Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
  • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
  • C07D241/40—Benzopyrazines
  • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring

Definitions

• the invention relates to the use of quinoxaline derivatives as photostable UV filters in cosmetic and pharmaceutical preparations for protecting the human epidermis or human hair against
• UV radiation especially in the range of 280-400 nm.
• the light stabilizers used in cosmetic and pharmaceutical preparations have the task of preventing harmful effects of sunlight on human skin, or at least of theirs
• these light stabilizers also serve to protect other ingredients from destruction or degradation by UV radiation. In hair cosmetic preparations, damage to the keratin fiber by UV rays is to be reduced.
• 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 therefore lead to premature aging. Sometimes you can also see dermatoses, and in extreme cases skin cancer occurs.
• UV-A radiation is essentially the trigger for skin pigmentation. It is also desirable to protect hair against photochemical damage in order to prevent changes in color shades, discoloration or mechanical damage.
• 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 some of the solar radiation, the lower limit of the ultraviolet rays that reach the earth's surface is approximately 280 nm. All these findings therefore make the development of efficient filter substances for the UV-A and also for the UV-B range appear necessary.
• UV-A filters for cosmetic and pharmaceutical preparations, which can serve above all as UV-A filters and whose absorption maxima should therefore be in the range from approximately 320 to 400 nm.
• broadband protection i.e. UV-A and UV-B protection, in the range of 280-400 nm.
• light stabilizers should additionally have a highly specific absorbance.
• light stabilizers for cosmetic preparations have to meet a number of other requirements, for example good solubility in cosmetic oils or in
• the object was therefore to find a new structural class as a light stabilizer for cosmetic and pharmaceutical purposes which absorb in the UV-A and / or UV-B range and which are photostable, a low intrinsic color, i.e. have a sharp band structure, a high one
• R 1 and R 2 together with carbon atoms to which they are bonded can together form an unsaturated, partially or completely saturated 4-, 5-, 6- or 7-ring, which optionally contains heteroatoms such as S, N and / or O. can contain, further fused and / or can also be substituted one or more times,
• R 5 , R 6 each independently of one another H
• Alkyl, alkenyl, alkynyl, each with up to 20 C atoms, cycloalkyl, cycloalkenyl, bicyclic systems, each with up to 10 C atoms, these radicals being up to three times substituted by Sub 1 and / or one or two CH 2 - Groups can be replaced by C 0, and the cyclic systems also contain 1 to 3 heteroatoms such as S, N, and / or O. can,
• radicals R 5 and R 6 can also form an unsaturated, partially or completely saturated 4-, 5-, 6- or 7-ring with one another, in each case together with carbon atoms to which they are bonded, which optionally heteroatoms such as Can contain S, N and / or 0, can also be mono- or polysubstituted and / or fused further,
• Het is an unsubstituted or mono- or polysubstituted heteroaromatic ring with 5 to 7 ring members or a condensed ring system, one or more N, S and / or O atoms being contained as heteroatoms and also one or two CH groups in a or? position to the
• R 3 and R 4 are each independently H
• Alkyl, alkoxy, alkenyl, alkynyl, each with up to 20 C atoms, cycloalkyl, cycloalkoxy, cycloalkenyl, bicyclic systems, each with up to 10 C atoms, these radicals being up to three times substituted by Sub 2 and / or one or two CH 2 groups can be replaced by C 0 and the cyclic systems can also contain 1 to 3 heteroatoms such as S, N and / or O,
• radicals R 3 and R 4 can also together, in each case together with C atoms to which they are bonded, or one of the two radicals together with the adjacent N atom, together form an unsaturated, partially or completely saturated 4-, 5 - form a 6 or 7 ring which may optionally contain heteroatoms such as S, N and / or 0, may also be substituted one or more times and / or be fused further,
• R 7 and R 8 are each independently H
• Alkyl, alkoxy, alkenyl, alkynyl, each with up to 20 C atoms, cycloalkyl, cycloalkoxy, cycloalkenyl, bicyclic systems, each with up to 10 C atoms, these radicals being up to three times substituted by Sub 2 and / or one or two CH 2 groups can be replaced by C 0 and the cyclic systems can also contain 1 to 3 heteroatoms such as S, N and / or O, Sub 2 shark, hydroxy, cyano, amino, nitro, C 1 -C 4 alkyl or C 1 -C
• the compounds of this class of quinoxalins show excellent UV-absorbing properties both in the UV-A range and in the presence of an additional chormophoric group in the UV-B range, which ensures broadband protection.
• the solubility of the substances in water or in cosmetic oils can easily be induced by the choice of suitable substituents. Lipophilic, i.e. the
• radicals are, for example, aliphatic or cycloaliphatic radicals, in particular alkyl radicals having up to 20 carbon atoms, alkoxy, mono- and dialkylamino, alkoxycarbonyl, mono- and dialkylaminocarbonyl, mono- and dialkylaminosulfonyl radicals, and also also cyano, nitro, bromine, Chlorine, iodine or fluorine substituents.
