Title of Invention	AMINO SUBSTITUTED HYDROXYPHENYL BENZOPHENONE DERIVATIVES
Abstract	The present invention relates to a compound of formula wherein the substituents are as described in the description. This invention also relates to a process for preparing the same.

Full Text

Amino substituted hvdroxyphenyl benzophenone derivatives The present invention relates to amino substituted hydroxypheny! benzophenone derivatives, the process for the preparation of these compounds, the use of these UV absorbers, preferably for the protection of human and animal hairs and from the damage of UV radiation as well as cosmetic compositions comprising these compounds. C1-C20Aikyl denotes a linear or branched, unsubstituted or substituted alkyl group such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, n-hexyl, cyclohexyl, n-decyl, n-dodecyl, n-octadecyl. eicosyl, methoxyethyl, ethoxypropyl, 2-ethylhexyl, hydroxyethyl, chloropropyl, N.N-diethylaminopropyl, cyanoethyl, phenethyl, benzyl, p-tert-butylphenethyl, p-tert-octyl-phenoxyethyl, 3-(2,4-di-tert-amylphenoxy)-propyl, ethoxycarbonylmethyl-2-(2-hydroxy-ethoxy)ethyl or2-furylethyf. C1-C20alkenyl is for example allyl, methallyl, isopropenyl, 2-butenyl, 3-butenyl, isobutenyi, n-penta-2,4-dienyl, 3-methyl-but-2-enyl, n-oct-2-enyl, n-dodec-2-enyl, iso-dodecenyl, n-dodec-2-enyl or n-octadec^-enyl. C3-Ciocycloaikyl is for example cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl and preferably cyclohexyl. These radicals may besubstituted, for example by one or more Oder equal or different C1-C4alkyl radicals, preferably by methyl, and/or hydroxy. If cycloalkyl radicals are substituted by one or more radicals, they are preferably substituted by one. two or four, oreferablv bv one or two ecual or radicals C3-Cl0cycloafkenyr7s rdfexairiple'cycfopropenyl, cyclobutenyl, cyclopentenyl, cycloheptenyl, cycloocentyl, cyclononenyl or cyclodecenyl and preferably cyclohexenyl. These radicals may be substituted with one or more equal or different d-C4alkyl radical, preferably with methyl, and/or hydroxy. If cycloalkenyl radicals are substituted with one or more radicals they are preferably substituted with one, two, three or four, preferably with one or two equal or different radicals. Hydroxy substituted C1-C5alkyl groups are for example hydroxymehtyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or hydroxypentyl. An alklyene radical is preferably a C1-C12alkylene radical, like for example methylene, ethylene, propylene, butylene, hexylene or octylene. The alklyene radicals may optionally be substituted by one or more C1-C5alkyl radicals. If R1 and R2 are heterocyclic radicals, these comprise one, two, three or four equal or different ring hetero atoms. Special preference is given to heterocycles which contain one, two or three, especially one or two, identical cr different hetero atoms. The heterocycles may be mono- or poly-cycfic, for example mono-, bi- or tri-cyclic. They are preferably mono- or bi-cyclic, especially monocyclic. The rings preferably contain 5, 6 or 7 ring members. Examples of monocyclic and bicyclic heterocyclic systems from which radicals occurring in the compounds of formula (1) or (2) may be derived are, for example, pyrrole, furan, thiophene, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazoie. pyridine, pyridazine, pyrimidine, pyrazine, pyran, thiopyran, 1,4-dioxane, 1,2-oxazinet 1,3-oxazine, 1,4-oxazine, indole, benzothio-phene, benzofuran, pyrrolidine, pipericine, piperazine, morpholine and thiomorpholine. Preference is given to compounds of formula (1), wherein R1 and R2 independently from each other are hydrogen; C1-C20alkyl; C2-C2oalkenyl; C3- Ciocycloalkyl; C3-C10cycloalkenyl; or R: and R2 together with the linking nitrogen atom form a 5- or 6-membered heterocyclic ring; ni is a number from 1 to 4; wenn n-, is 1, R3 is a saturated or unsaturated heterocyclic radical; hydroxy-C1-C5alkyl; Cyclohexyl substituted with one or more C1-C5alkyl; wenn n^ is 2, R3 is an alkylene-, cycloalkylene- or alkenylene radical which is optionally interrupted by a carbonyl- or