WO2014139741A1

WO2014139741A1 - Combinations of alkylamidothiazoles and cyclodextrins

Info

Publication number: WO2014139741A1
Application number: PCT/EP2014/052614
Authority: WO
Inventors: Cathrin Scherner; Michael WÖHRMANN; Ludger Kolbe
Original assignee: Beiersdorf Ag
Priority date: 2013-03-11
Filing date: 2014-02-11
Publication date: 2014-09-18
Also published as: EP2968104A1; CN105073092A; DE102013204110A1

Abstract

Active ingredient combinations of alkylamidothiazoles and one or more cyclodextrins.

Description

description

COMBINATIONS OF ALKYLAMIDOTHIAZOLS AND CYCLODEXTRINS

The present invention relates to active ingredient combinations of N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) isobutyramide and one or more cyclodextrins. Furthermore, the present invention relates to cosmetic or dermatological preparations containing such active ingredient combination and their use for whitening the human skin.

Responsible for the pigmentation of the skin are the melanocytes, which are found in the lowest layer of the epidermis, the stratum basale, in addition to the basal cells - depending on the skin type either isolated or more or less frequently occurring - pigment-forming cells.

Melanocytes contain as characteristic cell organelles melanosomes, in which the melanin is formed. Among other things, upon excitation by UV radiation melanin is increasingly formed. This is transported via the living layers of the epidermis (keratinocytes) ultimately in the horny layer (corneocytes) and causes a more or less pronounced brownish to brown-black skin color.

Melanin is formed as the final stage of an oxidative process in which tyrosine is converted with the participation of the enzyme tyrosinase via several intermediates to the brown to brown-black eumelanins (DHICA and DHI melanin) or with the participation of sulfur-containing compounds to the reddish phaeomelanin. DHICA and DHI melanin are produced via the common intermediates dopaquinone and dopachrome. The latter is reacted, sometimes involving other enzymes, either in indole-5,6-quinone carboxylic acid or in indole-5,6-quinone, resulting in the two mentioned eumelanins.

The formation of phaeomelanin occurs inter alia via the intermediates

Dopaquinone and cysteinyl dopa. The expression of the melanin-synthesizing enzymes is controlled by a specific transcription factor (microphthalmia-associated transcription factor, MITF). In addition to the described enzymatic processes of melanin synthesis, other proteins for the melanogenesis of melanosomes interpretation. An important role here seems to be the so-called p-protein, the exact function is still unclear.

In addition to the process of melanin synthesis in the melanocytes described above, the pigmentation of the skin, the transfer of the melanosomes, their retention in the epidermis and their degradation and degradation of melanin is of crucial importance. It has been shown that the transport of melanosomes from the melanocytes into the keratinocytes, the PAR-2 receptor is significant (Seiberg M. et al., 2000, J. Cell, Sci., 1 13: 3093-101).

Furthermore, the size and shape of the melanosomes influence their light-scattering properties and thus the color appearance of the skin. For example, in black Africans, large spheroidal, isolated melanosomes are increasingly found, whereas in Caucasians, smaller, grouped melanosomes are found.

Problems with hyperpigmentation of the skin have many causes or are accompanying effects of many biological processes, e.g. UV radiation (e.g., freckles, ephelides), genetic predisposition, skin malignancy in wound healing or scarring (post-inflammatory hyperpigmentation) or aging of the skin (e.g., lentigines seniles).

After inflammatory reactions, the pigmentation system of the skin reacts with partially opposite reactions. Both postinflammatory hyper- and hypopigmentation can occur. Postinflammatory Hypomelanosen occur u. a. often associated with atopy, lupus erythematosus and psoriasis. The different reaction forms of the pigmentation system of the human skin as a result of inflammatory phenomena are understood only very incompletely.

Problems with postinflammatory hyperpigmentation often occur in darker skin types. The problem of pseudofolliculitis barbae, which accompanies or leads to cosmetically undesirable pigmentation of the pigmentation, is known in particular in male colored individuals. Also, forms of melasma, which occur especially in women of Asian affiliation in the face and décolleté area, as well as various forms of irregular pigmentation of the skin become the postinflammatory

Counted hyperpigmentation. In addition, dark circles are also considered to be a form of postinflammatory hyperpigmentation, with the underlying inflammation usually subclinical. In many cases, such postinflammatory Fehlpigmentierung by the action of sunlight (UV light) is enhanced without causing a UV-induced inflammation (sunburn).

