Synthesis and antihistaminic activity of 2-guanadino-3-cyanopyridines and pyrido[2,3-d]-pyrimidines

2-Guanadino-3-cyanopyridines 8–33 and pyrido[2,3-d]-pyrimidines 35–52 were synthesized by nucleophilic displacement and cyclization of the chloroamidines 6a–d easily obtained by reaction of 2-aminocyanopyridines 5a–d with phosgene iminium chloride and their action on the release of histamine by mast cells examined under immunological and chemical stimulus, with and without pre-incubation. Several 2-guanadino-3-cyanopyridines and pyrido[2,3-d]-pyrimidines are shown to be inhibitors of the release of histamine when stimulated with ovoalbumin as antigen or with polymer 4880 as chemical stimulus. Guanadino-3-cyanopyridine 30 and pyrido[2,3-d]-pyrimidine 49 are the more active of all, inhibiting the release of histamine in all the conditions tested (30–60% inhibition). Guanadinocyanopyridines 15, 17, and 19 are very potent stimulators of the release of histamine (150–300%) while pyrido[2,3-d]-pyrimidines are mostly inactive. Compounds 28 and 14 present moderate in vitro cytotoxic activity against P-388, A-549, HT-29, and MEL-28 cell lines.