carboxy group; wenn n, is 3, R3 is an alkantriyl radical; wenn nt is 4, R3 is an alkanetetrayl radical; A is-O-; or-N(R5)-; and R5 is hydrogen; C1-C5alkyl; or hydroxy-C1-C5aiky!. Of preferred interest are compounds of formula (1 j, wherein R, and R2 are C1-C20alkyl, preferably C1-C5alkyl; and most preferably ethyl. Preferably R, and R2 in formula (1) have the same definition. If in formula (1) N1 is 1, compounds are preferred, wherein R3 is a saturated or unsaturated heterocyclic radical, most preferably a saturated hetero¬cyclic radical. Among these compounds are those preferred, wherein R3 is a monocyclic radical of 5, 6 or 7 ring members with one or more heteroatoms, preferably wherein R3 is morphonlinyl; piperazinyl; piperidyl; pyrazolidinyl; imadazolidinyl; or pyrrolidinyl. When ni is 1 further compounds of formula (1) are of interest wherein R3 is an unsaturated heterocyclic radical, preferably a polycyclic radical. Furthermore compounds of the present invention are preferred which correspond-to formula The reaction is usually carried out at a temperature from 25 to 200°C, preferably at room temperature. Generally a solvent is not necessary for this reaction step. If a solvent is usee however, preferably the solvents as used in the working examples are preferred. The compounds of formula (1) are suitable especially as UV filters, that is to say for the protection of organic materials that are sensitive to ultraviolet light, especially human and animal skin and hair, against the action of UV radiation. Such compounds are accordingly suitable as light-protective agents in cosmetic, pharmaceutical and veterinary medicine preparations. A further object of the present invention is therefore a cosmetic preparation comprising at least one of the compounds of formula (1) together with cosmetically acceptable carriers or adjuvants. The UV absorbers according to the present invention can be used either in the dissolved state (soluble organic filters, solubilised organic filters) or in the micronised state (nanoscalai organic filters, particulate organic filters, UV-absorber pigments). As milling apparatus for the preparation of the micronised organic UV absorbers there may be used, for example, a jet mill, ball mill, vibratory mill or hammer mill, preferably a high¬speed mixing mill. Even more preferable mills are modern ball mills; manufacturers of these types of mill are, for example, Netzsch (LMZ mill), Drais (DCP-Viscoflow or Cosmo), Buhler AG (centrifugal mills) or Bachhofer. The grinding is preferably carried out with a grinding aid. Examples of kneading apparatus for the preparation of the micronised organic UV absorbers are typical sigma-blade batch kneaders but also serial batch kneaders (IKA-Werke) or continuous kneaders (Continua from Werner und Pfleiderer). Useful low molecular weight grinding aids for all the above micronisation processes are dispersing agents and surfactants and emulsifiers as disclosed below in the sections entitled "Emulsifiers", "Surfactants" and "Fatty alcohols". Useful polymeric grinding aids for water dispersion are cosmetically acceptable water-soluble polymers with Mn > 500 g/mol, for example: acrylates (Salcare types), modified or non-modified polysaccharides, polyglucosides or xanthan gum. Furthermore an alkylated vinyi-pyrrolidone polymer, a vinylpyrrolidcne/vinyi acetate copolymer, an acyl glutamate, an aikyl polyglucoside, Ceteareth-25 or a phospholipid may be used. Oil dispersions may comprise cosmetically acceptable waxy polymers or natural waxes as polymeric grinding aid to adjust the viscosity during and after processing. Examples of other useful polymeric grinding aids are disclosed below in the section entitled "Polymers'1. Useful solvents are water, brine, (poly-)ethylene glycol, glycerol or cosmetically acceptable oils. Other useful solvents are disclosed below in the sections entitled "Esters of fatty acids'1, "Natural and synthetic triglycerides, including glyceryl esters and derivatives", "Pearlescent waxes", "Hydrocarbon oils" and "Silicones or siloxanes". The micronised