DE3320106A1 - N-SUBSTITUTED ALKYLAMINE, THEIR PRODUCTION AND THEIR USE AS AN ANTIMICROBIAL ACTIVE SUBSTANCES - Google Patents

Abstract

N-[3-morpholinyl-(4)-1-methylpropyl]-amines and N-[3-azolyl-(4)-1-methylpropyl]-N-alkylamines having the general formula (I), wherein R<1> 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 R<2> 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 R<2>H, wherein R<2> 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 R<1>NH2, wherein R<1> 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 active ingredients. The invention relates to N-C3-morpholinyl- (4) -l-methylpropyg- and N-i-azolyl-t4) -1-methylpropyX -N-alkylamines of the general formula I. in which R1 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 R2 for optionally alkyl-substituted five- or six-membered cyclic hydrocarbon radicals containing a nitrogen atom and optionally further heteroatoms stands, as well as 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 'one nitrogen atom and optionally further hydrocarbons of the formula R2H containing heteroatoms, in the R2 has the meaning given above, reacts 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 R¹NH2, in which R¹ has the meaning given above.

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

Examples of linear alkyl radicals for which R1 stands are octyl, decyl, n-dodecyl and n-tetradecyl and mixtures of essentially dodecyl and tetradecyl, commonly referred to as coconut alkyl. R1 can also be used for long-chain Ether or amino groups, for example n-dodecyloxytrimethylene or n-dodecyl / tetradecylaminotrimethylene.

Examples of heterocyclic hydrocarbon radicals for which R2 stands, are 4-morpholinyl, 2,6-dimethyl-4-morpholinyl, 1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl and imidazolyl.

Preference is given to compounds of the general formula (I) in which R1 for an n-dodecyl or an n-tetradecyl radical and R2 for an unsubstituted one Morpholinyl, or imidazolyl radical or a substituted pyrazolyl radical.

The N- 2-SorpholSnyl- (4) -1-methylpropy- and N- 6-Azolyl- (4) -1-methylpropyD -N-alkylamines of the general formula (I) are prepared according to processes known per se (. Reimlinger and J.F.M. Oth, Chem. Ber. 97: 331 (1964); Houben-Weyl Methods of Organic Chemistry, Vol. 11/1, pp. 285 ff., Georg-Thieme-Verlag, Stuttgart, 1957; N.C. Ross and R.

Levine, J. Org. Chem. 29, 2346 (1964) and Organikum, Organisch-chemisches Basic internship, 15th edition, p.

542-544, VEB Deutscher Verlag der Wissenschaften, Berlin 1981) according to the reaction scheme below. Heterocyclic secondary amines R2 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 50 ° C. or with heating at 10,000 in bulk or in ether or toluene as the solvent (stage A).

By reductive alkylation of the long-chain primary amines R1NH2 (V) with the 1-substituted 3-butanones (IV) formed in stage A the desired compounds of the general formula (I) are prepared.

Examples of long chain primary amines used in the reaction stage B are n-octylamine, n-decylamine, n-dodecylamine and n-tetradecylamine and coconut amine, in which the alkyl radical is mainly R1 from mixtures of n-dodecyl and n-tetradecyl.

You can also find n-dodecyloxypropylamine and n-dodecyl / tetradecylpropylenediamine Use.

Examples of five- and six-membered heterocyclic hydrocarbons R2H, which are added to the activated double bond of methyl vinyl ketone (III), are morpholine, 2,6-dimethylmorpholine, pyrazole, 3,5-dimethylpyrazole and imidazole.

Toluene is used as the solvent for the reductive alkylation Palladium on carbon catalyst. The hydrogenation is at 50 to 60 "C and a hydrogen pressure from 50 to 60 bar completed after 6 to 8 hours.

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

The compounds of the general formula (I) according to the invention and Their salts are also suitable due to their microbistatic and microbicidal effect as a preservative for technical products in the non-medical and non-therapeutic areas Area. They are used in the preservation of glue bases and adhesives as well as cooling lubricants. They can also be used for cosmetics, e.g. Effectively preserve creams, bl-in-water and water-in-oil emulsions.

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

For use in antimicrobial agents, the inventive Compounds in a known manner in liquid, pasty or solid preparations, which are present as solutions, suspensions or emulsions, are incorporated.

