Synthesis, recyclization under the action of methanol and analgetic activity of N'-(5-aryl-2-oxofuran-3(2 H )- ylidene)furan-2-carbohydrazides

New methyl 5-aryl-1-(furan-2-carbonyl)-1 H -pyrazole-3-carboxylates were obtained via decyclization reaction of N'-(5-aryl-2-oxofuran-3(2 H )- ylidene)furan-2-carbohydrazides under the action of methanol. Starting N'- (5-aryl-2-oxofuran-3(2 H )-ylidene)furan-2-carbohydrazides were obtained


Experimental
IR spectra were recorded on an FSM-1202 instrument in vaseline oil. The 1 H NMR spectra were recorded at 400 MHz at the temperature of 313 K; the chemical shifts (δ) were measured in ppm with respect to the solvent ([D6] DMSO, 1 H: δ= 2.50 ppm). The coupling constants (JHH) are given in Hertz. The splitting patterns of apparent multiplets associated with an averaged coupling constants were designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets) and br (broadened). Elemental analysis was performed on a LECO CHNS-932 instrument. The chemical purity of the compounds and the reactions progress were monitored by TLC on Sorbfil plates in the diethyl ether-benzene-acetone (10:9:1) system, detection in UV light and iodine vapor. Melting points were determined on an SMP40 apparatus.

General procedure for the synthesis of 4-aryl-2-[2-(furan-2-carbonyl)hydrazinylidene]-4oxobutanoic acids 3a-e
To a solution of 0.01 mol of furan-2-carboxylic acid hydrazide (1) in 30 mL of acetonitrile was added 0.01 mol of 4-aryl-2,4-dioxobutanoic acid 2a-e. The resulting mixture was heated to 50 °C and kept for 5 min at this temperature. The solution was cooled to 0 °C; the formed precipitate was filtered off and recrystallized from dioxane.

General method of synthesis of N'-(5-aryl-2oxofuran-3(2H)-ylidene)furan-2carbohydrazides 4a-e
Propionic anhydride (8 mL) was added to 0.01 mol of acid 3a-е. The resulting mixture was slowly heated with stirring to 150 °C and kept for 5 min. The precipitate formed after cooling was filtered off, washed with anhydrous diethyl ether, and recrystallized from anhydrous toluene or dioxane.

Evaluation of biological activity of target compounds
Evaluation of analgesic activity was carried out in the Perm State National Research University, the Research Laboratory of Biologically Active Substances. Analgesic activity was determined on outbred white mice of both sexes weighing 18-22 g using the "hot plate" method [60]. The studied compounds were administered intraperitoneally in the form of a suspension in a 2% starch solution at a dose of 50 mg/kg 30 min before the animals were placed on a metal plate heated to 53.5 °C [61]. Studies were performed 30, 60, 90, 120 min after administration of the compound.
The indicator of the change in pain sensitivity was the length of time the animals stay on the hot plate until adefensive pain reflex occurs -licking the hind legs or trying to tear off all four paws from the surface of the plate. The time of onset of this reflex from the beginning of the placement of the animal on the plate was meas-ured in seconds (latent period). The maximum duration of the latent period is the interval of 40 s. In the experiment we used animals with the initial time of the onset of the defensive reflex of no more than 15 s. Each compound was tested on 6 animals. The results were evaluated by increasing the time of the onset of the defensive reflex compared with the initial data. The control group of animals was injected with 2% starch mucus. Metamizole sodium (Farmkhimkomplekt LLC) at a dose of 93 mg/kg (ED50) was used as a comparison compound.
Statistical processing of experimental data was carried out using Student's confidence criteria. The effect was considered significant at p<0.05 [62]. The studies were carried out in accordance with all applicable international, national and institutional guidelines for the care and use of animals. Compounds 4a-е, obtained in 53-78% yields, are yellow crystalline substances, readily soluble in DMSO, when heated -in toluene and ethanol, and insoluble in water and alkanes. The IR spectra of compounds 4a-е contain an absorption band in the region 1776-1803 cm -1 , which is characteristic of the stretching vibrations of the lactone carbonyl of the furan ring, and an absorption band in the region 3125-3188 cm -1 , which is characteristic of the stretching vibrations of the NH group.
Compounds 5a-e are apparently formed due to the addition of methanol to the lactone carbonyl group of furanones 4a-e, opening of the furanone ring at the O1-C2 bond, and subsequent closing of the pyrazole ring due to the addition NH group to carbonyl group of aroyl fragment followed by dehydration (Scheme 4).
Compounds 5a-е, obtained in 58-69% yields, are colorless crystalline substances. The IR spectra of compounds 5a-е are characterized by the absence of NH group signal, in contrast to the spectra of compounds 4a-e, and the presence of the absorption band of two carbonyl groups in region 1685-1751 cm -1 . In 1 Н NMR spectra, in addition to the signals of the protons of arylic and heterocyclic fragments, there are singlet signals of the methoxycarbonyl groups in the region 3.89-3.94 ppm.
Some of the compounds obtained were examined for analgesic activity. Table 1 that all the studied compounds have a pronounced analgesic effect, surpassing the effect of the comparison drug metamizole.

Limitations
We have obtained new methyl 5-aryl-1-(furan-2carbonyl)-1H-pyrazole-3-carboxylates with 58-69% yields, yields are significantly declining after recrystallisation of obtained compounds. Therefore, we are going to improve a method of purification for achievement higher product yields in our further studies.

• Funding
This study was performed under financial support of the "Rational Use of the Earth Interior" Perm Scientific Educational Center 2023 and Ministry of Science and Higher education of Russian Federation FSEG-2022-0012.