WO2015090850A1

WO2015090850A1 - Use of alkylamidothiazoles as an antioxidant or free-radical scavenger in cosmetic or dermatological preparations

Info

Publication number: WO2015090850A1
Application number: PCT/EP2014/075309
Authority: WO
Inventors: Ludger Kolbe; Cathrin Scherner; Ursula Wensorra; Tobias Mann
Original assignee: Beiersdorf Ag
Priority date: 2013-12-19
Filing date: 2014-11-21
Publication date: 2015-06-25
Also published as: DE102013226746A1

Abstract

The invention relates to the use of physiologically compatible alkylamidothiazoles as an antioxidant and/or as a free-radical scavenger in cosmetic or dermatological preparations.

Description

description

Use of alkylamidothiazoles as antioxidant or radical scavenger in cosmetic or dermatological preparations

The present invention relates to cosmetic and dermatological preparations with an effective content of physiologically acceptable alkylamidothiazoles. In particular, the present invention relates to cosmetic preparations with effective protection against harmful oxidation processes in the skin, but also for the protection of cosmetic preparations themselves or for the protection of the components of cosmetic preparations from harmful oxidation processes.

The present invention further relates to antioxidants, preferably those which are used in skin-care cosmetic or dermatological preparations. In particular, the invention also relates to cosmetic and dermatological preparations containing such antioxidants. In a preferred embodiment, the present invention relates to cosmetic and dermatological preparations for the prophylaxis and treatment of cosmetic or dermatological lesions, e.g. Skin aging, especially skin aging caused by oxidative processes.

Furthermore, the present invention relates to active substances and preparations containing such active ingredients, for the cosmetic and dermatological treatment or prophylaxis of erythema-töser, inflammatory, allergic or autoimmune reactive phenomena, especially dermatoses.

The present invention further relates to active compound combinations and preparations which are used for the prophylaxis and treatment of the photosensitive skin, in particular of photodermatoses. The damaging effect of the ultraviolet part of solar radiation on the skin is well known. While rays having a wavelength smaller than 290 nm (the so-called UVC region) are absorbed by the ozone layer in the earth's atmosphere, rays in the range between 290 nm and 320 nm, the so-called UVB region, cause erythema simple sunburn or even more or less severe burns.

As a maximum of the erythema efficiency of sunlight, the narrower range around 308 nm is given.

For protection against UVB radiation, numerous compounds are known, which are derivatives of 3-Benzylidencamphers, 4-aminobenzoic acid, cinnamic acid, salicylic acid, benzophenone and also of 2-phenylbenzimidazole.

Also for the range between about 320 nm and about 400 nm, the so-called UVA range, it is important to have available filter substances, since its rays can cause reactions in photosensitive skin. It has been proven that UVA radiation leads to damage of the elastic and collagenous fibers of the connective tissue, causing the skin to age prematurely, and that it is to be regarded as the cause of numerous phototoxic and photoallergic reactions. The damaging influence of UVB radiation can be amplified by UVA radiation.

For protection against the rays of the UVA range, therefore, certain derivatives of dibenzoylmethane are used whose photostability (Int J. Cosm. Science 10, 53 (1988)) is not sufficiently given.

However, the UV radiation can also lead to photochemical reactions, in which case the photochemical reaction products intervene in the skin metabolism.

Predominantly, such photochemical reaction products are free-radical compounds, for example hydroxy radicals. Undefined radical photoproducts, which are formed in the skin itself, can also be used because of their high reactivity uncontrolled follow-up reactions to the day. But singlet oxygen, a non-traditional excited state of the oxygen molecule, can also occur on UV irradiation, as can short-lived epoxides and many others. Singlet oxygen, for example, is distinguished from the normally present triplet oxygen (radical ground state) by increased reactivity. However, there are also excited, reactive (radical) triplet states of the oxygen molecule.

Furthermore, UV radiation counts as ionizing radiation. Thus, there is the risk that ionic species may also be formed on exposure to UV radiation, which in turn may intervene oxidatively in the biochemical processes.

In order to prevent these reactions, additional antioxidants and / or radical scavengers can be incorporated in the cosmetic or dermatological formulations. It has already been proposed to use vitamin E, a substance with known antioxidant activity in sunscreen formulations, yet here again, the effect achieved lags far behind the hoped for.

The object of the invention was therefore also to provide cosmetic, dermatological and pharmaceutical active ingredients and preparations as well as light protection formulations which serve for the prophylaxis and treatment of photosensitive skin, in particular photodermatoses, preferably PLD.

Other names for the polymorphic light dermatosis are PLD, PLE, Mallorca acne and a variety of other names, as in the literature (eg A. Voeickel et al, Zentralblatt skin and venereal diseases (1989), 156, p.2), are indicated.

Erythematous skin manifestations also appear as side effects in certain skin diseases or irregularities. For example, the typical rash in the appearance of acne is regularly more or less reddened.

Mainly antioxidants are used as protective substances against spoilage of preparations containing them. Nevertheless, it is known that also in the human and animal skin unwanted oxidation processes can occur. Such processes play an essential role in skin aging.

In the article "Skin Diseases Associated with Oxidative Injury" in "Oxidative Stress in Dermatology", p. 323 et seq. (Marcel Decker Inc., New York, Basel, Hong Kong, publishers: Jürgen Fuchs, Frankfurt, and Lester Packer, Berkeley, California), oxidative damage to the skin and its nearer causes are listed.

If human hair is to be permanently dyed, in practice only oxidizing hair dyeing methods are considered. In oxidative hair dyeing, the formation of the dye chromophore takes place by reaction of precursors (phenols, aminophenols, more rarely diamines) and bases (usually p-phenylenediamine) with the oxidizing agent, usually hydrogen peroxide. Hydrogen peroxide concentrations around 6% are usually used.

It is usually assumed that in addition to the coloring effect, a bleaching action by the hydrogen peroxide takes place. In oxidatively dyed human hair, similar to bleached hair, microscopic holes are detectable at sites where melanin granules were present.

The fact is that the oxidizing agent hydrogen peroxide react not only with the color precursors, but also with the hair substance, thereby possibly causing damage to the hair. Antioxidants are substances which prevent oxidation processes and / or which prevent the oxidation of unsaturated compounds containing auto-oxidation. Antioxidants which are also used in the field of cosmetics and pharmacy are, for example, α-tocopherol, in particular in the form of α-tocopheryl acetate, sesamol, gallic acid derivatives, butylhydroxyanisole and butylhydroxytoluene.

