Derivatives of pyrrolo[3,4-d]pyridazinone, a new class of analgesic agents

A series of N2-{2-[4-aryl(benzyl)-1-piperazinyl(piperidinyl)]ethyl}pyrrolo[3,4-d]pyridazinones 4 and related derivatives 5 were synthesized as potential analgesic agents. The structures of the new compounds were elucidated by micro, spectral and X-ray analysis. Analgesic activity of the compounds was investigated in the phenylbenzoquinone induced ‘writhing’ and ‘hot plate’ test in mice and at radioligand binding assay. At ‘writhing’ test all compounds, without exception, were more active than acetylsalicylic acid (ASA) with ED50 values ranging from 0.04 to 11 mg/kg (i.p.) (ED50 for ASA – 39.15 mg/kg). Analgesic effect at the ‘hot plate’ test was observed for three compounds 4c,e,f at the dose 3–5 times higher then that of morphine (ED50-3.39 mg/kg). At radioligand binding assay of 4c,e,f only compound 4f exhibited affinity for the μ-opioid receptors similar to that of Tramadol. The acute toxicity of the pyrrolopyridazinones 4, 5 were also studied and non toxic effect was observed at the 2000 mg/kg (5a 1420 mg/kg) i.p. dose level. On the basis of the available pharmacological data S-A relationship is discussed. The preferred conformational characteristic of 4, taken 4c as an example, was also described.

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► Pyrrolo[3,4-d]pyridazinones were synthesized and evaluated their analgesic activity.
► All compounds exhibited higher analgesic activity than the reference drug ASA.
► The new pyrrolo[3,4-d]pyridazinones were not toxic (LD50 ≥ 2000 mg/kg).