WO2000026399A2 - Method for the production of quercetin and isoquercetin derivatives - Google Patents
Method for the production of quercetin and isoquercetin derivatives Download PDFInfo
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- WO2000026399A2 WO2000026399A2 PCT/EP1999/007685 EP9907685W WO0026399A2 WO 2000026399 A2 WO2000026399 A2 WO 2000026399A2 EP 9907685 W EP9907685 W EP 9907685W WO 0026399 A2 WO0026399 A2 WO 0026399A2
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- cosmetic
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- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
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- OVSQVDMCBVZWGM-QSOFNFLRSA-N quercetin 3-O-beta-D-glucopyranoside Chemical class O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OVSQVDMCBVZWGM-QSOFNFLRSA-N 0.000 title description 14
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- GLCJMPWWQKKJQZ-UHFFFAOYSA-L disodium;2-[4-(4,6-disulfonato-1h-benzimidazol-2-yl)phenyl]-1h-benzimidazole-4,6-disulfonate;hydron Chemical compound [Na+].[Na+].C1=C(S(O)(=O)=O)C=C2NC(C3=CC=C(C=C3)C3=NC4=C(C=C(C=C4N3)S(=O)(=O)O)S([O-])(=O)=O)=NC2=C1S([O-])(=O)=O GLCJMPWWQKKJQZ-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- HUVYTMDMDZRHBN-UHFFFAOYSA-N drometrizole trisiloxane Chemical compound C[Si](C)(C)O[Si](C)(O[Si](C)(C)C)CC(C)CC1=CC(C)=CC(N2N=C3C=CC=CC3=N2)=C1O HUVYTMDMDZRHBN-UHFFFAOYSA-N 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 229960003747 ecamsule Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 210000002468 fat body Anatomy 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 239000004872 foam stabilizing agent Substances 0.000 description 1
- 235000015201 grapefruit juice Nutrition 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 108010030923 hesperidinase Proteins 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 235000013980 iron oxide Nutrition 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000008486 nectar Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940038580 oat bran Drugs 0.000 description 1
- 235000015205 orange juice Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- SOQBVABWOPYFQZ-UHFFFAOYSA-N oxygen(2-);titanium(4+) Chemical class [O-2].[O-2].[Ti+4] SOQBVABWOPYFQZ-UHFFFAOYSA-N 0.000 description 1
- 235000014594 pastries Nutrition 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000011252 protective cream Substances 0.000 description 1
- 230000001543 purgative effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003306 rutin derivatives Chemical class 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000015067 sauces Nutrition 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 239000002884 skin cream Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- CXVGEDCSTKKODG-UHFFFAOYSA-N sulisobenzone Chemical compound C1=C(S(O)(=O)=O)C(OC)=CC(O)=C1C(=O)C1=CC=CC=C1 CXVGEDCSTKKODG-UHFFFAOYSA-N 0.000 description 1
- 230000037072 sun protection Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 235000015193 tomato juice Nutrition 0.000 description 1
- 235000015113 tomato pastes and purées Nutrition 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- RNWHGQJWIACOKP-UHFFFAOYSA-N zinc;oxygen(2-) Chemical class [O-2].[Zn+2] RNWHGQJWIACOKP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/44—Preparation of O-glycosides, e.g. glucosides
- C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- 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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the invention relates to a process for the preparation of compounds of the formula I.
- tet referred to as isoquercetin derivatives.
- the compounds of the formula II are referred to as rutin derivatives.
- the compounds of formula I have one or more advantageous properties, e.g. antioxidative, cardiovascular, antiviral, prostaglandin metabolism influencing and / or spasmolytic properties. In mixtures with other flavonoids, they also have synergistic, for example purgative, properties.
- the quercetin and isoquercetin derivatives of the formula I have better water solubility than quercetin and isoquercetin themselves. In addition, they are less colored and therefore more suitable for use in cosmetics. They are also advantageously suitable for use in the food sector.
- R 1 can be prepared from a single starting compound.
- the present invention further relates to foods which have been enriched with one or more compounds of the formula I and to the use of the compounds of the formula I as a dietary supplement.
- the foodstuffs which can be enriched with one or more compounds of the formula I according to the present invention include all materials which are suitable for consumption by animals or for the
- Foods that can be fortified with one or more compounds of Formula I according to the present invention are, for example, foods that come from a single natural source, such as 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. More examples of foods that according to the present invention can be enriched with one or more compounds of the formula I are grain or cereals of a single plant species and materials which are produced from such plant species, such as, for example, cereal syrup, rye flour,
- Foodstuffs are suitable for being enriched according to the present invention with one or more compounds of the formula I, for example multi-vitamin preparations, mineral mixtures or sugared juice.
- Further examples of foods which can be enriched according to the present invention with one or more compounds of the formula I include food preparations, for example prepared cereals, pastries, mixed drinks, foods specially prepared for children such as yoghurt, diet foods, low-calorie foods or animal feed.
- the foods which can be enriched with one or more compounds of the formula I according to the present invention thus comprise all edible combinations of carbohydrates, lipids, proteins, inorganic elements, trace elements, vitamins, water and active metabolites of plants and animals.
- the foodstuffs which can be enriched with one or more compounds of the formula I according to the present invention and the food supplements which contain one or more compounds of the formula I are preferably administered orally, e.g. in the form of food, pills, tablets, capsules, powders, syrups, solutions or suspensions.
- the foods of the invention enriched with one or more compounds of formula I can be prepared using techniques that are well known to those skilled in the art.
- the invention further relates to cosmetic or pharmaceutical
- Formula I in cosmetic or pharmaceutical formulations.
- the cosmetic formulations which contain one or more compounds of the formula I and the use of one or more
- the skin is sensitive to the sun's rays, which can cause normal sunburn or erythema, but also more or less pronounced burns.
- sun rays also have other negative effects: they cause the skin to lose its elasticity and wrinkles and thus lead to premature aging. Sometimes you can also see dermatoses, and in extreme cases skin cancer occurs.
- the most dangerous part of the sun's rays is formed by the ultraviolet rays with a wavelength of less than 400 nm. It is also known that due to the presence of the ozone layer in the earth's atmosphere, which absorbs part of the sun's radiation, the lower limit of the ultraviolet rays that reach the earth's surface is approximately 280 nm.
- Substance classes are, for example, organic or inorganic UVA and UVB filters, IR or VIS filters. The is particularly preferred
- the invention therefore also relates to the use of one or more compounds of the formula I in cosmetic formulations, such as sunscreens, skin creams or gels, hair gels or cosmetic sticks, in particular as UV filters.
- UVA and UVB filters known to the person skilled in the art are suitable as further suitable organic UV filters.
- organic UV filters there are many substances that are known and proven from the specialist literature, e.g. Benzylidene camphor derivatives such as
- 3- (4 ' -methylbenzylidene) dl-camphor e.g. Eusolex ® 6300
- 3-benzylidene camphor e.g. Mexoryl ® SD
- Methoxy cinnamic acid esters such as
- Isopentyl 4-methoxycinnamate for example as a mixture of the isomers (for example Neo Heliopan ® E 1000),
- Salicylate derivatives such as
- organic UV filters are generally incorporated into cosmetic formulations in an amount of 0.5 to 10 percent by weight, preferably 1-8%.
- organic UV filters are generally incorporated into cosmetic formulations in an amount of 0.5 to 20 percent by weight, preferably 1-15%.
- inorganic UV filters those from the group of titanium dioxides such as coated titanium dioxide (eg Eusolex ® T-2000), zinc oxides (eg Sachtotec ® ), iron oxides or cerium oxides are also conceivable. These inorganic UV filters are generally incorporated into cosmetic formulations in an amount of 0.5 to 20 percent by weight, preferably 2 to 10%.
- the compounds of the formula I act e.g. as an antioxidant and radical scavenger.
- broad-spectrum UV protection is achieved with such formulations.
- the invention thus also relates to the use of one or more compounds of the formula I in cosmetic or pharmaceutical formulations as a UV filter, antioxidant and / or radical scavenger.
- the invention further relates to a method for protecting the skin and / or natural or sensitized hair from the sun's rays, a cosmetic preparation comprising one or more compounds of the formula I as a light protection filter being applied to the skin or the hair.
- a cosmetic preparation comprising one or more compounds of the formula I as a light protection filter being applied to the skin or the hair.
- the sunscreens according to the invention can also contain one or more chemical substances with self-tanning agents
- formulations according to the invention can also be used for the preventive treatment of inflammation and allergies to the skin and, in certain cases, for the prevention of certain types of cancer.
- the preparation according to the invention is used as an agent for protecting the human epidermis or the hair or else the sensitized hair or as a sunscreen.
- hair By “sensitized hair” is meant hair that has been subjected to a permanent wave treatment, a coloring or decolorization process.
- the cosmetic preparation according to the invention is used to protect the human epidermis against solar radiation. It is available in various forms commonly used for this type. In particular, it can be in the form of a lotion or emulsion, such as a cream or milk (OW, W / O), in the form of oily-alcoholic, oily-aqueous or aqueous-alcoholic gels, or as solid sticks, or as an aerosol.
- a lotion or emulsion such as a cream or milk (OW, W / O)
- OW, W / O oily-alcoholic, oily-aqueous or aqueous-alcoholic gels, or as solid sticks, or as an aerosol.
- the formulation may contain cosmetic adjuvants that are commonly used in this type of preparation, such as thickeners, plasticizers, wetting agents, surfactants, emulsifiers, preservatives, anti-foaming agents, perfumes, waxes, lanolin, blowing agents, dyes and / or pigments which color the agent itself or the skin, and other ingredients commonly used in cosmetics.
- cosmetic adjuvants that are commonly used in this type of preparation, such as thickeners, plasticizers, wetting agents, surfactants, emulsifiers, preservatives, anti-foaming agents, perfumes, waxes, lanolin, blowing agents, dyes and / or pigments which color the agent itself or the skin, and other ingredients commonly used in cosmetics.
- An oil, wax or other fatty substance, a low monoalcohol or a low polyol or mixtures thereof can be used as the dispersing or solubilizing agent.
- the particularly preferred monoalcohols or polyols include ethanol, i-propanol,
- a preferred embodiment of the invention is an emulsion which is present as a protective cream or milk and, in addition to the compound or compounds of the formula I as a UV filter - and, if appropriate, further light protection filters - fatty alcohols, fatty acids, fatty acid esters, in particular triglycerides of fatty acids, lanolin, natural or synthetic oils or waxes and emulsifiers in the presence of water.
- the cosmetic preparation according to the invention can also be in the form of an alcoholic gel which contains one or more lower alcohols or polyols, such as ethanol, propylene glycol or glycerol
- Thickeners 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 fat bodies.
- a preparation is packaged as an aerosol, the usual propellants, such as alkanes, fluoroalkanes and chlorofluoroalkanes, are generally used.