Also for the reason of preventing such reactions, antioxidants and / or radical scavengers may additionally be incorporated into cosmetic formulations. Although some antioxidants and radical scavengers are known. For example, it has already been proposed in US Pat. Nos. 4,144,325 and 4,248,861, as well as numerous other documents, to use vitamin E, a substance with known antioxidant activity in sunscreen formulations, but the effect achieved remains far below the hoped-for effect.

An object of the present invention was to eliminate the disadvantages of the prior art. In particular, active ingredients or preparations containing such active ingredients should be made available, in the use of which damage to the skin and / or the hair is at least reduced by oxidative influence, if not completely prevented.

A further object of the present invention was to provide cosmetic preparations which, before or after treatment of the hair with hair-dyeing preparations, even those containing a strong oxidizing agent, such as e.g. Hydrogen peroxide, whose damaging oxidation effect counteract.

In particular, active substances and preparations containing such active ingredients should be made available for the cosmetic and dermatological treatment and / or prophylaxis of erythematous, inflammatory, allergic or autoimmune-reactive phenomena, in particular dermatoses, but also the appearance of "stinging".

It was surprising and unforeseeable for a person skilled in the art that cosmetic or dermatological preparations containing physiologically tolerated alkylamide dothiazoles or the use of physiologically tolerated alkylamidothiazoles as antioxidant and / or radical scavenger in cosmetic or dermatological preparations represents the solution to these problems, and to remedy the disadvantages of the prior art. Advantageous alkylamidothiazoles in the context of the present invention are substances of the general formula

in which R ¹ , R ² , X and Y can be different, partly identical or completely identical and can mean independently of one another:

Ri = -Ci-C24-alkyl (linear and branched), -Ci-C24-alkenyl (linear and branched), -d-Cs-cycloalkyl, -Ci-Ce-cycloalkyl-alkylhydroxy, -C1-C24 alkylhydroxy (linear and .alpha Branched), -C1-C24 alkylamine (linear and branched), -Ci-C24-alkylaryl (linear and branched), -Ci-C24-alkyl-aryl-alkyl-hydroxy (linear and branched), -Ci-C24-alkylheteroaryl (linear and branched), -d-C24-alkyl-0-Ci-C24-Alkyl (linear and branched), -C1-C24 Alky-Morpholino, -C1-C24 Alky-Piperidino, -C1-C24 Alky-Piperazino, -C1-C24 Alky-piperazino-N-alkyl, R2 = H, -Ci-C24-alkyl (linear and branched), -Ci-C24-alkenyl (linear and branched), -Ci-Ce- cycloalkyl, -d -C24-hydroxyalkyl (linear and branched), -Ci-C24-alkylaryl (linear and branched), -Ci-C24-alkylheteroaryl (linear and branched),

X = -H, -Ci-C24-alkyl (linear and branched), -Ci-C24-alkenyl (linear and branched), -Ci-Ce- cycloalkyl, -Ci-C24-aryl (optionally mono- or polysubstituted with -OH, -F, -Cl, -Br, -I, - OMe, -NH ₂ , -CN), -Ci-C24 heteroaryl (optionally mono- or polysubstituted by -OH, -F, - Cl, - Br, -I, -OMe, -NH ₂ , -CN), -Ci-C ₂ 4-alkylaryl (linear and branched), -Ci-C ₂ 4-alkyl heteroaryl (linear and branched), -aryl (if necessary monosubstituted or polysubstituted by -OH, -F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN), -phenyl, -2,4-dihydroxyphenyl, -2,3-dihydroxyphenyl, - 2,4-dimethoxyphenyl, -2,3-dimethoxyphenyl, Y = H, -CC-C24-alkyl (linear and branched), -Ci-C24-alkenyl (linear and branched), -Ci-Ce- cycloalkyl, -Ci-C24-aryl, -Ci-C24-heteroaryl, - Ci-C24-Alkylaryl (linear and branched), -Ci-C24-Alkylheteroaryl (linear and branched), -aryl, -phenyl, -2,4-dihydroxyphenyl, -2,3-dihydroxyphenyl, -2,4-dimethoxyphenyl, -2,3-dimethoxyphenyl, -COO-alkyl, -COO-alkenyl, - COO-Cylcloalkyl, -COO-aryl, -COO-heteroaryl, and X, Y may optionally also = = condensed aromatic, where X and Y can form aromatic or aliphatic homo- or heterocyclic ring systems with up to n ring-forming atoms, and where the number n can assume values of 5 to 8, and the respective ring systems in turn contain up to n-1 alkyl groups, hydroxyl groups, carboxyl groups, amino groups , Nitrile functions, sulfur-containing substituents, ester groups and / or ether groups may be substituted. The stated thiazoles can be present both as free base and as salt: for example as fluoride, chloride, bromide, iodide, sulfate, carbonate, ascorbate, acetate or phosphate. In particular, as halogen salts, such as chloride and bromide.

Advantageously, X is selected from the group of substituted phenyls, where the substituents (Z) can be selected from the group -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH2, - CN, acetyl and the same or different.

X is particularly preferably selected from the group of phenyl groups substituted by one or more hydroxyl groups, where the substituent (Z) can be selected from the group -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH2, -CN, acetyl and the following generic Structure is preferred in which Y, R ¹ and R ² may have the properties defined above.

Particularly advantageous are those compounds in which

Y = H

Ri = -Ci-C24-alkyl (linear and branched), -Ci-C24-alkenyl (linear and branched), -d-Cs-cycloalkyl, -Ci-Ce-cycloalkyl-alkylhydroxy, -C1-C24 alkylhydroxy (linear and .alpha Branched), -C1-C24 alkylamine (linear and branched), -Ci-C24-alkylaryl (linear and branched), -Ci-C24-alkyl-aryl-alkyl-hydroxy (linear and branched), -Ci-C24-alkylheteroaryl (linear and branched), -d-C24-alkyl-0-Ci-C24-Alkyl (linear and branched), -C1-C24 Alky-Morpholino, -C1-C24 Alky-Piperidino, -C1-C24 Alky-Piperazino, C1-C24 Alky-piperazino-N-alkyl,

R2 = H, -Ci-C24-alkyl (linear and branched).

Z = -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN, acetyl.

