DE3040993A1 - Antimicrobially active guanidine salt derivs. - prepd. by reacting amino-alkanol salt of non-toxic acid with equimolar cyanamide proportion - Google Patents

Abstract

New N-substd. guanidine salts have formula (HO-CHR1-CHR2-(NH(CH2)m)n- NR3-C (=NH2)-NH2)pX (I) (where R1 is 1-18C alkyl; R2 is H or 1-17C alkyl, provided the C sum in R1 and R2 is 8-18; R3 is H or 1-3C alkyl; X is the anion of a p-basic non-toxic acid; m is integer 2-6; n is 0 or 1 and p is 1,2 or 3). (I) use as anti-microbial substances is claimed. (I) can be used in cleansing-, disinfectant- and preservative compsns., for textiles, floors, hospital equipment, medical instruments, schools, swimming pools, public transport, dairies, breweries and laundries, also in glues, sizes, dispersion dyes, cutting and drilling oils. (I) dissolve well in water; are stable at acid pH and have bacteriostatic and bactericidal activity.

Description

"Salts of N-substituted guanidines, their production

development and use as antimicrobial substances11 The invention relates to new guanidine salts of the formula in which R1 denotes an alkyl group with 1 to 18 carbon atoms and R2 denotes hydrogen or an alkyl group with 1 to 17 carbon atoms, the sum of the carbon atoms present in R1 and R2 being 8 to 18, R3 denotes hydrogen or an alkyl group with 1 to 3 carbon atoms and X. represents the anion of a p-basic, physiologically harmless acid, while m is an integer from 2 to 6, n can have the values 0 and 1 and p can assume the values 1, 2 and 3.

The invention further relates to a process for the preparation of the guanidine salts of the formula I, in which salts of physiologically acceptable acids with aminoalkanols of the formula I are used in which R1, R2, R3, m and n have the meaning given for the formula I, in a molar ratio of 1: 1 with cyanamide at 80 to 1400C.

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

The aminoalkanols of the formula II can, for example, be prepared from epoxyalkanes of the formula analogously to the processes given in German patent application P 25 20.267.9 and ammonia or amines of the formula getting produced. 1,2-epoxyalkanes with 10 to 20 carbon atoms and all epoxyalkanes with internal epoxy groups and 10 to 20 carbon atoms are suitable as starting material. The alkyl chains of these epoxyalkanes are preferably unbranched.

In the case of the epoxyalkanes with an internal epoxy group, preference is given to Mixtures of such compounds with different chain lengths and / or isomeric Position of the epoxy group used.

The epoxyalkanes of the formula III are otherwise in a known manner accessible by epoxidation of corresponding olefins. Olefins with terminal double ties can, for example, by cracking paraffinic hydrocarbons according to the geelgneten process or can be obtained in good yields and high purity by the aluminochemical route. Olefins or olefin mixtures with internal double bonds are for example via catalytic dehydrogenation or chlorination / dehydrochlorination of linear Paraffins of the chain length range mentioned and subsequent selective extraction the Monoo: Lefine accessible with an internal double bond.

Primary amines are used as amines of the formula IV. like methylamine, ethylamine, n-propylamine and i-propylamine, alkylenediamines such as ethylenediamine, propylenediamine, Butylenediamine, pentylenediamine and hexylenediamine, as well as N-substituted alkylenediamines such as N-methylethylenediamine, N-ethylethylenediamine, N-methylpropylenediamine, N-ethylpropylenediamine, N-n-propylethylenediamine, N-ethyltetramethylenediamine, N-i-propylpentamethylenediamine, N -methylpentamethylenediamine and ethylhexamethylenediamine are possible. The rest of R3 however, it is preferably a methyl group or hydrogen.

The aminoalkanols of the formula II fall during the preparation in the Usually as free bases and can be easily mixed with one equivalent of acid per mole of aminoalkanol in the as starting material for the preparation of the invention Transfer compounds required salts. As physiologically harmless acids mainly hydrochloric acid, phosphoric acid, acetic acid, glycolic acid, lactic acid, Propionic acid, succinic acid, malic acid, tartaric acid, citric acid and adipic acid into consideration ..

