RU2783158C2 - Substituted hydrazides of 2-diarylmethylene hydrazone-5,5-dimethyl-4-oxohexanoic acids exhibiting anti-inflammatory activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, to new biologically active substances of the class of derivatives of 2,4-dioxohexanoic acids. Proposed are substituted hydrazides of 2-diarylmethylene hydrazone-5,5-dimethyl-4-oxohexanoic acids (1 to 5), wherein R, R¹, R² are defined in the claim, exhibiting pronounced anti-inflammatory activity with low toxicity.

EFFECT: creation of new biologically active substances with pronounced anti-inflammatory activity.

1 cl, 1 tbl, 6 ex

Description

The invention relates to the field of organic chemistry, to new biologically active substances of the class of 2,4-dioxohexanoic acids, namely to substituted hydrazides of 2-diarylmethylenehydrazono-5,5-dimethyl-4-oxohexanoic acids (1-5) with the structural formula:

possessing anti-inflammatory activity, which suggests their use in medicine as drugs with anti-inflammatory properties.

Analogous in structure to the claimed compounds is N-(1,3-thiazol-2-yl)amide 2-diphenylmethylenehydrazono-5,5-dimethyl-2,4-dioxohexanoic acid (6), which has a pronounced analgesic and anti-inflammatory effect [US Pat. No. 2345072, Russian Federation, s. 2007128279/04; dec. 07/23/07; publ. 27.01.09, Bull. No. 3] structural formula:

Data on anti-inflammatory activity and acute toxicity of compound (6) are given:

Compound Dose, mg/kg LD ₅₀ mg/kg Inhibition of edema after 3 hours, % 6 fifty >1500 53.80

Nimesulide of the structural formula was chosen as the standard for comparison:

,

,

which is widely used in medical practice and is analogous in action [Mashkovsky M.D. Medicines / M.D. Mashkovsky. - 16th ed., revised, corrected. and additional - Moscow: New Wave LLC, 2020. - S. 164, 185].

The objective of the invention is to search in a series of derivatives of 2-imino(hydrazono)-4-oxohexanoic acids for substances with a pronounced anti-inflammatory effect, as well as low toxicity.

The task is achieved by obtaining substituted hydrazides of 2-diarylmethylenehydrazono-5,5-dimethyl-4-oxohexanoic acids (1-5), which have an anti-inflammatory effect.

The claimed compounds (1-5) are synthesized by the interaction of 3-arylidenehydrazono-5-tert-butyl-3H-furan-2-ones (7-9) with acid hydrazides (10-12) by boiling in absolute toluene or dioxane, followed by isolation target product by known methods according to the scheme

Example 1 Preparation of Compound (1)

To a mixture of 0.0006 mol of hydrazofuranone (9) and 0.0006 mol of hydrazide (11) was added 5 ml of absolute toluene. The reaction mixture was boiled with stirring for 10–15 min. The solution was cooled at room temperature and left for 24 h for further reaction. The resulting precipitate was filtered off and recrystallized from toluene. Yield 0.286 g (99%), mp. 205-207°C. 1H NMR spectrum ⁽ DMSO-d ₆ ), δ, ppm (form B): 1.06 s (9H, t-Bu), 4.04 s (2H, CH ₂ ), 7.49 m (14H _arom ), 10.66 s (1H, NH). Found, %: C 69.68; H 5.44; N 11.60. C ₂₈ H ₂₆ N ₄ O ₄ . Calculated, %: C 69.70; H 5.43; N 11.61. The resulting compound (1) is an orange crystalline substance, soluble in chloroform, acetone, DMSO, sparingly soluble in toluene, insoluble in water and hexane.

Example 2 Preparation of Compound (2)

To a mixture of 0.0006 mol of hydrazofuranone (9) and 0.0006 mol of hydrazide (12) was added 5 ml of absolute dioxane. The reaction mixture was boiled with stirring for 10–15 min. The solution was cooled at room temperature and left for 24 h for further reaction. The resulting precipitate was filtered off and recrystallized from acetonitrile. Yield 0.261 g (90%), mp. 213-215°C. 1H NMR spectrum ⁽ DMSO-d ₆ ), δ, ppm (form A): 1.25 s (9H, t-Bu), 5.90 s (1H, CH), 7.58 m (14H _arom ), 9.72 s ( 1Н, ОН), 10.54 s (1Н, CO NH NHCO), 10.70 s (1Н, CONH NH CO), 13.44 s (1Н, NHN). Found, %: C 69.69; H 5.43; N 11.60. C ₂₈ H ₂₆ N ₄ O ₄ . Calculated, %: C 69.70; H 5.43; N 11.61. M 482.54. The resulting compound (2) is an orange crystalline substance, soluble in chloroform, acetone, DMSO, sparingly soluble in toluene, insoluble in water and hexane.

