Antimicrobial compound, process for preparation thereof and use of the antimicrobial compound for production of a cosmetic or pharmaceutical composition

Abstract

The present invention provides an antimicrobial compound having formula (I) where R1 is an alkyl radical having 4 to 18 carbon atoms or a cycloalkyl radical having 5 to 12 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and R2 is an alkyl group having 2 or 3 or 4 carbon atoms, and R3 is hydrogen or an alkyl radical having 1 to 8 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or is a benzyl radical, and n is an integer from 1 to 15, and [(2+n) A-] represents a number of anions which provide a total of (2 + n) negative charges. The present invention further discloses a process for preparing the antimicrobial compound, use thereof, and a cosmetic or pharmaceutical composition.

Description

[0001] Antimicrobial compound, process for its preparation and use of the antimicrobial compound for the preparation of a cosmetic or pharmaceutical composition

[0002] The invention relates to an antimicrobial compound, a process for preparing the antimicrobial compound and the use of the antimicrobial compound for preparing a cosmetic or pharmaceutical composition for application to skin, as well as a cosmetic or pharmaceutical composition comprising the antimicrobial compound.

[0003] The antimicrobial compound octenidine dihydrochloride ((V,V'-decane-1,10-diyldi-1(4,7)-pyridyl-4-ylidene)bis(octylammonium)dichloride) is known from the state of the art as an antiseptic with bactericidal, fungicidal, and antiviral properties, primarily used in skin, mucous membrane, and wound antiseptics. Octenidine dihydrochloride is typically used in a mass fraction of 0.1 to 2.0 wt.% for the disinfection of skin and mucous membrane wounds, as well as for disinfection before medical procedures, and is marketed in various dosage forms under the trade name Octenisept® by Schülke & Mayr GmbH, Germany.

[0004] Octenidine or octenidine dihydrochloride and its derivatives are described in US 4,206,215 A as an antimicrobial compound bis-[4-(R-amino)-1-pyridium]-alkane of the formula where Y is an alkylene group having 4 to 18 carbon atoms. R can be an alkyl group having 6 to 18 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, or a phenyl group substituted with a methylenedioxy group or one or two substituents from the group consisting of halogen atoms, lower alkyl, lower alkoxy, nitro, cyano, and trifluoromethyl groups. R i can be hydrogen or an alkyl group having 1 to 4 carbon atoms. The bis-[4-(R-amino)-1-pyridium]-alkane is obtained by reacting a 4-(R-amino)pyridine and a disubstituted alkane in a molar ratio of two to one. The reaction takes place either in an inert solvent at 80 to 150 °C for 15 to 20 hours, or without solvent at 120 to 150 °C for 2 to 6 hours.The reaction product can be isolated, for example, by filtration if the product is insoluble in the reaction medium, or by diluting the reaction mixture with a non-polar solvent to precipitate the product, or by evaporating the reaction medium to obtain the product as a residue.

[0005] Based on this prior art, it is the object of the present invention to provide an antimicrobial compound suitable for use in cosmetic or pharmaceutical compositions with improved efficiency and effectiveness.

[0006] This object is achieved by an antimicrobial compound having the features of independent claim 1.

[0007] The further object of producing the antimicrobial compound efficiently with high yield is achieved by the process having the features of independent claim 7.

[0008] The use of the antimicrobial compound for the preparation of a cosmetic or pharmaceutical composition is disclosed by the features of independent claim 10.

[0009] The further object of providing an improved cosmetic or pharmaceutical composition is achieved by the cosmetic or pharmaceutical composition having the features of independent claim 11.

[0010] Further developments or preferred embodiments are set out in the respective subclaims.

[0011] According to a first embodiment, the antimicrobial compound according to the invention has the formula (I) where R 1 an alkyl radical having 4 to 18 carbon atoms or a cycloalkyl radical having 5 to 12 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and

[0012] R 2is an alkyl group having 2 or 3 or 4 carbon atoms,

[0013] R 3 is hydrogen or an alkyl radical having 1 to 8 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and n is an integer from 1 to 15, and

[0014] [(2+n) A'] for a number of anions that provide a total of (2 + n) negative charges. These can be two + n monovalent anions (2+n A') or one correspondingly (2+n) polyvalent anion (A (2+n)_ ). (If n > 1, charge balance requires correspondingly more anions.) Furthermore, for even-numbered n [(2+n) A-] for (1+n / 2) divalent anions (1+n / 2 A 2 '). For example, [3 A'] at n = 1 can represent three monovalent anions (3 A') or one trivalent anion (A 3- ) stand.

