RU2342361C1 - Methyl amide and benzylamide of n-acetyl-3,5-dibrom-anthranilic acid, demonstrating anti-inflmammatory and analgetic activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: described compounds are obtained by intramolecular cyclisation of N-acetyl-3,5-dibrom-anthranilic acid with further amidating with methylamine or benzylamine with isolation of target products in form of substituted amides. Methylamide (1) or benzylamide(II) of N-acetyl-3,5-dibrom-anthranilic acid of formula

can be used in medicine as medication possessing anti-inflammatory and analgetic activity, are low-toxic. Compounds are white crystalline substances with Tm=222-224°C (I) and Tm=240-242°C (II), insoluble in water, soluble in ethanol, DMSO, DMF. Structure is confirmed with ¹H NMR spectrum. Compounds possess anti-inflammatory and analgetic activity, are low-toxic. LD₅₀ for intra-abdominal introduction constituted >1500mg/kg.

EFFECT: obtaining compounds possessing anti-inflammatory and analgetic activity, low-toxic.

1 cl, 1 tbl

Description

The invention relates to biologically active compounds, namely methylamide (I) and benzylamide (II) N-acetyl-3,5-dibromanthranilic acid of the formula dibromanthranilic acid of the formula

being low toxic, having anti-inflammatory and analgesic effects, which suggests their use in medicine. The closest structural analogue of the claimed compound is hydrazide N-acetyl-3,5-dibromanthranilic acid (III) of the formula

[Suetina, Yu.V., Mardanova, L.G., Korkodinova, L.M. Anti-inflammatory and analgesic activity of substituted amides of N-acetyl-3,5-dibromanthranilic acid. T1. New materials and chemical technologies // Innovation potential of the natural sciences: in 2 tons. Proceedings of the Intern. scientific conf. Perm. un-t; Natural Sciences Institute and other Perm, S. 265-267, (2006)].

In medical practice, the drug Ortophen is used, which has anti-inflammatory and analgesic effects [Mashkovsky M.D. Medicines: practical benefit. - M .: New wave, p.170-171, (2005)], which we have taken as a standard for comparing the anti-inflammatory activity of compounds I and II.

The aim of the invention is the search among substituted amides of N-acyl-3,5-dibromanthranilic acid compounds with analgesic and anti-inflammatory activities.

This goal is achieved by obtaining methylamide (I) and benzylamide (II) N-acetyl-3,5-dibromanthranilic acid. The compounds described are prepared by intramolecular cyclization of N-acetyl-3,5-dibromanthranilic acid, followed by amidation with methylamine or benzylamine to isolate the desired products as substituted amides.

6,8-Dibromo-2-methyl-4H-3,1-benzoxazin-4-one is obtained from N-acetyl-3,5-dibromanthranilic acid by intramolecular cyclization with acetic anhydride

The method of obtaining 6,8-dibromo-2-methyl-4H-3,1-benzoxazin-4-one. To 10.1 g (0.03 mol) of N-acetyl-3,5-dibromanthranilic acid, 35 ml (37.8 g) (0.12 mol) of acetic anhydride are measured and boiled for 1 hour. The reaction mass is cooled and filtered, washed with acetic anhydride. Yield: 8.1 g (85%). T _pl. = 173-175 ° C.

Then, in order to obtain the desired products, the amidation reaction of 6,8-dibromo-2-methyl-4H-3,1-benzoxazin-4-one with methylamine (I) or benzylamine (II) is carried out.

The method of obtaining methylamide N-acetyl-3,5-dibromanthranilic acid (I). To a solution of 9.54 g (0.03 mol) of 6.8-dibromo-2-methyl-4H-3,1-benzoxazin-4-one in 160 ml of 96% ethanol is added a solution of 0.93 g (0 , 03 mol) of methylamine in 100 ml of 96% ethanol with stirring. After stirring for 3 hours at 18 ° C, a white precipitate formed, which was filtered off, dried and recrystallized from ethanol. Yield: 5.02 g (48%). _Mp = 222-224 ° C.

The method of obtaining benzylamide N-acetyl-3,5-dibromanthranilic acid (II). To a solution of 9.54 g (0.03 mol) of 6.8-dibromo-2-methyl-4H-3,1-benzoxazin-4-one in 160 ml of 96% ethanol is added a solution of 3.21 g (0 , 03 mol) of benzylamine in 100 ml of 96% ethanol with stirring. After stirring for 3 hours at 18 ° C, a white precipitate forms, which is filtered off, dried and recrystallized from a mixture of water: ethanol, 1: 2. Yield: 5.50 g (43%). _Mp = 240-242 ° C.

The inventive compounds are white crystalline substances, insoluble in water, soluble in ethanol, DMSO, DMF. The ¹ H NMR spectrum (BS-567A Fourier spectrometer (100 MHz) in DMSO-d ₆ , internal standard - HMDS) of compound I contains: two singlets of three protons of two methyl groups: in the region of 1.90 ppm (amide group) and 2.60 ppm. (NH - acyl group); the multiplet of two protons of the benzene ring is 7.45-7.85 ppm; the quadruplet of one proton of the amide (CONH) group at 8.05 ppm and a singlet proton of N-carbonyl in the region of 9.40 ppm. The following are recorded in the ¹ H NMR spectrum of compound II: three protons of the methyl group in the form of a singlet — 1.85 ppm; methylene group at 4.30 ppm; multiplet of protons of two benzene rings - 7.15-7.85 ppm; amide triplet (CONH) group at 8.60 ppm and the broadened signal of the NHCO group is 9.40 ppm.

