老年痴呆症药物石杉碱甲的类似物研究　Ⅰ　5－取代氨甲基－2（1H）－吡啶酮和5－取代氨基－5，6，7，8－四氢喹诺酮的合成

STUDIES ON ANALOGUES OF HUPERZINE A FOR TREATMENT OF SENILE DEMENTIA ⅠSynthesis of 5-substituted aminomethyl-2(1H)-pyridones and 5-substituted amino-5,6,7,8-tetrahydroquinolones

石杉碱甲（１）是从中草药千层塔中分离的新型石松类生物碱。药理试验表明它是一个可逆性的强效乙酰胆碱酯酶抑制剂。初步临床试验证实它对记忆衰退、重症肌无力和多发梗死痴呆症具有明显的疗效，有可能成为新一代治疗老年痴呆药物。基于计算机分子模拟研究，石杉碱甲分子中的５－氨甲基－２（１Ｈ）－吡啶酮（２）结构可能是其药效部分，因此设计并合成了５－取代氨甲基－２（１Ｈ）－吡啶酮类似物（５）．（８），（１３）和５－取代氨基－５，６，７，８－四氢喹诺酮类似物（１６）．（１７）．生物试验表明，这些石杉碱甲简化结构类似物几无抗乙酰胆碱酯酶活性。

Huperzine A(Hup.A)(1),isolated from the Chinese drug Huperzia Serrata,is a potent inhibitor of acetylcholinesterase.Preliminary clinical trails conducted in China have demonstrated that Hup.A is effective in the treatment of memory impairment,myasthenia gravis and multi-infarct dementia with minimal side effects.Because of the comparatively long duration of action and high therapeutical index,Hup.A is a promising drug candidate for senile dementia diseases,including Alzheimer's disease.In this paper,we report the preparation and bio-assay of simplified analogues of Hup.A,5-substituted aminomethyl-2(1H)-pyridones(5),(8),and 5-substituted amino-quinolones.(16),(17).Ethyl 6-methoxy-nicotinate was effectively converted into 6-methoxy-N,N-diethylnicotinamide(3)by reaction with dimethylaluminum diethylamide in refluxing benzene. Reduction of amide(3)with borane-disulfide affording 2-methoxy-5-diethylaminomethyl-pyridine (4),followed by deprotection with chlorotrimethysilane and sodium iodide in acetonitrile gave 5-diethylaminomethyl-2(1H)-pyridone(5).Similarly,5-dimethylaminomethyl-2(1H)pyridone(8)was prepared by using methylchloroalluminum dimethylamide instead of dimethyl-aluminum diethylamide.Amide(3)could also be prepared from 6-hydroxynicotinic acid by reaction with diethylamine and phosphorus oxychloride in refluxing toluene,followed by methanolysis of the resulting 6-chloro-N,N-diethylnicotinamide(9)in 50% yield.Similarly,5-piperidinomethyl-2(1H)-pyridone (13) was prepared.The preparation of analogues(16)and(17)started from 5-oxo-5,6,7,8-tetrahydroquinolone,which was protected as methyl ether(14).Reductive amination of(14),in the presence of titanium(Ⅳ)chloride,with sodium cyanoborohydride and dimethylamine hydrochloride,followed by deprotection with iodotrimethylsilane gave 5-dimethylamino-5,6,7,8-tetrahydroquinolone(16).While reductive amination of(14)with benzylamine under the same condition,methyl ether protection was simultaneously cleaved and 5-benzylamino-5,6,7,8-tetrahydroquinolone(17)was afforded in 38% yield.All the analogues were tested for their inhibitory activities of acetylcholinesterase from rats'erythrocyte membrane and were proved almost inactive.