WO1984004919A1

WO1984004919A1 - N-substituted alkylamines, preparation thereof and utilization thereof as antimicrobial agents

Info

Publication number: WO1984004919A1
Application number: PCT/EP1984/000158
Authority: WO
Inventors: Werner Gerhardt; Rudolf Lehmann
Original assignee: Henkel Kgaa
Priority date: 1983-06-03
Filing date: 1984-05-25
Publication date: 1984-12-20
Also published as: IT8421215A0; DE3320106A1; IT8421215A1; IT1176232B

Abstract

N- AD3-morpholinyl-(4)-1-methylpropyl BD-amines and N- AD3-azolyl-(4)-1-methylpropyl BD-N-alkylamines having the general formula (I), wherein R1 represents separated linear alkyl rests containing from 8 to 14 atoms of carbon or mixtures thereof, a rest n-dodecyloxytrimethylene or n-dodecyl/tetradecylaminotrimethylene and wherein R2 represents optionally alkyl substituted cyclic hydrocarbon rests with five or six chain branchings, containing an hydrogen atom and optionally other hetero atoms, as well as salts thereof with organic and inorganic acids. The present invention further relates to a process for the preparation of the compounds having the general formula (I), characterized in that the cyclic hydrocarbons with five or six chain branchings, which are optionally alkyl substituted, and containing a nitrogen atom and optionally other hetero atoms, having the formula R2H, wherein R2 has the same representation as hereabove, are replaced by methylvinylketone and in that the resultant substituted ethylmethylketone, at a higher temperature and in solution in the presence of molecular hydrogen and a catalyst, is replaced by a long chain amine having the formula R1NH2, wherein R1 has the same representation as hereabove. Finally the present invention relates to the utilization of compounds having the general formula (I) as antimicrobial agents.

Description

N-substituted alkylamines, their preparation and their use as antimicrobial agents

The invention relates to N- [3-morpholinyl- (4) -1-methylpropyl] - and N- [3-azolyl- (4) -1-methylpropyl] -N-alkylamines of the general formula I.

CH ₃

R ¹ -NH- H ³ -CH ₂ -CH ₂ -R ² (I)

in R ¹ for individual linear alkyl radicals with 8 to 14

C atoms or mixtures thereof, represents an n-dodecyloxytrimethylene or an n-dodecyl / tetradecylaminotrimethylene radical and R ^{2 represents} optionally alkyl-substituted five- or six-membered cyclic hydrocarbon radicals containing a nitrogen atom and optionally further heteroatoms, and their salts with organic and inorganic acids .

The invention further relates to a process for the preparation of compounds of the general formula (I), which is characterized in that, optionally alkyl-substituted five- or six-membered cyclic hydrocarbons of the formula R ² H containing one nitrogen atom and optionally further heteroatoms, in which R ^{2 has} the meaning given above, reacted with methyl vinyl ketone and the resulting substituted ethyl methyl ketone at elevated temperature in solution in the presence of molecular hydrogen and a catalyst with a long-chain amine of the formula R ¹ NH ₂ , in which R ^{1 has} the meaning given above , implements.

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

Examples of linear alkyl radicals represented by R ¹ are octyl, decyl, n-dodecyl and n-tetradecyl and mixtures of essentially dodecyl and tetradecyl, which are commonly referred to as cocoalkyl. R ¹ can also represent long-chain ether or amino groups, for example n-dodecyloxytrimethylene or n-dodecyl / tetradecylaminotrimethylene.

Examples of heterocyclic hydrocarbon radicals which R ² represents are 4-morpholinyl, 2,6-dimethyl-4-morpholinyl, 1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl and imidazolyl.

Compounds of the general formula are preferred

(I) in which R ^{1 is} an n-dodecyl or an n-tetradecyl radical and R ^{2 is} an unsubstituted morpholinyl or imidazolyl radical or a substituted pyrazolyl radical.

The N- [3-morpholinyl- (4) -1-methylpropyl] - and N- [3-azolyl- (4) -1-methylpropyl] -N-alkylamines of the general formula (I) are obtained by processes known per se ( H. Reimlinger and JFM Oth, Chem. Ber. 97, 331 (1964); Houben-Weyl Methods of Organic Chemistry, Vol. 11/1, pp. 285 ff., Georg-Thieme-Verlag, Stuttgart, 1957; NC Ross and R. Levine, J. Org. Chem. 29, 2346 (1964) and Organikum, Organochemical Basic Internship, 15th Edition, pp. 542-544, VEB Deutscher Verlag der Wissenschaften, Berlin 1981) according to the following reaction scheme shown. Heterocyclic secondary amines R ² H (II) are added to the activated double bond of methyl vinyl ketone (III). Depending on the reactivity of the NH compound, the reactions are carried out with cooling at 0 to 5 ° C. or with heating at 100 ° C. in bulk or in ether or toluene as solvent (stage A).

