7-Heteroaryl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin -2(1H)-one derivatives with cardiac stimulant activity.
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/dtmax) 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-tetrahydroimidaz o [2,1-b]quinazolin-2(1H)-one (11) (23% increase in dP/dtmax, 2 micrograms/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 (20% increase in dP/dtmax) at low dose levels (25 micrograms/kg) while, after 100 micrograms/kg, the marked response (50% increase in dP/dtmax) 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 (greater than 150% increase in dP/dtmax) 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.
Bell
A S
AS
Department of Discovery Chemistry, Pfizer Central Research, Sandwich, Kent, United Kingdom.
Campbell
S F
SF
Roberts
D A
DA
Ruddock
K S
KS
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D007275:Injections, Intravenous; D009200:Myocardial Contraction / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D011799:Quinazolines