊厥活性。以旋转法测化合物的神经毒性,评价所合成化合物的神经毒性作用。
药理实验结果显示：
1.在Tla-p(2-取代-7-烷氧基-4,5-二氢-[1,2,4]三唑[4,3-α]喹啉-1-酮)系列中,化合物2-乙酰基-7-正庚氧基-4,5-二氢-2H-[1,2,4]-三唑[4,3-a]并喹啉-1-酮(T1a)的抗惊厥活性最好,其最大抗惊厥活性ED50是7.23 mg/kg,神经毒性TD50是88mg/kg,相比之下化合物2-丙酰基-7-正庚氧基-4,5-二氢-2HH-[1,2,4]-三唑[4,3-a]并喹啉-1-酮(T1b)的抗惊厥活性与其相近,其最大抗惊厥活性ED50是8.18 mg/kg,但是神经毒性尤为优良,TD50是318mg/kg, PI值为39,总体比较,远远优于对照药卡马西平；但是口服给药后活性不如卡马西平。
2.在T2a'-n(7-烷氧基-4,5-二氢-[1,2，4]三唑[4,3-a]喹啉-1-甲酰胺和1-甲酸乙酯)系列中,所有化合物的神经毒性都很低,同时,抗惊厥活性也很低,并未发现有活性好与对照药的化合物。
3.由于化合物T3a-s和T4a-q同属于一类,所以放在一起综合看：所有的化合物抗惊厥活性都很差。
总之,通过对先导化合物的结构改造,得到66个新化合物,并对所合成的化合物进行抗惊厥活性的筛选,得到化合物2-丙酰基-7-正庚氧基-4,5-二氢-2H-[1,2,4]-三唑[4,3-a]并喹啉-1-酮的抗惊厥活性很好,神经毒性也很低,但是口服给药后活性不如卡马西平,揭示可能这类化合物口服吸收较差。深入的研究仍在进行中。
In this study, a new series of 2-substituted-7-heptyloxy-4,5-dihydro[1,2,4]triazolo [4,3-a]quinolin-1(2H)-ones (Tla-p), 1-Formamide-triazolo[4,3-a]quinoline derivatives (T2a-n),2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles (T3a-s) and 6-(3-substituted-4H-1,2,4-triazol-4-yl)-2-phenylbenzo[d]oxazoles (T4a-q) were designed and synthesized using 7-alkoxy-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one (L3) and 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (L4) as leading compound, starting form 6-hydroxyl-3,4-dihydro-2(1H)-quinoline and 2-amino-5-nitrophenol, respectively.
All the structures of the synthesized compounds were characterized by 1H-NMR, IR and MS. The pharmacological experiments were carried out using (KunMing) mice in two different methods, the intraperitoneal injection and oral gavage administration. The maximal electroshock seizure test (MES) and convulsions caused by PTZ were used as anticonvulsant model experiments to evaluate the anti-epileptic activity of these new compounds. Their neurotoxicity was measured by the rotarod test (Tox).
The pharmacological results showed:
1. Among series T1a-p, compound Tla (with the 2acetyl-substituted group) being the most active compound. It exhibited more potent anticonvulsant activity than referenced drug carbamazepine and leading compound L3 with ED50 values of 7.2 mg/kg in anti-MES activity. But it had high neurotoxicity with TD50= 88.0 mg/kg and PI= 12.2. So, compare with T1a, T1b (with the 2-propionyl-substituted group) could be the potentially most usefuland safe therapeutic compound with ED50= 8.2 mg/kg, TD50= 318 mg/kg and PI= 39.0. Its neurotoxicity was much lower than carbamazipine.
2. Among the series T2a'-n, compound 7-(hexyloxy)-4,5-dihydro-[1,2,4]triazolo [4,3-a] quinoline-1-carboxamide was the most active one. In the anti-MES test, it showed ED50=30.1 mg/kg, TD5o= 286 mg/kg, the PI value 9.5 was better than the reference drug carbamazepine with Pivalue of 6.0.
3. Among the series T3a-s and T4a-q, all the synthesized compounds, compound 2-phenyl-6-(4H-1,2,4-triazol-4-yl) benzo[d]oxazole(T3a) could be the most useful and safe therapeutic compound, with ED50= 29.5 mg/kg, TD50= 285 mg/kg,and PI= 9.7, its neurotoxicity was lower than the reference drug of carbamazepine with PI value of 6.0.
In a word, a process screening novel potential anti-epilepsy drugs was stated in the paper.66 New compounds were abtained and evaluated for anticonvulsant activity, compound 7-Heptyloxy-2-propionyl-4,5-dihydro-2H-[1,2,4]triazolo[4,3-a]quinolin-l-one (Tla) was considered for the potentially most usefuland safe therapeutic compound with ED50= 8.2 mg/kg, TD5o= 318 mg/kg and PI= 39.0. Its neurotoxicity was much lower than carbamazipine. But it was lower anticonvulsant activity when oral in mice. Other work was cointinuring.
