EP1286654A1

EP1286654A1 - Use of aryl oximes for the prophylaxis and/or treatment of erythema formation and/or inflammatory reactions of the skin

Info

Publication number: EP1286654A1
Application number: EP01940418A
Authority: EP
Inventors: Joachim BÜNGER; Hansjürgen Driller; Michael Schwarz; Wolfgang Wohlrab
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2000-05-24
Filing date: 2001-05-08
Publication date: 2003-03-05
Also published as: US20030157037A1; WO2001089468A1; JP2003534262A; AU7400201A

Abstract

The invention relates to the use of at least one aryl oxime of formula (I), wherein Y and Z, independent of one another, represent H, C1-18 alkyl, C2-18 alkenyl, C2-18 carboxyalkyl, C3-18 carboxyalkenyl or C2-18 alkanoyl; R represents C1-18 alkyl, C2-18 alkenyl, C3-8 cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or condensed systems; R<1>, R<2>, R<3> and R<4>, independent of one another, represent H, C1-12 alkyl, C2-12 alkenyl, C1-12 alkoxy, C3-8 cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, carboxy, hydroxy, chlorine, dialkylamine or sulfonyl. The inventive aryl oxime is used for the prophylaxis and/or treatment of erythema formation and/or inflammatory reactions of the skin.

Description

Use of aryloximes for the prophylaxis and / or treatment of erythema formation and / or inflammatory reactions of the skin

The present invention relates to the use of at least one aryloxime for the prophylaxis and / or treatment of erythema formation and / or inflammatory reactions of the skin.

In many diseases, inflammation can be observed as symptoms that either appear causally or appear secondarily as a result of pathological changes. They can also be caused by chemical or physical contaminants, bacteria, viruses and fungi. Inflammation is a multifunctional process of different morphological and functional factors. These factors affect both disorders in the cellular area, in blood circulation, inflammation-related transudation and exudation, infiltration and proliferation. As a result of these disorders, further changes can occur, so that Spongiosis, acanthosis or para-keratosis occur.

Mediator systems are involved in triggering, the sequence and the control of many of these processes. For example, the lymphokinins released by sensitized T lymphocytes are significantly involved in the cellular immune response with a large number of biological effects (Schöpf, E., Körting, GW (editor) Dermatologie u. Praxis, Vol. 1, Thieme: Stuttgart, New York ( 1980)). Furthermore, the effects of kinins, activated complement factors, lysosomal enzymes, cyclic nucleotides and various epidermal factors are known in this context. Prostaglandins and leukotrienes play a special role. As an example of a prostaglandin effect, a chemotactic effect on leukotrienes is known which reduces the vascular permeability after the kinins. In contrast, leukotrienes have a chemotactic effect on granulocytes and influence the contractility and permeability of vessels.

Apart from the histamine release, UV-B erythema is mediated by the arachidonic acid cascade, with an increased cyclooxygenase-mediated prostaglandin synthesis, in particular of PGE ₂ and PGF ₂ , being present. The lipoxygenase away via 5-HPETE and LTA4 leads to essential elements of inflammation, such as cellular infiltration of the inflamed tissue and edema formation (overview at: Gallin, J., Goldstein, IM, Snyderman R. (editor), Inflamation. Basic principles and clinical correlates, New York, Raven Press (1988)).

Various active substances are known for the treatment of inflammation. Corticosteroids are of greatest importance in the treatment of the above-mentioned mechanisms that lead to different skin diseases. Weak to moderately strong corticosteroids, mostly non-fluorinated derivatives of hydrocortisone, are mainly used to treat inflammatory, allergic and pruriginous skin diseases. However, depending on the active ingredient used, the type and duration of the treatment, undesirable side effects occur during treatment with corticosteroids, which must be observed and taken into account when using these substances (overview: Symposium in Topical Corticosteroids. In: Drugs Vol. 36 , 5 (1988)). For these reasons, non-steroidal anti-inflammatory active substances are preferably used, although the therapeutic effectiveness of the substances known hitherto is very limited and is usually below that of hydrocortisone. This applies to active ingredients such as salicylic acid, acetylsalicylic acid, bufexamac, bendazac, phenylbutazone, oxyphenbutazone, diflumidone, indomethacin and sometimes also antihistamines (Gloor, M .: pharmacology of dermatological external agents. Springer Verlag Berlin Heidelberg New York, (1982)).

UV radiation is one of the physical pollutants and has both positive and negative effects on human skin and the entire organism. With a suitable dosage, sun exposure increases the well-being and performance of the organism. The vitamin D synthesis is stimulated, and finally the coveted tan or pigmentation of the skin develops as a result of the radiation. The pigmentation is part of the skin's own protection, which is based on a variety of mechanisms. In connection with the intrinsic protection of the skin, in addition to pigmentation, the thickening of the homolayer (light calluses), the dark repair system (enzymatic DNA repair), the redox systems for controlling radical reactions and the synthesis of urocanic acid are particularly important (P. Finke, "Sunscreen" in W. Limbach, Cosmetics, 2nd edition, 1995, 147-163, Georg T ieme Verlag, Stuttgart). Excessive exposure to the sun leads to both acute skin damage, such as sunburn, and chronic changes, such as skin aging or skin cancer. Sunburn (erythema solare) mainly develops as a result of UV-B radiation. In contrast, UV-A radiation has a comparatively minor influence on its formation. Sunburn can range from mild redness to severe burns with blistering. Since these consequences occur at the earliest 4 to 6 hours after radiation, it is too late for countermeasures. Sunburn is evidence of acute skin damage that can be relevant to chronic skin changes. Multiple sunburns, especially in childhood, significantly increase the risk of skin cancer. The causes of this are damage, in particular the nucleic acids of human skin cells and faulty repair of the damaged deoxyribonucleic acid in the cell nucleus, and probably the immunosuppressive effect of UV radiation, ie the weakening of the immune response by UV radiation. Excessive UV-A and UV-B exposure contributes to skin aging or light aging, for example in the form of structural changes in the connective tissue (actinic elastosis). Excessive UV-B exposure is the main cause of chronic skin changes.

