DE2948186A1 - Antimicrobial higher n-alkyl-sulphonamide derivs. - prepd. by reaction of sulphonyl halide with higher alkylamine hydrochloride in the presence of aq. alkali hydroxide - Google Patents

Abstract

New higher N-alkyl sulphonamide derivs. are cpds. of formula (I) R1SO2NR2R3 (where R1 is 1-3C alkyl, phenyl or p-tolyl; R2 is 10-20C alkyl; and R3 is H, 1-3C alkyl or 2-3C hydroxyalkyl). (I) are antimicrobial agents with good bacteriostatic and bactericidal activity, adequate solubility in water, reasonable to very good solubility in organic solvents, and stability over a wide pH range. They are suitable for use as cleansing, disinfectant and preservative agents for textiles, floors, medical instruments, hospital equipment, or installations such as dairies, breweries and laundries. (I) can also be used as preservatives for technical products. Because they are physiologically well tolerated, (I) may be used as antimicrobials in body-care preparations and/or cosmetics. The activity of (I) may be enhanced by combining with complexing agents having a CaCO3-binding capacity greater than 230 mg/g in the Hamshire test.

Description

"New sul fonaniides, their manufacture and their uses

as antimicrobial substances "The invention relates to new sulfonamides of the formula I, in which R1 is an alkyl group with 1 to 3 carbon atoms, a phenyl group or a p-tolyl group, R2 is an alkyl group with 10 to 20 carbon atoms and R3 is hydrogen, an alkyl group with 1 to 3 carbon atoms or a hydroxyalkyl group with 2 or 3 carbon atoms.

The invention further relates to a process for the preparation of sulfonamides of the formula I, in which amine hydrochlorides of the formula II, in which R2 and R3 have the meaning given for the formula I, in aqueous solution with sulfonic acid chlorides of the formula III, R1 - S02C1 III in which R1 has the meaning given for the formula I and converts sodium hydroxide to the sodium salts of the sulfonamides of the formula II , the sulfonamides are precipitated by acidification with mineral acid and then separated off.

Finally, the invention relates to the use of the compounds of formula 1 as antimicrobial substances.

The amine hydrochlorides of the formula II are known Substances that can be obtained in a simple manner from amines of the formula R2R) NH by reaction can be obtained with hydrochloric acid. As amines of the formula R2R3NH come under other n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, n-decylmethyl, n-decylethyl, n-dodecylmethyl, n-dodecylpropyl, n-tetradecylethyl, n-Hexadecylmethyl-, n-Octadecylpropyl-, n-Eicosylmethyl-, n-Decylhydroxyethyl-, n-dodecylhydroxyethyl, n-dodecylhydroxypropyl, n-hexadecylhydroxyethyl, n-octadecylhydroxypropyl and n-eicosylhydroxyethylamine. Amine hydrochlorides are preferred primary amines with 10 to 20 carbon atoms and of these in particular those with 12 to 14 carbon atoms as starting material for the preparation of the invention Sulfonamides used.

As sulfonic acid chlorides of the formula II, the Chlorides methane, ethane, propane, benzene and p-toluenesulfonic acid are used.

The reaction of the amine hydrochlorides of the formula II with the sulfonic acid chlorides of the formula III and the alkali metal hydroxide is expediently in aqueous Solution carried out. The alkali metal hydroxides are in particular sodium and Potash hydroxide into consideration. The reaction is generally stoichiometric Amounts of amine hydrochloride and sulfonic acid chloride carried out. But you can too Work with an excess of sulfonic acid chloride, provided this is complete Implementation of the amine hydrochloride appears necessary. The sulfonic acid chloride is in this case compared to the amine hydrochloride in an excess of up to 30 mol% used. The amount of the alkali metal hydroxide is to be measured in each case in such a way that that it is sufficient, that present in the amine hydrochloride and that in the reaction with to neutralize the amount of hydrogen chloride produced by the sulfonic acid chloride. the Alkali metal hydroxides are generally used in the reaction mixture as aqueous, relative concentrated solutions present.