Reaction scheme

Level A

Level B

The desired compounds of the general formula (I) are prepared by reductive alkylation of the long-chain primary amines R ¹ NH ₂ (V) with the 1-substituted 3-butanes (IV) formed in step A.

Examples of long-chain primary amines which are alkylated in reaction stage B are n-octylamine, n-decylamine, n-dodecylamine and n-tetradecylamine and cocosamine, in which the alkyl radical R ¹ consists primarily of mixtures of n-dodecyl and n- Tetradecyl exists. In addition, n-dodecyloxypropylamine and n-dodecyl / tetradecylpropylenediamine are used.

Examples of five- or six-membered heterocyclic hydrocarbons R ² H which are activated on the

Double bond of methyl vinyl ketone (III) added are morpholine, 2,6-dimethylmorpholine, pyrazole, 3,5-dimethylpyrazole and imidazole.

Toluene is used as the solvent for the reductive alkylation and palladium on carbon as the catalyst. The hydrogenation is complete at 50 to 60 ° C and a hydrogen pressure of 50 to 60 bar after 6 to 8 hours.

In order to achieve an improved water solubility of the compounds of the general formula (I) according to the invention, the reaction products (I) are converted into the corresponding salts in the presence of an excess of organic or inorganic acids. Preferred acids for salt formation are hydrochloric acid and acetic acid. With this approach, the Hydrochlorides or acetates of the compounds of general formula (I) in almost quantitative yield.

The compounds of the general formula (I) according to the invention and also their salts are, owing to their microbistatic and microbicidal activity, suitable as preservatives for technical products in the non-medical and non-therapeutic area. So they are used in the preservation of glue base materials and adhesives as well as cooling lubricants. They can also be used to make cosmetics, e.g. Preserve creams, oil-in-water and water-in-oil emulsions effectively.

The compounds according to the invention can also be used for disinfection, for example as a surface disinfectant in a disinfectant cleaner.

For use in antimicrobial agents, the compounds according to the invention can be incorporated in a known manner into liquid, pasty or solid preparations which are in the form of solutions, suspensions or emulsions.

The invention is explained in more detail in the examples below.

1. Synthesis of the N- [3-morpholinyl- (4) -1-methylpropyl] - and N- [3-azolyl- (4) -1-methylpropyl] -N-alkylamines of the general formula (I) and their salts. a) Synthesis of the 1-substituted 3-butanones (IV). The 1-substituted 3-butanones (IV) were prepared by adding the heterocyclic secondary amines or azoles R ² H to the activated double bond of methyl vinyl ketone (III) by generally known methods. The yields of (IV) ranged from 63 to 96%.

The reaction components were reacted in equimolar amounts in a solvent, preferably ether or toluene, at 0 to 100 ° C. The use of a solvent was not necessary for the reaction of the pyrazoles with methyl vinyl ketone.

b) Synthesis of the compounds of general formula (I) and their salts from intermediates (IV).

A solution of 0.13 mol of the ketones (IV) shown in section a) and 0.11 to 0.13 mol of a long-chain primary amine R ¹ NH ₂ (V) in 250 to 300 ml of toluene were in an autoclave on palladium Charcoal hydrogenated as a catalyst for 6 to 8 h at 50 to 60 ° C and 50 to 60 bar hydrogen pressure.

After filtering off the catalyst and distilling off the toluene, the oily residue was acidified with hydrochloric acid. Non-basic products were separated off and discarded by extraction with ether. The acidic solution was then made alkaline with sodium hydroxide solution and the released basic product several times Ether extracted. After washing the combined organic phases with water, drying over sodium sulfate and distilling off the ether, the compounds of the general formula (I) were obtained in the form of colorless to yellow oils. If necessary (thin layer chromatographic control), any remaining small amounts of the amines (V) were removed by steam distillation.

The salts of the compounds of the general formula (I) were obtained by reacting the basic N- [3-morpholinyl- (4) -1-methylpropyl] - and N- [3-azolyl- (4) -1-methylpropyl] -N -alkylamines (I) with equimolar amounts or an excess of an organic or inorganic acid. This is how the hydrochlorides of the

Compounds of the general formula (I) after the introduction of dried. Hydrogen chloride gas in the ethereal solutions of (I) as colorless solids. The acetates of the compounds of the general formula (I) which are readily soluble in water are formed by reaction with equivalent amounts of glacial acetic acid in ether or ethyl acetate.