UV absorbers so obtained usually have an average particle size from 0.02 to 2 micrometres, preferably from 0.03 to 1.5 micrometres and more especially from 0.05 to 1.0 micrometres. The UV absorbers according to the present invention can also be used dry in powder form. For that purpose, the UV absorbers are subjected to known grinding methods, such as vacuum atomisation, countercurrent spray-drying etc.. Such powders haveja particle size of from 0.1 micrometers to 2 micrometers. To avoid the occurrence of agglomeration, the UV absorbers can be coated with a surface-active compound prior to the pulverisation process, for example with an anionic, non-ionic or amphoteric surfactant, e.g. a phospholipid or a known polymer, such as PVP, an acrylate etc.. The UV absorbers according to the present invention can also be used in specific carriers for cosmetics, for example in solid lipid nanoparticles (SLN) or in inert sol-gel microcapsules wherein the UV absorbers are encapsulated. The cosmetic formulations or pharmaceutical compositions according to the present invention can also comprise one or more than one further UV filter. The cosmetic or pharmaceutical preparations can be prepared by physically mixing the UV absorber(s) with the adjuvant using customary methods, for example by simply stirring together the individual components, especially by making use of the dissolution properties of already known cosmetic UV absorbers, for example octyl methoxycinnamate, salicylic acid isooctyl ester etc.. The UV absorber can be used, for example, without further treatment, or in the micronised state, or in the form of a pcwder. Cosmetic or pharmaceutical preparations contain from 0.05 % to 40 % by weight, based on the total weight of the composition, of one UV absorber or a mixture of UV absorbers. Preference is given to the use of mixing ratios of the UV absorber of formula (1) according to the present invention and optional further light-protective agents of from 1:99 to 99:1, especially from 1:95 to 95:1 and preferably from 10:90 to 90:10, based on weight. Of special interest are mixing ratios of from 20:30 to 30:20, especially from 40:60 to 60:40 and preferably approximately 50:50. Such mixtures can be used, inter alia, to improve solubility or increase UV absorption. The UV absorbers of formula (1) according tc the present invention or combinations of UV filters are useful for protecting skin, hair and/'cr natural or artificial hair colour. Suitable UV filter substances which can additionally be used with the UV absorbers according to the present invention are any UV-A and UV-B filter substances. The cosmetic or pharmaceutical preparations may be, for example, creams, gels, lotions, al¬coholic and aqueous/alcoholic solutions, emulsions, wax/fat compositions, stick preparations, powders or ointments. In addition to the above-mentioned UV filters, the cosmetic or pharma¬ceutical preparations may contain further adjuvants as described below. As water- and oil-containing emulsions (e.g. W/O, O/W, O/W/O and W/O/W emulsions or mi-croemulsions) the preparations contain, for example, from 0.1 to 30 % by weight, preferably from 0.1 to 15 % by weight and especially from 0.5 to 10 % by weight, based on the total weight of the composition, of one or more UV absorbers, from 1 to 60 % by weight, espec¬ially from 5 to 50 % by weight and preferably from 10 to 35 % by weight, based on the total weight of the composition, of at least one oil component, from 0 to 30 % by weight, especially from 1 to 30 % by weight und preferably from 4 ;o 20 % by weight, based on the total weight of the composition, of at least one emulsifier, frcm 10 to 90 % by weight, especially from 30 to 90 % by weight, based on the total weight of :ne composition, of water, and from 0 to 88.9 % by weight, especially from 1 to 50 % by weight, of further cosmetically acceptable adju¬vants. The cosmetic or pharmaceutical compositions/preparations according to the invention may also comprise one or one more additional compounds as described below, for example fatty alcohols, esters of