DE4005178A1 - New alkylamino-1-N-alkyl-pyridinium salts - are antimicrobial agents useful against bacteria, yeasts and fungi, e.g. Candida albicans - Google Patents

Abstract

Pyridinium salts of formula (R1-NH-(Py+)-R2)X- (I), are new, where R1 = 2-22C alkyl. R2 = 3-18C alkyl or 7-10C aralkyl. X = Cl or Br. Py(+) = a pyridinium gp covalently N-bonded to R2. USE/ADVANTAGE - (I) are antimicrobial agents useful against a wide range of bacteria, yeasts and fungi. They have in vitro activity against Candida albicans. They may be used as disinfectants, eg for treating wounds or surfaces, as preservatives eg in paints or oils, or in protection of materials, eg wood. The concentration of various (I) which inhibited growth of certain bacteria in suspensions of the bacteria were measured. ((I): R1 = butyl; R2 = octyl; X = Br) inhibited growth of S aureus (suspension contg x 10 power 9 cells/ml) when present in amts of 50 ppm, and E coli (as above) when present in amts of 100 ppm.

Description

The invention relates to alkylamino-1-N-alkylpyridinium salts, a Process for their preparation and their use for manufacture treatment of antimicrobial agents.

From J. Chem. Soc. Perkin. Trans I, 4, 454 (1976) are 4-methylamino and 4-dodecylamino-1-N-methylpyridinium iodides known by nucleophilic substitution of 4-Cyanopyridiniumsalzen won become. This reference contains no reference to a antimicrobial efficacy of these pyridinium salts.

Chem. Res., Synop., 7, 224 (1989) discloses 4-dibutylamino-1-i-pen tylpyridiniumchloride and their use as phase transfer described catalysts. Also this quote contains no hin indicates antimicrobial efficacy of these pyridinium salts.

Pyridinium salts of the bis [4- (substituted amino) 1-pyri type dinium] alkanes and their use for inhibiting plaquebil on artificial teeth are known from US Pat. No. 4,206,215 known. In Zbl. Hyg., 188, 188 (1989) and Caries Res., 19, 458 (1985) refers to the antimicrobial properties of such bispyr Ridiniumsalze noted. The publications in Antimicrob. Ag. Chemotherap., 786 (1985) and Hyg. Med., 14, 372 (1989), the germicidal properties of such preparations are unfavorable is bound to the presence of two cationic centers.  

Bispyridinium salts of this type, however, show the crucial Disadvantage that for their production a high preparative effort is required.

The object of the invention was therefore, antimicrobially effective To develop pyridinium salts that are easily accessible.

The invention relates to alkylamino-1-N-alkylpyridinium salts of the formula (I),

[R¹-NH- (py⁺) -R²] X ^- (I)

in the R¹ for a linear or branched alkyl radical mi 2 bis 22 carbon atoms, R² for a linear or branched Alkyl radical having 3 to 18 carbon atoms or an aralkyl radical with 7 to 10 carbon atoms, X is chlorine or bromine and py⁺ for is a pyridinium group whose nitrogen atom is covalent with R² connected is.

Surprisingly, it has been found that in particular 4-alkylamines no-1-N-alkylpyridinium chlorides and bromides are readily available and have good antimicrobial properties, although over have only one cation active center.

In formula (I), R¹ is a linear or branched alkyl radical 2 to 22 carbon atoms, such. Ethyl, n-propyl, i-propyl, n-butyl, sec. Butyl, i-butyl, tert. Butyl, n-pentyl, i-pentyl, n-hexyl, i-hexyl, n-octyl, 2-ethylhexyl, decyl, lauryl, Myristyl, cetyl, stearyl or behenyl residues. Preferably stands R¹ represents linear alkyl radicals having 3 to 18, in particular 8 to 12 Carbon atoms.  

In formula (I), R² is a linear or branched alkyl radical 3 to 18 carbon atoms or aralkyl radicals having 7 to 10 carbon atoms atoms, such. N-propyl, i-propyl, n-butyl, n-pentyl, i-pentyl, n-hexyl, i-hexyl, benzyl, n-octyl, 2-ethylhexyl, Decyl, lauryl, myristyl, cetyl or stearyl radicals. Preferably R² represents linear alkyl radicals having 4 to 12 carbon atoms or a benzyl radical.

In formula (I), (py⁺) represents a pyridinium group whose stick is covalently linked to R². The pyridinium group can in this case be substituted by further alkyl radicals or as part a fused aromatic ring system.