Active ingredients and preparations are known which counteract skin pigmentation. In practical use are essentially preparations based on hydroquinone, but on the one hand only after several weeks of application show their effect, the excessively long use on the other hand is of concern for toxicological reasons. By Albert Kligman et al. A so-called "Triformula" was developed, which is a combination of 0.1% tretinoin, 5.0% hydroquinone, 0.1% dexamethasone (A. Kligman, 1975, Arch. Dermatol., 1 1 1: 40-48). However, this formulation is also because of possible irreversible changes in the pigmentation system of the skin very controversial.

Skin peeling methods (chemical and mechanical "peelings") are also used, however, which often lead to inflammatory reactions and may even lead to greater instead of reduced pigmentation due to postinflammatory hyperpigmentation become, are characterized by crucial side effects.

Furthermore, various other substances are known for which a skin-lightening activity is described. Et al mention may be made here of hexadecene-1, 16-dicarboxylic acid, kojic acid and derivatives, arbutin, ascorbic acid and derivatives, flavonoids, ellagic acid and derivatives, tranexamic acid and various resorcinol derivatives, e.g. 4-n-butylresorcinol, 4-n-hexylresorcinol and 4- (1-phenylethyl) benzene-1, 3-diol.

J.M. Ready describes in a publication (Bioorganic & Medicinal Chemistry Letter 17 (2007) 6871-6875 the effect of, inter alia, substituted thiazole derivatives for the inhibition of Mushroom tyrosinase.

The patent application of Shiseido (WO 2009/099195) describes substituted thiazolamines or hydrothiazolamines for skin lightening.

The substances described in the above-mentioned prior art are characterized by a moderate effectiveness. Dark circles can also be the result of a pigmentation disorder, and they also appear as a reaction to generalized stress, such as lack of sleep or simply eye strain. In younger people, the symptoms disappear after a good night's sleep, but over longer periods, the condition can be chronic and very disturbing for the affected persons. Even against such skin symptoms, there is a lack of sufficient promising active ingredients and treatment options.

The aim of the following invention, therefore, was to remedy the disadvantageous state of the art.

Another object of the invention was to provide active substances, drug combinations or preparations containing such substances, with particularly good release of the active ingredient from the preparation.

This problem is solved by drug combinations of one or more

Alkylamidothiazoles and one or more cyclodextrins.

Advantageous embodiments of the present invention are also cosmetic or dermatological preparations containing such active ingredient combination and their use for lightening the human skin.

Cyclodextrins (cycloamyloses, cycloglucans) are known per se in cosmetic and pharmaceutical preparations. These substances are often used for "molecular encapsulation", ie as a protective coating of sensitive molecules, and are not encapsulations in the true sense (core / shell), but rather inclusion complexes with non-polar organic compounds Water solubility or stabilize the substance.

These are 6, 7, 8 or even more a-1, 4-linked glucose units, wherein the Cyclohexaamylose (α-cyclodextrin) by the structure

distinguished. The cycloheptaamylose (ß-cyclodextrin) is characterized by the structure

out. The Cyclooctaamylose (γ-cyclodextrin) is characterized by the structure

out.

Furthermore, polar and non-polar substituted cyclodextrins can be used in the context of this patent. These preferably but not exclusively include methyl, ethyl and hydroxypropyl cyclodextrin.

Advantageously, the preparations according to the invention contain 0.1 to 10.0% by weight of one or more cyclodextrins, preferably 0.5 to 5.0% by weight of one or more Cyclodextrins, more preferably 1, 0 - 3.0 wt% of one or more

Cyclodextrins.

Particularly advantageous are preparations or uses according to the invention, characterized in that the preparations 0.000001 to 10 wt .-%, in particular 0.0001 to 3 wt .-%, most preferably 0.001 to 1 wt .-% of one or more

Alkylamidothiazolen contain, based on the total weight of the preparation.

