Chemical Modification Of Ligustrazine And Bioactivity Tests Of Ligustrazine Derivatives

2,3,5,6-tetramethylpyrazine (IMP) is one of the biologically active ingredients of a traditional herbal medicine Ligusticum wallichii Franch or Ligusticum chuanxiong Hort. TMP has been shown to have various pharmacological actions such as antiplatelet aggregation, vasodilation, antihypertension and blood flow enhancement in stomach viscous membrane. It was found that 2-hydroxylmethyl-3,5,6-trimethylpyrazine, one of the metabolites of TMP, possesses antiplatelet aggregation activity. In this study 19 new derivatives of this metabolite were synthesized by combining the metabolite with different drugs bearing carboxyl groups such as aspirin.On the basis that introducing a methyl group to the carbon atom linked with a hydroxyl group in the molecule of the metabolite can lead to a longer elimination half-life and stronger pharmacological activity, an analog (2-(1-hydroxylacetyl)-3,5,6- trimethylpyrazine ) of the metabolite and three other new compounds were synthesized by introducing the molecules of drugs exhibiting different activities to the parent structure of the analog. Another analog, 2-aminomethyl-3,5,6-trimethylpyrazine, and five derivatives were also synthesized.Since the pharmacological activity of TMP heavily depends on the electron cloud density of the nitrogen atom, eight new compounds were synthesized by replacing one of its methyl groups with a alkenyl group in order to increase the density of nitrogen atom in the ring of pyrazine and to improve its pharmacological activity.Pharmacological tests on antiplatelet aggregation, anti-inflammatory and vasodilation were performed with the synthesized compounds. The results suggest that some of the compounds are pharmacologically active.cc-methyl-4 ' -(2-methyl propanyl) benzenacetic acid 2-hydroxyl-methyl-3,5, 6-trimethylpyrazine ester, one of the target compounds was collected to do pharmacokinetic study in dogs. The result showed that the prodrug can be hydrolyzed into its original two parts2-hydroxylmethyl -3,5,6-trimethylpyrazine and ibuprofen.