Classifications

• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/225—Polycarboxylic acids
• • 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
  • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
• • 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
  • A61Q19/04—Preparations for care of the skin for chemically tanning the skin
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
  • C07C57/13—Dicarboxylic acids
  • C07C57/15—Fumaric acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Definitions

• the present invention relates to the use of
• Dihydroxyfumaric acid derivatives for lightening the skin, for inhibiting tyrosinase and for the prophylaxis, treatment and / or follow-up of pigmentary disorders of the skin, as well as cosmetic and dermatological preparations and medicaments containing dihydroxyfumaric acid derivatives and novel dihydroxyfumaric acid derivatives.
• Skin and hair color are dependent on the content, size, distribution and type of the nitrogen-containing, dark dye melanin, which is produced in the melanocyte-capable cells (melanocytes).
• melanin is synthesized within the melanocytes.
• the melanin is transferred to the keratinocytes in the form of so-called melanosomes.
• melasma also called chloasma
• chloasma irregularly shaped yellowish-brown spots.
• Freckles are especially prone to skin type I, i. with very light skin and reddish hair.
• Hyperpigmentation (chloasma), on the other hand, is common in those women who routinely deliver estrogen to their bodies. Very often the sun plays an important role. You can prevent it mainly by regular sunscreen with a high SPF. In order to remove unsightly pigment spots, different ones are available
• a large number of skin-whitening compounds for the treatment of pigmentation marks are available on the market.
• these are compounds such as e.g. Kojic acid, arbutin, aloesin, niacinamide, vitamin C or rucinol, which inhibit melanin production in the skin.
• plant extracts such as e.g. from Morus alba or
• a first object of the present invention is therefore the
• R1 and R2 are independently selected from:
• - mono-, di- or trinuclear aromatic or heteroaromatic ring system having 5 to 20 carbon atoms, which may be substituted by -CH 3 or -OCH 3 , and wherein one or more CH groups are denoted by N and / or one or more non-adjacent CH 2 groups may be replaced by O, and / or their physiologically acceptable salts, tautomers and / or solvates, including mixtures thereof in all ratios,
• Another object of the present invention is the use of at least one compound of formula (I) as defined above for
• Another object of the present invention is the use of at least one compound of formula (I) as defined above for
• WO 01/66105 A1 describes a skin lightening formulation consisting of a combination of kojic acid, an antioxidant and a
• Dihydroxyfumaric acid is listed as a possible antioxidant or as a possible hydroxy acid.
• the skin lightening effect comes in particular through the three present in combination
• dihydroxyfumaric acid alone also has a skin-lightening effect which has the effect of
• Lactic acid, glycolic acid and even kojic acid surpasses many times. This is shown in the embodiments.
• the compounds of the formula (I) and their salts while being well tolerated, have at the same time valuable cosmetic and / or pharmacological properties in that the lightening of the skin is accompanied by a relative melanin content of less than 90%, preferably less than 80%, more preferably less than 70%.
• Tyrosinase inhibitors and show due to this property the desired activity as a skin brightener.
• An object of the invention thus relates to the use of at least one compound of formula (I) and / or its physiologically acceptable salts, tautomers and / or solvates, including mixtures thereof in all ratios, for the inhibition of tyrosinase, preferably also in vitro.
• the term "inhibition” refers to any reduction in activity based on the action of the specific compounds of the present invention, by being able to interact with the target molecule to allow recognition, binding and blocking
• the compounds are particularly preferably mono-specific in order to guarantee exclusive and immediate recognition of the selected oxidase.
• recognition refers to any kind of
• Target molecules especially covalent or non-covalent bonds, e.g. a covalent bond, hydrophobic / hydrophilic
• Concentrations are incubated for a time sufficient to allow the active agents to inhibit the synthesis of melanin, usually between about one hour and one week.
• Cultured cells from a biopsy sample can be used for testing in vitro. The amount of post-treatment melanin in the cells is then determined.
• the use in vitro is particularly for samples of mammalian species suffering from skin pigmentation disorders.
• the host or patient may be of any mammalian species, e.g. B. a Primatenspezies, especially humans, but also rodents
• mice including mice, rats and hamsters
• rabbits horses, cattle, dogs, cats, etc.
• Animal models are experimental
• the testing of multiple specific compounds allows selection of the drug most appropriate for the treatment of the patient.
• the in vivo dose of the chosen compound is advantageously matched to the susceptibility of the tyrosinase and / or severity of the patient's pigment disorder with respect to the in vitro data, thereby appreciably increasing therapeutic efficacy.
• the dose varies depending on the specific compound used, the specific one
• Use will generally continue until there is a significant reduction in tyrosinase activity and melanin production, e.g. at least about 10% reduction in melanin content and can be continued until essentially no undesirable
• IC 50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.
• the tyrosinase is inhibited to 50% when the concentration of
• IC 50 value Compounds smaller than 1 ⁇ , preferably less than 0.5 ⁇ , more preferably less than 0.1 ⁇ . This concentration is referred to as IC 50 value.
• compounds of the formula (I) and / or their physiologically acceptable salts, tautomers and / or solvates, including mixtures thereof in all ratios are suitable for use in the prophylaxis, therapy and / or follow-up of diseases caused by tyrosinase activity , mediated and / or disseminated.
• the invention thus relates to the use of the compounds of the formula (I) and / or their physiologically acceptable salts, tautomers and / or solvates, including mixtures thereof in all ratios, for the prophylaxis, therapy and / or follow-up of diseases caused by the activity of tyrosinase caused mediated and / or disseminated.
• the invention therefore also relates to the use of compounds of the formula (I) and / or their physiologically acceptable salts, tautomers and / or solvates, including mixtures thereof in all ratios, for the preparation of a medicament for prophylaxis, therapy and / or
• the interacting compounds can be used to modulate the signal (Stephens et al (2000) Biochemical J 351: 95).
• the compounds according to the invention can also be used as reagents for testing oxidase-dependent signal transduction pathways in animals and / or cell culture models or in the clinical diseases mentioned in this application. As discussed herein, these signaling pathways are relevant to various diseases. Accordingly, the compounds of the present invention are useful in the prophylaxis, therapy and / or follow-up of diseases caused by
• compounds of the formula (I) and / or their physiologically acceptable salts, tautomers and / or solvates, including mixtures thereof in all ratios are suitable for use in the prophylaxis, therapy and / or follow-up of pigment disorders selected from the group of hyperpigmentation , Freckles, age spots and sunspots are selected.
• the use of the compounds of the formula (I) as defined above may therefore be more cosmetic or pharmaceutical, in particular
• dermatological being nature. It is preferably a
• cosmetic use more preferably a non-therapeutic cosmetic use.
