WO2009021590A1 - Inhibiteurs de la tyrosinase - Google Patents

Inhibiteurs de la tyrosinase Download PDF

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Publication number
WO2009021590A1
WO2009021590A1 PCT/EP2008/005832 EP2008005832W WO2009021590A1 WO 2009021590 A1 WO2009021590 A1 WO 2009021590A1 EP 2008005832 W EP2008005832 W EP 2008005832W WO 2009021590 A1 WO2009021590 A1 WO 2009021590A1
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acid
formula
compounds
compound
polyethylene glycol
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PCT/EP2008/005832
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German (de)
English (en)
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Sylvia Huber
Teresa Mujica-Fernaud
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Merck Patent Gmbh
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Publication of WO2009021590A1 publication Critical patent/WO2009021590A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/40—Succinic acid esters
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/28—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with dihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/533—Monocarboxylic acid esters having only one carbon-to-carbon double bond
    • C07C69/58—Esters of straight chain acids with eighteen carbon atoms in the acid moiety

Definitions

  • the invention relates to compounds of the formula I.
  • substituents AAi, AA 2 and R have the meaning given in claim 1, and their salts and solvates and mixtures, a process for their preparation, preparations and their use, in particular as tyrosinase inhibitors, suitable for whitening human skin or for the prophylaxis and / or treatment of pigmentary disorders such as hyperpigmentation, freckles, age spots, sun spots, and environmental aging.
  • Skin and hair color are dependent on the content, size and type of
  • Melanin (a nitrogenous dark dye) which is produced from melanocytes, the cells capable of melanin formation. Based on tyrosine and the help of various melanocyte-specific enzymes such as tyrosinase or tyrosinase-related proteins, melanin is produced within the melanosomes, with subsequent transformation of the melanosomes into keratinocytes.
  • the melanin in the skin is a suitable protection against UV radiation, darker or over-pigmented skin, as already mentioned, the
  • Hyperpigmented skin conditions or lesions contain melasma (also called chloasma), i. irregularly shaped yellowish-brown spots.
  • a large number of skin-whitening compounds for the treatment of pigmentation marks are available on the market. These include compounds such as kojic acid, arbutin, aloesin or rucinol, which inhibit melamine production in the skin. They delay the conversion of tyrosine into melanin by blocking the enzyme tyrosinase.
  • Unsubstituted 4-alkylresorcinols are compounds known to have the ability to reduce skin pigmentation. This is described in many publications, for example in EP 0341664, EP 904774, WO 2004/103940, EP 1317425, US 2006/0210498, US 2004/0109832.
  • a first subject of the present invention are therefore compounds of the formula I 1
  • AAi and AA 2 each independently represent OH or a residue of a monocarboxylic acid (fatty acid) or a dicarboxylic acid,
  • R each independently, optionally substituted, a linear or branched alkyl group having 1 to 12 carbon atoms, cycloalkyl having 3 to 9
  • Solvates of the compounds of the formula I mean additions of inert solvent molecules to the compounds of the formula I, which are formed on the basis of their mutual attraction. Solvates are e.g. Mono or dihydrate or addition compounds with alcohols, e.g. with methanol or ethanol.
  • the compounds of the formula I have at least one chiral center, they can occur in several stereoisomeric forms. All of these forms (e.g., D and L forms) and mixtures thereof (e.g., the DL forms) are included in the formula.
  • a fatty acid or dicarboxylic acid is preferably derived from acids which may be saturated or unsaturated and contain 4 to 30 C atoms, preferably 8 to 22 C atoms, particularly preferably 12 to 20 C atoms.
  • fatty acids examples include lauric acid (C 11 H 23 COOH), myristic acid (C 3 H 27 COOH), palmitic acid (C 15 H 3 iCOOH), stearic acid (C 7 H 35 COOH), oleic acid (C 7 H 33 COOH), linoleic acid (Ci 7 H 3I COOH), ricinoleic acid (Ci 7 H 32 (OH) COOH), linolenic acid
  • Atoms more preferably with 12, 14, 16, 18 or 20 C atoms.
  • synthetic fatty acids with an odd number of carbon atoms.
  • a fatty acid or dicarboxylic acid furthermore corresponds in a preferred embodiment to the radical OCOR 1 , where
  • R 1 is a linear or branched alkyl group having 8 to 30 carbon atoms, a linear or branched by OH, OR, SH, SR, NH 2 , NHR, NR 2 , substituted or unsubstituted guanidinium, (NR 3 ) + , COOH, COOR , CONH 2 , CONHR, CONR 2 , COR, Ar or Het, substituted alkyl group having 1 to 30 C atoms or a linear or branched alkenyl group having 8 to 30 C atoms, Ar unsubstituted or by R, OH or OR mono- denotes di- or trisubstituted phenyl,
  • a preferred group of compounds of the formula I are compounds of the formula Ia
  • R is a linear or branched alkyl group having 1 to 12 C atoms, preferably methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, and also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1, 1, 2, 1, 3, 2,2, 2,3 or 3,3-dimethylbutyl, 1 - or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl or cycloalkyl having 3 to 9
  • R may optionally also be substituted, i. at least one H can for example be substituted by a substituent selected from the group consisting of linear, branched or cyclic alkyl having 1 to 12 C atoms, linear, branched or cyclic alkenyl having 1 to 12 C atoms or Ar.
  • R is a linear or branched alkyl group having 1-12 C atoms.
  • R is particularly preferably hexyl.
  • R in the definition of R 1 , Ar and Het is preferably methyl, ethyl or propyl, more preferably methyl.
  • Ar is unsubstituted or mono-, di- or trisubstituted by R, OH or OR phenyl, for example phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p- Propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl or o-, m- or p-propoxyphenyl.
  • phenyl for example phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-
  • the heterocyclic radical having 5 to 13 ring members, where 1, 2 or 3 N and / or 1 or 2 S or O atoms may be present, means preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, A- or 5-imidazolyl, 3-, A- or 5-pyrazolyl , 2-, A- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, A- or 5-isothiazolyl, 2-, 3- or 4-pyridyl , 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1, 2,3-triazoM-, -A- or -5-yl, 1, 2,4-
  • a preferred group of compounds are compounds of the formula Ia, where AAi corresponds to the partial formula OCOR 1 and AA 2 OH or AA 2 of the partial forms! OCOR 1 and AAi Q is H, where R 1 is a linear or branched alkyl group having 15 to 30 carbon atoms.
  • a preferred group of compounds are compounds of the formula Ia, where AAi of the partial formula corresponds to OCOR 1 and AA 2 OH or AA 2 corresponds to the partial formula OCOR 1 and AAi OH, where R 1 is a linear or branched alkenyl group having 15 to 30 C Atoms means.