Advantageous alkylamidothiazoles in the context of the present invention are substances of the general formula

in which

R ¹ , R ² , X and Y may be different, partly the same or completely the same and may independently of one another mean:

Ri = -C ₁ -C ₂ 4-alkyl (linear and branched), -C ₁ -C ₂ 4-alkenyl (linear and branched), -C- | -C ₈ -cycloalkyl, -C- | -C ₈ - Cycloalkyl-alkylhydroxy, -C- | -C ₂ alkylhydroxy (linear and branched), -Cr C ₂ 4 alkylamine (linear and branched), -C "| -C ₂₄ -alkylaryl (linear and branched), -C- | -C ₂₄ -alkyl-aryl-alkyl-hydroxy (linear and branched), -Ci-C ₂₄ -alkyl heteroaryl (linear and branched), -d-C ₂₄ -alkyl-0-Ci-C ₂₄ alkyl (linear and branched ) -CrC ₂₄ Alky-Morpholino, -Ci-C ₂₄ Alky-Piperidino, -CrC ₂₄ Alky-Piperazino, -CrC ₂₄ Alky-piperazino-N-alkyl,

R ₂ = H, -Ci-C ₂₄ -alkyl (linear and branched), -Ci-C ₂₄ -alkenyl (linear and branched), -CrC ₈ - cycloalkyl, -Ci-C ₂₄ -hydroxyalkyl (linear and branched), -Ci-C ₂₄ -alkylaryl (linear and branched), -Ci-C ₂₄ -alkyl heteroaryl (linear and branched),

X = -H, -Ci-C ₂₄ -alkyl (linear and branched), -Ci-C ₂₄ -alkenyl (linear and branched), -CiC ₈ - cycloalkyl, -Ci-C ₂₄ -aryl (optionally mono- or polysubstituted substituted with -OH, -F, -Cl, -Br, -I, - OMe, -NH ₂ , -CN), -Ci-C ₂₄ -heteroaryl (optionally mono- or polysubstituted by -OH, -F, - Cl, -Br, -I, -OMe, -NH ₂ , -CN), -Ci-C ₂₄ -alkylaryl (linear and branched), -Ci-C ₂₄ -alkyl heteroaryl (linear and branched), -aryl ( optionally monosubstituted or polysubstituted by -OH, -F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN), -phenyl, -2,4-dihydroxyphenyl, -2,3-dihydroxyphenyl, -2,4-dimethoxyphenyl, -2,3-dimethoxyphenyl,

Y = H, -Ci-C ₂₄ -alkyl (linear and branched), -Ci-C ₂₄ -alkenyl (linear and branched), -CrC ₈ -cycloalkyl, -Ci-C ₂₄ -aryl, -Ci-C ₂₄ - heteroaryl, -C-C ₂₄ alkylaryl (linear and branched), -ci- C ₂₄ -alkyl (linear and branched), aryl, phenyl, 2,4-dihydroxyphenyl, -2,3-dihydroxyphenyl, -2 , 4-dimethoxyphenyl, -2,3-dimethoxyphenyl, -COO-alkyl, -COO-alkenyl, - COO-Cylcloalkyl, -COO-aryl, -COO-heteroaryl, and X, Y may optionally also = = condensed aromatic in which X and Y can form aromatic or aliphatic homo- or heterocyclic ring systems with up to n ring-forming atoms, and where the number n can assume values of 5 to 8, and the respective ring systems in turn contain up to n-1 alkyl groups, Hydroxyl groups, carboxyl groups, amino groups, nitrile functions, sulfur-containing substituents, ester groups and / or ether groups may be substituted.

The said thiazoles can be present both as free base and as salt: e.g. as fluoride, chloride, bromide, iodide, sulfate, carbonate, ascorbate, acetate or phosphate. In particular, as halogen salts, e.g. Chloride and bromide.

Furthermore, there is an advantageous realization of the present invention in cosmetic or dermatological preparations having an effective content of one or more above-mentioned alkylamidothiazoles.

The invention furthermore relates to the use of the abovementioned alkylamidothiazoles for the treatment and / or prophylaxis of undesired skin pigmentation.

In this case, treatment and / or prophylaxis of unwanted skin pigmentation can take place both in the cosmetic and in the pharmaceutical context.

In this case, the pharmaceutical (or dermatological) treatment is understood primarily in the case of diseased skin conditions, whereas the cosmetic treatment and / or prophylaxis of undesired skin pigmentation relates primarily to the healthy skin. Advantageously, X is selected from the group of substituted phenyls, where the substituents (Z) can be selected from the group -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN, acetyl and the same or different.