• the compounds of the formula (I) are defined as including pharmaceutically or cosmetically usable derivatives, salts, hydrates, solvates, precursors of the compounds and
• Solvates are e.g. Mono or dihydrate or alcoholates.
• pharmaceutically or cosmetically usable derivatives is meant e.g. the salts of the compounds of the invention as well as so-called precursors of the compounds.
• precursors is meant e.g. modified with alkyl or acyl groups, sugars or oligopeptides
• Metabolism of a compound according to the invention results is a metabolite in the context of the present invention.
• alkyl is an abbreviation for
• Alkyl group The alkyl radical can be unbranched (straight-chain) or branched.
• An unbranched or branched alkyl having 1 to 8 C atoms is understood as meaning, for example, methyl, ethyl, isopropyl, propyl, butyl, sec-butyl or tert-butyl, pentyl, isopentyl, 1-, 2- or 3-methylbutyl, 1,1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 or 1,2,2-trimethylpropyl , 1,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-, 2-, 3- or 4- Methylpentyl, hexyl, heptyl, 2-ethyl-pentyl, octyl or 2-ethyl-hexyl.
• the above-listed C1 to C8-alkyl radicals may, for example, also be nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
• Alkenyl stands as an abbreviation for Alkenylsti, whereby also several
• Double bonds may be present.
• unbranched alkenyl group having 2 to 8 carbon atoms is, for example, allyl, vinyl, propenyl, 2- or 3-butenyl, isobutenyl, sec-butenyl, 2-methyl-1 - or 2-butenyl, 3-methyl-1-butenyl, 1,3-butadienyl, 2-methyl-1,3-butadienyl, 2,3-dimethyl-1,3-butadienyl, 1-, 2-, 3- or 4-pentenyl, isopentenyl, hexenyl, heptenyl or octenyl ,
• Alkynyl stands as an abbreviation for alkynyl group, whereby also several triple bonds can be present.
• Examples of a branched or unbranched alkynyl group having 2 to 8 C atoms are ethynyl, 1- or 2-propynyl, 2- or 3-butynyl, furthermore 4-pentynyl, 3-pentynyl, hexynyl,
• the backbone of formula (I) can be used over any member of the ring
• Cycloalkyl group take place.
• suitable cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclooctadienyl.
• Heteroaromatic ring systems having 5 to 20 C atoms in the context of the present invention are phenyl, methylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, methoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,4-dimethoxyphenyl , 2,4,6-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, biphenyl, naphthyl, binaphthyl, anthracenyl,
• Phenanthrenyl pyridinyl, furanoyl or benzofuranoyl.
• R1 and R2 in formula (I) are independently selected from:
• - aromatic or heteroaromatic ring system having 5 to 10 carbon atoms, which may be substituted by -CH 3 or -OCH 3 and wherein one or more CH groups replaced by N and / or one or more non-adjacent CH 2 groups by O. could be.
• R1 and R2 in formula (I) are independent
• - aromatic or heteroaromatic ring system having 5 to 6 carbon atoms, which may be substituted by -CH 3 or -OCH 3 and wherein one or more CH groups replaced by N and / or one or more non-adjacent CH 2 groups by O. could be.
• R 1 and R 2 simultaneously represent H.
• Formula (I) then corresponds to dihydroxyfumaric acid. This means that in a very particularly preferred embodiment of the present invention Dihydroxyfumarcic acid and / or their
• Dihydroxyfumaric acid can be prepared from dl-tartaric acid in the presence of iron ions, for example, according to Roumanian Biotechnological Letters 2002, 7 (5), 897-904 or Russian Journal of Physical Chemistry 1986, 60 (1), 43-46.
• esterification of the carboxylic acid functionalities is feasible with standard esterification methods which are familiar to the person skilled in the art.
• the starting compounds are generally known. If they are new, they can be prepared by methods known per se.
• the present invention also provides the use of these compounds in the form of their physiologically acceptable salts which can be derived from various organic and inorganic acids and bases by art-known procedures.
• physiologically acceptable salt forms of the compounds of formula (I) are mostly prepared conventionally. If the connections a
• Containing carboxylic acid group one of their suitable salts can be formed by reacting the compound with a suitable base to the corresponding salt.
• suitable bases are for example
• Alkali metal hydroxides e.g., potassium hydroxide, sodium hydroxide and
• Lithium hydroxide Lithium hydroxide
• alkaline earth metal hydroxides e.g., barium hydroxide and calcium hydroxide
• alkali metal alcoholates e.g., potassium ethanolate
• a base of the formula (I) can be used 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 evaporation followed.
• an inert solvent such as ethanol
• the physiologically acceptable salts such as
• Hydrogen halides e.g., hydrochloric, hydrobromic, or hydrobromic
• Hydrogen iodide other mineral acids and their corresponding salts (e.g., sulfate, nitrate or phosphate, and the like), alkyl and potassium
• Monoarylsulfonates e.g., ethanesulfonate, toluenesulfonate and benzenesulfonate
• organic acids and their corresponding salts e.g.
• Carboxylate groups such as those contained in the compounds of formula (I) can be based by their acidic proton can be exchanged for a metal.
• the salts according to the invention can also be based on compounds of the formula (I) in which the proton is exchanged for an ion on the alcohol function of the dihydroxyfumaric acid derivatives.
• These may be monovalent ions, such as Li + , Na + , K + or NH 4 + , but also polyvalent ions, which salts of the type
• this drug can only be a desired cosmetic and / or pharmacokinetic property and may even positively affect the pharmacodynamics of this drug in terms of its therapeutic efficacy in the body.
• Preferred salts in the context of the invention are the lithium, sodium, potassium, magnesium, calcium, zinc, copper and ammonium salts of the compounds of the formula (I).
• a further subject of the present invention is a cosmetic or dermatological preparation containing at least one compound of the formula (I)
• R1 and R2 are independently selected from:
• - mono-, di- or trinuclear aromatic or heteroaromatic ring system having 5 to 20 carbon atoms, which may be substituted by -CH 3 or -OChh and wherein one or more CH groups by N and / or one or more non-adjacent CH 2 groups can be replaced by O,
• radicals R 1 and R 2 are defined as described above.
• preparation is synonymous with the term “agent”, “composition” or “formulation” used.
• the preparations are usually topically applicable preparations, e.g. cosmetic or dermatological formulations or medical devices.
• Topically applicable means according to the invention that the preparation externally and locally
• the preparation is applied, i. that the preparation must be suitable, for example, to be applied to the skin can.
