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] ANTIMMICROBIAL COMPOUND, METHOD FOR ITS PREPARATION AND USE OF THE ANTIMMICROBIAL COMPOUND FOR THE PREPARATION OF A COSMETIC OR PHARMACEUTICAL COMPOSITION

[0002] The invention relates to an antimicrobial compound, a method for producing the antimicrobial compound and the use of the antimicrobial compound for the production of a cosmetic or pharmaceutical composition for application to the skin, as well as a cosmetic or pharmaceutical composition with the antimicrobial compound.

[0003] The antimicrobial compound octenidine dihydrochloride ( / V, / V'-fDecan-1,10-diyldi-1 (4 / 7)-pyridyl-4-ylidene)bis(octylammonium)dichloride) is known from the prior art as an antiseptic with bactericidal, fungicidal, and antiviral properties, and is 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 disinfecting skin and mucous membrane wounds and for disinfection prior to medical procedures. It is marketed in various formulations under the trade name Octenisept® by Schülke & Mayr GmbH, Germany.

[0004] Octenidine or octenidine dihydrochloride and its derivatives are listed in US 4,206,215 A as the antimicrobial compound bis-[4-(R-amino)-1-pyridium]-alkane of the formula The following is described, where Y is an alkylene group with 4 to 18 carbon atoms. R can be an alkyl group with 6 to 18 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms, or a phenyl group substituted with a methylendioxy group or one or two substituents from the group comprising halogen atoms, lower alkyl, lower alkyloxy, nitro, cyano, and trifluoromethyl groups. Ri can be hydrogen or an alkyl group with 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 two-to-one molar ratio. 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 nonpolar solvent to precipitate the product, or by evaporating the reaction medium to obtain the product as a residue.

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

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

[0007] The further task of efficiently producing the antimicrobial compound with high yield is solved by the method with the features of independent claim 7.

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

[0009] The further objective 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 described in the respective subclaims.

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

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

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

[0014] [(2+n) A'] represents a number of anions that collectively provide (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 n, [(2+n) A-] can be used for (1+n / 2) divalent anions (1+n / 2 A). 2 '). For example, [3 A'] can represent three monovalent anions (3 A') or one trivalent anion (A) when n = 1. 3- ) stand.

[0015] That is, that the two 4-(R 1-amino)pyridine residues of the antimicrobial compound according to the invention are spaced apart from each other by an alkylamino chain, which has one to fifteen alkylamino groups -R 2 NR 3 -, for example -R 2 NH-, has. Preferably, the alkylamino chain can have one to fifteen alkylamino groups -R 2 NR 3 - exhibit. 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 can have two different alkylamino groups, ethylamino and propylamino or ethylamino and butylamino or propylamino and butylamino groups, or all three alkylamino groups, ethylamino, propylamino and butylamino groups, in random, alternating or block-like order.

[0016] Regarding R 1 and R 3The alkyl or cycloalkyl group can be saturated or unsaturated, straight or branched, singly or polysubstituted or unsubstituted. The alkoxy unit of the alkylene glycol group is designated as R. 1 or R 3 It can be an ethylene oxide, propylene oxide, or butylene oxide unit. Is R 1 or R 3 A polyalkylene glycol residue with 2 to 6 alkoxy units, which can be ethylene oxide, propylene oxide, butylene oxide units, or combinations thereof. A phenyl or benzyl residue as R 1 or R 3 It can be singly or multiply substituted or unsubstituted. Compared to octenidine or octenidine dihydrochloride and their derivatives, the antimicrobial compound according to the invention exhibits very good water solubility and high efficacy even at low concentrations.

[0017] Furthermore, according to another embodiment, the antimicrobial compound according to the invention is efficient and yields a 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 (Hl) can be obtained in a molar ratio of 2:1. Here too,

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

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

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

[0023] X is a monovalent anionic residue, wherein either the two + n monovalent anionic residues X of the disubstituted polyamine derivative salt of formula (III) correspond to the number of anions [(2+n) A'] of the antimicrobial compound of formula (I) that together provide the (2 + n) negative charges, or after the reaction of the 4-(R 1-amino)pyridine of formula (II) with the disubstituted polyamine derivative salt of formula (III) is replaced in an ion exchange process by the anions [(2+n) A'] of the antimicrobial compound of formula (I) in the number that together provide the (2 + n) negative charges. That is, 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 the reaction of the 4-(R) 1 -amino)pyridines of formula (II) with the disubstituted polyamine derivative salt of formula (III) the two + n monovalent anionic residues 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 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, [(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., wherein chloride and bromide are 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- ) which are selected from a group containing 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 for n = 1, 4, 7, 10, 13 [(2+n) A'] for (2+n) / 3 trivalent anions (A 3 j stands for, which are selected from a group that contains phosphate and anions of organic tricarboxylic acids, such as citrate, aconitate, isocitrate, oxalosuccinate, etc.