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

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 l-substituted 3-butanones (IV) were obtained by addition of the heterocyclic secondary amines or

Azoles R2 H on the activated double bond of methyl vinyl ketone (III) represented by well-known methods. The yields of (IV) were in the range from 63 to 96%.

The reaction components were in equimolar amounts in a solvent, preferably ether or toluene, reacted at 0 to 1000C. For the implementation of the pyrazoles with methyl vinyl ketone it was not necessary to use a solvent.

b) Synthesis of the compounds of general formula (I) and their Salts from the intermediate stages (IV).

A solution of 0.13 mol of the ketones shown in section a) (IV) and 0.11 to 0.13 mol of a long-chain primary amine R NH2 (V) in 250 to 300 ml of toluene were in an autoclave over palladium on charcoal as a catalyst Hydrogenated 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. By extraction with ether were non-basic products separated and discarded. The acidic solution was then with Sodium hydroxide solution made alkaline and the released basic product several times with Ether extracted. After washing the combined organic phases with water, drying The compounds of the were obtained via sodium sulfate and distilling off the ether general formula (I) in the form of colorless to yellow oils. As far as necessary (thin-layer chromatographic Control), small residual amounts of the amines (V) that were still present were removed by steam distillation severed.

The salts of the compounds of the general formula (I) were obtained by reaction of the basic N- -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 one Acid. This is how the hydrochlorides of the compounds of the general formula (I) were formed after passing dried hydrogen chloride gas into the ethereal solutions of (I) as colorless solids. The water-soluble acetates of the compounds of the general formula (I) resulted from reaction with equivalent amounts of glacial acetic acid in ether or ethyl acetate.

The physical properties of N- [3-morpholinyl- (4) -1-methylpropyl] - and N- [3-Azolyl- (4) -1-methylpronyl-N-alkylamines of Examples 1 to 29 are the Tables 1 to 3 can be found.

Table 1: Physical data of the compounds of the general formula (I) with 20th Example R1 R3 n20 mp (° C) yield D (%) 1 C8H17 H 1.4626 81 2 C1OH21 H 1.4610 79 3 C12H25 H 1.4638 81 4 C12H25 CH3 1.4602 54 5 C14H29 H 1.4650 88 6 C14H29 CH3 1.4587 46 7 C14H29 H 37-41 96 (Acetate) 8 coconut alkyl H 1.4631 74 9 C12H25-o- (CH2) 3 H 1.4633 83 10 C12 / 14H25 / 29-NH H 1.4697 91 (CH2) 3 Table 2: Physical data of the compounds of the general formula (I) with Example R1 R4 n20 MP Yield D (° C) (%) 11 C8H17 H 69-72 76 (dihydrochloride) 12 C10H21 H 1.4615 82 13 CloH2l H 102-3 69 (dihydrochloride) 14 C12H25 H 1.4718 90 15 C12H25 H 92-4 59 (dihydrochloride) 16 C12H25 H 40 100 (acetate) 17 C12H25 CH3 1.4732 77 18 C12H25 CH3 1.4767 100 (acetate) 19 C14H29 H 1.4716 73 20 C14H29 CH3 1.4714 69 21 C14H29 H 132-4 66 (dihydrochloride) 22 coconut alkyl H 1.4620 58 23 coconut alkyl H 119-22 52 (dihydrochloride) 24 C12H25O (CH2) 3 H 1.4654 65 Table 3: Physical data of the compounds of the general formula ( I) with Example R1 n20 Fp (OC) yield (%) D. 25 C12H25 1.4734 86 26 C12H25 solid 86 (Dihydrochloride) 27 C14H29 oil 21 28 C12H250 (CH2) 3 45-55 41 29 C12 / 14H25 / 29H 1.4950 20 (CH2) 3 2. Antimicrobial activity of the compounds of the general formula (I).

a) Microbistatic effectiveness.

