Nitrogen bridgehead compounds. 38. New antiallergic 4H-pyrido[1,2-a]pyrimidin-4-ones. 3

• Published in: Journal of medicinal chemistry 1983-10, Vol.26 (10), p.1494-1499
• Main Authors: Hermecz, Istvan, Breining, Tibor, Vasvari-Debreczy, Lelle, Horvath, Agnes, Meszaros, Zoltan, Bitter, Istvan, DeVos, Christine, Rodriguez, Ludovic
• Format: Article
• Language: English
• Subjects: Animals; Drug Evaluation, Preclinical; Histamine H1 Antagonists - chemical synthesis; Indicators and Reagents; Magnetic Resonance Spectroscopy; Passive Cutaneous Anaphylaxis - drug effects; Pyrimidinones - chemical synthesis; Pyrimidinones - therapeutic use; Rats; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00364a025

The weak antiallergic activity of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (4) on the rat reaginic passive cutaneous anaphylaxis test was enhanced by the introduction of appropriate functional groups into position 9 of the pyridopyrimidine ring. The most active 9-substituted pyridopyrimidinecarboxylic acids contained an oxime, a phenylamino, or a (phenylamino)thioxomethyl group in position 9. The 9-phenylcarboxamido and 9-phenylhydrazono moieties may be regarded as bioisosteric groups in the pyridopyrimidinone series. In the series of 9-(arylamino)dihydropyridopyrimidines, the structure-activity relationship study revealed similar relationships as found for the 9-(arylhydrazono)tetrahydropyridopyrimidines. The biological activity was due to the 6S enantiomers. A monosubstituted arylamino moiety in position 9 was necessary for the intravenous activity. The most active compound, 9-[(3-acetylphenyl)amino]-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- pyrido[1,2-a]pyrimidine-3-carboxylic acid (40) was three times as active as the reference sodium chromoglycate (DSCG) in the passive cutaneous anaphylaxis (PCA) test.