Due to a change in leisure behavior, such as extensive sunbathing or long-distance travel to countries with strong sun exposure, the dangers of UV damage to skin cells have increased significantly in recent years, which in turn has resulted in an increase in the risk of skin cancer (P. Finkel, "Sunscreen" in W. Umbach, Kosmetik, 2nd edition, 1995, 147-163, Georg Thieme Verlag, Stuttgart). Long-distance trips to countries with strong sunshine in winter represent a particular potential hazard. by Northern Europeans, is little pigmented and is not protected against strong sun exposure in tropical regions near the equator with a long sunshine per day. In addition, the risk of skin cancer has recently increased significantly due to the longer life expectancy of mankind and increasing UV radiation on the earth's surface, triggered by the decrease in the ozone layer.

To protect the skin against UV radiation, commercially available UV filters are conventionally used, which are incorporated into formulations, such as sun lotions or oils. be tested. However, if these sunscreens are used too late or too little, skin redness or even sunburn occurs.

PUVA therapy is a special form of UV radiation. The abbreviation PUVA stands for Psoralene plus UV-A and denotes photo-activated chemotherapy for the treatment of psoriasis. PUVA therapy is also used for vitiligo, cutaneous T-cell lymphoma, mastocytosis, scierodermia circumscripta, granuloma annular, polymorphic light dermatosis (prophylactic), prurigo, lying ruber planus, light urticaria, graft versus host reaction and akinic reticuloid. The area to be treated is selectively irradiated with UV-A rays (320-400 nm). Before exposure to UV-A rays, a photosensitizing substance, e.g. 8- or 5-methoxypsoralen, applied locally or orally. Cell division is impeded by the cross-linking of DNA strands.

The disadvantage of PUVA therapy is an increased risk of skin cancer with long-term treatment with high cumulative doses. Increased UV exposure during PUVA therapy therefore risks damaging the skin through a long treatment period.

It is therefore the object of the present invention to provide an agent which is suitable for the prophylaxis and / or treatment of erythema formation and / or inflammatory reactions of the skin, and in particular for the prophylaxis and / or treatment of by physical or chemical noxa and / or inflammatory reactions of the skin caused by foreign organisms is effective and, when irradiated with UV light, avoids and minimizes the formation of erythema and inflammatory reactions of the skin, so that an increase in the radiation intensity is made possible, especially in PUVA therapy, without causing it Risk of skin damage or even an increased risk of skin cancer.

This object is achieved according to the invention by using at least one aryloxime of the formula (I) in which mean:

Y, Z independently of one another H, Cι _ι-8 -alkyl, C _2-18 -alkenyl, C ₂ - ₁₈ - carboxyalkyl, C _3- i8-carboxyalkenyl, or C _2- ι ₈ alkanoyl;

R β C- alkyl, _2-1 C 8 alkenyl, C _{_3-8} cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or condensed systems;

Ri, R ₂ , ₃ and R independently of one another H, C _1-12 alkyl, C _2- -ι ₂ alkenyl, Cι-12 alkoxy, C ₃ - ₈ cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl , Carboxy, hydroxy, chlorine, dialkylamine or sulfonyl,

for the prophylaxis and / or treatment of erythema formation and / or inflammatory reactions of the skin.

It has surprisingly been found that aryl oximes of the formula (I) can be used in advance in clinically healthy patients and / or in the clinically symptom-free interval to suppress erythema formation or an inflammatory reaction of the skin.

Furthermore, it was surprisingly found that the aryloximes of the formula (I) also effectively combat skin damage caused by physical or chemical noxa and / or foreign organisms and that the active ingredient can also be applied prophylactically to the skin in order to provide effective protection against inflammatory reactions To serve skin caused by physical or chemical noxa and / or foreign organisms.

The aryloxime used according to the invention is represented by the formula (I):

in which mean:

Y, Z independently of one another H, -CC ₈ alkyl, C _2-18 alkenyl, C _{2- 8} -

Carboxyalkyl, C _3- i8 carboxyalkenyl or C _2- ι ₈ alkanoyl;

R Ci-is-alkyl, C ₂ -ιβ-alkenyl, C _3- 8 cycloalkyl, aryl, aralkyl, heteroaryl,

Heteroaralkyl or condensed systems;

R 1, R ₂ , R ₃ and R independently of one another are H, Cι_ι ₂ alkyl, C _2- ι ₂ alkenyl, C _1-12 alkoxy, C _3-8 cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, Carboxy, hydroxy, chlorine, dialkylamine or sulfonyl.

Alkyl, alkenyl, carboxyalkyl, carboxyalkenyl, alkanoyl, cycloalkyl, alkoxy, aryl, aryloxy and aralkyl can be unsubstituted or substituted. Alkyl, alkoxy, alkenyl, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, hydroxy, carboxy, carboxyalkylene, dialkylamine, sulfonyl and combinations thereof are preferred as substituents of these groups.

Alkyl in each case means straight-chain or branched alkyl and therefore preferably means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl , Heptadecyl and octadecyl.

Alkenyl means that one or more double bonds can be present in the specified alkylene.

Aryl stands for an aromatic C _6-2 o-hydrocarbon residue and preferably means phenyl. Aralkyl means an aryl-substituted alkyl group and preferably has the meaning of benzyl or phenethyl.

Cycloalkyl means a cyclic alkyl group and is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

Heteroaryl stands for an aromatic ring with heteroatoms, preferably for a nitrogen-containing ring, such as pyridinyl or pyrimidinyl.

Heteroaralkyl means an alkyl group substituted with heteroaryl and is preferably pyridinylmethyl and pyrimidinylmethyl.

The condensed systems are preferably the residues naphthyl, benzofuryl, quinolinyl, indolyl or cinnolinyl.

Dialkylamine stands for NRsRe, where R ₅ and R _{6 can be the} same or different and denote d- ₁₂ alkyl.

Z and Y are preferably independently a hydrogen atom, a Cι _-6 - alkyl group which may have at least one substituent selected from -OH, -COOH, -S0 ₃ H or NR ₅ R, an alkanoyl group, represented by -C ( O) R ₇ , in which R _{7 is} a C _1-6 alkyl group which may have at least one substituent selected from -OH, -COOH or -S0 ₃ H, or a CONHR ₈ group, in which R _{8 is} a C _{6- 2} means aryl group. Z and Y are particularly preferably independently of one another a hydrogen atom, - (CH ₂ ) _1-6 COOH, -CH ₂ CH (0H) CH ₂ 0H, - (CH ₂ ) _1-6 S0 ₃ H, - (CH ₂ ) _{1 -6} NR ₅ R ₆ or C (0) (CH ₂ ) _1-6 COOH.