In the practical implementation of the manufacturing process according to the invention it is advisable to submit the entire amine hydrochloride solution and the intended Slowly add amounts of sulfonic acid chloride and alkali metal hydroxide while stirring. Care must be taken that the reaction mixture always has a weakly alkaline reaction. One can alkali metal hydroxide and sulfonic acid chloride with about the same Admit speed. However, it is also possible to use the base and the acid chloride to be added alternately in aliquots.

The reaction is spontaneous and exothermic. It is therefore advisable the heat of reaction generated by appropriate cooling of the reaction mixture to stir off.

From the alkali salts of the sulfonamides formed during the reaction. the desired compounds are made by acidification with mineral acids such as hydrochloric acid or sulfuric acid released and separated in a known manner, washed and dried.

The sulfonamides of the formula I obtained in this way are it is mostly a matter of well-defined crystallizing substances; part falls as thick liquid. As a rule, these substances can be processed without further processing their use as antimicrobial agents. These substances are Sufficiently soluble in water.

At the same time, they have a satisfactory to very good solubility in organic solvents. They are also stable over a wide pH range.

For use in antimicrobial agents, the substances in liquid, pasty or solid preparations are incorporated, e.g.

aqueous solutions, suspensions, emulsions and solutions in organic Solvents. Such antimicrobial agents can be in a variety of ways Areas are used, e.g. as cleaning agents, disinfectants and preservatives for textiles, floors, medical instruments, hospital facilities, commercial Establishments such as dairies, breweries and laundries. They are also suitable for Preservation of technical products that lead to bacterial and bacterial infestation Tend to decompose. Leave because of their good physiological tolerance The substances according to the invention are advantageously used in body care preparations use, for example in soaps, shampoos and other KCI cleaning agents, Deodorants and other cosmetic preparations for skin and body care that Can be attacked by bacteria, w5e 'iautcrellcs, lotions, and makeup Powder. The sub-stables according to the invention are used in the antibacterial agents in amounts of 0.1 to 10 wt .-%, preferably 0.5 to 5 wt .-%, based on the entire antimicrobial composition used. In preparations against bacteria are to be preserved, the substances according to the invention come in amounts of 0.1 to 2% by weight, based on the total amount of the product to be preserved, to use.

In preparations in which the addition of complexing agents is appropriate the sulfonamides of the formula I according to the invention can also be used with complexing agents which in the Hamshire test have a greater calcium carbonate binding capacity than 230 mg per g of complexing agent. This may result in a further Increased effectiveness possible.

The substances according to the invention are distinguished by one very good bacteriostatic and bactericidal effectiveness, which makes their use particularly Permitted in areas where it is not only due to the inhibition of the bacterial Growth, but rather on killing the bacteria in technically acceptable periods of time using lower concentrations.

The following examples are intended to illustrate the subject matter of the invention in greater detail explain without, however, restricting it to this.

Examples I. Preparation of the sulfonamides of the formula I Example 1 To a solution of 33.3 g (0.15 mol) of dodecylamine hydrochloride in 300 ml of water while stirring and ice cooling from 2 dropping funnels at the same time 60 Inl (0,) Ilol) 5 N sodium hydroxide solution and 17.1 g (0.15 mol) methanesulphonic acid chloride were added dropwise. The feed was regulated so that the solution always reacted weakly alkaline. After the addition had ended, stirring was continued for 1 hour at room temperature.

The solution was then acidified with concentrated hydrochloric acid and constricted. After cooling, the precipitated product was filtered off and removed Recrystallized acetone. 56.6 g of white crystals (92.6 ß d. Th.) Were from M.p. 73 ° C.

Example 2 In analogy to Example 1, a number of further sulfonamides of the formula I made from corresponding aminoalkanols. All the substances obtained are shown in Table I.

