The Synthesis Of Tacrine Derivatives

Tacrine(1,2,3,4-tetrahydroacridin-9-amine, Cognex, THA), was marketed to treat senile dementia by FDA in 1993. Senile dementia also called Alzheimer's disease (AD) is degeneration of central nervous system which often happened in senium and presenium. Its clinical manifest includes: Progressive hypomnesis and dysgnosia and individuality change. Its prevalence rise follows the increase of age. The danger of Alzheimer's disease for human health is increasingly outstanding, which has been one of the most important question that geraeology faced.The research of high effect and less toxic medicine to treat Alzheimer's disease is an important topic now. In the recent years, progression about etiological factor and relevant risk factors of Alzheimer's disease was acquired. Many scholars proposed various hypothesis and inference from different point of view. For instance, damage of cholinergic nerve, inflammation mechanism, dysbolismus of brain energy metabolism, gene mutation, cerebral stroke, hyperlipemia all can lead to Alzheimer's disease. Acetylcholine esterase inhibitor is the main medicine used to treat Alzheimer's disease in clinical as damage of cholinergic nerve obtained widespread confirmation. Acetylcholine esterase inhibitor has obviously curative effect to improve cognition functional impairment of Alzheimer's disease patients in earlier period and intermediate stage. Tacrine has high lipsolubility to permeate blood brain barrier easily, and can increase acetylcholine energy in brain, so it is an effective cholinesterase inhibitor in clinical. Unfortunately, tacrine will make serious damage to liver, which restricts its widely use.Many researches of tacrine have been done to reduce the toxicity. The design of this experiment is to synthesis amide derivatives of tacrine. We synthesized molecular conjugates of some drugs or compounds as follow: Brufen, indomethacin, sulfacetic acid, pyrrolidone, 2-(4-chlorophenoxy) aceticacid, 2 -(4-chlorophenoxy)-2methyl propanoic acid and palmitic acid, which provide experiment reference for new drugs used to treat Alzheimer's disease.Objective:To design and synthesize amides derivatives of tacrine, to reduce its hepatotoxicity, to look for new drugs less toxical which can cure or improve Alzheimer's disease symptoms.Methods:1 Tacrine was synthesized via scission and cyclization reactions using indigo carmine.2 Amide derivatives are synthesised by brufen acyl -chloride, indomethacin acylchloride and tacrine.3 2-(4-chlorophenoxy)-2-methylpropanoic acid, 2-phenyl -aceticacid, palmiticacid, are reacted with tacrine to synthesize amide compounds using DCC and DMAP as catalyst.4 Amide compound is synthesized by the reaction of chloracetyl tacrine and pyrrolidone.Result:1 Tacrine was synthesized as starting material2 We obtained compounds as follow: 2-(4-isobutylphenyl) -N-(1,2,3,4-tetrahydroacridin-9-yl)propanamide (â… ); 2-phenyl-N-(1,2,3,4-tetrahydroacridin-9-yl)acetamide(â…¡); N-(1,2,3,4-tetrahydroacridin-9-yl) palmitamide(â…¢);2-(4-chlorop -henoxy)-2-methyl-N-(1,2,3,4-tetrahydroacridin-9-yl)propanami-de(â…£); 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H -indol-3-yl)-N-(1,2,3,4-tetrahydroacridin-9-yl)acetamide(â…¤); 2-(4-chlorophenoxy)-N-(1,2,3,4-tetrahydroacridin-9-yl)actamide(â…¥); 2-(2-oxopyrrolidin-1-yl)-N-(1,2,3,4-tetrahydroacridin-9-yl) acetamide(â…¦)Conclusion:1 The structure of compoundsâ… -â…£is identified by mass spectrum and 1H-NMR, which establishes the foundation for further research.2 The molecular weight of compoundsâ…¤-â…¦matches the molecular weight of compounds we designed.3 Some synthesis technologies have been optimized.