The substituent R is preferably a C 12 alkyl group, C _1-5 and Cn alkyl groups are particularly preferred.

The substituent Ri is preferably a hydrogen or chlorine atom.

The substituent R ₂ is preferably a hydrogen or chlorine atom or one Cι- ₆ alkyl group. A hydrogen atom, a chlorine atom and a methyl group are particularly preferred.

The substituent R ₃ is preferably a hydrogen atom or a Cι _-6 alkyl group, a C _1-6 alkoxy group, an O-cyclohexyl group or a benzyl group.

The substituent R ₄ is preferably a hydrogen or chlorine atom.

Ri, R ₂ , R ₃ and R ₄ can, if possible, preferably be substituted with -OH, -COOH, -S0 ₃ H or -NR ₅ R ₆ , for example to increase water solubility.

Preferred examples of the aryl oxime used in the present invention include:

4-methyl-2-hydroxy-caprophenone oxime, 5-methyl-2-hydroxy-caprophenone oxime, 5-methyl-2-hydroxy-caprophenone (N-phenylcarbamoyl) oxime, 5-methyl-2-hydroxy laurophenone oxime (2-hydroxy-5-methyl-laurophenone oxime), 3-chloro-2-hydroxycaprophenone oxime, 4-pentoxy-2-hydroxyacetophenone oxime, 4-decyloxy-2-hydroxyacetophenone -oxime, 4-benzyloxy-2-hydroxy-acetophenone-oxime, 4-decyloxy-2-hydroxy-propiophenone-oxime, 4-butoxy-5-n-hexyl-2-hydroxy-acetophenone-oxime, 4-pentoxy-2 - hydroxy-caprophenone oxime, 4-decyloxy-2-hydroxy-caprophenone oxime, 4-octyloxy-2-hydroxy-laurophenone oxime, 4-cyclohexyl-oxy-2-hydroxy-propiophenone oxime, 5-chloro-2 - Hydroxy-caprophenone oxime, 3-chloro-2-hydroxy-laurophenone oxime, 5-chloro-2-hydroxy-laurophenone oxime, 4-butoxy-2-hydroxy-acetophenone oxime, 4-dodecyloxy-2-hydroxy - propiophenone-oxime, 4-hexadecyloxy-2-hydroxy-acetophenone-oxime, 4 octadecyloxy-2-hydroxy-acetophenone-oxime, 4-decyloxy-2-hydroxy-laurophenone-oxime, and the following oxime derivatives of 2-hydroxy-5 -methyl-laurophenone oxi m: as well as mixtures of these compounds.

2-Hydroxy-5-methyl-laurophenone oxime and its oxime derivatives mentioned above are particularly preferred.

The aryl oximes of the formula (I) are used according to the invention for the prophylaxis and / or treatment of inflammatory reactions of the skin caused by physical or chemical noxious substances and / or foreign organisms. The physical noxae include electromagnetic radiation or mechanical irritation. Examples of chemical pollutants include agrochemicals, drugs, insecticides, solvents and dusts. Skin infections with different bacteria, viruses, skin pathogenic fungi and parasites are to be counted under the term "foreign organisms".

It is preferred that at least one aryloxime of the formula (I) is used according to the invention for the prophylaxis and / or treatment of inflammatory reactions of the skin, the physical noxa being UV radiation.

It is further preferred that at least one aryloxime of the formula (I) is used according to the invention for the prophylaxis and / or treatment of inflammatory reactions of the skin in PUVA therapy as a special case of UV radiation.

According to the invention, the aryl oximes of the formula (I) are usually used in the form of a topical composition.

According to the invention, at least one aryloxime of the formula (I) is used in the topical composition in a sufficient amount to be suitable for prophylactic use. Usually at least one 1- (2-hydroxyaryl) alkan-1-one oxime of the formula (I) is added to the topical composition in an amount of 0.005 to 5% by weight, preferably 0.02 to 2% by weight more preferably 0.05 to 1.5% by weight.

The topical composition is prepared by at least one of the compounds used according to the invention, optionally with auxiliaries and / or carriers. materials are brought into a suitable formulation. The auxiliaries and carriers come from the group of carriers, preservatives and other customary auxiliaries.

The topical composition based on at least one compound used according to the invention is applied externally on the skin or the skin adnexa as a prophylactic.

As an application form e.g. called: solutions, suspensions, emulsions, pastes, ointments, gels, creams, lotions, pens, powders, soaps, surfactant-containing cleaning preparations, oils and sprays. In addition to one or more compounds used according to the invention, any customary carriers, auxiliaries and, if appropriate, further active ingredients are added to the composition.

Preferred auxiliaries come from the group of preservatives, antioxidants, stabilizers, solubilizers, vitamins, colorants and odor improvers. In addition to one or more compounds used according to the invention, ointments, pastes, creams and gels can contain the usual carriers, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide, xanthan gum, glycerin, carboxypolymethylene or mixtures of these substances.

In addition to one or more compounds used according to the invention, powders and sprays can contain the usual carriers, e.g. Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also contain the usual propellants, e.g. Chlorofluorocarbons, propane / butane or dimethyl ether.

In addition to one or more compounds used according to the invention, solutions and emulsions can contain the customary carriers, such as solvents, solubilizers and emulsifiers, for example water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, oils, in particular Cottonseed oils, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin fatty acid esters, polyethylene glycols, xanthan gum, glycerin, carboxypolymethylene and fatty acid esters of sorbitan or mixtures of these substances.

In addition to one or more compounds used according to the invention, suspensions can contain the usual carriers, such as liquid diluents, e.g. Water, ethanol or propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, xanthan gum, glycerol, carboxypolymethylene or mixtures of these substances.

In addition to one or more compounds used according to the invention, soaps can contain the usual carriers, such as alkali metal salts of fatty acids, salts of fatty acid semiesters, fatty acid protein hydrolyzates, isothionates, lanolin, fatty alcohol, vegetable oils, vegetable extracts, glycerol, sugar or mixtures of these substances.