引文
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[15]Chen J,Sun XY,Chai KY,Lee JS,Song MS,Quan ZS.Synthesis and anticonvulsant evaluation of 4一(4-alkoxylphenyl)-3-ethyl一4H一1,2,4-triazoles as open-chain analogues of 7-alkoxyl-4,5-dihydro[1,2,4] triazolo[4,3-a]quinolines.Bioorg Med Chem.2007,15,6775-6781.
[16]Cui XS,Chen J,Chai K Y,Lee JS,Quan ZS.Synthesis and anticonvulsant evaluation of 3-substituted-4-(4-hexyloxyphenyl)-4H一1,2,4-triazoles. Med Chem Res.2009,18(1):49-58.
[1]Zhang CB,Cui X,Hong L,Quan ZS,Piao HR.Synthesis and positive inotropic activity of N一(4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(piperazin-1-yl)acetamide derivatives.Bioorg Med Chem Lett. 2008,18(16):4606-4609.
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[4]Jin HG, Sun XY, Chai KY, Piao HR, Quan ZS. Anticonvulsant and toxicity evaluation of some 7-alkoxy-4,5-dihydro-[1,2,4]triazolo [4,3-a]quinoline-1(2H)-ones. Bioorg Med Chem.2006,14(20): 6868-6873.
[5]Cui LJ, Xie ZF, Piao HR, Li G, Chai KY, Quan ZS. Synthesis and anticonvulsant activity of 1-substituted-7-benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline. Biol Pharm Bull.2005,28(7):1216-1220.
[6]Zimmer H, Kokosa JM, Shah KJ. Synthesis of Condensed Heterocyclic systems. Ⅵ.1a some Ring Closure Reactions Involving 1-Hydrazinophthalazine. J. Org. Chem.1975,40(20):2901-2906.
[7]王俊敏,南云哲,谢志峰,全哲山.1-取代苄基-N-环己基-[1,2,3]-三唑-4-甲酰胺衍生物的合成.延边大学医学学报。2005,28(1)：38-41.
[8]Stocks MJ, Cheshire DR, Reynolds R. Efficient and regiospecific one-pot synthesis of substituted 1,2,4-triazoles. Org Lett.2004,6(17): 2969-2971.
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[13]Hester J B Jr, Rudzik A D, Von Voigtlander P.2,4-Dihydro-6-phenyl-(1H)-triazolo[4,3-a][1,4]benzoidiazepin-1-ones with antianxiety and antidepressant activity. J Med Chem,1980,23:402-405.
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[1]陈芬儿,刘兴勤.镇静催眠药阿普唑仑的合成.中国医药工业杂志,1990,21(8)：345
[2]彭玲玲,张秀,马洁等.联二烯丁基硫醚衍生物合成呋哺的反应.中国科学B辑：化学2009,39(10)：1184-1193
[3]Xian-Yu Sun,Cheng-Xi Wei,et al.,Zhe-Shan Quan.Evaluation of the anticonvulsant activity of 6-(4-chlorophenyoxy)-tetrazolo[5,1-a] phthalazine in various experimental seizure models in mice. Pharmacological Repots,2010,62,273-277.
[4]Xian-Yu Sun,Cheng-Xi Wei,et al.,Zhe-Shan Quan.Synthesis and primary anticonvulsant activity evaluation if 6-alkyoxyl-tetrazolo [5,1-a]phthalazine derivatives.Arzneimitteforschung,2010.(in press)
[5]Xian-Yu Sun,Cheng-Xi Wei,et al.,Zhe-Shan Quan Synthesis and Anti-inflammatory Activity Evaluation of Novel 7-Alkoxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-a]quinolities.Arch.Pharm.2008,341, 288-293.
[6]Zimmer H,Kokosa JM,Shah KJ.Synthesis of Condensed Heterocyclic systems.Ⅵ.1a some Ring Closure Reactions Involving 1-Hydrazinophthalazine.J.Org.Chem.1975,40(20):2901-2906
[7]王俊敏,南云哲,谢志峰,全哲山.1-取代苄基-N-环己基-[1,2,3]-三唑-4-甲酰胺衍生物的合成.延边大学医学学报。2005,28(1)：38-41.
[8]Piao ZT,Guan LP,Zhao LM,Piao HR,Quan ZS.Synthesis of Novel 7-benzyl-amino-2H-benzo[1,4]oxazin一3(4H)-ones as Anticonvulsant Agents.Eur J Med Chem,2008,43,1216-1221
[9]Stocks MJ,Cheshire DR,Reynolds R.Efficient and regiospecific one-pot synthesis of substituted 1,2,4-triazoles.Org Lett.2004, 6(17):2969-2971.
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[1]Zhang CB,Cui X,Hong L,Quan ZS,Piao HR.Synthesis and positive inotropic activity of N一(4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(piperazin-1-yl)acetamide derivatives.Bioorg Med Chem Lett. 2008,18(16):4606-4609.
[2]John HMH,John HE.Nucleophilic Heteroaromatic Substitution.II. Phthalazines.J Org Chem.1971,36:3248-3251.
