Design, Synthesis And Hypoglycemic Activity Of Amino Acid Parallel Dicyanopyrrolidine Compounds

Type 2 diabetes mellitus has become the third chronic disease affecting human health,and its incidence is on the rise year by year.DPP-IV inhibitors can reduce glucose by inhibiting the degradation of glucagon-like peptide（GLP-1）by DPP-IV enzyme.DPP-IV inhibitors have been attracted extensive attention in the development of diabetes therapeutic drugs because of the advantages of multiple regulation,effectiveness and safety.The structure of N-glycyl-2-cyanopyrrolidine is the basic structural unit of many peptide DPP-IV inhibitors.It was found that the activity of this kind of DPP-IV enzyme inhibitor was decreased significantly in vivo because the cyano group on the pyrrolidine ring and the amino group on glycine were prone to intramolecular cyclization.A class of compounds containing dipyrrolidine-2-carbonitrile unit were designed as candidate molecules of DPP-IV inhibitors.The main tasks are as follows:（1）Synthesis of intermediate（2S）-2-cyanopyrrolidine.An important raw material（2S）-2-cyanopyrrolidine was synthesized from L-proline as the initial material by four steps,protected by di-tert-tert-butyl dicarbonate（Boc）2O,ammonification,dehydration and deprotection.（2）Synthesis of target compoundsThe amino group of aspartic acid was protected by di-tert-butyldicarbonate and then acylated with（2S）-2-cyanopyrrolidine to form peptides,then deprotected and salted to synthesize the target compound.The（2S）-2-amino-glutamic diacyl-bis（2S,2S’）-2-cyanopyrrolidine)（TFA salt）was synthesized by the same method.The compounds were characterized by ¹H NMR and ¹³C NMR.（3）OGTT activity testThe pharmacokinetics of the target compound was evaluated by oral glucose tolerance test（OGTT）in mice.The results showed that compound 1 and compound 2had good oral hypoglycemic activity,and had the possibility of further development.（4）N-alkylation of dimethyl aspartateFor the need of structural modification,the N-alkylation of dimethyl aspartate was studied.The study of N-alkylation was carried out by Na BH4 reductive imine.The influencing factors were studied including imine reaction time,methanol water content,reaction temperature,post-treatment solvent,reaction substrate and so on.The N-alkylation of dimethyl aspartate was realized by adding Na BH4 below 0℃to reduce imine,which was obtained with Dimethyl aspartic acid ester and carbonyl compound after 10 min in anhydrous methanol solution by adding desiccant.Twelve N-alkylated dimethyl aspartate derivatives were synthesized.（5）N-alkylation of dimethyl glutamateThe N-alkylation of glutamate dimethyl ester can be achieved by the method of separation of imine before reduction by Na BH4.Two N-alkylated dimethyl glutamate derivatives were synthesized.