Particularly preferred are those compounds in which

Y = H

Ri = -Ci-C24-alkyl (linear and branched), -Ci-C24-alkenyl (linear and branched), -Ci-Ce- cycloalkyl, -d-Ce-cycloalkyl-alkylhydroxy, -C1-C24 alkylhydroxy (linear and Branched), -C1-C24 alkylamine (linear and branched), -Ci-C24-alkylaryl (linear and branched), -Ci-C24-alkyl-aryl-alkyl-hydroxy (linear and branched), -Ci-C24-alkylheteroaryl (linear and branched), C1-C24-alkyl-0-Ci-C24-Alkyl (linear and branched), -C1-C24 Alky-Morpholino, -C1-C24 Alky-Piperidino, -C1-C24 Alky-Piperazino, C1-C24 Alky-piperazino-N-alkyl,

R ₂ = H.

The connections

- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) pivalamide

IV- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) Isobutyramide

10

A '- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) cyclohexanecarboxamide

and

A '- (4- (2,4-dihydroxyphenyl) thiazo1-2-yl) -2- (4- (hydroxymethyl) phenyl) acetamides are the preferred according to the invention.

It was therefore unforeseeable for the skilled person that the physiologically tolerated alkylamidothiazoles used according to the invention or cosmetic or dermatological preparations containing such

act better as an antioxidant

- work better as radical scavengers

better prevent the binding of harmful photoproducts to lipids, DNA and proteins

better to work against skin aging

better protect the skin against photoreactions

- would prevent better inflammatory reactions

as the active ingredients, drug combinations and preparations of the prior art. Furthermore, it had not been foreseen that the alkylamidothiazoles in cosmetic or Dermatological preparations have higher stability than comparable active ingredients, for example as vitamin C.

According to the invention, therefore, the use of physiologically acceptable alkylamidothiazoles as antioxidants and their use for the control and / or prophylaxis of caused by oxidative stress skin aging and inflammatory reactions.

The cosmetic or dermatological formulations according to the invention may be composed as usual and used for the treatment, care and cleansing of the skin and / or the hair and as a make-up product in decorative cosmetics. They preferably contain 0.000001 wt .-% to 10 wt .-%, preferably 0.0001 wt .-% to 3 wt .-%, in particular 0.001 - 1, 0 wt .-%, based on the total weight of the composition , on one or more physiologically acceptable alkylamidothiazoles.

For use, the cosmetic and dermatological preparations according to the invention are applied to the skin and / or the hair in a sufficient amount in the manner customary for cosmetics. Advantageously, the active ingredient used according to the invention can be incorporated into customary cosmetic and dermatological preparations which may be in various forms. So they can z. A solution, a water-in-oil (W / O) or oil-in-water (O / W) type emulsion, or a multiple emulsions, such as water-in-oil-in-water type (W / O / W) or oil-in-water-in-oil (O / W / O), a hydrodispersion or lipodispersion, a Pickering emulsion, a gel, a solid stick or even an aerosol.

According to the invention emulsions, z. B. in the form of a cream, a lotion, a cosmetic milk are advantageous and contain z. As fats, oils, waxes and / or other fatty substances, and water and one or more emulsifiers, such as are commonly used for such a type of formulation.

It is also possible and advantageous for the purposes of the present invention to according to the active ingredient used in aqueous systems or surfactant preparations for cleaning the skin and hair.

It is of course known to the person skilled in the art that sophisticated cosmetic compositions are usually not conceivable without the customary auxiliaries and additives. These include, for example, bodying agents, fillers, perfume, dyes, emulsifiers, additional active ingredients such as vitamins or proteins, light stabilizers, stabilizers, insect repellents, alcohol, water, salts, antimicrobial, proteolytic or keratolytic substances, etc.

Mutatis mutandis, corresponding requirements apply to the formulation of medical preparations.

Medicinal topical compositions according to the present invention usually contain one or more drugs in effective concentration. For the sake of simplicity, a clear distinction between cosmetic and medical use and corresponding products is made to the statutory provisions of the Federal Republic of Germany (eg Cosmetics Ordinance, Food and Medicinal Products Act). It is also advantageous to add the active ingredient used according to the invention as an additive to preparations which already contain other active ingredients for other purposes.

Accordingly, cosmetic or topical dermatological compositions according to the present invention, depending on their structure, for example, be used as skin protection cream, cleansing milk, sunscreen lotion, nutrient cream, day or night cream, etc. It is possible and advantageous, the compositions of the invention as a basis for pharmaceutical To use formulations. For use, the cosmetic and dermatological preparations are applied according to the invention in the usual manner for cosmetics on the skin and / or hair in sufficient quantity. Particularly preferred are those cosmetic and dermatological preparations which are in the form of a sunscreen. Advantageously, these may additionally contain at least one further UVA filter and / or at least one further UVB filter and / or at least one inorganic pigment, preferably an inorganic micropigment.

The cosmetic and dermatological preparations according to the invention may contain cosmetic adjuvants such as are commonly used in such preparations, e.g. Preservatives, bactericides, perfumes, foaming inhibitors, dyes, pigments having a coloring effect, thickeners, moisturizing and / or moisturizing substances, fats, oils, waxes or other common ingredients of a cosmetic or dermatological formulation such as alcohols, polyols, Polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives. An additional level of conventional antioxidants is generally preferred. According to the invention, all antioxidants which are suitable or customary for cosmetic and / or dermatological applications can be used as favorable antioxidants.

The amount of the aforementioned antioxidants (one or more compounds) in the preparations is preferably from 0.001 to 30% by weight, particularly preferably from 0.05 to 20% by weight, in particular from 1 to 10% by weight, based on the Total weight of the preparation.

If the cosmetic or dermatological preparation in the sense of the present invention is a solution or emulsion or dispersion, the following can be used as solvent:

Water or aqueous solutions

Oils, such as triglycerides of capric or caprylic acid, but preferably castor oil; Fats, waxes and other natural and synthetic fats, preferably esters of fatty acids with lower C-number alcohols, e.g. with isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with alkanoic acids low C number or with

fatty acids;

Alcohols, diols or polyols of low C number, and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether and analogous products.

In particular, mixtures of the abovementioned solvents are used. For alcoholic solvents, water can be another ingredient.

