Triethylamine 4-aryl-2-hydroxy-4-oxo-3-(2-oxo-3,4-dihydro - 2h-1,4-benzoxazine)-2-buta ene acid, exhibiting anti-inflammatory activity

 

(57) Abstract:

The invention relates to the field of organic chemistry, namely to new derivatives of amides heterylamine butenova acids that have anti-inflammatory activity. Describes triethylamine 4-aryl-2-hydroxy-4-oxo-3-(2-oxo-3,4-dihydro-2H-1,4-benzoxazine)-2-butenova acid of General formula

< / BR>
where R=R1- H (I);

R - H, R1- CH3(II);

R=R1- CH3(III);

R - H, R1- OCH3(IV)

exhibiting anti-inflammatory activity. The technical result - expanding Arsenal of tools have useful biological properties. table 2.

The invention relates to organic chemistry and synthesis of new chemical compounds - triethylamine 4-aryl-2-hydroxy-4-oxo-3-(2-oxo-3,4-dihydro-2H-1,4-benzoxazine)-2-butenova acid of General formula

< / BR>
where R= R1- H (I); R IS H, R1- CH3(II); R=R1- CH3(III); R IS H, R1- OCH3(IV)

possessing anti-inflammatory activity. This property suggests the possibility of using this series of compounds in medicine.

Available to the applicant sources known structural analog - pyridi the
has a weak antimicrobial activity, but does not have anti-inflammatory actions (I. C. Mashevsky, P. P. Makhmudov, A. Alexandrova, O. S. Kudinov, S. C. Koltsov, A. F. goleniów, A. N. Maslivets. The products of interaction of heterene[] 2,3-dihydro-2,3-pyrrolidino with aryl - and heteroarylboronic and their pharmacological activity. Chem. Pharm. Journe. Volume 34, 12, 2000, S. 13-16).

In medical practice known anti-inflammatory drug Voltaren, which is taken by the applicant as a benchmark to compare the anti-inflammatory activity of the claimed compounds. Practice standard for comparison of diclofenac sodium (ortofena, voltaren), which is a toxic compound showed the following side effects:

- medicinal hepatitis and cirrhosis of the liver - hepatotoxicity (Polunin I.e., Ter. Arch., 2,1988, S. 119-121);

- degenerative effect on the myocardium - cardiotoxicity (Stepanyuk, I., Stolyarchuk A. A. Pharmacol. and toxicol., 5, 1987, S. 89-93);

- nephrotoxic effect (Androsova S. O., Nikolaev A. Y. Rheumatology, 2, 1984, S. 54-57);

- gastrotoxicity (Subev R. D., Mashkovsky M. D., Schwartz, J., Pokryshkin C. I. Chem. forms. zhurn., 1, 1985, S. 33-39)

The objective of the invention is the synthesis of new p is SIRENIA Arsenal of means of influence on a living organism.

The method of obtaining compounds of General formula

< / BR>
where R= R1- H (I); R IS H, R1- CH3(II); R=R1- CH3(III); R IS H, R1- OCH3(IV)

lies in the interaction of 3-aroyl-1,2-dihydro-4H-pyrrolo-[5,1-C] [1,4] -benzoxazine-1,2,4-trions with 4-amino-1,2,4-triazole at room temperature when merging reagents in acetonitrile with the formation of triethylamine 4-aryl-2-hydroxy-4-oxo-3-(2-oxo-3,4-dihydro-2H-1,4-benzoxazine)-2-butenova acid (I-IV):

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The invention is illustrated by the following examples.

Example 1. Triazine 4-phenyl-2-hydroxy-4-oxo-3-(2-oxo-3,4-dihydro-2H-1,4-benzoxazine)-2-butenova acid (I).

To a solution 3,19 g (10 mmol) of 3-benzoyl-2,4-dihydro-1H-pyrrolo[5,1-C] [1,4]benzoxazine-1,2,4-trione in 50 ml of acetonitrile is poured with stirring, a solution of 0.84 g (10 mmol) 4-amino-1,2,4-triazole in 30 ml of acetonitrile, precipitated pale yellow precipitate of compound I is filtered off and recrystallized from DMF.