The microbistatic activity of the compounds of Examples 1 up to 29 was determined against the following test germ suspensions: 1. Staphylococcus aureus 2 x 109 germs / ml 2. Escherichia coli 2 x 109 germs / ml 3. Candida albicans 2 x 108 germs / ml 4. Aspergillus niger 2 x 107 germs / ml 5. Penicillium camerunense 5 x 107 germs / ml. The concentrations of the compounds to be investigated were with the help of the dilution test according to the guidelines for testing chemical disinfection middle der Deutschen Geseflschãft ~ fur Hygiene und Mikrobiologie (1972). The trials were carried out in sterile test tubes, the standard I broth (pH 7.5 Merck) or wort broth (pH 5.5, Merck). After adding the active ingredients was the volume of nutrient solution in each tube is 5 ml.

Subsequently, 0.1 ml of the test microbial suspension of the specified Concentration brought into the tubes. The nutrient solution samples inoculated with bacteria were kept in an incubator at 370C for 3 days. Those inoculated with mushrooms Samples were incubated at 30 ° C. for 4 days. Then it was determined which dem The concentration of active substance supplied to the nutrient medium just barely prevents the germs from growing had inhibited.

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: Table 4: Microbistatic activity of the compounds of the general formula (I): minimum inhibitory concentration (ppm) [x #> 1000 ppm] Conn. R1 R2 test germ the end Example 1 2 3 4 5 1 C8H17 7 oC- 50 500 500 1000 1000 2 C10 H21 N- 100 100 500 500 250 3 C12H25 O- 10 100 250 250 250 4 C12H25 cm 50 50 100 100 100 5 C14H29 o - 410 50 50 100 50 6 C14H29 O v - = 10 50 50 50 50 7 C14H29 O 9-10 50 50 100 50 (Acetate) 8 coconut alkyl O J- A10 250 100 250 100 9 C12H25O (CH2) 3 9 c 9 - A10 x 50 100 100 12 / 14H25 / 29lHO 9 - = 10 = 10 100 250 100 (cit2) 3 Continuation of table 4 Conn. R1 R2 test germ the end Example 1 2 3 4 5 11 17 t - 100 500 xxx (Dihydrochloride) - 12 CloH21 t ~ 50 1000 xxx 13 CloH21 gt 50 100 500 xx (Dihydrochloride) 2 14 C12H25 t * 10 50 50 100 50 15 C12H25 t ~ 10 50 50 100 50 (Dihydrochloride) 16 C12H25 g # = 10 50 100 100 100 (Acetate) 17 C12H25 83C ty ~ 410 50 50 100 50 18 C12H25 £ N 410 50 50 100 50 (Acetate) 19 C14H29 eH3 410 x 50 50 50 20 C14H29 CH3 to '-10 100 '10 0 100 50 21 C14H29 910 100 50 50 50 (Dihydrochloride) al- 22 coconut alkyl t S ~ * 10 x 50 100 50 Continuation of table 4 Conn. R1 R2 test germ the end Example 1 2 3 4 5 23 coconut alkyl t ~ 10 100 100 100 100 (Dihydrochloride) 24 Cl2H25o (CH2) 3 t 50 50 50 50 25 C12H25 = 10 50 100 100 250 26 C12H25 §10 50 250 500 250 (Dihydrochloride) U 27 C14H29 t 10 '10 50 250 50 28 C12H25o (CH2) 3 W 90 L'10 50 100 50 12/14 25/29 10 250 250 500 25.29yH N10 (CH2) 3 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 effect.

The microbicidal effect of the compounds of Examples 1 to 29 was determined against the following test germ suspensions: 9 1. Staphylococcus aureus 2 x 10 germs / ml 2. Escherichia coli 2 x 109 germs / ml 3. Pseudomonas aeruginosa 5 x 108 germs / ml 4. Candida albicans 2 x 108 germs / ml 5. Aspergillus niger 2 x 107 germs / ml 6. Penicillium camerunense 2 x 107 germs / ml The killing times of the examined Products were tested using the suspension test according to the guidelines for testing chemical disinfectant of the German Society for Hygiene and Microbiology (1972) determined. The substances to be tested were first dissolved in a little alcohol. The ethanolic solutions were diluted with hard water to obtain a hardness of 170 dH test solutions produced that contain 3000 ppm and 500 ppm active ingredient and a maximum Contained 1% by weight of ethanol. There were 0.1 ml of the test germ suspension at room temperature pipetted into test tubes. For this purpose, 10 ml of each of the above-described Test solution given. After different exposure times up to 120 minutes At room temperature, the test tubes were given a drop with the help of a pipette Material removed and placed in 10 ml nutrient solution containing 3% Tween 80 and 0.3% lecithin contained as a disinhibitor, inoculated. The nutrient medium consisted of 2.5% strength by weight standard I broth (Merck) and from 3.3% by weight wort bouillon (Merck) for mushrooms. The samples were incubated at 37 or 30 ° C. After 3 to 5 days at the earliest, the cultures became macroscopic assessed for growth and determined in this way the killing times, which in Table 5 below.

