2023-11-062023-11-0619731973https://hdl.handle.net/10388/15223Nitrogen heterocyclic ring systems, particularly pteridines and pyrazines, are known to possess effective potassium-sparing diuretic activity. 2-Amino-1,8-naphthy-ridine-3-carboxamide hydrochloride monohydrate has also been shown, in our laboratories, to be a potent anti-kaliuretic diuretic agent. The aim of this research Was to prepare some substituted 1,6- and 1,8-naphthyridine analogs of pteridine diuretics, which would be tested in a classical saline-loaded rat screen. A series of 2-amino-3-substituted 1,6-naphthyridines was synthesized from 4-aminonicotinaldehyde and cyano-methylene compounds employing a modification of the classical Friedlander reaction. Additional 2,3-disubstituted 1,6-naphthyridines have been prepared either directly from 4-aminonicotinaldehyde, or by subsequent reaction of the bicyclic products. A representative series of compounds was prepared for the purpose, of structure-activity relation-ship studies. The scope and versatility of the Friedlander reaction was explored. The base-catalyzed condensations of 4-amino-nicotinaldehyde with a variety of ketones and esters containing an activated methylene moiety have been investigated. A number of bifunctional a-disubstituted methylene compounds where two modes of cyclization are possible were also investigated. Under the conditions employed, normal Friedlander-type ring-closure was found to occur. The method provides a convenient synthetic route to a previously inaccessible series of 2,3-disubstituted 1,6-naphthyridines. A series of novel tricyclic compounds was synthesized from mono- and disubstituted 1,6-naphthyridines prepared in this work. Examples of pyrimido[4,5-b-, thieno[2,3-b]-, pyrazalo[3,4-b- and pyrimido[1,2-a]-l1,6]naphthyridines have been prepared. The 1,8-naphthyridines required for screening were synthesized in a similar manner to the 1,6-naphthyridines. Thus these compounds were prepared either directly from 2-aminonicotinaldehyde or from intermediate 1,8-naphthyridines. Structure-activity relationships of the title compounds are discussed and comparisons are made to various standard diuretic agents. Most of the thirty-five 1,6-naphthyridines tested were active at 15 mg/Kg, but few showed a diuretic response at 2 mg/Kg (i.p.). In contrast, the 1,8-naphthyridines were generally inactive, although 2-amino-1,8- naphthyridine-3-carboxamide was the most potent naph- thyridine screened in this work. This compound has been extensively investigated by a pharmaceutical company and has been shown to be a very potent diuretic orally in the rat and monkey.Nitrogen heterocyclic ring systemspotassium-sparing diuretic activity1,6- AND 1,8-NAPHTHYRIDINE ANALOGSThesis