[0015] This means that the two 4-(R 1-amino)-pyridine residues of the antimicrobial compound according to the invention are spaced from each other by an alkylamino chain containing one to fifteen alkylamino groups -R 2 NR 3 -, for example -R 2 NH-. Preferably, the alkylamino chain can contain one to fifteen alkylamino groups -R 2 NR 3 - The alkylamino chain can be represented as alkylamino groups or ethylamino groups -C2H4NR 3 - or n- or iso-propylamino groups -CsHeNR 3 - or n- or iso-butylamino groups -C4H8NH-. Or the alkylamino chain may have two different alkylamino groups, ethylamino and propylamino, or ethylamino and butylamino, or propylamino and butylamino, or all three alkylamino groups, ethylamino and propylamino and butylamino, in random, alternating, or blockwise order.

[0016] Regarding R 1 and R 3The alkyl or cycloalkyl radical can be saturated or unsaturated, straight or branched, mono- or polysubstituted or unsubstituted. The alkoxy unit of the alkylene glycol radical as R 1 or R 3 can be ethylene oxide or propylene oxide or butylene oxide unit. If R 1 or R 3 a polyalkylene glycol radical with 2 to 6 alkoxy units, these can be ethylene oxide, propylene oxide, or butylene oxide units, or combinations thereof. A phenyl or benzyl radical as R 1 or R 3 can be mono- or polysubstituted or unsubstituted. Compared to octenidine or octenidine dihydrochloride and its derivatives, the antimicrobial compound according to the invention exhibits very good water solubility and high efficacy even at low concentrations.

[0017] Furthermore, according to a further embodiment, the antimicrobial compound of the invention is efficiently and with high yield from the reaction of a 4-(R 1 -amino)-pyridine of the formula (II)

[0018] (II), with a disubstituted polyamine derivative salt of formula (III)

[0019] X-(R 2 NR 3 ) n -R 2 -X ■ n HX (III) in a molar ratio of 2:1. Here too,

[0020] R 1 an alkyl radical having 4 to 18 carbon atoms or a cycloalkyl radical having 5 to 12 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and

[0021] R 2 an alkyl group having 2 or 3 or 4 carbon atoms,

[0022] R 3is hydrogen or an alkyl radical having 1 to 8 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and n is an integer from 1 to 15.

[0023] X is a monovalent anionic residue, where either the two + n monovalent anionic residues X of the disubstituted polyamine derivative salt of the formula (III) correspond in number to the anions [(2 + n) A'] of the antimicrobial compound of the formula (I) which in total provide the (2 + n) negative charges, or after reaction of the 4-(R 1-amino)-pyridine of formula (II) with the disubstituted polyamine derivative salt of formula (III) in an ion exchange process by the anions [(2+n) A'] of the antimicrobial compound of formula (I) in the number that in total provide the (2 + n) negative charges. This means that the two + n monovalent anionic residues X of the disubstituted polyamine derivative salt of formula (III) can correspond to the two + n monovalent anions (2+n A') of the antimicrobial compound of formula (I), or after reaction of the 4-(R 1 - amino)-pyridine of the formula (II) with the disubstituted polyamine derivative salt of the formula (III) the two + n monovalent anionic radicals X in an ion exchange process by the two + n monovalent anions (2 + n A') or the corresponding two + n polyvalent anion (A (2+n) j or for even-numbered n by (1+n / 2) divalent anions (1+n / 2 A 2 j the antimicrobial compound of formula (I) can be replaced.

[0024] According to a further embodiment of the antimicrobial compound according to the invention, it is provided that [(2+n) A'] represents two + n monovalent anions (2+n A') selected from a group comprising chloride, bromide, fluoride, iodide, nitrate and anions of organic monocarboxylic acids, such as formate, acetate, propionate, benzoate, nicotinate, etc., with chloride and bromide being preferred.

[0025] According to an alternative embodiment of the antimicrobial compound according to the invention, it is provided that for even-numbered n [(2+n) A'] for (1+n / 2) divalent anions (A 2- ) selected from a group comprising sulfate and anions of organic dicarboxylic acids, such as oxalate, malonate, adipate, tartrate, succinate, phthalate, etc.

