Milrinone, cardiotonic

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. 

From this series, compound MCI-154 (CAS 98326-33-1) (30) has been investigated in detail [95,96]. In vivo studies (anaesthetized dogs) revealed that doses of 0.3-100 tg/kg (i.v. administration) of MCI-154 produce dose-dependent increases in dF/dtmax and cardiac output, and decreases in arterial blood pressure and total peripheral resistance. The positive inotropic effect of (30) has been found to be superior to that exhibited by amrinone and milrinone [97,98]. It has been stated that MCI-154 exerts its activity probably by increasing the calcium-ion sensitivity of the contractile protein system of the cardiac skinned fibres [99,100]. A recent investigation suggests that inhibition of phosphodiesterase III is an important component of its cardiotonic activity [101]. 

An analogous scheme is used for the synthesis of the cardiotonic agent milrinone [28]. The key aminoformyl derivative (26-2) is obtained in this case by condensation of 4-pyridylacetone (26-1) with DMF acetal. Reaction with cyanoacetamide in the presence of a strong base proceeds exactly as above to give the pyridone (26-3) by a parallel set of transformations. Note that the nitrile is left as such in this drug. 

Azinoboronic acids have been prepared and applied to coupling reactions (Scheme 57). 3-Bromo- and 4-bromopyridines can be lithiated and reacted with boronates to form pyridineboronic acids, which have been coupled with methyl 5-bromonicotinate to furnish 256 when Pd(OAc)2(dppf) is the catalyst. Coupling with the 4-isomer has been applied to the appropriate 3-bromopyridine for the synthesis of the 4-methyl derivative (258) of the cardiotonic milrinone (259) (88JOC2052). 

Miscellaneous dru witli positive inotropic action such as inamrinone and milrinone (Primacor) are nonglycosides used in the short-term management of HE. AMiough in tlie past the cardiotonics were the mainstay in the treatment of HE, currently tliey are used as the fourtli line of treatment for patients who continue to experience symptoms after using the ACE inhibitors, diuretics, and beta blockers. See the Summary Drug Table Cardiotonics and Miscellaneous Inotropic Dru for infonnation concerning tliese dru. ... 

---