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

[0028] According to a further embodiment of the antimicrobial compound according to the invention, formula (I) R 1 a linear octyl residue, R 2 an ethyl group, R 3Hydrogen, n equals 1, and the resulting three monovalent anions (3 A') are chloride. This antimicrobial compound, which can be obtained from the reaction of 4-(octylamino)pyridine with 2,2'-dichlorodiethylammonium hydrochloride (another name N,N'-bis(2-chloroethane)ammonium hydrochloride) in a molar ratio of 2:1, can be called N,N-(diethylamino-1,5-diyldi-1 (4 / 7)-pyridyl-4-ylidene)bis(octylammonium)trichloride and has the molecular formula C30H53N53HCl.

[0029] According to a first embodiment, a method according to the invention for producing the antimicrobial compound according to the invention comprises the following 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 reaction partners in a molar ratio of 2:1 , wherein

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

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

[0034] R 3 hydrogen or an alkyl group with 1 to 8 carbon atoms or a (poly)alkylene glycol group with 1 to 6 alkoxy units or a phenyl group or a benzyl group, 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 the 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 to the number of anions [(2+n) A-] of the antimicrobial compound of formula (I) that together provide the (2 + n) negative charges, obtain 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 to the number of anions [(2+n) A'] of the antimicrobial compound of formula (I) that together provide the (2 + n) negative charges, obtain the antimicrobial compound of formula (I) by replacing the two + n monovalent anionic residues X in an ion exchange process with the number of anions [(2+n) A'] of the antimicrobial compound of formula (I) that together provide the (2 + n) provide negative charges.

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

[0039] - if the three monovalent anionic residues 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 the three monovalent anionic residues X in an ion exchange process with 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 the short reaction time with high yields, making the production of the antimicrobial compound highly efficient.

[0042] Preferably, the reaction temperature can be in the range of 110 °C to 150 °C and the reaction time 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 reaction partners can preferably be carried out without additional solvent, since the disubstituted polyamine derivative salt reacts with the 4-(R 1-amino)pyridine dissolves upon heating. If necessary, further steps for isolating 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, dimethylpropylenurea, dimethyl sulfoxide, and sulfolane.

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

[0045] One use of the antimicrobial compound disclosed herein according to the invention is in the manufacture of a cosmetic or pharmaceutical composition intended for application to the skin and comprising at least one cosmetic or pharmaceutical base material. The cosmetic or pharmaceutical composition contains the antimicrobial compound in a concentration of 0.001 to 6% by weight.

[0046] This can include skin as well as mucous membranes.

[0047] Furthermore, in other embodiments of the invention, the antimicrobial compound is also used as a preservative in technical compositions within the specified concentration range to extend the shelf life or storage stability of the technical compositions and to prevent infestation by microorganisms. Examples of technical compositions include plant protection products, (cooling) lubricants, varnishes and paints, and in particular water-miscible or water-based compositions.

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

[0049] Another object of the invention is a cosmetic or pharmaceutical composition comprising the antimicrobial compound according to an 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 production of a cosmetic or pharmaceutical composition by dilution with a solvent, such as (purified) water, and which may have correspondingly higher concentrations of the antimicrobial compound.

[0052] The cosmetic or pharmaceutical composition can be a skincare, skin treatment, or skin refreshing product for beauty care or for disinfecting the skin or mucous membranes. Hair care products are also included here as products that represent an application to the skin. In the area of ​​skincare, skin treatment, and skin refreshing products, the boundaries between cosmetic compositions, which primarily serve beauty care, and pharmaceutical compositions, which achieve a pharmacological effect, are fluid, since cosmetic products also frequently contain active ingredients that achieve a pharmacological effect. Therefore, cosmetic and pharmaceutical compositions are distinguished here 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 is effective as a disinfectant against bacteria, fungi, etc.

[0053] Cosmetic or pharmaceutical base materials are defined as all cosmetic and / or pharmaceutical carrier substances and / or solvents that, alone or in mixtures, form the basis for a skin care, skin refreshing, skin treatment, or skin disinfection product. The cosmetic or pharmaceutical composition can therefore have an aqueous, milky, or semi-solid (creamy or ointment-like) consistency, depending on the type of base material(s) and their proportions.