Example 3 Preparation of Compound (3)

To a mixture of 0.0006 mol of hydrazofuranone (8) and 0.0006 mol of hydrazide (11) was added 5 ml of absolute toluene. The reaction mixture was boiled with stirring for 10–15 min. The solution was cooled at room temperature and left for 24 h for further reaction. The resulting precipitate was filtered off and recrystallized from toluene. Yield 0.304 g (99%), mp. 191-193°C. 1H NMR spectrum ⁽ DMSO-d ₆ ), δ, ppm (form B): 1.18 s (9H, t-Bu), 4.18 s (2H, CH ₂ ), 7.49 m (14H _arom ), 9.75 s (1H, NH). Found, %: C 67.94; H 5.52; N 10.91. C ₂₉ H ₂₈ N ₄ O ₅ . Calculated, %: C 67.96; H 5.51; N 10.93. The resulting compound (3) is a yellow crystalline substance, soluble in chloroform, acetone, DMSO, sparingly soluble in toluene, insoluble in water and hexane.

Example 4 Preparation of Compound (4)

To a mixture of 0.0006 mol of hydrazofuranone (7) and 0.0006 mol of hydrazide (10) was added 5 ml of absolute toluene. The reaction mixture was boiled with stirring for 10–15 min. The solution was cooled at room temperature and left for 24 h for further reaction. The resulting precipitate was filtered off and recrystallized from toluene. Yield 0.25 g (88%), mp. 136-138°C. 1H NMR spectrum ⁽ DMSO-d ₆ ), δ, ppm (form A): 1.01 s (9H, t-Bu), 3.59 s (2H, CH ₂ ), 5.48 s (1H, CH), 7.27 m (2H _arom ), 7.30 m (3H _arom ), 7.37 m (4H _arom ), 7.51 m (4H _arom ), 7.68 m (2H _arom ), 10.36 s (1H, CO NH NHCO), 10.50 s (1H, CONH NHCO ), 12.19 s (1Н, NHN). The spectrum of JAMR ¹³ C (DMSO-D ₆ ), Δ, m.: 27.42, 42.42, 91.35, 126.99, 127.82, 128.69, 129.56, 130.35, 132.37, 136.12, 137.17, 151.76, 153.39, 162.25, 169.31, 205.84. Found, %: C 72.20; H 6.29; N 11.64. C ₂₉ H ₃₀ N ₄ O ₃ . Calculated, %: C 72.18; H 6.27; N 11.61. The resulting compound (4) is a yellow crystalline substance, soluble in chloroform, acetone, DMSO, sparingly soluble in toluene, insoluble in water and hexane.

Example 5 Preparation of Compound (5)

To a mixture of 0.0006 mol of hydrazofuranone (7) and 0.0006 mol of hydrazide (11) was added 5 ml of absolute toluene. The reaction mixture was boiled with stirring for 10–15 min. The solution was cooled at room temperature and left for 24 h for further reaction. The resulting precipitate was filtered off and recrystallized from toluene. Yield 0.26 g (89%), mp. 184-186°C. 1H NMR spectrum _{(CDCl 3} ⁾ , δ, ppm: Form A (29%): 1.10 s (9H, t-Bu), 6.43 s (1H, CH), 6.83 m (3H _arom ), 6.93 m (2H _arom ), 7.01 m (2H _arom ), 7.39 m (4H _arom ), 7.50 m (3H _arom ), 11.51 s (1H, OH), 12.56 d (1H, J = 6.0 Hz, CONHNHCO), 13.07 s ( 1H, NH); form B (71%): 1.18 s (9Н, t-Bu), 4.22 s (2Н, _CH2 ), 7.39 m (4H _arom ), 7.50 m (4H _arom ), 7.63 m (2H _arom ), 7.72 m ( 4H _arom ), 9.11 d (1H, J = 4.7 Hz, CONHNHCO), 9.17 d (1H, J = 4.7 Hz, CONHNHCO), 11.34 s (1H, OH). Спектр ЯМР ¹³ C (CDCl ₃ ), δ, м. д.: 26.47, 27.02, 35.69, 44.86, 95.62, 105.63, 112.41, 118.40, 118.50, 119.07, 119.27, 125.89, 126.04, 127.89, 128.21, 128.31, 128.49, 129.54, 129.84, 129.96, 130.16, 130.24, 130.34, 130.81, 134.79, 137.30, 144.89, 153.53, 154.53, 158.14, 161.12, 161.33, 165.42, 166.89, 206.40, 210.3. Found, %: C 69.43; H 5.84; N 11.58. C ₂₈ H ₂₈ N ₄ O ₄ . Calculated, %: C 69.41; H 5.82; N 11.56. M 484.55. The resulting compound (5) is a yellow crystalline substance, soluble in chloroform, acetone, DMSO, sparingly soluble in toluene, insoluble in water and hexane.

