7-alkylcarbonyl and 7-alkyloxycarbonyl prodrugs of theophylline

Five members (6-10) of an homologous series of 7-alkyloxycarbonyltheophylli ne (7-AOC-Th) and four members (2-5) of a homologous series of 7-alkylcarbo nyltheophylline (7-AC-Th) prodrugs have been synthesized by known methods a nd characterized. All of the members in both series were much more soluble in isopropyl myristate (S-1mp) (10-200 times) anal in each series, at least one member was more soluble in pH 4.0 buffer (S-AQ) than Th. However, in t he 7-AC-Th series, only the acetyl member, 2, which exhibited about 90% of the S-AQ of Th, was sufficiently stable to be evaluated - it gave four time s the flux of Th/IPM (isopropyl myristate). In the 7-AOC-Th series, all the members were sufficiently stable to be evaluated but the member which exhi bited the greatest S-AQ 6 (methyloxycarbonyl), did not exhibit the greatest flux. Instead, 8 (propyloxycarbonyl), which exhibited the second greatest S-AQ (about 80% of the S-AQ of Th), but exhibited over ten times the S-1pm of 6 gave the greatest flux - two times the flux of Th/IPM. Thus, good biph asic solubility was the best predictor of increased flux. All of the prodru gs delivered only Th through the mouse skin. Only 2/IPM actually delivered more Th into the skin than Th/IPM which correlated with its ability to incr ease the flux of Th through the skin.(C) 2000 Elsevier Science B.V. All rig hts reserved.