If the cosmetic or dermatological preparation in the sense of the present invention is a solution or emulsion or dispersion, it is possible to use as solvent:

- water or aqueous solutions

Oils, such as triglycerides of capric or caprylic acid, but preferably castor oil; Fats, waxes and other natural and synthetic fats, preferably esters of fatty acids with lower C-number alcohols, e.g. with isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with alkanoic acids of low C number or with fatty acids;

Alcohols, diols or polyols of low C number, and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether and analogous products ,

Suitable propellants for cosmetic and / or dermatological preparations which can be sprayed from aerosol containers in the context of the present invention are the customary known highly volatile, liquefied propellants, for example hydrocarbons (propane, butane, isobutane), which can be used alone or mixed with one another. Also, compressed air is advantageous to use. Of course, those skilled in the art will recognize that there are inherently nontoxic propellants which would generally be useful in the practice of the present invention in the form of aerosol preparations, but which are nevertheless of concern for the environment or other uses. should be avoided, in particular fluorocarbons and chlorofluorocarbons (CFCs).

Cosmetic preparations in the context of the present invention may also be present as gels which, in addition to an effective content of the active ingredient according to the invention and solvents used for this purpose, preferably water, also organic thickening agents, e.g. Gum arabic, xanthan gum, sodium alginate, cellulose derivatives, preferably methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or inorganic thickening agents, e.g. For example, aluminum silicates such as bentonites, or a mixture of polyethylene glycol and polyethylene glycol stearate or distearate. The thickener is present in the gel e.g. in an amount between 0, 1 and 30 wt .-%, preferably between 0.5 and 15 wt .-%, included. It is advantageous according to the invention to use, in addition to the combinations according to the invention, further oil-soluble UVA filters and / or UVB filters in the lipid phase and / or further water-soluble UVA filters and / or UVB filters in the aqueous phase.

According to the invention, the sunscreen formulations can advantageously comprise further substances which absorb UV radiation in the UVB range, the total amount of the filter substances being e.g. 0, 1 wt .-% to 30 wt .-%, preferably 0.5 to 10 wt .-%, in particular 1 to 6 wt .-%, based on the total weight of the preparations in order to provide cosmetic preparations, which protect the skin from the entire range of ultraviolet radiation. They can also serve as sunscreen.

Wirkunqsnachweis:

Neutrophil granulocytes are capable of releasing large amounts of reactive oxygen species (ROS) in response to a stimulus in an "oxidative burst." These oxygen radicals are designed to kill bacteria or (yeast) fungi that have invaded wounds, for example Experimentally, the oxidative burst can be triggered by bacterial components such as formylated peptides, which in principle means that the production of ROS by granulocytes is a protective reaction of the body against microbial infections It is also important to avoid tissue damage (oxidative stress) and an excess granulocyte reaction. A reduction in the release of reactive oxygen radicals by antioxidants can therefore also be interpreted as a reduction of the oxidative stress and thus demonstrate their general anti-oxidative activity.

For the assay used here, neutrophil granulocytes were isolated by gradient centrifugation from human blood and incubated with different concentrations of the drug. Subsequently, the burst with the bacterial peptide formyl-methionyl-leucyl-phenylalanine (fMLP) was triggered and the release of the radicals detected by a luminol chemiluminescence. The test is known from the literature and should therefore not be continued here.

The active ingredient N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) -isobutyramide was investigated in the test described above and shows in this experiment a dose-dependent activity in the concentration range> 5.56 μΜ (see FIG ). N- (4- (2,4-

Dihydroxyphenyl) thiazol-2-yl) -isobutyramide thus shows a very good anti-oxidative effect.

Synthesis Instructions of Exemplary Selected Alkylamidothiazoles:

2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone:

PG = COOCH ₃

Mitchell, David; Doecke, Christopher W .; Hay, Lynne A .; Koenig, Thomas M .; Wirth, David D. Tetrahedron Letters, 1995

A solution of 60 g (369 mmol) of 2,4-dihydroxyacetophenone and 186 ml of triethylamine in 900 ml of tetrahydrofuran was cooled to 0 ° C. and 93 ml of methyl chloroformate in 400 ml of tetrahydrofuran were slowly added dropwise. It forms a white precipitate. After 3 Stirring at room temperature for hours, the reaction is complete (TLC control). The precipitate was filtered off with suction and washed with plenty of tetrahydrofuran. The filtrate was evaporated to dryness, taken up in ethyl acetate, washed with 1 N HCl and NaCl solution (sat.) And dried over magnesium sulfate, filtered from magnesium sulfate and the ethyl acetate was concentrated on a rotary evaporator. 105 g of 2,4-bismethoxycarbonyloxy-acetophenone were obtained. ¹ H NMR (DMSO-D ₆ ): 8.05 (d, 1H), 7.38 (d, 1H), 7.36 (s, 1H), 3.86 (d, 6H). The product was used without further purification. To the solution of 105 g of 2,4-bis-methoxycarbonyloxy-acetophenone in chloroform (1000 ml), 63 g (392 mmol) of bromine in 450 ml of chloroform were added dropwise over 3 hours. Thereafter, the reaction was 15 minutes. Stirred at room temperature, the solvent was evaporated. The residue was stirred in ethyl acetate / n-hexane, the resulting precipitate was filtered off with suction. Recrystallization from ethyl acetate / n-hexane gave 100 g of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone. ¹ H NMR (DMSO-D ₆ ): 8.1 1 (d, 1H), 7.42 (m, 2H), 4.87 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H) ppm; mp 73-74 ° C.

