Synthesis And Positive Inotropic Effect Of Derivatives Of Secondary And Tertiary Alcohols Of Ligustrazine

Ligustrazine(Lig;tetramethylpyrazine,TMP)is an alkaloid monomer extracted from Chinese traditional medicine herb Chuanxiong(Ligusticum wallichii Franch),which is currently widely used in China as a new kind of calcium channel antagonists for the treatment of coronary atherosclerotic cardiovascular disease and ischemic cerebrocardiac vascular disease.Researches on the pharmacological activity of ligustrazine derivatives found that some alcohols and their esters synthesized previously have different extents of positive inotropic effects.And liguzinediol which has low toxicity and good water solubility could induce obviously positive inotropic effect in the normal isolated rat hearts with no arrhythmia risk.Pharmacokinetics studies demonstrated that liguzinediol presented a short half-life in vivo,the reasons as follows:First it could be quickly formed glucuronic acid conjugates excreted in vitro by urine and excrement.Second the diol hydroxyl groups and the side chain methyl could be oxidized into metabolins with high polarity and solubility and excreted easily in vitro by urine.This article,which remains the nucleus para-hydroxy,is mainly to design and synthesize series of the secondary and tertiary alcohols derivatives and to investigate their inotropic effects.Furthermore,the halogenated derivatives were synthesized with bioisosteric principle and their inotropic activities were observed.The result show that all these compounds have varying degrees of positive inotropic effect,and with the change of spatial structure,the activity also declined.So we can speculated that such change on the spatial structure of compound affect the ability to bind with the target,then resulting in a decline in activity.(I)Synthesis of ligustrazine derivatives1 Synthesis of the secondary alcohol derivativesThe intermediates 3,6-dimethyl-2,5-pyrazine formaldehyde was oxidized from liguzinediol through manganese dioxide(MnO2),and then reacted with Grignard reagent in tetrahydrofuran as the solvent to get the secondary alcohol derivatives.2 Synthesis of the tertiary alcohol derivativesThe intermediates 2,5-diacetyl-3,6-dimethylpyrazine was obtained through the free radical addition reaction which started from 2,5-dimethylpyrazine and acetaldehyde,and then reacted with Grignard reagent in tetrahydrofuran as the solvent to get the tertiary alcohol derivatives.3 Synthesis of the halogenated derivatives(1)At 0?5?,a well stirred mixture of liguzinediol and diethylaminosulfur trifluoride(DAST)could obtain the 2,5-difluoromethyl-3,6-dimethylpyrazine and 2-hydroxymethyl-5-fluo-ro-methyl-3,6-dimethylpyrazine.And the 2,5-dichloromethyl-3,6-dimethylpyrazine was obtained by a well stirred mixture of liguzinediol and thionyl chloride.(2)At 0?5?,the 2-fluoromethyl-3,5,6-trimethylpyrazine was obtained by a well stirred mixture of 2-hydroxymethyl-3,5,6-trimethylpyrazine and diethylaminosulfur trifluoride(DAST).The structures of these compounds were characterized by UV,IR,NMR and MS.(II)Bioavailability screening of ligustrazine derivativesThe normal isolated rat hearts were perfused by the Langendorff technique and observed the effect of these compounds on left ventricular inotropic effects.The result demonstrated that the secondary and tertiary alcohols derivatives,and the halogenated derivatives can induce positive inotropic effects on myocardium with no arrhythmia risk.