- the agent according to the invention is intended to protect natural or sensitized hair from the sun, it can be in the form of a shampoo, lotion, gel or emulsion for rinsing, the respective formulation before or after shampooing, before or after dyeing or decoloring, before or after the perm is applied; or the agent is in the form of a lotion or gel for styling and treatment, as a lotion or gel for brushing or laying a water wave, as a hair varnish, permanent waving agent, dye or decolorizer for the hair.
- this agent can contain various adjuvants used in this type of agent, such as surfactants, thickeners, polymers, plasticizers,
- fragrances silicone derivatives, oils, waxes, anti-greasing agents, dyes and / or pigments that color the agent itself or the hair or other ingredients commonly used for hair care.
- the cosmetic preparations according to the invention can be produced using techniques which are well known to the person skilled in the art.
- the compounds of the formula I include those compounds
- n *, n * and p * each independently represent 2 to 8.
- the present invention also relates to these compounds of the formula I * .
- the compounds of the formula I * are colorless.
- m, n and p or m *, n * and p * are each independently 2, 3, 4, 5, 6, 7 or 8.
- m, n and p or m are *, n * and p * each independently of the other 2, 3 or 4.
- m, n and p or m *, n * and p * are particularly preferably the same, very particularly preferably m, n and p or m * , n * and p * 2.
- Foodstuffs according to the invention which are enriched with one or more compounds of the formula I * and cosmetic formulations according to the invention which contain one or more compounds of the formula I * are particularly preferred. Accordingly, the use of one or more compounds of the formula I * as a dietary supplement or their use in cosmetic formulations, for example as a UV filter, is particularly preferred.
- the present invention provides an advantageous process for the preparation of compounds of the formula I by enzymatic cleavage of compounds of the formula II which takes place in an aqueous medium.
- the compounds of formula II are dissolved in water and contacted with a suitable amount of an enzyme.
- the reaction is carried out with thorough mixing, e.g. by stirring.
- Both the quercetin derivatives of the formula I and the isoquercetin derivatives of the formula I can be prepared by the process according to the invention.
- essentially only the quercetin derivatives of the formula I or essentially only the isoquercetin derivatives of the formula I are prepared by the process according to the invention.
- Suitable enzymes for the process according to the invention are hydrolases. Hydrolases obtained from the Penicillium decumbens strain are preferably used, in particular the enzymes naringinase and hesperidinase. The enzyme naringinase is very particularly preferred.
- the starting materials and the enzymes for the process according to the invention are commercially available or can be prepared using methods which are well known to the person skilled in the art and are described in the literature (for example in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart), won or manufactured.
- Suitable reaction temperatures for the process according to the invention are temperatures between 15 and 80 ° C.
- the process according to the invention is preferably carried out at reaction temperatures of 30 to 50 ° C., in particular at reaction temperatures of 35 to 45 ° C.
- reaction temperature is too low, the reaction proceeds at an inappropriately slow reaction rate. On the other hand, if the reaction temperature is too high, the enzyme, which is a protein, is denatured and thus deactivated.
- Suitable pH values for the method according to the invention are pH values between 3 and 8.
- the method according to the invention is preferably carried out at pH values from 4.5 to 7, in particular at pH values from 4.8 to 6.8.
- further preferred pH values can vary within the given limits, depending on the enzyme used.
- pH values of 6.4 to 6.8 are extremely preferred when using the enzyme naringinase.
- the method is preferably carried out in such a way that the pH is adjusted using a buffer system. In principle, all common buffer systems that are suitable for setting the above-mentioned pH values can be used. However, preference is given to aqueous
- Suitable weight ratios of starting material: water for the process according to the invention are ratios from 0.001: 99.999 to 40:60.
- the process according to the invention is preferably carried out with weight ratios of starting material: water from 0.005: 99.995 to 20:80, in particular with weight ratios of 0.5: 99, 5 to 10: 90.
- Processes are ratios from 0.005: 99.995 to 50:50.
- the process according to the invention is preferably carried out with weight ratios of enzyme:
- the process according to the invention is carried out, for example, in such a way that the reaction when the enzyme naringinase is used preferably takes place at a temperature of 35 to 45 ° C. and a pH of 4.8 to 6.8 and after about 12 to 18 hours.
- the reaction is preferably continuously checked analytically.
- the formation or production of the quercetin derivatives of the formula I can be achieved, for example, by suitably extending the reaction time.
- the progress or the end of the reaction and the analysis of the reaction products can be carried out, for example, by means of HPLC, for example using standard HPLC devices and columns containing reversed-phase materials with C 18 alkyl coating.
- the progress or the end of the reaction can also be checked by means of thin layer chromatography (TLC).
- reaction mixture consists mainly of water, buffer, enzyme, small amounts of unreacted
- the quercetin and / or isoquercetin derivatives of the formula I are isolated by customary methods. Under
- customary workup is understood to mean the following:
- the reaction mixture is cooled, for example to a temperature of 0 ° C.
- the quercetin and / or isoquercetin derivative of the formula I which crystallizes out is separated from the remaining reaction mixture, for example by suction or filtration under reduced pressure or by centrifuging off the precipitated crystals.
- the solid is then washed, preferably with water, and then dried, e.g. at a temperature of 50 ° C and a pressure of 200 mbar.
- the substances remaining in the filtrate can be separated off by known methods, for example by ultrafiltration, by passing the filtrate over cations and / or
- Anion exchangers by crystallization and by mechanical Separation such as filtration. Any glucose present in the filtrate can also be separated, for example, by yeast fermentation.
- Enzyme can be recirculated and thus used for further reactions.
- the sources of supply for the substances used are as follows:
- HPLC HPLC conditions when using a standard HPLC system:
- Sample preparation dissolve 5 mg of the sample in 3 ml of methanol and make up to 10 ml with the eluent
- Trihydroxyethyl isoquercetin 11.4 min, trihydroxyethylquercetin: 42.7 min.
- Th (hydroxyethyl) rutin 5 g are dissolved in 150 ml of deionized water and adjusted to a pH of 6.6 by adding 0.64 g of citric acid and 1.4 g of 32% strength aqueous sodium hydroxide solution. Then 0.5 g of naringinase is introduced and the reaction mixture is stirred at a reaction temperature of 40 ° C. for 16 h. After the usual work-up, 2.41 g of tri (hydroxyethyl) isoquercetin are obtained in a purity of 96%.
Abstract
Disclosed is a method for the production of compounds of formula (I), whereby m, n, p and R1 have the meanings given in Claim 1. Said compounds can be used in an advantageous manner as food supplements. They are particularly suitable for use in cosmetic formulations as UV filters for example.
Description
Verfahren zur Herstellung von Quercetin- und Isoquercetin-DerivatenProcess for the preparation of quercetin and isoquercetin derivatives
Die Erfindung betrifft ein Verfahren zur Herstellung von Verbindungen der Formel IThe invention relates to a process for the preparation of compounds of the formula I.
worin m, n und p jeweils unabhängig voneinander 2 bis 8 und der Rest R1 wherein m, n and p are each independently 2 to 8 and the radical R 1
-OH oder bedeuten, dadurch gekennzeichnet, daß-OH or mean, characterized in that
Verbindungen der Formel IICompounds of formula II
Im Rahmen der vorliegenden Erfindung werden die Verbindungen der Formel I, in denen der Rest R1 OH bedeutet, als Quercetin-Derivate bezeichnet. Im Rahmen der vorliegenden Erfindung werden die Verbin-In the context of the present invention, the compounds of the formula I in which the radical R 1 is OH are referred to as quercetin derivatives. In the context of the present invention, the connection
düngen der Formel I, in denen der Rest R bedeu-fertilize the formula I in which the radical R means
Die Verbindungen der Formel I weisen eine oder mehrere vorteilhafte Eigenschaften auf, z.B. antioxidative, kardiovaskuläre, antivirale, den Prostaglandin-Metabolismus beeinflussende und/oder spasmolytische Eigenschaften. In Mischungen mit anderen Flavonoiden besitzen sie auch synergistische, beispielsweise purgative, Eigenschaften.The compounds of formula I have one or more advantageous properties, e.g. antioxidative, cardiovascular, antiviral, prostaglandin metabolism influencing and / or spasmolytic properties. In mixtures with other flavonoids, they also have synergistic, for example purgative, properties.
Die Quercetin- und Isoquercetin-Derivate der Formel I besitzen eine bessere Wasserlöslichkeit als Quercetin und Isoquercetin selbst. Zudem sind sie weniger farbig und somit für Anwendungen in der Kosmetik besser geeignet. Sie eignen sich zudem in vorteilhafter Weise für eine Anwendung auf dem Nahrungsmittelsektor.The quercetin and isoquercetin derivatives of the formula I have better water solubility than quercetin and isoquercetin themselves. In addition, they are less colored and therefore more suitable for use in cosmetics. They are also advantageously suitable for use in the food sector.
Bekannte Verfahren zur Herstellung der Verbindungen der Formel I haben den Nachteil, daß sie z.B. toxische Verbindungen und/oder organische Lösungsmittel verwenden.
Somit bestand die Aufgabe, ein Verfahren zur Herstellung von Quercetin- und Isoquercetin-Derivaten zu entwickeln, welches die Nachteile bekannter Verfahren vermeidet oder zumindest vermindert und insbesondere eine einfache Durchführung ermöglicht.Known processes for the preparation of the compounds of the formula I have the disadvantage that they use, for example, toxic compounds and / or organic solvents. The task was therefore to develop a process for the preparation of quercetin and isoquercetin derivatives which avoids or at least reduces the disadvantages of known processes and in particular enables simple implementation.
Überraschend wurde nun gefunden, daß diese Aufgabe gelöst wird, wenn das Verfahren zur Herstellung der Verbindungen der Formel IIt has now surprisingly been found that this object is achieved if the process for the preparation of the compounds of the formula I
worin m, n und p jeweils unabhängig voneinander 2 bis 8 und der Rest R1 wherein m, n and p are each independently 2 to 8 and the radical R 1
-OH oder bedeuten, so durchgeführt wird, daß Ver--OH or mean is carried out so that ver
Das erfindungsgemäße Verfahren zeichnet sich insbesondere dadurch aus, daß die Herstellung der Verbindungen der Formel I aus ungiftigenThe process according to the invention is characterized in particular in that the preparation of the compounds of the formula I from non-toxic
Substanzen in einfacher Weise erfolgt. Die Aufarbeitung wird z.B. dadurch vereinfacht, daß die Löslichkeit der Produkte unter den Bedingungen des erfindungsgemäßen Verfahrens überraschenderweise geringer als die derSubstances done in a simple manner. The processing is e.g. simplified by the fact that the solubility of the products under the conditions of the process according to the invention surprisingly less than that of
Edukte ist. Zudem hat das erfϊndungsgemäße Verfahren den Vorteil, daß alle gleich substituierten Verbindungen der Formel I für beideEducts is. In addition, the process according to the invention has the advantage that all of the compounds of the formula I which have the same substitution are present for both
Bedeutungen von R1 aus einer einzigen Ausgangsverbindung hergestellt werden können.Meanings of R 1 can be prepared from a single starting compound.