X is particularly preferably selected from the group of phenyl groups substituted by one or more hydroxyl groups, where the substituent (Z) can be selected from the group -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN, acetyl and the following generic structure is preferred in which Y, R ¹ and R ² may have the properties defined above.

Particularly advantageous are those compounds in which

Y = H

Ri = -Ci-C ₂ 4-alkyl (linear and branched), -Ci-C ₂ 4-alkenyl (linear and branched), -CrC ₈ - cycloalkyl, -C- | -C ₈ -cycloalkyl-alkylhydroxy, -C - | -C ₂₄ alkylhydroxy (linear and branched), -Cr C ₂₄ alkylamine (linear and branched), -C "| -C ₂₄ -alkylaryl (linear and branched), -C- | -C ₂₄ -alkyl-aryl- Alkyl-hydroxy (linear and branched),

(linear and branched), -C C ₂ 4-alkyl-0-C 1 -C 24 -alkyl (linear and branched), C 1 -C 24 alkyl-morpholino, C 1 -C 24 alkylpiperidino, C 1 -C 24 alkylpiperazino, C 1 -C 24 alkylpiperazino-N Alkyl means

R ₂ = H, -Ci-C ₂ 4-alkyl (linear and branched).

Z = -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN, acetyl.

Particularly preferred are those compounds in which

Y = H

R1 = -Ci-C ₂ 4-alkyl (linear and branched), -Ci-C ₂ 4-alkenyl (linear and branched), -CrC ₈ - cycloalkyl, -Ci-C ₈ -cycloalkyl-alkylhydroxy, -C1-C24 Alkylhydroxy (linear and branched), -d-C24 Alkylamine (linear and branched), -Ci-C ₂ 4-Alkylaryl (linear and branched), -Ci-C ₂ 4-Alkyl-aryl-alkyl-hydroxy (linear and branched ), -Ci-C ₂ 4-alkylheteroaryl (linear and branched), -d-C ₂ 4-alkyl-0-C ₁ -C 24 -alkyl (linear and branched), C ₁ -C 24 -alky-morpholino, -Cl-C 24 -alkyl Piperidino, -C1-C24 Alky-piperazino, -C1-C24 Alky-piperazino-N-alkyl,

R ₂ = H.

The connections

V- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) pivalamide

V- (4- (2,4-dihydroxypheny]) thiazol-2-yl) butyramides

A ⁱ - (4- (2,4-dihydroxyphenyl) thiazol-2-yl) heptanamide

A ^, - (4- (2,4-dihydroxyphenyl) thiazol-2-yl) -6-hydroxyhexanamide

(V- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) -3-hydroxypropanamide 

jV- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) -2- (4- (hydroxymethyl) phenyl) acetamides are the preferred according to the invention.

Surprisingly, it could be shown that the inventive

Alkylamidothiazole in combination with cyclodextrins invention have improved release.

Method description of the Liberation experiments:

The in vitro model is used to estimate the liberation (release) of active ingredients from cosmetic bases. Beiersdorf AG uses a modified Franz cell for this bioavailability test.

The measuring device consists of the donor chamber, in which the test medium (product) is located, and the acceptor chamber, in which the receptor liquid is located. Both chambers are separated by a permeable membrane. It is a commercial filter membrane made of nitrocellulose with a pore size of 0.025 μηη (Millipore VSWP04700). For the kinetic determination of the release, samples are taken from the acceptor chamber at fixed intervals. The from the product into the

Receptor fluid diffused amount of the drug is determined by standard analytical methods. Release: [% of the applied test substance] Mean values from n = 3 / Reze torphase: ethanol 25%

Synthesis Examples of Selected Alkylamidothiazoles:

2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone:

PG = COOCH ₃

Mitchell, David; Doecke, Christopher W .; Hay, Lynne A .; Koenig, Thomas M .; Wirth, David D. Tetrahedron Letters, 1995

A solution of 60 g (369 mmol) of 2,4-dihydroxyacetophenone and 186 ml of triethylamine in 900 ml of tetrahydrofuran was cooled to 0 ° C. and 93 ml of methyl chloroformate in 400 ml of tetrahydrofuran were slowly added dropwise. It forms a white precipitate. After stirring for 3 hours at room temperature, the reaction is complete (TLC control). The precipitate was filtered off with suction and washed with plenty of tetrahydrofuran. The filtrate was evaporated to dryness, taken up in ethyl acetate, washed with 1 N HCl and NaCl solution (sat.) And dried over magnesium sulfate, filtered from magnesium sulfate and the ethyl acetate was concentrated on a rotary evaporator. 105 g of 2,4-bismethoxycarbonyloxy-acetophenone were obtained. ¹ H NMR (DMSO-D ₆ ): 8.05 (d, 1H), 7.38 (d, 1H), 7.36 (s, 1H), 3.86 (d, 6H). The product was used without further purification. To the solution of 105 g of 2,4-bis-methoxycarbonyloxy-acetophenone in chloroform (1000 ml), 63 g (392 mmol) of bromine in 450 ml of chloroform were added dropwise over 3 hours. Thereafter, the reaction was 15 minutes. Stirred at room temperature, the solvent was evaporated. The residue was stirred in ethyl acetate / n-hexane, the resulting precipitate was filtered off with suction. Recrystallization from ethyl acetate / n-hexane gave 100 g of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone. ¹ H NMR (DMSO-D ₆ ): 8.1 1 (d, 1H), 7.42 (m, 2H), 4.87 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H) ppm; mp 73-74 ° C. N- (4- (2,4-dihydroxy) vi) thiazole-2-y-pivalamide:

126 g (1.66 mmol) of thiourea were initially charged in toluene (1000 ml) and 100 g (829 mmol) of pivaloyl chloride were added dropwise. The reaction solution was boiled under reflux for 3 hours to give 2 phases. The upper phase was decanted off and cooled. The precipitated colorless needles were filtered off with suction and washed with cyclohexane and dried in vacuo. Yield: 64 g. ¹ H NMR (DMSO-D ₆ ): 10.27 (s, 1H), 9.74 (s, 1H), 9.40 (s, 1H), 1.19 (s, 9H) ppm.

107.7 g (310 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were refluxed with 49.7 g (13.6 mmol) of N-pivaloylthiourea and 39.2 g (466 mmol) of NaHCO ₃ in 1 .21 ethanol for 0.5 h cooked. The reaction solution was cooled and treated with 50.6 g (1.27 mol) of NaOH in 250 ml of water. After stirring for 30 min at room temperature, the reaction solution was taken up in 300 ml of water and neutralized with 2N HCl. The resulting precipitate was filtered off and recrystallized from ethanol / water. There were obtained 80 g of thiazole. ¹ H NMR (DMSO-D ₆ ): 1.77 (bs, 1H), 1.102 (bs, 1H), 9.47 (bs, 2H), 7.65 (d, 1H), 7.39 (s, 1 H), 6.30 (s, 1H), 6.28 (d, 1H), 1.27 (s, 9H) ppm; mp 257-259 ° C.

N- (4- (2,4-DihvdroxyDhenyl) thiazol-2-yl) -isobutyramide:

1 14 g (1.5 mol) of thiourea were initially charged in toluene (800 ml) and 80 g (0.75 mol) of isobutyryl chloride were added dropwise. The reaction solution was boiled under reflux for 3 hours to give 2 phases. The upper phase was decanted off and cooled. The precipitated white crystals were filtered off and washed with toluene and dried in vacuo. Yield: 62 g. ¹ H NMR (DMSO-D ₆ ): 1.103 (bs, 1H), 9.66 (bs, 1H), 9.35 (bs, 1H), 2.72 (m, 1H), 1 .03 (2 , 6H) ppm;

89 g (260 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were refluxed with 37.5 g (260 mmol) of N-isobutyrylthiourea and 32 g (380 mmol) of NaHCO ₃ in 1000 ml of ethanol for 0.5 h cooked. The reaction solution was cooled and treated with 41 g (0.93 mol) of NaOH in 250 ml of water. After stirring for 30 min at room temperature, the reaction solution was taken up in 300 ml of water and adjusted to pH = 3 with 2N HCl. The resulting precipitate was filtered off and recrystallized from ethanol / water. There were obtained 56 g of thiazole. ¹ H NMR (DMSO-D ₆ ): 12.16 (bs, 1H), 10.88 (bs, 1H), 9.47 (bs, 1H), 7.65 (m, 1H), 7.41 (s, 1H), 6.32 (m, 2H), 2.75 (m, 1H), 1.14 (d, 6H) ppm. mp: 243-245 ° C.