• Hydrophilic i.e. residues permitting the water solubility of the compounds of the formulas I, II and / or III are e.g. Carboxy and sulfoxy radicals and in particular their salts with any physiologically compatible cations, such as the alkali salts or the T kalkyiammioniumsalze.
• the alkyl radicals in the radicals R 1 to R 8 have up to 20 carbon atoms and can be unbranched or branched and are therefore preferably methyl, ethyl, n-propyl, i-propyl, butyl, sec-butyl, i-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, 1-methylpentyl, 2-methylpentyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl, they also mean 2,2- Dimethylpropyl, 1-ethylpropyl, 3-methylpentyl, 4-methylpentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2,3-d
• Tetradecyl pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl.
• alkenyl radicals are branched and unbranched alkenyl chains with preferably up to 10 carbon atoms: vinyl, propenyl,
• Preferred alkynyl radicals are branched or unbranched
• Alkynyl chains with up to 10 carbon atoms such as, for example, ethynyl, propynyl, butynyl, i-butynyl, pentynyl, hexynyl, heptynyl or octynyl.
• Preferred cycloalkyl radicals are branched or unbranched C 3 -C 10 cycloalkyl chains such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 1, 2-dimethylcyclopentyl, 1-methyl-2-ethylcyclopropyl, cyclononyl or also cyclodecyl called.
• Suitable alkoxy radicals are branched or unbranched alkoxy chains with up to 20 C atoms, preferably with up to 12 C atoms, particularly preferably with 1 to 8 C atoms, such as e.g. Methoxy, ethoxy, propoxy, i-propoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, pentoxy,
• the preferred cycloalkyl radicals for R 1 to R 8 are branched or unbranched cycloalkyl chains having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl,
• Preferred cycloalkenyi radicals are branched or unbranched
• C 3 -C- ⁇ 0 -cycloalkenyl chains with one or more double bonds such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1, 3-cyclohexadienyl, 1, 4-cyclohexadienyl, cycloheptenyl, cycloheptatrienyl, cyclooctenyl or cyclonyltenyl, cyclonylyltenyl, cyclonyl or cyclonylyltenyl, cyclonyl or cyclonyl.
• bicycloalkyl or bicycloalkenyl radicals saturated or unsaturated bicyclic ring systems with preferably up to 10 carbon atoms, preferably bicyclic terpenes such as pinane, pinene, bornane, camphor derivatives, decalin or also adamantane, may be mentioned.
• cyclic systems can also contain 1 to 3 heteroatoms such as sulfur, nitrogen or oxygen.
• Be exemplary ring systems such as pipe din, pyrrolidine, pyrazdin, morpholine, tetrahydrofuran, dihydrofuran, thiolane, piperazine, thiazolidine or also oxazolidine groups are mentioned.
• Sub 1 is preferably halogen, such as fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, further preferably C 1 -C 4 -alkylamino or CrC -dialkyamino, C- ⁇ -C 4 alkyl or CC 4 alkoxy or hydroxy or amino.
• halogen such as fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, further preferably C 1 -C 4 -alkylamino or CrC -dialkyamino, C- ⁇ -C 4 alkyl or CC 4 alkoxy or hydroxy or amino.
• Sub 2 is preferably halogen, such as fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, further preferably CC 4 - alkylamino or C 1 -C 4 - Dialkyamino, dC -alkyl or CC 4 -alkoxy or also hydroxy or amino, further preferred is also the meaning COR 5 ,
• Suitable mono- or dialkylamino radicals are preferably methylamines, dimethylamino, ethylamino, methylethylamino, diethylamino, propylamino, methylpropylamino, dipropylamino, ethylpropylamino, butylamino, dibutylamino, methylbutylamino, isopropylamino, and also 1, 1-dimethylpropylamino, pentylamino, hexylamino, 1-methyl-1-ethylpropylamino, heptylamino or octylamino.
• the following preferred compounds are given by way of example, but they have no limiting character:
• n 1, 2, 3 or 4, preferably 1 or 2;
• Unsubstituted or substituted phenyl or naphthyl may be mentioned as particularly preferred groups.
• the heterocyclic rings preferably have 1-13 C atoms and 1-6 heteratoms, in particular 3-9 C atoms and 1-4 heteroatoms.
• heteroaromatic radicals such as 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 4-pyridyl, pyrimidyl, pyrazolyl, pyrazolonyl, imidazolyl, triazinyl, pyrazinyl, thiazolyl, indolyl, quinolyl, quinoxalinyl or Isoquinolyl in question.
• the Ar and Het groups described above are preferably unsubstituted or mono-, di- or trisubstituted, all substituents being possible in principle as long as they have no toxic effect on the overall compounds.
