Synthesis And Pharmacokinetics Of Benzyloxyurea Derivatives

Benzyloxyurea derivatives were synthesized by hydroxyurea as lead compound, benzyloxyurea were the compounds which were introduced benzyl in the hydroxyl and imino of hydroxyurea. The fat-soluble of benzyloxyurea derivatives was significantly greater than hydroxyurea. So it is expected to change the disadvantages of hydroxyurea, such as short half-life, large oral dose and many side effects, to improve the bioavailability.This thesis verified the design of benzyloxyurea derivatives by the following aspects, established basis for the study of new anticancer drugs.1、Benzyloxyurea and N-substituted benzyloxyurea derivatives HX-4, HX-5, HX-D, HX-L, HY-10, HY-11, HY-D and HY-L were synthesized, these compounds were confirmed by IR, MS,1H-NMR and 13C-NMR.We made the purity of those compounds to meet the requirement of animal experiments by optimizing synthetic route, creating purification method.2、HY-11, HY-D and HX-D were selected to do acute toxicity tests and pharmacodynamics of animals according to the results of in vitro efficacy.HY-11 was selected to do pharmacokinetic research, according to the results of acute toxicity and pharmacodynamics. In addition, to identify that 600mg/kg,200mg/kg and 66.7mg/kg are oral doses of pharmacokinetic study in rats, integrated the doses of generic drug hydroxyurea, maximum tolerated dose of HY-11 in mouse and the results of pharmacodynamics.3、An HPLC-UV assay method was developed to determine the concentration of HY-11 in rat plasma, using Kromasil ODS C18 column, mobile phase is acetonitrile-water(73:27), flow is 0.8ml/min, detection wavelength is 225nm, column temperature is 30℃, the injection volume is 20ul. In the condition, the linearity is good in a certain range of plasma concentration(R2=0.999), the absolute recoveries are more than 99.0% of low concentration, medium concentration and high concentration, the relative recoveries are in the range of 94.16% and 102.29%, the precisions of intra-day are less than 5.78%, the precisions of intre-day are less than 8.28%, the stability of HY-11 is good.4、HY-11 was applied to investigate the pharmacokinetics in rats. Following treatment with HY-11 at 600mg/kg and 200mg/kg to rats by oral administration, tl/2z were 3.667±0.516 and 3.358±0.682, there was no significant difference. In the dose range of 200-600 mg/kg, the results of the compartment analysis indicated that the kinetic process of HY-11 in rats in vivo was not only fitted one-compartment model, but also to two-compartment model, can choose the two model, but better to two-compartment model. There was no clear gender difference in pharmacokinetics of HY-11, rat dynamics are linearly related, individual differences of the rats are relatively large.This is the first determination of benzyloxyurea derivatives in rats, the pharmacokinetics of HY-11 in rats was studied, the results play a guiding role in the dose, interval and efficacy evaluation of benzyloxyurea derivatives.