Table 5: Microbicidal activity of the compounds of the general formula I: Killing times (min) [x #> 120 min] Comb. From killing conc. Test germs example (ppm) 1 2 3 4 5 6 1 3000 # 15 # 15 # 15 # 15 # 15 x 500 # 15 60 # 15 # 15 120 x 2 3000 # 15 # 15 # 15 # 15 # 15 60 500 # 15 # 15 # 15 # 15 # 15 x 3 3000 # 15 # 15 60 # 15 # 15 # 15 500 # 15 # 15 x # 15 # 15 60 4 3000 # 15 # 15 120 # 15 xx 500 60 # 15 120 60 5 3000 # 15 60 x # 15 # 15 60 500 # 15 120 # 15 # 15 60 6 3000 # 15 # 15 # 15 # 15 60 60 500 # 15 # 15 # 15 # 15 120 x 8 3000 # 15 # 15 x # 15 # 15 120 500 # 15 # 15 # 15 # 15 120 9 3000 # 15 120 x # 15 60 120 500 # 15 £ 5 120 120 10 3000 # 15 # 15 # 15 # 15 120 # 15 500 # 15 60 C15 f15 120 x Continuation of Table 5: Combination from killing conc. Test germs example (ppm) 1 2 3 4 5 6 14 3000 # 15 # 15 x # 15 60 120 500 # 15 # 15 x # 15 60 x 15 3000 60 15 # 15 60 x 120 500 x # 15 # 15 60 17 3000 # 15 # 15 # 15 # 15 120 x 500 # 15 # 15 60 # 15 120 18 3000 # 15 # 15 # 15 # 15 # 15 # 15 500 # 15 # 15 # 15 # 60 # 60 # 60 19 3000 # 15 120 120 # 15 60 # 15 500 60 xx # 15 120 60 20 3000 # 15 '15 # 15 -15 60 120 500 60 # 15 x # 15 120 x 22 3000 # 15 # 15 x # 15 60 x 500 # 15 # 15 x # 15 60 x 24 3000 # 15 # 15 # 15 # 15 # 15 120 500 # 15 # 15 # 15 # 15 60 120 25 3000 # 15 # 15 # 15 # 15 # 15 x 500 # 15 # 15 # 15 # 15 # 15 x 26 3000 x # 15 # 15 # 15 xx 500 # 15 # 15 x 27 3000 # 15 # 15 60 # 15 60 60 500 # 15 60 120 # 15 120 120 28 3000 # 15 # 15 # 15 # 15 # 15 60 500 # 15 # 15 # 15 # 15 # 15 60 29 3000 # 15 # 15 # 15 # 15 x 60 500 # 15 # 15 # 15 # 15 x Result: In the suspension test, even at active ingredient concentrations of 500 ppm, the reaction was carried out numerous derivatives achieved a good to very good microbicidal effect.

c) Microbicidal effect im fection test.

The application solutions with an active substance content of 2000 ppm were from 10% gen aqueous stock solutions of the compounds according to the invention of Formula (I), which contains 10% surfactant (nonylphenol + 9.5 mol Ethylene oxide) by diluting 1:50 with water of 170dH obtain. These solutions were applied to test areas made of wood and PVC, each measuring 6 x 6 cm brought into action at 20 "C against the following test germs: 1. Staphylococcus aureus 2 x 109 germs / ml 2. Candida albicans 2 x 108 germs / ml For this purpose Evenly spread the test areas with 0.1 ml of the relevant bacterial or yeast suspension filled with a spatula and dried for approx. 30 minutes at room temperature. After that were the application solutions are applied to the test areas with the help of cotton swabs, that they were evenly wetted. After exposure times of 1, 2, 4 and 6 hours a quadrant was then rubbed off from each test area with a sterile cotton swab. The swabs were placed on sterile plates made of casein / soy agar, which was used for neutralization 3% Tween 80, 0.3% lecithin and 0.1% histidine of any active ingredient that may have been transferred contained, streaked out to determine the number of surviving germs. the Agar plates were stored for 48 hours at 37 ° C for Staphylococcus aureus and for Candida albicans incubated at 30 ° C for 72 hours.