N- (4- (2,4-dihydrophenyl) -thiazol-2-yl) -butyramide:

143 g (1.88 mol) of thiourea were initially charged in toluene (1000 ml), and 100 g (0.93 mol) of n-butyryl chloride were added dropwise. The reaction solution was boiled under reflux for 3 hours to give 2 phases. The upper phase was decanted off and cooled. The precipitated slightly yellowish crystals were filtered off and washed with toluene and dried in vacuo. Yield: 88 g. ¹ H NMR (DMSO-D ₆ ): 1.03 (bs, 1H), 9.65 (bs, 1H), 9.33 (bs, 1H), 2.33 (t, 2H), 1.53 (m, 2H) , 0.86 (t, 3H) ppm; mp: 1 15-188 ° C

92 g (265 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were refluxed with 38.75 g (265 mmol) of N-butyrylthiourea and 34 g (397 mmol) of NaHCO ₃ in 900 ml of ethanol for 0.5 h cooked. The reaction solution was cooled and treated with 37 g (0.93 mol) of NaOH in 300 ml of water. After stirring for 30 min at room temperature, the reaction solution was taken up in 300 ml of water and neutralized with 2N HCl. The standing precipitate was filtered off and recrystallized from ethanol / water. There were obtained 67 g of thiazole. ¹ H NMR (DMSO-D ₆ ): 12.18 (bs, 1H), 10.89 (bs, 1H), 9.48 (bs, 1H), 7.65 (1 arom. H), 7.40 (s, 1H), 6.31 (2 arom. H), 2.43 (t, 2H), 1.64 (m, 2H), 0.91 (t, 3H) ppm. mp: 227-229 ° C.

N- (4- (2,4-dihydroxyphene) -thiazol-2-yl) -azecamide:

4.71 g (13.6 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were treated with 1.61 g (13.6 mmol) of N-acetylthiourea and 1.72 g (20.4 mmol) of NaHCO ₃ in 45 ml of ethanol for 0.5 h cooked under reflux. The reaction solution was cooled and treated with 2.0 g (50 mmol) of NaOH in 20 ml of water. After stirring for 20 min at 0 ° C., the reaction solution was taken up in 30 ml of water and treated with half-conc. HCl neutralized. The resulting precipitate was filtered off and recrystallized from ethanol / water. 2.73g of product was obtained. ¹ H NMR (DMSO-D ₆ ): 12.20 (b, 1H), 10.85 (s, 1H), 9.46 (s, 1H), 7.64 (m, 1H), 7.38 (s, 1H), 6.28 (m, 2H), 2.15 (s, 3H) ppm; mp 264-264 ° C.

N- (4- (2A-Dihvdroxyphenyl) thiazol-2-yl) -4- (Hvdroxymethyl) cvclohexancarboxamid:

Carrying out analogous literature.

BANYU Pharmaceutical Co., Ltd., EP2072519A1, 2009

Yield: 96%, ¹ H NMR (DMSO-D ₆ ): 12.03 (bs, 1H), 3.85, 3.82 (2 xd, 2H), 2.50, 2.47 (2 xm, 1H), 2.00 (s, 3H) , 0.95-1.90 (m, 9H) ppm;

95 g (0.47 mol) of 4-acetoxymethylcyclohexanecarboxylic acid were refluxed in 350 ml of thionyl chloride for 2 h. After removal of the excess thionyl chloride in vacuo, the residue was taken up in 11 toluene and 71 g (0.94 mol) of thiourea added. The reaction solution was refluxed for 3 hours and then filtered hot. After cooling the mother liquor, the resulting white crystals were filtered off, washed with toluene and dried in vacuo. Yield: 59 g. ¹ H NMR (DMSO-D ₆ ): 1: 1.03, 10.97 (2 xs, 1H), 9.64 (bs, 1H), 9.35 (bs, 1H), 3.93, 3.82 (2 xd, 2H), 2.61, 2.42 (2 xm, 1H), 2.00 (s, 3H), 1.60 (m, 8H), 1.35, 0.94 (2 xm, 1H) ppm;

