RU2841268C1 - Use of 4-[4-hydroxy-3-(4-methylbenzoyl)-5-oxo-2-(3-chlorophenyl)-2,5-dihydro-1h-pyrrol-1-yl]benzoic acid as anti-inflammatory agent - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: disclosed is use of 4-[4-hydroxy-3-(4-methylbenzoyl)-5-oxo-2-(3-chlorophenyl)-2,5-dihydro-1H-pyrrol-1-yl]benzoic acid of formula (I) as an anti-inflammatory agent.

EFFECT: invention provides treating diseases associated with the onset of inflammatory processes by using 4-[4-hydroxy-3-(4-methylbenzoyl)-5-oxo-2-(3-chlorophenyl)-2,5-dihydro-1H-pyrrole-1-yl]benzoic acid.

1 cl, 1 tbl, 2 ex

Description

The invention relates to an anti-inflammatory agent based on 4-[4-hydroxy-3-(4-methylbenzoyl)-5-oxo-2-(3-chlorophenyl)-2,5-dihydro-1 H- pyrrol-1-yl]benzoic acid of formula ( I ):

which suggests the possibility of its use in medicine as a drug for the treatment of diseases associated with the occurrence of inflammatory processes.

The closest analogues in structure are 4-(2-aryl-3-acyl-4-hydroxy-5-oxo-2,5-dihydro-1 H -pyrrol-1-yl)benzoic acids ( II – VI ) [Synthesis and analgesic activity of 4-(2-aryl-3-acyl-4-hydroxy-5-oxo-2,5-dihydro-1 H -pyrrol-1-yl)benzoic acids / V.L. Gein, D.V. Chalkov, A.V. Romanova, O.V. Bobrovskaya, S.V. Chashchina // Chemical and pharmaceutical journal. – 2024. – Vol. 58, No. 5. – Pp. 14-17] formulas:

R = CH ₃ ( II) , C ₆ H ₅ ( III , IV ), 4-CH ₃ OC ₆ H ₄ ( V ), R = 3,4-(CH ₃ O) ₂ C ₆ H ₃ ( VI );

R¹ = H (II,III), 4-F (IV), 2-Br (V), 4-Cl (VI).

Structural analogues ( II – VI ) have not been studied for anti-inflammatory activity.

In medical practice, nimesulide is widely used, which is similar in pharmacological action to the claimed compound ( I ), which we have taken as a comparison standard [Mashkovsky, M.D. Medicines / M.D. Mashkovsky. - 16th ed., revised, corrected and supplemented. - M .: Novaya Volna, 2012. - P. 185].

The objective of the invention is to search for new compounds with high anti-inflammatory action and low toxicity in the series of 4-(2-aryl-3-aroyl-4-hydroxy-5-oxo-2,5-dihydro-1 H- pyrrol-1-yl)benzoic acids.

The problem is solved by using 4-[4-hydroxy-3-(4-methylbenzoyl)-5-oxo-2-(3-chlorophenyl)-2,5-dihydro-1 H- pyrrol-1-yl]benzoic acid ( I ), which has high anti-inflammatory activity and low toxicity.

Compound ( I ) is synthesized by the interaction of methyl 4-methylbenzoylpyruvic acid with 3-chlorobenzaldehyde and 4-aminobenzoic acid in equimolar amounts according to the method [Synthesis and analgesic activity of 4-(2-aryl-3-acyl-4-hydroxy-5-oxo-2,5-dihydro-1 H -pyrrol-1-yl)benzoic acids / V.L. Gein, D.V. Chalkov, A.V. Romanova, O.V. Bobrovskaya, S.V. Chashchina // Chemical and Pharmaceutical Journal. - 2024. - Vol. 58, No. 5. - Pp. 14-17] according to the following scheme:

The invention is illustrated by the following examples.

