DE1695566C3 - N to the power of 1-square bracket on p-aminobenzoteuHonyl square bracket to -N to the power of 3-square bracket on 4,5dimethyloxazolyl- (2) square bracket to -guanidine - Google Patents

Description

43.0

3.5

4 hours
(mg "/"}

36.5

1.6

X hours

I mg% l

32.6

0.7

According to Gabe
of the preparation

up to 4.5% of the total dose can be recovered. In contrast, under the same conditions with 2- [p-aminobenzenesulfonyl] -amine-4,5-dimethyloxazole in the urine 80% and more of the administered Dose eliminated. Sulfaguanidine, known as an intestinal chemotherapeutic agent, is used according to Po th (Texas Reports on Biol. And Mcd. 4 [1946], p. 68), 50% excreted with the urine.

From these results it follows that the N ^l - | p-aminobenzenesulfonyl] - N ³ - [4.5 - dimethyloxazolyl - (2)] - guanidine is practically not absorbed from the gastrointestinal tract.

Table 2 shows the chemotherapeutic effect of N '- [p-aminobenzenesulfonyl] -N ³ - [4,5-dimethyloxazolyl- (2)] - guanidine in the intestinal tract with that of the well-known sulfaguanidine and the well-known 2 - [p - aminobenzenesulfonyl ] - amino - 4,5 - dimethyloxazoles.

Table 2
Comparison of the chemotherapeutic effects (bacteriostasis) in the intestinal tract of the white mouse

preparation Sulfaguanidine number of
Trial st rc Dose, p.o. Bakleriostasis Unsafe
effect Ineffectiveness 2- [p-aminobenzenesulfonyl] -amino- (mg kg) 1%) (%) (%) 4,5-dimathyloxazole 29 1000 24.1 3.4 72.4 DT-PS 1 121 052 30th 250 16.5 27.5 56.6 N '- [p-aminobenzenesulfonyl] -N ³ - [4,5-di- methyloxazolyl- {2)] guanidine 29 250 48.2 24.1 27.5

In the experiments on which Table 2 is based, the effect of the substance on the for tested in humans in general, optionally pathogenic coliform bacteria of the intestine. One determined on each test animal in a weighed amount of feces, the number of Coli bacteria before and after 6 hours after administration of the substances. In Table 2, bacteriostasis means a decrease in number the coli germs by more than 90%, uncertain effect a reduction of less than 90% and more than 50% and ineffectiveness a reduction in the number of germs by less than 50% after administration of the medication. The investigations and determination of the germ count was carried out according to H. R. R. Seel iger and H. Werner. Arzneimittelforschung 13 (1963), pp. 860 to 865. and P. Klein, Bakteriologische Basics of chemotherapeutic laboratory practice. Springer-Verlag, 1957. p. 9 ff. Carried out.

It can be seen from Table 2 that N ¹ - [p - aminobenzenesulfonyl] - N ³ - [4,5 - dimethyloxazolyl - (2)] - guanidine is chemotherapeutically much more effective than the known sulfaguanidine. It is also more effective in the gastrointestinal tract than the chemotherapeutically effective 2- [p-aminobenzenesulfonyl] -amino-4,5-dimethyloxazole. because the latter is reabsorbed too much. The three above test substances have such a low toxicity in mice. that they were tolerated without symptoms at a dose of 5000 mg kg orally.

The new formula 1 product is intended to be used as an intestinal chemotherapeutic agent.

example 1

23.9 g (0.1 mol) N '- [p-aminobenzenesulfonyl] -

N'-cyanguanidine.
13.2 g (0.15 mole) acetoin.
25 ecm conc. Hydrochloric acid,
120 ecm water + 120 ecm methanol.

The starting materials are stirred in the methanol-water mixture and lets the hydrochloric acid drop into the suspension at 40.degree. After 30 minutes A clear solution is obtained, which is kept at 40 ° C. for 1 hour. Then the methanol is in vacuo distilled off, the remaining solution treated with activated charcoal and with vigorous stirring 10% sodium hydroxide solution quickly brought to pH 11.

The first precipitate formed is at pH 11 solved again. It is treated with activated charcoal and added, with stirring and cooling, with glacial acetic acid Water 1: 1 to pH 7, the reaction product crystallizing out.

For cleaning, acetone is recrystallized from 15 times the amount of a mixture to give water 9: 1. The N '- [p-aminobenzenesulfonyl] -N ³ - [4,5-dimethyloxazolyl - (2)] -guanidine obtained forms colorless crystals with a melting point of 233 to 236 C.

