EP1286654A1 - Utilisation d'aryloximes pour assurer la prophylaxie et/ou le traitement de la formation d'erytheme et/ou de reactions inflammatoires de la peau - Google Patents

Utilisation d'aryloximes pour assurer la prophylaxie et/ou le traitement de la formation d'erytheme et/ou de reactions inflammatoires de la peau

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Publication number
EP1286654A1
EP1286654A1 EP01940418A EP01940418A EP1286654A1 EP 1286654 A1 EP1286654 A1 EP 1286654A1 EP 01940418 A EP01940418 A EP 01940418A EP 01940418 A EP01940418 A EP 01940418A EP 1286654 A1 EP1286654 A1 EP 1286654A1
Authority
EP
European Patent Office
Prior art keywords
skin
acid
hydroxy
oxime
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01940418A
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German (de)
English (en)
Inventor
Joachim BÜNGER
Hansjürgen Driller
Michael Schwarz
Wolfgang Wohlrab
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE2000125557 external-priority patent/DE10025557A1/de
Priority claimed from DE2000125555 external-priority patent/DE10025555A1/de
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1286654A1 publication Critical patent/EP1286654A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation

Definitions

  • 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.
  • 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.
  • 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. Kir, Vol. 1, Thieme: Stuttgart, New York ( 1980)).
  • 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.
  • a chemotactic effect on leukotrienes is known which reduces the vascular permeability after the kinins.
  • leukotrienes have a chemotactic effect on granulocytes and influence the contractility and permeability of vessels.
  • 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)).
  • 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)).
  • 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.
  • 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 wished 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.
  • 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.
  • Sunburn erythema solare
  • 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.
  • 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).
  • 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.
  • Y, Z independently of one another H, C ⁇ ⁇ -8 -alkyl, C 2-18 -alkenyl, C 2 - 18 - carboxyalkyl, C 3- i8-carboxyalkenyl, or C 2- ⁇ 8 alkanoyl;
  • R 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- - ⁇ 2 alkenyl, C ⁇ -12 alkoxy, C 3 - 8 cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl , Carboxy, hydroxy, chlorine, dialkylamine or sulfonyl,
  • 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.
  • 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):
  • 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- ⁇ 8 alkanoyl
  • R 1, R 2 , R 3 and R independently of one another are H, C ⁇ _ ⁇ 2 alkyl, C 2- ⁇ 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 C ⁇ -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 C ⁇ - 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 C ⁇ -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:
  • 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".
  • 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.
  • 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.
  • the aryl oximes of the formula (I) are usually used in the form of a topical composition.
  • At least one aryloxime of the formula (I) is used in the topical composition in a sufficient amount to be suitable for prophylactic use.
  • 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.
  • 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.
  • solutions, suspensions, emulsions, pastes, ointments, gels, creams, lotions, pens, powders, soaps, surfactant-containing cleaning preparations, oils and sprays are added to the composition.
  • any customary carriers, auxiliaries and, if appropriate, further active ingredients are added to the composition.
  • auxiliaries come from the group of preservatives, antioxidants, stabilizers, solubilizers, vitamins, colorants and odor improvers.
  • 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.
  • 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.
  • 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.
  • solvents 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 acids, fatty alcohol amines, fatty acid fatty alcohols, fatty acid fatty acids, fatty alcohol amides, fatty acid fatty alcohols
  • customary carriers such as salts of fatty alcohol sulfates, fatty alcohol