Acute toxicity was studied according to Prozorovsky on white mice weighing 18-22 g with a single intraperitoneal injection of compounds [Prozorovsky V.V., Prozorovskaya M.P., Demchenko V.M. Farmakol. Toxicol., T.41, No. 4, p.497-502, (1978)].

Anti-inflammatory activity was studied on a model of carrageenan inflammation. The magnitude of the inflammatory reaction was determined oncometrically [Salyamon L.S. Drug regulation of the inflammatory process. L., pp. 11-43, (1958)].

To assess the analgesic effect was used the method of "hot plate" [Eddy N.V., Liembach D.J. Studies of anastetics // Pharm. and Exp. Ther., P. 385-393, (1953)].

Orthophene and a structural analogue, N-acetyl-3,5-dibromanthranilic acid hydrazide, were used as a comparison of anti-inflammatory and analgesic effects. The studied substances and the analogue were administered intraperitoneally in the form of a suspension in 2% starch mucus at a dose of 50 mg / kg, and orthophene - 10 mg / kg. The control animals were injected with an equivolume amount of starch mucus. The results of the experiments were subjected to statistical processing using the student coefficient [Sernov L.N., Gatsura V.V. Elements of experimental pharmacology // All-Russian Scientific Center for the Safety of Biologically Active Substances. Moscow, p. 311-312 (2000)] and was considered reliable at p≤0.05. The test results are presented in the table.

As can be seen from the table, compounds I and II (claimed) in anti-inflammatory activity an hour after the administration of carrageenan are 1.8 and 1.4 times superior to the analogue in structure and 1.9 and 1.5 times orthophene. The inventive compounds I and II exhibit an anti-inflammatory effect comparable to orthophene and the analogue in structure 4 hours after administration of carrageenin. They have high analgesic activity, while orthophene (10 mg / kg) and the analogue in structure (50 mg / kg) do not.

Compounds I and II are more than 20 times less toxic, and by the relative breadth of pharmacological action (USPD) they are 4 times higher than the reference drug in terms of anti-inflammatory and analgesic effects.

Thus, N-acetyl-3,5-dibromanthranilic acid methylamide (I) and N-acetyl-3,5-dibromanthranilic acid (II) benzylamide exhibit high anti-inflammatory and analgesic activity and are more than 20 times higher than LD _{50 in} orthophene.

Therefore, the claimed compounds I and II can find application in medicine as a drug having anti-inflammatory and analgesic effects.

Table Acute toxicity, anti-inflammatory and analgesic effects of the claimed compounds (I and II), its analogue in structure (III) and orthophene Compound LD ₅₀ , mg / kg Inhibition of foot edema compared with control,% Analgesic activity tested using the hot plate technique USFD after 1 h after 4 hours I > 1500 72.1 (p ¹ <0.001, p ² <0.001) 53.5
(p ² <0.1, p ³ <0.25) 21.4 ± 1.5
(p ¹ <0.001) > 30 II > 1500 55.1 (p ¹ <0.001, p ³ <0.001) 34.1 (p ² <0.01, p ³ <0.001) 27.4 ± 1.1
(p ¹ <0.001) > 30 III > 1500 39.2 56.5 16.4 ± 0.2
(p ¹ <0.01) > 30 ortofen 74.0 37.8 61.3 17.4 ± 1.6
(p ¹ <0.002) 7.4 the control 11.4 ± 0.2 Note: p ¹ - in comparison with the control;
p ² - in comparison with the analogue in structure;
p ³ - in comparison with orthophene.

Information sources

1. Suetina Yu.V., Mardanova L.G., Korkodinova L.M. Anti-inflammatory and analgesic activity of substituted amides of N-acetyl-3,5-dibromanthranilic acid. T1. New materials and chemical technologies // Innovation potential of the natural sciences: in 2 tons. Proceedings of the Intern. scientific Conf., Perm. un-t; Natural Sciences Institute and others. Perm, p. 265-267, (2006).

2. Mashkovsky M. D. Medicines: practical benefit. - M.: New Wave, p. 170-171 (2005).

3. Prozorovsky V.V., Prozorovskaya M.P., Demchenko V.M. Farmakol. Toxicol., T.41, No. 4, p. 497-502, (1978).

4. Salyamon L.S. Drug regulation of the inflammatory process. L., p. 11-43, (1958).

5. Eddy N.V., Liembach D.J. Studies of anastetics // Pharm. and Exp. Ther., P. 385-393, (1953).

6. Sernov L.N., Gatsura V.V. Elements of experimental pharmacology // All-Russian Scientific Center for the Safety of Biologically Active Substances. Moscow, p. 311-312, (2000).

Claims (1)

Methylamide (I) and benzylamide (II) N-acetyl-3,5-dibromanthranilic acid of the formula

showing anti-inflammatory and analgesic activity.