In formula (I), the group R¹-NH- in the 2- or 4-position on the Pyridine ring are located. As 4-alkylamino-1-N-alkyl-pyridinium salts However, produce with less preparative effort and in hö harder yields than the positionally isomeric 2- Pyridinium salts, this group of compounds is preferred.

The invention further relates to a process for the preparation of alkylamino-1-N-alkylpyridinium salts of the formula (I)

[R¹-NH- (py⁺) -R²] X ^- (I)

in the R¹ for a linear or branched alkyl radical having 2 to 22 carbon atoms, R² for a linear or branched Alkyl radical having 3 to 18 carbon atoms or an alkyl radical with 7 to 10 carbon atoms, X is chlorine or bromine and py⁺ for a pyridinium group whose nitrogen is covalent with R² is connected by reaction of Alkylaminopyridinen of the formula (II)

R¹-NH- (py) (II)

in which py is a pyridine radical and R¹ is the abovementioned Meaning, with alkylating agents of the formula (III),

R²X (III)

in which R² and X have the meanings given above.

Alkylaminopyridines are known substances and can be used according to conventional methods of organic chemistry are synthesized. In In a particularly advantageous manner can Alkylaminopyridine z. B. by reductive alkylation of aminopyridines with alipha tables aldehydes in the presence of hydrogenation catalysts such. B. Raney nickel or palladium on charcoal [J. Med. Chem., 27, 1462 (1984)]. Here, the condensation of Amino groups and aldehyde function to form a Schiff's Base instead, which in the second step to the Alkylaminoverbindung hy is drilled.

Typical examples of aminopyridines NH₂- (py), wherein (py) for egg NEN optionally substituted pyridine ring are 2-amino pyridine, 4-aminoquinoline or 4-aminoquinaldine. Preferably, the Use of 4-aminopyridine.

The choice of aldehydes depends preferably on their techni availability. Here come z. Acetaldehyde, propionalde hyd, butyraldehyde, capric aldehyde, 2-ethylhexyl aldehyde, cetyl aldehyde hyd or stearyl aldehyde into consideration. Preference is given to the use of Caprylaldehyde, capric aldehyde or lauryl aldehyde.  

Alkylaminopyridines, which are used as starting materials for the preparation of serve pyridinium salts according to the invention, thus follow the formula (II)

R¹-NH- (py) (II)

in the py for a pyridine radical and R¹ for a linear or branched alkyl radical having 2 to 22, especially 8 to 12 carbon atoms atoms. Preferably, the group is R¹-NH-in 4-position on the pyridine ring.

For the preparation of the pyridinium salts according to the invention is the Nitrogen atom of pyridinium group of Alkylaminopyridins quater ned. A suitable general rule for quaternization of Pyridine compounds are contained in J. Org. Chem., 26, 2740 (1961) th.

The alkylating agents follow the formula (III),

R²X (III)

in the R² for a linear or branched alkyl radical with 3 bis 18 carbon atoms or an aralkyl radical having 7 to 10 carbon atoms atoms and X is chlorine or bromine.

Typical examples are butyl chloride, butyl bromide, benzyl bromide, Octyl chloride, octyl bromide, decyl chloride, decyl bromide, dodecyl chloride chloride or dodecyl bromide. Due to their technical availability is the use of alkyl chlorides of 4 to 12 carbon atoms men and in particular of benzyl chloride is particularly preferred.  

The alkylation is carried out at temperatures of 20 to 100 ° C leads. To achieve sufficient sales, it makes sense Do not carry out the reaction below 75 ° C. To the pro did not cause excessive thermal stress and the formation of To avoid olefins from the alkylating agent is largely it further favorable, the reaction temperature up to 85 ° C. limit. Under these conditions, reaction times of 4 reached until 24 h; at lower temperatures become natural for equal yields longer times of 24 to 36 h needed.

The molar use ratio of alkylaminopyridine and alkyl is 1: 1.0 to 1: 1.3. An excess of alky lierungsmittel is useful in cases where the reaction runs at unsatisfactory speed, such. B. when used of 2-alkylaminopyridines. Otherwise, it is recommended from Wirt For economic reasons, the reactants in equimolar Ver the distance, especially in these circumstances Excess alkylating agent deleted.

The reaction is preferably in such polar with stirring Solvents that have a boiling point of 75 to 85 ° C as they allow the reactants within the To keep the preferred temperature range under reflux. typical Examples of these are acetonitrile or ethanol. However, it is it is also possible to carry out the alkylation without solvent to lead. Due to the high viscosity of the products, the stirring however, this embodiment of the invention is less complicated prefers.

