Pyridine-Based Fused Tricyclic Compounds

Benzene rings often serve in drugs simply as flat, relatively electron-rich moieties. Many examples have been noted thus far where such rings can be replaced by heterocycles that have some degree of aromatic character. 

In a related vein, one of the benzene rings in dibenzepin (36-7) can be replaced by pyridine. In a one-pot reaction, condensation of the 2-chloronicotinic acid (43-2) with ortho-phenylenediamine (43-1) leads to the lactam (43-3). The order in which the two steps, aromatic displacement and amide formation, take place has not been elucidated. Simple alkylation of the anion from the product with 3-chloro-2-(AA -drmethylamino)propane (43-4) affords the antidepressant agent propizepine (43-5) [43]. 

The antidepressant agent tampramine (44-6) can be viewed as a distant analogue of imipramine that contains an extra benzene ring and two additional nitrogen atoms. The preparation of this compound starts by Ullman coupling of chloropyridine (44-1) with the aminobenzophenone (44-2) more frequently used for benzodiazepine syntheses. Reduction of the nitro group in the product (44-3) leads to a diamine (44-4) that readily cyclizes to form the pyridodiazepine (44-5). Alkylation of the anion from the treatment of this with sodium hydride with 3-chloro-1 -dimethylaminopropane affords tampramine (44-6) [44]. 

Hunziker, R Fischer, E. Schmutz, J. Helv. Chim. Acta 1967, 50, 1588. 

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