Synthesis and Trazodone-like Analgesic Activity of 4-Phenyl-6-aryl-2-(3-(4-arylpiperazin-1-yl)propyl)pyridazin-3-ones.

Abstract

A series of 4,6-diaryl pyridazinones, chemically related to trazodone, ws synthesized and evaluated for analgesic activity. With ED50 values ranging from 8.4 to 46.7 mg kg(-1) i.p. in the phenylbenzoquinone-induced writhing test (PBQ test), most compounds were several times more potent than acetaminophen (ED50 = 231.3 mg kg(-1) i.p.) and noramidopyrine (ED50 = 68.5 mg kg(-1) i.p.). A multiple linear regression analysis demonstrated a correlation between antinociceptive activity and lipophilicity, as well as electronic and steric factors. The most active pyridazinones 2c and 2j exhibited minimal sedative and neurotoxic effects at the dose of 25 mg kg(-1) i.p. They were devoid of activity in the hot plate test and their analgesic activity was not significantly reversed by naloxone in the PBQ test. The antinociceptive response induced by morphine (0.15 mg kg(-1) s.c.) in the PBQ test was greatly potentiated by 2c and 2j administered at the low doses of 1 and 2.5 mg kg(-1) i.p., respectively. On the other hand, their analgesic effects were enhanced synergistically by 5-hydroxytryptophan combined with carbidopa. All these data imply that a significant part of the antinociceptive effect induced by 2c and 2j may involve both opioid and serotonergic pathways. In addition, these two pyridazinones did not exhibit any antidepressant properties in the forced swimming test, nor did they potentiate yohimbine-induced toxicity.

Catalytic Markovnikov and anti‐Markovnikov Functionalization of Alkenes and Alkynes: Recent Developments and Trends

“…[54] The carbonylation occurs preferentially at the b position due to the steric hindrance of the silyl group and the product is obtained in 46-98 % yield. [55] Heterofunctionalized amines such as g-and d-aminoethers, amines and silanes, are easily synthesized by one-pot hydroaminomethylation of the corresponding allylic compounds (Scheme 14).…”

Investigations of New Pyridazinone Derivatives for the Synthesis of Potent Analgesic and Anti‐Inflammatory Compounds with Cyclooxygenase Inhibitory Activity

“…We then proceeded to investigate the 3(2H)-pyridazinones and derivatives carrying acetamide and propanamide moieties at position 2 of the pyridazinone ring and found that these compounds also showed good analgesic and antiinflammatory properties [14,15]. Furthermore, many pyridazinone derivatives have been reported to function as novel potent analgesic and anti-inflammatory agents and some have been shown to selectively inhibit COX-2 function [18][19][20].…”

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

“…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] .…”

“…Recently it was reported that a considerable number of 3(2H)-pyridazinone derivatives have analgesic activity [6,[13][14][15][16][17][18] . Among these compounds, one of the 3(2H)-pyridazinone derivatives, 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (emorfazone) is a well-known analgesic and antiinflammatory agent ( Figure 1) [13,14] .…”

“…Rohet and co-workers also synthesized some 4,6-diphenyl-2-[3-(4-arylpiperazin-1-yl)propyl]-3(2H)-pyridazinone derivatives and showed that these compounds have trazodone-like analgesic activity [6] . Santagati and co-workers claimed that 2-substituted 4,5-dihalo-3(2H)-pyridazinone derivatives have high analgesic activity.…”