N- (4- (2,4-DihvdroxyDhenyl) thiazol-2-yl) -Divalamid:

126 g (1.66 mmol) of thiourea were initially charged in toluene (1000 ml) and 100 g (829 mmol) of pivaloyl chloride were added dropwise. The reaction solution was boiled under reflux for 3 hours to give 2 phases. The upper phase was decanted off and cooled. The precipitated colorless needles were filtered off with suction and washed with cyclohexane and dried in vacuo. Yield: 64 g. ¹ H NMR (DMSO-D ₆ ): 10.27 (s, 1H), 9.74 (s, 1H), 9.40 (s, 1H), 1.19 (s, 9H) ppm. 107.7 g (310 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were boiled with 49.7 g (13.6 mmol) of N-pivaloylthiourea and 39.2 g (466 mmol) of NaHCO ₃ in 1.21 ethanol under reflux for 0.5 h , The reaction solution was cooled and treated with 50.6 g (1 .27 mol) of NaOH in 250 ml of water. After stirring for 30 min at room temperature, the reaction solution was taken up in 300 ml of water and neutralized with 2N HCl. The resulting precipitate was filtered off and recrystallized from ethanol / water. There were obtained 80 g of thiazole. ¹ H NMR (DMSO-D ₆ ): 1.77 (bs, 1H), 1.02 (bs, 1H), 9.47 (bs, 2H), 7.65 (d, 1H), 7.39 (s, 1H) , 6.30 (s, 1H), 6.28 (d, 1H), 1 .27 (s, 9H) ppm; mp 257-259 ° C. N- (4- (2A-dihydroxyphenyl) tiazole-2-yl) -isobutyramide:

1 14 g (1 .5 mol) of thiourea were initially charged in toluene (800 ml) and 80 g (0.75 mol) of isobutyryl chloride were added dropwise. The reaction solution was boiled under reflux for 3 hours to give 2 phases. The upper phase was decanted off and cooled. The precipitated white crystals were filtered off with suction and washed with toluene and dried in vacuo. Yield: 62 g. ¹ H NMR (DMSO-D ₆ ): 1.103 (bs, 1H), 9.66 (bs, 1H), 9.35 (bs, 1H), 2.72 (m, 1H), 1.03 (2, 6H ) ppm;

89 g (260 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were refluxed with 37.5 g (260 mmol) of N-isobutyrylthiourea and 32 g (380 mmol) of NaHCO ₃ in 1000 ml of ethanol for 0.5 h cooked. The reaction solution was cooled and treated with 41 g (0.93 mol) of NaOH in 250 ml of water. After stirring for 30 min at room temperature, the reaction solution was taken up in 300 ml of water and adjusted to pH = 3 with 2N HCl. The resulting precipitate was filtered off and recrystallized from ethanol / water. There were obtained 56 g of thiazole. ¹ H NMR (DMSO-D ₆ ): 12.16 (bs, 1H), 10.88 (bs, 1H), 9.47 (bs, 1H), 7.65 (m, 1H), 7.41 (s, 1H), 6.32 (m, 2H), 2.75 (m, 1H), 1.14 (d, 6H) ppm. mp: 243-245 ° C.

N- (4- (2,4-DihvdroxyDhenyl) thiazol-2-yl) -butyramide:

143 g (1 .88 mol) of thiourea were initially charged in toluene (1000 ml) and 100 g (0.93 mol) of n-butyryl chloride were added dropwise. The reaction solution was boiled under reflux for 3 hours to give 2 phases. The upper phase was decanted off and cooled. The precipitated slightly yellowish crystals were filtered off and washed with toluene and dried in vacuo. Yield: 88 g. Ή NMR (DMSO-D ₆ ): 1.03 (bs, 1H), 9.65 (bs, 1H), 9.33 (bs, 1H), 2.33 (t, 2H), 1.53 (m, 2H), 0.86 ( t, 3H) ppm; mp: 1 15-188 ° C

92 g (265 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were boiled under reflux for 0.5 h with 38.75 g (265 mmol) of N-butyrylthiourea and 34 g (397 mmol) of NaHCO 3 in 900 ml of ethanol , The reaction solution was cooled and treated with 37 g (0.93 mol) of NaOH in 300 ml of water. After stirring for 30 min at room temperature, the reaction solution was taken up in 300 ml of water and neutralized with 2N HCl. The resulting precipitate was filtered off and recrystallized from ethanol / water. There were obtained 67 g of thiazole. ¹ H NMR (DMSO-D ₆ ): 12.18 (bs, 1H), 10.89 (bs, 1H), 9.48 (bs, 1H), 7.65 (1 arom. H), 7.40 (s, 1H), 6.31 (2 arom. H), 2.43 (t, 2H), 1.64 (m, 2H), 0.91 (t, 3H) ppm. mp: 227-229 ° C. N- (4- (2,4-DihydroxyDhenyl) thiazol-2-yl) -acetamide:

4.71 g (13.6 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were refluxed with 1.61 g (13.6 mmol) of N-acetylthiourea and 1.72 g (20.4 mmol) of NaHCO 3 in 45 ml of ethanol for 0.5 h , The reaction solution was cooled and treated with 2.0 g (50 mmol) of NaOH in 20 ml of water. After stirring for 20 min at 0 ° C., the reaction solution was taken up in 30 ml of water and treated with half-conc. HCl neutralized. The resulting precipitate was filtered off and recrystallized from ethanol / water. There were 2.73g

Product received. ¹ H NMR (DMSO-D ₆ ): 12.20 (b, 1H), 10.85 (s, 1H), 9.46 (s, 1H), 7.64 (m, 1H), 7.38 (s, 1H), 6.28 (m, 2H), 2.15 (s, 3H) ppm; mp 264-264 ° C.

N- (4- (2A-DihvdroxyDhenyl) thiazol-2-yl) -4- (Hvdroxymethyl) cvclohexancarboxamid:

Carrying out analogous literature.

BANYU Pharmaceutical Co., Ltd., EP2072519A1, 2009

Yield: 96%, ¹ H NMR (DMSO-D ₆ ): 12.03 (bs, 1H), 3.85, 3.82 (2 xd, 2H), 2.50, 2.47 (2 xm, 1H), 2.00 (s, 3H) , 0.95-1.90 (m, 9H) ppm;

95 g (0.47 mol) of 4-acetoxymethylcyclohexanecarboxylic acid were refluxed in 350 ml of thionyl chloride for 2 h. After removal of the excess thionyl chloride in vacuo, the residue was taken up in 11 toluene and 71 g (0.94 mol) of thiourea added. The reaction solution was refluxed for 3 hours and then filtered hot. After cooling the mother liquor, the resulting white crystals were filtered off, washed with toluene and dried in vacuo. Yield: 59 g. ¹ H NMR (DMSO-De): 1, 1 .03, 10.97 (2 xs, 1H), 9.64 (bs, 1H), 9.35 (bs, 1H), 3.93, 3.82 (2 xd, 2H), 2.61 , 2.42 (2 xm, 1H), 2.00 (s, 3H), 1.60 (m, 8H), 1.35, 0.94 (2 xm, 1H) ppm;