fatty acids, natural or synthetic trigiycerides, including glyceryl esters and derivatives Pearlescent waxes, Hydrocarbon oils, silicones or siloxanes (organo-substituted polysiloxanes), fluorinated or perfluorinated oils,emulsifiers, adjuvants and additives, uperfatting agents, surfactants, consistency regulators/thickeners and rheology modifiers, polymers, anti-dandruff agents, film formers, antioxidants, hydrotropic agents, preservatives and bacteria-inhibiting agents, perfume oils, colorants, or polymeric beads or hollow spheres as SPF enhancers Cosmetic or pharmaceutical preparations Cosmetic or pharmaceutical formulations are contained in a wide variety of cosmetic preparations. There come into consideration, for example, especially the following preparations: skin-care preparations, e.g. skin-washing and cleansing-preparations in the form of tablet-form or liquid soaps, soapless detergents or washing pastes; bath preparations, e.g. liquid (foam baths, milks, shower preparations) or solid bath preparations, e.g. bath cubes and bath salts; skin-care preparations, e.g. skin emulsions, multi-emulsions or skin oils; cosmetic personal care preparations, e.g. facial make-up in the form of day creams or powder creams, face powder (loose or pressed), rouge or cream make-up, eye-care preparations, e.g. eyeshadow preparations, mascara, eyeliner, eye creams or eye-fix creams; lip-care preparations, e.g. lipsticks, lip gloss, lip contour pencils, nail-care preparations, such as nail varnish, nail varnish removers, nail hardeners or cuticle removers; foot-care preparations, e.g. foot baths, foot powders, foot creams or foot balsams, Special deodorants and antiperspirants or callus-removing preparations; light-protective preparations, such as sun milks, lotions, creams or oils, sunblocks or tropicals, pre-tanning preparations or after-sun preparations; skin-tanning preparations, e.g. self-tanning creams; depigmenting preparations, e.g. preparations for bleaching the skin or skin-lightening preparations; insect-repellents, e.g. insect-repellent oils, lotions, sprays or sticks; deodorants, such as deodorant sprays, pump-action sprays, deodorant gels, sticks or roll-ons; antiperspirants, e.g. antiperspirant sticks, creams or roll-ons; preparations for cleansing and caring for blemished skin, e.g. synthetic detergents (solid or liquid), peeling or scrub preparations or peeling masks; hair-removal preparations in chemical form (depilation), e.g. hair-removing powders, liquid hair-removing preparations, cream-or paste-form hair-removing preparations, hair-removing preparations in gei form or aerosol foams; shaving preparations, e.g. shaving soap, foaming shaving creams, non-foaming shaving creams, foams and gels, preshave preparations for dry shaving, aftershaves or aftershave lotions; fragrance preparations, e.g. fragrances (eau de Cologne, eau de toilette, eau de parfum, parfum de toilette, perfume), perfume oils or perfume creams; cosmetic hair-treatment preparations, e.g. hair-washing preparations in the form of shampoos and conditioners, hair-care preparations, e.g. pretreatment preparations, hair tonics, styling creams, styling gels, pomades, hair rinses, treatment packs, intensive hair treatments, hair-structuring preparations, e.g. hair-waving preparations for permanent waves (hot wave, mild wave, cold wave), hair-straightening preparations, liquid hair-setting preparations, hair foams, hairsprays, bleaching preparations, e.g. hydrogen peroxide solutions, lightening shampoos, bleaching creams, bleaching powders, bleaching pastes or oils, temporary, semi-permanent or permanent hair colourants, preparations containing self-oxidising dyes, or natural hair colourants, such as henna or camomile. Presentation forms The final formulations listed may exist in a wide variety of presentation forms, for example: in the form of liquid preparations as a W/O, O/W, O/W/O, W/O/W or PIT emulsion and all kinds of microemuisions, in the form of a gel, in the form of an oil, a cream, milk or lotion, in the form of a powder, a lacquer, a tablet or