[3]Xie ZF,Chai K Y,Piao HR,et al.Synthesis and anticonvulasant activity of 7一alkoxyl一4,5一dihydro-[1,2,4]triazole[4,3-a]quinolines.Bioorg.Med. Chem.Lett.,2005,15,4803-4805.
[4]Jin HG, Sun XY, Chai KY, Piao HR, Quan ZS. Anticonvulsant and toxicity evaluation of some 7-alkoxy-4,5-dihydro-[1,2,4]triazolo [4,3-a]quinoline-1(2H)-ones. Bioorg Med Chem.2006,14(20): 6868-6873.
[5]Cui LJ, Xie ZF, Piao HR, Li G, Chai KY, Quan ZS. Synthesis and anticonvulsant activity of 1-substituted-7-benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline. Biol Pharm Bull.2005,28(7):1216-1220.
[6]Zimmer H, Kokosa JM, Shah KJ. Synthesis of Condensed Heterocyclic systems. Ⅵ.1a some Ring Closure Reactions Involving 1-Hydrazinophthalazine. J. Org. Chem.1975,40(20):2901-2906.
[7]王俊敏,南云哲,谢志峰,全哲山.1-取代苄基-N-环己基-[1,2,3]-三唑-4-甲酰胺衍生物的合成.延边大学医学学报。2005,28(1)：38-41.
[8]Stocks MJ, Cheshire DR, Reynolds R. Efficient and regiospecific one-pot synthesis of substituted 1,2,4-triazoles. Org Lett.2004,6(17): 2969-2971.
[9]Krall R J, Penry J K, White B G, et al. Antiepileptic drug development: Ⅱ. Anticonvulsant drug screening. Epilepsia,1978,19:409-428.
[10]Poter R J, Cereghino J J, Gladding G D, et al. Antiepileptic drug development program. Clev Clin J Med,1984,51:293-305.
[11]Castel-Branco MM, Alves GL, Figueiredo IV, Falcao AC, Caramona MM:The maximal electroshock seizure (MES) model in the preclinical assessment of potential new antiepileptic drugs._Methods Find Exp Clin Pharmacol,2009,31,101-106.
[12]Hester J B Jr, Von Voigtlander P.6-Aryl-4H-s-triazolo[4,3-a][1,4] benzodiazepines. Influence of 1-substitution on pharmacological activity. J Med Chem,1979,22:1390-1398.
[13]Hester J B Jr, Rudzik A D, Von Voigtlander P.2,4-Dihydro-6-phenyl-(1H)-triazolo[4,3-a][1,4]benzoidiazepin-1-ones with antianxiety and antidepressant activity. J Med Chem,1980,23:402-405.
[14]Loscher W, Nolting B. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. IV. Protective indices. Epilepsy Res,1991,9:1-10.
[15]Hamilton M A, Russo R C, Thurston R C.Trimmed Spearman-Karber method for estimating median lethal concentration in toxicity bioassays. Env Sci Technol,1977,7,714-719.
[1]陈芬儿,刘兴勤.镇静催眠药阿普唑仑的合成.中国医药工业杂志,1990,21(8)：345
[2]彭玲玲,张秀,马洁等.联二烯丁基硫醚衍生物合成呋哺的反应.中国科学B辑：化学2009,39(10)：1184-1193
[3]Xian-Yu Sun,Cheng-Xi Wei,et al.,Zhe-Shan Quan.Evaluation of the anticonvulsant activity of 6-(4-chlorophenyoxy)-tetrazolo[5,1-a] phthalazine in various experimental seizure models in mice. Pharmacological Repots,2010,62,273-277.
[4]Xian-Yu Sun,Cheng-Xi Wei,et al.,Zhe-Shan Quan.Synthesis and primary anticonvulsant activity evaluation if 6-alkyoxyl-tetrazolo [5,1-a]phthalazine derivatives.Arzneimitteforschung,2010.(in press)
[5]Xian-Yu Sun,Cheng-Xi Wei,et al.,Zhe-Shan Quan Synthesis and Anti-inflammatory Activity Evaluation of Novel 7-Alkoxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-a]quinolities.Arch.Pharm.2008,341, 288-293.
[6]Zimmer H,Kokosa JM,Shah KJ.Synthesis of Condensed Heterocyclic systems.Ⅵ.1a some Ring Closure Reactions Involving 1-Hydrazinophthalazine.J.Org.Chem.1975,40(20):2901-2906
[7]王俊敏,南云哲,谢志峰,全哲山.1-取代苄基-N-环己基-[1,2,3]-三唑-4-甲酰胺衍生物的合成.延边大学医学学报。2005,28(1)：38-41.
[8]Piao ZT,Guan LP,Zhao LM,Piao HR,Quan ZS.Synthesis of Novel 7-benzyl-amino-2H-benzo[1,4]oxazin一3(4H)-ones as Anticonvulsant Agents.Eur J Med Chem,2008,43,1216-1221
[9]Stocks MJ,Cheshire DR,Reynolds R.Efficient and regiospecific one-pot synthesis of substituted 1,2,4-triazoles.Org Lett.2004, 6(17):2969-2971.