• the preparations in this case contain a cosmetic, pharmaceutical or
• dermatologically suitable carrier and as desired
• topical preparations are preferably used as a cosmetic or dermatological preparation, particularly preferably as a cosmetic
• the preparations may comprise or contain, consist essentially of or consist of the necessary and optional ingredients mentioned above and / or below. All connections or
• the further active ingredient is preferably selected from the group of UV filters, antioxidants, vitamins,
• skin-lightening active ingredients anti-aging agents, anti-inflammatory agents, antimicrobial agents, agents for improving the moisture content of the skin (skin moistness regulators), anti-cellulite agents, anti-wrinkle agents, anti-dandruff agents, anti-acne Active ingredients, deodorants, pigments and
• Self-tanning substances more preferably from the group of UV filters, antioxidants, vitamins, skin lightening agents,
• Preparations preferred according to the invention also comprise one or more UV filters in addition to at least one compound of the formula (I).
• UV filters whose physiological harmlessness has already been demonstrated. Both for UVA and UVB filters, there are many known and proven substances from the literature. The compounds listed in the following lists are to be considered as examples only. Of course, other UV filters can be used.
• preferred preparations may comprise organic UV filters, so-called hydrophilic or lipophilic sunscreen filters, which are in the UVA range and / or UVB range and / or IR and / or VIS range (Absorber) are effective.
• organic UV filters so-called hydrophilic or lipophilic sunscreen filters, which are in the UVA range and / or UVB range and / or IR and / or VIS range (Absorber) are effective.
• These substances can be selected, in particular, from p-aminobenzoic acid derivatives, salicylic acid derivatives, ⁇ , ⁇ -diphenylacrylate derivatives, camphor derivatives, triazine derivatives, cinnamic acid derivatives, and polymeric filters and silicone filters, which are described in the application WO 93/04665. Further examples of organic filters are given in patent application EP-A 0 487 404.
• UV filters are usually named according to the INCI nomenclature. Particularly suitable for a combination are: para-aminobenzoic acid and its derivatives: PABA, ethyl PABA, ethyl dihydroxypropyl PABA, ethylhexyl dimethyl PABA, e.g. sold under the name "Escalol 507" by the company ISP, glyceryl PABA, PEG-25 PABA, e.g. sold under the name "Uvinul P25” from BASF.
• PABA para-aminobenzoic acid and its derivatives: PABA, ethyl PABA, ethyl dihydroxypropyl PABA, ethylhexyl dimethyl PABA, e.g. sold under the name "Escalol 507" by the company ISP, glyceryl PABA, PEG-25 PABA, e.g. sold under the name "Uvinul P25” from BASF.
• Salicylates homosalates sold under the name "Eusolex HMS” by Merck; Ethyl hexyl salicylates, e.g. sold under the name “Neo Heliopan OS” by Symrise; Dipropylene glycol salicylates, e.g.
• ⁇ , ⁇ -diphenylacrylate derivatives octocrylenes, for example sold under the name “Eusolex® OCR” by Merck; "Uvinul N539” from BASF, Etocrylene, for example sold under the name “Uvinul N35” by BASF ,
• Benzophenone Derivatives Benzophenone-1, e.g. sold under the name "Uvinul 400"; Benzophenone-2, e.g. sold under the name “Uvinul D50”; Benzophenone-3 or oxybenzone, e.g. sold under the name "Uvinul M40"; Benzophenone-4, e.g. sold under the name "Uvinul MS40”; Benzophenone-9, e.g. sold under the name "Uvinul DS-49" by BASF; Benzophenone-5, benzophenone-6, e.g. sold under the name "Helisorb 11" by Norquay; Benzophenone-8, e.g.
• Benzylidene camphor derivatives 3-Benzylidene camphor, e.g. sold under the name "Mexoryl SD” from Chimex; 4-methylbenzylidene camphor, e.g. sold under the name "Eusolex 6300" from the company.
• Terephthalylidenedicamphorosulfonic acid e.g. sold under the name "Mexoryl SX” by Chimex
• Polyacrylamidomethylbenzylidene camphor sold under the name “Mexoryl SW” from Chimex.
• Phenylbenzimidazole derivatives phenylbenzimidazole sulfonic acid, e.g.
• Phenylbenzotriazole derivatives Drometrizol trisiloxanes, for example sold under the name "Silatrizole” by the company Rhodia Chimie; Methylenebis (benzotriazolyl) tetramethylbutylphenol in solid form, for example sold under the name "MIXXIM BB / 100" from the company. Fairmount Chemical, or in micronized form as an aqueous dispersion, for example sold under the name "Tinosorb M" from the Fa. BASF.
• Triazine derivatives ethylhexyltriazone, e.g. sold under the name "Uvinul T150" from BASF; Diethylhexylbutamidotriazone, e.g.
• 1,3,5-triazines sold as Tinosorb A2B by BASF
• BASF N2, N4-bis [4- [5- (1, 1-dimethylpropyl) -2-benzoxazolyl] phenyl] -N6- (2-ethylhexyl) -1, 3,5-triazine
• Anthraniline derivatives menthyl anthranilate, e.g. distributed under the
• Imidazole derivatives ethylhexyldimethoxybenzylidenedioxoimidazoline
• Benzalmalonate Derivatives Polyorganosiloxanes containing functional benzalmalonate groups, e.g. Polysilicone-15, e.g. sold under the name "Parsol SLX” by Hoffmann LaRoche.
• 4,4-Diarylbutadiene derivatives 1,1-dicarboxy (2,2'-dimethylpropyl) -4,4-diphenylbutadiene.
• Benzoxazole derivatives 2,4-bis [5- (1-dimethylpropyl) benzoxazol-2-yl (4-phenyl) imino] -6- (2-ethylhexyl) imino-1,3,5-triazine, for example sold under the Names Uvasorb K2A from the company Sigma 3V and mixtures containing this.
• Suitable organic UV-protective substances are preferably to be selected from the following list: ethylhexyl salicylate,
• Phenylbenzimidazole sulfonic acid benzophenone-3, benzophenone-4,
• Benzophenone-5 n-hexyl 2- (4-diethylamino-2-hydroxybenzoyl) benzoate, 4-methylbenzylidene camphor, terephthalylidenedicamphorosulfonic acid, disodium phenyldibenzimidazole tetrasulfonate,
• organic UV filters are incorporated usually in an amount of 0.01 to 20 weight percent, preferably 1 to 20 wt .-%, in formulations.
• the preparations may contain, in addition to the compounds of the formula (I) and the optionally organic UV filters, as described above, further inorganic UV filters, so-called particulate UV filters.
• these combinations with particulate UV filters are possible both as a powder and as a dispersion or paste of the following types. In this case, both those from the group of titanium dioxides, such as
• coated titanium dioxide for example Eusolex ® T-2000, Eusolex ® T-AQUA, Eusolex ® T-AVO, Eusolex ® T-OLEO), zinc oxides (for example Sachtotec® ®),
• Iron oxides or else cerium oxides and / or zirconium oxides are preferred.