Example 6. Biological activity of compounds (1-5)

Acute toxicity was determined in experiments on non-linear white mice-males weighing 20-22 g, contained on the usual diet of the vivarium. The method of Prozorovsky V.B. was used for calculations. [Prozorovsky V.B. Statistical processing of the results of pharmacological studies / V.B. Prozorovsky // Psychopharmacology and biological narcology. - 2007. - No. 7. - C. 2090-2120]. The test compound was administered intragastrically as a suspension in a 2% starch solution. Each dose was administered to two animals. The animals were observed for 14 days. The general condition and behavior of the animals, the condition of the coat were recorded, and the body weight was determined. In each group of animals, the number of deaths for the entire observation period was taken into account. For the studied compounds (1-5) LD ₅₀ is >2000 mg/kg. According to the classification of drug toxicity according to Hodge, Sterner [Hodge, HC Tabulation of toxicity classes / HC Hodge, J. H Sterner // Amer. Industr. Hyd. Ass. Quart. - 1943. - No. 10. - P. 93] and GOST 32419-2013 compounds (1-5) belong to the V class of practically non-toxic drugs.

The study of anti-inflammatory activity was carried out on white non-linear rats weighing 160-180 g, females (control and experimental groups included 6 animals each) on a model of acute inflammatory edema caused by subplantar injection of 0.1 ml of 1% aqueous solution of carrageenan into the hind paw of a rat. The volume of the foot was assessed oncometrically [Guidelines for conducting preclinical studies of drugs: monograph / A.N. Mironov, N.D. Bunyatyan, A.N. Vasilyeva [i dr.]. - Moscow: Grif and K, 2012. - C. 944] before and 3 hours after the administration of carrageenan. An increase in the volume of the foot, indicating the development of edema, was calculated as a percentage of the initial value. The test substances were administered orally at a dose of 50 mg/kg 1 hour before the administration of the phlogogenic agent. Animals treated with 1% starch solution in equivolume quantities served as controls. Nimesulide (Unimark Remedies, India), which was administered orally at a dose of 50 mg/kg, was used as a reference drug. The presence of anti-inflammatory action was judged by the severity of inhibition of the inflammatory response.

The results of the experiments were processed statistically with the calculation of the Fisher-Student criterion [Belenky M.L. Elements of quantitative pharmacological effect / M.L. Belenky. - 2nd ed. - Leningrad, 1963. - C. 152]. The test results are presented in table 1.

Table 1.

Anti-inflammatory activity and acute toxicity of compounds (1-5) and reference drug nimesulide

Compound Dose, mg/kg LD ₅₀ mg/kg Increase in foot volume after 3 hours, % Inhibition of edema after 3 hours, % Control - - 66.47 ± 10.19 - Nimesulide fifty 74 33.90 ± 6.78 48.99 one fifty >5000 18.95 ± 2.43 71.49 2 fifty >5000 20.59 ± 4.27 69.02 3 fifty >5000 21.85 ± 2.48 67.13 four fifty >5000 21.31 ± 4.61 67.94 5 fifty >5000 27.19 ± 5.71 59.09

p <0.05 compared to control.

As can be seen from table 1, the effect of the claimed compounds (1-5) exceeds the effect of the reference drug nimesulide with less toxicity. Therefore, the claimed compounds (1-5) can be used in medical practice as anti-inflammatory drugs.

Claims (10)

Substituted 2-diarylmethylenehydrazono-5,5-dimethyl-4-oxohexanoic acid hydrazide (1-5) with structural formula:

where when R and R ¹ together are fluorenyl, then R ² is selected from 2-NOS ₆ H ₄ - (compound 1) or 3-NOS ₆ H ₄ - (compound 2); when R is Ph and R ¹ is -COPh, then R ² is 2-NOS ₆ H ₄ - (compound 3); when each of R and R ¹ is Ph-, then R ² is PhCH ₂ - (compound 4) or 2-NOS ₆ H ₄ - (compound 5), having anti-inflammatory activity.