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

[0055] Depending on its 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 can vary:

[0056] 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 wt.%, for example in a range of 0.002 to

[0057] The concentration of the antimicrobial compound as a preservative in the cosmetic composition is preferably in the range of 0.005 to 0.03 wt.%, particularly preferably in the range of 0.008 to 0.02 wt.%, and especially 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 of 0.005 to 6 wt.%, for example in a range of 0.01 to 3 wt.%, preferably in a range of 0.02 to 2 wt.%, particularly preferably in a range of 0.03 to 1 wt.% and especially in a range of 0.05 to 0.5 wt.%.

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

[0060] A cosmetic or pharmaceutical composition according to the invention may, according to a further embodiment, comprise at least one further ingredient compatible with the antimicrobial compound, which is selected from a group comprising surfactants, emulsifiers, gelling agents, oxidation inhibitors, 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 other substances compatible with the antimicrobial compound are, for example, cationic, amphoteric, or non-ionic active ingredients or other substances. Anionic active ingredients and other substances are generally not compatible with the antimicrobial compound due to its cationic structure.

[0062] Further embodiments and some of the advantages associated with these and other embodiments will become clearer and more easily understood through the following detailed description. The antimicrobial compound according to the invention with formula (I) can be efficiently prepared in high yield from the reaction of a 4-(R 1 -amino)pyridines of formula (II) with a disubstituted polyamine derivative salt of formula (III) are obtained. To carry out the reaction, the 4-(R 1 -amino)-pyridine of formula (II) and the disubstituted polyamine derivative salt of formula (III) in a molar ratio of 2:1 are heated 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, 4-(Octylamino)pyridine (CAS: 64690-19-3) is used as a reaction partner as 4-(R 1Aminopyridine 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) are heated in a molar ratio of 2:1 to the 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. A slight orange discoloration with a simultaneous increase in viscosity is to be expected during the reaction. The reaction is almost complete, as 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 method (filtration, precipitation, evaporation, etc.). A variety of alternative antimicrobial compounds according to the invention are obtained 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 formula (II) can alternatively have a butyl, pentyl, hexyl, heptyl or nonyl, decyl, dodecyl, etc. residue up to an octadecyl or stearyl residue instead of the octyl residue in the example above.

[0066] The disubstituted polyamine derivative salt of formula (III), which in the example above is 2,2'-dichlorodiethylammonium hydrochloride, can contain alternative anionic groups instead of chlorine, e.g., bromine, iodine, or alkyl or arylsulfonyloxy groups. These can be replaced, if necessary, by 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 groups. 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 different chain lengths 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 and 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, and disubstituted amine derivative salts which in total have 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 block-like order, which is why the possible variants are not listed individually here due to their large number, but should nevertheless be included. The propyl and butylamine units can each be selected from n-propyl or i-propylamine units or n-butyl or i-butylamine units.

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

[0070] Experiments on the efficacy of the antimicrobial compound as a preservative were carried out using as an example 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% by weight.

[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 microorganism individually) and determining the microbial count. The inoculated samples were then stored under defined conditions, and the microbial counts were determined at specified intervals, along with the microbial count development. To verify whether the microbial counts were reduced as specified, the logarithmic reduction values ​​were determined. These values, along with the microbial count development at 20 °C to 25 °C after inoculation of the samples with the listed microbial suspensions, are shown in Table 1 below. All microbial 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 load 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] Furthermore, 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, each of which was < 10 CFU / g (colony-forming units per gram), so that the microbiological quality of the samples was not objectionable with regard to the investigations 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% by weight. The fungicidal, yeasticidal, and bactericidal efficacy was determined in quantitative suspension tests according to the test method and minimum requirements of EN 13624:2021 and TS EN 1372+A2, respectively. In these tests, the disinfectant solution was applied to the listed test organisms at varying dilutions, and the logarithmic reduction values ​​were determined to verify whether the microbial counts were reduced as specified 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 three-fold logarithmic reduction in C. albicans and at least a four-fold 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) (I) where R 1 an alkyl group with 4 to 18 carbon atoms or a cycloalkyl group with 5 to 12 carbon atoms or a (poly)alkylene glycol group with 1 to 6 alkoxy units or a phenyl group or a benzyl group, and R 2 an alkyl group with 2, 3, or 4 carbon atoms, and R 3 hydrogen or an alkyl group with 1 to 8 carbon atoms or a (poly)alkylene glycol group with 1 to 6 alkoxy units or a phenyl group or a benzyl group, and n is an integer from 1 to 15, and [(2+n) A'] represents 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 group with 4 to 18 carbon atoms or a cycloalkyl group with 5 to 12 carbon atoms or a (poly)alkylene glycol group with 1 to 6 alkoxy units or a phenyl group or a benzyl group, and R 2 an alkyl group with 2, 3, or 4 carbon atoms, and R 3 hydrogen or an alkyl group with 1 to 8 carbon atoms or a (Po- AMENDED SHEET (ARTICLE 19) Iy)alkylene glycol residue with 1 to 6 alkoxy units or a phenyl residue or a benzyl residue, 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 formula (III) either correspond to the number of anions [(2+n) A'] of the antimicrobial compound of formula (I) that together provide the (2 + n) negative charges, or after the reaction of the 4-(R 1 -amino)-pyridines of formula (II) with the disubstituted polyamine derivative of formula (III) are replaced in an ion exchange process by the anions [(2+n) A'] of the antimicrobial compound of formula (I) in the number which in sum 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, wherein chloride and bromide are preferred.

