RU2367651C1 - 4-n-(4-aryl-2,4-dioxybutyryl)aminobenzensulphamides displaying anti-inflammatory, analgetic and antimicrobic activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: 4-N-(4-aryl-2,4-dioxybutyryl)aminobenzensulphamides of general formula:

whereat R=H, C₂H₅O, CL are claimed.

EFFECT: displaying of anti-inflammatory, analgetic and antimicrobic activity.

2 cl, 3 ex, 3 tbl

Description

The invention relates to organic chemistry, namely to previously unknown sulfamides of 4-aryl-2,4-dioxobutane aroylpyruvic acids exhibiting biological activity.

From the sources available to the applicant, there is a known method for producing aroylpyruvic acid acids similar in structure to β-arylsulfonylaminoethylamides, which exhibit weak anti-inflammatory and analgesic activity (A.V. Milyutin, PP Makhmudov, Yu.S. Andreichikov, A.F. Goleneva, G.A. T.I.Kovina.Physical-Pharmaceutical Journal. 1996. T. 30. No. 6. S.20-22).

where R = H, Me, MeO, 2,4-Me, F, Br, Cl; Ar = Ph, C ₆ H ₄ Me-p.

The disadvantage of these compounds is a weak anti-inflammatory and analgesic effect and the absence of antimicrobial activity.

The objective of the present invention is the synthesis of 4-N- (4-aryl-2,4-dioxobutyryl) aminobenzenesulfonamides, free from this drawback, and the expansion of the arsenal of means of exposure to a living organism. This problem is solved by 4-N- (4-aryl-2,4-dioxobutyryl) aminobenzenesulfamides of the general formula:

where R = H, C ₂ H ₅ O, Cl,

exhibiting anti-inflammatory, analgesic and antimicrobial activity.

The synthesis of the above compounds is carried out by reacting 5-aryl-2,3-dihydrofuran-2,3-diones with p-aminobenzenesulfamide in dioxane at room temperature for 30-60 minutes, followed by isolation of the target product by known methods.

where R = H, C ₂ H ₅ O, Cl.

The reaction of furandion with p-aminobenzenesulfamide proceeds at room temperature in a solution of dioxane. Regardless of the reagent ratio (1: 1 or 2: 1), 4-N- (4-aryl-2,4-dioxobutyryl) aminobenzenesulfamides are formed. With an excess of furandion, the above amide and unreacted furandion are present in the reaction mixture (according to the chromatogram). An increase in temperature to 100 ° С does not affect the course of the reaction, however, instead of an excess of furandion, the known 6-aryl-3-aroyl-4-hydroxy-2-pyranone is observed in the chromatogram (Yu.S. Andreichikov, Yu.A. Nalimova, A. P. Kozlov, I. A. Rusakov. Journal of Organic Chemistry. 1978. V.14. Issue 11. P.2436-2440).

The following are examples of the synthesis of the claimed compounds.

Example 1. 4-N- (4-Phenyl-2,4-dioxobutyryl) aminobenzenesulfamide

In a solution of 0.01 mol of phenylfurandion in 20 ml of anhydrous dioxane, 0.01 mol of n-aminobenzenesulfamide is added and stirred on a magnetic stirrer for one hour. The solvent was evaporated, the precipitate formed was recrystallized from DMF.

2.84 g (85%) of substance are obtained. C ₁₆ H ₁₄ N ₂ O ₅ S. 218-220 ° C (DMF).

Calculated,%: C = 57.8; H = 4.2; N = 8.4;

Found,%: C = 57.6; H = 4.1; N = 8.5.

Example 2. 4-N- (4-p-ethoxyphenyl-2,4-dioxobutyryl) aminobenzenesulfamide

0.01 mol of n-aminobenzenesulfamide is added to a solution of 0.01 mol of p-ethoxyphenylfurandione in 20 ml of anhydrous dioxane and stirred on a magnetic stirrer for 30 minutes. The solvent was evaporated, the precipitate formed was recrystallized from DMF.

Obtain 3.5 g (91%) of the substance. C ₁₈ H ₁₈ N ₂ O ₆ S. 225-226 ° C (DMF).

Calculated,%: C = 57.3; H = 4.7; N = 7.4;

Found,%: C = 57.2; H = 4.5; N = 7.5.

Example 3. 4-N- (4-chlorophenyl-2,4-dioxobutyryl) aminobenzenesulfamide

0.01 mol of n-aminobenzenesulfamide is added to a solution of 0.01 mol of p-chlorophenylfurandion in 20 ml of anhydrous dioxane and stirred for 40 minutes on a magnetic stirrer. The solvent was evaporated, the precipitate formed was recrystallized from DMF.

Obtain 3.57 g (94%) of the substance. C ₁₆ H ₁₃ N ₂ O ₅ SCl. Mp 235-234 ° C (DMF).

Calculated,%: C = 52.4; H = 3.5; N = 7.6;

Found,%: C = 52.6; H = 3.4; N = 7.5.