Die vorliegende Erfindung betrifft weiterhin Nahrungsmittel, die mit einer oder mehreren Verbindungen der Formel I angereichert worden sind, sowie die Verwendung der Verbindungen der Formel I als Nahrungsergänzungsmittel.The present invention further relates to foods which have been enriched with one or more compounds of the formula I and to the use of the compounds of the formula I as a dietary supplement.
Die Nahrungsmittel, die nach der vorliegenden Erfindung mit einer oder mehreren Verbindungen der Formel I angereichert werden können, umfassen alle Materialien, die für den Verzehr durch Tiere oder für denThe foodstuffs which can be enriched with one or more compounds of the formula I according to the present invention include all materials which are suitable for consumption by animals or for the
Verzehr durch Menschen geeignet sind, beispielsweise Vitamine und Provitamine davon, Fette, Mineralien oder Aminosäuren. Nahrungsmittel, die nach der vorliegenden Erfindung mit einer oder mehreren Verbindungen der Formel I angereichert werden können, sind beispielsweise auch Nahrungsmittel, die aus einer einzigen natürlichen Quelle stammen, wie z.B. Zucker, ungesüßter Saft, Nektar oder Püree von einer einzigen Pflanzenspezies, wie z.B. ungesüßter Apfelsaft (z.B. auch eine Mischung verschiedener Sorten Apfelsaft), Grapefruitsaft, Orangensaft, Apfelkompott, Aprikosennektar, Tomatensaft, Tomatensauce, Tomatenpüree, usw.. Weitere Beispiele für Nahrungsmittel, die
nach der vorliegenden Erfindung mit einer oder mehreren Verbindungen der Formel I angereichert werden können, sind Korn oder Getreide einer einzigen Pflanzenspezies und Materialien, die aus derartigen Pflanzenspezies hergestellt werden, wie z.B. Getreidesirup, Roggenmehl,Are suitable for human consumption, for example vitamins and provitamins thereof, fats, minerals or amino acids. Foods that can be fortified with one or more compounds of Formula I according to the present invention are, for example, foods that come from a single natural source, such as 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. More examples of foods that according to the present invention can be enriched with one or more compounds of the formula I are grain or cereals of a single plant species and materials which are produced from such plant species, such as, for example, cereal syrup, rye flour,
Weizenmehl oder Haferkleie. Auch Mischungen von derartigenWheat flour or oat bran. Mixtures of such
Nahrungsmitteln sind geeignet, um nach der vorliegenden Erfindung mit einer oder mehreren Verbindungen der Formel I angereichert zu werden, beispielsweise MultiVitaminpräparate, Mineralstoffmischungen oder gezuckerter Saft. Als weitere Beispiele für Nahrungsmittel, die nach der vorliegenden Erfindung mit einer oder mehreren Verbindungen der Formel I angereichert werden können, seien Nahrungsmittelzubereitungen, beispielsweise zubereitete Zerealien, Gebäck, Mischgetränke, speziell für Kinder zubereitete Nahrungsmittel wie Joghurt, Diätnahrungsmittel, kalorienarme Nahrungsmittel oder Tierfutter genannt.Foodstuffs are suitable for being enriched according to the present invention with one or more compounds of the formula I, for example multi-vitamin preparations, mineral mixtures or sugared juice. Further examples of foods which can be enriched according to the present invention with one or more compounds of the formula I include food preparations, for example prepared cereals, pastries, mixed drinks, foods specially prepared for children such as yoghurt, diet foods, low-calorie foods or animal feed.
Die Nahrungsmittel, die nach der vorliegenden Erfindung mit einer oder mehreren Verbindungen der Formel I angereichert werden können, umfassen somit alle genießbaren Kombinationen von Kohlehydraten, Lipiden, Proteinen, anorganischen Elementen, Spurenelementen, Vitaminen, Wasser und aktiven Metaboliten von Pflanzen und Tieren.The foods which can be enriched with one or more compounds of the formula I according to the present invention thus comprise all edible combinations of carbohydrates, lipids, proteins, inorganic elements, trace elements, vitamins, water and active metabolites of plants and animals.
Die Nahrungsmittel, die nach der vorliegenden Erfindung mit einer oder mehreren Verbindungen der Formel I angereichert werden können sowie die Nahrungsergänzungsmittel, die eine oder mehrere Verbindungen der Formel I enthalten, werden vorzugsweise oral angewendet, z.B. in Form von Essen, Pillen, Tabletten, Kapseln, Pulver, Syrups, Lösungen oder Suspensionen.The foodstuffs which can be enriched with one or more compounds of the formula I according to the present invention and the food supplements which contain one or more compounds of the formula I are preferably administered orally, e.g. in the form of food, pills, tablets, capsules, powders, syrups, solutions or suspensions.
Die mit einer oder mehreren Verbindungen der Formel I angereicherten erfindungsgemäßen Nahrungsmittel können mit Hilfe von Techniken hergestellt werden, die dem Fachmann wohl bekannt sind.
Weiterhin betrifft die Erfindung kosmetische oder pharmazeutischeThe foods of the invention enriched with one or more compounds of formula I can be prepared using techniques that are well known to those skilled in the art. The invention further relates to cosmetic or pharmaceutical
Formulierungen, welche eine oder mehrere Verbindungen der Formel I enthalten sowie die Verwendung einer oder mehrerer Verbindungen derFormulations which contain one or more compounds of the formula I and the use of one or more compounds of the
Formel I in kosmetischen oder pharmazeutischen Formulierungen. Die kosmetischen Formulierungen, welche eine oder mehrere Verbindungen der Formel I enthalten sowie die Verwendung einer oder mehrererFormula I in cosmetic or pharmaceutical formulations. The cosmetic formulations which contain one or more compounds of the formula I and the use of one or more
Verbindungen der Formel I in kosmetischen Formulierungen ist bevorzugt.Compounds of formula I in cosmetic formulations are preferred.
Während vor etwa 30 Jahren Sonnenlicht aufgrund der Vitamin D- Synthese als heilend und unbedenklich angesehen wurde, hat sich in den letzten Jahren die Einstellung in dieser Beziehung nicht nur aus medizinischer Sicht erheblich geändert. Das Gefahrenpotential, welches sowohl natürliche als auch künstliche Bestrahlung mit Sonnenlicht in sich birgt, ist im Bewußtsein in den Vordergrund gerückt. Insbesondere ist auch eine Verhaltensänderung hervorgerufen worden durch das Wissen über den Einfluß von Sonnenlicht auf die Hautalterung und die Entstehung von Hautkrebs.While sunlight was considered to be healing and harmless about 30 years ago due to the vitamin D synthesis, the attitude in this regard has changed significantly in recent years, not only from a medical point of view. The potential for danger, which contains both natural and artificial radiation with sunlight, has come to the fore in consciousness. In particular, a change in behavior has also been brought about by knowledge of the influence of sunlight on skin aging and the development of skin cancer.
Bekanntlich reagiert die Haut empfindlich auf Sonnenstrahlen, welche einen gewöhnlichen Sonnenbrand oder ein Erythem, aber auch mehr oder weniger ausgeprägte Verbrennungen hervorrufen können.As is known, the skin is sensitive to the sun's rays, which can cause normal sunburn or erythema, but also more or less pronounced burns.
Sonnenstrahlen haben aber auch andere negative Wirkungen: sie bewirken, daß die Haut ihre Elastizität verliert und sich Falten bilden und führen somit zu einer frühzeitigen Alterung. Manchmal kann man auch Dermatosen beobachten, und im extremen Fall kommt es zum Auftreten von Hautkrebs.However, sun rays also have other negative effects: they cause the skin to lose its elasticity and wrinkles and thus lead to premature aging. Sometimes you can also see dermatoses, and in extreme cases skin cancer occurs.
Es ist auch wünschenswert, Haare gegen photochemische Schäden zu schützen, um Veränderungen von Farbnuancen, ein Entfärben oder Schäden mechanischer Art zu verhindern.
Bekanntlich wird der gefährlichste Teil der Sonnenstrahlen von den ultravioletten Strahlen mit einer Wellenlänge von weniger als 400 nm gebildet. Bekannt ist auch, daß durch das Vorhandensein der Ozonschicht der Erdatmosphäre, die einen Teil der Sonnenstrahlung absorbiert, die untere Grenze der ultravioletten Strahlen, welche die Erdoberfläche erreichen, bei ca. 280 nm liegt.It is also desirable to protect hair against photochemical damage in order to prevent changes in color shades, discoloration or mechanical damage. As is known, the most dangerous part of the sun's rays is formed by the ultraviolet rays with a wavelength of less than 400 nm. It is also known that due to the presence of the ozone layer in the earth's atmosphere, which absorbs part of the sun's radiation, the lower limit of the ultraviolet rays that reach the earth's surface is approximately 280 nm.
Daher liegt das Hauptziel im Bereich Sonnenschutz eigentlich darin, einen guten Schutz gegen UVB- und UVA-Strahlung zu gewährleisten.Therefore, the main goal in the field of sun protection is actually to ensure good protection against UVB and UVA radiation.
Die Verbindungen der Formel I können allein oder natürlich auch inThe compounds of the formula I can be used alone or, of course, in
Kombination mit weiteren Lichtschutzfiitern unterschiedlicher Substanzklassen, einzeln oder in Kombination, in der kosmetischen oder pharma. eutischen Zubereitung enthalten sein. Lichtschutzfilter andererCombination with other light protection filters of different substance classes, individually or in combination, in the cosmetic or pharmaceutical. eutical preparation. Sunscreen filters from others
Substanzklassen sind beispielsweise organische oder anorganische UVA- und UVB-Filter, IR- oder VIS-Filter. Insbesondere bevorzugt ist dieSubstance classes are, for example, organic or inorganic UVA and UVB filters, IR or VIS filters. The is particularly preferred
Kombination mit organischen UV-Filtern oder deren Gemischen.Combination with organic UV filters or their mixtures.
Gegenstand der Erfindung ist daher auch die Verwendung einer oder mehrerer Verbindungen der Formel I in kosmetischen Formulierungen wie Sonnenschutzmitteln, Hautcremes oder -gelen, Haargelen oder kosmetischen Stiften, insbesondere als UV-Filter.The invention therefore also relates to the use of one or more compounds of the formula I in cosmetic formulations, such as sunscreens, skin creams or gels, hair gels or cosmetic sticks, in particular as UV filters.
Als weitere geeignete organische UV-Filter kommen alle dem Fachmann bekannten UVA- als auch UVB-Filter in Frage. Für beide UV-Bereiche gibt es viele aus der Fachliteratur bekannte und bewährte Substanzen, z.B.
