| Background:Cerebral ischemia has already become one of the principal diseases threatening people's health,which behaves high morbidity rates,high mortality rates,high disability rates and high relapse rates.Therefore,developing new therapeutic medicine has been a huge medical value as soon as possible.Ligustrazine,a major effective component of Chinese traditional herbal medicine Chuanxiong(Ligusticum wallichii Franch),has been reported to be a multi-functional drug in treatment of cardiovascular diseases,with pharmacological activities such as anti-platelet aggregation,anti-hypertension,vasodilation,free radical scavenge effect and protection against vascular endothelial cells injury.According to the principles of hypridization and bioisosteric replacement in medicinal chemistry,we got a new compound which was called TMP-Vanillic acid(compound 26PH-1).A lot of experiments were made,including ethology application,light microscope,enzyme-linked immuno sorbent assay(ELISA)and immunohisto-chemical staining was used,further some effects and mechanisms were simply explored.This study was financially supported by the National Natural Science Foundation of China(No.81173519)and the Innovation Team Project Foundation of Beijing University of Chinese Medicine(Lead Compound Discovering and Developing Innovation Team Project Foundation 2011-CXTD-15)Objective:To simplify and optimize the synthetic process of compound 26PH-1 and the intermediate 2-bromomethyl-3,5,6-trimethylpyrazine,which were widely discussed and analyzed in this research.According to the quality of research work in China pharmacopoeia 2010 editions,quality specification draft of compound 26PH-1 was draw up.To discover possible metabolites in rat urine and plasma,based on pharmacodynamics experimental results and prior experimental conclusion.Methods:The reported synthetic methods of compound 26PH-1 and the intermediate 2-bromomethyl-3,5,6-trimethylpyrazine were analyzed and discussed in this paper.We discussed the significant effects of reaction time(h),raw materials(TMP,vanillic),light intensity and solvent on productivity of TMP-Br and compound 26PH-1,then acquired the optimum preparation methods by the orthogonal process.With the HPLC,LC-MS/MS and GC,methodological research of compound 26PH-1 was studied,including identification,clarity,related substance and assay.Results:Among all the influential factors of TMP-Br and compound 26PH-1 were discussed,and the synthetic technology were finally determined and established by small scale and optimization experiments.Quality specification of compound 26PH-1 was draw based on the China pharmacopoeia(2010 edition)related appendix.Study on the pharmacodynamics experimental results,and four phase I metabolites and three phase II metabolites were identified in rat urine.The metabolites were formed via O-demethylation,ether bond cleavage and ester bond cleavage.Compound 26PH-1 loaded poly(lactic-co-glycolic acid)(PLGA)was prepared and simply optimized its preparation technology.Conclusion:According to new drug research guidance(chemical drug),methodological research of compound 26PH-1 was studied.Experimental results about the relevant requirements of the leading compound were fit for the corresponding standards,which provided the basic proofs for evaluating the quality control in production stage.The permeability and solubility of drugs can be the limited factors in vivo absorption,thereby leading to a low bioavailability.As to permeability is an intrinsic drug property,two strategies have been developed with the aim of improving the dissolution rate.The methods refers to carrying out pharmaceutical work normally performed later at the candidate compounds discovery stage could not only save research time but also is useful for the similar structure compounds. |
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