4. Antimicrobial compound according to claim 1 or 2, wherein - for even n [(2+n) A'] for (1+n / 2) divalent anions (A 2 j stands for those selected from a group that contains at least sulfate, oxalate, or - for n = 1, 4, 7, 10, 13 [(2+n) A-] for (2+n) / 3 trivalent anions (A 3 j stands for, which are selected from a group that contains phosphate and anions of organic tricarboxylic acids, such as citrate, aconitate, isocitrate, oxalosuccinate, etc.

5. Antimicrobial compound according to at least one of claims 2 to 4, wherein the monovalent anionic residue X is selected from a group comprising chloride, bromide, iodide, alkyl sulfonyloxy residues, aryl sulfonyloxy residues.

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, wherein in formula (I) R 1 a linear octyl residue, and R 2an ethyl group, and AMENDED SHEET (ARTICLE 19) R 3 hydrogen is, and n equals 1, and [(2+n) A'] represents three monovalent anions that are chloride.

7. Method for producing 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) and a disubstituted polyamine derivative salt of formula (III) X-(R 2 NR 3 ) n -R 2 -X ■ n HX (III) as reaction partners in a molar ratio of 2:1, wherein R 1 an alkyl group with 4 to 18 carbon atoms or a cycloalkyl group with 5 to 12 carbon atoms or a (poly)alkylene glycol group with 1 to 6 alkoxy units or a phenyl group or a benzyl group, and R 2an alkyl group with 2, 3, or 4 carbon atoms, and R 3 hydrogen or an alkyl group with 1 to 8 carbon atoms or a (poly)alkylene glycol group with 1 to 6 alkoxy units or a phenyl group or a benzyl group, 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 the range of 100 °C to 160 °C for a reaction time in the 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 in number to the anions [(2+n) A'] of the antimicrobial compound of formula (I) which together provide the (2 + n) negative charges, obtaining the antimicrobial compound of formula (I), or AMENDED SHEET (ARTICLE 19) - if the two + n monovalent anionic residues X of the disubstituted polyamine derivative of formula (III) do not correspond to the number of anions [(2+n) A'] of the antimicrobial compound of formula (I) that together 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 with the number of anions [(2+n) A'] of the antimicrobial compound of formula (I) that together provide the (2 + n) negative charges.

8. The method of claim 7, wherein the heating of the two reactants - without solvents, 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 method of 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 in the range of 110 °C to 150 °C for a reaction time in the range of 4 to 7 minutes is carried out without additional solvent.

10. Use of the antimicrobial compound according to at least one of claims 1 to 6 for the manufacture of a cosmetic or pharmaceutical composition for application to the 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 wt.%.

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 material, wherein the cosmetic or pharmaceutical composition contains the antimicrobial compound in a concentration of 0.001 to 6 wt.%, preferably AMENDED SHEET (ARTICLE 19) from 0.003 to 3 wt.%.

12. Cosmetic or pharmaceutical composition according to claim 11, wherein the cosmetic or pharmaceutical base material is selected from the 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 the range of 0.001 to 0.5 wt.%, preferably from 0.003 to 0.05 wt.%, particularly preferably in the range of 0.005 to 0.03 wt.%, and especially in the 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 an antiseptic in the pharmaceutical composition is in the range of 0.005 to 6 wt.%, preferably 0.01 to 3 wt.%, particularly preferably in the range of 0.02 to 2 wt.%, and particularly in the range of 0.03 to 1 wt.%, and / or the pharmaceutical composition comprises at least one further antimicrobial agent compatible with the antimicrobial compound, selected from the 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, selected from the group consisting of 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. AMENDED SHEET (ARTICLE 19)

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