The physical properties of the N- [3-morpholinyl (4) -1-methylpropyl] - and N- [3-azolyl- (4) -1-methylpropyl] -N-alkylamines of Examples 1 to 29 are shown in Tables 1 to 3 refer to.

2. Antimicrobial activity of the compounds of the general formula (I). a) Microbistatic effectiveness.

The microbistatic activity of the compounds of Examples 1 to 29 was compared to the following

Test germ suspensions determined:

1. Staphyiococcus aureus 2 x 10 ⁹ germs / ml

2. Escherichia coli 2 x 10 ⁹ germs / ml

3. Candida albicans 2 x 10 ⁸ germs / ml

4. Aspergillus niger 5 x 10 ⁷ germs / ml

5. Penicillium camerunense 5 x 10 ⁷ germs / ml

The inhibitory concentrations of the compounds to be examined were determined using the dilution test according to the guidelines for testing chemical disinfection determined by the German Society for Hygiene and Microbiology (1972). The experiments were carried out in sterile test tubes containing standard I broth (pH 7.5 Merck) or wort broth (pH 5.5, Merck). After the addition of the active ingredients, the volume of nutrient solution in the tubes was 5 ml in each case. Then 0.1 ml of the test germ suspension of the stated concentration was introduced into the tubes. The bacterial inoculum samples were kept in the incubator at 37 ° C for 3 days. The mushroom inoculated samples were incubated at 30 ° C for 4 days. It was then determined which concentration of active ingredient added to the nutrient medium had just 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: 1,000, 500, 250, 100, 50 and 10.

The inhibitory concentrations listed in Table 4 below were determined for the compounds of Examples 1 to 29:

Result: The majority of the compounds of Examples 1 to 29 have a good to very good microbistatic action against bacteria, yeasts and fungi.

b) Microbicidal action.

The microbicidal activity of the compounds of Examples 1 to 29 was determined in relation to the following test germ suspensions:

1. Staphylococcus aureus 2 x 10 ⁹ germs / ml

2. Escherichia coli 2 x 10 ⁹ germs / ml

3. Pseudomonas aeruginosa 5 x 10 ⁸ germs / ml

4. Candida albicans 2 x 10 ⁸ germs / ml 5. Aspergillus niger 5 x 10 ⁷ germs / ml

6. Penicillium camerunense 5 x 10 ⁷ germs / ml

The killing times of the products to be examined were determined using the suspension test according to the guidelines for testing chemical disinfectants of the German Society for Hygiene and Microbiology (1972). The substances to be tested were first dissolved in a little alcohol. Test solutions were prepared from the ethanolic solutions by dilution with hard water with a hardness of 17 ° dH, which contained 3000 ppm and 500 ppm of active ingredient and a maximum of 1% by weight of ethanol. 0.1 ml of the test microbial suspension was pipetted into test tubes at room temperature. For this, 10 ml of the test solution described above were added. After different exposure times up to 120 minutes at room temperature, a drop of material was removed from the test tubes with the aid of a pipette and inoculated in 10 ml of nutrient solution which contained 3% Tween 80 and 0.3% lecithin as a demineralizer. The nutrient medium consisted of 2.5% by weight standard I broth (Merck) and 3.3% by weight wort broth (Merck) for mushrooms. The samples were incubated at 37 and 30 ° C, respectively. After at least 3 to 5 days at the earliest, the cultures were assessed macroscopically for growth and in this way the kill times determined, which are given in Table 5 below,

Result: In the suspension test, a good to very good microbicidal action was achieved with numerous derivatives, even at active substance concentrations of 500 ppm. c) Microbicidal action in the surface disinfection test.

The application solutions with an active substance content of 2000 ppm were made from 10% aqueous stock solutions of the compounds of formula (I) according to the invention, which contained 10% surfactant (nonylphenol + 9.5 mol ethylene oxide) for better wetting, by dilution in a ratio of 1:50 obtained with water at 17 ° dH. These solutions were applied to 6 x 6 cm test areas made of wood and PVC at 20 ° C against the following test germs:

1. Staphylococcus aureus 2 x 10 ⁹ germs / ml

2. Candida albicans 2 x 10 ⁸ germs / ml

For this purpose, the test areas were evenly filled with 0.1 ml of the bacterial or yeast suspension in question and dried at room temperature for about 30 minutes. The application solutions were then applied to the test areas using cotton swabs so that they were uniformly wetted. After exposure times of 1, 2, 4 and 6 hours, one quadrant from each test area was rubbed off with a sterile cotton swab. The swabs were spread on sterile casein / soy agar plates containing 3% Tween 80, 0.3% lecithin and 0.1% histidine to neutralize any co-transferred drug to determine the number of surviving germs. The agar plates were incubated with Staphylococcus aureus for 48 hours at 37 ° C and with Candida albicans for 72 hours at 30 ° C. The numbers in Table 6 indicate the exposure times after which no viable germs were detectable on the nutrient media.