  • a preferred group of compounds are compounds of the formula Ia in which AA 1 corresponds to the sub-formula OCOR 1 and AA 2 denotes OH or AA 2 corresponds to the sub-formula OCOR 1 and AA 1 denotes OH, where R 1 denotes COOH, COOR, CONH 2 , CONHR, CONR 2 or COR substituted, linear or branched alkyl group having 1 to 30 carbon atoms.
  • Particularly preferred compounds of the formula I or Ia are hexadecanoic acid (4-hexyl-3-hydroxyphenyl) esters, hexadecanoic acid (2-hexyl-5-hydroxyphenyl) esters, (Z) octadec-9-enoic acid ( 4-hexyl-3-hydroxyphenyl ester, (Z) octadec-9-enoic acid (2-hexyl-5-hydroxyphenyl) ester, succinic acid (4-hexyl-3-hydroxyphenyl) ester, Succinic acid (2-hexyl-5-hydroxyphenyl) esters, and their salts and solvates.
  • Another object of the invention is also a process for the preparation of compounds of formulas I or Ia and their salts and solvates, characterized in that (a) a compound of formula V or Va in which R and o have the meaning given in claim 1, with an acid of the formula VI,
  • R 1 COCI VII is reacted, wherein the substituent R 1 has one of the meaning indicated above, and
  • the compounds of the formulas V or Va are known compounds which are prepared by various methods or are in part also commercially available.
  • resorcinol or, in general, a hydroxyphenol can be reacted with a carboxylic acid RCOOH in the presence of zinc chloride and the resulting condensate can be reduced with zinc / amalgam / hydrochloric acid, analogously to Lille. J. Bitter et al, Inst. Slantsev 1969, 18, 127.
  • resorcinol, a hydroxy phenol with an MQ Qi-UR jn Ge n enwarte an aluminum Katah'sators be produced at high temperatures of 200 to 400 0 C or generally , analogous to GB 1581428.
  • carboxylic acid chlorides of the formula VII can be prepared by reaction of the carboxylic acids with thionyl chloride (SOCfe), phosgene (COCl 2 ), phosphorus (III) chloride or phosphorus (V) chloride.
  • the compounds of formulas I or Ia can be readily prepared in a one step synthesis from the compounds of formulas V or Va by esterification with the acids of formula VI.
  • Various methods are known in the literature in this regard.
  • the coupling reaction is preferably carried out in the presence of an activating reagent, for example a carbodiimide such as dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethyl-carbodiimide hydrochloride (EDC), diisopropylcarbodiimide (DIC), or with 4-dimethylaminopyridine (DMAP ) as an acylation catalyst (Aldrichchimia Acta, 36, 1, 2003) in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile, in dimethyl sulfoxide or in the presence thereof Solvent, at temperatures between about -10 and 40 °, preferably between 0 and 30 °.
  • the reaction time is between a few minutes and several days, depending on the conditions used.
  • Particularly advantageous is the addition of the coupling reagent TBTU (O ⁇ benzotriazole-i-yO-NNN'.N'-bis ⁇ tetramethylene ⁇ uronium tetrafluoroborate) or O- (benzotriazol-1-yl) -N, N, N ⁇ N'-bis (tetramethylene) - Uronium hexafluorophosphate proved because in the presence of one of these compounds only a slight racemization occurs and no cytotoxic by-products arise.
  • the coupling reagent TBTU O ⁇ benzotriazole-i-yO-NNN'.N'-bis ⁇ tetramethylene ⁇ uronium tetrafluoroborate
  • the compounds of formula I or Ia may also be formed by combining an alcohol of formula V or Va and a carboxylic acid of formula VI with an acid catalyst (e.g., concentrated sulfuric acid).
  • the compounds of formula I or la may also be formed by reacting an alcohol of formula V or Va and a carboxylic acid chloride of formula VII in the presence of a base (such as triethylamine).
  • a base such as triethylamine
  • a compound of the formula I can be converted with an acid into the associated acid addition salt, for example by reaction of equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • Particularly suitable acids for this reaction are those which yield physiologically acceptable salts.
  • inorganic acids can be used, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid.
  • Hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, Decanoic, hexadecanoic, octadecanoic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, Ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylic acid,
  • Cyclohexanecarboxylic acid glucose-1-phosphate, naphthalene mono- and disulfonic acids or lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates, can be used for isolation and / or purification of the compounds of formula I.
  • compounds of formula I can be converted with bases (e.g., sodium or potassium hydroxide or carbonate) into the corresponding metal, especially alkali metal or alkaline earth metal, or into the corresponding ammonium salts.
  • a further subject of the invention is therefore also a mixture containing at least one compound of the formula Ia-1
  • Another object of the invention is also a mixture containing at least one compound of formula Ia-1 and / or at least one
  • Claim 1 or 2 specified or have the preferred meanings.
  • Tyrosinase inhibitors as evidenced in the example part, and show due to this property the desired activity as a skin brightener.
  • enzymes in the skin for example lipases or esterases, cleave the present ester bond.
  • the compounds of the formula V or Va thus produced in vivo are known skin whiteners and display at least additive, or even synergistic, action.
  • the unsubstituted or substituted mono- or dicarboxylic acids, in particular acids of the formula VI, which are formed in this reaction have further properties which are advantageous for the skin. According to the invention, different stages of melangenesis can be attacked, eg:
  • mRNA messenger RNA
  • tyrosinase thus reducing the production of tyrosinase
  • Another object of the present invention is a preparation or composition containing at least one compound of the formulas I or Ia, as described above, or a mixture of at least the compounds of formula Ia-1 or Ia-2, with the embodiments as described above, as well as at least one carrier suitable for topical applications.
  • Suitable for topical purposes means suitable for a local, in particular superficially applicable form.
  • the preparations are usually either topically applicable preparations, for example cosmetic, pharmaceutical or dermatological formulations, or foods or food supplements.
  • the preparations in this case contain a cosmetically, pharmaceutically or dermatologically suitable carrier and, depending on the desired property profile, optionally further suitable ingredients.
  • the topical preparations are preferably used as a cosmetic or dermatological preparation, particularly preferably as a cosmetic preparation.
  • a food of suitable carrier is used.
  • agent for the purposes of the present invention, in addition to the term preparation, the term agent, composition or formulation is used synonymously.
  • the compounds of the formulas I or Ia or a mixture as described above are or will typically be used according to the invention in amounts of from 0.01 to 20% by weight, preferably in amounts of from 0.05% by weight to 10% by weight. used.
  • the expert does not have any difficulties in selecting the quantities according to the intended effect of the preparation.
  • the preparations according to the invention in particular for use as a skin lightening preparation or as a cosmetic and / or pharmaceutical preparation for the prophylaxis and / or treatment of pigmentary disorders such as hyperpigmentation, freckles, age spots, sunspots and environmental Skin aging, one or more antioxidants and / or one or more vitamins.
