Synthesis And Positive Inotropic Effects Of The Methyl Substitution Derivatives And Isostere Derivatives Of Liguzinediol

TMP(Ligustrazine,Lig;Tetramethylpyrazine,TMP)is the major chemical component extracted from traditional Chinese medicine Umbelliferae Chuanxiong rhizome,Euphorbiaceae Jatropha and Zingiberaceae Curcuma.In previous study,some secondary,tertiary alcohol,ester and ether derivatives of Ligustrazine were synthesized and pharmacological investigations showed a positive inotropic action with varying degree.Among them,liguzinediol,3,6-dimethyl-2,5-bis(hydroxymethyl)pyrazine exhibited its potent for being metabolized by Hepatic drug metabolism enzymes.Furthermore,pharmacological investigations indicated that Liguzinediol could evidently enhance left ventricular contractility on normal isolated hearts and improve the diastolic function of hearts in SD rats without any arrhythmia risks.By comparison of the mechanism through which the conventional inotropic agents work,Liguzinediol exerts its action by targeting on SERCA2a located in myocardial cell.Recently,considerale attention has been paid to this novel target for the treatment of heart failure.Less ideally,due to its short duration of action,drug must be frequently administrated for chronic heart failure patients to reach the efficacious blood concentration.Aiming at developing proper drug for chronic heart failure patients,the carbon chain of methyl functional at site 3 or 6 was extended and shortened with the two hydroxymethyl groups remaining the same.The results demonstrated that the positive inotroic effect decreased and even disappeared as the carbon chain either ascend or descend.After substituting the methyl functionals with isosteres,the positive inotroic effect totally vanished.On the grounds of these studies,entire molecular structure of liguzinediol has an irreplaceable role reflects with the positive inotropic activity.(I)Synthesis of liguzinediol derivatives1.methyl substituted derivatives of liguzinediolAlkyl acylation products were produced by treating 2,5-dimethylpyrazine,and 2,3,5-trimethylpyrazine with aldehyde,and following by reduction,oxidation,and BOEKELHEIDE rearrangement,methyl substituted derivatives of liguzinediol were yield.2.isostere derivatives of liguzinediolStarting from liguzinediol,with manganese dioxide serving as reductant,mixture was refluxed to give rise to 3,6-dimethyl-5-hydroxymethylpyrazine-2-carbaldehyde and 3,6-dimethylpyrazine-2,5-dicarboxaldehyde,which in turn was reduced by reacting with ammonia solution and four hydrogenboron sodium in methanol to produce liguzinediol isostere derivatives.3.dihydroxymethyl derivatives of liguzinediolBy treatment of 2,5-dimethylpyrazine with hydrogen peroxide and glacial acetic acid,resulted in the formation of 2,5-dimethylpyrazine-1,4-dioxide and afterwards via rearrangement in phosphorus oxychloride 3,6-dimethyl-2,5-dichloro-pyrazine was given.All structures described above were confirmed by UV,IR,NMR and MS.Pharmacological activity screenThe effect of liguzinediol derivatives on normal isolated hearts in SD rats was investigated by Langendorff infusion.The results showed that methyl substituted derivatives to some extent possessed positive inotropic action without arrhythmia,and as the carbon chain increased,the effect decreased obviously.As for liguzinediol isostere derivatives,neither positive inotropic action nor arrhythmia presented during Langendorff infusion.