CS269448B1

CS269448B1 - Derivatives of sulphonamides

Info

Publication number: CS269448B1
Application number: CS886934A
Authority: CS
Inventors: Alois Doc Ing Drsc Novacek; Venuse Ing Sedlackova; Jaroslav Ing Korner; Jiri Ing Csc Krepelka; Jaroslava Mudr Csc Grimova; Vladislava Mudr Csc Hola
Original assignee: Novacek Alois; Sedlackova Venuse; Korner Jaroslav; Krepelka Jiri; Grimova Jaroslava; Hola Vladislava
Priority date: 1988-10-20
Filing date: 1988-10-20
Publication date: 1990-04-11
Also published as: CS693488A1

Abstract

Řešení ee týká látek obecného vzorce X. Látky Jeou nové a připravují ee reakcí p-acetylsminobenxensulfonylchloridu ee sulfonamidy obecného vzorce II, ve kterém X značí skupinu jako ve vzorci I, působením vodného roztoku hydroxidu sodného a následnou alkalickou desacatylaci ochranné skupiny acetylová. Látky mají použití Jako chemoterapeutika.The ee solution relates to compounds of the general formula X. Substances Jeou new and prepare ee reactions p-acetylsminobenzene sulfonyl chloride ee the sulfonamides of formula (II) in which X represents a group as in Formula I by treatment aqueous sodium hydroxide solution and subsequent alkaline desacatylation acetyl protecting groups. They have substances use as chemotherapeutic agents.

Description

CS 269 X48 B1

The invention relates to sulfonamide derivatives of the general formula h-n -AA-so2-sh -Z λ-SO2-NH-2 (i) in which X is or CH.

or

These new, not yet described substances are antibacterially effective. Very good results were achieved with the substance and the methylisoxazole residue.

The compounds of the invention were prepared by reacting the p-acetylaminobenzenesulfonyl chloride of the sulfonyl amide of formula (II).

SC > 2-th — X (II) in which X denotes the group As in Formula I, by treatment with an aqueous solution of sodium hydroxide followed by alkaline desacetylation of the acetyl protecting group. The compounds of the invention are prepared by first condensing p-acetyl-aminobenzenesulfonyl chloride with the corresponding sulfonamide by dissolving the sulfonamide in water with the addition of sodium hydroxide while simultaneously adding p-acetyl-aainobenzenesulfonyl chloride to the solution while maintaining pH. at 8 to 9 by further addition of sodium hydroxide solution at 50 to 60 ° C. The condensation time depends on the type of sulfonamide and ranges from 8 to 10 hours. The progress of the reaction is monitored by chromatography. After completion of the reaction, the solution is filtered with the addition of activated charcoal and the product is precipitated by acidification with a solution of acetic acid or dilute hydrochloric acid to a pH of 4.5 to 5.5 according to the type of sulfonamide. The product is filtered off with suction, washed with water and, after addition of an excess of 3 H aqueous sodium hydroxide solution, is deacetylated at 50 to 80 ° C. The reaction time is different (2 to 15 hours). The end of the reaction is monitored by a solubility test in 1S hydrochloric acid. Upon completion of the desacetylation, the product is eliminated by acidification to pH 5.5 with acetic acid or dilute 2 CS 269 448. The final products are purified by crystallization from dilute ethanol or precipitation with acetic acid or hydrochloric acid from aqueous alkaline solutions.

The antibacterial efficacy was determined by determining the value of the ainial inhibitory concentration. It was compared with the value of the antibacterial activity of the known sulfoaaids such as sulfanilane, 5-ethyl-3- (p-aainobenzene sulfonylamino) isoxazole / sulfaethoxazole, 3-ethoxy-6- (p-aainobenzenesulfonyleaino) pyridazine (spofadazine) and 4-aninomethylbenzenesulfonate. fonaaid (aarfanil).

A total of 54 bacterial kaenes were used for the test, see table:

Kaeny počet

Streptococcus pyogenes Str. 5 'faecalis D 8

Staphylococeua aureus 9 epideraidis 8

Escherichia coli 10

Próteus sp. 7

Citrobacter sp. 2

Bnterobacter sp. 3

Klebsiela sp. 2

Cultivating Soils:

Brain - Heart Infusion

Mueller - Hinton broth (Iauna) + 5% lysed horse blood

Booster:

0.15 5aOH

Determination of ainia inhibitory concentration:

It was carried out by a long-term method in liquid aladium on the plates with the aid of Dynatech's aryrotitration devices. The minimum inhibitory concentration of the compounds was determined as the lowest concentration of the substance that inhibits the growth of the test kaene. Test compound concentrations tested were in the range of 512 to 4 ag / l. The preparation of the inoculum of the bacterial kaenes was performed by a standard method. The results were read after 24 hours of culture at 37 ° C.

Of the test substances, good antibacterial activity (8-16 g / L) was found in the kaen of the Bnterobaoteriaceae with an ethylisoxazole residue. a grapefruit positive aroroga-nisais was a significant antibacterial activity (8 to 16 ag / l in Staphylococeua aureus. Acute toxicity determination: Further acute toxicity assessment was performed after a single administration of substances to the stomach in the stomach of the current kaene HMRI conaric breeding in weight 25 to 30 g.