79 g (228 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were with 59 g (228 mmol) of N- (4-Acetoxymethylcyclohexylcarbonyl) thiourea and 29 g (340 mmol) of NaHCOs in 1000 ml of ethanol under Reflux cooked for 0.5h. The reaction solution was cooled and treated with 73 g (1.8 mol) of NaOH in 300 ml of water. After stirring for 30 min at room temperature, the reaction solution was taken up in 300 ml of water and adjusted to pH = 3 with 2N HCl. The resulting precipitate was filtered off and recrystallized from ethanol / water. There were obtained 47 g of thiazole. ¹ H NMR (DMSO-D ₆ ): 12.15, 12.10 (2 xs, 1H), 10.96 (2 xs, 1H), 9.47 (br, 2H), 7.64 (d, 1H), 7.39 (s, 1 H), 6.29 (m, 2H), 4.40 (br, 1H), 3.32, 3.23 (2 xd, 2H), 2.65, 2.44 (2 xm, 1H), 1.90 (m, 1H), 1.78 (m , 2H), 1.50 (m, 5H), 0.94 (m, 1H) ppm. mp: 152-160 ° C.

N- (4- (2A-Dihvdroxyphenyl) thiazol-2-yl) -cvclohexancarboxamid:

52 g (0.68 mol) of thiourea were initially charged in toluene (500 ml) and 50 g (0.34 mol) of cyclohexanoyl chloride were added dropwise. The reaction solution was boiled under reflux for 3 hours to give 2 phases. The upper phase was decanted off and cooled. The precipitated crystals were filtered off, washed with toluene and recrystallized from methanol. Yield: 35 g. ¹ H NMR (DMSO-D ₆ ): 10.98 (bs, 1H), 9.65 (bs, 1H), 9.32 (bs, 1H), 2.49 (t, 1H), 1.75 (m, 4H) , 1.61 (m, 1H), 1.18 (m, 5H) ppm. 92 g (265 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were boiled with 49.4 g (265 mmol) of N-cyclohexanoylthiourea and 34 g (397 mmol) of NaHCO 3 in 900 ml of ethanol under reflux for 0.5 h , The reaction solution was cooled and treated with 37 g (930 mmol) of NaOH in 300 ml of water. After stirring for 30 min at room temperature, the reaction solution was taken up in 300 ml of water and neutralized with 2N HCl. The ethanol was largely removed on a rotary evaporator. The resulting precipitate was filtered off and recrystallized from ethanol / water. There were obtained 70 g of thiazole. ¹ H NMR (DMSO-De): 12.14 (bs, 1H), 1 1 .00 (bs, 1H), 9.48 (bs, 1H), 7.64 (1 arom. H), 7.39 (s, 1H ), 6.30 (2 arom. H), 2.49 (m, 1H), 1.84 (m, 2H), 1.76 (m, 2H), 1.65 (m, 1H), 1.42 (m, 2H), 1.25 (m , 3H) ppm. mp: 262-266 ° C.

N- (4- (2A-dihvdroxyDhenyl) thiazol-2-yl) -2- (4- (hvdroxymethyl) Dhenyl) acetamide:

1. Ac ₂ O, pyridine

Carrying out analogous literature.

BANYU Pharmaceutical Co., Ltd., EP2072519A1, 2009

Yield: 76%, ¹ H NMR (DMSO-D ₆ ): 12.31 (bs, 1H), 7.26 (m, 4H), 5.05 (s, 2H), 3.57 (s, 2H), 2.05 (s, 3H) ppm;

3.7 g (18 mmol) of 4-acetoxymethylphenylacetic acid were refluxed in 40 ml of thionyl chloride for 2 h. After removal of the excess thionyl chloride in vacuo, the residue was taken up in 70 ml of toluene and 2.7 g (36 mmol) of thiourea was added. The reaction solution was refluxed for 3 hours and then the solvent was removed in vacuo. The purification was carried out by column chromatography with cyclohexane / ethyl acetate 1/1 on silica gel. Yield: 2.7 g. ¹ H NMR (DMSO-D ₆ ): 1 1 .29 (bs, 1H), 9.55 (bs, 1H), 9.40 (bs, 1H), 7.30 (m, 4H), 5.04 (s, 2H) , 3.71 (s, 2H), 2.05 (s, 3H) ppm;

3.5 g (10 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were mixed with 2.7 g (10 mmol) of N- [2- (4-acetoxymethylphenyl) acetyl] thiourea and 1 .3 g (15 mmol ) NaHCC boiled in 50 ml of ethanol at reflux for 0.5 h. The reaction solution was cooled and treated with 4.0 g (0.1 mol) of NaOH in 20 ml of water. After 2 h stirring at 60 ° C, the reaction solution was taken up in 100 ml of water and adjusted to pH = 3 with 2N HCl. The resulting precipitate was filtered off and recrystallized from ethanol / water. There were obtained 1.3 g of thiazole. ¹ H NMR (DMSO-D ₆ ): 12.44 (s, 1H), 10.80 (s, 1H), 9.48 (s, 1H), 7.66 (d, 1H), 7.41 (s, 1H), 7.29 (m, 4H), 6.32 (m, 2H), 5.13 (t, 1H), 4.47 (d, 2H), 3.77 (s, 2H) ppm. mp: 254-256 ° C.

The following examples are intended to illustrate the present invention without limiting it. Unless indicated otherwise, all amounts, proportions and percentages are based on the weight and the total amount or on the total weight of the preparations. formulation Examples

O / W emulsions

Acrylates / C 10-30 Alkyl Acrylate Crosspolymers 0,10

Trisodium EDTA + water (20%

aqueous solution) - 1.00

Tapioca strength 1, 00

Distarch phosphate 1, 00

Aluminum starch Octenyl succinate 2.00

Acrylonitrile-methacrylonitrile-methyl-methacrylate copolymer + Isopentane +

Magnesium hydroxides 1, 00

N- (4- (2,4-Dihydroxyphenyl) thiazol-2-yl) isobutyramide 0.10

Ethylhexyl methoxycinnamate 1, 00 2.00

Diethylamino Hydroxybenzoyl Hexyl benzoate 0.50 1.00

Homosalates (3,3,5-trimethylcyclohexylsalicylate) 2.00 2.00

Phenylbenzimidazole sulfonic acid 1, 00 1, 00

Titanium dioxide 0.20

Glyceryl Glucoside 3.00

Short chain hyaluronic acid 0.10

Long-chain hyaluronic acid 0.10

4-butyl-resorcinol 0.30

Magnolia Bark Extract 0.10

Octadecene Dioic acid 0.05

Folic acid 0.01

Carnitine 0.50

Creatine 0, 10

Alpha-glucosylrutin 0.01

Taurine 0.30

Mulberry Root Extract 0.01

Sodium Metabisulfite 0.10 - Diethylhexyl syringylidenmalonate 0, 13 0.13

Sodium hydroxide q.s. q.s.

