Synthesis and chemical properties of ibopamine and of related esters of N-substituted dopamines--synthesis of ibopamine metabolites

Abstract

The therapeutic usefulness of intravenously infused dopamine in congestive heart failure and in shock prompted us to synthesize a wide series of 3,4-O-diesters of dopamine and N-substituted derivatives to obtain an orally active dopamine-like prodrug having adequate absorption and duration of action. The pharmacological results and in particular, the hemodynamic studies in the dog led to the selection of ibopamine, i.e. the 3,4-diisobutyryl ester of N-methyldopamine and to its development as a useful drug for the chronic treatment of congestive heart failure. The choice of ibopamine from among several analogs was also influenced by other favourable properties such as good chemical stability in pharmaceutical formulations and in the biopharmaceutical phases of the absorption, and fast enzymatic activation of the prodrug by plasma and peripheral tissue esterases; the latter property appeared desirable to avoid any accumulation in the central nervous system and consequent undesired side effects. The isomeric mixture of 3-O- and 4-O-isobutyrates of N-methyldopamine as well as the main conjugated metabolites, i.e. the 3-O- and 4-O-sulphate and 4-O-beta-glucuronide of N-methyldopamine were synthesized as analytical references in metabolic studies and for the investigation on their pharmacokinetic and pharmacological properties. Dopamine O-sulphates were also prepared using the methods developed for the corresponding N-methyl derivatives.