Research Of Prodrug Venlafaxine

Major depression is becoming the main disease that affecting the health of people seriously. Targeting drugs have many advantages such as better specificity of treatment and weak side-effect. Aimed at short half life and strong side-effect of antidepressant Venlafaxine, we have changed its structure, synthesized its prodrugs and evaluated brain-targeting effect of its prodrugs. We have made primary progress.To synthesis prodrugs of ring closure-quaternaries, we got carboxylic monoester via quaterisation by methane iodide, alkylation and esterification, starting from material 4-methyl-5-thiazolee-thanol. Eight new compounds (B1-B8) were prepared by esterification of Venlafaxine via catalysis of dimethyl-amino-pyridin in dichloromethane. Meanwhile, we got fourteen prodrugs of memantine and hydroxyurea. Their structures were consistent with the assigned molecules by ~1H-NMR, MS and element analysis.The study for the determination of plasma and brain tissure concentrations of compounds B1,B2,B5 was carried out with the male SD rats. The sample of blood and brain homogenate were determinated by RP-HPLC internal standard method after extracted by diethyl ether and petroleum ether. The result revealed that the rate of metabolizability of compound B1, B2 in the brain were more slow than in the blood, the concentration of compound Bl, B2 in the brain were higher than in the blood, the eliminating time of venlafaxine released by compound B1, B2 in the brain were also longer than in the blood, But the rate of metabolizability of venlafaxine released by compound B5 in the brain was same as in the blood.Compound B1,B2 change pharmacokinetics of Venlafaxine, improve competence of penetrate BBB, possess brain-targeting effect, deserve for continued research, B5 excepted.