In addition to one or more compounds used in accordance with the invention, surfactant-containing cleaning products can contain the customary carriers, such as salts of fatty alcohol sulfates, fatty alcohol ether sulfates, sulfosuccinic acid half-esters, fatty acid protein hydrolysates, isothionates, imidazolinium derivatives, methyl taurates, sarcosinates, fatty acid amide ether sulfates, alkylohole fatty acids, fatty acid fatty acid fatty acids, fatty acid alkoxylates, fatty acid glyceryl fatty acids, fatty acid fatty acid fatty acids, fatty alcohol amide alcohols, fatty acid fatty acid fatty acids, fatty acid fatty alcohols, fatty acid fatty alcohols, fatty acid fatty alcohols, fatty acid fatty acids, fatty alcohol amines, fatty acid fatty alcohols, fatty acid fatty acids, fatty alcohol amides, fatty acid fatty alcohols, fatty acid fatty acids, fatty alcohol amides, fatty acid fatty alcohols, fatty acid fatty acids, fatty alcohol amines, fatty acid fatty alcohols, fatty acid fatty acids, fatty alcohol fatty acids Lanolin derivatives, ethoxylated glycerol fatty acid esters or mixtures of these substances.

In addition to one or more compounds used according to the invention, facial and body oils can contain the usual carriers, such as synthetic oils, such as fatty acid esters, fatty alcohols, silicone oils, natural oils, such as vegetable oils and oily plant extracts, paraffin oils, lanolin oils or mixtures of these substances.

Other typical cosmetic forms of application are also lipsticks, lip care sticks, mascara, eyeliner, eye shadows, blush, powder, emulsion and wax make-up as well as sun protection, pre-sun and after-sun preparations.

It is particularly preferred that, in addition to one or more compounds used according to the invention, at least one ester is additionally used as an emulsifier, whose carboxylic acid residue is derived from C ₅ - to Ci6 acids and whose hydroxyl residue is derived from monomers, dimers or trimers of lactic acid or one of its salts or a polyglycerol from 2 to 10 molecules of glycerol, 1 to 3 mol of carboxylic acid being present per mol of polyglycerol. This emulsifier serves to bring about an improved stability of the compound used according to the invention.

The carboxylic acid residue of these esters is derived from C _5- 16 acids, preferably C _8-12 acids. The carbon chain of the carboxylic acid residue can be saturated or partially unsaturated. Preferred examples of the carboxylic acid residue include hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid and mixtures thereof, eg coconut fatty acid (whose carboxylic acid residues are identified by "cocoyl"), which are a mixture of the above Represents fatty acids.

The hydroxyl radical of the ester can be derived from monomers, dimers or trimers of lactic acid or one of its salts. A monomer or dimer of lactic acid is preferably used. It is further preferred that the lactic acid is in salt form, i.e. as lactylate is used. Alkali metal and alkaline earth metal salts are particularly preferred, sodium salts being particularly emphasized. In addition, the hydroxyl radical of the ester can be derived from a polyglycerol from 2 to 10 molecules of glycerol. There are 1 to 3 moles of carboxylic acid per mole of polyglycerol. 2 to 3 mol of carboxylic acid are particularly preferably present per mol of polyglycerol.

Typical examples of this emulsifier include the dispersing agents which are disclosed in DE-A-197 22 405 column 2, lines 38 to 56 and in the examples. Polyglycerol-10-tricaprylate, polyglycerin-10-trilaurate, polyglycerin-2-oleate, sodium lauryl lactate, sodium cocoyl lactate, caprin / caprylic acid triglyceride and mixtures thereof are preferred. Polyglycerol-2-oleate and sodium cocoyl lactylate are particularly preferred.

This emulsifier is usually used in an amount of 0.5 to 30% by weight, preferably 0.5 to 20% by weight, more preferably 1 to 10% by weight, in the topical composition used according to the invention. In order to ensure the stability of the topical composition used according to the invention and the aryl oximes of formula (I) contained therein, at least one coemulsifier selected from glycerol and sorbitan ester derivatives, as well as cetearyl alcohol and ester derivatives thereof and mixtures of these compounds, is preferably used. The glycerol, sorbitan and Cetearylesterderivate are typically derived from esters whose acid residues from C ₅ - 6 ₁ derived acids, whose carbon chains can be saturated or unsaturated part. Of these, glycerol stearate, sorbitan stearate, sorbitan isostearate, sorbitan diisostearate, sorbitan dioleate, sorbitan distearate, sorbitan laurate, sorbitan palmitate, sorbitan sesquiisostearate, sorbitan sorbate, sorbitan trisorbate, sorbitan trisorbate, sorbitan trisorbate, sorbitan trisorbate,

This co-emulsifier is generally used in an amount of 0.1 to 40% by weight, preferably 0.5 to 15% by weight, more preferably 1 to 10% by weight, in the topical composition used according to the invention.

To further improve the solubility of the compounds used according to the invention, at least one lipophilic solvent is preferably further contained in the topical composition. Typical lipophilic solvents which are suitable for topical formulation include dimethicone, cyclomethicone, mineral oil, isostearyl isostearate, octyl palmitate, propylene glycol dicaprate / dicaprylate, Cι ₂ / - benzoate ₁ 5-alkyl, octyldecanol, ether derivatives of cetyl alcohol, such as ceteth-1, Ceteth-2, ceteth-3, ceteth-4, ceteth-5, ceteth-6 and ceteth 10, ethyl butyl acetylaminopropionate, ethanol, isopropanol, isopropyl myristate and mixtures thereof. Of these, ethylbutyl acetylaminopropionate, ethanol, isopropanol, isopropyl myristate and mixtures thereof are particularly preferred.

The lipophilic solvent is usually used in an amount of 0.1 to 20% by weight, more preferably 0.3 to 17% by weight, in the topical composition used according to the invention.