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, C ⁇ 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. Of these, ethy
  • 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.
  • At least one antioxidant is preferably used.
  • the antioxidants serve to protect against cell damage by radicals.
  • 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.
  • ⁇ -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, ⁇ -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
  • metal chelators e.g. ⁇ -hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), ⁇ -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.
  • 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- ⁇ -tocopherol, L- (+) - Ascorbyl palmitate, citric acid and lecithin (eg Oxynex ® LM) or butyl hydroxytoluene (BHT), L - (+) - ascorbyl palmitate and citric acid (eg Oxynex ® 2004).
  • butylated hydroxytoluene is used as the antioxidant.
  • one or more compounds selected from flavonoids and / or coumaranones are used as the antioxidant.
  • aglycones i.e. understood the sugar-free ingredients
  • 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 3-hydroxyflavones are characterized by the following basic structure:
  • the isoflavones are characterized by the following basic structure:
  • the flavonoids and coumaranones are preferably selected from the compounds of the formula (1):
  • 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,
  • R is a mono- or oligoglycoside residue
  • Z 6 to Z 1 0 have the meaning of the radicals Zi to Z 4 .
  • 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.
  • 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 ⁇ have a different meaning than H, in particular they mean OH, methoxy, ethoxy or 2-hydroxyethoxy.
  • 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.
  • 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.
  • rutin and troxerutin are particularly preferred.
  • Troxerutin is particularly preferred.
  • 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.
  • At least one UV filter can preferably be used as UV protection.
  • UV therapy such as PUVA therapy
  • no UV filter is used.
  • 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.
  • UVA and UVB filters known to the person skilled in the art are suitable as suitable organic UV filters.
  • suitable organic UV filters For both UV ranges there are many well-known and proven substances known from the specialist literature, e.g.
  • p-methoxycinnamic acid isopentyl ester for example as a mixture of the isomers (for example Neo Heliopan ® E 1000),
  • Salicylate derivatives such as
  • 2-ethyl-2-cyano-3,3-diphenylacrylate e.g. Eusolex ® OCR
  • 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.
  • 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.
  • 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.
  • 3- (4'-methylbenzylidene) dl-camphor 1- (4-tert-butyl
  • the UV filters 2-hydroxy-4-methoxybenzophenone and / or 2-ethylhexyl methoxycinnamate are additionally used.
  • aryl oximes with ectoine and ectoin derivatives is particularly effective for improving skin protection and immunosuppression of the skin.
  • 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 ⁇ l of the 14 C-labeled active ingredient solution were applied to the test area and evenly passed in the test area.
  • 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.
  • 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.
  • tissue cuts were made up to a tissue depth of 200 ⁇ m, whereby a skin depth of up to 160 ⁇ m was viewed in simplified terms as the epidermis.
  • the remaining tissue, the dermis was completely worked up in 40 ⁇ m sections.
  • each cut was individually placed in a test glass.
  • 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.
  • 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 ⁇ m for the epidermis and the other measured values for the dermis.
  • test substance A solution containing 2-hydroxy-5-methyl-laurophenone oxime was used as the test substance.
  • this substance was dissolved in absolute ethanol immediately before use and applied as a 10% solution (50 ⁇ l 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.
  • 50 ⁇ l of absolute ethanol from the same batch were used in the area of the left ear.
  • UVS 375-1 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).
  • 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
  • reflection photometry degree of skin reddening
  • Mahman 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 Verlagtechnik 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 ⁇ l of absolute ethanol as a control.
  • 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.

