Eur J Med Chem (1996) 31, 65-70 © Elsevier, Paris 65 Short communication 4,5-Functionalized 6-phenyl-3(2H)-pyridazinones: synthesis and evaluation of antinociceptive activity V Dal Piazl, MP Giovannonil, G Cicianil, D Barlocc02, G Giardina3, G Petrone3, GD Clarke3 1Dipartimento di Scienze Farmaceutiche, Universitd di Firenze, via G Capponi 9, 50121, Florence; 2Dipartimento di Scienze Farmaceutiche, Universit~ di Modena, via Campi 183, 41100, Modena; 3SmithKline Beecham Farmaceutici SpA, via Zambeletti, 20021, Baranzate, Milan, Italy (Received 29 June 1995; accepted 11 September 1995) Summary -- A series of 2-substituted 4,5-functionalized6-phenyl-3(2//)-pyridazinoneswere synthesized and their antinociceptive activities were evaluated in the mouse abdominal constrictionmodel. Single dose studies showed that compounds 11, 18a and 23 were more active than the reference drug, Emorfazone, in inhibiting the effects of the noxious chemical stimulus, p-phenylquinone. Subsequent dose-response studies revealed 18a to be almost seven-foldmore potent than Emorfazone. Emorfazone / pyridazinone/antinociceptive activity Introduction The search for new analgesic agents devoid of the side-effects typical of morphine-like opioid agonists (such as respiratory depression, constipation and physical dependence), as well as of the gastro-intesti- hal problems associated with nonsteroidal antiinflam- matory drugs (NSAIDs), has attracted considerable attention in recent years. In this regard a considerable number of 3(2H)-pyridazinone derivatives endowed with analgesic properties have been reported recently [1]. Among these compounds, Emorfazone 1 [2, 3] (which was launched as an analgesic in Japan at the beginning of the last decade), the 4,5-dihalo deriva- tives 2 [4], the 5-arylidene 3 [5] and the 4-carbamoyl- pyridazinones 4 [6] have emerged as being of particu- lar interest. In addition, Flouzat et al [7] have recently reported new potent analgesics corresponding to the general structure 5 (chart 1). These compounds, which contain a five-membered N-substituted lactamic system, are characterized by the absence of either anti- inflammatory activity or affinity for opioid receptors. Stimulated by these findings, our attention has been focused on a group of 2-substituted 4,5-functio- nalized 6-phenyl-3(2H)-pyridazinones, arising from Me R ¢ J N--N N--N X 2 1 X= CI, Br N-Ph R (CHz). N L--..../ N~N N-At CH2_ N ~ Me N~N 5 6 Chart 1.