In addition to one or more compounds used according to the invention, at least one antioxidant is preferably used. The antioxidants serve to protect against cell damage by radicals. According to the invention, the antioxidants known from the specialist literature can be used, for example flavonoids, coumaranones, amino acids (for example glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (for example urocanic acid) and their derivatives, peptides such as D, L-carnosine , D-camosin, L-camosin and their derivatives (e.g. anserine), carotenoids, carotenes (e.g. α-carotene, ß-carotene, lycopene) and their derivatives, chlorogenic acid and their derivatives, lipoic acid and their derivatives (e.g. dihydroliponic acid) , Aurothioglucose, propylthiouracil and other thiols (e.g. thioredoxin, glutathione, cysteine, cystine, cystamine and their glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl) , Oleyl, γ-linoleyl, cholesteryl and glyceryl esters) and their salts, diaurylthiodipropionate, distearylthiodipropionate, thiodipropioic acid and their derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds (e.g. buthioninsulfoximines, Homocysteine sulfoximine, buthionine sulfones, penta-, hexa-, heptathionine sulfoximine), also (metal) chelators (e.g. α-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), α-hydroxy acids (e.g. citric acid, lactic acid, malic acid), humic acid, bile acid, bile acid, bile acid Bilirubin, biliverdin, EDTA, EGTA and their derivatives, unsaturated fatty acids and their derivatives, vitamin C and derivatives (e.g. ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate) as well as coniferyl benzoate of the benzoin resin, rutinic acid and its derivatives, -Glycosylrutin, Ferulasidenglucuric acid, F Camosin, butyl hydroxyltoluene (BHT), butylated hydroxyanisole, nordohydroguajaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, zinc and its derivatives (e.g. ZnO, ZnS0 ₄ ), selenium and its derivatives (e.g. selenium methionine derivatives) and stilbenes (e.g. stilbene oxide, trans-stilbene oxide).

Mixtures of antioxidants are also suitable. Known and commercially available mixtures are, for example, mixtures containing lecithin, L - (+) - ascorbyl palmitate and citric acid (for example Oxynex ^® AP), natural tocopherpole, L - (+) - ascorbyl palmitate, L - (+) -Ascorbic acid and citric acid (e.g. Oxynex ^® K LIQUID), tocopherol extracts from natural sources, L - (+) - ascorbyl palmitate, L - (+) - ascorbic acid and citric acid (e.g. Oxynex ^® L LIQUID), DL-α-tocopherol, L- (+) - Ascorbyl palmitate, citric acid and lecithin (eg Oxynex ^® LM) or butyl hydroxytoluene (BHT), L - (+) - ascorbyl palmitate and citric acid (eg Oxynex ^® 2004). In a preferred embodiment of the invention, butylated hydroxytoluene is used as the antioxidant.

In a further preferred embodiment, one or more compounds selected from flavonoids and / or coumaranones are used as the antioxidant.

The glycosides of flavanones, flavones, 3-hydroxyflavones (= flavanols), aurones, isoflavones and redoids are regarded as flavanoids (Römpp Chemie Lexikon, Volume 9, 1993). Within the scope of the present invention, however, the aglycones, i.e. understood the sugar-free ingredients, and the derivatives of flavonoids and aglycones. In the context of the present invention, coumaranones are also understood to mean their derivatives.

Preferred flavonoids are derived from flavanones, flavones, 3-hydroxyflavones, aurones and isoflavones, in particular from flavanones, flavones, 3-hydroxyflavones and aurones.

The flavanones are characterized by the following basic structure:

The flavones are characterized by the following basic structure:

The 3-hydroxyflavones (flavonols) are characterized by the following basic structure: The isoflavones are characterized by the following basic structure:

The Aurones are characterized by the following basic structure:

The coumaranones are characterized by the following basic structure:

The flavonoids and coumaranones are preferably selected from the compounds of the formula (1):

in which mean:

Zi to Z ₄ each independently of one another are H, OH, alkoxy, hydroxyalkoxy, mono- or oligoglycoside radicals, and where the alkoxy and hydroxyalkoxy groups can be branched and unbranched and can have 1 to 18 carbon atoms and where the hydroxyl groups of the radicals mentioned sulfate or phosphate can also be bound,

is selected from the group consisting of the partial forms (1A), (1 B) and (1C)

Z ₅ H, OH or OR,

R is a mono- or oligoglycoside residue,

Z ₆ to Z ₁ 0 have the meaning of the radicals Zi to Z ₄ , and

The alkoxy groups are preferably linear and have 1 to 12, preferably 1 to 8, carbon atoms. These groups thus correspond to the formula -0- (CH ₂ ) _m -H, where m denotes 1, ₂ , 3, 4, 5, 6, 7 or 8 and in particular 1 to 5.

The hydroxyalkoxy groups are preferably linear and have 2 to 12, preferably 2 to 8, carbon atoms. These groups thus correspond to the formula -0- (CH ₂ ) _n -OH, where n is 2,3,4,5,6,7 or 8, in particular 2 to 5 and particularly preferably 2.

The mono- and oligoglycoside residues are preferably composed of 1 to 3 glycoside units. These units are preferably selected from the group of the hexosyl residues, in particular the rhamnosyl residues and glucosyl residues. But also other hexosyl Residues, for example allosyl, altrosyl, galactosyl, gulosyl, idosyl, mannosyl and talosyl, can optionally be used advantageously. It can also be advantageous according to the invention to use pentosyl residues.

In a preferred embodiment

Zi and Z ₃ mean H,

Z ₂ and Z have a different meaning than H, in particular they mean OH, methoxy, ethoxy or 2-hydroxyethoxy,

Z _{5 has} the meaning H, OH or a glycoside residue which is composed of 1 to 3, preferably 1 or 2, glycoside units.

Z ₆ , Z ₉ and Z _{10 have} the meaning H, and

Z ₇ and Z ₈ ι have a different meaning than H, in particular they mean OH, methoxy, ethoxy or 2-hydroxyethoxy.

In a further preferred embodiment, in particular if the water solubility of the flavonoids and coumaranones is to be increased, a sulfate or phosphate group is bonded to the hydroxyl groups. Suitable counterions are, for example, the ions of the alkali or alkaline earth metals, these e.g. can be selected from sodium or potassium.

In a further preferred embodiment, the flavonoids are selected from the following compounds: 4,6,3 ', 4'-tetrahydroxyauron, quercetin, rutin, isoquercetin, anthocyanidin (cyanidin), eriodictyol, taxifolin, luteolin, trishydroxyethylquercetin (troxequercetin), trishydroxyethylrutin ( ), Trishydroxyethylisoquercetin (Troxeisoquercetin), Trishydroxyethylluteolin (Troxeluteolin) as well as their sulfates and phosphates.