The reaction of the amine alkanol salts with cyanamide takes place at 80 to 1400C carried out without solvent in the melt flow. Solid cyanamide is preferred entered into a melt of the aminoalkanol salts.

In the interests of good mixing of the reactants, it has proved to be advantageous to introduce the cyanamide into the aminoalkanol salt melt, before the melt has reached the reaction temperature. The mixture of reactants is then heated to a temperature in the specified range for 3 to 30 minutes, wherein The higher the selected temperatures, the shorter the heating time. However, the reaction temperature must be so high that the reaction mixture melted is present.

The products obtained are mostly viscous liquids, individually Cases crystallizing solids. As a rule, these substances can be used without further processing can be used as antimicrobial agents. they draw are mainly characterized by the fact that they dissolve very well in water. So let yourself of the products according to the invention, aqueous solutions with a content of up to 20 Produce by weight without further ado. In addition, the substances according to the invention also have satisfactory solubility in organic solvents. Furthermore, they are stable in the acidic range.

For use in antimicrobial agents, the substances in liquid, paste or solid preparations are incorporated. Such antimicrobial agents can be used in a wide variety of areas, for example as a cleaning agent, disinfectant and preservative for textiles, Floors, Hospital facilities, medical instruments, schools, Bathing establishments, public transport, commercial operations such as dairies, Breweries and Laundries.

The finished antimicrobial agents contain in addition to those described Active ingredients usually other commonly used ingredients, depending on the the intended form of application and the intended use. For liquid Preparations come as solvents water and common organic solvents, in particular alcohols, optionally mixed with water. Such Solutions can be sprayed well using either compressed air or a propellant commonly used in aerosol technology for the production of sprays begins.

If in addition to the antimicrobial effect, an additional cleaning effect if desired, the agents can contain nonionic surfactants or amphoteric surfactants. Addition products of 4 to 40, preferably, are used as nonionic surfactants 4 to 20 moles of ethylene oxide in 1 mole of fatty alcohol, alkylcyclohexanol, alkylphenol, fatty acid, Fatty amine, fatty acid amide or alkanesulfonamide are possible.

Addition products of 5 to 16 mol are of particular interest Ethylene oxide on coconut or tallow fatty alcohols, on oleyl alcohol and on mono-, di- or trialkylphenols and monoalkylcyclohexanol with 6 to 14 carbon atoms in the alkyl radicals. As amphoteric surfactants, the derivatives come from secondary or tertiary aliphatic amines in question, the aliphatic radicals being straight-chain or branched and one radical from 8 to 18 carbon atoms and another one solubilizing anionic group, such as a carboxy, sulfo, sulfato, phosphato or phosphono group.

Garment substances can also be present in the antimicrobial agents be; as such, inorganic or acidic to slightly acidic reacting are suitable organic salts, in particular inorganic or organic complexing agents. Useful are for example acidic alkali ortho and pyrophosphates, the alkali salts of Nitrilotriacetic acid or ethylenediaminetetraacetic acid and the acidic alkali salts of organic, non-capillary-active sulfonic acids containing 1 - 8 carbon atoms, Carboxylic acids and sulfocarboxylic acids. These include, for example, water-soluble Salts of benzene, toluene or xylene sulfonic acid, water-soluble acidic salts of Sulfodicarboxylic acids, lactic acid, citric acid or tartaric acid. Go further than Builders are the acidic, water-soluble salts of higher molecular weight polycarboxylic acids into consideration, for example polymers of maleic acid, itaconic acid, fumaric acid and citraconic acid. Copolymers of these acids with one another or with other polymerizable ones Substances such as ethylene, propylene, acrylic acid, vinyl acetate, isobutylene, Acrylamide and styrene are useful.

The content of substances according to the invention is in the ready-to-use antimicrobial agents between 0.1 and 10 percent by weight, preferably 0.5 to 5 percent by weight, based on the total agent. For making such ready-to-use Means can be made up of concentrates or solid mixtures that up Contains 50 percent by weight of active ingredient.

