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.
Heber
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Department of Pharmaceutical Chemistry, University of Kiel.
Ravens
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Schulze
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D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D011725:Pyridines; D011743:Pyrimidines; D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol