EP1259219A2

EP1259219A2 - Topical cosmetic agents containing 2-hydrazino-1,3-heteroazoles

Info

Publication number: EP1259219A2
Application number: EP01916990A
Authority: EP
Inventors: Jakob Peter Ley; William Johncock; Roland Langner
Original assignee: Haarmann and Reimer GmbH
Current assignee: Haarmann and Reimer GmbH
Priority date: 2000-02-25
Filing date: 2001-02-13
Publication date: 2002-11-27
Also published as: KR20030005208A; CN1406122A; DE10008907A1; WO2001062208A3; US20030072725A1; WO2001062208A2; AU2001244137A1; JP2003523979A

Abstract

The inventive 2-hydrazino-1,3-heteroazoles or salts thereof are, as very good tyrosinase inhibitors, active constituents in topical cosmetic agents, especially in cosmetic or dermatological skin brightening agents.

Description

Topical cosmetic compositions containing 2-hydrazino-1,3-heteroazoles

The invention relates to topical cosmetic agents, in particular cosmetic or dermatological skin lightening agents, containing 2-hydrazino-1,3-heteroazoles, for cosmetic or dermatological applications.

Skin-lightening agents usually interfere with melanin metabolism or catabolism. The usually brown to black colored melanins are formed in the melanocytes of the skin, transferred to the keratinocytes and cause the coloring of the skin or hair. In mammals, the brown-black eumelanins are mainly formed from hydroxy-substituted aromatic amino acids such as L-tyrosine and L-DOPA, and the yellow to red phaeomelanins are additionally formed from sulfur-containing molecules (Cosmetics & Toiletries 1996, 111 (5), 43-51). Starting from L-tyrosine, the copper-containing key enzyme tyrosinase L-3,4-dihydroxyphenylalanine (L-DOPA) is formed, which in turn is oxidized to melanin by the tyrosinase via the red-brown colored dopaquinone. A comparison of tyrosinases from plants, fungi and mammalian cells shows that the mechanism and substrate specificity are comparable for all examined tyrosinases.

If for some reason the melanin-producing melanocytes in the human skin are not evenly distributed, pigment spots occur which are either lighter or darker than the surrounding areas of the skin. In order to remedy this problem, skin lightening agents are available on the market which help to at least partially compensate for such pigment spots. There is also a need for many people to lighten their naturally dark skin tone. This requires very safe and effective skin whitening agents. Many skin lightening agents contain more or less strong tyrosinase inhibitors. In commercial skin lightening agents in particular hydroquinone, hydroquinone derivatives such as arbutin, vitamin C, derivatives of ascorbic acid such as ascorbyl palmitate, kojic acid and derivatives of kojic acid such as kojic acid di-palmitate are used (Cosmetics & Toiletries 1996, 777 (5), 43-51) ,

One of the most common skin lighteners is hydroquinone. However, the substance has a cytotoxic effect against melanocytes and can damage the skin. Therefore such preparations are e.g. no longer permitted for cosmetic applications in Japan and South Africa. In addition, hydroquinone is very sensitive to oxidation and is difficult to stabilize in cosmetic formulations.

Vitamin C and ascorbic acid derivatives only have an insufficient effect on the skin. In addition, they do not act directly as tyrosinase inhibitors, but instead reduce the colored intermediate stages of melanin biosynthesis.

Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyranone) is a tyrosinase inhibitor which inhibits its catalytic action by chelating the copper atoms of the enzyme; it is used in commercial skin lightening agents. The substance is mainly formed in Aspergillus cultures and can be isolated from it in small quantities. In addition, kojic acid is not stable in aqueous solution and is therefore not suitable for most cosmetic products (Cosmetics & Toiletries 1999, 9, p. 27).

The object of the present invention was to find topical cosmetic agents, in particular cosmetic or dermatological skin lightening agents, which contain inexpensive, easy-to-prepare, highly effective tyrosinase inhibitors.

The invention therefore relates to topical cosmetic compositions containing 2-hydrazino-1,3-heteroazoles of the general formula

or their salts,

in which

Z represents a sulfur or an oxygen atom or -NH,

and

X represents a nitrogen atom or a carbon atom CQ ² substituted by Q,

and

either

Q ¹ and Q ² independently of one another are hydrogen atoms, optionally hydroxyl- or alkyloxy-substituted unbranched, branched or cyclic alkyl, alkenyl, 1-oxoalkyl or 1-oxoalkenyl groups with 1 to 18 carbon atoms, optionally substituted aryl groups with 6 to 15 carbon atoms, optionally substituted heterocyclyl groups with 2 to 15 carbon atoms and at least one heteroatom selected from the group consisting of oxygen, nitrogen or sulfur, optionally substituted arylalkyl or aryl-1-oxoalkyl groups of 7 to 16 carbon atoms, halogen atoms, nitro groups or Represent groups -COOR ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SO ₂ OR ⁵ , -SO ₂ NR ⁵ R ⁶ or -PO (OR ⁵ ) (OR ⁶ ),

or

Q ¹ and Q ² together represent a radical of the general formula (II) represent

in which

, XJ-2 _ and _ndJ X _V 3 independently of one another represent either nitrogen atoms or carbon atoms with the radicals R, R or R, and