The numbers in Table 6 indicate the exposure times after which no viable germs were detectable on the culture media.

+ - signs roughly quantitatively indicate the test germ content after an exposure time from 6 hours.

Table 6: Microbicidal activity of the compounds of the general formula (I) in the surface disinfection test: germ reduction to 0 to 9 germs / surface connection off Application test germs Example concentration 1 2 (ppm) Wood PVC Wood PVC 7 2000 6 6 1 1 15 2000 ++ a) + a) 4 4 16 2000 6 6 1 1 18 2000 + a) + a) 2 2 21 2000 + a) + a) 4 23 2000 ++ a) + a) 4 4 26 2000 6 4 4 4 Notes:) + + L50 residual germs / area ++ e 50-200 residual germs / area after 6 hours of exposure.

Result: The compounds of Examples 7 (I, R1 = C14H29, R2 = morpholinyl, Acetic acid salt), 16 (I, R1; C12H25, R2 = imidazolyl, acetic acid salt) and 26 (I, R1 = C12H25, R2 = pyrazolyl, dihydrochloride) meet in the surface disinfection test the DGHM standard for both test germs. The optimum effect of the compounds becomes apparent of the general formula (I) achieved with an alkyl chain length of 12 to 14 carbon atoms.

3. Toxicological studies.

The compounds of Examples 7 and 16 were toxicological Subject to basic test. The following results were obtained: a) N-13-morpholinyl- (4) -? - methylpropyL1-N-tetradecylamine, Acetic acid salt (Example 7) Acute toxicity (mouse, oral): LD50 at 625 mg / kg 3125 mg / kg absolutely fatal, strong nerve symptoms Skin tolerance (hairless mouse): 1- to 25% without findings.

Ames test: No evidence of mutagenicity.

b) N- [3-pyrazolyl- (1) -1 -methylpropyg -N-dodecylamine, acetic acid salt (Example 16): Acute toxicity (mouse, oral): LD50 mg / kg.

At 625 and 3125 mg / kg: death after 5 to 10 minutes.

Skin tolerance (hairless mouse): 1 to 25%: no findings.

Claims (11)

Patent claims: 1. N- [3-morpholinyl- (4) -1-methylpropyl] - and N-L3-azolyl (4) -1 methylpropyl-N-alkyiamine of the general formula (I) in which R1 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 R2 for optionally alkyl-substituted 5- or 6-membered cyclic, a nitrogen atom and optionally further hydrocarbon radicals containing heteroatoms, as well as their salts with organic and inorganic acids. 2. Compounds of general formula (1) according to claim 1, in which the heterocyclic hydrocarbon radical for which R² stands, 4-morpholinyl, 2,6-dimethyl-4-morpholinyl, is l-pyrazolyl, 3,5-dimethyl-l-pyrazolyl or l-imidazolyl. 3. Compounds of general formula (I) according to claim 1, wherein acetic acid or hydrochloric acid are preferably used for salt formation. 4. Process for the preparation of compounds of the general formula (I) according to claim 1, characterized in that one according to generally known methods optionally alkyl-substituted 5- or 6-membered cyclic, one nitrogen atom and optionally further hydrocarbons of the formula containing Ileteroatoms R2 H, in which R2 has the meaning given in claim 1, with methyl vinyl ketone implements and the resulting substituted ethyl methyl ketone elevated temperature in solution in the presence of molecular hydrogen and a catalyst with a long-chain amine of the formula R1NH2, in which R1 is specified in claim 1 Has meaning, implements. 5. The method according to claim 4, characterized in that as heterocyclic hydrocarbons R2H morpholine, 2,6-dimethylmorpholine, pyrazole, 3, 5-dimethylpyrazole or imidazole is used. 6. The method according to claims 4 and 5, characterized in that the hydrogenation is carried out in toluene as the solvent. 7. Process according to Claims 4 to 6, characterized in that palladium on charcoal 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 the long-chain amines R1NH2 used are preferably 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.