Benzylidenkampferderivate wieAll UVA and UVB filters known to the person skilled in the art are suitable as further suitable organic UV filters. For both UV ranges there are many substances that are known and proven from the specialist literature, e.g. Benzylidene camphor derivatives such as
- 3-(4'-Methylbenzyliden)-dl-kampfer (z.B. Eusolex® 6300), 3-Benzylidenkampfer (z.B. Mexoryl® SD),3- (4 ' -methylbenzylidene) dl-camphor (e.g. Eusolex ® 6300), 3-benzylidene camphor (e.g. Mexoryl ® SD),
- Polymere von N-{(2 und 4)-[(2-oxoborn-3-yliden)methyl]benzyl}- acrylamid (z.B. Mexoryl® SW),- Polymers of N - {(2 and 4) - [(2-oxoborn-3-ylidene) methyl] benzyl} - acrylamide (e.g. Mexoryl ® SW),
- N,N,N-Thmethyl-4-(2-oxoborn-3-ylidenmethyl)anilinium methylsulfat (z.B. Mexoryl® SK) oder- N, N, N-thmethyl-4- (2-oxoborn-3-ylidenemethyl) anilinium methyl sulfate (e.g. Mexoryl ® SK) or
- α-(2-Oxobom-3-yliden)toluol-4-sulfonsäure (z.B. Mexoryl® SL),α- (2-oxobom-3-ylidene) toluene-4-sulfonic acid (e.g. Mexoryl ® SL),
Benzoyl- oder Dibenzoyimethane wieBenzoyl or dibenzoyimethanes such as
- 1-(4-tert-Butylphenyl)-3-(4-methoxyphenyl)propan-1 ,3-dion (z.B. Eusolex® 9020) oder . 4-lsopropyldibenzoylmethan (z.B. Eusolex® 8020),- 1- (4-tert-Butylphenyl) -3- (4-methoxyphenyl) propan-1, 3-dione (e.g. Eusolex ® 9020) or. 4-isopropyldibenzoylmethane (e.g. Eusolex ® 8020),
Benzophenone wieBenzophenones like
- 2-Hydroxy-4-methoxybenzophenon (z.B. Eusolex® 4360) oder - 2-Hydroxy-4-methoxybenzophenon-5-sulfonsäure und ihr Natriumsalz (z.B. Uvinul® MS-40),- 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),
Methoxyzimtsäureester wieMethoxy cinnamic acid esters such as
- Methoxyzimtsäureoctylester (z.B. Eusolex® 2292),- octyl methoxycinnamate (e.g. Eusolex ® 2292),
- 4-Methoxyzimtsäureisopentylester, z.B. als Gemisch der Isomere (z.B. Neo Heliopan® E 1000),Isopentyl 4-methoxycinnamate, for example as a mixture of the isomers (for example Neo Heliopan ® E 1000),
Salicylatderivate wieSalicylate derivatives such as
- 2-Ethylhexylsalicylat (z.B. Eusolex® OS),- 2-ethylhexyl salicylate (e.g. Eusolex ® OS),
- 4-lsopropylbenzylsalicylat (z.B. Megasol®) oder- 4-isopropylbenzyl salicylate (e.g. Megasol ® ) or
- 3,3,5-Trimethylcyclohexylsalicylat (z.B. Eusolex® HMS),
4-Aminobenzoesäure und Derivate wie 4-Aminobenzoesäure,- 3,3,5-trimethylcyclohexyl salicylate (e.g. Eusolex ® HMS), 4-aminobenzoic acid and derivatives such as 4-aminobenzoic acid,
- 4-(Dimethylamino)benzoesäure-2-ethylhexylester (z.B. Eusolex® 6007),4- (dimethylamino) 2-ethylhexyl benzoate (e.g. Eusolex ® 6007),
- ethoxylierter 4-Aminobenzoesäureethylester (z.B. Uvinul® P25),- Ethoxylated 4-aminobenzoic acid ethyl ester (eg Uvinul ® P25),
und weitere Substanzen wieand other substances like
- 2-Cyano-3,3-diphenylacrylsäure-2-ethylhexylester (z.B. Eusolex® OCR), ^ - 2-Phenylbenzimidazol-5-sulfonsäure sowie ihre Kalium-, Natrium- und Triethanolaminsalze (z.B. Eusolex® 232),- 2-cyano-3,3-diphenylacrylic acid 2-ethylhexyl ester (e.g. Eusolex ® OCR), ^ - 2-phenylbenzimidazole-5-sulfonic acid and its potassium, sodium and triethanolamine salts (e.g. Eusolex ® 232),
- 3,3'-(1 ,4-Phenylendimethylen)-bis-(7,7-dimethyl-2-oxobicyclo- [2.2.1]hept-1-ylmethansulfonsäure sowie ihre Salze (z.B. Mexoryl® SX) 5 und- 3,3 '- (1, 4-phenylenedimethylene) bis (7,7-dimethyl-2-oxobicyclo- [2.2.1] hept-1-ylmethanesulfonic acid and salts thereof (for example Mexoryl SX ®) and 5
2,4,6-Trianilino-(p-carbo-2'-ethylhexyl-1 '-oxi)-1 ,3,5-triazin ( z.B. Uvinul® T 150).2,4,6-trianilino- (p-carbo-2 '-ethylhexyl-1' -oxi) -1, 3,5-triazine (for example Uvinul ® T 150).
Diese organischen UV-Filter werden in der Regel in einer Menge von 0,5 bis 10 Gewichtsprozent, vorzugsweise 1 - 8 %, in kosmetische Formulierungen eingearbeitet.These organic UV filters are generally incorporated into cosmetic formulations in an amount of 0.5 to 10 percent by weight, preferably 1-8%.
Weitere geeignete organische UV-Filter sind z.B. 5Other suitable organic UV filters are e.g. 5
- 2-(2H-Benzotriazol-2-yl)-4-methyl-6-(2-methyl-3-(1 ,3,3,3-tetramethyl-1- (trimethylsilyloxy)disiloxanyl)propyl)phenol (z.B. Silatrizole®), 4,4'-[(6-[4-((1 ,1-Dimethylethyl)aminocarbonyl)phenylamino]-1 ,3,5- triazin-2,4-diyl)diimino]bis(benzoesäure-2-ethylhexylester) (z.B. 0 Uvasorb® HEB), α-(Trimethylsilyl)-ω-[trimethylsilyl)oxy]poly[oxy(dimethyl [und ca. 6% methyl[2-[p-[2,2-bis(ethoxycarbonyl]vinyl]phenoxy]-1-methylenethyl] und ca. 1 ,5 % methyl[3-[p-[2,2-bis(ethoxycarbonyl)vinyl)phenoxy)- 5 propenyl) und 0,1 bis 0,4% (methylhydrogenjsilylen]] (n « 60) (z.B.- 2- (2H-Benzotriazol-2-yl) -4-methyl-6- (2-methyl-3- (1, 3,3,3-tetramethyl-1- (trimethylsilyloxy) disiloxanyl) propyl) phenol (e.g. silatrizole ® ), 4,4 ' - [(6- [4 - ((1, 1-dimethylethyl) aminocarbonyl) phenylamino] -1, 3,5-triazine-2,4-diyl) diimino] bis (benzoic acid-2- ethylhexyl ester) (e.g. 0 Uvasorb ® HEB), α- (trimethylsilyl) -ω- [trimethylsilyl) oxy] poly [oxy (dimethyl [and approx. 6% methyl [2- [p- [2,2-bis (ethoxycarbonyl] vinyl] phenoxy] -1-methyleneethyl] and about 1.5% methyl [3- [p- [2,2-bis (ethoxycarbonyl) vinyl) phenoxy) -5 propenyl) and 0.1 to 0.4% ( methylhydrogenjsilylen]] (n «60) (e.g.
Parsol® SLX),
- 2,2'-Methylen-bis-(6-(2H-benzotriazol-2-yl)-4-(1 ,1 ,3,3-tetramethyl- butyl)phenol) (z.B. Tinosorb® M),Parsol ® SLX), - 2,2 'methylene-bis- (6- (2H-benzotriazol-2-yl) -4- (1, 1, 3,3-tetramethyl- butyl) phenol) (Tinosorb eg ® M),
2,2'-(1 ,4-Phenylen)bis-(1 H-benzimidazol-4,6-disulfonsäure, Mononatriumsalz) (z.B. Neo Heliopan® AP) und 2,4-bis-{[4-(2-Ethyl-hexyloxy)-2-hydroxyl]-phenyl}-6-(4-methoxyphenyl)- 1 ,3,5-triazin (z.B. Tinosorb® S).2,2 '- (1, 4-phenylene) bis- (1 H-benzimidazol-4,6-disulfonic acid, monosodium salt) (for example Neo Heliopan AP ®) and 2,4-bis - {[4- (2-ethyl -hexyloxy) -2-hydroxyl] phenyl} -6- (4-methoxyphenyl) - 1, 3,5-triazine (e.g. Tinosorb ® S).
Diese organischen UV-Filter werden in der Regel in einer Menge von 0,5 bis 20 Gewichtsprozent, vorzugsweise 1 - 15 %, in kosmetische Formulierungen eingearbeitet.These organic UV filters are generally incorporated into cosmetic formulations in an amount of 0.5 to 20 percent by weight, preferably 1-15%.
Als anorganische UV-Filter sind solche aus der Gruppe der Titandioxide wie z.B. gecoatetes Titandioxid (z.B. Eusolex® T-2000), Zinkoxide (z.B. Sachtotec®), Eisenoxide oder auch Ceroxide denkbar. Diese anorganischen UV-Filter werden in der Regel in einer Menge von 0,5 bis 20 Gewichtsprozent, vorzugsweise 2 - 10 %, in kosmetische Formulierungen eingearbeitet.As inorganic UV filters, those from the group of titanium dioxides such as coated titanium dioxide (eg Eusolex ® T-2000), zinc oxides (eg Sachtotec ® ), iron oxides or cerium oxides are also conceivable. These inorganic UV filters are generally incorporated into cosmetic formulations in an amount of 0.5 to 20 percent by weight, preferably 2 to 10%.
In den Formulierungen, in denen Verbindungen der Formel I zusammen mit anderen UV-Filtern enthalten sind, wirken die Verbindungen der Formel I z.B. als Antioxidationsmittel und Radikalfänger. Zudem wird mit derartigen Formulierungen ein Breitband-UV-Schutz erreicht. Gegenstand der Erfindung ist somit auch die Verwendung von einer oder mehreren Verbindungen der Formel I in kosmetischen oder pharmazeutischen Formulierungen als UV-Filter, Antioxidans und/oder Radikalfänger.In the formulations in which compounds of the formula I are present together with other UV filters, the compounds of the formula I act e.g. as an antioxidant and radical scavenger. In addition, broad-spectrum UV protection is achieved with such formulations. The invention thus also relates to the use of one or more compounds of the formula I in cosmetic or pharmaceutical formulations as a UV filter, antioxidant and / or radical scavenger.