• halogen in particular F or Cl
• hydroxy, amino, cyano, CC 4 alkyl or dC 4 alkoxy COR 5 , COOR 5 , OAr, OHet, (CR 5 R 6 ) n -Ar or
• R 5 or R 6 then preferably denote H, -CC alkyl, Ar or Het.
• substituents are very particularly preferred: fluorine, chlorine, -COOH, alkoxy with up to 8 carbon atoms, -COOalkyl with up to 8 carbon atoms, -CO-phenyl, -CO-aryl, -CO-Het, - quinoxalinyl, -CO-NH-R 5 .
• fluorine chlorine, -COOH, alkoxy with up to 8 carbon atoms, -COOalkyl with up to 8 carbon atoms, -CO-phenyl, -CO-aryl, -CO-Het, - quinoxalinyl, -CO-NH-R 5 .
• Alkyl with up to 20 carbon atoms, alkoxy with up to 12 carbon atoms, in which one or more hydrogen atoms can also be substituted by Sub 1 and / or one or two CH 2 groups can be replaced by C 0,
• R 5 and R 6 each independently of one another are those given in formula I.
• radicals are H or alkyl having up to 7 carbon atoms and the other radical is then Ar or Het, each having up to 12 ring atoms, which can also preferably be substituted by 1-3 radicals, and n, R 3 and R 4 have the meanings given in formula I.
• R 1 is fluorine or chlorine, alkyl halogens such as -CH 2 Hal, -CHHal 2 or
• R 2 is H, alkyl or alkoxy, each with up to 10 C atoms,
• R 3 and R 4 have the meanings given in formula I.
• R 3 and R 4 are each independently H
• Alkyl with up to 20 C atoms or alkoxy with up to 12 C atoms, in which in each case one or more hydrogen atoms may be substituted by Sub 1 and / or one or two CH 2 groups may be replaced by C 0,
• R 5 and R 6 each independently of one another have the meanings given in formula I, but preferably one of these radicals H or alkyl having up to 7 carbon atoms and the other radical then Ar or Het, each having up to 12 ring atoms, which are also preferred can be substituted with 1-3 radicals means
• R 1 and R 2 have the meanings given in formula I.
• Alkyl halides in particular -CH 2 Hal, -CHHal 2 or CHal 3 , hydroxy, nitro,
• R 5 and R 6 each independently have the meanings given in formula I, but preferably one of these radicals
• R 1 and R 2 have the meanings given in formula I.
• R 2 , R 3 , R 4 , R 5 , R ', R "and n have the meanings given in formula I and X denotes Ar or Het with the definitions given therefor. X preferably denotes an unsubstituted or mono- to trisubstituted aromatic or heteroaromatic ring with 5 to 7 ring atoms.
• R 2 , R 1 , R 4 , R 5 , R ', R "and n have the meanings given in formula I and X denotes Ar or Het with the definitions given therefor. X preferably denotes an unsubstituted or mono- to trisubstituted aromatic or heteroaromatic ring with 5 to 7 ring atoms.
• the following compounds Im to In are also particularly preferred, for example:
• R 4 denotes phenyl or -NH-phenyl
• the compounds of the formula I and of the sub-formulas Ia to In contain the groups Ar and / or Het, these are preferably mono- to trisubstituted.
• Table 1 lists the preferred substituents with the preferred positions in the ring using the example of the phenyl ring, which is particularly preferably selected. Above all, compounds of the sub-formulas Ii to II are preferred which contain a phenyl ring as X.
• R 3 is -CH 2 -CH (NHR 5 ) COOR 6 and R 4 is H;
• R 3 is -CH 2 -2- [1,3- (2-alkyl) imidazol-one-4] and R 4 is H;
• R 3 is -CH 2 -CH 2 -PO (OR 7 ) 2 and R 4 is -CH 2 -CH (NH 2 ) COOH;
• R 3 is -O-phenyl (substituted by Oalkyl) and R 4 is H;
• R 3 is -O-phenyl, substituted by
• Formulas I, II and / or III also partially include new compounds.
• the invention therefore also relates to the new compounds of the formulas given above.
• Triazine and aminotriazine residues are also preferred as substituents on the quinoxaline skeleton. Accordingly, the following examples and their derivatives also belong to the invention substituted radicals to the compounds preferred according to the invention:
• quinoxaline derivatives are also preferably used for the use according to the invention.
• These compounds can be prepared by methods known from the literature, which are familiar to the person skilled in the art: - N- (2-quinoxalinyl) -2,4-dichloro-aniline N- [bis- (3-fluoro-quinoxalin-2-yl)] - 2-amino-pyhmidine 2-chloro-3-phenyl-quinoxaline 3- Phenyl-quinoxalin-2-one - 6-chloro-2,3-dimethyl-quinoxaline
• the quinoxaline derivatives according to the invention are outstandingly suitable as UV filter substances.