  • antioxidants Through the use of antioxidants, a protective effect against oxidative stress or against the action of radicals can generally be achieved, whereby the expert has no difficulty in selecting suitable fast or delayed-acting antioxidants.
  • Compounds having reducing / oxidizing properties may also have depigmenting activities, for example by interaction with quinones and, as a result, the avoidance of oxidative
  • antioxidants eg amino acids (eg glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles, (eg urocaninic acid) and their derivatives, peptides such as D, L- Camosine, D-camosine, L-camosine and their derivatives (eg anserine), carotenoids, carotenes (eg ⁇ -carotene, ⁇ -carotene, lycopene) and their derivatives, chlorogenic acid and its derivatives, lipoic acid and derivatives thereof (eg dihydrolipoic acid), Aurothioglucose, propylthiouracil and other thiols (eg thioredoxin, glutathione, cysteine, cystine, cystamine and their glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, buty
  • cholesteryl and glyceryl esters and their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds (eg buthionine sulfoximines, Homocysteinsu lfoximine, buthionine sulphones, penta, hexa, heptathionine sulfoximine) in very low tolerated dosages (eg pmol to ⁇ mol / kg), furthermore (metal) chelators (eg ⁇ -hydroxyfatty acids, palmitic acid, phytic acid, lactoferrin), ⁇ -hydroxy acids (eg citric acid, Lactic acid, malic acid), humic acid, bile acids, bil
  • Zinc and its derivatives eg ZnO, ZnSO 4
  • selenium and its derivatives eg selenium methionine
  • stilbenes and their derivatives eg stilbene oxide, trans-stilbene oxide.
  • Suitable antioxidants are also described in WO 2006/111233 and WO 2006/111234.
  • Suitable antioxidants are also compounds of the general formulas A or B.
  • R 1 can be selected from the group consisting of -C (O) CH 3 , -CO 2 R 3 , -C (O) NH 2 and -C (O) N (R 4 ) 2 , XO or NH,
  • R 2 is linear or branched alkyl having 1 to 30 C atoms
  • R 3 is linear or branched alkyl having 1 to 20 C atoms
  • R 4 are each independently of one another H or linear or branched alkyl having 1 to 8 C atoms,
  • R 5 is linear or branched alkyl having 1 to 8 C atoms or linear or branched alkoxy having 1 to 8 C atoms and R 6 denotes linear or branched alkyl having 1 to 8 C atoms, preferably derivatives of 2- (4-hydroxy-3,5-dimethoxybenzylidene) malonic acid and / or 2- (4-hydroxy-3,5-dimethoxybenzyl) - malonic acid, particularly preferably 2- (4-hydroxy-3,5-dimethoxybenzylidene) malonic acid bis- (2-ethylhexyl) ester (for example Oxynex ® ST Liquid) and / or 2- (4-hydroxy-3,5 dimethoxybenzy ) malonic acid-bis (2-ethylhexyl) ester (example RonaCare ® AP).
  • antioxidants are also suitable for use in the formulations of the invention.
  • Known and commercial mixtures mixtures are, for example comprising, as active ingredients, lecithin, L - (+) - ascorbyl palmitate and citric acid (for example (for example Oxynex ® AP), natural tocopherols, L - (+) - ascorbyl palmitate, L - (+) - ascorbic acid and citric acid (for example Oxynex ® K LIQUID), tocopherol extracts from natural sources, L - (+) - ascorbyl palmitate, L - (+) - ascorbic acid and citric acid (for example Oxynex ® L LIQUID), DL- ⁇ -tocopherol, L - (+) - ascorbyl palmitate, citric acid and lecithin (for example Oxynex ® LM) or butylhydroxytoluene (BHT), L - (+) -. ascorbyl palmitate and citric acid (for
  • compositions according to the invention can be used as further ingredients
  • vitamins and vitamin derivatives selected from vitamin A, vitamin A propionate, vitamin A palmitate, vitamin A
  • Vitamins are in this case with vitamin B, thiamin chloride hydrochloride (vitamin Bi), riboflavin (vitamin B 2 ), nicotinamide, vitamin C (ascorbic acid), vitamin D, ergocalciferol (vitamin D 2 ), vitamin E, DL- ⁇ -tocopherol, tocopherol-E Acetate, tocopherol hydrogen succinate, vitamin Ki, esculin (vitamin P active ingredient), thiamine (vitamin B 1 ), nicotinic acid (niacin), pyridoxine, pyridoxal, pyridoxamine, (vitamin B 6 ), pantothenic acid, biotin, folic acid acid and cobalamin (vitamin Bi 2 ) in the cosmetic preparations according to the invention, particularly preferably vitamin C and its derivatives, DL- ⁇ -tocopherol, tocopherol-E-acetate, nicotinic acid, pantothenic acid and biotin. Vitamins are in this case with vitamin
  • the polyphenols which are sometimes present as natural substances, are of particular interest for applications in the pharmaceutical, cosmetic or food sector.
  • the flavonoids or bioflavonoids which are mainly known as plant dyes, frequently have an antioxidant potential.
  • dihydroxyflavones having an OH group adjacent to the keto function or OH groups in the 3'4 'or 6,7 or 7,8 position have antioxidant properties, while other mono- and dihydroxyflavones are partially non-antioxidant
  • Quercetin (cyanidanol, cyanidolone 1522, meletin, sophoretine, ericin, S.S., S.T. pentahyuroxyfiavo ⁇ o) is often referred to as a particularly effective antioxidant (e.g., CA. Rice-Evans, N.J. Miller, et al.
  • K. Lemanska, H. Szymusiak, B. Tyrakowska, R. Zielinski, AEMF Soffers, IMCM Rietjens; Free Radical Biology & Medicine 2001, 31 (7), 869-881 investigate the pH dependence of the antioxidant action of hydroxyflavones. Quercetin shows the highest activity of the investigated structures over the entire pH range. So that the compounds of the formula I or Ia can develop their positive action on the skin particularly well, it may be preferable to allow the compounds of the formula I or Ia to penetrate into deeper skin layers. There are several options available.
  • the compounds of the formula I or Ia can have sufficient lipophilicity in order to be able to penetrate through the outer skin layer into epidermal layers.
  • suitable transport agents for example liposomes, can be provided in the preparation, which enable transport of the compounds of the formula I or Ia through the outer skin layers.
  • a systemic transport of the compounds of formula I or Ia is conceivable.
  • the preparation is then, for example, designed to be suitable for oral administration.
  • compositions which are preferred according to the invention comprise, in addition to the at least one compound of the formulas I or Ia or a mixture of at least one compound of the formula Ia-1 and a compound of the formula Ia-2, if appropriate also containing at least one compound of the formula Va, also UV filters.