The experimental groups were 10 animals each. 5-ethyl-3- (p-aainobenzenesulfonylaine) isoxazole / Sulfaaethoxazole / - standard substance 1 g / kg 0/10 5 g / kg 2/10 10 g / kg 5/10 5-ethyl-3- (4- (p)) -aainobinone-sulphonyl-8-amine / benzene-sulphonylaine) isoxazole / new substance / 1 g / kg 0/10 5 g / kg 0/10 1 0 g / kg 0/10 25 «diaethylsulfoxide (1 al / 20 g) 0/10 CS 269 448 B1 dosing of 1 g and 10 g per 1 kg of body weight was not observed in the new substance, whereas in the standard compound 5 B 2 mice were killed and 10 g of 5 mice. The results show that the new substance is comparable in effectiveness to antibacterial agents yet one of the most effective sulfonamides (sulfamethoxazole). However, it has significantly less toxicity. The following examples illustrate but not limit the invention. Example 1

To 50 L of the sodium hydroxide solution (8 g; 200 mL of water; 0.2 mol) of the present invention is added 5-methyl-3- (p-aminobenzeasulfonylamino) isoxazole (sulfamethoxazole), (12.66 g; 0.05 mol) and water (100 mL). It is heated with stirring to 50 ° C and after dissolution of sulfamethoxazole, p-acetylaminobenzenesulfonyl chloride (21.15 g; 0.06 mol; 66.3%) is metered in over 2 hours. hours while maintaining the pH at 9 and 10 with the remaining sodium hydroxide solution (150 ml). The solution was filtered with charcoal and the product precipitated to pH 5.5 (16.5 mL) by the addition of dilute hydrochloric acid (1: 1). Wash off the sea with water (150 mL). After drying at 60 ° C, 18 g (79.9%) of 5-methyl-3- (4- (p-acetylamino-benzenesulfonylamino) -benzenesulfonylamino) -oxazole were obtained, m.p. 136-141 ° C.

Desacetylation:

5-Methyl-3- [4- (p-acetylaminobenzenesulfonylamino) -benzenesulfonylamino] isoxazole (15 g; 0.033 mol) was added to the sodium hydroxide solution (150 ml; 3 H) and heated at 80 DEG C. for 15 hours with stirring. . The solution is filtered with charcoal and the product is precipitated at 60 ° C by the addition of dilute hydrochloric acid (1: 1; 65 ml) to pH 5.5. It was collected and washed with water (150 ml).

After drying at 60 ° C, 12 g (89.08%) of 5-methyl-3- [4- (p-aainobenzenesulfonylamino) benzenesulfonylamino] isoxazole was obtained which, after recrystallization from 50% ethanol (200 ml) m.p. 230-233 ° C, chromatographically pure and elemental analysis consistent with the above formula. Example 2

In an analogous manner to Example 1, 14 g (0.05 mol) of 3-methoxy-6-sulfanilamidopyridazine (Spofadazine) and p-acetylaminobenzenesulfonyl chloride (26.03 g; 0.078 mol; 70.15 mesh) were obtained 19 g (79, 59%) of 3-methoxy-6H- (p-acetylaminobenzenesulfonylamino) benzene sulfonylamino (pyridazine, m.p. 186-189 ° C).

Deaacetylation with an excess of 3N sodium hydroxide (325 mL) yielded 29.6 g (99%) of the final compound from 32.5 g (0.068 mol) of the previous acetyl derivative. The product was purified by dissolving it in dilute sodium hydroxide (35 ml; 3N; 250 ml of water) to a pH of 5.5 by diluting with dilute hydrochloric acid (1: 1). It is suctioned off, washed with water (100) and dried at 60 ° C. Melting point: 235-238 ° C. It is chromatographically pure and the elution analysis is satisfactory. Example 3

As in Example 1, 13.92 g (0.05 mol) of 4,6-dimethyl-2-sulfanilimidopyrimidine (sulfadimidine) and 17.54 g (0.05 mol; 66.6%) of p-acetylaminobenzenesulfonyl chloride were obtained. 7 g (7%, 52%) of 4,6-dimethyl-2- [1- (p-acetylamino-benzenesulfonylamino) -benzenesulfonyl-amino] -pyrimidine, m.p. 239-241 ° C.

Desacetylation of 15 g (0.03 mol) of the previous acetyl derivative with 3N sodium hydroxide (150 ml) was aspirated to pH 5.5 with hydrochloric acid (1: 5; 250 ml), washed with water (100 ml) and dried at 60 ° C. g (92.3%) of 4,6-dimethyl-2- (4- (p-aainobenzenesulfonylamino) benzenesulfonyl-4-mine / pyrimidine, which, after crystallization from 70% ethanol (260 ml), had a melting point of 252-253 ° C. It was chromatographically pure and elementary analysis was satisfactory.

Claims

4 CS 269 448 B1 PREVIOUS VYHALSZD Sulphoneaide Derivatives of General I I h2h ~ <zZ-so2-ira - <\ t

or or