Synthesis of ortho-functionalized 4-aminomethylpyridazines as substrate-like semicarbazide-sensitive amine oxidase inhibitors.

A series of 4-aminomethylpyridazines and -pyridazin-3(2H)-ones ("diaza-benzylamines"), bearing alkylamino side chains in ortho position relative to the CH(2)NH(2) unit, was synthesized by catalytic hydrogenation of the corresponding nitriles in strongly acidic medium. N-Benzyl protecting groups either at the pyridazinone ring nitrogen or at an exocyclic nitrogen were selectively removed hydrogenolytically or by treatment with a Lewis acid. The new compounds were tested in vitro for semicarbazide-sensitive amine oxidase (SSAO) inhibitory activity and 4-(aminomethyl)-N,N'-diethylpyridazine-3,5-diamine (22) was found to be the most active representative.

Unexpected hydrazinolysis behaviour of 1-chloro-4-methyl-5H-pyridazino[4,5-b]indole and a convenient synthesis of new [1,2,4]-triazolo[4',3':1,6]pyridazino[4,5-b]indoles.

Reaction of the title compound with hydrazine in the presence of air gives the 1-unsubstituted parent system via oxidative dehydrazination of the 1-hydrazino intermediate. The latter can be obtained in high yield by carrying out the hydrazinolysis step under inert gas, and it is smoothly converted into [1,2,4]-triazolo[4',3':1,6]pyridazino[4,5- b]indoles.