The guanidine salts according to the invention can also be used for preservation of technical products that lead to bacterial and fungal attack or other microbial Tend to be destroyed, such as paste, glue, emulsion paints and cutting and drilling oils are used. For this purpose, an addition of 0.1 to 2 percent by weight, based on the material to be preserved, sufficient.

The guanidine salts of the formula I according to the invention are distinguished by a very good bacteriostatic and bactericidal effectiveness from their use especially permitted in those areas where it is not just about the inhibition of bacterial growth, but rather a killing of the bacteria in technically reasonable 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 A. Preparation 1. 224.5 g (1 mol) of a mixture of N- (2-hydroxyalkyl) -N-methylamines of the formula in which R represents straight-chain alkyl radicals with 10 to 12 carbon atoms, with an average molecular weight of 224.5, the mixture was heated to 70.degree. C. with stirring and 60 g (1 mol) of glacial acetic acid were added, the temperature of the mixture rising to 100.degree.

After adding 42 g (1 mol) of cyanamide and lowering the temperature the mixture was heated to go ° c until the exothermic reaction began at 10500, which led to an increase in temperature to 13500 within 3 minutes. The mixture was then stirred for a further 10 minutes. The red-brown obtained Oil crystallized on cooling.

By recrystallizing the crude product from acetonitrile, the N- (2-Hydroxyalkyl) -N-methylguani dinacetat as a white solid substance with m.p. 114 - 120 ° C obtained.

Analysis: found (%): 61.15 C; 11.62 H; 13.01 N 2. In analogy to Example 1, 215 g (1 mol) of N- (2-hydroxydodecyl) -N-methylamine, 60 g (1 mol) of glacial acetic acid and 42 g (1 mol) of cyanamide reacted with one another at 125 to 1350C. The crude reaction product was recrystallized from acetonitrile N- (2-hydroxydodecyl) -N-methylguanidine acetate with melting point 113-118 ° C. was obtained.

3. In the manner described above, a number of other guanidine acetates of the formula made from corresponding aminoalkanols. The substances obtained are shown in Table I with their physical characteristics.

TABLE I. Substance R1 R2 R3 mn Fp ° C nD20 nD50 A C10H21 H CH3 O - 113-118 - - B C10-12-alkyl H CH3 O - 114-120 - - C C13-16-alkyl H CH3 O - 50-90 - - D C10-12 alkyl HH 1 2 - - 1.4791 E C10-12 alkyl HH 1 3 - - 1.4610 F C12-14-alkyl HH 1 2 - 1.4935 - G C12-14-alkyl HH 1 3 - 1.4793 - H C14-16 alkyl HH 1 2 - - 1.4811 I C14-16 alkyl HH 1 3 - - 1.4802 K R1 + R2 = C13-16-alkyl HO - - 1.4782 - L R1 + R2 = C9-12-alkyl CH3 O - - 1.4742 - M R1 + R2 = C13-16-alkyl CH3 O - - 1.4712 - N R1 + R2 = C9-12 alkyl H 1 2 - - 1.4783 O R1 + R2 = C9-12 alkyl H 13 - - 1.4823 P R1 + R2 = C13-16 alkyl H 1 2 - - 1.4765 Q R1 + R2 = C13-16-alkyl H 1 3 - 1.4850 - B. Microbistatic Activity The remnant activity of the N-substituted guanidine salts listed in Table I was determined against the following test germ suspensions: 1) Staphylococcus aureus 5. 107 germs / ml 2) Escherichia coli 5 107 germs / ml 3) Pseudomonas aeruginosa 5. Germs / ml 4) Candida albicans 5. 10 7 germs / ml The inhibitory concentrations of the products to be examined were determined with the aid of the dilution test according to the guidelines for testing chemical disinfectants of the German Society for Hygiene and Microbiology (1959). The substances to be tested were dissolved in a little ethanol. Standard solutions were prepared by dilution with deionized water, which were then introduced into sterile test tubes in the appropriate amount. After filling up with standard I broth (Merck) or wort (80BG), the nutrient solution volume was 10 ml in each case. The maximum alcohol content was 1.% by weight. Subsequently, 0.1 ml of test microbial suspension of the stated concentration was placed in each of the tubes. The inoculated nutrient solution samples were kept in the incubator for 3 days at 37 ° C. for bacteria and for 3 days at 30 ° C. for fungi. It was then determined which active ingredient concentration added to the nutrient medium had just barely inhibited the growth of the germs. The value found in this way was called the inhibitory concentration. The following active ingredient concentrations in ppm were tested: 1000, 750, 500, 250, 100, 50, 25, 10, 7.5, 5, 2.5, 1.