Gegenstand der Erfindung ist ferner ein Verfahren zum Schutz der Haut und/oder natürlicher oder sensibilisierter Haare vor Sonnenstrahlen, wobei auf die Haut oder die Haare eine kosmetische Zubereitung, enthaltend eine oder mehrere Verbindungen der Formel I als Lichtschutzfilter, aufgetragen wird.
Gegebenenfalls können die erfindungsgemäßen Sonnenschutzmittel auch eine oder mehrere chemische Substanzen mit selbstbräunendenThe invention further relates to a method for protecting the skin and / or natural or sensitized hair from the sun's rays, a cosmetic preparation comprising one or more compounds of the formula I as a light protection filter being applied to the skin or the hair. If necessary, the sunscreens according to the invention can also contain one or more chemical substances with self-tanning agents
Eigenschaften enthalten.Features included.
Als chemische Substanzen mit selbstbräunenden Eigenschaften können alle dem Fachmann bekannten natürlichen und synthetischen Substanzen, welche zur Herstellung von kosmetischen Formulierungen geeignet sind, eingesetzt werden. Solche können sowohl pflanzliche Extrakte als auch synthetische Selbstbräuner, wie z.B. Dihydroxyaceton oder α-Ketole, sein.All natural and synthetic substances known to the person skilled in the art which are suitable for the production of cosmetic formulations can be used as chemical substances with self-tanning properties. Such can include both vegetable extracts and synthetic self-tanners, e.g. Dihydroxyacetone or α-ketols.
Weiterhin können die erfindungsgemäßen Formulierungen auch zur vorbeugenden Behandlung von Entzündungen und Allergien der Haut sowie auch in bestimmten Fällen zur Verhütung bestimmter Krebsarten verwendet werden.Furthermore, the formulations according to the invention can also be used for the preventive treatment of inflammation and allergies to the skin and, in certain cases, for the prevention of certain types of cancer.
Die erfindungsgemäße Zubereitung wird als Mittel zum Schutz der menschlichen Epidermis oder der Haare oder auch der sensibilisierten Haare oder als Sonnenschutzmittel verwendet.The preparation according to the invention is used as an agent for protecting the human epidermis or the hair or else the sensitized hair or as a sunscreen.
Mit "sensibilisierten Haaren" sind Haare gemeint, welche einer Dauerwellenbehandlung, einem Färbe- oder Entfärbeprozeß unterzogen worden sind.By "sensitized hair" is meant hair that has been subjected to a permanent wave treatment, a coloring or decolorization process.
Die erfindungsgemäße kosmetische Zubereitung wird zum Schutz menschlicher Epidermis gegen Sonneneinstrahlung verwendet. Dabei liegt sie in verschiedenen, für diesen Typ üblicherweise verwendeten Formen vor. So kann sie insbesondere als Lotion oder Emulsion, wie als Creme oder Milch (O W, W/O), in Form ölig-alkoholischer, ölig-wäßriger oder wäßrig-alkoholischer Gele oder als feste Stifte vorliegen oder als Aerosol konfektioniert sein.
Die Formulierung kann kosmetische Adjuvanzien enthalten, welche in dieser Art von Zubereitungen üblicherweise verwendet werden, wie z.B. Verdickungsmittel, weichmachende Mittel, Befeuchtungsmittel, grenzflächenaktive Mittel, Emulgatoren, Konservierungsmittel, Mittel gegen Schaumbildung, Parfüms, Wachse, Lanolin, Treibmittel, Farbstoffe und/oder Pigmente, welche das Mittel selbst oder die Haut färben, und andere in der Kosmetik gewöhnlich verwendete Ingredienzien.The cosmetic preparation according to the invention is used to protect the human epidermis against solar radiation. It is available in various forms commonly used for this type. In particular, it can be in the form of a lotion or emulsion, such as a cream or milk (OW, W / O), in the form of oily-alcoholic, oily-aqueous or aqueous-alcoholic gels, or as solid sticks, or as an aerosol. The formulation may contain cosmetic adjuvants that are commonly used in this type of preparation, such as thickeners, plasticizers, wetting agents, surfactants, emulsifiers, preservatives, anti-foaming agents, perfumes, waxes, lanolin, blowing agents, dyes and / or pigments which color the agent itself or the skin, and other ingredients commonly used in cosmetics.
Man kann als Dispersions- bzw. Solubilisierungsmittel ein Öl, Wachs oder sonstigen Fettkörper, einen niedrigen Monoalkohol oder ein niedriges Polyol oder Mischungen davon verwenden. Zu den besonders bevorzugten Monoalkoholen oder Polyoien zählen Ethanol, i-Propanol,An oil, wax or other fatty substance, a low monoalcohol or a low polyol or mixtures thereof can be used as the dispersing or solubilizing agent. The particularly preferred monoalcohols or polyols include ethanol, i-propanol,
Propylenglycol, Glyce n und Sorbit.Propylene glycol, glycene and sorbitol.
Eine bevorzugte Ausführungsform der Erfindung ist eine Emulsion, welche als Schutzcreme oder -milch vorliegt und außer der oder den Verbindungen der Formel I als UV-Filter - und gegebenenfalls noch weiteren Lichtschutzfiltern - Fettalkohole, Fettsäuren, Fettsäureester, insbesondere Triglyceride von Fettsäuren, Lanolin, natürliche oder synthetische Öle oder Wachse und Emulgatoren in Anwesenheit von Wasser umfaßt.A preferred embodiment of the invention is an emulsion which is present as a protective cream or milk and, in addition to the compound or compounds of the formula I as a UV filter - and, if appropriate, further light protection filters - fatty alcohols, fatty acids, fatty acid esters, in particular triglycerides of fatty acids, lanolin, natural or synthetic oils or waxes and emulsifiers in the presence of water.
Weitere bevorzugte Ausführungsformen stellen ölige Lotionen auf Basis von natürlichen oder synthetischen Ölen und Wachsen, Lanolin, Fettsäureestern, insbesondere Triglyceriden von Fettsäuren, oder ölig- alkoholische Lotionen auf Basis eines Niedrigalkohols, wie Ethanol, oder eines Glycols, wie Propylenglykol, und/oder eines Polyols, wie Glycerin, und Ölen, Wachsen und Fettsäureestern, wie Triglyceriden von Fettsäuren, dar.
Die erfindungsgemäße kosmetische Zubereitung kann auch als alkoholisches Gel vorliegen, welches einen oder mehrere Niedrigalkohole oder -polyole, wie Ethanol, Propylenglycol oder Glycerin, und einFurther preferred embodiments are 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 glycol, such as propylene glycol, and / or a polyol such as glycerin and oils, waxes and fatty acid esters such as triglycerides of fatty acids. The cosmetic preparation according to the invention can also be in the form of an alcoholic gel which contains one or more lower alcohols or polyols, such as ethanol, propylene glycol or glycerol
Verdickungsmittel, wie Kieselerde umfaßt. Die ölig-alkoholischen Gele enthalten außerdem natürliches oder synthetisches Öl oder Wachs.Thickeners such as silica. The oily-alcoholic gels also contain natural or synthetic oil or wax.
Die festen Stifte bestehen aus natürlichen oder synthetischen Wachsen und Ölen, Fettalkoholen, Fettsäuren, Fettsäureestern, Lanolin und anderen Fettkörpem.The solid sticks consist of natural or synthetic waxes and oils, fatty alcohols, fatty acids, fatty acid esters, lanolin and other fat bodies.
Ist eine Zubereitung als Aerosol konfektioniert, verwendet man in der Regel die üblichen Treibmittel, wie Alkane, Fluoralkane und Chlorfluoralkane.If a preparation is packaged as an aerosol, the usual propellants, such as alkanes, fluoroalkanes and chlorofluoroalkanes, are generally used.
Soll das erfindungsgemäße Mittel natürliche oder sensibilisierte Haare vor Sonneneinstrahlung schützen, so kann es als Shampoo, Lotion, Gel oder Emulsion zum Ausspülen vorliegen, wobei die jeweilige Formulierung vor oder nach dem Schampoonieren, vor oder nach dem Färben oder Entfärben, vor oder nach der Dauerwelle aufgetragen wird; oder das Mittel liegt als Lotion oder Gel zum Frisieren und Behandeln, als Lotion oder Gel zum Bürsten oder Legen einer Wasserwelle, als Haarlack, Dauerwellmittel, Färbe- oder Entfärbern ittel der Haare vor. Dieses Mittel kann außer der oder den Verbindungen der Formel I als organische UV-Filter - und gegebenenfalls weiteren Lichtschutzfiltern - verschiedene, in diesem Mitteltyp verwendete Adjuvanzien enthalten, wie grenzflächenaktive Mittel, Verdickungsmittel, Polymere, weichmachende Mittel,If the agent according to the invention is intended to protect natural or sensitized hair from the sun, it can be in the form of a shampoo, lotion, gel or emulsion for rinsing, the respective formulation before or after shampooing, before or after dyeing or decoloring, before or after the perm is applied; or the agent is in the form of a lotion or gel for styling and treatment, as a lotion or gel for brushing or laying a water wave, as a hair varnish, permanent waving agent, dye or decolorizer for the hair. In addition to the compound (s) of formula I as organic UV filter - and optionally further light protection filters - this agent can contain various adjuvants used in this type of agent, such as surfactants, thickeners, polymers, plasticizers,
Konservierungsmittel, Schaumstabilisatoren, Elektrolyte, organischePreservatives, foam stabilizers, electrolytes, organic
Lösungsmittel, Silikonderivate, Öle, Wachse, Antifettmittel, Farbstoffe und/oder Pigmente, die das Mittel selbst oder die Haare färben oder andere für die Haarpflege üblicherweise verwendete Ingredienzien.
Die erfindungsgemäßen kosmetischen Zubereitungen können mit Hilfe von Techniken hergestellt werden, die dem Fachmann wohl bekannt sind.Solvents, silicone derivatives, oils, waxes, anti-greasing agents, dyes and / or pigments that color the agent itself or the hair or other ingredients commonly used for hair care. The cosmetic preparations according to the invention can be produced using techniques which are well known to the person skilled in the art.
Unter den Verbindungen der Formel I sind diejenigen Verbindungen be-The compounds of the formula I include those compounds
vorzugt, worin der Rest R' bedeutet.preferred, in which the radical R '.
Diese Verbindungen der Formel I werden vor- und nachstehend auch als Verbindungen der Formel I* These compounds of the formula I are mentioned above and below as compounds of the formula I *
worin m*, n* und p* jeweils unabhängig voneinander 2 bis 8 bedeuten, bezeichnet.wherein m *, n * and p * each independently represent 2 to 8.
