Tricyclic Systems Derived from 2-Amino-1,8-Naphthyridines

Abstract

Methods available for the synthesis of 2-amino~1,8- naphthyridines are described. A brief summary of their physical properties is followed by a survey of the substitution: reactions which these compounds undergo, and which can lead to the formation of various tricyclic systems. The angular systems formed are tetrazolo[1,5-a] [1,8] naphthyridines, imidazo[1,2-a] [1,8] naphthyriaines, and pyrimido [1,2-a] [1,8] naphthyridines; cyclisation in a linear fashion produces anthyridines. The antibacterial properties of some 1,8-naphthyridine derivatives are discussed, in particular those of the established antibacterial agent nalidixic acid (1-ethyl-7-methyl- 1,8-naphthyridin-4(1H)-one-3-carboxylic acid). The practical work described in this thesis concerned the preparation of some new 2-amino-1,8-naphthyridines from 2,6-diamino-4-ethoxypyridine, as well as known examples prepared from 2,6-diaminopyridine. The product of the reaction between 2,6-diaminopyridine and benzoylacetone has been assigned the structure 7-amino- 4-methyl-2-phenyl-1,8-naphthyridine and not 7-amino-2-methyl- 4-phenyl-1,8-naphthyridine as given in the literature. This assignment has been made on the results of spectroscopic studies. Several new 2-vinylamino-1,8=-naphthyridines. were prepared from the aminonaphthyridines; the three reagents employed were diethyl ethoxymethylenenalonate, ethyl ethoxymethyleneacetoacetate and ethyl ethoxymethylenecyanoacetate. Several new examples of the pyrimido [1, 2-a] [1,8] naphthyridine system have been prepared by the intramolecular electrophilic cyclisation of 2-vinylamino-1,8=naphthyridines. Two new anthyridines have been prepared; one of these was prepared from a 2-vinylaminonaphthyridinone, and since all the anthyridines in the literature which have been prepared have been derived from 2-vinylaminonaphthyridinones, the significance of this is discussed, and an explanation put forward regarding the difficulties of preparing anthyridines from vinylamino~ naphthyridines bearing only alkyl or aryl substituents. The other example of the anthyridine system formed, 3,7-dicarbethoxy-5~ethoxyanthyridin-4,6(1H,9H)-dione, was made by a direct reaction with 2,6-diamino-4-ethoxypyridine, the first recorded one-step synthesis of an anthyridine from a pyridine. Five new examples of the inidazo [1,2-a] [1,8] napnthyridine: system have been prepared, by reaction of 2-amino-1,8- naphthyridines with d-halocarbonyl compounds. Three of these compounds contained one substituent in the imidazole ring, and this substituent has been assigned to the position furthest from the bridgehead nitrogen atom, on the basis of n.m.r. studies on these and other imidazonaphthyridines. Three new 2-acetamido-1,8-naphthyridine-3-carboxamides have been prepared, and the cyclisation of these compounds: has given three examples of a hitherto unreported heterocylcid system, the pyrimido [4,5-b] [1,8] naphthyridines. N.m.r. and mass spectroscopic data has been presented in support of the structural assignments. A selection of compounds prepared in the course of this work has been submitted for inclusion in a screening programme for new antimicrobial compounds. Three compounds were also tested for anticonvulsant activity in rats. The results of these tests are presented; these show that none of the compounds submitted displayed any useful antimicrobial or anticonvulsant properties.