ABSTRACT
A new series of N-substituted pyrido[3,2-b]oxazinones has been synthesized, pharmacologically evaluated, and compared with acetyl salicylic acid. The compound with the maximal combination of safety and analgesic efficacy was 4-¿3-[4-(4-fluorophenyl-1-piperazinyl)propyl]¿-2H-pyrido[3,2-b]-1, 4-oxazin-3(4H)-one (6c) with ED50 values of 12.5 mg/kg po (mouse: phenylquinone writhing test) and 27.8 mg/kg po (rat: acetic acid writhing test), respectively. Compound 6c proved to be more active than aspirin with a safety index of 5.1.
Subject(s)
Analgesics/chemical synthesis , Benzeneacetamides , Nociceptors/drug effects , Oxazines/chemical synthesis , Pyridines/chemical synthesis , Analgesics/pharmacology , Animals , Cimetidine/analogs & derivatives , Cimetidine/metabolism , Enkephalin, Ala(2)-MePhe(4)-Gly(5)- , Enkephalins/metabolism , Guinea Pigs , Histamine Antagonists/metabolism , Male , Mice , Models, Chemical , Nociceptors/metabolism , Oxazines/pharmacology , Pyridines/pharmacology , Pyrilamine/metabolism , Pyrrolidines/metabolism , Receptors, Opioid/drug effects , Receptors, Opioid/metabolism , Structure-Activity RelationshipABSTRACT
Series of 6-aminoalkyloxazolo[4,5-b]pyridin-2(3H)-ones incorporating structural modifications both in the alkyl chain and basic amino moiety were tested for their analgesic efficacy and safety in mice and rats. Two of the synthesised compounds, 4a (3-methyl-6-[(4-phenyl-1-piperazinyl)methyl]oxazolo[4,5-b]pyridin-2(3H)-one) and 12a (3-methyl-6¿1-[2-(4-phenyl-1-piperazinyl)ethan-1-ol]¿oxazolo[4,5-b]pyridin- 2(3H)-one) were found to be more potent than aspirin with ED50 values of 26 (16.1-42.4) and 15.5 (11.4-21.2) mg/kg po (mouse, phenylquinone writhing test) respectively and 6 (3.1-9.8) and 5.5 (3.5-8.8) mg/kg po (rat, acetic acid writhing test). Compounds 4a and 12a proved to be potent nonopioid nonantiinflammatory analgesics but unfortunately have sedative properties at relatively low doses (respectively 64 and 16 mg/kg po, mice).
