Design,Synthesis And Preliminary Studies On Prodrugs Acting On Central Nervous System

Central nervous system disorders are becoming the main diseases that affecting the health of people seriously. Targeting drugs have many advantages such as better specificity of treatment and weak side-effect. Several prodrugs of antidepressant Venlafaxine, antidementia memantine and antitumor hydroxyurea were designed and synthesized in order to enhance up the specific selectivity.Memantine and iodochlorhydroxyquin were synthesized. One new prodrug of dihydropyridine pyridinium salt was synthesized via acylation , acylamination, quaterisation and reduction with nicotinic acid as starting material. To synthesis prodrugs of ring closure-quaternaries, we got carboxylic monoester via quaterisation , alkylation and esterification, starting from material 4-methyl-5-thiazoleethanol. Eight new compounds (B1-B8) were prepared by esterification of Venlafaxine. Eight new compounds(C1-C8) were also prepared by acylation of memantine and six new derivatives(D1, D2, D4-D6, D8) were got by esterification of hydroxyurea. The structures were consistent with the assigned molecules by 1H-NMR, MS and element analysis.The preliminary study for the determination of plasma and brain tissure concentrations of compounds B1,B2, B5, D2 and D6 was carried out with the male S-D rats. The result revealed that the concentrations in brain for compounds B1, B2 were higher than that in plasma. The concentrations in brain and in plasma for compounds B5, D2, D6 demonstrated no significant differences.