Synthesis and positive inotropic activity of several 5-aminopyrido[2,3-d]pyrimidines. Part 5: Compounds with positive inotropic activity.

Starting from 6-amino-1,3-dimethyluracil two approaches were developed for the preparation of 5-amino-pyrido[2,3-d]pyrimidine derivatives as potential cardiotonic agents. 1. Gould-Jacobs reaction followed by chlorination of the intermediate 5-hydroxypyrido-[2,3-d]pyrimidine using DMF/POCl3. 2. Cyclization of C-acetylated as well as C-cyano acetylated 6-amino-1,3-dimethyluracil by an application of the Vilsmeier reaction yielding 5-chloropyrido[2,3-d]pyrimidines. Subsequent nucleophilic substitution reactions formed the target compounds which were examined for positive inotropic activity on isolated left atria and papillary muscles from guinea-pig hearts. Structure-activity relationships indicated that the effect depended on the 4-aminopyridine-3-carboxylic acid derivative structure.