R, R, R and R independently of one another are hydrogen atoms, optionally hydroxyl- or alkyloxy-substituted unbranched, branched or cyclic alkyl, alkenyl, 1-oxoalkyl or 1-oxoalkenyl groups with 1 to 18 carbon atoms, optionally substituted aryl groups with 6 to 15 carbon atoms, optionally substituted heterocyclyl groups with 2 to 15 carbon atoms and at least one heteroatom selected from the group consisting of oxygen, nitrogen or sulfur, optionally substituted arylalkyl or aryl-1-oxoalkyl groups of 7 to 16 carbon atoms, halogen atoms, nitro groups or

Represent groups -COOR ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SO ₂ OR ⁵ , -SO ₂ NR ⁵ R ⁶ or -PO (OR ⁵ ) (OR ⁶ ) and

R ⁵ and R ⁶ independently of one another hydrogen atoms, optionally hydroxyl- or alkyloxy-substituted unbranched, branched or cyclic alkyl, alkenyl, 1-oxoalkyl or 1-oxoalkenyl groups with 1 to 18 carbon atoms, optionally substituted aryl groups with 6 to 15 carbon atoms , optionally substituted arylalkyl or aryl-1-oxoalkyl groups of 7 to 16 carbon atoms.

The 2-hydrazino-1,3-heteroazoles according to the invention can also be in the form of their

Tautomers are present.

An unbranched, branched or cyclic alkyl group can contain 1 to 18, preferably 1 to 8, particularly preferably 1 to 6 carbon atoms. Examples include: methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert-butyl, 2-

Methyl, 2-methylprop-l-yl, cyclopropyl, cyclopropylmethyl, 2,2-dimethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and various positional isomers of methylpentyl.

An unbranched, branched or cyclic alkenyl group can contain 2 to 18, preferably 2 to 8, particularly preferably 2 to 6 carbon atoms. Examples include: ethenyl, 1- or 2-propenyl, 1-, 2- or 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl , 1, 4-pentenyl, 2,4-pentenyl, the various different straight-chain, cyclic or branched isomers of the pentenyl, hexenyl radical. Ethenyl, 1- or are particularly preferred

2-propenyl, 1-, 2- or 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-1-pentenyl, 3-methyl-2-pentenyl, 3-methyl- 3-pentenyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl and cyclohexenyl.

An unbranched, branched or cyclic 1-oxo-alkyl group can contain 1 to 18, preferably 1 to 8, particularly preferably 1 to 5 carbon atoms. examples Examples include: formyl, acetyl, propionyl, 2-methylpropionyl, butanoyl, 2-methylbutanoyl, 3-methylbutanoyl, 2,2-dimethylpropionyl, cyclopropylcarboxyl.

An unbranched, branched or cyclic 1 -oxo-alkenyl group can contain 3 to 18, preferably 3 to 8, particularly preferably 3 to 5 carbon atoms. Examples include: prop-2-enoyl, 2-methylprop-2-enoyl, 2-ethyl-prop-2-enoyl, E- or Z- 2-butenoyl, 3-butenoyl, E- or Z- 2-methylbut- 2-enoyl, E- or Z- 3-methylbut-2-enoyl, Z- or E- 2-pentenoyl, Z- or E- 3-pentenoyl.

Aryl groups with 6 to 15 carbon atoms, preferably 6 to 10 carbon atoms, can be, for example: phenyl and naphthyl.

A heterocyclyl group with 2 to 15 carbon atoms and at least one atom from the group consisting of oxygen, sulfur or nitrogen in the ring generally consists of 1 to 3, preferably 1 or 2 five or six-membered rings. The

Heterocyclyl group preferably contains 1 to 4, particularly preferably 1 or 2 heteroatoms. Furan, pyrrole, thiophene, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, pyrazole, imidazole, 1,3- or 1,2-oxazole, 1,3- or 1,2-thiazole, 1,3 are preferred - or 1,2-benzimidazole, 1,3- or 1,2-benzoxazole, 1,3- or 1,2-benzothiazole, pyridine, pyrimidine, pyrazine, 1,2-, 1,3- or 1,4- oxazine,

1,2-, 1,3- or 1,4-thiazine, quinoline, isoquinoline, benzo-1,2-, -1,3- or -1,4-diazine or their partially or fully saturated derivatives, e.g. Tetrahydro furan, 1,3-dioxolane, pyrrolidine, pyrroline, 1,3- or 1,4-dioxane, piperidine, tetrahydro-2H-pyran, piperazine, oxirane or aziridine. Furan, pyrrole, indole, imidazole, 1,3-thiazole, 1,3-benzothiazole, pyridine, pyrimidine, quinoline are particularly preferred.