3-methyl-5-phenyl-1-pentanol 0, 10

Coumarin 0.05

Ethyl linalool 0.01

Ascorbyl palmitate 0.10 -

Perfume q.s. q.s.

Water ad 100 ad 100

Formulation Example 3 4

Chemical name% by weight% by weight

Glyceryl Stearate Citrate 2 1, 5

Behenyl Alcohol 1, 5 1

C12-15 alkyl benzoate 2 2,5

Caprylic acid / capric acid triglyceride 2 2

Cetyl Alcohol 2 2

Cetylstearyl alcohol 4

Cyclopentasiloxanes 1

Cyclomethicone 1 1

Dicaprylyl carbonate 2

Paraffin Liquidum (mineral oil) 0.5

Octyldodecanol 2

Isopropyl Palmitate 1.5 -

Dimethicone 0.5 1

Glycerol 3 5

Methylparaben 0.2 0.15

Phenoxyethanol 0.4 0.6

Propylparaben 0, 1

Methylisothiazolinone 0.05

Piroctone Olamine 0.1

Sodium benzoate 0, 1 0.1

Glyceryl caprylate 0.25 -

Ethylparaben 0, 1 -

Carbomer 0.2

Sodium polyacrylate 0.4

Xanthan gum 0.1

Acrylates / C 10-30 Alkyl Acrylate Crosspolymers 0.1

Tapioca starch 0.5 - Nylon 12 (1,8-diazacyclotetradecane-2,7-dione homopolymer) 1

Polymethylsilsesquioxanes 1

Aluminum starch Octenyl succinate 1

N- (4- (2,4-Dihydroxyphenyl) thiazol-2-yl) isobutyramide 0.25 0.15

N- (4- (2,4-Dihydroxyphenyl) thiazol-2-yl) pivalamide 0.10 0.10

N- (4- (2,4-Dihydroxyphenyl) thiazol-2-yl) -butyramide 0.01 0.25

N- (4- (2,4-Dihydroxyphenyl) thiazol-2-yl) cyclohexanecarboxamide 0.2 0.10

Glycyrrhiza Infi ata Root Extract 0.03 0.05

Titanium dioxide 1

Octocrylene 1 2

Bis-Ethylhexyloxyphenol Methoxyphenyl

Triazine 1 1

2-ethylhexyl methoxycinnamate 2 2

Homosalate (3,3,5-trimethylcyclohexylsalicylate) 1 1

Sodium hydroxide q.s. q.s.

Trisodium EDTA 0.15

1- (1,2,3,4,5,6,7,8-octahydro-2,3,8,8, -tetramethyl-2-naphthyl) ethane-1-ones 0, 1

Geraniol 0.05

Hexylcinnamal 0.05

Perfume 0.1 0.2

Water ad 100 ad 100 Formulation Examples 5 6

Chemical name% by weight% by weight

Polyglyceryl-3 methyl glucose distearate 2 2.5

Sorbitan Stearate 1, 5 3

C12-15 alkyl benzoate 2.5 2.5

Caprylic acid / capric acid triglycerides 2.5 2.5

Stearyl alcohol 1 1, 5

Cyclomethicone 3 1

Isopropyl myristate 2.5

Isopropyl palmitate 2

Ethylhexyl stearate - 1.5

Dimethicone 1

Decyl Oleate 1.5 -

Glycerol 5 7.5

Butyrospermum Parkii Butter 2 -

Squalane 0,5 -

Sodium benzoate 0, 1 0.1

Methylparaben 0.2 0.2

Phenoxyethanol 0.4 0.4

Propylparaben 0, 1

Benzethonium chloride - 0.1

Caprylyl glycol - 0.2

Ethylhexylglycerol - 0.2

Pentylene glycol - 0.1

Carbomer 0.15 0.1

Ammonium acryloyldimethyltaurate / VP

Copolymer - 0.2

Carrageenan 0, 1

Trisodium EDTA 1

Tapioca starch 1 Distarch phosphate 1

Acrylonitrile-methacrylonitrile-methyl-methacrylate copolymer + Isopentane +

Magnesium hydroxides 1

N- (4- (2,4-Dihydroxyphenyl) thiazol-2-yl) isobutyramide 0.01 0.25

N- (4- (2,4-Dihydroxyphenyl) thiazol-2-yl) pivalamide 0.2 0.10

N- (4- (2,4-Dihydroxyphenyl) thiazol-2-yl) -butyramide 0.25 0.15

N- (4- (2,4-Dihydroxyphenyl) thiazol-2-yl) cyclohexanecarboxamide 0.10 0.10

Diethylamino Hydroxybenzoyl Hexyl benzoate 1 2

Ethylhexyl methoxycinnamate 1 1

Butyl methoxydibenzoylmethane 2 2

Octocrylene 1 1

Titanium dioxide - 0.5

Sodium hydroxide q.s. q.s.

Ubiquinone 0, 1

Sodium metabisulfite 0.15

BHT (tert-butylhydroxytoluene) 0.05

Linalyacetate 0.05

Hexyl salicylate 0.05

Benzyl salicylate 0.01 -

Perfume q.s. q.s.

Water ad 100 ad 100

Claims

claims

Use of physiologically tolerated alkylamidothiazoles as antioxidant and / or as radical scavenger in cosmetic or dermatological preparations.

Use according to Claim 1, characterized in that the content of alkylamidothiazoles in the cosmetic or dermatological preparations is in the range from 0.000001 to 10.0% by weight, in particular from 0.0001 to 3.0% by weight and completely is particularly selected from 0.001 to 1 wt .-%, each based on the total weight of the composition.

