5-Acyl-6-aryl-4-nitro-3(2H)pyridazinones and related 4-amino compounds: synthesis and pharmacological evaluation

Several 4-nitro- and 4-amino-5-acyl-6-aryl-3(2 H )pyridazinones were prepared and their in vitro and ex vivo antiaggregatory properties were evaluated. 4-Nitro derivatives 3 generally showed good activity in vitro towards arachidonic acid (AA)-induced human blood platelet aggregation. The 4-amino compound 4a , which has weak in vitro activity, exhibited antiplatelet activity, particularly on adenosine dephosphate (ADP)-induced aggregation ex vivo in rabbit. Moreover, the same compound was shown to be active in platelet-activating factors (PAF)- induced rat paw hyperalgesia and to be endowed with low acute oral toxicity. The 4-amino derivatives 4a – m and the other pyridazinones 5–9 administered orally to rats were also found to be more potent antiinflammatory agents than acetyl salicylic acid (ASA). Compounds 3a and 4a , tested in vitro on lipopolysaccharide (LPS)-stimulated rat peritoneal macrophages, were seen to be active in the inhibition of prostaglandin E 2 (PGE 2 ) production and interleukin-1 activity. Structure–activity relationship studies in the series of antiaggregating pyridazinones 3 have shown the primary importance of the nitro and acetyl substituents at positions 4 and 5, respectively. Hydrophobic substituents at position 2 were also required for better activity.