Isoquinoline or its partially or completely saturated derivatives, for example tetrahydrofuran, 1,3-dioxolane, pyrrolidine, 1,3- or 1,4-dioxane, piperidine or tetrahydro-2H-pyran. An arylalkyl group can consist of 6 to 15 carbon atoms, preferably 7 to 8 carbon atoms and can be, for example: benzyl, 2- or 1-phenylethyl.

An aryl-1-oxo-alkyl group can consist of 6 to 15 carbon atoms, preferably 7 to 8 carbon atoms and can be, for example: benzoyl, phenylacetyl.

Substituents of the aryl, arylalkyl, aryl-1-oxoalkyl and heterocyclyl groups can be, for example: hydrogen atoms, alkyl, hydroxy, alkyloxy, thio, alkylthio, amino, alkylamino, dialkylamino, Nitro, iodine, bromine, fluorine, chlorine, azido, thiocyanato, isothiocyanato, cyanato, isocyanato, nitrile, isonitrile, phosphate, alkyl phosphate, dialkyl phosphate, sulfonic acid, alkyl sulfonate , Sulfonamide, dialkylsulfonamide or alkylsulfonamide residues. Particularly preferred are hydrogen atoms, alkyl, hydroxy, alkyloxy, amino, dialkylamino, bromine,

Fluorine, chlorine, nitrile, sulfonic acid, sulfonamide or alkyl sulfonate residues.

The 2-hydrazino-1,3-benzoheteroazoles according to the invention are preferably used as cosmetic or dermatological skin lightening agents.

Topical cosmetic compositions containing 2-hydrazino-1,3-benzo-heteroazoles of the general formula (I) are preferred

or their salts,

in which represents a sulfur or oxygen atom or -NH,

and

X represents a nitrogen atom or a carbon atom CQ ² substituted by Q ² ,

and

either

Q ¹ and Q ² independently of one another are hydrogen atoms, methyl, trifluoromethyl, ethyl, tert-butyl, allyl, 3-methylbut-2-en-1-yl or acetyl groups, chlorine or fluorine atoms, nitro groups, groups -COOR ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SO ₂ OR ⁵ , -SO ₂ NR ⁵ R ⁶ , -PO (OR ⁵ ) (OR ⁶ ), or on the aromatic optionally with alkyl, hydroxy, Alkyloxy, amino, dialkylamino, bromine, fluorine, chlorine, nitrile, sulfonic acid, sulfonamide or alkylsulfonate radicals represent substituted phenyl, pyridyl, pyrazinyl groups, phenylmethyl or benzoyl groups,

or

Q ¹ and Q ² together represent a radical of the general formula (II)

represent in which

X ¹ , X ² and X ^{3 represent} carbon atoms with the radicals R ¹ , R ² and R ³ ,

and

R, R, R and R independently of one another hydrogen atoms, methyl, trifluoromethyl, ethyl, tert-butyl, allyl, 3-methylbut-2-en-1-yl or acetyl groups, phenyl, pyridyl -, Pyrazinyl groups, phenylmethyl, 4-methylphenylmethyl, 4-methoxyphenylmethyl or benzoyl groups, chlorine or

Represent fluorine atoms, nitro groups, groups -COOR ⁵ , -OR ⁵ , -NR R ⁶ , -SO ₂ OR ⁵ , -SO ₂ NR ⁵ R ⁶ or -PO (OR ⁵ ) (OR ⁶ )

and

R ⁵ and R ⁶ independently of one another are hydrogen atoms, methyl, trifluoromethyl,

Ethyl, tert-butyl, allyl, 3-methylbut-2-en-1-yl, acetyl, propionyl or

Pivaloyl groups, phenyl, pyridyl, pyrazinyl groups, phenylmethyl, 4-

Represent methylphenylmethyl, 4-methoxyphenylmethyl or benzoyl groups.

Particular preference is given to topical cosmetic agents which contain 2-hydrazino-1,3-benzothiazole 5,6-dimethoxy-2-hydrazino-1,3-benzothiazole 6-methoxy-2-hydrazino-1,3-benzothiazole 2-hydrazino as the active ingredient 1,3-benzothiazole-5-sulfonic acid 2-hydrazino-1,3-benzothiazole-6-sulfonic acid 6-tert-butyl-2-hydrazino-1,3-benzothiazole 6-methyl-2-hydrazino-1, 3-benzothiazole 2-hydrazino-thiazolo- [5,4-b] pyridine 2-hydrazino-1,3-benzoxazole 2-hydrazino-1 H-benzimidazole 2-hydrazino-5- (4-fluorohenyl) -1,3,4-thiadiazole 2-hydrazino-4-phenyl-1,3-thiazole 2-hydrazino-4-methyl-l , 3-thiazole hydrochloride

contain.