[0026] According to an alternative embodiment of the antimicrobial compound according to the invention, it is provided that when n = 1, 4, 7, 10, 13 [(2+n) A'] for (2+n) / 3 trivalent anions (A 3 j stands for phosphates and anions of organic tricarboxylic acids, such as citrate, aconitate, isocitrate, oxalo-succinate, etc.

[0027] According to a further embodiment of the antimicrobial compound according to the invention, the monovalent anionic radical X of the disubstituted polyamine derivative salt of formula (III) can be selected from a group comprising chloride, bromide, iodide, alkyl and aryl sulfonyloxy radicals and metho- and ethosulfates.

[0028] According to a further embodiment of the antimicrobial compound according to the invention, in formula (I) R 1 a linear octyl radical, R 2 an ethyl group, R 3Hydrogen, n equals 1, and the resulting three monovalent anions (3 A') are chloride. This antimicrobial compound, which is obtained from the reaction of 4-(octylamino)pyridine with 2,2'-dichlorodiethylammonium hydrochloride (also known as N,N'-bis(2-chloroethane)ammonium hydrochloride) in a molar ratio of 2:1, can be designated as N,N-(diethylamino-1,5-diyldi-1(4 / 7)-pyridyl-4-ylidene)bis(octylammonium) trichloride and has the molecular formula C30H53N5 3 HCl.

[0029] A process according to the invention for producing the antimicrobial compound according to the invention comprises, according to a first embodiment, the steps:

[0030] - Providing a 4-(R 1 -amino)-pyridine of the formula (II) and a disubstituted polyamine derivative salt of formula (III)

[0031] X-(R 2 NH) n -R 2 -X' n HX (III) as reactant in a molar ratio of 2:1 , where

[0032] R 1 an alkyl radical having 4 to 18 carbon atoms or a cycloalkyl radical having 5 to 12 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and

[0033] R 2 is an alkyl group having 2 or 3 or 4 carbon atoms,

[0034] R 3 hydrogen or an alkyl radical having 1 to 8 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and n is an integer from 1 to 15, and

[0035] X is a monovalent anionic residue,

[0036] - heating the two reactants to a reaction temperature in a range of 100 °C to 160 °C for a reaction time of 3 to 10 minutes, and,

[0037] - if the two + n monovalent anionic residues X of the disubstituted polyamine derivative salt of formula (III) correspond in number to the anions [(2 + n) A-] of the antimicrobial compound of formula (I), which in total provide the (2 + n) negative charges, obtaining the antimicrobial compound of formula (I), or - if the two + n monovalent anionic residues X of the disubstituted polyamine derivative salt of formula (III) do not correspond in number to the anions [(2 + n) A'] of the antimicrobial compound of formula (I), which in total provide the (2 + n) negative charges, obtaining the antimicrobial compound of formula (I) by replacing the two + n monovalent anionic residues X in an ion exchange process by the anions [(2 + n) A'] of the antimicrobial compound of formula (I) in the Number that in sum provide the (2 + n) negative charges.

[0038] For example, for n = 1 this means

[0039] - if the three monovalent anionic radicals X of the disubstituted polyamine derivative salt of formula (III) correspond to the three monovalent anions (3 A') of the antimicrobial compound of formula (I), obtaining the antimicrobial compound of formula (I), where [3A'] represents the three monovalent anions (3 A'), or

[0040] - if the three monovalent anionic residues X of the disubstituted polyamine derivative salt of formula (III) do not correspond to the three monovalent anions (3 A') of the antimicrobial compound of formula (I), obtaining the antimicrobial compound of formula (I) by replacing each of three monovalent anionic residues X in an ion exchange process by three monovalent anions (3 A') or one trivalent anion (A 3- ) of the antimicrobial compound of formula (I), wherein [3A _ ] for the three monovalent anions (3Aj or one trivalent anion (A 3 j stands.

[0041] The reaction of the two reactants proceeds within a short reaction time with high yields, so that the production of the antimicrobial compound is highly efficient.

[0042] The reaction temperature can preferably be in a range of 110°C to 150°C, and the reaction time can be 4 to 7 minutes. The resulting antimicrobial compound exhibits good water solubility.

[0043] According to further embodiments of the process according to the invention, the heating of the two reactants can preferably be carried out without additional solvent, since the disubstituted polyamine derivative salt with the 4-(R 1-amino)-pyridine dissolves upon heating. If necessary, further steps to isolate the antimicrobial compound can even be omitted. Alternatively, the two reactants can be heated in a polar, preferably aprotic solvent whose boiling point is higher than the reaction temperature. Examples of aprotic, polar, high-boiling solvents include dimethylformamide, dimethylpropylene urea, dimethyl sulfoxide, and sulfolane.

