7-Heteroaryl-1,2,3,5-tetrahydroimidazoquinazolin-2(1H)-one Derivatives with Cardiac Stimulant Activity

Article abstract of DOI:10.1021/jm00129a005

A series of 7-heteroaryl-1,2,3,5-tetrahydroimidazo<2,1-b>quinazolin-2(1H)-ones was synthesized and evaluated in dogs for cardiac stimulant activity.Compounds were obtained by a palladium-catalyzed cross-coupling reaction between a heteroarylzinc chloride and a 7-iodo-1,2,3,5-tetrahydroimidazo<2,1-b>quinazolin-2(1H)-one or by cyclization of an N-<(2-aminophenyl)methyl>glycinate with cyanogen bromide.Compared to the parent ring system (3), introduction of a 2,6-dimethylpyridin-3-yl (6), 2,4-dimethylimidazol-1-yl (7), or 1,2,4-triazol-1-yl (8) moiety at the 7-position led to a 13-17-fold increase in positive inotropic activity (percentage increase in dP(dt_max) in anesthetized dogs.Potency could be further enhanced with a 9-methyl substituent (10-12).The most potent member of the series, 7-(2,4-dimethylimidazol-1-yl)-9-methyl-1,2,3,5-tetrahydroimidazo<2,1-b>quinazolin-2(1H)-one (11) (23percent increase in dP/dt_max, 2 μg/kg), was 80 times more active than 3 and displayed a 5-fold advantage over milrinone.In conscious dogs, 6 elicited marked and sustained positive inotropic activity (decrease in QA interval) after oral administration (1 mg/kg), whereas 10-12 were 10 times more potent. 11 produced an obvious increase in cardiac contractility (20percent increase in dP/dt_max) at low dose levels (25 μg/kg) while, after 100 μ/kg, the marked response (50percent increase in dP/dt_max) was maintained for the whole 7-h test period.In these experiments, 11 had no effect on heart rate, and the compound also displayed exceptional selectivity for increasing the force rather than the rate of cardiac contraction (> 150percent increase in dP/dt_max) in the Starling heart-lung preparation.These studies demonstrate that the tetrahydroimidazoquinazolinone nucleus is an effective bioisostere for the 2(1H)-quinolinone system and that 11 displays improved cardiac stimulant activity and duration of action when compared to milrinone.