Example 1. Obtaining the compound ( I )

To a solution of 1.37 g (10 mmol) of 4-aminobenzoic acid and 1.13 ml (10 mmol) of 3-chlorobenzaldehyde in 15 ml of glacial acetic acid were added 2.20 g (10 mmol) of methyl 4-methylbenzoylpyruvic acid, dissolved in 10 ml of glacial acetic acid. The reaction mixture was boiled for 5 min. The precipitate that formed upon cooling was filtered off and recrystallized from ethyl acetate. Yield 3.00 g (67%). mp 291–292°C. Found, %: C 66.92; H 4.12; N 3.22. C ₂₅ H ₁₈ ClNO ₅ . Calculated, %: C 67.04; H 4.05; N 3.13. IR spectrum (Fourier infrared spectrometer “InfraLUM FT-08”, in tablets with KBr, ν, cm ^-1 : 3154 (=C–OH, CO OH ), 1682 ( CO OH), 1668 (N–C=O), 1623 (C=O). ¹ H NMR spectrum (Bruker Avance III HD (400 MHz), DMSO- d ₆ , TMS, δ, ppm: 2.34 s (3H, CH ₃ ), 6.39 s (1H, C ² H), 7.16–7.91 m (12H, CH _Ar ), 11.84 br. s (1H, =C–OH), 12.79 br. s (1H, COOH). NMR ¹³ C (Bruker Avance III HD (100 MHz), DMSO- d ₆ , TMS, δ, ppm): 21.05, 60.35, 120.16, 121.42, 125.97, 127.13, 127.80, 128.00, 128.70, 128.91, 129.91, 130.17, 132.82, 135.07, 138.84, 139.97, 143.24, 149.28, 164.87, 166.50, 188.68.

Compound ( I ) is a white finely crystalline substance, soluble in dimethylformamide, dimethyl sulfoxide, and when heated – in glacial acetic acid, acetonitrile, dioxane, slightly soluble in ethanol, chloroform, ethyl acetate, acetone and insoluble in water.

Example 2. Study of anti-inflammatory activity and acute toxicity of compound ( I )

Acute toxicity (LD ₅₀ , mg/kg) of compound ( I ) was studied on white nonlinear female mice weighing 20-22 g. To determine the average lethal dose, the express method of Prozorovsky V.B. was used [Prozorovsky, V.B. Statistical processing of the results of pharmacological studies / V.B. Prozorovsky // Psychopharmacology and biological narcology. - 2007. - No. 7. - P. 2090-2120]. The test compound ( I ) was administered orally (p/o) as a suspension in a 1% starch solution in increasing doses, four consecutive doses were used for calculations. Each dose was administered to two animals. The animals were observed for 14 days, recording their behavior, intensity and nature of motor activity, presence of convulsions, coordination of movements, skeletal muscle tone, reactions to tactile, sound and light stimuli, frequency and depth of respiratory movements, heart rate, condition of hair and skin, color of visible mucous membranes, water and food consumption, and changes in body weight.

Acute toxicity was calculated in accordance with the recommendations of the State Pharmacological Committee for the Study of the General Toxic Effect of Biologically Active Substances [Methodological Recommendations for the Study of the General Toxic Effect of Pharmacological Agents. Approved 25.12.97 / Bulletin of the Pharmacopoeia Committee. – 1998. – No. 1. – P. 27-32].

It was found that the LD ₅₀ of the compound ( I ) when administered orally is 4170.0±400.0 mg/kg (Table 1). Consequently, the claimed compound ( I ) is less toxic than the reference standard nimesulide, the LD ₅₀ of which when administered via the same route is 392 mg/kg [US National Library of Medicine [Electronic resource] – Access mode: https://chem.nlm.nih.gov/chemidplus/name/nimesulide] and differs by 10.6 times.

According to the classification of toxicity of chemical substances, the claimed compound ( I ) belongs to hazard class 5 [GOST 32419-2013. Hazard classification of chemical products. General requirements. Approved and put into effect by the Order of the Federal Agency for Technical Regulation and Metrology dated November 22, 2013 No. 833-st], which corresponds to class 4 of low-toxic substances according to the classification of Hodge and Sterner [Berezovskaya, I.V. Classification of chemical substances by acute toxicity parameters for parenteral administration / I.V. Berezovskaya // Chemical and pharmaceutical journal. - 2003. - Vol. 37, No. 3. - P. 32-34].