• the quinoxalines can be designed synthetically in such a way that the presence of an additional chromophoric group results in UV-absorbing properties in both the UV-A and UV-B range. Broadband protection can thus be achieved.
• the solubility of the substances in water or cosmetic oils can also be influenced by the choice of the substituents.
• the quinoxaline derivatives can also be combined with any UV filter substances, which leads to an improvement in the protective performance (SPF boost) through synergistic effects.
• UV-A and UV-B filter substances are listed below, with which the quinoxalines according to the invention are preferably combined can be. This selection is not intended to be limiting in any way.
• the combination can be by chemical reaction (Table 2) and / or physical combination with UV filters, which are listed below.
• UV filters can be combined. Those UV filters whose physiological harmlessness has already been proven are particularly preferred. There are substances known from the specialist literature for both UV-A and UV-B filters, e.g.
• 2-hydroxy-4-methoxybenzophenone e.g. Eusolex® 4360
• 2-Hydroxy-4-methoxybenzophenone-5-sulfonic acid and its sodium salt e.g. Uvinul® MS-40
• - methoxycinnamic acid esters such as - methoxycinnamic acid octyl ester (e.g. Eusolex® 2292),
• Isopentyl 4-methoxycinnamate e.g. as a mixture of the isomers (e.g. Neo Heliopan® E 1000),
• - Salicylate de vate such as - 2-ethylhexyl salicylate (e.g. Eusolex® OS),
• 4-aminobenzoic acid and derivatives such as 4-aminobenzoic acid are 4-aminobenzoic acid and derivatives such as 4-aminobenzoic acid,
• 2-phenylbenzimidazole-5-sulfonic acid and its potassium, sodium and ethanolamine salts e.g. Eusolex ® 232
• UV filters are only examples. Of course, other UV filters can also be used. These organic UV filters are generally incorporated into cosmetic preparations in an amount of 0.5 to 10 percent by weight, preferably 1-8%.
• organic UV filters are, for example, 2- (2H-benzotriazol-2-yl) -4-methyl-6- (2-methyl-3- (1, 3,3,3-tetramethyl-1- (trimethylsilyloxy) disiloxanyl) propyl) phenol (e.g. Silatrizole ® ), - 4,4 '- [(6- [4 - ((1, 1-dimethylethyl) aminocarbonyl) phenylamino] -1, 3,5-triazine-2,4-diyl) diimino] bis (2-ethylhexyl benzoate) (e.g. UV-Asorb ® HEB),
• organic UV filters are generally incorporated into cosmetic preparations in an amount of 0.5 to 20 percent by weight, preferably 1-15%. In formulations according to the invention, they are usually in weight ratios of 15: 1 to 1:15, preferably from 10: 1 to 1:10 and particularly preferably from 5: 1 to
• Preferred compounds with UV-filtering properties are 3- (4 ' - methylbenzylidene) -dl-camphor, 1- (4-tert-butylphenyl) -3- (4-methoxyphenyl) - propane-1, 3-dione, 4-isopropyldibenzoylmethane , 2-hydroxy-4-methoxybenzophenone, octyl methoxycinnamate, octyl methoxycinnamate, 3,3,5-thmethylcyclohexyl salicylate, 2-ethylhexyl 4- (dimethylamino) benzoate, 2-ethylhexyl 2-cyano-3,3-diphenylacrylate, 2-phenyl-benzimidazole-5-sulfonic acid and its potassium, sodium and triethanolamine salts.
• Conceivable inorganic UV filters are, for example, those from the group of titanium dioxides, such as coated titanium dioxide (for example Eusolex ® T-2000, Eusolex® T-AQUA), zinc oxides (eg Sachtotec® ®), iron oxides and also Cerium oxides conceivable. Titanium oxide and zinc oxide are preferably in the form of micronized inorganic pigments. These inorganic UV filters are generally incorporated into cosmetic preparations in an amount of 0.5 to 20 percent by weight, preferably 2 to 10%. In formulations according to the invention, they are usually in
• the use of the quinoxaline derivatives according to the invention has a further, interesting and advantageous aspect.
• the combination with other UV filters often leads to a photostabilization of this other substance by the quinoxaline derivative.
• UV filters which have advantageous light protection filter properties per se, have the major disadvantage of a certain instability with respect to UV radiation.
• the dibenzoylmethane derivatives such as the Eusolex 9020 (4-t-butyl-4'-methoxy-dibenzoylmethane), are substances that are exposed to photochemical decomposition.
• the photochemical decomposition of this class of compounds follows a Norrish type I acyl cleavage.
• the resulting reaction products are no longer available as light protection filter substances.
• the quinoxaline derivatives described here are excellent for this, in particular the combination with Eusolex 9020 leads to a greatly improved photostabilization of the substance.