Among the flavonoids, rutin and troxerutin are particularly preferred. Troxerutin is particularly preferred. Among the coumaranones, 4,6,3 ', 4'-tetrahydroxybenzylcoumaranone-3 is preferred.

The antioxidants are generally used in an amount of 0.001 to 5% by weight, preferably 0.5 to 5% by weight, according to the invention in the topical composition.

In addition to one or more compounds used according to the invention, at least one UV filter can preferably be used as UV protection. With UV therapy, such as PUVA therapy, of course no UV filter is used. According to the invention, the UV filters known from the specialist literature can be used. Usual amounts of UV filter used according to the invention are 0.05 to 30% by weight, preferably 0.1 to 20% by weight, more preferably 1 to 15% by weight.

All UVA and UVB filters known to the person skilled in the art are suitable as suitable organic UV filters. For both UV ranges there are many well-known and proven substances known from the specialist literature, e.g.

Benzylidene camphor derivatives, such as

- 3- (4'-methylbenzylidene) dl-camphor (e.g. Eusolex ^® 6300),

- 3-benzylidene camphor (e.g. Mexoryl ^® SD),

- polymers of N- ^<i (2 and 4) - [(2-oxoborn-3-ylidene) methyl] benzyl r-acrylamide (eg Mexo- ryl ^® SW),

- N, N, N-trimethyl-4- (2-oxoborn-3-ylidenmethyl) anilinium methyl sulfate (e.g. Mexoryl ^® SK) or

α- (2-oxoborn-3-ylidene) toluene-4-sulfonic acid (e.g. Mexoryl ^® SL),

Benzoyl or dibenzoyl methanes, such as

- 1- (4-tert-Butylphenyl) -3- (4-methoxyphenyl) propan-1, 3-dione (e.g. Eusolex ^® 9020) or

4-isopropyldibenzoylmethane (e.g. Eusolex ^® 8020), Benzophenones, like

- 2-Hydroxy-4-methoxybenzophenone (e.g. Eusolex ^® 4360) or

- 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid and its sodium salt (e.g. Uvinul ^® MS-40),

methoxycinnamate; how

p-methoxycinnamic acid 2-ethylhexyl ester (e.g. Eusolex ^® 2292),

p-methoxycinnamic acid isopentyl ester, for example as a mixture of the isomers (for example Neo Heliopan ^® E 1000),

Salicylate derivatives such as

- 2-ethylhexyl salicylate (e.g. Eusolex ^® OS),

- 4-isopropylbenzyl salicylate (e.g. Megasol ^® ) or

- 3,3,5-trimethylcyclohexyl salicylate (e.g. Eusolex ^® HMS),

4-aminobenzoic acid and derivatives thereof, such as

4-aminobenzoic acid,

4- (dimethylamino) 2-ethylhexyl benzoate (e.g. Eusolex ^® 6007),

- Ethoxylated 4-aminobenzoic acid ethyl ester (eg Uvinul ^® P25),

and other substances, such as

2-ethyl-2-cyano-3,3-diphenylacrylate (e.g. Eusolex ^® OCR),

- 2-phenylbenzimidazole-5-sulfonic acid and its potassium, sodium and triethanolamine salts (eg Eusolex ^® 232),

- 3,3 '- (1, 4-phenylenedimethylene) bis (7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1-ylmethanesulfonic acid and salts thereof (for example Mexoryl SX ^®) and

- 2,4,6-trianilino- (p-carbo-2'-ethylhexyl-1'-oxi) -1, 3,5-triazine (for example Uvinul ^® T 150). These organic UV filters are generally used in an amount of 0.5 to 10% by weight, preferably 1 to 8% by weight, in the topical composition used according to the invention.

Other suitable organic UV filters are e.g.

- 2- (2H-Benzotriazol-2-yl) -4-methyl-6- (2-methyl-3- (1, 3,3,3-tetramethyl-1 - (trimethylsilyloxy) disiloxanyl) propyl) phenol (e.g. silatrizole ^® ),

- 4,4 '- [(6- [4 - ((1, 1-dimethylethyl) aminocarbonyl) phenylamino] -1, 3,5-triazine

- 2,4-diyl) diimino] bis (2-ethylhexyl benzoate) (e.g. Uvasorb ^® HEB),

- - (Trimethylsilyl) -ω [trimethylsilyl) oxy] poly [oxy (dimethyl] [and about 6% methyl [2- [p- [2,2-bis (ethoxycarbonyl] vinyl] phenoxy] -1-methyleneethyl] and approx. 1.5% methyl [3- [p- [2,2-bis (ethoxycarbonyl) vinyl) phenoxy) propenyl) and 0.1 to 0.4% (methylhydrogenjsilylene]] (n «60) (eg Parsol ^® SLX,

- 2,2'-methylene-bis- (6- (2H-benzotriazol-2-yl) -4- (1, 1, 33-tetramethyl- butyl) phenol (eg Tinosorb ^® M),

2,2 '- (1,4-phenylene) bis-1 H-benzimidazole-4,6-disulfonic acid, monosodium salt,

2,2 '- (1,4-phenylene) bis-1 H-benzimidazole-5-sulfonic acid, monosodium salt,

- 2,2 '- (1, 4-phenylene) bis-1 H-benzimidazole-5-sulfonic acid, monopotassium salt and

- 2,4-bis- ^ [4- (2-ethylhexyloxy) -2-hydroxyl] phenyl! ^> -6- (4-methoxyphenyl) -1, 3,5-triazine (e.g. Tinosorb ^® S).

These organic filters are generally used in an amount of 0.5 to 20% by weight, preferably 1 to 15% by weight, in the topical composition used according to the invention.

Inorganic UV filters from the group of titanium dioxides, for example coated titanium dioxide (for example Eusolex ^® T-2000 or Eusolex ^® T-Aqua), zinc oxides (for example Sachtotec ^® ), iron oxides or cerium oxides are also conceivable. These inorganic UV filters are generally used in an amount of 0.5 to 20% by weight, preferably 2 to 10% by weight, in the topical composition used according to the invention used.