Die vorliegende Erfindung betrifft auch diese Verbindungen der Formel I*.The present invention also relates to these compounds of the formula I * .
Überraschenderweise wurde gefunden, daß die Verbindungen der Formel I* farblos sind.
ln den Verbindungen der Formel I oder I* sind m, n und p oder m*, n* und p* jeweils unabhängig voneinander 2, 3, 4, 5, 6, 7 oder 8. Vorzugsweise sind m, n und p oder m*, n* und p* jeweils unabhängig voneinander 2, 3 oder 4. Besonders bevorzugt sind m, n und p oder m*, n* und p* gleich, ganz außerordentlich bevorzugt bedeuten m, n und p oder m*, n* und p* 2.Surprisingly, it has been found that the compounds of the formula I * are colorless. In the compounds of the formula I or I *, m, n and p or m *, n * and p * are each independently 2, 3, 4, 5, 6, 7 or 8. Preferably m, n and p or m are *, n * and p * each independently of the other 2, 3 or 4. m, n and p or m *, n * and p * are particularly preferably the same, very particularly preferably m, n and p or m * , n * and p * 2.
Erfindungsgemäße Nahrungsmittel, die mit einer oder mehreren Verbindungen der Formel I* angereichert sind, sowie erfindungsgemäße kosmetische Formulierungen, die eine oder mehrere Verbindungen der Formel I* enthalten, sind besonders bevorzugt. Dementsprechend ist auch die Verwendung einer oder mehrerer Verbindungen der Formel I* als Nahrungsergänzungsmittel bzw. deren Verwendung in kosmetischen Formulierungen, z.B. als UV-Filter, besonders bevorzugt.Foodstuffs according to the invention which are enriched with one or more compounds of the formula I * and cosmetic formulations according to the invention which contain one or more compounds of the formula I * are particularly preferred. Accordingly, the use of one or more compounds of the formula I * as a dietary supplement or their use in cosmetic formulations, for example as a UV filter, is particularly preferred.
Die vorliegende Erfindung stellt ein vorteilhaftes Verfahren zur Herstellung von Verbindungen der Formel I durch in wäßrigem Milieu stattfindende enzymatische Spaltung von Verbindungen der Formel II zur Verfügung. Nach diesem Verfahren werden die Verbindungen der Formel II in Wasser gelöst und mit einer geeigneten Menge eines Enzyms kontaktiert. Vorzugsweise wird die Reaktion unter guter Durchmischung, z.B. durch Rühren, durchgeführt.The present invention provides an advantageous process for the preparation of compounds of the formula I by enzymatic cleavage of compounds of the formula II which takes place in an aqueous medium. According to this process, the compounds of formula II are dissolved in water and contacted with a suitable amount of an enzyme. Preferably the reaction is carried out with thorough mixing, e.g. by stirring.
Nach dem erfindungsgemäßen Verfahren können sowohl die Quercetin- Derivate der Formel I als auch die Isoquercetin-Derivate der Formel I hergestellt werden. Bevorzugt werden nach dem erfindungsgemäßen Verfahren jedoch entweder im wesentlichen nur die Quercetin-Derivate der Formel I oder im wesentlichen nur die Isoquercetin-Derivate der Formel I hergestellt.
Geeignete Enzyme für das erfindungsgemäße Verfahren sind Hydrolasen. Vorzugsweise werden Hydrolasen, die aus dem Stamm Penicillium decumbens gewonnen werden, verwendet, insbesondere die Enzyme Naringinase und Hesperidinase. Ganz außerordentlich bevorzugt ist das Enzym Naringinase.Both the quercetin derivatives of the formula I and the isoquercetin derivatives of the formula I can be prepared by the process according to the invention. Preferably, however, essentially only the quercetin derivatives of the formula I or essentially only the isoquercetin derivatives of the formula I are prepared by the process according to the invention. Suitable enzymes for the process according to the invention are hydrolases. Hydrolases obtained from the Penicillium decumbens strain are preferably used, in particular the enzymes naringinase and hesperidinase. The enzyme naringinase is very particularly preferred.
Die Edukte und die Enzyme für das erfindungsgemäße Verfahren sind käuflich erwerbbar oder können nach Methoden, die dem Fachmann wohl bekannt und in der Literatur beschrieben sind (z.B. in Standard-Werken wie Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme- Verlag, Stuttgart), gewonnen oder hergestellt werden.The starting materials and the enzymes for the process according to the invention are commercially available or can be prepared using methods which are well known to the person skilled in the art and are described in the literature (for example in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart), won or manufactured.
Geeignete Reaktionstemperaturen für das erfindungsgemäße Verfahren sind Temperaturen zwischen 15 und 80 °C. Vorzugsweise wird das erfin- dungsgemäße Verfahren bei Reaktionstemperaturen von 30 bis 50 °C durchgeführt, insbesondere bei Reaktionstemperaturen von 35 bis 45 °C.Suitable reaction temperatures for the process according to the invention are temperatures between 15 and 80 ° C. The process according to the invention is preferably carried out at reaction temperatures of 30 to 50 ° C., in particular at reaction temperatures of 35 to 45 ° C.
Wenn die Reaktionstemperatur zu niedrig ist, läuft die Reaktion mit einer unangemessen langsamen Reaktionsgeschwindigkeit ab. Wenn die Reaktionstemperatur dagegen zu hoch ist, wird das Enzym, welches ein Protein ist, denaturiert und somit deaktiviert.If the reaction temperature is too low, the reaction proceeds at an inappropriately slow reaction rate. On the other hand, if the reaction temperature is too high, the enzyme, which is a protein, is denatured and thus deactivated.
Geeignete pH-Werte für das erfindungsgemäße Verfahren sind pH-Werte zwischen 3 und 8. Vorzugsweise wird das erfindungsgemäße Verfahren bei pH-Werten von 4,5 bis 7 durchgeführt, insbesondere bei pH-Werten von 4,8 bis 6,8. Weiterhin bevorzugte pH-Werte können jedoch je nach verwendetem Enzym innerhalb der gegebenen Grenzen variieren. Beispielsweise sind pH-Werte von 6,4 bis 6,8 bei Verwendung des Enzyms Naringinase ganz außerordentlich bevorzugt.
Vorzugsweise wird das Verfahren derart ausgeführt, daß der pH-Wert mit Hilfe eines Puffer-Systems eingestellt wird. Prinzipiell können alle gängigen Puffer-Systeme, die zur Einstellung der obengenannten pH- Werte geeignet sind, verwendet werden. Bevorzugt wird jedoch wäßrigerSuitable pH values for the method according to the invention are pH values between 3 and 8. The method according to the invention is preferably carried out at pH values from 4.5 to 7, in particular at pH values from 4.8 to 6.8. However, further preferred pH values can vary within the given limits, depending on the enzyme used. For example, pH values of 6.4 to 6.8 are extremely preferred when using the enzyme naringinase. The method is preferably carried out in such a way that the pH is adjusted using a buffer system. In principle, all common buffer systems that are suitable for setting the above-mentioned pH values can be used. However, preference is given to aqueous
Zitrat-Puffer verwendet.Citrate buffer used.
Geeignete Gewichtsverhältnisse Edukt : Wasser für das erfindungsgemäße Verfahren sind Verhältnisse von 0,001 : 99,999 bis 40 : 60. Vorzugsweise wird das erfindungsgemäße Verfahren mit Gewichtsverhältnissen Edukt : Wasser von 0,005 : 99,995 bis 20 : 80 durchgeführt, insbesondere mit Gewichtsverhältnissen von 0,5 : 99,5 bis 10 : 90.Suitable weight ratios of starting material: water for the process according to the invention are ratios from 0.001: 99.999 to 40:60. The process according to the invention is preferably carried out with weight ratios of starting material: water from 0.005: 99.995 to 20:80, in particular with weight ratios of 0.5: 99, 5 to 10: 90.
Geeignete Gewichtsverhältnisse Enzym : Edukt für das erfindungsgemäßeSuitable weight ratios of enzyme: educt for the invention
Verfahren sind Verhältnisse von 0,005 : 99,995 bis 50 : 50. Vorzugsweise wird das erfindungsgemäße Verfahren mit Gewichtsverhältnissen Enzym :Processes are ratios from 0.005: 99.995 to 50:50. The process according to the invention is preferably carried out with weight ratios of enzyme:
Edukt von 0,5 : 99,5 bis 30 : 70 durchgeführt, insbesondere mitEduct from 0.5: 99.5 to 30: 70 carried out, especially with
Gewichtsverhältnissen von 2 : 98 bis 20 : 80.Weight ratios from 2: 98 to 20: 80.
Zur Herstellung der Isoquercetin-Derivate der Formel I wird das erfindungsgemäße Verfahren beispielsweise derart durchgeführt, daß die Reaktion bei Verwendung des Enzyms Naringinase vorzugsweise bei einer Temperatur von 35 bis 45 °C und einem pH-Wert von 4,8 bis 6,8 stattfindet und nach ca. 12 bis 18 h abgebrochen wird. Vorzugsweise wird die Reaktion hierbei ständig analytisch kontrolliert. Die Bildung bzw. Herstellung der Quercetin-Derivate der Formel I kann beispielsweise dadurch erreicht werden, daß die Reaktionszeit in geeigneter Weise verlängert wird.To produce the isoquercetin derivatives of the formula I, the process according to the invention is carried out, for example, in such a way that the reaction when the enzyme naringinase is used preferably takes place at a temperature of 35 to 45 ° C. and a pH of 4.8 to 6.8 and after about 12 to 18 hours. The reaction is preferably continuously checked analytically. The formation or production of the quercetin derivatives of the formula I can be achieved, for example, by suitably extending the reaction time.
Das Fortschreiten bzw. das Ende der Reaktion sowie die Analyse der Reaktionsprodukte kann z.B. mittels HPLC erfolgen, z.B. unter Verwendung von Standard-HPLC-Geräten und Säulen enthaltend reversed- phase-Materialien mit C18-Alkyl-Belegung.
Alternativ kann das Fortschreiten bzw. das Ende der Reaktion auch mittels Dünnschichtchromatographie (DC) kontrolliert werden.The progress or the end of the reaction and the analysis of the reaction products can be carried out, for example, by means of HPLC, for example using standard HPLC devices and columns containing reversed-phase materials with C 18 alkyl coating. Alternatively, the progress or the end of the reaction can also be checked by means of thin layer chromatography (TLC).