Example 2

28.1 g (0.1 mol) of N'-tp-acetaminobenzolsuJfonyl] -N ³ -cyanguanidine and 13.2 g (0.15 mol) of acetoin are mixed in a mixture of 120 ecm of water and 120 ecm of methanol with stirring at 55.degree . 34 ecm of 36% hydrochloric acid are added dropwise with stirring. After 10 minutes, a clear solution is obtained, which is kept at 55 ° C. for a further 15 minutes. It is cooled, the methanol is evaporated off, diluted with an equal volume of water and treated with activated charcoal. Then it is quickly brought to a pH of 11 to 12 with sodium hydroxide solution while stirring thoroughly, a clear solution being formed. It is treated again with activated charcoal with stirring and brought to pH 4 with a mixture of glacial acetic acid and water 1: 1 and cooling. The reaction product separates out as a voluminous precipitate. The precipitate, which has been filtered off with suction and washed with water, is stirred with 150 ecm of 10% strength sodium hydroxide solution, the sodium salt of N ¹ - [p - acetaminobenzenesulfonyl] - N ³ - [4,5 - dimethyloxazolyl (2)] guanidine, with ice cooling crystallized out. It is suctioned off, washed with 20% brine, stirred the wet cake in 500 cc water and bring with hydrochloric acid to pH 7. In this case, the N ¹ - [p - Acetaminobenzolsulfonyl] - N ³ - [4,5 - dimethyioxazolyl - (2)] - guanidine deposited in colorless crystals that melt between 241 and 244 ° C. To split off the acetyl group, it is refluxed for 30 minutes in 150 ecm 10% sodium hydroxide solution. It is diluted with 150 ecm of boiling water, filtered from mechanical impurities and brought to pH 7 with acid. This gives the N ¹ - [p-aminobenzenesulfonyl] -N ³ - [4,5-dimethyloxazolyl- (2)] - guanidine in the form of colorless crystals with a melting point of 235 to 237 ° C.

Claims (2)

Patent claims: 1. N ^! - [p-AminotinzoIsulfonyl] -N ³ - [4,5-dimethyloxazolyl- (2)] guanidine. 2. Medicament, consisting of the compound of claim 1 and customary pharmaceutical auxiliaries Träaerstoffe. The invention relates to N '- [p-aminobenzenesulfonyl] -N ³ - [4,5-dimethyIoxazolyl- (2)] - guanidine of the formula I N C-CH, ^ Il Il " H, N- <> - SO, -NH-C-NH-C C-CH, (I) ■ N = / ■ Il \ / NH O To prepare the compound of the formula I, N ¹ - benzenesulfonyl - N ³ - cyano: iuanidines of the general formula II -SO ₂ -NH-C-NH-CN (II) NH heated with acetoin in water, in polar solvents or in mixtures of water and polar solvents in the presence of acids. The acid concentration can vary between wide limits. The pH of the reaction mixtures should not be above 3.5, since the reaction rate will then be too slow. The reaction temperature can be between 40 ^° C. and the boiling point of the solvent used. The separation of the reaction products from the reaction mixture is easy because of their poor solubility in the solvents used. Either they separate out in crystalline form during the reaction. or the crystallization takes place on cooling or on subsequent dilution with water. The substituent X mentioned in formula II, if it is not an amino group, is either through To convert saponification or by reduction into the amino group. A is preferred for X Acylamino group. z. B. the acetyl or a carboalkoxy-amino radical. Other acyl radicals are from Peptide chemistry known as protecting groups for the amino group. The N ¹ - [p-aminobenzenesulfonyl] - N ³ - [4,5 -dimethyloxazolyl - (2)] - guanidine of the formula I according to the invention is hitherto unknown and has excellent chemotherapeutic properties. As Table 1 shows, the substance is very little absorbed from the gastrointestinal tract. Tabel Comparison of the blood levels of the white mouse after a single oral dose of 1000 mg kg of N '- [p-aminobenzenesulfonyl] -N ³ - [4,5-dimethyloxazolyl- (2)] - guanidine and the known 2- [p-aminobenzo! See below ! fonyl] -amino-4,5-di- methyloxazole preparation 2- [p-AminobenzenesulfonyI] -amino-4,5-dimethyloxazole
(DT-PS 1 121 052) N '- [p-aminobenzoisulfonyl] -N ³ - [4,5-dimethyloxazolyl- (2)] guanidine 1 H.
(mg%) 41.0 2.1 The blood concentration of the new substance N ¹ - [p - aminobenzenesulfonyl] - N ³ - [4,5 - dimethyloxazolyl- (2)] - guanidine is very small compared to that under the same conditions with the 2 - [p - aminobenzenesulfonyl] - amino - 4,5 - dimethyloxazole obtained, which is known as a readily absorbable chemotherapeutic agent. The concentrations of the new substance in organs are correspondingly low. Examination of the excretion of N ¹ - [p - aminobenzenesulfonyl] - N ³ - [4,5 - dimcthyloxazolyl- (2)] - guanidine shows that in the collected faeces of the animals 80%, in the collected urine, however, only 2.5 60 2 hours
(mg "0}