  • UV filters are suitable for combination with the compounds of the formula I or Ia according to the invention. Particularly preferred are those UV filters whose physiological harmlessness has already been demonstrated.
  • Benzylidenecamphor derivatives such as 3- (4'-methylbenzylidene) -dl-camphor (for example Eusolex 6300), 3-benzylidenecamphor (for example Mexoryl® SD), polymers of N - ⁇ (2 and 4) - [(2-oxoborn-3- ylidene) methyl] benzyl ⁇ -acrylamide (eg Mexoryl® SW), N, N, N-trimethyl-4- (2-oxoborn-3-ylidenemethyl) anilinium methylsulfate (eg Mexoryl® SK) or (2-oxobrom-3-yl) yliden) toluene-4-sulfonic acid (eg
  • Benzoyl or dibenzoylmethanes such as 1- (4-tert-butylphenyl) -3- (4-methoxyphenyl) propane-1,3-dione (e.g., Eusolex® 9020) or 4-isopropyldibenzoylmethane (e.g., Eusolex® 8020),
  • Benzophenones such as 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),
  • Methoxycinnamic acid esters such as octyl methoxycinnamate (e.g., Eusolex® 2292), isopentyl 4-methoxycinnamate, e.g. as a mixture of isomers (e.g., 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 such as 4-aminobenzoic acid, 2-ethylhexyl 4- (dimethylamino) benzoate (e.g., Eusolex® 6007), ethoxylated 4-aminobenzoic acid ethyl ester (e.g., Uvinul® P25),
  • Phenylbenzimidazole sulfonic acids such as 2-phenylbenzimidazole-5-sulfonic acid and its potassium, sodium and triethanolamine salts (eg Eusolex® 232), 2,2- (1,4-phenylene) bisbenzimidazole-4,6-disulfonic acid or salts thereof ( eg Neoheliopan® AP) or 2,2- (1,4-phenylene) bisbenzimidazole-6-sulfonic acid; and other substances like
  • 2-ethylhexyl 2-cyano-3,3-diphenylacrylate for example Eusolex® OCR
  • - SS ' 1 -I-phenylenedimethylene ⁇ to -ZC.Z-dimethyl ⁇ -oxobicyclo-p-1-yl-1-ylmethanesulfonic acid and their salts (for example Mexoryl SX ®) and
  • organic UV filters are usually incorporated in an amount of 0.5 to 10 weight percent, preferably 1-8 wt .-%, in cosmetic formulations.
  • Benzotriazolyl Tetramethylbutylphenol such as Tinosorb ® M
  • Organic UV filters are usually incorporated in an amount of 0.5 to 20 percent by weight, preferably 1 to 15 wt .-%, in cosmetic formulations.
  • inorganic UV filters are those from the group of titanium dioxides such as coated titanium dioxide (eg Eusolex®T-2000, Eusolex ® T-AQUA, Eusolex ® T-AVO), zinc oxides (eg Sachtotec®), iron oxides or cerium oxides conceivable.
  • coated titanium dioxide eg Eusolex®T-2000, Eusolex ® T-AQUA, Eusolex ® T-AVO
  • zinc oxides eg Sachtotec®
  • iron oxides or cerium oxides conceivable.
  • These inorganic UV filters are usually incorporated in an amount of 0.5 to 20 percent by weight, preferably 2 to 10 wt .-%, in cosmetic preparations.
  • UV filters By combining one or more compounds of formula I or Ia with other UV filters, the protective effect against harmful effects of UV radiation can be optimized. This results in broadband protection systems that can be supplemented by the addition of inorganic UV filters.
  • UV filters can also be used in encapsulated form.
  • organic UV filters in encapsulated form.
  • the hydrophilicity of the capsule wall can be adjusted independently of the solubility of the UV filter.
  • hydrophobic UV filters can also be incorporated into purely aqueous preparations.
  • the often perceived as unpleasant oily impression when applying the hydrophobic UV filter containing preparation is suppressed.
  • Certain UV filters in particular dibenzoylmethane derivatives, show only reduced photostability in cosmetic preparations.
  • these filters or compounds that affect the photostability of these filters such as cinnamic acid derivatives, the photostability of the entire formulation can be increased.
  • UV filters it is preferred if one or more of the above-mentioned UV filters are present in encapsulated form. It is advantageous if the capsules are so small that they can not be observed with the naked eye. To achieve the o.g. Effects it is still necessary that the capsules are sufficiently stable and donate the encapsulated active ingredient (UV filter) not or only to a small extent to the environment.
  • Suitable capsules may have walls of inorganic or organic polymers.
  • Capsules particularly preferred for use have walls which can be obtained by a SolGel process as described in applications WO 00/09652, WO 00/72806 and WO 00/71084. Again, capsules whose walls are made up of silica gel (silica, undefined silicon oxide hydroxide) are preferred.
  • silica gel silicon, undefined silicon oxide hydroxide
  • the capsules in preparations according to the invention are preferably present in amounts which ensure that the encapsulated UV filters are present in the preparation in the amounts indicated above.
  • the preparations according to the invention may also contain one or more further skin-lightening active ingredients.
  • skin-lightening active ingredients can be all active ingredients known to the person skilled in the art. Examples of compounds with skin-lightening activity are hydroquinone, kojic acid, arbutin, aloesin or rucinol.
  • the preparations according to the invention can moreover be further
  • Skin-sparing or skin-care active ingredients can, in principle, be all active ingredients known to the person skilled in the art.
  • anti-aging agents are pyrimidinecarboxylic acids, aryloximes, bioflavonoids, bioflavonoid-containing extracts, chromones or retinoids.
  • Pyrimidinecarboxylic acids occur in halophilic microorganisms and play a role in the osmoregulation of these organisms (EA Galinski et al., Eur. J. Biochem., 149 (1985) page 135-139).
  • pyrimidinecarboxylic acids in particular ectoine ((S) -1, 4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid) and hydroxyectoine ((S, S) -1,5,6,6-tetrahydro-5- hydroxy-2-methyl-4-pyrimidinecarboxylic acid and derivatives thereof
  • ectoine ((S) -1, 4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid)
  • hydroxyectoine (S, S) -1,5,6,6-tetrahydro-5- hydroxy-2-methyl-4-pyrimidinecarboxylic acid and derivatives thereof
  • enzymes against denaturing conditions such as salts, extreme pH, surfactants, urea, guanidinium chloride and other compounds.
  • Ectoine and ectoine derivatives such as hydroxyectoine can be used to advantage in medicines.
  • hydroxyectoine can be used for the manufacture of a medicament for the treatment of skin diseases.
  • Other uses of hydroxyectoine and other ectoine derivatives are typically in areas where e.g. Trehalose is used as an additive. So may ectoin derivatives, such as
  • Hydroxyectoin as a protective substance in dried yeast and bacterial cells use.