The yield of compound I 3,57 (89%), So pl. 294-296oC.

Found, %: 59,47; N 2,70; N 17,43/ C20H11N5O5Calculated, %: 59,86; N Was 2.76; N 17,45.

Compounds II-IV are obtained similarly.

Characteristics of the synthesized sedimenation soluble in acetonitrile, acetone, toluene, soluble in DMSO, insoluble in water, hexane, benzene and giving a positive reaction (cherry staining) in the presence of the enol hydroxyl with an alcoholic solution of ferric chloride (III).

In the IR spectra of compounds I-IV are the bands of stretching vibrations lactone carbonyl benzoxazinones fragment WITH2=O in the field 1770-1780 cm-1, amide carbonyl WITH1=O in the field 1750-1760 cm-1, rolnego carbonyl in the field 1620's to 1640's cm-1and the absorption band of amide NH group in the field 3200-3250 cm-1and broad absorption band enol carbonyl - 3000-3160 cm-1.

In the PMR spectra of compounds I, III are the signals of aromatic protons in the region 6,80-of 7.90 M. D. , singlet amide NH groups in the area of 9.3 to 9.6 M. D., singlet 2 vinyl CH groups triazole fragment in the field 9,90-10,1 M. D. and two singlet methyl groups (compound III) when is 2.30 and 2.45 m D. the Signal of the proton enol group HE strongly broadened due to the intensive exchange with the solvent and is approximately in the region of 8 M. D.

Example 2. Pharmacological study of triethylamine 4-aryl-2-hydroxy-4-oxo-3-(2-oxo-3,4-dihydro-2H-1,4-benzoxazine)-2-butenova acid in the presence of the anti-Christ. sakh of both sexes weighing 180-220 g model carragenine edema [1]. Compounds were administered intraperitoneally one hour before subplanar injection of 0.1 ml of 1% aqueous solution carragenin. The effect was evaluated ecometrics at the 4th hour after the introduction of logogen by the percentage increase in the volume of inflamed feet to the original volume and was calculated the percentage inhibition of edema compared to control.

All compounds were administered intraperitoneally at a dose of 50 mg/kg in 2% starch mucus. Drug comparisons for anti-inflammatory activity served diclofenac sodium at a dose of 8 mg/kg [2]. Control group animals were injected equiano amount of 2% starch slime.

Each connection has been studied in 6 animals.

Acute toxicity of the compounds was determined by the method of C. B. Prozorovsky [3] on outbred white mice of both sexes weighing 18-22 g intraperitoneal route of administration.

Statistical processing of experimental data was performed using student's t-test [4]. The effect was considered significant at p<0,05.50more than 2000 mg/kg, which corresponds to the class practically non-toxic compounds according to the classification K. K. Sidorov [5].

All ISCA sodium (PL. 2).

Literature

1. Methodological guidance on experimental (preclinical) study of non-steroidal anti-inflammatory pharmacological substances. Approved by the Pharmacological Committee of the Ministry of health USSR (1982).

2. R. D. Shabaev, M. D. Mashkovsky, G. J. Schwarz, C. I. Pokryshkin, Chem. Pharm. journal.,19 (1), 33-39 (1985).

3. C. B. Prozorovskii, Pharmacol. and toxicol., 4, 497-502 (1978).

4. M. L. white, the Elements of a quantitative evaluation of the pharmacological effect, 2nd ed., Medical literature, Leningrad (1963).

5. K. K. Sidorov, " in proc.Toxicology of new industrial chemical substances (release 13), Moscow, Medicine, 47-51 (1973).

Triethylamine 4-aryl-2-hydroxy-4-oxo-3-(2-oxo-3,4-dihydro-2H-1,4-benzoxazine)-2-butenova acid of General formula

< / BR>
where R=R1-H(I);

R-H, R1-CH3(II);

R=R1-CH3(III);

R-H, R1-OCH3(IV)

exhibiting anti-inflammatory activity.

 

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