The partially known 2-hydrazino-1,3-thiazoles can, for example, according to the Int. In Organic Preparations and Procedures. 1974, 6 (4), 179-182

Process can be prepared from the 2-amino-1,3-thiazoles. The latter can be prepared, for example, from the corresponding anilines or heterocyclic amines by reaction with inorganic thiocyanate salts and subsequent oxidative ring closure of the N-arylthiourea (J. Indian Chem. Soc. 1989, 66, 39-41). The 2-hydrazino-1,3-oxazoles according to the invention can e.g. after the in J. Amer. Chem. Soc. 1953, 75, 712 described methods. A production process for the 2-hydrazino-1,3-imidazoles according to the invention has been described, for example, in DE 614,327.

The 2-hydrazino-1,3-benzothiazoles according to the invention can be prepared, for example, starting from an optionally substituted aniline by reaction with potassium, sodium or ammonium thiocyanate, then oxidative ring closure mediated by chlorine, bromine or iodine and finally by reaction with hydrazine or hydrazine hydrate.

The preparation can be explained using the exemplary example 2-hydrazino-6-tert-butyl-1,3-benzothiazole by the following formula:

Surprisingly, it has now been found that the 2-hydrazino-1,3-heteroazoles contained in the topical cosmetic compositions according to the invention are particularly strong inhibitors of tyrosinase. In particular, many of the 2-hydrazino-1,3-heteroazoles according to the invention are either comparable or better effective than kojic acid. The substituted and benzo-fused 2-hydrazino-l, 3-thiazoles or the substituted 2-hydrazino-l, 3,4-thiadiazoles are particularly suitable. Therefore, they can be used as active ingredients in cosmetic or dermatological skin lightening agents.

The topical cosmetic agents according to the invention, in particular the cosmetic or dermatological skin lightening agents containing the 2-hydrazino-1,3-heteroazoles, are produced by conventional methods known per se, in such a way that one or more of the 2-hydrazino-l agents according to the invention , 3-heteroazoles of the general formula I or their salts are incorporated into cosmetic or dermatological formulations which are composed as usual and, in addition to the skin-lightening effect, also for the treatment, protection, care and cleaning of the skin or hair and as make-up products can serve the decorative cosmetics.

The topical cosmetic compositions according to the invention contain 2-hydrazino-1,3-heteroazoles in an effective amount and optionally other constituents. They contain 0.001% by weight to 30% by weight, preferably 0.001 to 20% by weight, but in particular 0.001% by weight to 5% by weight, based on the total weight of the Formulation, on the 2-hydrazino-1,3-heteroazoles and can be used as "water in oil", "oil in water", "water in oil in water" or "oil in water in oil" emulsions, as microemulsions, as gels, as solutions, for example in oils, alcohols or silicone oils, as sticks, as aerosols, sprays or foams. Other conventional cosmetic auxiliaries and additives can be used in amounts of 5 to

99.999% by weight, preferably 10 to 80% by weight, based on the total weight of the formulation, may be present. Furthermore, the formulations can contain water in an amount of up to 99.999% by weight, preferably 5 to 80% by weight, based on the total weight of the formulation.

In a further embodiment, the 2-hydrazino-1,3-heteroazoles of the general formula I can also be prepared beforehand in liposomes, for example for the preparation of the topical cosmetic agents according to the invention, in particular the cosmetic and dermatological skin lightening agents. starting from phosphatidylcholine, in microspheres, in nanospheres or also in capsules from a suitable matrix, e.g. from natural or synthetic waxes, for example beeswax, carnauba wax, silicone wax or stearyl alcohol, eicosanol, cetyl alcohol, stearin or paraffin wax or from gelatin.

The topical cosmetic agents according to the invention, in particular the cosmetic and dermatological skin lightening agents, can contain cosmetic auxiliaries and additives, as are usually used in such preparations, e.g. Sunscreens (e.g. organic or inorganic light filter substances, preferably micropigments), preservatives, bactericides, fungicides, virucides, cooling agents, plant extracts, anti-inflammatory agents

Substances that accelerate wound healing (e.g. chitin or chitosan and its derivatives), film-forming substances (e.g. polyvinylpyrrolidones or chitosan or its derivatives), common antioxidants, vitamins (e.g. vitamin C and derivatives, tocopherols and derivatives, vitamin A and derivatives), 2-hydroxycarboxylic acids ( citric acid, malic acid, L-, D-, or dl-lactic acid), perfumes, substances to prevent foaming, dyes, pigments, which have a coloring effect have thickeners, surface-active substances, emulsifiers, softening, moisturizing and / or moisturizing substances (e.g. glycerol or urea), fats, oils, unsaturated fatty acids or their derivatives (e.g. linoleic acid, α-linolenic acid, γ-linolenic acid or arachidonic acid and their respective natural - Chen or synthetic esters), waxes or other usual components of a cosmetic or dermatological formulation such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents, silicone derivatives or chelating agents (eg ethylenediaminetetraacetic acid and derivatives).

The amounts of cosmetic or dermatological auxiliaries and additives and perfume to be used in each case can easily be determined by a person skilled in the art by simply trying them out, depending on the nature of the respective product.

For use, the topical cosmetic agents according to the invention, in particular the cosmetic or dermatological skin lightening agents containing 2-hydrazino-1,3-heteroazoles of the general formula I, are applied to the skin and / or the hair in a sufficient amount in the manner customary for cosmetics.

