Prodrugs of 6-thiopurines: enhanced delivery through the skin

Soft-alkylated derivatives of 6-mercaptopurine, its riboside, and 2-amino-6-mercaptopurine riboside have been prepared and evaluated to improve the delivery of the thiopurines through the skin. The soft-alkylated derivatives were prepared by the alkylation of the thiopurines with acylheteroalkyl halides under neutral or basic conditions. The penetration of the derivatives through hairless mouse skin was measured using diffusion cells. All of the derivatives underwent extensive degradation during their diffusion through skin so that the parent thiopurine, even in the case of the ribosides, was the major product observed in the receptor phase. The pivaloyloxymethyl derivatives showed the greatest potential for enhancing the penetration of the thiopurines through the skin. Among the 6-mercaptopurine derivatives, VII and XI were the most effective; they delivered 5 and 13 times, respectively, more 6-mercaptopurine than 6-mercaptopurine itself.