• pigmentary Titandixoxid or zinc oxide are possible, wherein the particle size of these pigments is greater than or equal to 200 nm, for example Hombitan® FG or Hombitan ® FF Pharma.
• the preparations may further be preferred if the preparations contain inorganic UV filters which are prepared by customary methods, such as, for example, in US Pat
• Cosmetics & Toiletries 1990, 105, 53 have been post-treated. This may include one or more of the following
• Aftertreatment components are selected: amino acids, beeswax, fatty acids, fatty acid alcohols, anionic surfactants, lecithin,
• Phospholipids sodium, potassium, zinc, iron or aluminum salts of fatty acids, polyethylenes, silicones, proteins (especially collagen or elastin), alkanolamines, silica, alumina, other metal oxides, phosphates, such as sodium hexametaphosphate or glycerol.
• Preferably used particulate UV filters are:
• untreated titanium dioxides e.g. the products Microtitanium Dioxide MT 500 B from Tayca; Titanium Dioxide P25 from Degussa,
• Silica post-treatment such as e.g. the product "Microtitanium Dioxide MT 100 SA of Tayca; or the product “Tioveil Fin” from Uniqema,
• micronized titanium dioxides with aluminum oxide and / or aluminum stearates / iodate aftertreatment such as, for example, Microtitanium Dioxide MT 100 T from Tayca, Eusolex T-2000 from Merck
• micronized titanium dioxides with iron oxide and / or iron stearates aftertreatment such as, for example, the product "Microtitanium Dioxide MT 100 F" from Tayca
• Alumina and silicone aftertreatment such as e.g. the product
• the treated micronized titanium dioxides used for combination may also be post-treated with:
• Alumina and stearic acid such as. the product UV-Titan M160 of the company Sachtleben,
• Aluminum and silicone oils e.g. the product UV-Titan M262 of the company Sachtleben,
• Polydimethylsiloxanes e.g. the product 70250 Cardre UF Ti02SI3 "from the company Cardre,
• Escalol Z100 from ISP (alumina aftertreated ZnO dispersed in an ethylhexyl methoxycinnamate / PVP-hexadecenes / methicone copolymer blend)
• Fuji ZNO-SMS-10 from Fuji Pigment (ZnO aftertreated with silica and polymethylsilsquioxane);
• mixtures of various metal oxides e.g. Titanium dioxide and cerium oxide with and without aftertreatment, e.g. the product Sunveil A of the company Ikeda.
• blends of alumina, silica, and silicone aftertreated titanium dioxide / zinc oxide blends such as those described in U.S. Pat. the product UV-Titan M261 from the company Sachtleben be used.
• inorganic UV filters are incorporated usually in an amount of 0.1 to 25 weight percent, preferably 2 to 10 wt .-%, in the preparations.
• UV filters can also be used in encapsulated form.
• organic UV filters it is beneficial to use organic UV filters in
• the capsules are in
• Preparations to be used according to the invention are preferably contained in amounts which ensure that the encapsulated UV filters are present in the above-mentioned weight percent ratios in the preparation.
• Substance that serves to maintain and / or improve the moisture content of the skin include, among others, substances that belong to the so-called natural
• Moisture factors include, e.g. 2-oxopyrrolidines 5-carboxylic acid.
• the preparation contains 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.
• suitable fast or delayed-acting antioxidants There are many known and proven substances in the literature that can be used as antioxidants, e.g.
• Amino acids e.g., glycine, histidine, tyrosine, tryptophan
• amino acids e.g., glycine, histidine, tyrosine, tryptophan
• imidazoles e.g., urocaninic acid
• derivatives thereof peptides, e.g. D, L-carnosine, D-carnosine, L-carnosine and their derivatives (e.g.
• carotenoids such as ⁇ -carotene, ⁇ -carotene, lycopene
• carotenes such as ⁇ -carotene, ⁇ -carotene, lycopene
• chlorogenic acid and its derivatives such as dihydrolipoic acid
• lipoic acid and its derivatives such as dihydrolipoic acid
• aurothioglucose propylthiouracil and other thiols (such as thioredoxin, glutathione , Cysteine, cystine, Cystamine and its glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl, ⁇ -lino, cholesteryl and
• Glyceryl esters and their salts, dilauryl thiodipropionate,
• Distearyl thiodipropionate, thiodipropionic acid and its derivatives such as esters, ethers, peptides, lipids, nucleotides, nucleosides and salts
• sulfoximine compounds such as buthionine sulfoximines
• Heptathioninsulfoximin in very low tolerated dosages (such as pmol to ⁇ / kg), further (metal) chelators (such as a-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), ⁇ -hydroxy acids (such as citric acid, lactic acid, Malic acid), humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA, pentasodium
• ethylenediaminetetramethylene phosphonate and its derivatives unsaturated fatty acids and their derivatives, vitamin C and derivatives (e.g.
• Ascorbyl palmitate magnesium ascorbyl phosphate, ascorbyl acetate
• Tocopherols and derivatives such as vitamin E acetate
• vitamin A and derivatives such as vitamin A palmitate
• Further suitable antioxidants are also described in WO 2006/111233 and WO 2006/111234.
• Suitable antioxidants are also compounds of the general
• X is O or H
• 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 H or linear or branched
• R 5 H linear or branched alkyl having 1 to 8 carbon atoms or
• R 6 is linear or branched alkyl having 1 to 8 carbon atoms.
• antioxidants are also suitable for use in the formulations of the invention.
• Known and commercially available mixtures are, for example, mixtures containing as active
• Citric acid such as Oxynex ® K LIQUID
• tocopherol extracts from natural sources L - (+) - ascorbyl palmitate, L - (+) - ascorbic acid and citric acid (such as Oxynex L LIQUID ®), DL-a-tocopherol, L- ( +) -
• antioxidants are used with compounds of formula (I) or sub-formulas thereof in such compositions usually in weight percent ratios in the range of 1000: 1 to 1: 1000, preferably in weight percent ratios of 100: 1 to 1: 100.
• 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 3'4'- or 6,7- or 7,8-position have antioxidant properties, while other mono- and Dihydroxyflavone partially have no antioxidant properties.
