An approach for synthesis of tropinone analogue N-substituted with triazine ring.

Tropane alkaloids have received much attention because many of them reveal remarkable biological activity (1-5). Compounds with tropinone structure or related 8-azabicyclo[3.2.1]octane skeletons have attracted considerable attention in medicinal chemistry because of their influence on neurotransmitters. They are of interest as analogues of cocaine and other physiologically active compounds and are considered as candidates for drug development, for example, for treatment of cocaine addiction, neurodegenerative diseases such as Alzheimer (6, 7) and Parkinson, etc. Several new tropinone analogues were prepared for the treatment of obstructive lung diseases (8), structure-activity studies (9, 10) inhibition of dopamine uptake (11) binding as ligand of nicotinic acetylcholine receptor (12) etc. There were also identified and prepared other pharmaceutically interesting alkaloids with tropane fragment incorporated into more complex structure (13, 14). Due to their unique structural feature, the synthesis of tropane skeleton was a challenge and involved long sequence of reactions until pioneering synthesis of R. Robinson (15). Recently, a variety of new synthetic approaches to this class of bicyclic nitrogen heterocycles has been developed, based mainly on cycloaddition, transition metal catalyzed reactions, tandem domino reactions and others (16-22). An alternative approach, very efficient in the search for the new derivatives, involved modification of tropane skeleton (23). The modifications were based on aldol type condensation (24, 25), modification of carbonyl group (26, 27), annulation (28), Wittig type reaction (29) and others. The often used modification pathway starts with N-demethylation of tropinone (30-32). Herein we attempted to use our new N-dealkylation procedure based on quaternization of tertiary amines after treatment with 2-chloro-4,6-disubstituted-1,3,5-triazine (33). It has been expected that this approach would be useful for the preparation of hybrid combining in one structure the tropane fragment, topoisomerase inhibitors based on aminotriazine and additional reactive center ready for incorporation of nitrogen mustards (NM) fragment used as antineoplastic agents. It is anticipated that the presence of all these pharmacophores would be benefical for improving therapeutic index of the hybrid structure.