Synthesis of Co-Drugs of Akylating Agents and Steroidal Anti-Inflammatories

Abstract

Co-drugs of the anti-inflammatory agents dexamethasone and prednisone, and antineoplastic agents melphalan and chlorambucil, were synthesized using an esterification reaction. The carboxylic acids were activated using dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) to give esters (11β, 16α)-9-fuoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione 21-{4'-[bis(2-chloroethyl)amino]-L-phenylalaninate} hydrochloride, 17,21-dihydroxypregna-1.4-diene-3,11,2O-trione 21-{4'-[bis(2-ch1oroethy1)amino]-l-phenylalaninate} hydrochloride, (11β, 16α)-9-fluoro-11, 17, 21-trihydroxy-l6-methyl-pregna-1, 4-diene-3,20-trione 21 -{4'-[p-[bis(2 chloroethy)amino]pheny1]-butyrate} and 17,21-dihydroxypregna-1.4-diene-3,11,20-trione 21 {4'-[p-[bis(2-ch1oroethyl)-amino]phenyll-butyrate)}. Preliminary investigations have shown that these esters are hydrolyzed to their component drugs and show comparable in vitro activity to the parent drugs.