The structure of the obtained sulfamides 1-3 is proved by IR and PMR spectra. In the IR spectra of sulfamides taken in liquid paraffin, a band is observed in the region of 1705-1710 cm ^-1 , corresponding to the absorption of amide carbonyl. In the region of 1600-1620 cm ^-1 there is a wide band of stretching vibrations = С-Н of two benzene rings and Н - of the chelate cycle. In the range of 3200-3280 and 3300-3370 cm ^-1 there are bond peaks = NH and -NH ₂ .

In the PMR spectrum of sulfamides recorded in a solution of deuterodimethyl sulfoxide in the range of 6.63–8.23 ppm, there are signals of protons of aromatic rings, on which signals of —NH and = —CH groups are superimposed. In the region of 10.76-10.93 ppm. there is a wide band of the —NH ₂ group. The absence of a methylene group signal indicates the presence of these compounds in a DMSO solution exclusively in enol form. The absence of the enol hydroxyl signal in the region of 14–16 ppm is apparently due to the exchange of solvent protons. Enol hydroxyl in the H-chelate cycle is detected by a qualitative reaction with oxide of iron chloride (a characteristic dark violet color appears).

Table 1 4-N- (4-Aryl-2,4-dioxobutyryl) aminobenzenesulfamides % v, cm ^-1 δ, ppm No. 1600 (C ₆ H ₅ , C ₆ H ₄ , C = O ... OH 7.00-8.23 m H 85 218-220 1710 (C = O amide) (11H, C ₆ H ₅ , C ₆ H ₄ , CH =, NH) one 3260, 3370 (NH, NH ₂ ) 10.83 pp (2H, NH ₂ ) 1600-1615 (2С ₆ Н ₄ , С = О ... ОН) 1.23 t (3H, CH ₃ ), 4.00 s (2H, CH ₂ ) C ₂ H ₅ O 91 225-226 1705 (C = O amide) 4.5 s (2H, CH ₂ ), 6.63-8.13 m (10H, 2 3230, 3300 (NH, NH ₂ ) 2C ₆ H ₄ , CH =, NH), 10.76 bp (2H, NH ₂ ) 1600 (2C ₆ H ₆ , C = O ... OH) 4.60 s (2H, CH ₂ ), 7.06-8.23 m (10H, Cl 94 234-235 1700 (C = O amide) 2C6H4, CH =, NH), 10.93 bp (2H, NH ₂ ) 3 3280, 3350 (NH, NH ₂ )

The effectiveness of the claimed 4-N- (4-aryl-2,4-dioxobutyryl) aminobenzenesulfamides is confirmed by screening for analgesic activity according to the "hot plate" method (N.V. Eddy, D. Leimbach. Pharmacology and Toxicology. 311, 1960), anti-inflammatory activity on the model of "carrageenin edema" {Methodical recommendations for the experimental study of non-steroidal anti-inflammatory substances. Pharmaceutical Committee, Moscow, 1982). The sensitivity of microorganisms to the claimed compounds was determined by the standard method of double serial dilutions with the assessment of activity at the minimum effective concentration. The results of biological activity are shown in table 2 and 3.

table 2 Anti-inflammatory and analgesic activity of 4-N- (4-aryl-2,4-dioxobutyryl) aminobenzenesulfamides Compound and comparison drug Toxicity LD ₅₀ , mg / kg Dose mg / kg Type of activity Anti-inflammatory Analgesic Inhibition of edema after 4 hours,% The value of the defensive reflex, sec one 1000 fifty 49 26.0 2 1000 fifty 60 27.8 3 1000 fifty thirty 23.8 Control (starch mucus) 0 11,2 Voltaren 380 8 53.9 26.0 β-arylsulfonylaminoethylamides of aroylpyruvic acids > 1000 fifty 18-43,4 17-24

Table 3 Antimicrobial activity of 4-N- (4-aryl-2,4-dioxobutyryl) aminobenzenesulfamides Compound and comparison drug Toxicity LD ₅₀ , mg / kg Antimicrobial activity μg / ml E.coli St.aureus one 1000 1000 500 2 1000 500 500 3 1000 250 500 Furatsillin 1000 500

Compounds 1-3 are comparable in toxicity to β-arylsulfonylaminoethylamides of aroylpyruvic acids. In terms of analgesic activity and anti-inflammatory effect, the claimed compounds are superior to β-arylsulfonylaminoethylamides of aroylpyruvic acids taken as a reference. In addition to the listed activities, the claimed compounds exhibit antimicrobial activity against Escherichia coli and staphylococcus comparable (compound 1) or superior (compound 2 and 3) action of the drug furacilin.

The proposed biologically active compounds after clinical testing will find application in practical health care.

Claims (1)

4-N- (4-Aryl-2,4-dioxobutyryl) aminobenzenesulfamides of the general formula

where R is H, C ₂ H ₅ O, Cl,
exhibiting anti-inflammatory, analgesic and antimicrobial activity.