The topical cosmetic compositions according to the invention, containing 2-hydrazino-1,3-heteroazoles of the general formula I or their salts, can preferably also contain other active ingredients for skin lightening. In particular, the topical cosmetic compositions according to the invention can also include benzaldoximes with at least one aromatic hydroxyl or alkoxy group, kojic acid,

Kojic acid derivatives, ascorbic acid, ascorbic acid derivatives, hydroquinone, hydroquinone derivatives, sulfur-containing molecules (for example glutathione or cysteine) or other synthetic or natural active ingredients for skin lightening, the latter also being in the form of an extract from plants (for example tocopherols and derivatives, arbutin (for example from Bearberry Extract), aloesin (e.g. from aloe extract), grapefruit

Extract and rice extract) can be used. The amount of the above-mentioned exemplary other active ingredients for skin lightening (one or more compounds) which are not identical to the 2-hydrazino-1,3-heteroazoles contained in the topical cosmetic compositions according to the invention can be 0.001 to 30% by weight in the skin lightening compositions according to the invention. %, preferably 0.001 to 20% by weight, particularly preferably 0.001 to 5% by weight, based on the total weight of the preparation.

Such topical cosmetic agents, in particular cosmetic and dermatological skin lightening agents, which are simultaneously in the form of a

Sunscreen available. In addition to an effective proportion of the 2-hydrazino-1,3-heteroazoles of the general formula I, these also contain sunscreen substances, preferably organic or inorganic light filter substances, in particular micropigments. However, the skin lightening agents according to the invention can also contain UVA and / or UVB filter substances, the total amount of

Filter substances can be 0.1 to 30 wt .-%, preferably 0.5 to 10 wt .-%, based on the total weight of the preparations, whereby sun protection agents for skin and hair are obtained. Examples of UV filter substances which can be used are 3-benzylidene camphor derivatives (e.g. 3- (4-methylbenzylidene) dl-camphor), aminobenzoic acid derivatives (e.g. 4- (N, N-dimethylamino) benzoic acid 2-ethylhexyl ester or

Menthyl anthranilate), 4-methoxycinnamate (e.g. 2-ethylhexyl p-methoxycinnamate or isoamyl p-methoxycinnamate), benzophenones (e.g. 2-hydroxy-4-methoxybenzophenone), single or multiple sulfonated UV filters [e.g. 2-phenylbenzimidazole-5-sulfonic acid, sulisobenzone or 1,4-bis (benzimidazolyl) benzene-4,4 ', 6,6'-tetra-sulfonic acid or 3,3' - (1,4-phenylenedimethylidene) -bis - (7,7-dimethyl-2-oxo-bicyclo-

[2,2, l] heptane-l-methanesulfonic acid) and their salts], salicylates (e.g. 2-ethylhexyl salicylate or homomenthyl salicylate), triazines {e.g. 2,4-bis- [4- (2-ethylhexyloxy) -2-hydroxyphenyl] -6- (4-methoxyphenyl) -l, 3,5-triazine, 4,4 '- ([6-

([(l, l-dimethylethyl) aminocarbonyl] phenylamino) -l, 3,5-triazine-2,4-diyl] diimino) bisbenzoic acid bis (2-ethylhexyl) ester)}, 2-cyanopropenoic acid derivatives (e.g. 2nd -

Ethylhexyl-2-cyano-3,3-diphenyl-2-propenoate), dibenzoyl derivatives (e.g. 4-tert- Butyl-4'-methoxydibenzoylmethane), polymer-bound UV filters (e.g. polymer of N- [2- (or. 4) - (2-oxo-3-bornylidene) methyl] benzylacrylamide) or pigments (e.g. titanium dioxide, zirconium dioxide, iron oxides, Silicas, manganese oxides, aluminum oxides, cerium oxides or zinc oxides) can be used.

In a further preferred embodiment of the invention, the topical cosmetic compositions containing 2-hydrazino-1,3-heteroazoles of the general formula I or their salts also contain antioxidants or radical scavengers. According to the invention, all the antioxidants suitable or customary for cosmetic and / or dermatological applications can be used as favorable antioxidants. The antioxidants are advantageously selected from the group consisting of amino acids (eg glycine, histidine, 3,4-dihydroxyphenylalanine, tyrosine, tryptophan) and their derivatives, imidazoles (eg urocanic acid) and their derivatives, peptides (D, L- Carnosine, D-carnosine, L-carnosine, anserine) and their derivatives, carotenoids, carotenes (e.g. ß-carotene, α-carotene,

