Synthesis of certain alkenyl purines and purine analogs as inhibitors of tumor necrosis factor alpha (TNFα)

The preparation of 2-penten-1-yl and 3-methyl-2-buten-1-yl derivatives of adenine 2a,b, 7-deazaadenine 2c,d, 2-aminopurine 4a,b and 5a,b, 4-aminopyrazolo[3,4-d]pyrimidine 7a,b and 7-amino-v-triazolo-[4,5-d]pyrimidine 8a–10a and 8b-10b is described. The synthesis of compounds 2a-d was accomplished by the functional group transformation reaction, whereas the synthesis of 4a-8a and 4b-8b was performed by the alkylation of the sodium salt of the heterocycles with alkenyl bromides. These alkenyl derivatives prepared as congeners of pentoxifylline (methylxanthine) were evaluated for their anti-tumor necrosis factor a activity in human monocytic leukemia cells. Only compounds 7a and 7b exhibited significant activity and a poor toxicity profile in this assay. In peripheral blood mononuclear cells, compounds 7a and 7b, inhibited tumor necrosis factor a production in a dose dependent manner.