Nach beendeter Reaktion besteht das Reaktionsgemisch hauptsächlich aus Wasser, Puffer, Enzym, geringen Mengen an nicht umgesetztemAfter the reaction has ended, the reaction mixture consists mainly of water, buffer, enzyme, small amounts of unreacted
Edukt, Rhamnose, Quercetin- und/oder Isoquercetin-Derivat der Formel I und gegebenenfalls an Glucose. Die Isolierung der Quercetin- und/oder Isoquercetin-Derivate der Formel I erfolgt nach gängigen Methoden. UnterEduct, rhamnose, quercetin and / or isoquercetin derivative of formula I and optionally glucose. The quercetin and / or isoquercetin derivatives of the formula I are isolated by customary methods. Under
"üblicher Aufarbeitung" wird im Rahmen der vorliegenden Erfindung folgendes verstanden:In the context of the present invention, “customary workup” is understood to mean the following:
Das Reaktionsgemisch wird abgekühlt, beispielsweise auf eine Temperatur von 0 °C. Das hierbei auskristallisierende Quercetin- und/oder Isoquercetin-Derivat der Formel I wird vom restlichen Reaktionsgemisch abgetrennt, beispielsweise durch Absaugen bzw. Filtration unter vermindertem Druck oder durch Abschleudern der ausgefallenen Kristalle. Anschließend wird der Feststoff gewaschen, vorzugsweise mit Wasser, und danach getrocknet, z.B. bei einer Temperatur von 50 °C und einem Druck von 200 mbar.The reaction mixture is cooled, for example to a temperature of 0 ° C. The quercetin and / or isoquercetin derivative of the formula I which crystallizes out is separated from the remaining reaction mixture, for example by suction or filtration under reduced pressure or by centrifuging off the precipitated crystals. The solid is then washed, preferably with water, and then dried, e.g. at a temperature of 50 ° C and a pressure of 200 mbar.
Die weitere Aufreinigung der Reaktionsprodukte oder eine eventuell erforderliche Trennung der Quercetin- und Isoquercetin-Derivate der Formel I voneinander kann beispielsweise durch HPLC erfolgen.Further purification of the reaction products or any separation of the quercetin and isoquercetin derivatives of the formula I which may be required can be carried out, for example, by HPLC.
Im Filtrat verbleiben Wasser, Puffer, Enzym, geringe Mengen Edukt, Rhamnose und gegebenenfalls Glucose.Water, buffer, enzyme, small amounts of starting material, rhamnose and possibly glucose remain in the filtrate.
Die Abtrennung der im Filtrat verbliebenen Substanzen kann durch bekannte Verfahren erreicht werden, beispielsweise durch Ultrafiltration, durch Überleiten des Filtrats über Kationen- und/oderThe substances remaining in the filtrate can be separated off by known methods, for example by ultrafiltration, by passing the filtrate over cations and / or
Anionenaustauscher, durch Kristallisation und durch mechanische
Abtrennung wie z.B. Filtration. Eventuell im Filtrat vorhandene Glucose kann z.B. auch durch Hefe-Vergärung abgetrennt werden.Anion exchangers, by crystallization and by mechanical Separation such as filtration. Any glucose present in the filtrate can also be separated, for example, by yeast fermentation.
Die in den Aufarbeitungsschritten angefallenen Substanzen, wie z.B. dasThe substances obtained in the processing steps, e.g. the
Enzym, können rezirkuliert und somit für weitere Umsetzungen verwendet werden.Enzyme, can be recirculated and thus used for further reactions.
Auch ohne weitere Ausführungen wird davon ausgegangen, daß ein Fachmann die obige Beschreibung in weitestem Umfang nutzen kann. Die bevorzugten Ausführungsformen sind deswegen lediglich als beschreibende, keinesfalls als in irgendeiner Weise limitierende Offenbarung aufzufassen.Even without further explanations, it is assumed that a person skilled in the art can use the above description to the greatest extent. The preferred embodiments are therefore only to be understood as a descriptive disclosure, and in no way as a limitation in any way.
Die vollständige Offenbarung aller vor- und nachstehend aufgeführten Anmeldungen und Veröffentlichungen sind durch Bezugnahme in diese Anmeldung eingeführt.The full disclosure of all applications and publications listed above and below are incorporated by reference into this application.
Das folgende Beispiel soll die vorliegende Erfindung verdeutlichen. Es ist jedoch keinesfalls als limitierend zu betrachten.The following example is intended to illustrate the present invention. However, it is by no means to be regarded as limiting.
Beispielexample
Die Bezugsquellen für die verwendeten Substanzen sind wie folgt:The sources of supply for the substances used are as follows:
Tπ(hydroxyethyl)rutin: Merck KGaA, Artikel-Nr. 501902Tπ (hydroxyethyl) rutin: Merck KGaA, article no. 501902
Naringinase: Sigma, Artikel-Nr. N-1385Naringinase: Sigma, article no. N-1385
Die Reaktionskontrolle und die Analyse der Reaktionsprodukte erfolgt mittels HPLC.
HPLC-Bedinqunqen bei Verwendung einer Standard-HPLC-Anlaqe:The reaction control and the analysis of the reaction products is carried out by means of HPLC. HPLC conditions when using a standard HPLC system:
Säule: LiChroSorb® RP18 (reversed phase-Material mit C18-Alkyl-Belegung und einer Korngröße von 5 μm (Merck KGaA, Artikel-Nr. 151355)),Column: LiChroSorb ® RP18 (reversed phase material with C 18 alkyl coating and a grain size of 5 μm (Merck KGaA, Article No. 151355)),
Eluent: Gemisch aus Acetonitril und Wasser im Volumenverhältnis 20 : 80 (pH 2,6),Eluent: mixture of acetonitrile and water in a volume ratio of 20:80 (pH 2.6),
Fluß: 1 ml/min,Flow: 1 ml / min,
Wellenlänge: 260 nm,Wavelength: 260 nm,
Temperatur: 30 °C,Temperature: 30 ° C,
Probenvolumen: 10 μl,Sample volume: 10 μl,
Probenvorbereitung: 5 mg der Probe in 3 ml Methanol lösen und mit dem Eluent auf 10 ml auffüllen,Sample preparation: dissolve 5 mg of the sample in 3 ml of methanol and make up to 10 ml with the eluent,
Retentionszeiten: Trihydroxyethylrutin: 10,1 min,Retention times: trihydroxyethylrutin: 10.1 min,
Trihydroxyethylisoquercetin: 11 ,4 min, Trihydroxyethylquercetin: 42,7 min.Trihydroxyethyl isoquercetin: 11.4 min, trihydroxyethylquercetin: 42.7 min.
Beispiel 1example 1
5 g Th(hydroxyethyl)rutin werden in 150 ml vollentsalztem Wasser gelöst und durch Zugabe von 0,64 g Zitronensäure und 1 ,4 g 32 %iger wäßriger Natronlauge auf einen pH-Wert von 6,6 eingestellt. Anschließend werden 0,5 g Naringinase eingetragen und das Reaktionsgemisch 16 h bei einer Reaktionstemperatur von 40 °C gerührt. Nach üblicher Aufarbeitung werden 2,41 g Tri(hydroxyethyl)isoquercetin in 96 %iger Reinheit erhalten.
5 g of Th (hydroxyethyl) rutin are dissolved in 150 ml of deionized water and adjusted to a pH of 6.6 by adding 0.64 g of citric acid and 1.4 g of 32% strength aqueous sodium hydroxide solution. Then 0.5 g of naringinase is introduced and the reaction mixture is stirred at a reaction temperature of 40 ° C. for 16 h. After the usual work-up, 2.41 g of tri (hydroxyethyl) isoquercetin are obtained in a purity of 96%.
Claims
1. Verfahren zur Herstellung von Verbindungen der Formel I1. Process for the preparation of compounds of the formula I
worinwherein
m, n und p jeweils unabhängig voneinander 2 bis 8, undm, n and p each independently 2 to 8, and
bedeuten,mean,
dadurch gekennzeichnet, daß Verbindungen der Formel II
characterized in that compounds of the formula II
worin m, n und p jeweils unabhängig voneinander die in Formel I angegebene Bedeutung besitzen, 5 in wäßrigem Milieu enzymatisch gespalten werden.in which m, n and p each independently have the meaning given in formula I, 5 are cleaved enzymatically in an aqueous medium.
2. Verfahren nach Anspruch 1 , dadurch gekennzeichnet, daß Verbin- o düngen der Formel I hergestellt werden, worin der Rest R1 2. The method according to claim 1, characterized in that compounds or fertilizers of the formula I are produced, in which the radical R 1
bedeutet. 0means. 0
3. Verfahren nach einem der Ansprüche 1 oder 2, dadurch gekennzeichnet, daß Verbindungen der Formel I hergestellt werden, worin m, n und p 2 bedeuten.3. The method according to any one of claims 1 or 2, characterized in that compounds of the formula I are prepared, in which m, n and p mean 2.
5
5
4. Verfahren nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß die Reaktion bei einer Reaktionstemperatur von 15 bis 80 °C durchgeführt wird.4. The method according to any one of claims 1 to 3, characterized in that the reaction is carried out at a reaction temperature of 15 to 80 ° C.
5. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß die Reaktion bei einem pH-Wert von 3 bis 8 durchgeführt wird.5. The method according to any one of claims 1 to 4, characterized in that the reaction is carried out at a pH of 3 to 8.
0 6. Verfahren nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, daß die Reaktion unter Verwendung von Hydrolasen durchgeführt wird.0 6. The method according to any one of claims 1 to 5, characterized in that the reaction is carried out using hydrolases.
C 7. Nahrungsmittel, dadurch gekennzeichnet, daß es mit einer oder mehreren Verbindungen der Formel I angereichert worden ist. C 7. Food, characterized in that it has been enriched with one or more compounds of formula I.
8. Verwendung von einer oder mehreren Verbindungen der Formel I als Nahrungsergänzungsmittel. 08. Use of one or more compounds of formula I as dietary supplements. 0
9. Kosmetische oder pharmazeutische Formulierung, dadurch gekennzeichnet, daß sie eine oder mehrere Verbindungen der Formel I enthält. 59. Cosmetic or pharmaceutical formulation, characterized in that it contains one or more compounds of formula I. 5
10. Formulierung nach Anspruch 9, dadurch gekennzeichnet, daß sie weitere UV-Filter enthält.10. Formulation according to claim 9, characterized in that it contains further UV filters.
Q 11. Verwendung von einer oder mehreren Verbindungen der Formel I in kosmetischen oder pharmazeutischen Formulierungen. Q 11. Use of one or more compounds of formula I in cosmetic or pharmaceutical formulations.
12. Verwendung von einer oder mehreren Verbindungen der Formel I nach Anspruch 11 als UV-Filter, Antioxidans und/oder Radikalfänger. 5
12. Use of one or more compounds of the formula I according to claim 11 as a UV filter, antioxidant and/or radical scavenger. 5
3. Verbindungen der Formel I*3. Compounds of the formula I*
worin m*, n* und p* jeweils unabhängig voneinander 2 bis 8 bedeuten.where m * , n * and p * each independently mean 2 to 8.