After completion of the alkylation, the reaction mixture is allowed cool and remove the solvent and optionally  excess alkylating agent in vacuo. The raw implementation product is subsequently mixed with ether, filtered off with suction and in vacuo dried under vacuum. The alkylamino-1-N-pyridinium salts fall as hygroscopic, colorless to pale yellow solids.

Alkylamino-1-N-alkylpyridinium salts have microbistatic and microbicidal properties against a variety of bacteria, Yeasts and mushrooms, such. B. Escheria coli, Staphylococcus aureus, Candida albicans, Aspergillus niger or Penicillium camerunense. A particularly high activity is observed compared to Pseudomo nas aeruginosa.

The alkylamino-1-N-alkylpyridinium salts of the invention are suitable Therefore, for the production of antimicrobial agents such. B. Products for wound and mucous membrane disinfection as well as products for surface disinfection in hospitals, schools, bathing establishments, public transport, commercial or agricultural farms, dairies, breweries and other establishments the food and beverage industry. Furthermore, the are suitable Pyridinium salts according to the invention for the preservation of technical Products such as dye dispersions, adhesives, drilling and cutting oils, for paper, paperboard or leather processing products Industry as well as industrial and service water. Finally, Kings They are also used for material protection, for example for impregnating wood.

In the simplest case, the alkylamino-1-N-alkylpyridinium salts They are used as dilute aqueous solutions, they can ever but also in liquid, pasty or solid preparations incorporated in addition to the described active ingredients in usually contain other commonly used ingredients  can. For liquid preparations come as a solvent in addition Water, alcohols and glycol ethers into consideration. If in addition to the anti microbial effect an additional cleaning effect desired is, the agents selected anionic, nonionic or contain amphoteric surfactants. Typical examples of this are Fatty alcohol ether sulfates, sulfosuccinates, fatty alcohol polyglycol ether and the like. Furthermore, builders such. B. Polyphosphates, zeolites, nitrilotriacetic acid, polycarboxylates or Citrate be used. Contain the antimicrobial Medium organic solvents, the addition may further solution mediating substances, such. As glycol ethers, may be required.

The content of alkylamino-1-N-alkylpyridinium salts in the appl ready-to-use antimicrobial agents is 0.01 to 5% by weight (relative to the total mean). For the production use finished compositions can Herge concentrates or solid mixtures which are the pyridinium salts of the invention up to 50 wt .-% included.

The following examples are intended to illustrate the subject matter of the invention explain.

Examples A. Starting substances General procedure for the preparation of 4-alkylaminopyridines

0.3 mol of 4-aminopyridine (Aldrich) and 0.9 mol of an aliphati aldehyde were dissolved in 400 ml of ethanol, with 7 g 10 wt .-% Palladium on charcoal and at T = 70 to 90 ° C and p = 2 to 3.5 bar t = 8 to 18 h hydrogenated. Subsequently, the Ka filtered off, the filtrate at 90-100 ° C and 0.25-2.5 kPa and worked up according to a), b) or c):

• a) The evaporation residue was heated with petroleum ether, to 0 ° C. cooled, filtered off and recrystallized from toluene.
• b) The evaporation residue was cooled with two 200 ml portions of 200 ml (0 ° C) hexane stirred, filtered with suction, again with cold hexane washed and dried at 40 ° C in a vacuum oven.
• c) The evaporation residue was placed in a distillation apparatus converted and formed in the reductive alkylation Fatty alcohol distilled off in vacuo at 0.05 kPa. The Frak tion distilling at 150-155 ° C / 0.05 kPa was ge collected, stirred with petroleum ether in the heat, to 0 ° C ge cooled, filtered off with suction and then dried at 40 ° C in a vacuum cupboard dried.

General procedure for the preparation of 2-alkylaminopyridines

0.3 mol of 2-aminopyridine (Aldrich) and 0.9 mol of an aliphati aldehyde were dissolved in 400 ml of ethanol, with 7 g 10 wt .-% Palladium on charcoal and at T = 70 to 90 ° C and p = 2 to 3.5 bar t = 8 to 18 h hydrogenated. Subsequently, the Ka filtered off, the filtrate at 90-100 ° C and 0.25 to 2.5 kPa and worked up according to a), b) or c):