79 g (228 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were mixed with 59 g (228 mmol) of N- (4-acetoxymethylcyclohexylcarbonyl) thiourea and 29 g (340 mmol) of NaHCO ₃ in 1000 ml of ethanol cooked under reflux for 0.5h. The reaction solution was cooled and treated with 73 g (1 .8 mol) of NaOH in 300 ml of water. After stirring for 30 min at room temperature, the reaction solution was taken up in 300 ml of water and adjusted to pH = 3 with 2N HCl. The resulting precipitate was filtered off and recrystallized from ethanol / water. There were obtained 47 g of thiazole. ¹ H NMR (DMSO-D ₆ ): 12.15, 12.10 (2 xs, 1H), 10.96 (2 xs, 1H), 9.47 (br, 2H), 7.64 (d, 1H), 7.39 (s, 1 H), 6.29 (m, 2H), 4.40 (br, 1H), 3.32, 3.23 (2 xd, 2H), 2.65, 2.44 (2 xm, 1 H), 1.90 (m, 1 H), 1 .78 (m, 2H), 1 .50 (m, 5H), 0.94 (m, 1H) ppm. mp: 152-160 ° C.

N- (4- (2A-DihvdroxyDhenyl) thiazol-2-yl) -cvclohexancarboxamid

52 g (0.68 mol) of thiourea were initially charged in toluene (500 ml) and 50 g (0.34 mol) of cyclohexanoyl chloride were added dropwise. The reaction solution was refluxed for 3 hours cooked, with 2 phases arise. The upper phase was decanted off and cooled. The precipitated crystals were filtered off, washed with toluene and recrystallized from methanol. Yield: 35 g. ¹ H NMR (DMSO-D ₆ ): 10.98 (bs, 1H), 9.65 (bs, 1H), 9.32 (bs, 1H), 2.49 (t, 1H), 1.75 (m, 4H) , 1.61 (m, 1H), 1.18 (m, 5H) ppm.

92 g (265 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were refluxed with 49.4 g (265 mmol) of N-cyclohexanoylthiourea and 34 g (397 mmol) of NaHCO ₃ in 900 ml of ethanol for 0.5 h cooked. The reaction solution was cooled and washed with 37 g

(930 mmol) of NaOH in 300 ml of water. After stirring for 30 min at room temperature, the reaction solution was taken up in 300 ml of water and neutralized with 2N HCl. The ethanol was largely removed on a rotary evaporator. The resulting precipitate was filtered off and recrystallized from ethanol / water. There were obtained 70 g of thiazole. ¹ H NMR (DMSO-D ₆ ): 12.14 (bs, 1H), 1 1 .00 (bs, 1H), 9.48 (bs, 1H), 7.64 (1 arom. H), 7.39 (s, 1 H), 6.30 (2 arom. H), 2.49 (m, 1H), 1.84 (m, 2H), 1.76 (m, 2H), 1.65 (m, 1H), 1.42 (m, 2H ), 1 .25 (m, 3H) ppm. mp: 262-266 ° C.

N- (4- (2A-dihvdroxyDhenyl) thiazol-2-yl) -2- (4- (hvdroxymethyl) Dhenyl) acetamide

1 . Ac ₂ O, pyridine

Carrying out analogous literature.

BANYU Pharmaceutical Co., Ltd., EP2072519A1, 2009

Yield: 76%, ¹ H NMR (DMSO-D ₆ ): 12.31 (bs, 1H), 7.26 (m, 4H), 5.05 (s, 2H), 3.57 (s, 2H), 2.05 (s, 3H) ppm;

OH

3.7 g (18 mmol) of 4-acetoxymethylphenylacetic acid were refluxed in 40 ml of thionyl chloride for 2 h. After removal of the excess thionyl chloride in vacuo, the residue was taken up in 70 ml of toluene and 2.7 g (36 mmol) of thiourea was added. The reaction solution was refluxed for 3 hours and then the solvent was removed in vacuo. The purification was carried out by column chromatography with cyclohexane / ethyl acetate 1/1 on silica gel. Yield: 2.7 g. ¹ H NMR (DMSO-D ₆ ): 1 1 .29 (bs, 1H), 9.55 (bs, 1H), 9.40 (bs, 1H), 7.30 (m, 4H), 5.04 (s, 2H) , 3.71 (s, 2H), 2.05 (s, 3H) ppm;