Preferred UV filters are zinc oxide, titanium dioxide, 3- (4'-methylbenzylidene) -dl-camphor, 1 - (4-tert-butylphenyl) -3- (4-methoxyphenyl) propane-1, 3-dione, 4-isopropyldibenzoyl methane, 2-hydroxy-4-methoxybenzophenone, 2-ethylhexyl methoxycinnamate, 3,3,5-trimethylcyclohexyisalicylate, 2-ethylhexyl 4- (dimethylamino) benzoate, 2-ethylhexyl 2-cyano-3,3-diphenylacrylate, 2-phenylbenzimidazole-5-sulfonic acid and its potassium, sodium and triethanolamine salts.

Zinc oxide and titanium dioxide are particularly preferred UV filters.

If titanium dioxide is used according to the invention, it is preferred that, in addition to titanium dioxide, one or more further UV filters selected from 3- (4'-methylbenzylidene) dl-camphor, 1- (4-tert-butylphenyl) -3- (4th -methoxyphenyl) propane-1,3-dione, 4-isopropyl-dibenzoylmethane, 2-hydroxy-4-methoxybenzophenone, 2-ethylhexyl methoxycinnamate, 3,3,5-trimethylcyclohexylsalicylate, 2-ethylhexyl 4- (dimethylamino) benzoate, 2-Cyano-3,3-diphenylacrylic acid 2-ethylhexyl ester, 2-phenylbenzimidazole-5-sulfonic acid and their potassium, sodium and triethanolamine salts can be used.

It is particularly preferred that, in addition to titanium dioxide, the UV filters 2-hydroxy-4-methoxybenzophenone and / or 2-ethylhexyl methoxycinnamate are additionally used.

The combination of aryl oximes with ectoine and ectoin derivatives is particularly effective for improving skin protection and immunosuppression of the skin.

The invention is illustrated by the following examples. example 1

Investigation of the prophylactic effect

material and methods

A 10% solution of 2-hydroxy-5-methyl-laurophenone oxime in absolute ethanol was used as the test substance. Radiolabeling was carried out with 2-hydroxy-5-methyl- [1- ¹⁴ C] -laurophenon-oxime, specific activity: 110 MBq / g, so that for the tests 100 of a 10% solution .mu.l an activity of 27.46 uCi contained.

The investigations were carried out on human skin from surgical specimens after a mother's amputation. The subcutis was dissected postoperatively, the skin cut to the size required for the test, packed in aluminum foil and stored at -20 ° C for a short time. The test procedure was according to Dermatol. Mon.schr. 167 (1981) pp. 277-283.

The piece of skin to be examined was attached without tension on a synthetic fiber sieve at the corners with needles after an area of 4 cm ^{2 had been} marked on the skin. 20 μl of the ¹⁴ C-labeled active ingredient solution were applied to the test area and evenly passed in the test area. Immediately after the application, the synthetic fiber sieve was fastened in a glass vessel with physiological NaCl solution in such a way that the NaCl solution, which was constantly moved with a magnetic stirrer, was in contact with the lower surface of the skin. The entire apparatus was installed in an incubator so that a temperature of 32 ° C. could be kept constant during the entire test period.

The penetration measurements were carried out on two or three different surgical specimens. The skin was worked up 30, 300 and 1000 minutes after application of the substance solution. For this purpose, the skin surface was first wiped with cotton wool and attached to a plastic base. A template was then attached to the test area, in which an area of 1 cm ^{2 was} cut out. The horny layer was removed in layers on this surface with an adhesive film by tearing, each tear being transferred individually to a test glass. After removal of the horny layer, several skin cylinders were punched out using a rapidly rotating punch (diameter 4 mm) and horizontal sections were made on the freezing microtome. Initially, 20 μm cuts were made up to a tissue depth of 200 μm, whereby a skin depth of up to 160 μm was viewed in simplified terms as the epidermis. The remaining tissue, the dermis, was completely worked up in 40 μm sections. As with the horny layer demolitions, each cut was individually placed in a test glass. For scintillation measurement, the tissue sections were incubated for solubilization with 0.2 ml each of Protosol (New England Nuclear) for about 12 hours and then mixed with 2 ml of methanol. For the measurement in the liquid scintillation spectrophotometer, all test glasses were each loaded with 10 ml scintillator liquid (4.0 g PPO + 0.1 g POPOP + 1000 ml toluene). The respective quench was taken into account with the help of an external standard. Calibration curves were used to convert cpm to dpm. The dpm was converted into μCi using further calibration curves. Knowing the amount of substance applied, the specific activity, the area of the stripped area of the skin, the volume (area and layer thickness) of the histological sections and their assignment to the individual skin layers, the amount of the penetrated substance in percent of the amount applied or in molar concentration in the corresponding Skin layer can be calculated.

The results are shown in Table 1.

By summarizing all the activities found in the strata of the horny layer, the percentage of the amount of externally applied active substance penetrated in the horny layer can be determined for each penetration time. The same is possible by summing the measured values of the tissue sections up to a layer depth of 160 μm for the epidermis and the other measured values for the dermis.

It can be determined from the measurement results shown in Table 1 that the predominant amount of active substance which has penetrated the human skin can be found in the horny layer. The distribution of the amounts of active substance penetrated into the stratum corneum within the horny layer is shown in Table 2. The active ingredient penetrates into the superficial ridges relatively quickly, with a clear concentration gradient to the deeper horny layers. This ratio shifts with increasing Duration of action more and more, so that after 1000 minutes there is an almost uniformly distributed amount of active ingredient over the entire horny layer.

This corresponds to the active ingredient concentrations achieved in the individual skin layers with increasing exposure time, as shown in Table 3. An increase in the epidermal active ingredient concentration can be recognized only after longer exposure times, which is clearly lower in the dermal area.

Overall, these results show that 2-hydroxy-5-methyl-laurophenone oxime forms an active ingredient depot which enables prophylactic use or care to protect the skin against pro-inflammatory factors.

Table 1 :

Penetration of 2-hydroxy-5-methyl-laurophenone oxime into human skin after external application (in% of the amount applied)

Application: 10% 2-hydroxy-5-methyl-laurophenone oxime in ethanol (abs.); 20 μl / 4 cm ^{2 •} N = 3.

so

Table 2:

Penetration of 2-hydroxy-5-methyl-laurophenone oxime (in% of the amount applied) in the horny layer of human skin after external application

Application: 10%) 2-hydroxy-5-methyl-laurophenone oxime in ethanol (abs.); 20 μl / 4 cm ² ■ N = 3.