• Quercetin (cyanidanol, cyanidolone 1522, meietin,
• the preparations according to the invention may contain vitamins as further ingredients. Preference is given to vitamins and vitamin derivatives selected from vitamin A, vitamin A propionate, vitamin A palmitate, vitamin A acetate, retinol, vitamin B, thiamin chloride hydrochloride (vitamin B, riboflavin (vitamin B 2 ), nicotinamide, vitamin C (ascorbic acid), vitamin D, ergocalciferol (vitamin D 2 ), vitamin E, DL-a-tocopherol, tocopherol-E-acetate, tocopherol hydrogen succinate, vitamin K1, esculin (vitamin P-active ingredient), thiamine (vitamin Bi), nicotinic acid (niacin),
• Preparations contain, in particular preferably vitamin A palmitate, vitamin C and its derivatives, DL-a-tocopherol, tocopherol E acetate, nicotinic acid, pantothenic acid and biotin. Vitamins are with the
• Preparations usually in cosmetic use in the range of 0.01 to 5 wt .-%, based on the total weight added.
• Nutritional physiology applications are based on the recommended vitamin requirement.
• the preparations according to the invention comprise one or more further skin-lightening active ingredients (or synonymously depigmentation active ingredients) or extracts having one
• skin-lightening active ingredients can be all active ingredients known to the person skilled in the art. Suitable for combination are commercially available melanogenesis inhibitors, e.g. Ascorbic acid and its derivatives, aloesin, niacinamide, emblica, elagic acid, licorice extract, mulberry extract, kojic acid, liquorice root extract, rucinol,
• melanogenesis inhibitors e.g. Ascorbic acid and its derivatives, aloesin, niacinamide, emblica, elagic acid, licorice extract, mulberry extract, kojic acid, liquorice root extract, rucinol,
• Preferred examples of compounds having skin-lightening activity are hydroquinone, niacinamide, ascorbic acid and physiologically acceptable salts thereof, kojic acid, arbutin, aloesin, azelaic acid, elagic acid or rucinol.
• Preferred examples of extracts with skin-lightening activity are licorice extract, mulberry extract or emblica.
• the preparations according to the invention may additionally contain anti-aging active ingredients, anti-cellulite active ingredients or conventional skin-friendly or skin-care active ingredients. Skin-friendly or
• skin-care active ingredients may be all active ingredients known to the person skilled in the art.
• Particularly preferred anti-aging agents are
• Pyrimidinecarboxylic acids aryloximes, bioflavonoids, bioflavonoid-containing extracts, chromones or retinoids.
• Suitable anti-aging ingredients especially for skin care
• Preparations are preferably also so-called compatible solutes. These are substances that are involved in the osmoregulation of
• osmolytes Plants or microorganisms are involved and can be isolated from these organisms. Under the generic term compatible solutes also the described in the German patent application DE-A-10133202 osmolytes are taken. Suitable osmolytes are, for example, the polyols, methylamine compounds and amino acids and in each case their precursors. As osmolytes are in the sense of the Germans
• Patent application DE-A-10133202 especially substances from the group of polyols, such as myo-inositol, mannitol or sorbitol and / or understood one or more of the following osmolytically active substances: taurine, choline, betaine, phosphorylcholine, Glycerophosphorylcholine, glutamine, glycine , ⁇ -alanine, glutamate, aspartate, proline, and taurine.
• Precursors of these substances are, for example, glucose, glucose polymers, phosphatidylcholine, phosphatidylinositol, inorganic phosphates, proteins, peptides and polyamic acids. Precursors are e.g.
• compatible solute substances selected from the group consisting of Pyrimidincarbonklaren (such as ectoine and hydroxyectoine), proline, betaine, glutamine, cyclic
• DIP di-myo-inositol phosphate
• cDPG cyclic 2,3-diphosphoglycerate
• DGP 1, 1-diglycerol phosphate
• .beta.-mannosylglycerate firoin
• ectoine ((S) -1,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid) and hydroxyectoine ((S, S) -1,4,5,6-tetrahydro-5 are among the pyrimidinecarboxylic acids hydroxy-2-methyl-4-pyrimidinecarboxylic acid) and their derivatives.
• RonaCare Luremine ® ® Ronacare isoquercetin, Ronacare ® tiliroside or Ronacare ® cyclopeptides are used. 5
• chromones for example retinol (vitamin A), retinoic acid, retinaldehyde or else synthetically modified
• An object of the invention is likewise a preparation containing at least one compound of the formula (I) as described above and one or more self-tanning substances. Such a preparation usually has a contrast-reducing effect and enables the achievement of an even skin tone.
• the invention likewise relates to the use of compounds of the formula (I), as described, in combination with one or more self-tanning substances for reducing the contrast and achieving an even skin tone.
• a contrast reducing agent is therefore a substance that has a reduces uneven skin coloration by reducing the contrast between stronger and less-colored areas of the skin. In this case, such an uneven skin coloration can be caused by an uneven pigmentation and / or a different distribution of the cornea. Uneven pigmentation is in the
• a contrast reduction can be achieved, in particular, by preparations in which at least one compound according to formula (I) additionally contains a self-tanning substance, preferably dihydroxyacetone (DHA) and derivatives derived therefrom, DHA rapid, DHA plus or erythrulose, or a mixture of self-tanning substances DHA, DHA rapid, containing DHA plus and / or erythrulose.
• a self-tanning substance preferably dihydroxyacetone (DHA) and derivatives derived therefrom, DHA rapid, DHA plus or erythrulose, or a mixture of self-tanning substances DHA, DHA rapid, containing DHA plus and / or erythrulose.
• Dihydroxyacetone-containing mixture or preparation can be used inter alia: glycerol aldehyde, hydroxymethylglyoxal, ⁇ -dialdehyde, 6-aldo-D-fructose, ninhydrin, 5-hydroxy-1, 4-naphthoquinone (juglone) or 2-hydroxy-1, 4- naphtochinon (Lawson) or a mixture of said compounds.
• Erythrulose is particularly preferably used in the mixture containing dihydroxyacetone.
• the at least one compound of formula (I) may also be used in the present invention together with a mixture of self-tanning substances containing at least dihydroxyacetone and another self-tanner selected from the aforementioned group.
• exemplary consists of the eggfindungshunt to use mixture
• Layer structure of the pigments is not limited.
• the color pigment should be skin colored or brownish at a level of from 0.5 to 5% by weight.
• the selection of a corresponding pigment is familiar to the person skilled in the art.
• compositions or preparations described are particularly suitable for use in the lightening of skin, inhibition of tyrosinase and / or prophylaxis, therapy and / or follow-up
• Skin pigmentation disorders in all cases especially hyperpigmentation, freckles, age spots, sunspots, and
• Examples of applications of the preparations according to the invention are: solutions, suspensions, emulsions, PIT emulsions, pastes, ointments, gels, creams, lotions, powders, soaps, surfactant-containing cleaning preparations, oils, aerosols, patches, envelopes, dressings and sprays, in particular for the external application.
