二甲吡唑联苯并噻唑的合成及抗惊厥活性研究
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摘要
根据药物设计原理,设计合成了一系列二甲吡唑联苯并噻唑衍生物并且研究其抗惊厥活性。实验结果表明:在所有衍生物中,当取代基为烷氧基且碳链长度为4和5时化合物表现出短时效抗惊厥活性,而碳链继续延长或是用苄基取代时,活性消失。这说明丁氧基和戊氧基取代时化合物可以透过血脑屏障进而发挥作用。安全性评价显示该系列化合物未表现出明显的神经毒性。
According to the principle of drug design,a series of dimethyl pyrazole with benzothiazole derivatives was designed and synthesized and the experimental results showed that when the substituent group was alkoxy and carbon chain length of substituents was 4 and 5,the compounds showed short-term anticonvulsants activity in all derivatives. The activity was decreased when the carbon chain was prolonged or substituted with benzyl group. It meant that when butylated and pentoxyl substituted the compounds could penetrate the blood-brain barrier to do their work. Safety evaluation showed that all the series of compounds showed no obvious neurotoxicity.
According to the principle of drug design,a series of dimethyl pyrazole with benzothiazole derivatives was designed and synthesized and the experimental results showed that when the substituent group was alkoxy and carbon chain length of substituents was 4 and 5,the compounds showed short-term anticonvulsants activity in all derivatives. The activity was decreased when the carbon chain was prolonged or substituted with benzyl group. It meant that when butylated and pentoxyl substituted the compounds could penetrate the blood-brain barrier to do their work. Safety evaluation showed that all the series of compounds showed no obvious neurotoxicity.
引文
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[11] Mc Omie J F W,West D E. 3,3'-DIHYDROXYBIPHENYL[J].Organic Syntheses,Coll,2003,5:412; 49:50.
[2] Logroscino G,Hesdorffer D C,Cascino G,et al. Time trends in incidence,mortality,and case-fatality after fi rst episode of status epilepticus[J]. Epilepsia,2001,42:1031-1035.
[3] Knake S,Rosenow F,Vescovi M,et al. Incidence of status epilepticus in adults in Germany:a prospective,population-based study[J].Epilepsia,2001,42:714-718.
[4] Deng X Q,Song M X,Wei C X,et al. Synthesis and Anticonvulsant Activity of 7-Alkoxy-Triazolo-[3,4-b]Benzo[d]Thiazoles[J].Medicinal Chemistry,2010,6(5):313-320.
[5] Krall R J, Penry J K, White B G, et al. Antiepileptic drug development:II[J]. Anticonvulsant drug screening. Epilepsia,1978,19:409-428.
[6] Poter R J,Cereghino J J,Gladding G D,et al. Antiepileptic drug development program[J]. Clev Clin J Med,1984,51:293-305.
[7] Castel-Branco M M,Alves G L,Figueiredo I V,et al. The maximal electroshock seizure(MES)model in the preclinical assessment of potential new antiepileptic drugs[J]. Methods Find Exp Clin Pharmacol,2009,31:101-106.
[8] 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]. J Med Chem,1979,22:1390-1398.
[9] 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]. J Med Chem,1980,23:402-405.
[10] Lscher W, Nolting B. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. IV. Protective indices[J]. Epilepsy Res,1991,9:1-10.
[11] Mc Omie J F W,West D E. 3,3'-DIHYDROXYBIPHENYL[J].Organic Syntheses,Coll,2003,5:412; 49:50.
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