For the substances A to Q from Table I, those in the following Table II listed inhibitory concentrations against the aforementioned test germs found.

Table II Inhibitory concentration of substances A - Q in ppm Substance test germ 1 2 3 3 | 4th A <10 25 50 25 B 2.5 | 10 50 5 C, 1 10 50 7.5 D | <10 50 50 50 E <10 50 50 50 F <io 25 25 <10 G <io 25 <10 25 H | <10 | 50 | 50 | 50 1 <10 50 50 50 KK 2.5 25 100 7.5 L 50 100 500 <10 M | 10 50 500 25 N | <10 50 50 100 O | <OK 50 50 50 P <10 <10 <10 50 Q 2.5 7.5 10 10 C. Microbicidal activity The microbicidal activity of the substances listed in Table III was determined against the following test germ suspensions: 1) Staphylococcus aureus 2 * 108 germs / ml 2) Escherichia coli 3. 108 germs / ml 3) Pseudomonas aeruginosa 2. 108 germs / ml 4) Candida albicans 6. 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 prepared containing 500 ppm, 250 ppm and 100 ppm active ingredient and maximum Contained 1% by weight of ethanol.

According to the guidelines, 0.1 ml of test germ suspension pipetted into test tubes. For this purpose, 10 ml of the given test solutions described above. After exposure times of 2 1/2, 5, 10, 20, 40, 60 and 120 minutes was added to the test tubes with the help of a pipette Drops of material are removed and put in. 10 ml of nutrient solution containing 3% Tween 80 and 0.3 * lecithin contained as a disinhibitor, inoculated. The nutrient medium consisted of the bacteria 1% strength by weight standard I broth (Merck) Candida albicans from 1% by weight beer wort solution.

The samples inoculated with bacteria were at 370C, those with Candida albicans inoculated samples incubated at 300C. 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 500, 250 and 100 ppm in minutes Substance ppm test germ pH 1 2 3 4 A 500 5 2.5 20 2.5 6.9 250 40 2.5 20 10 100 40 2.5 40 10 B 500 2.5 2.5 2.5 2.5 7.0 250 2.5 2.5 2.5 2.5 100 5 2.5 10 5 C 500 2.5 5 40 2.5 5.7 250 2.5 20 - 2.5 100 5 20 - 10 D 500 5 40 40 5 4.95 250 5 40 60 10 100 10 60> 120 60 Table III continued Substance ppm test germ ph 1 2 4 E 500 5 20 40 20 4.90 250 10 20 60 40 100 20 60> 120 60 FF 500 10 10 2.5 2.5 5.25 250 20 20 | 2.5 10 100 60 60 20 10 G 500 2.5 2.5 2.5 10 6.5 250 20 10 2.5 20 100 60 40 10 20 H 500 5 20 40 10 5.0 250 5 60 60 10 100 | 10 | > 120 | > 120 | 10 I 500 5 20 40 20 5.0 250 | 5 | 40 | 60 | 40 100 10 120 120 120 K 500 2.5 2.5 2.5 5 5.9 250 2.5 2.5 2.5 5 10 100 2.5 2.5 20 10 N 500 2.5 20 43 120 5.9 250 10 60 60 120 100 120>120> 120 120 Table III continued Substance ppm test germ pH 1 2 3 4 O 500 2.5 20 40 20 5.9 250 10 40 60 40 100 20 120> 120 60 P 500 2.5 2.5 5 10 5.05 250 5 5 10 40 100 10 10 20 60 Q 500 2.5 2.5 2.5 2.5 5.95 250 5 10 2.5 10 100 20 10 10 10 D. Microbicidal effectiveness in surface disinfection The microbicidal effect of substances A and B in surface disinfection was determined after the scrub disinfection test. This test method is also taken from the guidelines for testing chemical disinfectants, published by the German Society for Hygiene and Microbiology (1959).