• Other forms of application include sticks, shampoos and shower baths.
• typical cosmetic applications are also lipsticks, lip balms, Powder, emulsion and wax make-up as well as sunscreen, pre-sun and after-sun preparations.
• Cosmetic and dermatological preparations according to the invention may in particular be an anhydrous preparation, a lotion or emulsion, such as cream or milk, or microemulsion, in each case of the water-in-oil (W / O) or of the oil-in-water type (O / W ), a multiple emulsion, for example of the type Waser-in-oil-in-water (W / OW) or vice versa (O / W / O), gels or solutions (especially oily-alcoholic, oily-aqueous or aqueous-alcoholic Gels or solutions), a solid stick, an ointment or even an aerosol.
• the cosmetic and dermatological according to the invention may in particular be an anhydrous preparation, a lotion or emulsion, such as cream or milk, or microemulsion, in each case of the water-in-oil (W / O) or of the oil-in-water type (O / W ), a multiple emulsion, for example of the type Waser
• One embodiment of the invention is an emulsion which is present as cream or milk and, 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
• Embodiments provide oily lotions based on natural or synthetic oils and waxes, lanolin, fatty acid esters, especially triglycerides of fatty acids, or oily-alcoholic lotions based on a lower alcohol such as ethanol or a glycerol such as
• a particularly preferred preparation according to the invention may also be present as an alcoholic gel containing one or more lower alcohols or polyols, such as ethanol, propylene glycol or glycerin, and a thickening agent such as silica.
• the oily-alcoholic gels also contain natural or synthetic oil or wax.
• the solid sticks are preferably made of natural or synthetic waxes and oils, fatty alcohols, fatty acids, fatty acid esters, lanolin and others Fatty substances. If a preparation is formulated as an aerosol, it is preferable to use the customary propellants, such as alkanes, air, nitrogen,
• Nitrous oxide more preferably alkanes or air.
• the one or more compounds of formula (I) as described may be obtained in the usual way in cosmetic or dermatological
• the preparations may comprise, contain, consist essentially of, or consist of the stated necessary or optional ingredients or ingredients. Any compounds or components which may be used in the compositions are either known and commercially available or may be synthesized by known methods. 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, dyes, emulsifiers or odor improvers.
• Ointments, pastes, creams and gels may contain the usual excipients suitable for topical administration, e.g.
• Powders and sprays may contain the usual carriers, e.g. Lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.
• Sprays may additionally contain the usual volatile, liquefied propellants, e.g.
• Chlorofluorocarbons propane / butane or dimethyl ether.
• compressed air is advantageous to use.
• air can also be used in non-pressurized metering devices, such as pump sprays.
• Solutions and emulsions may be the usual carriers such as
• Solvents, solubilizers and emulsifiers e.g. Water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol,
• Cottonseed oil peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin fatty acid esters, polyethylene glycols and fatty acid esters of
• Sorbitans or mixtures of these substances are preferred solubilizer in general.
• a preferred solubilizer in general is 2-isopropyl-5-methylcyclohexanecarbonyl-D-alanine methyl ester.
• Suspensions may be 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
• Soaps may contain the usual excipients such as alkali metal salts of fatty acids, salts of fatty acid monoesters, fatty acid protein hydrolysates, isothionates, lanolin, fatty alcohol, vegetable oils, plant extracts, glycerol, sugars or mixtures of these substances.
• surfactant-containing cleaning products the usual carriers such as salts of fatty alcohol sulfates, fatty alcohol ether sulfates,
• Sulfosuccinic acid esters fatty acid protein hydrolysates, isothionates, imidazolinium derivatives, methyltaurates, sarcosinates,
• Fatty acid diethanolamides vegetable and synthetic oils, lanolin derivatives, ethoxylated glycerol fatty acid esters or mixtures of these substances.
• Facial and body oils may 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 vegetable extracts paraffin oils, lanolin oils or mixtures of these substances.
• the preferred preparation forms according to the invention include in particular emulsions.
• O / W emulsions are particularly preferred.
• Emulsions, W / O emulsions and O / W emulsions are available in the usual way.
• Emulsions of the invention are advantageous and contain e.g. the said fats, oils, waxes and other fatty substances, and water or an aqueous phase, for example with solvents or hydrophilic surfactants, and an emulsifier, as is commonly used for such a type of preparation.
• Oils such as triglycerides of capric or caprylic acid, also 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
• Silicone oils such as dimethylpolysiloxanes, diethylpolysiloxanes,
• 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 of 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
• ester oils can then be advantageously selected from the group
• 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 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
• 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 aqueous phase of the preparations according to the invention may advantageously contain alcohols, diols or polyols of low C number, and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, Diethylene glycol monomethyl or monoethyl ether and analogous products, further low C-number alcohols, such as ethanol, isopropanol, 1, 2-propanediol, glycerol and in particular one or more
• Thickening agents which may be advantageously selected from the group of silica, aluminum silicates, polysaccharides and 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 Carbopole, for example, Carbopols types 980, 981, 1382, 2984, 5984, each individually or in combination.
• Carbopole for example, Carbopols types 980, 981, 1382, 2984, 5984, each individually or in combination.
• mixtures of the abovementioned solvents are used.
• Solvents can be another component of water.
• the preparations according to the invention contain hydrophilic surfactants.
• the hydrophilic surfactants are preferably selected from the group of alkylglucosides, acyl lactylates, betaines and cocoamphoacetates.
• emulsifiers for example, the known W / O and O / W emulsifiers can be used. It is advantageous to use other common co-semulsifiers.
• 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 have unsaturated radicals R and / or R ', or if isoalkyl derivatives are present, the preferred HLB value of such emulsifiers may also be lower or higher. It is advantageous to include the fatty alcohol ethoxylates from the group of
• fatty acid ethoxylates from the following group:
• Polyethylene glycol (12) isostearate, polyethylene glycol (13) isostearate,
• Polyethylene glycol (14) isostearate, polyethylene glycol (15) isostearate,
• Polyethylene glycol (24) isostearate, polyethylene glycol (yco ((25) isostearate,
• Polyethylene glycol (20) oleate Polyethylene glycol (20) oleate.
• the sodium laureth-11-carboxylate can be advantageously used.
• the alkyl ether sulfate sodium laureth sulfate can be advantageously used.
• polyethylene glycol (30) cholesteryl ether can be advantageously used.
• polyethylene glycol (25) soybean oil has been proven.
