Inotropic agents pyridazinones

In the United States, two potent orally active positive inotropic agents, CI-914 [imazodan hydrochloride CAS 89198-09-4, (15)] and CI-930 [CAS 86798-59-6, (16)], both characterized by a 4T(l/7-imidazol-l-yl)phenyl substituent attached to C-6 of a 4,5-dihydro-3(2//)-pyridazinone system, have been developed [16]. Patents exist on compounds of this type and related unsaturated pyridazinones [17-21] and also on homologues in which the... 

Another pyridazinone-derived inotropic agent with cAMP phosphodiesterase inhibitory activity is pimobendan [UD-CG-115-BS CAS 74150-27-9, (21)], which has been developed in Germany. In contrast to the imidazolyl-phenylpyridazinone CI-930 (16) discussed above, in pimobendan the imidazole nucleus (substituted at C-2 by a 4-methoxyphenyl group) is fused to the benzene moiety attached to C-6 of the 4,5-dihydro-5-methyl-3(2//)-pyri-dazinone system. 

In the United States, compound RGW-2938 (47) has been developed as a selective positive inotropic agent its synthesis and pharmacological actions have been reviewed [161]. Related compounds, in which the dihydro-pyridazinone system is replaced by a benzoxazinyl system instead of the quinazoline system, have recently been studied in India and in the United States [162,163]. From this series, bemoradan (48) was found to be a very potent orally active, long-acting inotropic vasodilator agent in canine models (i.v. ED5o = 5.4 //g/kg 24h duration of action) [163]. 

The discovery of the positive inotropic and systemic vasodilator activities of bipyridine-derived compounds, like amrinone (7) and milrinone (8), has markedly stimulated research aimed at the development of structurally related non-steroidal, non-catecholamine cardiotonics. In this context, a wide variety of pyridazinone derivatives have been prepared and investigated in search for novel agents useful for the chronic management of congestive heart failure. 

---