O

Table 3:

Penetration of 2-hydroxy-5-methyl-laurophenone oxime into human skin after external application

(in micromolar concentration)

Application: 10% 2-hydroxy-5-methyl-laurophenone oxime in ethanol (abs.); 20 μl / 4 cm ² • N = 3.

O

Example 2

Investigation of UV-related inflammatory reactions of the skin

material and methods

Five albino guinea pigs were used as experimental animals.

A solution containing 2-hydroxy-5-methyl-laurophenone oxime was used as the test substance. For the test, this substance was dissolved in absolute ethanol immediately before use and applied as a 10% solution (50 μl each) using an automatic pipette to the right dorsal ear repidermis. The dorsal ear sides are suitable as test areas, since these skin sections are almost hairless. As a control, 50 μl of absolute ethanol from the same batch were used in the area of the left ear.

An HG high-pressure lamp UVS 375-1 was used as the UV source, which emits predominantly in the UV-B range. A group-specific standardization of UV-B erythema on the dorsal ear repidermis in albino guinea pigs was carried out according to Höfer et al .: On the course of UV erythema on guinea pig ear, lecture: 4th photodermatological colloquium with international participation, Angry October 10th to 12th, 1988 ,

The dorsal, hairless ear sections were irradiated with an irradiance of 0.12 mW / cm ² + 10% (single animal irradiation). The dose applied was 0.108 J / cm ² per animal with the same tolerance. The dosimetric measurement, which is decisive for the defined erythema induction and reproduction, was carried out analogously according to Höfer et al., Dermatol. Mon.schr. 174: 87-93 (1988).

Measurement methods and exposure

The determination of the degree of inflammation was carried out using two different, independent objective measurement methods, each measuring different inflammation symptoms. Pyrometry (skin temperature) and reflection photometry (degree of skin reddening) were used as measuring principles (Gloor, pharmacology dermatological externals, Springer Verlag Berlin Heidelberg New York, 1982, p. 134; Gloor et al., Dermatol. Mon.schr. 125 ( 1979), 665-669; Vane et al: Antiinflammatory Drug 5, Springer Verlag Berlin Heidelberg New York 1979, pp. 44-74 and Walter et al: Infrared measurement technology, VEB Verlag Technik Berlin, 1st edition 1981, p. 224) , The digital handheld pyrometer HPM 15 and a Spekol 11 device (VEB Carl Zeiss, Jena) with reflectance measurement approach R d / O were used.

The animals were 5 hours before UV-B radiation in the dorsal region of the right ear 50 ul of a 10% 2-hydroxy-5-methyl-laurophenone oxime solution evenly applied. The left side was treated with 50 μl of absolute ethanol as a control. Before this treatment, the animals were measured to objectify the initial values. The room temperature was between 18 and 21 ° C during the entire test period. The erythema course was measured 2, 4, 6, 7, 24, 48, 72 and 96 hours after the erythema was triggered in all animals at the same time of day.

Results

According to the available findings, after a 300 minute penetration time of 50 μl of a 0% 2-hydroxy-5-methyl-laurophenone oxime solution, the course of a UV-B-stressed erythema on the guinea pig ear can be influenced in terms of suppression. This result was confirmed by both measuring principles. The phenomenon of erythema suppression compared to the control is particularly pronounced in the early phase of the inflammatory process. The results are shown in Table I and Table II. Table I: Pyrometric characterization of the UV-B erythema on guinea pig epidermis after the application of 50 μl of a 10% 2-hydroxy-5-methyl-laurophenone oxime-ethanol solution (right ear) 5 hours before erythema was triggered. li. Ear = control

a = before treatment x = mean b = 2 h after irradiation + s = standard deviation c = 4 h after irradiation ns = not significant d = 6 h after irradiation s. = significant e = 7 h after irradiation f = 24 h after irradiation g = 48 h after irradiation h = 72 h after irradiation i = 96 h after irradiation

Table II: Characterization of the UV-B erythema on guinea pig epidermis by reflection photometry after the application of 50 μl of a 10% 2-hydroxy-5-methyl-laurophenone oxime ethanol solution (right ear) 5 hours before the erythema was triggered. li. Ear = control

a = before treatment X = mean b = 2 h after irradiation + s = standard deviation c = 4 h after irradiation n.s. = not significant d = 6 h after irradiation s. = significant e = 7 h after irradiation f = 24 h after irradiation g = 48 h after irradiation h = 72 h after irradiation i = 96 h after irradiation

Claims

claims

1. Use of at least one aryloxime of the formula (I)

in which mean:

Y, Z independently of one another H, C _1-18 alkyl, C _2- ι ₈ alkenyl, C _2- ι ₈ -

Carboxyalkyl, C _3- ₈ ι -carboxyalkenyl or C _2-18 -alkanoyl;

R d- ₁₈ alkyl, C _2-18 alkenyl, C _3-8 cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or condensed systems;

Ri, R _2, R _3, R independently is H, Cι _ι-2 alkyl, C _2- ι ₂ alkenyl, d.ι ₂ -alkoxy, C _3-8 - cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, Heteroaralkyl, carboxy, hydroxy, chlorine, dialkylamine or sulfonyl,

2. Use according to claim 1 for prophylaxis and / or treatment of inflammatory reactions of the skin caused by physical or chemical noxa and / or foreign organisms.

3. Use according to claim 1 or 2 for the prophylaxis and / or treatment of inflammatory reactions of the skin caused by UV radiation.

4. Use according to claim 3 in PUVA therapy.

5. Use according to one of claims 1 to 4 in the form of a topical composition.

6. Use according to claim 5, characterized in that at least one aryloxime of the formula (I) is present in a topical composition in an amount of 0.02 to 2% by weight, based on the composition.

7. Use according to claim 5 or 6, characterized in that the topical composition further contains at least one antioxidant and / or at least one UV filter.

8. Use according to claim 7, characterized in that the antioxidant is present in the topical composition in an amount of 0.001 to 5% by weight, based on the composition.

9. Use according to claim 7, characterized in that the UV filter is present in the topical composition in an amount of 0.01 to 30% by weight, based on the composition.