  • pharmaceutical products such as non-glycosylated, pharmaceutically active peptides and proteins e.g. t-PA can be protected with Ectoin or its derivatives.
  • EP-A-0 671 161 describes that ectoine and hydroxyectoine are used in cosmetic preparations, such as powders, soaps, surfactant-containing
  • a pyrimidinecarboxylic acid according to the formula below is preferably used, wherein R 1 is a radical H or Ci -8 alkyl, R 2 is a radical H or Ci -4 alkyl and R 3 , R 4 , R 5 and R 6 are each independently a radical from the group H 1 OH, NH 2 and Ci -4 alkyl.
  • R 1 is a radical H or Ci -8 alkyl
  • R 2 is a radical H or Ci -4 alkyl
  • R 3 , R 4 , R 5 and R 6 are each independently a radical from the group H 1 OH, NH 2 and Ci -4 alkyl.
  • pyrimidinecarboxylic acids ectoine ((S) -1, 4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid) and hydroxyectoine ((S 1 S) -1, 4,5,6- Tetrahydro-5-hydroxy-2-methyl-4-pyrimidine-carboxylic acid) used.
  • the preparations according to the invention contain such pyrimidinecarboxylic acids, preferably in amounts of up to 15% by weight.
  • the pyrimidinecarboxylic acids are preferably used in weight percent ratios of from 100: 1 to 1: 100 to give the compounds of the formula I, weight percent ratios in the range from 1:10 to 10: 1 being particularly preferred.
  • 2-hydroxy-5-methyllaurophenone oxime which is also referred to as HMLO, LPO or F5
  • HMLO 2-hydroxy-5-methyllaurophenone oxime
  • LPO 2-hydroxy-5-methyllaurophenone oxime
  • Preparations containing 2-hydroxy-5-methyllaurophenone oxime are accordingly suitable for the treatment of skin diseases which accompany inflammation.
  • the preparations preferably contain from 0.01 to 10% by weight of the aryloxime, and it is particularly preferred if the preparation contains from 0.05 to 5% by weight of aryloxime.
  • bioflavonoids are, for example, troxerutin, tiliroside, ⁇ -
  • Bioflavonoid Vietnamese extracts are for example Gingko Biloba or Emblica.
  • retinoids for example retinol (vitamin A), retinoic acid, retinaldehyde or also synthetically modified compounds of vitamin A.
  • the described chromones and retinoids are also effective anti-cellulite agents.
  • Another well known anti-cellulite drug is caffeine.
  • compositions may comprise or contain, consist essentially of or consist of the necessary or optional ingredients or ingredients mentioned. Any compounds or components which may be used in the compositions are either known and commercially available or may be synthesized by known methods.
  • the one or more compounds of the formula I or Ia or the mixture as described above can be incorporated in the usual way into cosmetic or dermatological preparations. Suitable preparations for external use, for example as a cream, lotion, gel, or as a solution that can be sprayed on the skin.
  • administration formulas such as capsules, dragees, powders, tablet solutions or solutions are suitable.
  • preparations for example: solutions, suspensions, emulsions, PIT emulsions, pastes, ointments, gels, creams, lotions, powders, soaps, surfactant-containing cleaning compositions. preparations, oils, aerosols and sprays. Other forms of application include sticks, shampoos and shower baths. Any customary carrier substances, adjuvants and optionally further active ingredients can be added to the preparation.
  • Preferable excipients come from the group of preservatives, stabilizers, solubilizers, colorants, i. Pigments or dyes or odor improvers.
  • Ointments, pastes, creams and gels may contain the usual excipients, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
  • excipients e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
  • Powders and sprays may contain the usual carriers, e.g.
  • Sprays may additionally contain the usual propellants, e.g. Chlorofluorocarbons, propane / butane or dimethyl ether.
  • Solutions and emulsions may contain the usual excipients such as solvents, solubilizers and emulsifiers, e.g. Water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyric glycol, oils, in particular cottonwort oil, peanut oil, maize germ oil, olive oil, castor oil and sesame oil, glycerin fatty acid esters, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
  • solvents e.g. Water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyric glycol, oils, in particular cottonwort oil, peanut oil, maize germ oil, olive oil, castor oil and sesame oil,
  • Suspensions may be the customary carriers such as liquid diluents, for example water, ethanol or propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and polyoxyethylene sorbitol esters.
  • suspending agents for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and polyoxyethylene sorbitol esters.
  • ethylene sorbitan ester microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.
  • Soaps may contain the usual excipients such as alkali salts of fatty acids, salts of fatty acid monoesters, fatty acid protein hydrolysates, isothionates,
  • Lanolin fatty alcohol, vegetable oils, plant extracts, glycerol, sugar or mixtures of these substances.
  • Surfactant-containing cleaning products may include the usual excipients such as salts of fatty alcohol sulfates, fatty alcohol ether sulfates, sulfosuccinic monoesters, fatty acid protein hydrolysates, isothionates, imidazolinium derivatives, methyl taurates, sarcosinates, fatty acid amide ether sulfates, alkyl amidobetaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable and synthetic oils, lanolin derivatives, ethoxylated glycerol - Contain fatty acid esters or mixtures of these substances.
  • excipients such as salts of fatty alcohol sulfates, fatty alcohol ether sulfates, sulfosuccinic monoesters, fatty acid protein hydrolysates, isothionates, imidazolinium derivatives, methyl taurates, sarcosinate
  • Facial and body oils may contain the usual excipients such as synthetic oils such as fatty acid esters, fatty alcohols, silicone oils, natural oils such as vegetable oils and oily vegetable 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 vegetable extracts, paraffin oils, lanolin oils or mixtures of these substances.
  • the preferred preparation forms according to the invention include in particular emulsions.
  • Emulsions of the invention are advantageous and contain z.
  • the lipid phase can advantageously be selected from the following substance group:
  • Oils such as triglycerides of capric or caprylic, further natural oils such. Castor oil;
  • Fats, waxes and other natural and synthetic fats preferably esters of fatty acids with lower C-number alcohols, e.g. with isopropanol, propylene glycol or glycerol, or esters of fatty acids
  • Alcohols with low C-alkanoic acids or with fatty acids Alcohols with low C-alkanoic acids or with fatty acids
  • Silicone oils such as dimethylpolysiloxanes, diethylpolysiloxanes, diphenylpolysiloxanes and mixed forms thereof.
  • the oil phase of the emulsions, oleogels or hydrodispersions or lipodispersions in the context of the present invention is advantageously selected from the group of esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids having a chain length of 3 to 30 carbon atoms and saturated and / or or unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms, from the group of esters of aromatic carboxylic acid and saturated and / or unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms.