• a) The evaporation residue was placed in a distillation apparatus converted and the resulting in the reductive alkylation Fatty alcohol distilled off in vacuo at 0.05 kPa. The Frak tion distilling at 112-170 ° C / 0.01 kPa collected, stirred with petroleum ether in the heat, to 0 ° C from cooled, filtered off with suction and then at 40 ° C in Vakuumtroc cupboard dried.
• b) The evaporation residue was placed in a distillation apparatus transferred and the resulting fatty alcohol in vacuo at 0.05 distilled off kPa. The fraction at 115-174 ° C / 0.01 kPa distilled over, was collected, umkri from petroleum ether stalled and then at 40 ° in a vacuum oven dried.
• c) The evaporation residue was placed in a distillation apparatus transferred and the resulting fatty alcohol in vacuo at 0.05 distilled off kPa. The fraction which is at 140-174 ° C / 0.05 kPa distilled over, was collected, from petroleum ether to crystallized and then dried at 40 ° C in a vacuum cupboard dried.

B. Invention examples example 1.1-2.15 General procedure for the preparation of 4-alkylamino-1-N-alkyl pyridinium salts

In a 250 or 500 ml three-necked flask with Stirrer, reflux condenser and internal thermometer were added 0.05 moles of 4- Alkylaminopyridine presented in 100 to 200 ml of acetonitrile, with 0.05 mol of alkyl or Aralkylhalogenid added and then t = 12 to 24 h at T = 80 to 85 ° C stirred. After cooling it was the solvent distilled off in vacuo, the solid, hygrosko washed residue with 50 ml of ether and ge in vacuo dries. The characteristics of the examples are given in Tab.

Examples 2.1-2.3 General procedure for the preparation of 2-alkylamino-1-N-alkyl pyridinium salts

In a 250 ml three-necked flask with stirrer, Reflux and internal thermometers were 0.015 mol of 2-alkylamino pyridine in 25 to 50 ml of acetonitrile, with 0.0165 mol Alkyl or aralkyl halide added and then t = 12 to Stirred at T = 80 to 85 ° C for 24 h. After cooling, the Lö distilled off in vacuo, the solid, hygroscopic Washed residue with 50 ml of ether and dried in vacuo. The Characteristics of the examples are contained in Tab. 2.  

Tab. 1

4-Alkylamino-1-N-alkylpyridinium salts [R¹-NH- (Py⁺) -R²] X ^-

Tab. 2

2-Alkylamino-1-N-alkylpyridinium salts [R¹-NH- (Py⁺) -R²] X ^-

C. Antimicrobial activity Microbistatic Activity (Liquid Inhibitor Series)

The mikrobi static activity of the 4-aminoalkyl-1-alkyl pyridinium salts of Ex. 1.1-1.15 were compared to the following Test germ suspension determines:

1. Staphylococcus aureus 2 × 10⁹ germs / ml 2. Escheria colie 2 × 10⁹ germs / ml 3. Pseudomonas aeruginosa 5 × 10⁸ germs / ml 4. Candida albicans 2 × 10⁸ germs / ml 5. Aspergillus niger 5 × 10⁷ germs / ml 6. Penicillium cameroon 5 × 10⁷ germs / ml

The inhibitory concentrations of the compounds to be investigated were using the dilution test according to the guidelines for the test chemical disinfectants of the Deutsche Gesellschaft für Hygiene and Microbiology (1981). The experiments were in sterile test tubes, for germs 1 to 3 Casein-Soy Bouillion (pH 7.5 from Merck) and for germs 4 to 6 Wort bouillon (pH 5.5 Fa. Merck) contained. After the addition of the Active ingredients was the nutrient solution volume in the tubes, respectively 5 ml. Subsequently, in each case 0.1 ml of the test microbial suspension of given concentration in the tubes. The ones with Bak Inoculations were incubated for 3 days at 37 ° C in the brood kept. The mushrooms inoculated samples were 4 days incubated at 30 ° C for a long time. Then it was determined which the Nutrient medium supplied drug concentration growth of the Germs had just barely inhibited. The found in this way Value was called inhibitory concentration. Following active ingredient Concentrations in ppm were tested: 1000, 500, 250, 100, 50  and 10. The inhibitory concentrations for the substances according to example 1.1 to 1.15 are summarized in Tab.