• the polyethylene glycol (60) Evening Primrose Glycerides can advantageously be used (Evening Primrose
• Polyethylene glycol (20) to choose sorbitan monooleate
• W / O emulsifiers can be used:
• Fatty alcohols having 8 to 30 carbon atoms monoglycerol esters of saturated and / or unsaturated, branched and / or unbranched
• Alkanecarboxylic acids having a chain length of 8 to 24, in particular 12 to 18 carbon atoms diglycerol esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids having a chain length of 8 to 24, in particular 12 to 18 carbon atoms, monoglycerol ethers saturated and / or unsaturated , branched and / or unbranched alcohols of a
• W / O emulsifiers are glyceryl monostearate, glyceryl monoisostearate, glyceryl monomyristate, glyceryl monooleate, diglyceryl monostearate, diglyceryl monoisostearate,
• 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 monocaprylate or PEG-30 dipolyhydroxystearate.
• the preparation may contain cosmetic adjuvants which are commonly used in this type of preparations, e.g.
• Thickeners emollients, moisturizers,
• surfactants emulsifiers, preservatives, antifoaming agents, perfumes, waxes, lanolin, propellants, dyes and / or pigments which color the agent itself or the skin, and other ingredients commonly used in cosmetics.
• polyol or mixtures thereof include ethanol, i-propanol, propylene glycol, glycerine and sorbitol.
• the invention also provides a process for the preparation of a preparation according to the invention, characterized in that the at least one compound of the formula (I) and / or its physiological non-hazardous salts, tautomers and / or solvates, including mixtures thereof in all ratios, with at least one carrier suitable for topical applications and optionally with physiological
• the method of preparation comprises the steps of: (a) mixing at least one compound of formula (I) and / or its physiologically acceptable salts, tautomers and / or solvates, including mixtures thereof in all proportions, with at least one further active ingredient and at least a carrier suitable for topical applications and optionally physiologically
• Preparations according to the invention can be prepared by techniques which are well known to the person skilled in the art.
• the mixing may result in dissolution, emulsification or dispersion of the at least one compound of formula (I) as described above in the carrier.
• decoration may consist of: a) particular design of the substance or thing, that is, if it is so individualized that suitability for the use according to the patent is clearly evident; b) Addition of instructions for use (eg leaflet) during distribution; c) formulation, packaging, dosage and ready to use
• Packaging d) therapy plan, dose recommendation; e) Use of a use-specific description of goods (Schulte / kuhnen, PatG, 8th edition, ⁇ 14 marginal 101).
• a further subject of the present invention are furthermore compounds of the formula of the formula (I)
• R1 and R2 are independently selected from:
• Cyclic alkyl having 3 to 8 carbon atoms, wherein one or more CH 2 - groups replaced by -O-, an -NH-, -N (CH 3 ) -, -CH CH and / or -CEC- group could be,
• - mono-, di- or trinuclear aromatic or heteroaromatic ring system having 5 to 20 carbon atoms, which may be substituted by -CH 3 or -OCH 3 and wherein one or more CH groups by N and / or one or more non-adjacent CH 2 groups can be replaced by O,
• Another object of the present invention is therefore also a process for the preparation of compounds of formula (I) as described above, wherein the carboxylic acid functionalities of
• these compounds can also be combined with self-tanning substances which are based on the principle of producing color pigments by non-enzymatic browning reaction of the self-tanning substances with keratin-containing matrices, so that a more even skin tone is achieved.
• self-tanning substances which are based on the principle of producing color pigments by non-enzymatic browning reaction of the self-tanning substances with keratin-containing matrices, so that a more even skin tone is achieved.
• Another embodiment of the present invention relates to a pharmaceutical composition comprising at least one compound of the formula (I) and / or its physiologically acceptable salts, tautomers and / or solvates, including mixtures thereof in all ratios.
• compositions pharmaceutical formulations
• “Pharmaceutical preparation” here is any agent which in the prophylaxis, therapy, follow-up or treatment of
• Patients can be used, at least temporarily show a pathogenic modification of the overall condition or the condition of individual parts of the patient's organism, preferably as a result of pigmentation of the skin.
• Adjuvants are added.
• any substance capable of potentiating, enhancing or modifying the compounds of the invention is an "adjuvant.”
• Known adjuvants are, for example, aluminum compounds such as aluminum hydroxide or aluminum phosphate, saponins such as QS 21, muramyl dipeptide or
• Muramyl tripeptide proteins such as gamma interferon or TNF, MF 59, phosphate dibylcholine, squalene or polyols.
• DNA the a protein with Adjuvans capable encoded, be applied in parallel or in a construct.
• the introduction of the pharmaceutical agent into a cell or an organism according to the invention can be done in any way that allows tyrosinase with those in the
• the pharmaceutical agent of the present invention may be administered orally, topically, transdermally, transmucosally, transurethally, vaginally, rectally, pulmonarily, enterally and / or parenterally, preferably topically or transdermally.
• the chosen mode of administration depends on the indication to be given
• the different modes of administration allow for site-specific therapy that minimizes side effects and that
• the dosage forms of the pharmaceutical agent are prepared with the usual solid or liquid carriers and / or diluents and the commonly used excipients according to the desired mode of administration in a suitable dosage and in a conventional manner.
• pharmaceutically acceptable excipients known to those skilled in the art may form part of the pharmaceutical composition of the invention, the amount of excipient material combined with the active ingredient to produce a single dosage varying with the individual to be treated and the mode of administration.
• pharmaceutically acceptable additives include salts, buffers, fillers, stabilizers, chelants, antioxidants, solvents, binders, lubricants, tablet coatings, flavors, colors, preservatives, sizing agents, and the like.
• excipients examples include water, vegetable oils, benzyl alcohols, alkylene glycol, polyethylene glycol, Glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petrolatum.
• the pharmaceutical formulation may be in the form of tablet, film-coated tablet, dragee, lozenge, capsule, pill, powder, granule, syrup, juice, drops, solution, dispersion, suspension, suppository, emulsion, implant, cream, gel, ointment, paste, lotion, serum , Oil, spray, aerosol, glue, plaster or dressing.
• the oral dosage form used is preferably tablets, film-coated tablets, dragees, lozenges, capsules, pills, powders, granules, syrups, juices, drops, solutions, dispersions or
• parenteral dosage forms such as e.g. Suppositories, suspensions,
• the active pharmaceutical ingredient is at least one pharmaceutical
• a acceptable carrier e.g. microcrystalline cellulose
• excipients such as e.g. Moisturizers
• skin solid formulations such as Creams, gels, ointments, pastes, powders or emulsions, or to skin-applied liquid formulations, e.g. Solutions, suspensions, lotions, serums, oils, sprays or aerosols formulated in a conventional manner.
• the pharmaceutical agent is for topical application.
• the pharmaceutical agent may also be present as a solid composition, for example in the lyophilized state, and then by addition of a dissolving agent, such as e.g. distilled water, before the
• Lyophilisates are familiar to the skilled worker.