  • ester oils can then advantageously be selected from the group isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexadecyl stearate, 2 Octyl dodecyl palmitate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate and synthetic, semisynthetic and natural mixtures of such esters, eg.
  • the oil phase can advantageously be selected from the group of branched and unbranched hydrocarbons and waxes, silicone oils, dialkyl ethers, the group of saturated or unsaturated, branched or unbranched alcohols, and fatty acid triglycerides, in particular the triglycerol esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids of a chain length of 8 to 24, in particular 12-18 C-atoms.
  • the fatty acid triglycerides can be selected, for example, advantageously from the group of synthetic, semi-synthetic and natural oils, for. Olive oil, sunflower oil, soybean oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil and the like.
  • any mixtures of such oil and wax components are also advantageous to use in the context of the present invention. It may also be advantageous, if appropriate, to use waxes, for example cetyl palmitate, as the sole lipid component of the oil phase.
  • the oil phase is advantageously selected from the group 2-ethylhexyl isostearate, octyldodecanol, isotridecyl isononanoate, isoeicosane, 2-ethylhexyl cocoate, CI2 C15 alkyl benzoate, caprylic capric triglyceride, dicapryl ether.
  • Ci2-is-alkyl benzoate and 2-ethylhexyl isostearate mixtures of C 2 -i 5 alkyl benzoate and isotridecyl isononanoate and mixtures of 2-ethyl! Hexy! Isostearate and isotridecyl isononanoate.
  • hydrocarbons paraffin oil, squalane and squalene are to be used advantageously in the context of the present invention.
  • the oil phase may also have a content of cyclic or linear silicone oils or consist entirely of such oils, although it is preferred, except for the silicone oil or silicone oils to use an additional content of other oil phase components.
  • cyclomethicone octamethylcyclotetrasiloxane
  • Silicone oils are to be used advantageously in the context of the present invention, for example hexamethylcyclotrisiloxane, polydimethylsiloxane, poly (methylphenylsiloxane).
  • mixtures of cyclomethicone and Iso tridecylisononanoat from cyclomethicone and 2-Ethylhexylisostearat.
  • the aqueous phase of the preparations according to the invention advantageously contains alcohols, diols or polyols of low C number, and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, diethylene - Glykolmonomethyl- or -monoethylether and analogous products, also low C-number alcohols, z.
  • alcohols, diols or polyols of low C number, and their ethers preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, diethylene - Glykolmonomethyl- or -monoeth
  • isopropanol, 1, 2-propanediol, glycerol and in particular one or more thickening agents which or which can be advantageously selected from the group of silica, aluminum silicates, polysaccharides or their derivatives, e.g. Hyaluronic acid, xanthan gum, hydroxypropylmethylcellulose, particularly advantageous from the group of polyacrylates, preferably a polyacrylate from the group of so-called Carbopols, for example Carbopols types 980, 981, 1382, 2984, 5984, each individually or in combination.
  • Carbopols for example Carbopols types 980, 981, 1382, 2984, 5984, each individually or in combination.
  • Emulsions of the invention are advantageous and contain z.
  • the preparations according to the invention contain hydrophilic surfactants.
  • hydrophilic surfactants are preferably selected from the group of alkylglucosides, acyl lactylates, betaines and cocoamphoacetates.
  • alkylglucosides in turn are advantageously selected from the group of alkylglucosides, which are represented by the structural formula
  • R is a branched or unbranched alkyl radical
  • the value DP represents the degree of glucosidation of the alkylglucosides used in the invention and is defined as
  • pi, p 2 , P 3 ••• or Pi represent the proportion of the products which are mono-, di-trisubstituted ... times glucosylated in weight percentages.
  • the value DP takes into account the fact that alkylglucosides, as a rule, are mixtures of mono- and oligoglucosides.
  • Advantageously in accordance with the invention is a relatively high content of 10 monoglucosides, typically of the order of 40-70% by weight.
  • Alkylglylcosides used particularly advantageously according to the invention are selected from the group of octylglucopyranoside, nonylglucopyranoside, decylglucopyranoside, undecylglucopyranoside, dodecylglucopyranoside, tetra-15-decylglucopyranoside and hexadecylglucopyranoside.
  • acyl lactylates are advantageously selected from the group of substances which are defined by the structural formula
  • R 1 is a branched or unbranched alkyl radical having 1 to 30 carbon atoms and M + from the group of alkali metal ions and the group having one or more alkyl and / or with one or more hydroxyalkyl radicals substituted ammonium ions is selected or corresponds to half the equivalent of an alkaline earth metal ion.
  • sodium is advantageous, for example the product Pathionic ® ISL from the American Ingredients
  • R 2 is a branched or unbranched alkyl radical having 1 to 30 carbon atoms.
  • R 2 is a branched or unbranched alkyl radical having 6 to 12 carbon atoms.
  • capramidopropylbetaine for example the product Tego ® betaine 810 from Th. Goldschmidt AG.
  • Sodium for example, selected as inventively advantageous cocoamphoacetate as under the name Miranol ® Ultra C32 from Miranol Chemical Corp. is available.
  • compositions according to the invention are advantageously characterized in that the hydrophilic or surfactant (s) in concentrations of
  • the cosmetic and dermatological preparations according to the invention are applied in sufficient quantity to the skin in the manner customary for cosmetics.
  • Cosmetic and dermatological preparations according to the invention can be present in various forms. So they can z.
  • Oil-in-water (W / O / W) a gel, a solid stick, an ointment or even an aerosol.
  • Ectoine in encapsulated form, e.g. In collagen matrices and other common encapsulating materials, e.g.
  • wax matrices As encapsulated cellulose, in gelatin, wax matrices or liposomally encapsulated. In particular, wax matrices as described in DE-OS 43 08282, have been found to be favorable. Preference is given to emulsions. O / W emulsins are especially preferred. Emulsions, W / O emulsions and O / W emulsions are commonly available.
  • emulsifiers for example, the known W / O and O / W emulsifiers can be used. It is advantageous to use further customary co-emulsifiers in the preferred O / W emulsions according to the invention.
  • suitable co-emulsifiers are, for example, O / W emulsifiers, primarily from the group of substances with HLB values of 11-16, very particularly advantageously with HLB values of 14.5-15.5, provided that the O / W emulsifiers have W emulsifiers have saturated radicals R and R '. If the O / W emulsifiers unsaturated radicals R and / or R 1 or, if isoalkyl derivatives are present, the preferred HLB value of such emulsifiers may also be lower or higher.
  • fatty alcohol ethoxylates from the group of ethoxylated stearyl alcohols, cetyl alcohols, cetylstearyl alcohols (cetearyl alcohols).