Table 1 Substance R1 R2 R3 A CH3 C10H21 H. B CH3 C11H23 H C CH3 C12H25 H. D CH3 C13H27 H. E CH3 C14H27 H. F CH3 C12H25 CH2CH2OH G C6H5 C12H25 H. H C6H5 C14H29 H. I C6H5 C12H25 CH2CH2OH J p-CH3C6H4 C10H21 H. K p -CH3C6H4 C12H25 H. L p-CH3C6H4 C14H29 H. M p -CH3C6H4 C12H25 CH2CH20H II. Antimicrobial Activity of the Sulphonamides of Formula I Example 2 The microbistatic activity of substances A to M from Table I was determined against the following test germ suspensions: 1) Staphylococcus aureus 5 x 107 germs / ml 2) Escherichia coli 5 x 107 germs / ml 3 ) Pseudomonas aeruginosa 5 x 107 germs / ml 4) Candida albicans 5 x 107 germs / ml The inhibitory concentrations of the products to be examined were determined using the dilution test according to the guidelines for testing chemical disinfectants of the German Society for Hygiene and Microbiology (1959). The experiments were carried out in sterile test tubes containing standard I broth (Merck) or wort (8 ° BG). After the addition of the active ingredients, the volume of nutrient solution in each tube was 10 ml. Subsequently, 0.1 ml of test germ suspension at the given concentration was added to each tube. The nutrient solution samples inoculated with bacteria were stored in an incubator at 570 ° C. for 5 days. The samples inoculated with Candida albicans were incubated at 500 ° C. for 3 days.

It was then determined which concentration of active substance added to the nutrient medium had just inhibited the growth of the germs. The one found this way ert was referred to as the inhibitory concentration.

The following active ingredient concentrations in ppm were tested: 1,000, 750, 500, 250, 100, 50, 10 Those for Substances A to M became those in the following Inhibitory concentrations listed in Table II were determined.

Table II Inhibitory concentration of substances A to M in ppm Substance test germ 1 2 3 4 A 50 50 100 250 B 50 100 500 1000 C 10 50 100 100 D 5 10 100 50 E 1 10 500 50 F 10 25 1000 100 G 25 50 500 250 H 10 25 1000 500 I 50 1000 1000 500 J 250 500 1000 1000 K 10 25 500 100 L 10 25 1000 25 M 50 1000 1000 250 Example 4 The microbicidal effect of the substances listed in Table III was determined against the following test germ suspensions: 1) Staphylococcus aureus 2 x 108 germs / ml 2) Zscherichia coll 3 x 108 germs / ml 3) Pseudomonas aeruginosa 2 x 108 germs / ml 4) Candida albicans 8 x 107 germs / ml The killing times of the products to be examined were determined with the aid of the suspension test according to the guidelines for testing chemical disinfectants of the German Society for Hygiene and Microbiology (1959).

The substances to be tested were first dissolved in a little alcohol. The ethanolic solutions were diluted with deionized water Test solutions made that contain 1G00 pprti, 750 ppm, 500 ppm, 250 ppm, and 100 ppm Contained active ingredient and a maximum of 1% by weight of ethanol. According to the guidelines 0.1 ml of test germ suspension was pipetted into test tubes at room temperature. To this end, 10 ml of the test solutions described above were added in each case. After exposure times of 2 1/2, 5, 10, 20, 40, 60 and 120 minutes was added to the test tubes using a A drop of material is removed from the eyelet and placed in iO ml of nutrient solution containing 3% Tween 80 and 0.3% lecithin contained as a disinhibitor. The nutrient medium consisted of the Bacteria from 1% by weight standard I broth (Merck), in Candida albicans 1% by weight beer wort solution.

The samples inoculated with bacteria were stored at 370 C, those with Canida albicans inoculated samples incubated at 300 ° C. After 5 days at the earliest, the Cultures assessed macroscopically for growth and in this way the killing times determined, which are given in Table III below.