The anti-inflammatory activity of compound ( I ) was studied in white nonlinear male rats weighing 200–210 g (the group included 6 animals) on a model of acute inflammatory edema caused by subplantar injection of 0.1 ml of a 1% aqueous solution of carrageenan into the hind paw of the rat [Guidelines for Conducting Preclinical Studies of Drugs / edited by A.N. Mironov, N.D. Bunyatyan, A.N. Vasiliev, O.L. Verstakova, M.V. Zhuravleva, V.K. Lepakhin, N.V. Korobov, V.A. Merkulov, S.N. Orekhov, I.V. Sakaeva, D.B. Uteshev, A.N. Yavorsky. – Moscow: Grif i K, 2012. – Part 1. – 944 p]. The test compounds were administered intragastrically as a suspension in a 1% starch solution at a dose of 50 mg/kg 1 hour before the induction of inflammation. Nimesulide (Nimesil (INN: nimesulide), Laboratorios Menarini S.A., Spain) at a dose of 50 mg/kg, administered in a similar manner, was used as a comparison standard. Foot volume was assessed oncometrically before and 3 hours after the administration of carrageenan. The severity of the inflammatory reaction in the control and experimental groups was assessed by the increase in foot volume as a percentage in relation to the initial value. The anti-inflammatory effect was assessed by the edema inhibition index, which was expressed as a percentage of the control group indices.

Statistical processing of the results was performed using the methods of variation statistics in the MS program. The reliability of differences between the groups was assessed using Student's t -test. The data are presented as the sample mean M , the error of the mean m , and the achieved significance level p . The minimum level of significance of differences was taken as corresponding to p ≤ 0.05 [Belenkiy, M.L. Elements of quantitative assessment of the pharmacological effect / M.L. Belenkiy. - 2nd ed. - Leningrad: Medgiz, 1963. - P. 81-106].

The obtained results of the claimed compound ( I ) on anti-inflammatory activity were compared with the data of the reference standard nimesulide (Table 1). The results of the tests of anti-inflammatory activity and acute toxicity are presented in Table 1.

Table 1

Anti-inflammatory activity and acute toxicity of compound ( I )

Compound Dose
mg/kg, (p/o) Acute toxicity of compounds
LD ₅₀ , mg/kg, (p/o) Inhibition of edema to control after administration of phlogogen after 3 hours, % The claimed compound ( I ) 50 4170.0±400.0 63.64±5.12* ^, ** Nimesulide 50 392*** 48.99±4.08* Control - - - * – significant difference of indicators from the control (at p < 0.05),
** – significant difference in indicators from nimesulide (at p < 0.05).

Note: *** – literature data: US National Library of Medicine [Electronic resource] – Access mode: https://chem.nlm.nih.gov/chemidplus/name/nimesulide.

As can be seen from Table 1, the claimed compound ( I ) exhibits pronounced anti-inflammatory activity in the carrageenan edema model at a dose of 50 mg/kg and is 1.3 times greater than the activity of nimesulide at the same dose.

Thus, the claimed compound 4-[4-hydroxy-3-(4-methylbenzoyl)-5-oxo-2-(3-chlorophenyl)-2,5-dihydro-1 H -pyrrol-1-yl]benzoic acid ( I ) exhibits high anti-inflammatory activity, which exceeds the effect of the reference drug nimesulide, and is also a low-toxic compound and can find application in medicine as a potential anti-inflammatory drug.

Claims (2)

Use of 4-[4-hydroxy-3-(4-methylbenzoyl)-5-oxo-2-(3-chlorophenyl)-2,5-dihydro-1 H -pyrrol-1-yl]benzoic acid of formula ( I ) as an anti-inflammatory agent.