  • Particularly preferred are: polyethylene glycol (13) stearyl ether (steareth-13), polyethylene glycol (14) stearyl ether (steareth-14), polyethylene glycol (15) stearyl ether (steareth-15), polyethylene glycol (16) stearyl ether (steareth-16), Polyethylene glycol (17) stearyl ether (steareth-17), polyethylene glycol (18) stearyl ether (steareth-18), polyethylene glycol (19) stearyl ether (steareth-19), polyethylene glycol (20) stearyl ether (steareth-20), polyethylene glycol (12) isostearyl ether (isosteareth-12), polyethylene glycol (13) isostearyl ether (isosteareth-13), polyethylene glycol (14) - iso
  • the ethoxylated alkyl ether carboxylic acid or its salt may advantageously be the sodium laureth-11-carboxylate.
  • alkyl ether sulfate sodium laureth-4 sulfate can be advantageously used.
  • polyethylene glycol (30) may advantageously be cholesteryl ether be used.
  • polyethylene glycol (25) soybean oil has been proven.
  • polyethylene glycol glycerol fatty acid esters from the group consisting of polyethylene glycol (20) glyceryl laurate, polyethylene glycol (21) glyceryl laurate, polyethylene glycol (22) glyceryl laurate, polyethylene glycol (23) glyceryl laurate, polyethylene glycol (6) glyceryl caprate / citrate, polyethylene glycol (20 ) glyceryl oleate, polyethylene glycol (20) glyceryl isostearate, polyethylene glycol (18) glyceryl oleate (cocoate).
  • polyethylene glycol (20) glyceryl laurate polyethylene glycol (21) glyceryl laurate
  • polyethylene glycol (22) glyceryl laurate polyethylene glycol (23) glyceryl laurate
  • polyethylene glycol (6) glyceryl caprate / citrate polyethylene glycol (20 ) glyceryl oleate
  • sorbitan esters from the group of polyethylene glycol (20) sorbitan monolaurate, polyethylene glycol (20) sorbitan monostearate, polyethylene glycol (20) sorbitan monoisostearate, polyethylene glycol (20) sorbitan monopalmitate, polyethylene glycol (20) sorbitan monooleate.
  • W / O emulsifiers can be used:
  • W / O emulsifiers are glyceryl monostearate,
  • Glyceryl monoisostearate glyceryl monomyristate, glyceryl monooleate, diglyceryl monostearate, Diglycerylmonoisostearat, propylene glycol monostearate, propylene glycol monoisostearate, propylene glycol monocaprylate, propylene glycol monolaurate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monocaprylate, Sorbitanmonoisooleat, sucrose distearate, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, Isobehenyl- alcohol, selachyl alcohol, chimyl alcohol, polyethylene glycol ( 2) stearyl ether (steareth-2), glyceryl monolaurate, glyceryl monocaprinate, glyceryl mono- caprylate or PEG-30 dipolyhydroxystearate.
  • compositions or preparations described are particularly useful for protecting human skin against UV radiation, aging processes and oxidative stress, i. against damage by radicals. They are present in various dosage forms commonly used for this application.
  • the preparation in particular as a lotion or emulsion, such as cream or milk (O / W, W / O, O / W / O, W / O / W), in the form of oily-alcoholic, oily-aqueous or aqueous-alcoholic Gels or solutions, be present as solid pens or formulated as an aerosol
  • the preparation may contain cosmetic adjuvants commonly used in this type of preparation, such as thickeners, emollients, humectants, surfactants, emulsifiers, preservatives, antifoaming agents, perfumes, waxes, lanolin, propellants, dyes and / or pigments which stain the agent itself or the skin, and other ingredients commonly used in cosmetics.
  • cosmetic adjuvants commonly used in this type of preparation, such as thickeners, emollients, humectants, surfactants, emulsifiers, preservatives, antifoaming agents, perfumes, waxes, lanolin, propellants, dyes and / or pigments which stain the agent itself or the skin, and other ingredients commonly used in cosmetics.
  • AIs dyes are preferably used approved dyes listed in the Cosmetics Regulation, Appendix 3 as a positive list.
  • preservatives are preferably approved
  • Preservatives used which are listed in the Cosmetics Regulation, Appendix 6 as a positive list or antimicrobial pigments, as described for example in WO 2004/0092283 or WO 2004/091567.
  • Suitable preservatives are therefore also alkyl esters of p-hydroxybenzoic acid, hydantoin derivatives, propionate salts or a variety of ammonium compounds.
  • Preservatives are methylparaben, propylparaben, imidazolidinyl urea, sodium dehydroxyacetate or
  • Benzyl alcohol Preservatives are used in amounts between 0.5 to 2 wt .-%.
  • Emollients or plasticizers are often incorporated into cosmetic preparations. They are preferably used in 0.5 to 50 wt .-%, preferably between 5 and 30 wt .-% based on the total composition.
  • plasticizers can be classified into classes, such as the category of esters, fatty acids or fatty alcohols, polyols, hydrocarbons and oils containing at least one amide structure unit.
  • oils containing at least one amide structure unit together with their synthesis are described in particular in EP 1044676 and EP 0928608.
  • a particularly preferred compound is isopropyl N-lauroyl sarcosinate, which is commercially available under the product name Eldew SL-205 from Ajinomoto.
  • esters mono or diesters may be selected. Examples in this regard are dibutyl adipate, diethyl sebacate, diisopropyl dimerate or dioctyl succinate.
  • Branched fatty acid esters are, for example, 2-ethylhexyl myristate, isopropyl stearate or isostearyl palmitate.
  • Tribasic esters are, for example, trisopropyl trilinoleate or trilauryl citrate. straight-
  • Fatty acid esters are, for example, lauryl palmitate, myristyl lactate, oleyl eurcat or stearyl oleate.
  • Suitable fatty alcohols and acids are compounds having 10 to 20 carbon atoms. Particularly preferred compounds are cetyl, myristyl, palmitic or stearic alcohol or acid.
  • Suitable polyols are linear or branched-chain alkyl polyhydroxy compounds, for example propylene glycol, sorbitol or glycerol. However, it is also possible to use polymeric polyols, for example polypropylene glycol or polyethylene glycol. Butylene and propylene glycol are also particularly suitable compounds for enhancing the penetration.
  • hydrocarbons as plasticizers are compounds that generally have 12 to 30 carbon atoms. Specific examples are arylalkyl benzoates, alkyl benzoates, mineral oils, petrolatum, squalene or isoparaffins.
  • Additional emollients or hydrophobizing agents are preferably C 2 to C 5 - alkyl benzoates, dioctyladipate, octyl stearate, octyldodecanol, hexyl laurate, octyldodecyl neopentanoate, cyclomethicone, Dicapryl ether, dimethicone, phenyl trimethicone, isopropyl myristate, Capriylic / capric glycerides, propylene glycol dicaprylate / dicaprate or decyl oleate.
