ABSTRACT
Fosinopril sodium (I), a new angiotensin converting enzyme inhibitor, is a diester prodrug of the active moiety II. We report here a novel transformation of fosinopril into beta-ketoamide, III, and a phosphonic acid, IV, mediated through metal ion participation. The interaction of fosinopril with magnesium ions was studied in a solution model system in which methanol was used as the solvent and magnesium acetate as the source of metal ions. Kinetic analysis indicated the degradation to be a bimolecular process, with the rate being first order in both metal ion and fosinopril concentration. The degradation products II, III, and IV effectively retarded the magnesium ion mediated reaction of fosinopril. Based on the results of 31P-NMR, 1H-NMR, Mn(II)-EPR spectroscopy experiments and mass spectrometry, a mechanism is postulated for this transformation. A key reactive intermediate has been characterized that supports the proposed mechanism. The results can account for the observed degradation profile of the fosinopril sodium in a prototype tablet formulation.
Subject(s)
Fosinopril/chemistry , Magnesium/chemistry , Electron Spin Resonance Spectroscopy , Hydrolysis , Kinetics , Mass Spectrometry , Methanol/chemistry , Models, Molecular , Phosphorus Isotopes , Solvents , TabletsABSTRACT
Based upon the known dopaminergic properties of 2-aminodihydroxy-1,2,3,4-tetrahydronaphthalenes (ADTN's), heterocyclic congeners were prepared. Several 2-(alkylamino)-5,6- and -6,7-dihydroxy-3,4-dihydroquinazolines were synthesized and tested for a dopamine-like vasodilatory action in the canine renal artery. The 6,7-disubstituted series had a weak antagonist effect against dopamine. Neither 5,6- nor 6,7-dihydroxy substitution gave dopamine agonists. Measured pKa values confirmed the expectation that the dihydroquinazolines were more basic than dopamine, one possible reason for the lack of dopamine-like action.
Subject(s)
Quinazolines/chemical synthesis , Receptors, Dopamine/drug effects , Animals , Chemical Phenomena , Chemistry , Dogs , Heart Rate/drug effects , Kinetics , Male , Quinazolines/pharmacology , Vasodilator Agents/pharmacologyABSTRACT
Based on the known biological activity of a variety of guanidine-containing agents, several N-substituted 3,4-dihydroquinazolines were synthesized. These compounds can be considered to be rigid analogues of phenylguanidines. In anesthetized rats the compounds decreased blood pressure and were antagonists of the pressor response to norepinephrine.