[0044] According to a specific embodiment of the process according to the invention, for the preparation of the antimicrobial compound N,N-(diethylamino-1,5-diyldi-1(4 / 7)-pyridyl-4-ylidene)bis(octylammonium)trichloride, 4-(octylamino)pyridine and 2,2'-dichlorodiethylammonium hydrochloride (N,N'-bis(2-chloroethane)ammonium hydrochloride) can be provided as reactants in a molar ratio of 2:1, wherein heating to the reaction temperature in the range from 110°C to 150°C for a reaction time in a range from 4 to 7 minutes, preferably of about 5 minutes and according to the invention takes place without additional solvent.

[0045] One inventive use of the antimicrobial compound disclosed herein is in the manufacture of a cosmetic or pharmaceutical composition intended for application to skin and comprising at least one cosmetic or pharmaceutical base substance. The cosmetic or pharmaceutical composition comprises the antimicrobial compound in a concentration of 0.001 to 6 wt.%.

[0046] Here, skin can also include mucous membrane.

[0047] Furthermore, in further embodiments, the antimicrobial compound can also be used according to the invention as a preservative in technical compositions within the stated concentration range, in order to extend the shelf life or storage stability of the technical compositions and to prevent infestation by microorganisms. Examples of technical compositions include crop protection agents, (cooling) lubricants, varnishes and paints, and in particular the water-miscible or water-based compositions.

[0048] The concentration of the antimicrobial compound in a cosmetic, pharmaceutical or technical composition may depend to a certain extent on the length of the alkylamino chain through which the two 4-(R 1-amino)-pyridine residues of the antimicrobial compound of the invention are spaced apart from each other. Longer alkylamino chains tend to be associated with higher concentrations of the antimicrobial compound compared to shorter alkylamino chains to achieve the same efficacy.

[0049] A further subject matter of the invention is a cosmetic or pharmaceutical composition comprising the antimicrobial compound according to one embodiment of the invention and at least one cosmetic or pharmaceutical base substance. According to a first embodiment, the cosmetic or pharmaceutical composition according to the invention comprises the antimicrobial compound in a concentration of 0.001 to 6 wt.%, preferably 0.003 to 3 wt.%.

[0050] The cosmetic or pharmaceutical composition containing the antimicrobial compound is suitable and intended for use on damaged and undamaged skin, including mucous membranes.

[0051] The invention also relates to concentrates intended for the preparation of a cosmetic or pharmaceutical composition by dilution with a solvent, such as (purified) water, and which may contain correspondingly higher concentrations of the antimicrobial compound.

[0052] The cosmetic or pharmaceutical composition can be skin care, skin treatment, or skin refreshment products for beauty care or for disinfecting the skin or mucous membranes. Hair care products are also counted here among the products that represent an application to the skin. In the area of ​​skin care, skin treatment, and skin refreshment products, the boundaries between cosmetic compositions that primarily serve beauty care and pharmaceutical compositions that achieve a pharmacological effect are fluid, since cosmetic products also frequently contain active ingredients with which a pharmacological effect is achieved. Therefore, a distinction is made here between cosmetic and pharmaceutical compositions based on the intended use of the antimicrobial compound according to the invention: A cosmetic composition contains the antimicrobial compound as a preservative, i.e.The antimicrobial compound protects the cosmetic composition from contamination. A pharmaceutical composition contains the antimicrobial compound as an antiseptic agent, so that when applied to the skin, the pharmaceutical composition acts as a disinfectant, acting as an antiseptic against bacteria, fungi, etc.

[0053] A cosmetic or pharmaceutical base substance is understood to mean all cosmetic and / or pharmaceutical carriers and / or solvents that, alone or as a mixture, form the basis for a skin care, skin refreshment, skin treatment, or skin disinfection product. Depending on the type of base substance or substances or their components, the cosmetic or pharmaceutical composition can therefore have a watery, milky, or semi-solid (creamy or ointment-like) consistency.