14. Verbindungen der Formel I* nach Anspruch 13, dadurch gekennzeichnet, daß m*, n* und p* 2 bedeuten.
14. Compounds of the formula I* according to claim 13, characterized in that m * , n * and p * mean 2.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020017005369A KR20010080347A (en) | 1998-10-30 | 1999-10-13 | Method for the production of quercetin and isoquercetin derivatives |
| CA002348728A CA2348728A1 (en) | 1998-10-30 | 1999-10-13 | Method for the production of quercetin and isoquercetin derivatives |
| AU10366/00A AU1036600A (en) | 1998-10-30 | 1999-10-13 | Method for the production of quercetin and isoquercetin derivatives |
| JP2000579771A JP2002528132A (en) | 1998-10-30 | 1999-10-13 | Method for producing quercetin and isoquercetin derivatives |
| EP99953802A EP1124980A2 (en) | 1998-10-30 | 1999-10-13 | Method for the production of quercetin and isoquercetin derivatives |
| BR9914811-0A BR9914811A (en) | 1998-10-30 | 1999-10-13 | Process for the preparation of quercetin and isoquercetin derivatives |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19850282A DE19850282A1 (en) | 1998-10-30 | 1998-10-30 | Preparation of new or known tris-hydroxyalkyl quercetin and isoquercetin derivatives by enzymatic cleavage of rutin derivatives, used e.g. as nutritional supplements, cosmetic UV filters or cardiovascular drugs |
| DE19850282.6 | 1998-10-30 | ||
| DE19850570A DE19850570A1 (en) | 1998-11-02 | 1998-11-02 | Production of new or known tri-O-hydroxyalkyl quercetin or isoquercetin derivatives, e.g. useful as food supplements, comprises enzymatic hydrolysis of tri-O-hydroxyalkyl rutin derivatives in an aqueous medium |
| DE19850570.1 | 1998-11-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2000026399A2 true WO2000026399A2 (en) | 2000-05-11 |
| WO2000026399A3 WO2000026399A3 (en) | 2000-08-10 |
Family
ID=26049877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1999/007685 WO2000026399A2 (en) | 1998-10-30 | 1999-10-13 | Method for the production of quercetin and isoquercetin derivatives |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1124980A2 (en) |
| JP (1) | JP2002528132A (en) |
| KR (1) | KR20010080347A (en) |
| CN (1) | CN1325452A (en) |
| AU (1) | AU1036600A (en) |
| BR (1) | BR9914811A (en) |
| CA (1) | CA2348728A1 (en) |
| WO (1) | WO2000026399A2 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1055411A2 (en) * | 1999-05-22 | 2000-11-29 | Beiersdorf Aktiengesellschaft | Cosmetic or dermatologic sunscreen compositions containing flavone and/or flavanone derivatives, especially flavonoids and s-triazine |
| EP1055412A2 (en) * | 1999-05-22 | 2000-11-29 | Beiersdorf Aktiengesellschaft | Cosmetic or dermatologic sunscreen compositions containing flavone derivatives and/or flavanone derivatives, especially flavonoids and benzotriazol |
| EP1055413A2 (en) * | 1999-05-22 | 2000-11-29 | Beiersdorf Aktiengesellschaft | Combinations of sulfonated sunscreens and flavone derivatives and/or flavanone derivatives, especially flavonoids, cosmetic compositions containing the same |
| WO2000076992A1 (en) * | 1999-06-16 | 2000-12-21 | Merck Patent Gmbh | Recovery of isoquercetin from bioflavanoid pastes |
| EP1127572A3 (en) * | 2000-02-25 | 2003-05-02 | Basf Aktiengesellschaft | Use of flavones for treating cycloxygenase-2 mediated diseases |
| JP2004051637A (en) * | 2002-07-18 | 2004-02-19 | Merck Patent Gmbh | Photoprotictive agent |
| WO2006105843A2 (en) * | 2005-04-05 | 2006-10-12 | Merck Patent Gmbh | Method for producing rhamnose and aglycones by splitting rutinosides using yeast |
| US10639294B2 (en) | 2018-10-02 | 2020-05-05 | Janssen Pharmaceutica Nv | Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide metabolite |
| US11304968B2 (en) | 2018-11-16 | 2022-04-19 | Janssen Pharmaceutica Nv | Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101985439B (en) * | 2010-11-18 | 2012-05-09 | 桂林市三棱生物制品有限公司 | Process for separating and extracting 98% quercetin from aboveground part of pubescent holly root |
| JP2016013075A (en) * | 2014-07-01 | 2016-01-28 | イビデン株式会社 | Quercetin-containing extract |
| CN105412074A (en) * | 2015-12-24 | 2016-03-23 | 厦门大学 | Application of quercetin in preparation of medicine for preventing and treating diseases related to ApoE protein level |
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| US3420815A (en) * | 1965-10-25 | 1969-01-07 | Zyma Sa | Quercetin and quercetin glycoside |
| US4603046A (en) * | 1985-08-23 | 1986-07-29 | Charles Of The Ritz Group Ltd. | Improved sunscreen or sunblock composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01308476A (en) * | 1988-06-06 | 1989-12-13 | Showa Denko Kk | Ultraviolet ray absorber |
| JPH03255013A (en) * | 1990-03-01 | 1991-11-13 | San Ei Chem Ind Ltd | Cosmetic |
| JP3477628B2 (en) * | 1995-06-19 | 2003-12-10 | アサヒビール株式会社 | Polyphenol preparation obtained from hop bract and its manufacturing method |
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1999
- 1999-10-13 JP JP2000579771A patent/JP2002528132A/en active Pending
- 1999-10-13 EP EP99953802A patent/EP1124980A2/en not_active Withdrawn
- 1999-10-13 KR KR1020017005369A patent/KR20010080347A/en not_active Application Discontinuation
- 1999-10-13 CN CN99812942A patent/CN1325452A/en active Pending
- 1999-10-13 CA CA002348728A patent/CA2348728A1/en not_active Abandoned
- 1999-10-13 BR BR9914811-0A patent/BR9914811A/en not_active IP Right Cessation
- 1999-10-13 WO PCT/EP1999/007685 patent/WO2000026399A2/en not_active Application Discontinuation
- 1999-10-13 AU AU10366/00A patent/AU1036600A/en not_active Abandoned
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3420815A (en) * | 1965-10-25 | 1969-01-07 | Zyma Sa | Quercetin and quercetin glycoside |
| US4603046A (en) * | 1985-08-23 | 1986-07-29 | Charles Of The Ritz Group Ltd. | Improved sunscreen or sunblock composition |
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| DATABASE WPI Section Ch, Week 199005 Derwent Publications Ltd., London, GB; Class A96, AN 1990-032314 XP002137677 & JP 01 308476 A (SHOWA DENKO KK), 13. Dezember 1989 (1989-12-13) * |
| DATABASE WPI Section Ch, Week 199202 Derwent Publications Ltd., London, GB; Class D21, AN 1992-011304 XP002137679 & JP 03 255013 A (DAIICHI PHARM CO LTD), 13. November 1991 (1991-11-13) * |
| DATABASE WPI Section Ch, Week 199711 Derwent Publications Ltd., London, GB; Class B04, AN 1997-115173 XP002137678 & JP 09 002917 A (ASAHI BREWERIES LTD), 7. Januar 1997 (1997-01-07) * |
| IOKU ET AL.: "b-Glucosidase activity in the rat small intestine toward quercetin monoglucosides" BIOSCI. BIOTECHNOL. BIOCHEM., Bd. 62, Nr. 7, 1998, Seiten 1428-1431, XP000882413 * |
| ISHIDA ET AL.: "Studies on the antihemorrhagic substances in herbs ..." CHEM.PHARM.BULL., Bd. 36, Nr. 11, 1988, Seiten 4414-4420, XP002134480 * |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1055412A3 (en) * | 1999-05-22 | 2003-06-18 | Beiersdorf Aktiengesellschaft | Cosmetic or dermatologic sunscreen compositions containing flavone derivatives and/or flavanone derivatives, especially flavonoids and benzotriazol |
| EP1055412A2 (en) * | 1999-05-22 | 2000-11-29 | Beiersdorf Aktiengesellschaft | Cosmetic or dermatologic sunscreen compositions containing flavone derivatives and/or flavanone derivatives, especially flavonoids and benzotriazol |
| EP1055413A2 (en) * | 1999-05-22 | 2000-11-29 | Beiersdorf Aktiengesellschaft | Combinations of sulfonated sunscreens and flavone derivatives and/or flavanone derivatives, especially flavonoids, cosmetic compositions containing the same |
| EP1055411A2 (en) * | 1999-05-22 | 2000-11-29 | Beiersdorf Aktiengesellschaft | Cosmetic or dermatologic sunscreen compositions containing flavone and/or flavanone derivatives, especially flavonoids and s-triazine |
| EP1055411A3 (en) * | 1999-05-22 | 2003-06-18 | Beiersdorf Aktiengesellschaft | Cosmetic or dermatologic sunscreen compositions containing flavone and/or flavanone derivatives, especially flavonoids and s-triazine |
| EP1055413A3 (en) * | 1999-05-22 | 2003-06-11 | Beiersdorf Aktiengesellschaft | Combinations of sulfonated sunscreens and flavone derivatives and/or flavanone derivatives, especially flavonoids, cosmetic compositions containing the same |
| WO2000076992A1 (en) * | 1999-06-16 | 2000-12-21 | Merck Patent Gmbh | Recovery of isoquercetin from bioflavanoid pastes |
| US6683164B1 (en) | 1999-06-16 | 2004-01-27 | Merck Patent Gmbh | Recovery of isoquercetin from bioflavanoid pastes |
| EP1127572A3 (en) * | 2000-02-25 | 2003-05-02 | Basf Aktiengesellschaft | Use of flavones for treating cycloxygenase-2 mediated diseases |
| JP2004051637A (en) * | 2002-07-18 | 2004-02-19 | Merck Patent Gmbh | Photoprotictive agent |
| WO2006105843A2 (en) * | 2005-04-05 | 2006-10-12 | Merck Patent Gmbh | Method for producing rhamnose and aglycones by splitting rutinosides using yeast |
| WO2006105843A3 (en) * | 2005-04-05 | 2007-03-29 | Merck Patent Gmbh | Method for producing rhamnose and aglycones by splitting rutinosides using yeast |
| US10639294B2 (en) | 2018-10-02 | 2020-05-05 | Janssen Pharmaceutica Nv | Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide metabolite |
| US11304968B2 (en) | 2018-11-16 | 2022-04-19 | Janssen Pharmaceutica Nv | Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9914811A (en) | 2001-07-03 |
| CN1325452A (en) | 2001-12-05 |
| WO2000026399A3 (en) | 2000-08-10 |
| JP2002528132A (en) | 2002-09-03 |
| AU1036600A (en) | 2000-05-22 |
| KR20010080347A (en) | 2001-08-22 |
| CA2348728A1 (en) | 2000-05-11 |
| EP1124980A2 (en) | 2001-08-22 |
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