Congestive Heart Failure/β-Adrenergic Antagonist: Novel Pyridazinones with Combined β-Adrenergic and PDE III Activity for the Treatment of Congestive Heart Failure

Summary

Novelty: Novel pyridazinones, which are both positive inotropes and β-adrenergic blocking agents, are disclosed. As such, they are considered useful in the treatment of congestive heart failure.

Biology: A rat aorta relaxation screen identified PDE inhibitors. The IC₅₀ for the preferred compound is 0.34 μM. Inotropic activity is demonstrated in the anaesthetised dog (ED₅₀ = 0.11 μg/kg), and is not blocked by atenolol. Inotropic activity is also shown in a guinea pig left atrial test (ED₅₀ = 9μM). A pIC₅₀ of 7.57 was reported in a β-adrenoceptor binding assay.

Chemistry: The patent is exemplified by the synthesis of fifty final compounds using standard procedures. The preferred compound is 6-(4-[N-[2-[3-phenoxy-2-hydroxypropylamino]ethyl]-carbamoylmethoxy]-3-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone.