2-Amino/azido/hydrazino-5-alkoxy-5H-[1]benzopyrano[4,3-d]pyrimidines: synthesis and pharmacological evaluation.
New series of 5-alkoxy-benzopyranopyrimidine derivatives were developed from the chemical modulation of the substituent in position 2 of the scaffold, with the aim to produce analgesic/antiphlogistic agents more potent than analogues previously reported. The 2-hydrazino derivatives exhibited a good analgesic activity in writhing test; the analgesic doses of the compounds did not affect mice spontaneous locomotor activity thus any confounding sedative effect could be excluded. These derivatives revealed an aspirin-like profile with a strong inhibition of AA-induced platelet aggregation, probably due to a strong, non selective, inhibition of cyclooxygenases. In spite of the inhibition of COX activity displayed in vitro, the compounds did not cause gastric damage in rats after acute oral administration. A different pharmacological profile was observed for the 2-azido derivatives, particularly in vivo.
Bruno
O
O
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV, 3-16132 Genova, Italy. obruno@unige.it
Brullo
C
C
Bondavalli
F
F
Ranise
A
A
Schenone
S
S
Tognolini
M
M
Ballabeni
V
V
Barocelli
E
E
D019342:Acetic Acid; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001792:Blood Platelets / Q000187:drug effects; D002351:Carrageenan; D051545:Cyclooxygenase 1 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005334:Fever / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008070:Lipopolysaccharides; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D013329:Structure-Activity Relationship
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D008070:Lipopolysaccharides; D010975:Platelet Aggregation Inhibitors; D011743:Pyrimidines; D002351:Carrageenan; D051545:Cyclooxygenase 1; D019342:Acetic Acid