N-Substituted Oxazolo[5,4-b]pyridin-2(1H)-ones: A New Class of Non-Opiate Antinociceptive Agents

Abstract

A series of 1-(aminoalkyl)- and 1-[(4-aryl-1-piperazinyl)alkyl]oxazolo[5,4-b]pyridin-2(1H)-one derivatives of oxazolo[5,4-b]pyridin-2(1H)-one, incorporating modifications to the length of the alkyl side chain and to the amino or 4-aryl-1-piperazinyl substituents, were tested for safety and analgesic efficacy in mice and rats. Some compounds with 4-(substituted or nonsubstituted phenyl)-1-piperazinyl substituents and a 3-4-carbon alkyl side chain had significantly greater analgesic activity than that of the oxazolo[4,5-b]pyridin-2(3H)-one analogs. To reduce the metabolic N-dealkylation of the piperazine observed in our previous work on oxazolo[4,5-b]-pyridin-2(3H)-ones, analogs of the most active compounds with steric hindrance on the alkyl side chain were prepared and tested. The compound with the maximal combination of safety and analgesic efficacy was 1-[[4-(4-fluorophenyl)-1-piperazinyl]propyl]oxazolo[5,4-b]pyridin- 2(1H)-one (compound 3b), with ED50 values of 5.6 mg/kg po (mouse, phenylquinone writhing test) and 0.5 mg/kg po (rat, acetic acid writhing test). Compound 3b is a potent, rapid-acting, non-opioid, nonantiinflammatory analgesic with low acute toxicity and sustained effect.

Synthesis, Analgesic and Antiinflammatory properties of Certain 5‐/6‐Acyl‐3‐(4‐substituted‐1‐piperazinylmethyl)‐2‐benzoxazolinones Derivatives

“…Some of them have turned out to be potent inhibitors of the iNOS [8]. The introduction of (4-aryl-piperazine-1-yl)alkyl moieties on various heterocyclic nuclei such as benzoxazolinones [5,9], oxazolopyridine [6,10], pyridazine [11,12], and pyrazolotriazine [13] led to favourable antinociceptive compounds.…”

Synthesis and Analgesic and Antiinflammatory Activity of Methyl 6‐Substituted‐3(2H)‐pyridazinone‐2‐ylacetate Derivatives

“…The main objective in current pain research is to develop improved non-opioid analgesics which do not show the side effects but are as effective as the opioids [29].…”

Studies on Some 3(2H)-Pyridazinone Derivatives with Antinociceptive Activity

“…It was previously reported that various derivatives of 2-benzoxazolinone, 2-benzothiazolinone, and oxazolopyridinone show significant analgesic activity [1][2][3][4][5] . A common characteristic of these compounds is the N-substituted lactam functional group.…”

“…Another heterocyclic moiety which has this functional group is the pyridazinone ring system. Many authors previously reported that benzoxazolinone, oxazolopyridinone, and pyridazinone derivatives bearing an arylpiperazine moiety at the side chain on the lactam nitrogen of the rings have significant analgesic activity, and stressed the significance of this structural feature [1,5,6] . In addition, some authors claimed that these compounds exhibit better analgesic activity if they have a three carbon chain between the nitrogen of the lactam and the amine component on the side chain [5,6] .…”