Pieces measuring 6 x 6 cm served as models for contaminated surfaces of lacquered wood panels and PATC floor panels. For contamination of the surfaces suspensions of 1) Staphylococcus aureus 108 germs m / l 2) Klebsiella pneumoniae 108 germs m / l 3) Candida albicans 108 germs m / l used. on 0.1 ml of germ suspension was pipetted into each test area and with the aid of a glass spatula equally distributed. After the germ suspension had dried on, the test areas became evenly moistened with the disinfectant solution using a cotton swab.

The following concentrates were used to prepare the disinfectant solution Composition: 10% by weight active ingredient (substance A or B) 10% by weight C10-C12 fatty alcohol + 7 moles of ethylene oxide 10% by weight ethanol 70% by weight water These concentrates were diluted with water in a ratio of 1: 100 for use.

After exposure times of 1, 2, 4 and 6 hours, a Quarter of the treated areas rubbed with sterile swabs, the short through Dipping in bouillon were moistened. The swabs were placed on broth agar plates (Merck Standard I-Broth + 3% by weight Tween 80 + 0.3% by weight lecithin).

The agar plates were used for Staphylococcus aureus and Klebsiella pneumoniae 48 hours at 37? C, in Candida albicans incubated at 300 0 for 72 hours.

The evaluation gave the kill times given in Table IV.

Table IV Killing time of products A and B in hours Kill time in h Product test germ 1 2 3 A 6 6 6 B 6 6 6 E. Acute toxicity and skin tolerance Product A from Table I was used as the test substance.

When administered orally to mice, the acute toxicity was LD50 = 625 mg / kg. A dose of 3125 mg / kg was fatal for all test animals. There were general Symptoms and æm part nerve symptoms of poisoning observed.

The skin tolerance was determined by a single application of a small Amount of substance tested on hairless mice. The order of a 1% and a 5% Solution gave no result. The application of a 25% solution had flaking skin with no signs of inflammation.

Both in the acute oral toxicity test and in the Trial about skin tolerance were made Three experimental animals each Used depending on the concentration.

F. Uses: As Antimicrobial Agents The following are some Examples of the use of the salts of N-substituted guanidines according to the invention indicated as antimicrobial agents (GT = parts by weight).

1. Deodorant spray 10 pbw 2-octyldodecanol, 1 pbw perfume, 2 pbw substance E, 87 GT ethanol, 100 GT propellant.

In this composition, the substance E can be replaced by the substances K, 0 or Q can be replaced.

2. Disinfectant cleaning agent for hard surfaces 13 GT C10-C12 fatty alcohol + 10 EO, 10 pbw of substance A, 5 pbw of nitrilotriacetic acid, sodium salt, 10 pbw isopropanol, 67 pbw water.

Instead of substance A, products B, F and P can also be used can be used with equal success.

3. Foam bath 70 GT N-.trium lauryl ether sulfate (27 - 28 wt .-% washing active substance), 5 pbw of coconut fatty acid ethanolamide, 0.5 pbw of substance D, 24.5 pbw of water.

In this composition, the substance D can also through the products I, L or N can be replaced.

Claims (3)

Patent claims guanidine salts of the formula in which R1 denotes an alkyl group with 1 to 18 carbon atoms and R2 denotes hydrogen or an alkyl group with 1 to 17 carbon atoms, the sum of the carbon atoms present in R1 and R2 being 8 to 18, R3 denotes hydrogen or an alkyl group with 1 to 3 carbon atoms and X. represents the anion of a p-base, physiologically harmless acid, while my integer is from 2 to 6, n can take the values 0 and 1 and p can take the values 1, 2 and 9. 2. Process for the preparation of the compounds of the formula I according to claim 1, characterized in that salts of physiologically acceptable acids with aminoalkanols of the formula are used in which R1, R2, R3, m and n have the meaning given for the formula I, with cyanamide in a molar ratio of 1: 1 at 80 to 140.degree. 3. Use of the guanidine salts of the formula I according to claim 1 as antimicrobial Substances.