• the UV light protection filters described here can each be used individually or, of course, in combination, which is preferred, in sunscreens. They can be combined with UV-B / A chromophores, eg all filters that are approved and known worldwide to improve the protective performance (SPF boost) through synergistic effects. They can preferably be used in combination with both inorganic and organic UV-A and UV-B filters or mixtures thereof.
• the protective effect against harmful effects of UV radiation can be optimized by combining one or more compounds of the formula I with further UV filters.
• Combination shows both a protective effect as an antioxidant and against burns by UV radiation. This means that you can also achieve a protective effect against oxidative stress or against the effects of radicals.
• the invention therefore also relates to the use of a compound of the formula I according to claim 1 in combination with antioxidants in cosmetic or pharmaceutical preparations.
• the present invention therefore also relates to cosmetic and pharmaceutical preparations which contain one or more of the compounds of the formulas I, II and / or III, if appropriate in combination with further light stabilizers or antioxidants.
• the invention also relates to a method for protecting the skin and natural or sensitized hair from the sun's rays an effective amount of at least one compound of the formula I, II and / or III is applied to the skin or hair in a cosmetic preparation.
• "Sensitized hair” means hair that has been subjected to a permanent wave treatment, a coloring or decolorization process.
• the filters according to the invention for protection against UV-A and UV-B radiation can each be incorporated into cosmetic preparations in concentrations of 0.1 to 20% by weight, preferably 1 to 15% by weight. It is possible in this way to prepare preparations in which up to
• UV filters 100% of the light protection filters used are the UV filters described here. These are substances that are easily dissolved, dispersed or emulsified in water and oils, depending on the substituents on the framework.
• the preparations according to the invention can also contain other customary skin-protecting or skin-care active ingredients. In principle, these can be all active substances known to the person skilled in the art.
• Particularly preferred active ingredients are pyrimidinecarboxylic acids and / or
• Aryioxime as well as coumaranone derivatives.
• Pyrimidinecarboxylic acids occur in halophilic microorganisms and play a role in the osmoregulation of these organisms (E. A. Galinski et al., Eur. J. Biochem., 149 (1985) pages 135-139).
• pyrimidinecarboxylic acids are especially ectoin ((S) -1, 4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid) and hydroxyectoin ((S, S) - 1, 4,5,6-tetrahydro-5 -hydroxy-2-methyl-4-pyrimidinecarboxylic acid and its derivatives, which stabilize enzymes and other biomolecules in aqueous solutions and organic solvents.
• enzymes against denaturing Conditions such as salts, extreme pH, surfactants, urea, guanidinium chloride and other compounds.
• Ectoin and ectoin derivatives such as hydroxyectoin can advantageously be used in medicinal products.
• hydroxyectoin can be used for
• hydroxyectoin and other ectoin derivatives are typically in areas in which e.g. Trehalose is used as an additive.
• Ectoin derivatives, such as hydroxyectoin can be used as a protective substance in dried yeast and bacterial cells
• pharmaceutical products such as non-glycosylated, pharmaceutically active peptides and proteins e.g. t-PA can be protected with ectoin or its derivatives.
• Cosmetic applications include in particular the use of ectoin and ectoin dehvates for the care of aged, dry or irritated skin.
• European patent application EP-A-0 671 161 describes in particular that ectoin and hydroxyectoin in cosmetic preparations such as powders, soaps, surfactant-containing cleaning products, lipsticks, blushes, make-ups, skin care creams and
• a pyrimidine carboxylic acid according to the formula below is preferably used,
• R 1 is H or C1 -8-alkyl
• R 2 is H or C1-4-alkyl
• R 3 , R 4 , R 5 and R 6 are each independently a group from the group H, OH, NH 2 and are C1-4 alkyl.
• Pyrimidinecarboxylic acids in which R 2 is a methyl or an ethyl group and R 1 or R 5 and R 6 are H are preferably used.
• the preparations according to the invention preferably contain pyrimidinecarboxylic acids of this type in amounts of up to 15% by weight.
• 2-hydroxy-5-methyllaurophenone oxime which is also referred to as HMLO, LPO or F5
• HMLO 2-hydroxy-5-methyllaurophenone oxime
• LPO 2-hydroxy-5-methyllaurophenone oxime
• Preparations which contain 2-hydroxy-5-methyllaurophenone oxime are therefore suitable for the treatment of skin diseases which are associated with inflammation. It is known that such preparations e.g. for the therapy of psioriasis, different forms of eczema, irritative and toxic dermatitis,
• UV dermatitis and other allergic and / or inflammatory diseases of the skin and the appendages can be used.
• Preparations according to the invention which, in addition to the compound of the formula I, additionally contain an aryl oxime, preferably 2-hydroxy-5-methyllaurophenone oxime, show surprising anti-inflammatory suitability.
• the preparations preferably contain 0.01 to 10% by weight of the aryloxime, it being particularly preferred if the preparation contains 0.05 to 5% by weight aryloxime.
