SYNTHESIS AND CARDIOTONIC ACTIVITY OF NOVEL PYRIMIDINE-DERIVATIVES - CRYSTALLOGRAPHIC AND QUANTUM-CHEMICAL STUDIES

The synthesis of ethyl or methyl 4-substituted or unsubstituted 2-(dim ethylamino)-5-pyrimidinecarboxylates 10-20, which is mainly carried ou t by reaction of ethyl or methyl 2-[(dimethylamino)methylene]-3-oxoalk anoates with 1,1-dimethylguanidine, is described, The above esters wer e hydrolyzed to the relative carboxylic acids 21-30, which were decarb oxylated to the corresponding 2,4-disubstituted pyrimidines 31-40. All the new synthesized pyrimidines were evaluated in spontaneously beati ng and electrically driven atria from reserpine-treated guinea pigs, T heir effects were compared to those induced by milrinone in both atria preparations, Compound 28 (4-benzyl-2-(dimethylamino)-5-pyrimidinecar boxylic acid) was the most effective positive inotropic agent, while t he corresponding methyl ester 17 reduced both the contractile force an d the frequency of guinea pig atria. An antagonism toward the negative influence exerted by endogenous adenosine on the heart seems to be in volved in the contractile activity of compound 28. By contrast, compou nd 17 might be partial agonist at the purinergic inhibitory (A1) recep tor. X-ray-analysis carried out on 17 and 28 and molecular modeling in vestigations extended also to related derivatives allowed a possible r ationalization between structure and inotropic activity for this serie s of compounds.