摘要
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.
出处
《中国药物化学杂志》
CAS
CSCD
1994年第4期257-263,共7页
Chinese Journal of Medicinal Chemistry
基金
国家自然科学基金
关键词
石杉碱甲类似物
化学合成
痴呆
老年人
Huperzine A analogues
Chemical synthesis
Acetylcholinesterase inhibitor
Senile dementia
Alzheimer's disease