[0054] According to a further embodiment of the cosmetic or pharmaceutical composition according to the invention, the cosmetic or pharmaceutical base substance can be selected from a group comprising purified water, vegetable oils and fats, and mineral oils and fats. The cosmetic or pharmaceutical composition can thus be an aqueous composition, i.e., with water as the base substance, a milky composition (oil-in-water emulsion) as a lotion, or a semi-solid composition (water-in-oil / fat emulsion) as a cream or ointment, with the oil or fat content of an ointment being greater than that of a cream.

[0055] Depending on the intended use as a preservative or as an antiseptic and possibly also depending on the respective base substance(s), the concentration of the antimicrobial compound in the cosmetic or pharmaceutical composition according to the invention may vary:

[0056] Thus, according to certain embodiments of the cosmetic or pharmaceutical composition according to the invention, the concentration of the antimicrobial compound as a preservative in the cosmetic composition can be in a range of 0.001 to 0.5% by weight, for example in a range of 0.002 to

[0057] 0.1 wt.%, preferably from 0.003 to 0.05 wt.%. The concentration of the antimicrobial compound as a preservative in the cosmetic composition can preferably be in a range from 0.005 to 0.03 wt.%, particularly preferably in a range from 0.008 to 0.02 wt.%, and in particular 0.0125 wt.%.

[0058] In pharmaceutical compositions of a further embodiment of the cosmetic or pharmaceutical composition according to the invention, the concentration of the antimicrobial compound as an antiseptic can be in a range from 0.005 to 6 wt.%, for example in a range from 0.01 to 3 wt.%, preferably in a range from 0.02 to 2 wt.%, particularly preferably in a range from 0.03 to 1 wt.% and in particular in a range from 0.05 to 0.5 wt.%.

[0059] Furthermore, according to a further embodiment of the cosmetic or pharmaceutical composition according to the invention, the pharmaceutical composition may comprise at least one further antimicrobial active ingredient compatible with the antimicrobial compound, which is selected from a group comprising phenoxyethanol, 1-propanol and 2-propanol, ethanol and cationic surfactants such as benzalkonium chloride.

[0060] According to a further embodiment, a cosmetic or pharmaceutical composition according to the invention may further comprise at least one further ingredient compatible with the antimicrobial compound, which ingredient is selected from a group comprising surfactants, emulsifiers, gelling agents, antioxidants, acid-base regulators, vitamins, provitamins, plant substances and plant extracts, chemical UV filters, mineral UV filters, dyes, fragrances, proteins, protein hydrolysates and flavorings.

[0061] Active ingredients or substances compatible with the antimicrobial compound are, for example, cationic, amphoteric, or non-ionic active ingredients or other ingredients. Anionic active ingredients and substances are less likely to be compatible with the antimicrobial compound due to the cationic structure of the antimicrobial compound.

[0062] Further embodiments, as well as some of the advantages associated with these and other embodiments, will become clear and better understood from the detailed description below. The antimicrobial compound of the invention having formula (I) can be efficiently prepared in high yield from the reaction of a 4-(R 1 -amino)-pyridine of formula (II) with a disubstituted polyamine derivative salt of formula (III). To carry out the reaction, the 4-(R 1 -amino)-pyridine of the formula (II) and the disubstituted polyamine derivative salt of the formula (III) in a molar ratio of 2:1 to a reaction temperature of 100 °C to 160 °C, preferably 110 °C to 150 °C, for 3 to 10 minutes, preferably 4 to 7 minutes, for example five minutes.

[0063] For example, as an antimicrobial compound according to the invention / V, / V-(diethylamino-1,5-diyldi-1(4 / - / )-pyridyl-4-ylidene)bis(octylammonium) trichloride with the following structural formula To obtain, the reaction partner is 4-(octylamino)-pyridine (CAS: 64690-19-3) as 4- (R 1-amino)-pyridine of formula (II) and 2,2'-dichlorodiethylammonium hydrochloride (also N,N'-bis(2-chloroethane)ammonium hydrochloride, CAS: 821-48-7) as a disubstituted polyamine derivative salt of formula (III) in a molar ratio of 2:1 were heated to a reaction temperature of 100 °C to 150 °C without additional solvent. Upon heating, the amine salt dissolves in the molten aminopyridine. The reaction proceeds efficiently with a high yield in the short reaction time of approximately 5 minutes. During the course of the reaction, a slight orange discoloration with a simultaneous increase in viscosity is to be expected. The reaction is almost complete, since no insoluble residues of the reactants remain when the reaction product is dissolved in water. If necessary, a purification step can be carried out to completely isolate the reaction product.