  • Another category of functional ingredients of cosmetic preparations are thickening agents. Thickeners are used in dr rule in amounts between 0.1 to 20 wt .-%, preferably between 0.5 to 10 wt .-% based on the total amount. Exemplary for this
  • Compounds are cross-linked polyacrylate materials, available commercially under the trademark Carbopol from B.F. Goodrich Company. It is also possible to use thickeners, such as xanthan gum, carrageenan gum, gelatin gum, karaya gum, pectin gum or locust bean gum.
  • thickeners such as xanthan gum, carrageenan gum, gelatin gum, karaya gum, pectin gum or locust bean gum.
  • a compound may be both a thickener and a plasticizer.
  • these are silicone gums (kinematic viscosity> 10 centistokes), esters such as glycerol stearate or cellulose derivatives, for example hydroxypropyl cellulose.
  • dispersion or solubilizing agent an oil, wax or other fatty substance, a low monoalcohol or a low polyol or mixtures thereof.
  • Particularly preferred monoalcohols or polyols include ethanol, i-propanol, propylene glycol, glycerine and sorbitol.
  • a preferred embodiment of the invention is an emulsion which is present as a protective cream or milk and contains, for example, fatty alcohols, fatty acids, fatty acid esters, in particular triglycerides of fatty acids, lanolin, natural and synthetic oils or waxes and emulsifiers in the presence of water.
  • oily lotions based on natural or synthetic oils and waxes, lanolin, fatty acid esters, in particular triglycerides of fatty acids, or oily alcoholic lotions based on a lower alcohol, such as ethanol, or a glycerol, such as propylene glycol, and / or a polyol, such as glycerol, and oils, waxes and fatty acid esters, such as triglycerides of fatty acids.
  • the preparation according to the invention may also be in the form of an alcoholic gel which comprises one or more lower alcohols or polyols, such as ethanol, propylene glycol or glycerol, and a thickening agent, such as silica.
  • the oily-alcoholic gels also contain natural or synthetic oil or wax.
  • the solid sticks consist of natural or synthetic waxes and oils, fatty alcohols, fatty acids, fatty acid esters, lanolin and other fatty substances.
  • the customary propellants such as alkanes, fluoroalkanes and chlorofluoroalkanes, are generally used.
  • Further objects of the present invention are a process for the preparation of a preparation which is characterized in that one or more compounds of the formula I or Ia with residues as described above or at least one mixture as described above with a carrier suitable for topical applications, for example a cosmetically, pharmaceutically or dermatologically suitable carrier.
  • a dietary supplement which comprises mixing one or more compounds of the formula I or Ia with radicals as described above or at least one mixture as described above with a carrier suitable for foods.
  • the preparations according to the invention can be prepared using techniques which are well known to the person skilled in the art.
  • the mixing may involve dissolving, emulsifying or dispersing the at least one compound according to formula I or Ia or of
  • the foods include all materials that are suitable for consumption by animals or for human consumption, for example, vitamins and provitamins thereof, fats, minerals or amino acids. "The foods may be solid or liquid, so as a beverage
  • the present invention accordingly provides the use of at least one compound of the formula I or Ia or of the mixture comprising at least one compound of the formula Ia-1 and at least one compound of the formula Ia-2 as a food additive for human or animal nutrition and preparations, the food or Dietary supplements are included and appropriate carriers.
  • foods are, for example, foodstuffs derived from a single natural source, e.g. Sugar, unsweetened juice, nectar or puree from a single natural source, e.g. Sugar, unsweetened juice, nectar or puree from a single natural source, e.g. Sugar, unsweetened juice, nectar or puree from a single natural source, e.g. Sugar, unsweetened juice, nectar or puree from a single natural source, e.g. Sugar, unsweetened juice, nectar or puree from a single
  • Plant species such as unsweetened apple juice (eg a mixture of different types of apple juice), grapefruit juice, orange juice, apple compote, Apricot nectar, tomato juice, tomato sauce, tomato puree, etc.
  • foods that can be enriched with one or more compounds of formula I according to the present invention are the grains or cereals of a single plant species and materials made from such plant species, such as
  • Corn syrup, rye flour, wheat flour or oat bran are also suitable, for example multi-vitamin preparations, mineral mixtures or sweetened juice.
  • Other examples of foods include food preparations such as prepared cereals, biscuits, mixed drinks, foods specially formulated for children, such as yoghurt, diet foods, low calorie foods or animal foods.
  • the foods thus include all edible combinations of carbohydrates, lipids, proteins, inorganic elements,
  • the foods are preferably administered orally, e.g. in the form of food, pills, tablets, capsules, powders, syrups, solutions or suspensions.
  • the foods of the invention can be prepared by techniques well known to those skilled in the art.
  • Example 1 Synthesis of hexadecanoic acid (4-hexyl-3-hydroxyphenyl) ester (1) and hexadecanoic acid (2-hexyl-5-hydroxyphenyl) ester (2)
  • Example 2 Synthesis of (Z) octadec-9-enoic acid (4-hexyl-3-hydroxyphenyl) ester (3) and (Z) octadec-9-enoic acid (2-hexyl-5-hydroxy) phenyl) ester (4)
  • Oleic acid chloride reacted.
  • Tyrosinase was prepared using fungal and tyrosinase tyrosinase.
  • DOPA rated as a substrate DOPA rated as a substrate.
  • the compounds (1) and (2), as obtained in Example 1, the compounds (3) and (4) as obtained in Example 2 and L-Dopa are for 10 minutes at 25 ° C in phosphate buffer (pH 6.8) pre- incubated and then fungal tyrosinase (16U) (Fluka) is added.
  • the optical density of the samples is measured at 470 nm against a negative control (without active substance) measured.
  • Kojic acid and 4-hexyl-resorcinol are tested as a tyrosinase reference, ie positive control.
  • the tanned epidermal tissues (11 days old, size 0.5 cm 2 ) are treated daily for 4 days with 5 ⁇ l of a phosphate buffer solution of the compound of formula I or Ia to be tested or a mixture.
  • a negative control epidermal tissue dosed with pure phosphate buffer only
  • a positive control epidermal tissue dosed with pure phosphate buffer only
  • UV-Pearl, OMC stands for the preparation with the INCI name: Water (for EU: Aqua), Ethylhexyl Methoxycinnamate, Silica, PVP, Chlorphenesin, BHT; this composition is commercially available under the name Eusolex ® UV Pearl TM OMC from Merck KGaA, Darmstadt.

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Abstract

L'invention concerne des composés de la formule (I), la signification des substituants AA1, AA2 o et ayant une signification indiquée dans la revendication 1, ainsi que leurs sels et solvates et mélanges, un procédé pour les produire, des préparations et leur utilisation.
PCT/EP2008/005832 2007-08-13 2008-07-17 Inhibiteurs de la tyrosinase WO2009021590A1 (fr)

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