Use according to any one of the preceding claims, characterized in that the alkylamidothiazole (s) are substances of the general formula

are at which

R ¹ , R ² , X and Y can be different, sometimes identical or identical, and can mean independently of one another:

Ri = -Ci-C24-alkyl (linear and branched), -Ci-C24-alkenyl (linear and branched), -Ci-Ce-cycloalkyl, -d-Ce-cycloalkyl-alkylhydroxy, -C1-C24 alkylhydroxy (linear and .alpha branched), -C1-C24 alkylamine (linear and branched), -Ci-C24-alkylaryl (linear and branched), -Ci-C24-alkylaryl-alkyl-hydroxy (linear and branched), -Ci-C24-alkylhetero - aryl (linear and branched), -Ci-C24-alkyl-0-Ci-C24-Alkyl (linear and branched), -C1-C24 Alky-Morpholino, -C1-C24 Alky-Piperidino, -C1-C24 Alky- Piperazino, C1-C24 alkylpiperazino-N-alkyl, R2 = H, -Ci-C24-alkyl (linear and branched), -Ci-C24-alkenyl (linear and branched), - d-Ce-cycloalkyl, -d-C24-hydroxyalkyl (linear and branched), -Ci- C24-Alkylaryl (linear and branched), -Ci-C24-Alkylheteroaryl (linear and branched), means

X = -H, -CC-C24-alkyl (linear and branched), -Ci-C24-alkenyl (linear and branched), --C1-Ce-cycloalkyl, -Ci-C24-aryl (optionally mono- or polysubstituted with -OH, -F, - Cl, -Br, -I, -OMe, -NH _2, -CN), -C-C24-heteroaryl (optionally mono- or poly-substitu ated with -OH, -F, -Cl. -Br, -I, -OMe, -NH ₂ , -CN), -Ci-C ₂ 4-alkylaryl (linear and branched), -Ci-C 24 -alkylheteroaryl (linear and branched), -aryl (optionally mono- or straight-chain) polysubstituted by -OH, -F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN), -phenyl, -2,4-dihydroxyphenyl, -2,3-dihydroxyphenyl, -2,4 Dimethoxyphenyl, -2,3-dimethoxyphenyl,

Y = H, -Ci-C24-alkyl (linear and branched), -Ci-C24 alkenyl (linear and branched), -C1 Ce-cycloalkyl, -Ci-C24-aryl, -Ci-C24-heteroaryl, -Ci -C24-alkylaryl (linear and branched), -Ci-C24-alkylheteroaryl (linear and branched), -aryl, -phenyl, -2,4-dihydroxyphenyl, -2,3-dihydroxyphenyl, -2,4-dimethoxyphenyl, - 2,3-dimethoxyphenyl, COO-alkyl, -COO-alkenyl, -COO-Cylcloalkyl, -COO-aryl, -COO-heteroaryl, and X, Y may optionally also = = condensed aromatic mean, wherein X and Y with each other aromatic or aliphatic homo- or heterocyclic ring systems having up to n ring-forming atoms, and where the number n can assume values of 5 to 8, and the respective ring systems in turn contain up to n-1 alkyl groups, hydroxyl groups, carboxyl groups, amino groups, nitro functions, Sulfur-containing substituents, ester groups and / or ether groups may be substituted, wherein the or the alkylamidothiazoles both as a free base as well as cosmetically and dermatologically usable salts may be present.

4. Use according to one of the preceding claims, characterized in that X is selected from the group of substituted phenyl groups and Y, R ¹ and R ^{2 are} the can have defined properties in claim 3.

5. Use according to one of the preceding claims, characterized in that X is selected from the group of substituted phenyl groups, in particular selected from the group of substances having the following structure:

where the substituents (Z) can be chosen from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -OMe, -Nh, -CN, acetyl and the same or different and Y, R ¹ and R ² may have the properties defined in claim 3,

6. Use according to one of the preceding claims, characterized in that the alkylamidothiazole (s) have the structure:

wherein the substituent (Z) can be selected from the group -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN and Y, R ¹ and R ² as claimed in 3 defined properties can have.

7. Use according to one of the preceding claims, characterized in that the alkylamidothiazole (s) have the structure:

Y = H

Ri = -Ci-C24-alkyl (linear and branched), -Ci-C24-alkenyl (linear and branched), -Ci-Ce-cycloalkyl, -Ci-Ce-cycloalkyl-alkylhydroxy, -C1-C24 alkylhydroxy (linear and Branched), -C1-C24 alkylamine (linear and branched), -Ci-C24-alkylaryl (linear and branched), -Ci-C24-alkylaryl-alkyl-hydroxy (linear and branched), -Ci-C24-alkyl heteroaryl (linear and branched), -Ci-C24-alkyl-0-Ci-C24-Alkyl (linear and branched), -C1-C24 Alky-Morpholino, -C1-C24 Alky-Piperidino, -C1-C24 Alky-Piperazino, C1-C24 Alky-piperazino-N-alkyl,

R2 = H, -Ci-C24-alkyl (linear and branched).

Z = -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN, acetyl.

8. Active substance combinations according to one of the preceding claims, characterized in that the one or more alkylamidothiazoles have the structure:

Y = H

R1 = -Ci-C24-alkyl (linear and branched), -Ci-C24-alkenyl (linear and branched), -C1-Ce-cycloalkyl, -Ci-Ce-cycloalkyl-alkylhydroxy, -C1-C24 alkylhydroxy (linear and .alpha Branched), -C1-C24 alkylamine (linear and branched), -Ci-C24-alkylaryl (linear and branched), -Ci-C24-alkylaryl-alkyl-hydroxy (linear and branched), -Ci-C24-alkyl heteroaryl (linear and branched), -Ci-C24-alkyl-0-Ci-C24-Alkyl (linear and branched), -C1-C24 Alky-morpholino, -C1-C24 Alky-piperidino, -C1-C24 Alky-piperazino, -C1-C24 Alky-piperazino-N-alkyl,

R ₂ = H.

9. active substance combinations according to one of the preceding claims, characterized in that the one or more alkylamidothiazoles have the structure:

JV (4- (2,4-dihydroxyphenyl) thiazol-2-yl) pivalamide

A ^r - (4- (2,4-dihydroxyphenyl) thiazol-2-yl) butyramide

A / - (4- (2,4-dihydroxyphenyl) thiazol-2-yl) heptanamide

W- (4- (2,4-dihydroxyphenyl) tazole-2-yl) -6-hydroxyhexanamide

A '- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) -3-hydroxypropanamide

W (4- (2,4-dihydroxyphenyl) thiazol-2-yl) -2-methoxyacetamides

40