+ - Roughly quantitatively indicate the test microbial content after an exposure time of 6 hours.

Result: The compounds of Examples 7 (I, R ¹ =

C ₁₄ H ₂₉ , R ² = morpholinyl, acetic acid salt), 16 (I, R ¹ =

C ₁₂ H ₂₅ , R = imidazolyl, acetic acid salt) and 26 (I, R ¹

= C ₁₂ H ₂₅ , R ² = pyrazolyl, dihydrochloride) meet in

Surface disinfection test for both test germs

DGHM standard. Apparently, the effectiveness of the

Compounds of the general formula (I) in a

Alkyl chain length of 12 to 14 carbon atoms reached. 3. Toxicological investigations.

The compounds of Examples 7 and 16 were subjected to a basic toxicological test. The following results were obtained: a) N- [3-morpholinyl- (4) -1-methylpropyl] -N-tetradecylamine. Acetic acid salt (Example 7)

Acute toxicity (mouse, oral): LD ₅₀ at 625 mg / kg 3125 mg / kg absolutely fatal, strong nerve symptoms

Skin compatibility (hairless mouse): 1- to 25% without any findings.

Arnes test: No evidence of mutagenicity.

b) N- [3-pyrazolyl- (1) -1-methylpropyl] -N-dodecylamine, acetic acid salt (Example 16):

Acute toxicity (mouse, oral): LD ₅₀ mg / kg. At 625 and 3125 mg / kg: death after 5 to 10 min.

Skin compatibility (hairless mouse): 1- to 25%: without any findings.

Claims

Patent claims:

1. N- [3-morpholinyl- (4) -1-methylpropyl] - and

N- [3-Azolyl- (4) -1-methylpropyl] -N-alkylamines of the general formula (I) 3

R ¹ -NH- -CH ₂ -CH ₂ -R ² (I)

in R ¹ for individual linear alkyl radicals with 8 to

14 carbon atoms or mixtures thereof, for an n-dodecyloxytrimethylene or an n-dodecyl / tetradecylaminotrimethylene radical and R ² for optionally alkyl-substituted 5- or 6-membered cyclic, a nitrogen atom and optionally further

Hydrocarbon radicals containing heteroatoms, and their salts with organic and inorganic acids.

2. Compounds of the general formula (I) according to Claim 1, in which the heterocyclic hydrocarbon radical for which R ² stands is 4-morpholinyl, 2,6-dimethyl-4-morpholinyl, 1-pyrazolyl,

3,5-Dimethyl-1-pyrazolyl or 1-imidazolyl.

Compounds of general formula (T) according to claim 1, wherein acetic acid or hydrochloric acid are preferably used for salt formation.

4. A process for the preparation of compounds of the general formula (I) according to claim 1, characterized in that hydrocarbon of the formula R ² H, optionally containing alkyl-substituted 5- or 6-membered cyclic hydrocarbons containing a nitrogen atom and optionally further heteroatoms, according to generally known methods, in which R ^{2 has} the meaning given in claim 1, is reacted with methyl vinyl ketone and the resulting substituted ethyl methyl ketone is reacted at elevated temperature in solution in the presence of molecular hydrogen and a catalyst with a long-chain amine of the formula R ¹ NH ₂ , in which R ^{1 has} the meaning given in claim 1.

5. The method according to claim 4, characterized in that R ² H as heterocyclic hydrocarbons

Morpholine, 2,6-dimethylmorpholine, pyrazole, 3,5-dimethylpyrazole or imidazole.

6. Process according to claims 4 and 5, characterized in that the hydrogenation is carried out in toluene as a solvent.

7. Process according to Claims 4 to 6, characterized in that palladium on carbon is used as the hydrogenation catalyst.

8. Process according to Claims 4 to 7, characterized in that the hydrogenation is carried out at 50 to 60 ° C and 50 to 60 bar hydrogen pressure.

9. The method according to claims 4 to 8, characterized in that preferably used as long-chain amines R ¹ NH ₂ n-dodecylamine or n-tetradecylamine.

10. Antimicrobial agents containing at least one of the compounds according to claim 1, together with customary formulation substances.

11. Use of the compounds according to claim 1 as antimicrobial substances.