[0064] Alternatively, the reaction can also be carried out in a high-boiling, polar solvent whose boiling point is above the reaction temperature. The antimicrobial compound can then be isolated from the solvent by a conventional separation process (filtration, precipitation, evaporation, etc.). A variety of alternative antimicrobial compounds according to the invention are produced by varying the reactants, the 4-(R 1 -amino)-pyridine of formula (II) and the disubstituted polyamine derivative salt of formula (III).

[0065] The 4-(R 1 -amino)-pyridine of the formula (II) can, as an alternative to the octyl radical in the above example, have a butyl, pentyl, hexyl, heptyl or nonyl, decyl, dodecyl radical, etc. up to octadecyl or stearyl radical.

[0066] The disubstituted polyamine derivative salt of formula (III), which in the above example is 2,2'-dichlorodiethylammonium hydrochloride, can contain alternative anionic radicals instead of chlorine, e.g., bromine, iodine, or alkyl or arylsulfonyloxy radicals, which can optionally be replaced in an ion exchange process after the reaction of the two reactants to obtain the desired antimicrobial compound of formula (I) with the two + n monovalent anions (2+n A') or the respective corresponding polyvalent anion(s) instead of the anionic radicals. Furthermore, the disubstituted polyamine derivative salt of formula (III) can contain polyalkylamine chains with different chain lengths and / or different alkylamine units.

[0067] Exemplary alternatives to 2,2'-dichlorodiethylamine or its hydrochloride with a different chain length include 1,8-dichloro-3,6-diazaoctane, 1,11-dichloro-3,6,9-triazaundecane, 1,14-dichloro-3,6,9,12-tetraazatetradecane) or 1,17-dichloro-3,6,9,12,15-pentaazaheptadecane or their hydrochlorides as well as their derivatives with substituents other than chlorine.

[0068] Exemplary alternatives to 2,2'-dichlorodiethylammonium chloride with a different alkylamine unit include disubstituted propylamine and butylamine derivative salts, such as 3,3'-dichlorodipropylammonium chloride and 4,4'-dichlorodibutylammonium chloride, corresponding variants with i-propylamine or i-butylamine, as well as with three, four or more propylamine or butylamine units and their derivatives with substituents other than chlorine, as well as disubstituted amine derivative salts which have a total of two to fifteen ethyl and propylamine units or ethyl and butylamine units or propyl and butylamine units or ethyl and propyl and butylamine units, in random, alternating or blockwise order, which is why the possible variants are not listed individually here due to the large number, but are nevertheless intended to be included. The propyl and butylamine units can be selected from n-propyl or i-propylamine units or n-butyl or i-butylamine units, respectively.

[0069] The reaction product of the reactants 4-(R 1 -amino)-pyridine and disubstituted polyamine derivative salt obtained according to the invention has good water solubility.

[0070] Tests on the effectiveness of the antimicrobial compound as a preservative were carried out using the antimicrobial compound N, N -(diethylamino-1,5-diyldi-1(4 / 7)-pyridyl-4-ylidene)bis(octylammonium)trichloride, which is obtained from the reaction of 4-(octylamino)pyridine and 2,2'-dichlorodiethylammonium hydrochloride in a molar ratio of 2:1.

[0071] The preservative stress tests were carried out on a skin refreshing spray, a water-based cosmetic composition containing the antimicrobial compound as a preservative at a concentration of 0.01 wt%.

[0072] The test procedure was carried out according to DIN EN ISO 11930:2022-08 by inoculating samples of the skin refreshing spray with the specified microorganisms (each germ individually) and determining the germ count. The inoculated samples were stored under defined conditions, and the germ counts were determined at specified times and the germ count development was determined. To verify whether the germ counts were reduced according to the specifications, the logarithmic reduction values ​​were determined. These values, along with the germ count development at 20 °C to 25 °C after inoculating the samples with the listed germ suspensions, are listed in Table 1 below. All germ counts are expressed in CFU / g or ml (CFU = colony-forming units):

[0073] Table 1

[0074] Table 2 lists the evaluation criteria A and B (logarithmic reduction values) defined for the stress tests according to DIN EN ISO 11930, according to which a deviation of 0.5 log steps is permissible.

[0075] Table 2: no increase since the last count

[0076] The result shows that the cosmetic composition containing the antimicrobial compound as a preservative meets the requirements of criteria A + B of the preservative stress test according to DIN EN ISO 11930.

