THE SYNTHESIS AND SCREENING OF 1,6- AND 1,8-NAPHTHYRIDINE ANALOGS OF PTERIDINE DIURETIC AGENTS
Date
1973
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Degree Level
Doctoral
Abstract
Nitrogen 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.
Description
Keywords
Nitrogen heterocyclic ring systems, potassium-sparing diuretic activity, 1,6- AND 1,8-NAPHTHYRIDINE ANALOGS
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Pharmacy and Nutrition