Tab. 3

Inhibitory Concentrations 4-Alkylamino-1-N-alkylpyridinium salts

In ppm

Microbicidal activity (suspension test)

The microbicidal action The activity of the 4-alkyl-amino-1-N-alkylpyridinium salts was compared following test microbial suspensions:

1. Staphylococcus aureus 2 × 10⁹ germs / ml 2. Escheria colie 2 × 10⁹ germs / ml 3. Pseudomonas aeruginosa 5 × 10⁸ germs / ml 4. Candida albicans 2 × 10⁸ germs / ml 5. Aspergillus niger 5 × 10⁷ germs / ml Penicillium cameroon 5 × 10⁷ germs / ml

The killing times of the products to be examined were with help of the suspension test. Using water one Hardness of 16 ° d, test solutions were prepared containing 2000 and 500 ppm, respectively Active ingredient contained. At room temperature, 0.1 ml Test germ suspension in test tubes pipetted and each with 10 ml mixed with the test solution described above. After difference exposure times of up to 60 min were added to the test tubes 0.1 ml of material and in 10 ml of nutrient solution, which is called Enthem 3 wt .-% Tween 80 and 0.3 wt .-% lecithin contained, pipet advantage. The nutrient solution consisted of germs 1 to 3 from 3.0 % casein soy broth (Merck) and for germs 4 to 6 from wort broth (pH = 5.5 Fa. Merck). The samples were at 37 ° or 30 ° C incubated. After 2 to 3 days, the cultures became macro scopically assessed for growth and in this way the killing time determined. The killing levels for the substances according to Example 1.1 to 1.15 are summarized in Tab. 4.  

Tab. 4

killing concentration

4-alkylamino-1-N-alkyl pyridinium salts

Specification of exposure time in min

Claims (18)

1. Alkylamino-1-N-alkylpyridinium salts of the formula (I), [R¹-NH- (py⁺) -R²] X ^- (I) in the R¹ for a linear or branched alkyl radical having 2 to 22 carbon atoms, R² for a linear or branched alkyl radical having 3 to 18 carbon atoms or an aralkyl radical having 7 to 10 carbon atoms, X is chlorine or bromine and py⁺ is a pyridinium group whose nitrogen atom is covalently bonded to R². 2. pyridinium salts according to claim 1, characterized in that the group R¹-NH- is in the 4-position on the pyridine ring. 3. pyridinium salts according to claim 1, characterized in that the group R¹-NH- is in the 2-position on the pyridine ring. 4. pyridinium salts according to claims 1 to 3, characterized characterized in that R¹ is a linear alkyl radical having 6 to 18 Carbon atoms. 5. pyridinium salts according to claims 1 to 4, characterized gekenn characterized in that R² is a linear alkyl radical having 4 to 12 Carbon atoms. 6. pyridinium salts according to claims 1 to 5, characterized gekenn characterized in that R² is a benzyl radical.   7. A process for the preparation of alkylamino-1-N-alkylpyridinium salts of the formula (I), [R¹-NH- (py⁺) -R²] X ^- (I) in the R¹ for a linear or branched alkyl radical having 2 to 22 Carbon atoms, R² is a linear or branched th alkyl radical having 3 to 18 carbon atoms or an aralkyl radical having 7 to 10 carbon atoms, X is chlorine or bromine and py⁺ is a pyridinium whose nitrogen is ko valent connected with R², by reacting Alkylamino pyridines of the formula (II), R¹-NH- (py) (II) in which py is a pyridine radical and R¹ has the abovementioned meaning, with alkylating agents of the formula (III), R²X (III) in the R² and X have the meanings given above. 8. A process for the preparation of pyridinium salts according to claim 7, characterized in that the group R¹-NH- in 4- Position is located on the pyridine ring. 9. A process for the preparation of pyridinium salts according to claim 7, characterized in that the group R¹-NH- in 2- Position is located on the pyridine ring.   10. A process for the preparation of pyridinium salts according to the An Proverbs 7 to 9, characterized in that R¹ for a linear alkyl radical having 6 to 18 hydrocarbon atoms. 11. A process for the preparation of pyridinium salts according to the An Proverbs 7 to 10, characterized in that R² for a linear alkyl radical having 4 to 12 carbon atoms. 12. A process for the preparation of pyridinium salts according to the An Proverbs 7 to 11, characterized in that R² for a Benzylrest stands. 13. A process for the preparation of pyridinium salts according to the An Claims 7 to 12, characterized in that the alkylation is carried out at 20 to 100 ° C. 14. A process for the preparation of pyridinium salts according to the An Proverbs 7 to 13, characterized in that the molar Use ratio between alkylaminopyridine and alkylation average 1: 1.0 to 1: 1.3. 15. Use of the pyridinium salts according to claims 1 to 6 as antimicrobial agents. 16. Use of the method according to claims 7 to 14 obtained pyridinium salts as antimicrobial agents. 17. Use of the pyridinium salts according to claims 1 to 6 for Production of antimicrobial agent.   18. Use of the method according to claims 7 to 14 obtained pyridinium salts for the preparation antimicrobial effective means.