• -X- stands for a single bond
• Heteroaryl and / or heteroarylcarbonyl groups these groups being substituted by alkyl, hydroxyl, alkoxy, amino, mono- and dialkylamino,
• Me stands for a proton or an alkali metal ion, in particular a sodium or potassium ion.
• the solubility of this compound in water can be improved, for example, by selecting the radicals R 1 , R 2 , R 3 and R 4 as sulfate or phosphate groups.
• the cosmetic and pharmaceutical preparations containing light stabilizers are generally based on a vehicle which contains at least one oil phase.
• preparations based on water alone are also possible when using compounds with hydrophilic substituents. Accordingly come oils, oil-in-water and
• Water-in-oil emulsions, creams and pastes, lip protection stick masses or fat-free gels can be considered.
• Such sun protection preparations can thus be in liquid, pasty or solid form, for example as water-in-oil creams, oil-in oils
• Water creams and lotions W / O / W systems or O / W / O systems, Aerosol foam creams, gels, oils, fat sticks, powders, sprays or alcoholic-aqueous lotions.
• W / O / W systems O / W / O systems
• Aerosol foam creams gels, oils, fat sticks, powders, sprays or alcoholic-aqueous lotions.
• they can also be formulated as micronized systems or as PIT (phase inversion temperature) emulsions.
• Typical oil components in cosmetics are, for example, paraffin oil, glyceryl stearate, isopropyl myristate, diisorpopyl adipate, 2-ethylhexanoic acid acetylstearyl ester, hydrogenated polyisobutene, petrolatum, caprylic acid / capric acid triglycerides, microcrystalline wax, lanolin, mineral oils, ester oils, mineral waxes low C number, e.g. With paraffin oil, glyceryl stearate, isopropyl myristate, diisorpopyl adipate, 2-ethylhexanoic acid acetylstearyl ester, hydrogenated polyisobutene, petrolatum, caprylic acid / capric acid triglycerides, microcrystalline wax, lanolin, mineral oils, ester oils, mineral waxes low C number, e.g. With paraffin oil, glyceryl stea
• the preparations can contain cosmetic adjuvants which are commonly used in this type of preparation, such as e.g. Thickeners, softening agents, wetting agents, surfactants, emulsifiers, preservatives, anti-foaming agents, perfumes, fats and waxes, lanolin, blowing agents, stabilizers, antioxidants, bactericides, dyes and / or pigments which color the agent itself or the skin , and other ingredients commonly used in cosmetics.
• cosmetic adjuvants which are commonly used in this type of preparation, such as e.g. Thickeners, softening agents, wetting agents, surfactants, emulsifiers, preservatives, anti-foaming agents, perfumes, fats and waxes, lanolin, blowing agents, stabilizers, antioxidants, bactericides, dyes and / or pigments which color the agent itself or the skin , and other ingredients commonly used in cosmetics.
• Known W / O and, in addition, also O / W emulsifiers such as some polyglycine nests, sorbitan esters or partially esterified gyicerides can be considered as emulsifiers.
• Typical examples of fats are glycerides; waxes include beeswax, camamauba wax, paraffin wax or micro waxes, optionally in combination with hydrophilic waxes.
• Metal salts of fatty acids such as magnesium, aluminum and / or zinc stearate can be used as stabilizers.
• Suitable thickeners are, for example, crosslinked polyacrylic acids and their derivatives, Poiysacchahde, in particular special xanthan gum, guar guar, agar agar, alginates and tyloses, carboxymethyl cellulose and hydroxyethyl cellulose, also fatty alcohols, monoglycade and fatty acids, polyacrylates, polyvinyl alcohol and polyvinylpyrrolidone. Plant extracts, protein hydrolyzates and vitamin complexes can also be added.
• Antioxidants that can be used are, for example, amino acids, imidazoles, peptides, carotenoids, ⁇ -hydroxy acids, unsaturated fatty acids, vitamins A, C and / or E and suitable derivatives of these substances.
• antioxidants There are many well-known and proven substances known from the literature that can be used as antioxidants, e.g. Amino acids (e.g. glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (e.g. urocanic acid) and their derivatives, peptides such as D, L-camosine, D-
• Carnosine, L-carnosine and their derivatives e.g. anserine
• carotenoids e.g. carotenoids
• carotenes e.g. ⁇ -carotene, ß-carotene, lycopene
• chlorogenic acid and their derivatives e.g. dihydroliponic acid
• lipoic acid and its derivatives e.g. dihydroliponic acid
• aurothioglucose e.g. dihydroliponic acid
• propylthiouracil and other thiols e.g. thioredoxin, glutathione, cysteine, cystine, cystamine and their
• Glycosyl N-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl, ⁇ -linoleyl, cholesteryl and glyceryl esters) and their salts, diaurylthiodipropionate, distearylthiodipropionate, thiodipropioic acid and their derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) as well as sulfoximine compounds (e.g. buthioninsulfoximines,
• Homocysteine sulfoximine, buthionine sulfones, penta-, hexa-, heptathionine sulfoximine) in very low tolerable doses e.g. pmol to ⁇ mol / kg
• metal chelators e.g. ⁇ -hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin
• ⁇ - Hydroxy acids e.g. citric acid, lactic acid, malic acid
• humic acid bile acid, bile extracts
• Camosin butylated hydroxytoluene, butylated hydroxyanisole, nordohydroguaretic acid, thhydroxybutyrophenone, quercitin, uric acid and its derivatives, mannose and its derivatives, zinc and its derivatives (eg ZnO, ZnS04), selenium and its derivatives (eg selenium methionine), stilbenes and their derivatives (eg Stilbene oxide, trans-stilbene oxide).
