New 2-aryl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-4-one derivatives as diuretics.
2-Aryl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-4-one derivatives having various substituents at the 4'-position, H or methyl at 1,3-positions and nitro or amino at 6-position were prepared and tested for their diuretic, natriuretic and kaliuretic activities on male Wistar rats at a dosage of 25 mg/kg or less. 2-(3-Pyridyl) derivatives were inactive. 1,3-Dimethyl-6-nitro-2-phenyl derivatives (1) were active depending on the electronic character of the 4'-substituent but at the same time were sodium-sparing. However, 1(H),3(H)-6-nitro-2-phenyl derivatives (2) were generally inactive as diuretics but active as potassium-sparing drugs. 6-Amino-1(H),3(H)-2-phenyl derivatives (4) were active as diuretics depending on dipolar moment of the substituent at the 4'-position, and induced moderate potassium release. The 6-amino-2-(4-trifluoromethylphenyl)-1, 2,3,4-tetrahydropyrido [2,3-d]pyrimidin-4-one (4f) remained active up to a dosage of 3 mg/kg. The structure-activity relationships were carried out in light of the adaptative least squares (ALS) method and discriminant functions for diuretic compounds were established.
Monge
A
A
Department of Organic and Pharmaceutical Chemistry, Universidad de Navarra, Pamplona, Spain.
Martinez-Merino
V
V
Simon
M A
MA
Sanmartin
C
C
D000818:Animals; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D004232:Diuretics / Q000138:chemical synthesis* / Q000494:pharmacology; D004563:Electrochemistry; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D011188:Potassium / Q000652:urine; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D004095:Dihydropyridines; D004232:Diuretics; D011744:Pyrimidinones; D011188:Potassium