STUDIES OF CARDIOTONIC AGENTS .8. SYNTHESIS AND BIOLOGICAL-ACTIVITIESOF OPTICALLY-ACTIVE NAZOLINYL)-4,5-DIHYDRO-5-METHYL-3(2H)-PYRIDAZINONE (KF15232)

We previously reported that (+/-)-6-(4-(benzylamino)-7-quinazolinyl)-4 pyridazinone ((+/-)-1, KF15232) showed potent cardiotonic activity wi th a strong myofibrillar Ca2+-sensitizing effect. As an extension of o ur work, we attempted to synthesize optically active 1. Benzylamino)-7 -quinazolinyl)-3-methyl-4-oxobutyric acid (-)-menthyl ester (6) was se parated into both diastereoisomers, and each was converted to opticall y pure 1 (> 99% eel in an enantioselective manner. In order to determi ne the absolute configuration of the isomers, an alternative synthesis of optically active 1 was employed. The precursor of(-)-1 ((+)-9) was obtained by enantioselective synthesis from (R)-D-alanine. Consequent ly, we concluded that the absolute configuration of(-)-1 at the 5-posi tion of the pyridazinone ring was R. The cardiotonic effects and inhib itory activities to PDE III and V of racemic 1 and (-)-1 were more pot ent than those of(+)-1. These compounds also demonstrated greater vaso relaxant effects in guinea pig aorta. In contrast, (+)-1 showed only w eak cardiotonic and vasodilating effects, although the compound displa yed potent Ca2+-sensitizing activity. Racemic and (-)-1 attracted our interest for the treatment of congestive heart failure.