• antioxidants are also suitable for use in the cosmetic preparations according to the invention.
• Known and commercially available mixtures are, for example, mixtures containing lecithin, L - (+) - ascorbyl palmitate and citric acid (e.g.
• the quinoxaline derivatives of the formulas I, II or III for the antioxidants are usually in
• the preparations according to the invention can contain vitamins as further ingredients.
• Vitamins and vitamin derivatives are preferably selected from vitamin A, vitamin A propionate, vitamin A palmitate, Vitamin A acetate, retinol, vitamin B, thiamine chloride hydrochloride (vitamin Bi), riboflavin (vitamin B 2 ), nicotinic acid amide, vitamin C (ascorbic acid), vitamin D, ergocalciferol (vitamin D 2 ), vitamin E, DL- ⁇ -tocopherol , Tocopherol E-acetate, tocopherol hydrogen succinate, vitamin Ki, escuiin (vitamin P active ingredient), thiamine (vitamin B- ⁇ ), nicotinic acid (niacin), pyridoxin, pyridoxal, pyridoxamine, (vitamin B 6 ), pantothenic acid, biotin , Folic acid and cobalamin (vitamin B ⁇ 2 ) contained in the cosmetic preparations according to the invention, particularly preferably vitamin A palm
• the aqueous phase of the preparations according to the invention advantageously advantageously contain alcohols, diols or polyols of low C number, and also their ethers, preferably ethanol, isopropanol, propylene glycol, glycine, ethylene glycol, ethylene glycol monoethyl or monobutyl ether or similar products, and also alcohols such as ethanol, isopropanol, 1 , 2-propanediol and in particular one or more thickeners, such as Silicon dioxide, aluminum silicates, polysaccharides or their derivatives, e.g. Hyaluronic acid, xanthan gum, hydroxypropyl methyl cellulose, or a polyacrylate from the group of the so-called carbopols.
• alcohols, diols or polyols of low C number and also their ethers, preferably ethanol, isopropanol, propylene glycol, glycine, ethylene glycol, ethylene glycol monoeth
• Common film formers are, for example, hydrocolloids such as chitosan, microcrystalline chitosan or quaternary chitosan, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, polymers of the acrylic acid series, quaternary cellulose derivatives and similar compounds.
• Suitable preservatives are, for example, formaldehyde solutions, p-hydroxybenzoate or sorbic acid.
• Suitable pearlizing agents are, for example, glycol distearic acid esters such as ethylene glycol distearate, but also fatty acids and fatty acid monoglycol esters.
• the dyes which can be used are those substances which are suitable and approved for cosmetic purposes, as described, for example, in the publication "Cosmetic Dyes medium”of the Dye Commission of the German Research Foundation, published by Verlag Chemie, Weinheim, 1984. These dyes are usually used in concentrations of 0.001 to 0.1% by weight, based on the mixture as a whole.
• the sunscreen agents according to the invention can also contain one or more chemical substances with self-tanning properties.
• 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 out, the respective preparation 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 treating, as a lotion or gel for brushing or laying a water wave, as a hair lacquer, hairspray, aerosol foam cream, permanent waving agent, coloring or decolorizing agent for the hair.
• this agent can contain various adjuvants used in this type of agent, such as surfactants, thickeners, polymers, plasticizers, preservatives, foam stabilizers - Sators, electrolytes, organic solvents, silicone derivatives, oils, waxes, anti-grease agents, dyes and / or pigments that the agent itself or dye the hair or other ingredients commonly used for hair care.
• adjuvants used in this type of agent such as surfactants, thickeners, polymers, plasticizers, preservatives, foam stabilizers - Sators, electrolytes, organic solvents, silicone derivatives, oils, waxes, anti-grease agents, dyes and / or pigments that the agent itself or dye the hair or other ingredients commonly used for hair care.
• the light protection filters according to the invention can be incorporated directly into cosmetic preparations without further preparatory measures.