make-up, in the form of a stick, in the form of a spray (spray with propeilent gas or pump-action spray) or an aerosol, in the form of a foam, or in the form of a paste. Of special importance as cosmetic preparations for the skin are light-protective preparations, such as sun milks, lotions, creams, oils, sur.olocks or tropicals, pretanning preparations or after-sun preparations, also skin-tanning preoarations, for example self-tanning creams. Of special interest are sun protection creams, sun protection lotions, sun protection milk and sun protection preparations in the form of a spray. Of special importance as cosmetic preparations for the hair are the above-mentioned prepa¬rations for hair treatment, especially hair-washing preparations in the form of shampoos, hair conditioners, hair-care preparations, e.g. pretreatment preparations, hair tonics, styling creams, styling gels, pomades, hair rinses, treatment packs, intensive hair treatments, hair-straightening preparations, liquid hair-setting preparations, hair foams and hairsprays. Of special interest are hair-washing preparations in the form of shampoos. A shampoo has, for example, the following composition: from 0.01 to 5 % by weight of a UV absorber according to the invention, 12.0 % by weight of sodium laureth-2-sulfate, 4.0 % by weight of cocamidopropyl betaine, 3.0 % by weight of sodium chloride, and water ad 100%. For example, especially the following hair-cosmetic formulations may be used: ai) spontaneously emulsifying stock formulation, consisting of the UV absorber according to the invention, PEG-6-CioOxoalcohoi and sorbitan sesquioleate, to which water and any desired quaternary ammonium compound, for example 4 % minkamidopropyl dimethyl-2-hydroxyethylammonium chloride or Quaternium 80, is added; a2) spontaneously emulsifying stock formulation consisting of the UV absorber according to the invention, tributyl citrate and PEG-20-sovbitan monooleate, to which water and any desired quaternary ammonium compound, for example 4 % minkamidopropyl dimethyl-2-hydroxyethylammonium chloride or Quaternium 80, is added; b) quat-doped solutions of the UV absorber according to the invention in butyl triglycol and tributyl citrate; c) mixtures or solutions of the UV absorber according to the invention with n-aikylpyrrolidone. Other typical ingredients in such formulations are preservatives, bactericides and bacterio¬static agents, perfumes, dyes, pigments, thickening agents, moisturising agents, humectants, fats, oils, waxes or other typical ingredients of cosmetic and personal care formulations such as alcohols, poly-alcohols, polymers, electrolytes, organic solvents, silicon derivatives, emollients, emulsifiers or emulsifying surfactants, surfactants, dispersing agents, antioxidants, anti-irritants and anti-inflammatory agents etc.. are suspended in a reaction vessel at room temperature under stirring in 400 g acetic acid ethyl ester. A solution of 44.4 g dicyclohexylcarbodiimid, dissolved in 200 g acetic acid ethyl ester is mixed in this suspension. The temperature rises up to about 30°C. The suspension is stirred vigorously at room temperature during about 10 hours and filtered afterwards. After 7.2 g of 2-(4-aminophenyl)-6-methyl-benzothiazol are suspended in 60 ml diethylenglycoi-dimethylether at room temperature. A solution of 10.6g of the compound of formula (101), dissolved in 20 ml diethylenglycol-dimethylether, are added under stirring and the reaction mass is heated up 90°C. After a reaction time of 4 hours the reaction mass is cooled down to room temperature and the raw product is filtered off. The pure compound is obtained by extraction of the raw product with ethanol. 6 g of the compound of formula (101) are dissolved in 40 ml Dioxan. 2.5 g 4-aminobenz-amide are added to this solution while stirring. After a reaction time of 2 hours at 85°C dioxan is removed under vacuum and the residue is worked up by recrystallization from 2-methoxy-ethanol to the pure product. 