[0077] In addition, the total number of aerobic mesophilic bacteria (according to ISO 21149:2022-08) and the total number of yeasts and molds (according to ISO 16212:2022-08) were determined for this cosmetic composition, which were each < 10 CFU / g (colony forming units per gram), so that the microbiological quality of the samples was not objectionable with regard to the tests carried out.

[0078] Further tests were conducted using an aqueous disinfectant solution as the basis for a cosmetic or pharmaceutical composition containing the antimicrobial compound as an antiseptic at a concentration of 0.1 wt.%. The fungicidal, yeasticidal, or bactericidal activity was determined in quantitative suspension tests according to the test method and minimum requirements of EN 13624:2021 and TS EN 1372+A2. The disinfectant solution is applied to the listed test organisms at different dilutions, and the logarithmic reduction values ​​are determined to verify whether the bacterial counts are reduced according to the specifications after a contact time of 30 or 60 seconds. It is shown that the tested disinfectant solution, especially at low dilution (80%), achieves at least a threefold logarithmic reduction in C. albicans and at least a fourfold logarithmic reduction in P. aeruginosa and S. aureus. This demonstrates that the antimicrobial compound according to the invention is suitable for use as an antiseptic.

Claims

AMENDED CLAIMS received by the International Bureau on 28 July 2025 (28.07.2025) 1. Antimicrobial compound with formula (I) where R 1 an alkyl radical having 4 to 18 carbon atoms or a cycloalkyl radical having 5 to 12 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and R 2 is an alkyl group having 2 or 3 or 4 carbon atoms, and R 3 is hydrogen or an alkyl radical having 1 to 8 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and n is an integer from 1 to 15, and [(2+n) A"] stands for a number of anions that provide a total of (2 + n) negative charges.

2. Antimicrobial compound according to claim 1 from the reaction of a 4-(R 1 -amino)-pyridine of the formula (II) (II), with a disubstituted polyamine derivative salt of formula (III) X-(R 2 NR 3 ) n -R 2 -X . n HX (III) in a molar ratio of 2:1 , where R 1 an alkyl radical having 4 to 18 carbon atoms or a cycloalkyl radical having 5 to 12 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and R 2 is an alkyl group having 2 or 3 or 4 carbon atoms, and R 3 Hydrogen or an alkyl radical having 1 to 8 carbon atoms or a (po- Iy)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and n is an integer from 1 to 15, and X is a monovalent anionic residue, wherein the two + n monovalent anionic residues X of the disubstituted polyamine derivative of the formula (III) either correspond in number to the anions [(2 + n) A"J of the antimicrobial compound of the formula (I) which in total provide the (2 + n) negative charges, or after reaction of the 4-(R 1 -amino)-pyridine of formula (II) with the disubstituted polyamine derivative of formula (III) in an ion exchange process by the anions [(2+n) A'] of the antimicrobial compound of formula (I) in the number which in total provide the (2 + n) negative charges.

3. Antimicrobial compound according to claim 1 or 2, wherein [(2+n) A'] represents two + n monovalent anions (2+n A") selected from a group comprising at least chloride, bromide, fluoride, iodide, nitrate, acetate, with chloride and bromide being preferred.

4. Antimicrobial compound according to claim 1 or 2, wherein - for even-numbered n [(2+n) A'] for (1+n / 2) divalent anions (A 2- ) selected from a group comprising at least sulfate, oxalate, or - at n = 1, 4, 7, 10, 13 [(2+n) A"J for (2+n) / 3 trivalent anions (A 3- ) selected from a group comprising phosphate and anions of organic tricarboxylic acids, such as citrate, aconitate, isocitrate, oxalo-succinate, etc.

5. Antimicrobial compound according to at least one of claims 2 to 4, wherein the monovalent anionic radical X is selected from a group comprising chloride, bromide, iodide, alkylsulfonyloxy radicals, arylsulfonyloxy radicals.

6. Antimicrobial compound according to at least one of claims 1 to 5, wherein the antimicrobial compound is N,N'-(diethylamino-1,5-diyldi-1(4H)-pyridyl-4-ylidene)bis(octylammonium)trichloride, in which in the formula (I) R 1 is a linear octyl radical, and R 2is an ethyl group, and R 3 is hydrogen, and n is 1, and [(2+n) A"] represents three monovalent anions which are chloride.