Lycopene) and their derivatives, chlorogenic acid and their derivatives, lipoic acid and their derivatives, aurothioglucose, propylthiouracil and other thiols (eg thio redoxin, glutathione, cysteine, cystine, cystamine and their glycosyl and N-acyl derivatives or their alkyl esters) and their salts , dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof, and phenolic acid amides of phenolic benzylamines (eg Homovanillinsäure-, 3,4-di- hydroxyphenylessigsäure-, ferulasäure-, Sinapinsäure-, caffeic, dihydro- ferulasäure-, Dihydrokaffeesäure-, Vanillomandelsäure- or 3 , 4-dihydroxy-mandelic acid amides of 3,4-dihydroxybenzyl-, 2,3,4-trihydroxybenzyl- or 3,4,5-trihydroxybenzylamine), catecholoximes or catecholoxime ethers (e.g. 3,4-dihydroxybenzaldoxime or 3,4- Dihydroxybenzaldehyde-O-ethyloxime), also (metal) chelators (eg 2-hydroxy fatty acids, phytic acid, lactoferin), humic acid, bile acids, bile extracts, bilirubin, biliverdin, folic acid and the like nd their derivatives, ubiquinone and ubiquinol and their derivatives, vitamin C and its derivatives (e.g. ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherol and derivatives (e.g. vitamin E acetate), vitamin A and derivatives (e.g. vitamin A-palmitate), rutinic acid and its derivatives, flavonoids (e.g. quercetin, glucosylrutin) and their derivatives, phenolic acids (e.g. gallic acid, ferulic acid) and their derivatives (e.g. propyl gallic acid, ethyl ester, octyl ester), fur furylidene glucitol, butylated hydroxytoluene, butylated hydroxytoluene, butyl Uric acid and its derivatives, mannose and its derivatives, zinc and its derivatives (e.g. ZnO,

ZnSO), selenium and its derivatives (e.g. selenomethionine), stilbenes and their derivatives (e.g. stilbene oxide, resveratrol) and the derivatives of these active substances which are suitable according to the invention.

The amount of the aforementioned antioxidants (one or more compounds) in the topical cosmetic compositions according to the invention is preferably 0.001 to 30% by weight, particularly preferably 0.01 to 10% by weight, particularly preferably 0.01 to 5% by weight , based on the total weight of the preparations.

The lipid phase in the topical cosmetic compositions according to the invention, containing 2-hydrazino-1,3-heteroazoles of the general formula I or their salts, can advantageously be selected from the following groups of substances: mineral oils (advantageously paraffin oil), mineral waxes, hydrocarbons (advantageously squalane or squalene) , synthetic or semi-synthetic triglyceride oils (e.g. triglycerides of capric or caprylic acid), natural oils (e.g. castor oil, olive oil, sunflower oil, soybean oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil, borage seed oil and the like), natural ester oils (e.g. jojoba oil) ), synthetic ester oils (preferably esters of saturated and / or unsaturated, linear and / or branched alkane carboxylic acids of 3 to 30 C atoms with saturated and / or unsaturated, linear and / or branched alcohols with 3 to 30 C atoms and

Esters of aromatic carboxylic acids with saturated and / or unsaturated, linear and / or branched alcohols having 3 to 30 carbon atoms, especially selected from the group of isopropyl myristate, isopropyl stearate, isopropyl palmitate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n- Decyl laurate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyl decyl stearate, 2-octyl decyl palmitate, oleyl oleate, olerlerucate, erucyl oleate, erucyl erucate and synthetic or natural mixtures of such esters), fats, waxes and other natural and synthetic fat bodies, preferably esters of fatty alcohols with alcohols of low C number (e.g. with isopropanol, propylene glycol or glycerol) or esters of fatty alcohols with alkanoic acids of low C number or with fatty acids, alkyl benzoates (e.g. mixtures of n-dodecyl, n-tridecyl, n-

Tetradecyl and n-pentadecyl benzoate) as well as cyclic or linear silicone oils (such as dimethylpolysiloxanes, diethylpolysiloxanes, diphenylpolysiloxanes and mixed forms thereof).

The aqueous phase of the topical cosmetic compositions according to the invention, containing 2-hydrazino-1,3-heteroazoles of the general formula I or their salts, optionally advantageously contains alcohols, diols or polyols of low C number, and their ethers, preferably ethanol, isopropanol, propylene glycol , Glycerin, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl ether, monoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether and analogous products, furthermore low carbon number alcohols, for example ethanol, isopropanol, 1, 2 Propanediol, glycerol and in particular one or more thickeners, which one or which can advantageously be selected from the group consisting of silicon dioxide, aluminum silicates, polysaccharides or their derivatives, for example hyaluronic acid, xanthan gum, hydroxypropylmethyl cellulose, particularly advantageously from the group of polyacrylates, preferably a Polyacrylate from the group of the so-called Carbopole, jewei ls individually or in combination or from the group of polyurethanes.

Examples

Example 1: "Oil in water" emulsion

Part A was mixed and heated to 80 ° C. Part B was mixed and heated to 90 ° C and added to Part A with stirring. For part C, Carbopol was carefully dispersed in water and neutralized with sodium hydroxide solution (pH 6.9). Part C was then added to the mixture of parts A and B at 60 ° C. Part D was added to the mixture of parts A, B, and C at room temperature.