9.2 g of the compound of formula (101), 14.4g of the racemic mixture of menthol, 18 ml of diethyiengiycol-dimethylether, 0.1g of 1.8-diazabicycIo(5.4.0)-undec-7-ene(1,5,5) are stirred at 100°C during 2 hours. Then the solvent is resolved in vacuum and the residue separated with column chromatographic methods (Kieselgel 60/Toluene-acetic acid ester 8:2 ). Yield: 12.8g of a glassy non-crystalline mass Analyses: C/H/N = 74.5%/8.4%/3.04% corresponding to the theory. 6 g of the compound of formula (101) are dissolved in 30 ml dioxan at room temperature. 1.16 g 1.6-diaminohexane, dissolved in 20 ml dioxan are added to this solution under stirring. Stirring of the reaction masse at room temperature is continued during 12 hours, then dioxan is removed in the vacuum and the raw product is recrystallized after extraction with water from methanol. Yield: 4.2 g , yellow crystals Fp: 160°C Elemental analysis corresponds to the theoretical values. 9 g of the compound of formula (101) and 8.4g aniline are dissolved in 18 ml diethylenglycol-dimethylether. The reaction is warmed up to 70°C and stirred at this temperature for 3 hours. After evaporation of the reaction mass in vacuum the pure product is obtained after recrystallization from methanol. 9 g of the compound of formula (101), 9.5 g diethanolamine, dissolved in 30 ml diehylengly-col-dimethylether are stirred at 85°C during 3 hours. The reaction mass is narrowed in vacuum (0.03 mB/70°C). The residue is extracted with ca. 250 ml water at 70°C. The pure compound recrystallizes from the aqueous phase after cooling down. Analogous to example 11 17.3g 2,2-Dimethyl-1,3-propandiol instead of 2-buten-1,4-diol are reacted with the anhydrous form of the BB-acid. The working up of the raw product can be carried out according to the methods as described above. The obtained compound is an amorphous, yellow powder Solubility in Finsolve TN > 30% UV Spectrum in Ethanol: Max. 354 nm , mol. Ext. 65296 Examples 13 to 23: Preparation of further hvdroxyphenyl benzophenone derivatives According to the method as described in Example 11 the follwing compounds can be prepared: What is claimed is: R1 and R2 independently from each other are; C1-C2oaIkyl; C2-C2oalkenyl; C3-C10cycloalkyl; C3-C10cycloalkenyl; or R, and R2 together with the linking nitogen atom form a 5- or 6- membered heterocyclic ring; n, is a number from 1 to 4; when n1 = 1, n, is a number from 1 to 4; wenn n, is 1, R3 is a saturated or unsaturated heterocyclic radical; hydroxy-C1-C5aikyl; Cydohexyl substituted with one or more C1-C5alkyl; wenn n1is 2, R3 is an alkylen-, cycloalkylen- or aikenylene radical which is optionally interrupted by a carbonyl- or carboxy group; wenn n, is3, R3 is an alkantriyl radical; wenn n1 is 4, R3 is an alkantetrayl radical; A is -0-; or -N(R5)-; and R5 is hydrogen; C1-C5alkyl; or hydroxy-C1-C5alkyl. 3. Compound according to claim 1 or 2, wherein RT and R2 are Ci^alkyl. 4. Compound according to one of claims 1 to 3, wherein R1 and R2 independently from each other are C1-C5alkyl. 5. Compound according to one of claims 1 to 4, wherein R, and R2 in formula (1) have the same definition 6. Compound according to one of claims 1 to 5, wherein if n1 is 1, R3 is a saturated or unsaturated heterocyclic radical. 7. Compound according to one of claims 1 to 5, wherein if nt is 1. R3 is a saturated heterocyclic radical. 8. Compound according to claim 7, wherein R3 is a monocyclic radical of 5, 6 or 7 ring members with one or more hetero atoms. 9. Compound according to claim 8, wherein R3 is morpholinyi; piperazinyl; piperidyl; pyrazolidinyl; imadazolidinyi; or pyrrolidinyl 10. Compound according to claim 6, wherein R3 is an unsaturated heterocyclic radical. 11. Compound according to claim 10, wherein R3 a polycyclic radical. 24. Use of compounds of formula (1) in protecting human and animal hair and skin from UV radiation. 25. Use according to claim 24, wherein the compounds of formula (1) are present in micronized form. 26. A cosmetic preparation comprising at least one or more compounds of formula (1) according to claim 1 with cosmetically acceptable carriers or adjuvants.

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