Table III Kill times at concentrations of 1000, 750, 500, 250 and 100 ppm in minutes Substance ppm test germ pH 1 2 3 4 A 500 40 60 60 120 6.9 250 40 60 60 120 100 120 120 120 120 C 500 20 5 10 120 7.1 250 20 20 20 120 100 40 120 120 120 D 500 20 2.5 6 40 6.9 250 20 10 10 120 100 20 20 40 120 E 500 10 2.5 5 10 6.4 250 20 2.5 5 20 100 20 5 10 40 F 1000-20-7.1 750 - - 40 - 500 2.5 2.5 - 2.5 250 2.5 2.5 - 2.5 100 20 120 - 120 G 500 60 20 10 40 7.2 250 60 20 40 60 100 120 120 - 120 Table III continued Substance ppm test germ pH 1 2 3 4 H 1000 - - 5 - 6.2 750 - - 5 - 500 10 2.5 - 2.5 250 10 5 - 60 100 60 60 - 120 K 1000 - - 2.5 - 500 20 10 5 120 6.0 250 20 20 - 120 100 60 120 - 120 L 500 20 60 - 10 6.6 250 240 60 - 40 100 60 120 - 120 III. Skin compatibility Product C from Table I was used as the test substance.

The skin tolerance was initially determined by a single application a small amount of substance tested on hairless mice. 1, 5 and 25 percent by weight Solutions in ethanol gave no result after 24 hours. Became a 5 weight percent When ethanolic solution was applied twice a day, there was moderate skin irritation after 10 days to observe.

The Burkhard test on humans, with a 1 percent by weight ethanolic Solution carried out on 5 test persons gave no result.

IV. Use of the sulfonamides of the formula I as antimicrobial substances Below are some examples of the use of the sulfonamides of the invention indicated as antimicrobial agents (GT = parts by weight).

1. Disinfecting hand washing paste 52 GT sodium lauryl sulfate (approx. 35 Wt .-% washing active substance) 3 pbw coconut fatty acid monoethanolamide 43 pbw pumice stone, fine ground 2 parts by weight of substance A instead of substance A can be used with equally good success products G and M are used.

2. Antimicrobial soap In the usual manufacture of a toilet soap from a mixture of 60% by weight coconut fatty acid sodium salt and 40% by weight tallow fatty acid sodium salt one works in the screw press together with the dye and the perfume such Amounts of substance F that the finished rope contains 1% by weight thereof. The antimicrobial Effect is increased if you also use so much complexing agent (nitrilotriacetate, Ethylenediamine tetraacetate or 1-hydroxyethanediphosphonate) incorporates that (leren The proportion in the soap is 8% by weight.

Instead of the substance F, the products C, I and L can be used with comparable Success can be used.

3. Foam bath 70 parts by weight sodium auryl ether sulfate (27 - 28% by weight detergent substance) 5 pbw coconut acid diethanolamide 0.5 pbw substance B 24.5 pbw water instead of Substance B can also incorporate the compounds E, H and K into the composition will.

4. Deodorant spray 10 parts by weight octyldodecanol 1 part by weight perfume 2 parts by weight substance C 87 pbw ethanol 100 pbw propellant gas In this composition can Substance C can be replaced by products D, H and J.

Claims (5)

"New sulfonamides, their production and their use as antimicrobial substances" Patent claims 1./Sulfonamides of the formula I, in which R1 is an alkyl group with 1 to 3 carbon atoms, a phenyl group or a p-tolyl group, R2 is an alkyl group with 10 to 20 carbon atoms and R3 is hydrogen, an alkyl group with 1 to 3 carbon atoms or a hydroxyalkyl group with 2 or 3 carbon atoms. 2. sulfonamides of the formula I according to claim 1, characterized in that that R3 is hydrogen. 3. sulfonamides of the formula I according to claim 1, characterized in that that R2 is an alkyl radical with 12 to 14 carbon atoms and R3 is hydrogen. 4 Process for the preparation of the sulfonamides of the formula I according to claim 1, characterized in that amine hydrochlorides of the formula II, in which R2 and R3 have the meaning given for the formula I, in aqueous solution with sulfonic acid chlorides of the formula III, R1 - SO2Cl III in which R1 has the meaning given for the formula 1, and converts alkali metal hydroxide to the alkali metal salts of the sulfonamides of the formula I. , the sulfonamides are precipitated by acidification with mineral acid and then separated off. 5. Use of the sulfonamides of the formula I according to claim 1 as antimicrobial Substances.