Abstract

L'invention concerne l'utilisation pour assurer la prophylaxie et/ou le traitement de la formation d'érythème et/ou de réactions inflammatoires de la peau, d'au moins un aryloxime de formule (I) dans laquelle Y,Z désignent indépendamment l'un de l'autre H, alkyle C1-18, alkényle C2-18, carboxyalkyle C3-18, carboxyalkényle C3-18 ou alkanoyle C2-18 ; R désigne alkyle C1-18, alkényle C2-18, cycloalkyle C3-8, aryle, aralkyle, hétéroaryle, hétéroaralkyle ou des systèmes condensés ; R1,R2,R3,R4 désignent indépendamment les uns des autres, H, alkyle C1-12, alkényle C2-12, alcoxy C1-12, cycloalcoxy C3-8, aryle, aryloxy, hétéroaryle, hétéroaralkyle, carboxy, hydroxy, chlore, dialkylamine ou sulfonyle.
EP01940418A 2000-05-24 2001-05-08 Utilisation d'aryloximes pour assurer la prophylaxie et/ou le traitement de la formation d'erytheme et/ou de reactions inflammatoires de la peau Withdrawn EP1286654A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10025555 2000-05-24
DE10025557 2000-05-24
DE2000125557 DE10025557A1 (de) 2000-05-24 2000-05-24 Verwendung von Aryloximen zur Prophylaxe und/oder Behandlung von Entzündungsreaktionen der Haut
DE2000125555 DE10025555A1 (de) 2000-05-24 2000-05-24 Verwendung von Aryloximen zur Prophylaxe von Erythembildung und/oder Entzündungsreaktionen der Haut
PCT/EP2001/005222 WO2001089468A1 (fr) 2000-05-24 2001-05-08 Utilisation d'aryloximes pour assurer la prophylaxie et/ou le traitement de la formation d'erytheme et/ou de reactions inflammatoires de la peau

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EP1286654A1 true EP1286654A1 (fr) 2003-03-05

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US (1) US20030157037A1 (fr)
EP (1) EP1286654A1 (fr)
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WO (1) WO2001089468A1 (fr)

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DE10025558A1 (de) * 2000-05-24 2001-11-29 Merck Patent Gmbh Topische Zusammensetzung, enthaltend mindestens ein Aryloxim, und Verfahren zu ihrer Herstellung
DE10025553A1 (de) * 2000-05-24 2001-11-29 Merck Patent Gmbh Zusammensetzung, enthaltend mindestens ein Aryloxim und mindestens einen Wirkstoff zur Behandlung von Akne und ihre Verwendung
DE102004007966A1 (de) * 2004-02-18 2005-09-08 Merck Patent Gmbh Topische Zusammensetzung, enthaltend mindestens ein Aryloxim und Bisabolol
EP2358269B1 (fr) 2007-03-08 2019-04-10 Sync-RX, Ltd. Traitement d'image et activation d'outil pour procédures médicales
US20090187060A1 (en) 2008-01-22 2009-07-23 E-Z-Em, Inc. Method and Formulation for Neutralizing Toxic Chemicals and Materials
US9974509B2 (en) 2008-11-18 2018-05-22 Sync-Rx Ltd. Image super enhancement
US11064903B2 (en) 2008-11-18 2021-07-20 Sync-Rx, Ltd Apparatus and methods for mapping a sequence of images to a roadmap image
JP2021506958A (ja) 2017-12-13 2021-02-22 オンクォリティ ファーマシューティカルズ チャイナ エルティーディーＯｎｑｕａｌｉｔｙ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｈｉｎａ Ｌｔｄ． Ｅｇｆｒ阻害に関連する疾患を予防又は治療する方法
EP3782618A4 (fr) 2018-04-16 2022-01-26 OnQuality Pharmaceuticals China Ltd. Méthode pour prévenir ou traiter les effets secondaires d'une cancérothérapie

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DD235450B1 (de) * 1983-12-29 1988-02-03 Humboldt Uni Z Berlin Verfahren zur herstellung neuer 1-(2-hydroxyaryl)-alkan-1-on-oxime
DE4116123B4 (de) * 1991-05-17 2006-03-09 Merck Patent Gmbh Mittel zur Behandlung von Hauterkrankungen
WO1995001157A1 (fr) * 1993-06-29 1995-01-12 The Procter & Gamble Company Utilisation d'oximes hydroxyphenyliques comme agents photoprotecteurs chelatants
FR2788694B1 (fr) * 1999-01-27 2002-09-13 Oreal Composition pour application topique sur la peau et/ou ses phaneres comprenant au moins un compose comportant un fragment phenyloxime
AU4267500A (en) * 1999-07-08 2001-01-11 Haarmann & Reimer Gmbh Topical cosmetic compositions comprising benzaldoximes

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AU7400201A (en) 2001-12-03

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