Example 2: "Water in Oil" sunscreen emulsion with UVA / B broadband protection

For part A, all substances except the zinc oxide were heated to 85 ° C. and the zinc oxide was carefully dispersed in the mixture. The components of Part B were mixed, heated to 85 ° C and added to Part A with stirring. Part C was added to the mixture of parts A and B and then the mixture was homogenized using a dispersing tool. Example 3: "Oil in water" sunscreen emulsion with UVA / B broadband protection

For Part A, all substances were mixed except for the titanium dioxide and heated to 85 ° C; the titanium dioxide was carefully dispersed into the mixture. For part B, all substances apart from Veegum and Natrosol were mixed, heated to 90 ° C., Natrosol and Veegum were dispersed in and the mixture was added to Part A with stirring. Part C was added to the mixture of parts A and B and then the mixture was homogenized using a dispersing tool.

Example 4: "Oil in water" sunscreen emulsion with UVA / B broadband protection

Part A was heated to 85 ° C. Carbopol and Keltrol were cold dispersed into the remaining constituents, the mixture was heated to 85 ° C. and added to part A. Part C was immediately added to the mixture of parts A and B at 80 ° C. and homogenized for 5 minutes using a dispersing tool. Part D was finally Lich added at room temperature and the mixture homogenized with a dispersing tool.

Comparative example

The tyrosinase inhibitory activity of the exemplary compounds was compared to that of kojic acid as follows:

The enzyme tyrosinase extracted from fungi was obtained from Sigma-Aldrich. The tyrosinase (2000 units / mg) was in phosphate buffer (pH 6.8,

0.067 mol / 1) to a concentration of 120 units / ml and 100 μl of this tyrosinase solution were placed in a cavity of a polystyrene microtiter plate. 25 μl of phosphate buffer (pH 6.8, 0.067 mol / 1) and 75 μl of gradually diluted exemplary compound or kojic acid were added. The resulting mixtures were incubated at 37 ° C for 10 min. to

Dilution of the test compounds, phosphate buffer (pH 6.8, 0.067 mol / 1) was used. Phosphate buffer (pH 6.8, 0.067 mol / 1) was used as a control.

100 μl of a 0.03% strength solution of the substrate L-DOPA in phosphate buffer (pH 6.8, 0.067 mol / 1) were added and the absorption (A) at 475 nm using a photometer after 3 min incubation at 37 ° C. measured. The residual activity of tyrosinase in the presence of Examples 1 to 11 or of kojic acid were calculated according to the following equation: residual activity of tyrosinase (%) = _(S Aτe tverbindun _g ontroiie A) x 100

From the remaining activities (%) of tyrosinase in a series of dilutions of the test compounds were HK o ₅ calculates for each test compound. This is the concentration of a test compound at which the tyrosinase is 50% inhibited. Table 1

Claims

claims

1. Topical cosmetic compositions containing 2-hydrazino-1,3-heteroazoles of the general formula

or their salts,

in which

represents a sulfur or an oxygen atom or -NH,

and

X represents a nitrogen atom or a carbon atom CQ ² substituted by Q,

and

either

1 ") •

Q and Q independently of one another are hydrogen atoms, optionally hydroxyl- or alkyloxy-substituted unbranched, branched or cyclic alkyl, alkenyl, 1-oxoalkyl or 1-oxoalkenyl groups with 1 to 18 carbon atoms, optionally substituted aryl groups with 6 to 15 carbon atoms, optionally substituted heterocyclyl groups with 2 to 15 carbon atoms and at least one heteroatom selected from the group consisting of oxygen, nitrogen or sulfur, optionally substituted arylalkyl or aryl-1-oxoalkyl groups of 7 to 16 carbon atoms,

Halogen atoms, nitro groups or

Represent groups -COOR ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SO ₂ OR ⁵ , -SO ₂ NR ⁵ R ⁶ or -PO (OR ⁵ ) (OR ⁶ ),

or

in which

X, X and X independently of one another either nitrogen atoms or

Represent carbon atoms with the radicals R ¹ , R ² or R ³ , and

R ¹ , R ² , R ³ and R ⁴ independently of one another are hydrogen atoms, optionally hydroxyl- or alkyloxy-substituted unbranched, branched or cyclic alkyl, alkenyl, 1-oxoalkyl or 1-oxoalkenyl groups having 1 to 18 carbon atoms, optionally substituted aryl groups 6 to 15 carbon atoms, optionally substituted heterocyclyl groups with 2 to 15 carbon atoms and at least one heteroatom selected from the group consisting of oxygen, nitrogen or sulfur, optionally substituted arylalkyl or aryl-1-oxoalkyl groups of 7 to 16 carbon atoms,

Halogen atoms, nitro groups or

Represent groups -COOR ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SO ₂ OR ⁵ , -SO ₂ NR ⁵ R ⁶ or -PO (OR ⁵ ) (OR ⁶ )

and

R ⁵ and R ^{6 are} independently hydrogen atoms, if appropriate

Hydroxy- or alkyloxy-substituted unbranched, branched or cyclic alkyl, alkenyl, 1-oxoalkyl or 1-oxoalkenyl groups with 1 to 18 carbon atoms, optionally substituted aryl groups with 6 to 15 carbon atoms, optionally substituted arylalkyl or aryl-1-oxoalkyl groups Represent 7 to 16 carbon atoms.

