Alkylation of 6-mercaptopurine (6-MP) with N-alkyl-N-alkoxycarbonylaminomethyl chlorides: S6-(N-alkyl-N-alkoxycarbonyl)aminomethyl-6-MP prodrug structure effect on the dermal delivery of 6-MP.

The S6-(N-alkyl-N-alkoxycarbonyl)aminomethyl-6-MP (6-CARB-6-MP) prodrugs 5-20 were synthesized from the reaction of 6-MP with N-alkyl-N-alkyoxycarbonylaminomethyl chlorides (4) in dimethyl sulfoxide in overall yields of 5-62%, depending on the N-alkyl and the alkoxy groups involved. The derivatives were fully characterized by spectral and microanalyses. The assignment of the substitution pattern as S6-alkyl was based on comparisons of the UV, 1H NMR and 13C NMR spectra with model compounds.

The effect of vehicle on the diffusion of salicylic acid through hairless mouse skin.

The solubilities of salicylic acid in, and the fluxes through, hairless mouse skin from isopropyl myristate, 1-octanol, 1-propanol, propylene glycol, and formamide have been determined experimentally. Values for permeability coefficients (Kp) corresponding to the respective fluxes were determined from: flux/solubility = Kp. These values were then compared with values for the respective partition coefficients (P) which were calculated from the known solubility parameters for the vehicles (delta v), salicylic acid (delta i), and skin (delta s).

Use of solubility parameters of drug and vehicle to predict flux through skin.

The solubilities of theophylline in, and fluxes through skin from, isopropyl myristate, octanol, dimethylformamide, propylene glycol, ethylene glycol, and formamide have been determined experimentally. Values for experimental permeability coefficients (Kp) corresponding to the respective fluxes were determined from, flux/solubility = Kp, which were then compared with values for the respective theoretical partition coefficients (PC) calculated from the known solubility parameters for the vehicles (delta v), theophylline (delta i) and skin (delta s). There was a good correlation for theoretical log PC - 2.