• the light protection preparations according to the invention can advantageously contain further UV filter substances, the total amount of the filter substances e.g. 0.1% by weight to 30% by weight, preferably 0.5 to 10% by weight, in particular 1 to 6% by weight, based on the total weight of the preparations.
• the preparations according to the invention can also be used as pharmaceutical compositions for the preventive treatment of inflammation and allergies of the skin and also in certain cases for the prevention of certain types of cancer.
• the pharmaceutical agent according to the invention can be administered orally or topically.
• the pharmaceutical preparation is in the form of pastilles, gelatin capsules, dragees, as a syrup, solution, emulsion or suspension.
• Topical application takes place, for example, as an ointment, cream, gel, spray, solution or lotion.
• the cosmetic and pharmaceutical preparations according to the invention can be produced using techniques which are well known to the person skilled in the art.
• the foodstuffs which can be enriched with one or more of the compounds according to the invention according to the present invention comprise all materials which are suitable for animal or human consumption, for example vitamins and provitamins thereof, fats, minerals or amino acids " .
• Food can be solid but also liquid, i.e. it can be in the form of a drink).
• Foodstuffs which, according to the present invention, can be enriched with one or more compounds of the formulas I, II and / or III are, for example, foods which come from a single natural source, such as e.g. Sugar, unsweetened juice,
• Nectar or puree from a single plant species such as unsweetened apple juice (eg also a mixture of different types of apple juice), grapefruit juice, orange juice, apple compote, apricot nectar, tomato juice, tomato sauce, tomato puree, etc.
• Further examples of foods which, according to the present invention, can be enriched with one or more compounds of the formula I. Grain or cereals from a single plant species and materials made from such plant species, such as Cereal syrup, rye flour, wheat flour or oat bran. Mixtures of such foods are also suitable according to the present
• Invention to be enriched with one or more of the compounds according to the invention for example multi-vitamin preparations, Mineral mixtures or sweetened juice.
• Other examples of foodstuffs include food preparations, for example prepared cereals, pastries, mixed drinks, foods specially prepared for children, such as yogurt, diet foods, low-calorie foods or animal feed.
• the foods that can be enriched according to the present invention with one or more compounds of the formulas I, II and / or III thus include all edible combinations of carbohydrates, lipids, proteins, inorganic elements,
• the foods that can be fortified with one or more compounds of formulas 1, 11 and / or III according to the present invention are preferably administered orally, e.g. in the form of dishes, pills, tablets, capsules, powders, syrups, solutions or suspensions.
• the product mixture is separated by column chromatography on silica gel with cyclohexane / ethyl acetate (4: 1). The separated products are recrystallized from methanol.
• the Substance (A) is obtained in the form of yellow crystals in a yield of 72%, the compound (B) in a yield of 4% as yellow crystals.
• N, N-benzoyl- (2-quinoxalinyl) -4-amino-benzoic acid can be obtained as a pale yellow powder in a yield of 27%.
• Example I N - 2- [3- (ethoxycarbonyl) quinoxalinyl] -4-aminobenzoic acid Preparation: 2-chloro-3-ethoxycarbonyl ester quinoxaün (100g, 4.46 mmol) and p-aminopbenzoic acid (0.91 g, 6.69 mmol) are heated under reflux in 20 mL EtOH. The product precipitates as a yellow solid during the reaction. After suction, the recrystallization from EtOH takes place. N-2 [3- (ethoxycarbonyl) quinoxalinyl] -4-amino-benzoic acid is obtained as a yellow solid.
• Example K 1- (2-quinoxalinyl) -3 - [4- (/ ' so-propyl) phenyl] - prop-2-ene-1-one (A) and 1 - (2-quinoxalinyl) -3 - [3,4- (oxolano) phenyl] prop-2-en-1-one (B)
• Example N Carbohydrate-substituted quinoxaline derivatives were prepared according to
• the table below shows the structural formulas of quinoxaline derivatives which can be used according to the invention and the maxima of their UV-A or UV-B absorption.
• the measurement was carried out in 2-propanol at a concentration of 1 mg substance per 100 ml solvent.
• Oxynex K liquid (Art.No. 08324) 0) 0.10
• phase B water and Eusolex 232 is added with stirring. After complete dissolution, the remaining raw materials of phase B are added and heated to 80 ° C. Combine phase A to Pemulen and heat to 80 ° C. Stir in Pemulen in phase A. Slowly add phase B to phase A while stirring, homogenize and add
• phase D disperse the Pemulen TR-1 homogeneously in the water and add the pre-dissolved phase C while stirring.
• the Ths (hydroxymethyl) aminomethane is dissolved in the water of phase B and the Eusolex 232 is added with stirring. After the solution is complete, the remaining raw materials of phase B are added.
• Glycerin (approx. 87%) (Art.No. 1.04091) 0) 5.00

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• 2000
  • 2000-03-17 DE DE10013318A patent/DE10013318A1/de not_active Withdrawn
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