2. Topical cosmetic compositions containing 2-hydrazino-1,3-benzoheteroazoles of the general formula (I)

or their salts,

in which represents a sulfur or oxygen atom or -NH,

and

X is a nitrogen atom or a carbon atom substituted by Q ²

CQ ² represents

and

either

Q and Q independently of one another are hydrogen atoms, methyl,

Trifluoromethyl, ethyl, tert-butyl, allyl, 3-methylbut-2-en-1-yl or acetyl groups, chlorine or fluorine atoms, nitro groups, groups

-COOR ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SO ₂ OR ⁵ , -SO ₂ NR ⁵ R ⁶ , -PO (OR ⁵ ) (OR ⁶ ), or on the aromatic optionally with alkyl, hydroxy, Alkyloxy, amino, dialkylamino, bromine, fluorine, chlorine, nitrile, sulfonic acid, sulfonamide or alkylsulfonate radicals represent substituted phenyl, pyridyl, pyrazinyl groups, phenylmethyl or benzoyl groups,

or

Q -.1, and "ndj together a radical of the general formula (II)

represent in which

X Λ ¹ , X v2. u. "ndJ X v3 'r K / o.ιh.ιlens .t-.o" .f "f ^• a" + tome m: i, t dje ".n Rn l ¹ , τ R-.2 and R ^J represent

and

R ¹ , R ² , R ³ and R ⁴ independently of one another are hydrogen atoms, methyl,

Trifluoromethyl, ethyl, tert-butyl, allyl, 3-methylbut-2-en-l-yl or acetyl groups, phenyl, pyridyl, pyrazinyl groups, phenylmethyl, 4-methylphenylmethyl, 4-methoxyphenylmethyl or benzoyl groups, chlorine or fluorine atoms, nitro groups, groups -COOR ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SO ₂ OR ⁵ , -SO ₂ NR ⁵ R ⁶ or -PO (OR ⁵ ) (OR ⁶ )

and

R ⁵ and R ⁶ independently of one another are hydrogen atoms, methyl,

Trifluoromethyl, ethyl, tert-butyl, allyl, 3-methylbut-2-en-1-yl, acetyl, propionyl or pivaloyl groups, phenyl, pyridyl,

Pyrazinyl groups, phenylmethyl, 4-methylphenylmethyl, 4-methoxyphenylmethyl or benzoyl groups.

3. Topical cosmetic agents, in particular cosmetic or dermatological skin lightening agents according to claims 1 and 2, containing

2-hydrazino-1,3-benzothiazole

5,6-dimethoxy-2-hydrazino-l, 3-benzothiazol

6-methoxy-2-hydrazino-1,3-benzothiazole

2-hydrazino-l, 3-benzothiazole-5-sulfonic acid 2-hydrazino-1,3-benzothiazole-6-sulfonic acid

6-tert-butyl-2-hydrazino-1,3-benzothiazole 6-methyl-2-hydrazino-1,3-benzothiazole 2-hydrazino-thiazolo- [5,4-b] pyridine 2-hydrazino-1,3-benzoxazole 2-hydrazino-1 H-benzimidazole 2-hydrazino-5- (4-fluorophenyl) -l, 3,4-thiadiazol

2-hydrazino-4-phenyl-1,3-thiazole 2-hydrazino-4-methyl-1,3-thiazole hydrochloride.

4. Topical cosmetic compositions according to Claims 1 to 3, containing 0.001% by weight to 30% by weight, based on the total weight of the formulation, of the 2-hydrazino-1,3-heteroazoles.

5. Use of the 2-hydrazino-1,3-heteroazoles according to Claims 1 to 4 in cosmetic preparations.

6. Use of the 2-hydrazino-1,3-heteroazoles according to Claims 1 to 4 in dermatological preparations.

7. Use of the 2-hydrazino-1,3-heteroazoles according to Claims 1 to 4 in cosmetic or dermatological skin lightening agents.

8. Use of the 2-hydrazino-1,3-heteroazoles according to Claims 1 to 4 in sunscreens.

9. Use of the 2-hydrazino-1,3-heteroazoles according to Claims 1 to 4 in hair care products.

10. Use of the 2-hydrazino-1,3-heteroazoles according to Claims 1 to 4 in anti-skin aging products.

11. Use of the 2-hydrazino-1,3-heteroazoles according to Claims 1 to 4 in combination with other skin-lightening active ingredients or active ingredient mixtures in topical cosmetic compositions, in particular cosmetic or dermatological skin lightening compositions.

12. Use of the 2-hydrazino-1,3-heteroazoles according to Claims 1 to 4 in combination with antioxidative or radical-catching active ingredients or active ingredient mixtures in topical cosmetic compositions, in particular cosmetic or dermatological skin lightening compositions.