• the concentration of the active compound in the formulation may be from 0.01 to 100% by weight. It is crucial that the concentration of the active compound in the formulation.
• an effective amount of the compound together with the pharmaceutically acceptable excipients includes.
• effective amount or “effective dose” are used interchangeably herein to denote an amount of
• prophylactic effect prevents the onset of a disease and includes an increase in the normal physiological function prophylaxis is particularly advisable if an individual has predispositions for the onset of the aforementioned diseases, such as a family history, a genetic defect or a recent Illness, one
• “Therapeutically relevant effect” partially or completely relieves one, several or all disease symptoms or leads to the partial or complete return of one or more or all physiological or biochemical parameters related to or causative of the disease or pathological alteration
• follow-up is understood as a mode of therapeutic treatment when the compounds are administered at certain intervals, for example, to completely eliminate the symptoms of a disease.
• the particular dose or dose range for the administration of the compounds of the invention is large enough to achieve the desired prophylactic or therapeutic effect of inducing a biological or medical response In general, the dose is determined by the age, constitution and sex of the patient
• administration will depend on a variety of factors, e.g. the targeting and binding ability of the compounds, dietary habits of the individual to be treated, route of administration, excretion rate and combination with others
• the individual dose may be both in relation to the primary disease and in relation to eventuality Complications are set.
• the exact dose is through one
• the compounds are administered at a dose of 0.01 mg to 1 g per dosage unit, preferably between 1 to 700 mg, more preferably 5 to 100 mg.
• the daily dosage is in particular between 0.02 and 100 mg / kg body weight.
• the pharmaceutical composition in order to promote the medicinal effect, may also comprise one or more further active ingredients, simultaneous or sequential administration being conceivable.
• the therapeutic effect of the pharmaceutical composition according to the invention may be, for example, that the inhibition of the
• the invention further teaches a method for the prophylaxis, therapy and / or follow-up of pigmentary disorders of the skin, wherein an effective amount of at least one compound of formula (I) and / or its physiologically acceptable salts, tautomers and / or solvates including mixtures thereof in all proportions one too
• administered subjects is administered.
• Preferred subjects within the meaning of the invention are humans or animals, particularly preferably humans.
• the skilled person is hereby known that he the aforementioned compounds of the invention, which of course as the
• pharmaceutical agents can be used in various dosages an organism, in particular a human patient, can apply.
• the effective amount and type of application can be determined by the skilled person through routine experimentation.
• the prior teaching of the invention and its embodiments are valid and without Restrictions applicable to the treatment procedure, if deemed appropriate.
• dihydroxyfumaric acid derivatives of the formula (I) have been provided.
• the compounds of formula (I) are characterized by a high specificity and stability and light
• the invention also includes the
• compositions containing said compounds and the use of these compounds for treatment are provided.
• Tyrosinase-mediated disorders are a promising approach to provide direct and immediate palliation in humans and animals
• the compounds of formula (I) according to the invention Due to the strong and selective inhibition of tyrosinase, which regulates the melanin synthesis the skin tone, the compounds of formula (I) according to the invention at a considerably low concentration while giving similar or even superior biological efficacy compared to the less potent skin lightening substances of the prior art. They advantageously show a high and long-lasting activity with regard to their action as skin-lightening active ingredients.
• the active compounds according to the invention are distinguished not only by improved effectiveness, but also by application safety and good formability. So they are easy to incorporate into preparations and have increased stability in the preparations.
• Example 1 B16V mouse melanoma cell assay
• B16V mouse melanoma cells (manufacturer: DSMZ, article number: ACC370) are mixed in RPMI medium (Invitrogen, article no .: 31870), which additionally contains 10% FBS (fetal bovine serum; Invitrogen, article no: 10499044 ), 2 mM L-glutamine (Invitrogen, item no: 25030) and 1 mM sodium pyruvate (Invitrogen, item no: 11360) are added and incubated for 72 h at 37 ° C and 5% C0 2 . The medium is separated and the cells are washed once with 10mL DPBS (Dulbecco's Phosphate-Buffered Salines, Invitrogen, Item No.
• HyQtase-Cell Detachment Solution (Hyclone, article number SV30030.01) is added to the cells.
• the bottle is swiveled several times and the HyQtase- Cell Detachment Solution is then removed by suction.
• the cells are incubated for 5 min in the incubator at 37 ° C and 5% CO 2.
• the cells are taken up in the modified RPMI medium (see above) and the number of cells determined. For this, the cells are stained with trypan blue and counted in a Neubauer counting chamber. Subsequently, the cells are resuspended in the modified RPMI Medium (see above) seeded in a defined cell number of 80,000 cells per well (6-well Clear Plate, TCT, PS (Nunc)).
• the cells are incubated for 24 h at 37 ° C. and 5% CO 2, after which the medium is removed. Then 1980 ⁇ _ of the dilution of each substance to be tested are added. For this dilution of the substance, the substance is dissolved in DMSO and then filtered through a sterile filter (0.2 ⁇ , Millipore, article no. SLLG013SL). The solution is then diluted with the modified RPMI medium (s.o., but in this case the FBS content is only 5%) so that the final concentration of the
• Substance dilution has the desired final concentration as shown in Table 1, having.
• alpha-MSH solution alpha-melanocyte stimulating hormone, DMSO, Sigma, sacred-Nr.:D2650
• Hyclone Item No. SV30030.01
• Hyclone Item No. SV30030.01
• the 6-well plate is pivoted several times and the HyQtase- Cell Detachment Solution is then removed by suction. Then the cells are incubated for 5 min in the incubator at 37 ° C and 5% CO 2 .
• the cells are taken up in 1.5mL DPBS (Invitrogen, Item No. 14190) and transferred to a cup (SARSTEDT, Ref. 72.692.005). Subsequently, the cell number is determined. For this, the cells are stained with trypan blue and counted in a Neubauer counting chamber. Centrifuge the cells at 3500g for 1min. The obtained pellets are photographed and
• the supernatant is sucked off.
• the pellets are in 1mL 1 N NaOH for 1 h at 80 ° C and then cooled to RT. Then 200 ⁇ _ (as quadruple determination) are pipetted four times per cup into a 96 well plate (VWR, article no. 4100636981) and the absorption at 405 nm wavelength determined (Safire, Tecan). By means of a calibration line, the content of melanin can be determined.
• Example 2 Q / W emulsions for skin lightening, data in% by weight
• phase A Heat phase A to 75 ° C, phase B to 80 ° C. Slowly add phase B into phase A with stirring. Homogenize. Allow to cool with constant stirring and add phase C at 40 ° C.
• Phase B completely dissolved to phase A give.

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