7. A process for preparing the antimicrobial compound according to at least one of claims 1 to 6, comprising the steps - Providing a 4-(R 1 -amino)-pyridine of the formula (II) (II), and a disubstituted polyamine derivative salt of formula (III) (III) as reactant in a molar ratio of 2:1, where R 1 an alkyl radical having 4 to 18 carbon atoms or a cycloalkyl radical having 5 to 12 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and R 2 is an alkyl group having 2 or 3 or 4 carbon atoms, and R 3is hydrogen or an alkyl radical having 1 to 8 carbon atoms or a (poly)alkylene glycol radical having 1 to 6 alkoxy units or a phenyl radical or a benzyl radical, and n is an integer from 1 to 15, and X is a monovalent anionic residue, - Heating the two reactants to a reaction temperature in a range of 100 °C to 160 °C for a reaction time in a range of 3 to 10 minutes and, - if the two +1 monovalent anionic residues X of the disubstituted polyamine derivative salt of formula (III) correspond to the anions [(2+n) A'] of the antimicrobial compound of formula (I) in the number which in total provide the (2 + n) negative charges, obtaining the antimicrobial compound of formula (I), or - if the two + n monovalent anionic residues X of the disubstituted polyamine derivative of formula (III) do not correspond to the anions [(2 + n) A"J of the antimicrobial compound of formula (I) in the number which in total provide the (2 + n) negative charges, obtaining the antimicrobial compound of formula (I) by replacing the two + n monovalent anionic residues X in an ion exchange process by the anions [(2 + n) A"J of the antimicrobial compound of formula (I) in the number which in total provide the (2 + n) negative charges.

8. The process according to claim 7, wherein the heating of the two reactants - without solvent, or - in a polar solvent whose boiling point is higher than the reaction temperature, wherein the polar solvent is preferably an aprotic solvent.

9. The process according to claim 7 or 8, wherein the reactants are 4-(octylamino)pyridine and 2,2'-dichlorodiethylammonium hydrochloride in a molar ratio of 2:1, wherein heating to the reaction temperature is carried out in the range of 110°C to 150°C for a reaction time in the range of 4 to 7 minutes without additional solvent.

10. Use of the antimicrobial compound according to at least one of claims 1 to 6 for the preparation of a cosmetic or pharmaceutical composition for application to skin, wherein the cosmetic or pharmaceutical composition comprises at least one cosmetic or pharmaceutical base substance and the antimicrobial compound in a concentration of 0.001 to 6% by weight.

11. Cosmetic or pharmaceutical composition suitable for application to skin, comprising the antimicrobial compound according to at least one of claims 1 to 6 and at least one cosmetic or pharmaceutical base substance, wherein the cosmetic or pharmaceutical composition comprises the antimicrobial compound in a concentration of 0.001 to 6% by weight, preferably from 0.003 to 3 wt.%.

12. Cosmetic or pharmaceutical composition according to claim 11, wherein the cosmetic or pharmaceutical base is selected from a group comprising purified water, vegetable oils and fats and mineral oils and fats.

13. Cosmetic or pharmaceutical composition according to claim 11 or 12, wherein the concentration of the antimicrobial compound as a preservative in the cosmetic composition is in a range of 0.001 to 0.5 wt.%, preferably from 0.003 to 0.05 wt.%, particularly preferably in a range of 0.005 to 0.03 wt.%, in particular in a range of 0.008 to 0.02 wt.%.

14. Cosmetic or pharmaceutical composition according to claim 11 or 12, wherein the concentration of the antimicrobial compound as antiseptic in the pharmaceutical composition is in a range of 0.005 to 6 wt.%, preferably from 0.01 to 3 wt.%, particularly preferably in a range of 0.02 to 2 wt.%, and in particular in a range of 0.03 to 1 wt.%, and / or the pharmaceutical composition comprises at least one further antimicrobial active ingredient compatible with the antimicrobial compound, which is selected from a group comprising phenoxyethanol, 1-propanol and 2-propanol, ethanol and cationic surfactants such as benzalkonium chloride.

15. Cosmetic or pharmaceutical composition according to at least one of claims 11 to 14, wherein the cosmetic or pharmaceutical composition comprises at least one further ingredient compatible with the antimicrobial compound, which ingredient is selected from a group comprising surfactants, emulsifiers, gelling agents, antioxidants, acid-base regulators, vitamins, provitamins, plant substances and plant extracts, chemical UV filters, mineral UV filters, dyes, fragrances, proteins, protein hydrolysates and flavorings.

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