3.5 g (10 mmol) of 2-bromo-2 ', 4'-bis-methoxycarbonyloxy-acetophenone were mixed with 2.7 g (10 mmol) of N- [2- (4-acetoxymethylphenyl) acetyl] thiourea and 1.3 g (15 mmol) of NaHC0 ₃ in 50 ml of ethanol boiled under reflux for 0.5 h. The reaction solution was cooled and treated with 4.0 g (0.1 mol) of NaOH in 20 ml of water. After 2 h stirring at 60 ° C, the reaction solution was taken up in 100 ml of water and adjusted to pH = 3 with 2N HCl. The resulting precipitate was filtered off and recrystallized from ethanol / water. There were obtained 1 .3 g of thiazole. ¹ H NMR (DMSO-D ₆ ): 12.44 (s, 1H), 10.80 (s, 1H), 9.48 (s, 1H), 7.66 (d, 1H), 7.41 (s, 1H), 7.29 (m, 4H), 6.32 (m, 2H), 5.13 (t, 1H), 4.47 (d, 2H), 3.77 (s, 2H) ppm. mp: 254-256 ° C.

It is advantageous, in particular, if such preparations contain 0.000001 to 10% by weight, in particular 0.0001 to 3% by weight, very particularly 0.001 to 1% by weight, of one or more of the alkylamidothiazoles used according to the invention, based on the total weight of the preparation

Cosmetic and dermatological preparations according to the invention can be present in various forms. So they can e.g. a solution, an anhydrous preparation, an emulsion or microemulsion of the water-in-oil (W / O) type or of the oil-in-water (O / W) type, a multiple emulsion, for example of the water-in-oil type in water (W / O / W), a gel, a solid stick, an ointment or even an aerosol.

It is also possible and advantageous for the purposes of the present invention to incorporate the substances and / or their derivatives used according to the invention into aqueous systems or surfactant formulations for cleaning the skin and hair.

The cosmetic and dermatological preparations according to the invention may contain cosmetic adjuvants such as are conventionally used in such preparations For example, preservatives, bactericides, perfumes, foaming inhibitors, dyes, pigments that have a coloring effect, thickeners, surfactants, emulsifiers, softening, moisturizing and / or moisturizing substances, fats, oils, waxes or other conventional ingredients a cosmetic or dermatological formulation such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives.

The lipid phase can advantageously be selected from the following substance group:

Mineral oils, mineral waxes

Oils such as triglycerides of capric or caprylic acid, further natural oils such as e.g. Castor oil;

Fats, waxes and other natural and synthetic fats, preferably esters of fatty acids with lower C-number alcohols, e.g. with isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with alkanoic acids of low C number or with fatty acids;

benzoates;

Silicone oils such as dimethylpolysiloxanes, diethylpolysiloxanes, diphenylpolysiloxanes and mixed forms thereof.

The oil phase of the emulsions, oleogels or hydrodispersions or lipodispersions in the context of the present invention is advantageously selected from the group of esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids having a chain length of 3 to 30 carbon atoms and saturated and / or or unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms, from the group of esters of aromatic carboxylic acids and saturated and / or unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms. Such ester oils can then advantageously be selected from the group isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2 Hexyldecyl stearate, 2-octyl dodecyl palmitate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate and synthetic, semi-synthetic and natural mixtures of such esters, eg Jojoba oil.

It is particularly advantageous according to the invention to use the active compound combinations according to the invention in emulsions which contain as emulsifier one or more partially neutralized esters of monoglycerides and / or diglycerides of saturated fatty acids Citric acid, in particular glyceryl stearate citrate, which is marketed under the name IMWITOR® 372 P by the company Sasol.

The aqueous phase of the preparations according to the invention optionally contains, if desired, humectants, e.g. Propylene glycol, panthenol or hyaluronic acid and in particular one or more thickeners, which or which can be advantageously selected from the group of silica, aluminum silicates, hydroxypropylmethylcellulose, particularly advantageously a polyacrylate such as Carbopols type 980, in each case individually or in combination.

In particular, mixtures of the abovementioned solvents are used. For alcoholic solvents, water can be another ingredient.

Emulsions of the invention are advantageous and contain e.g. the said fats, oils, waxes and other fatty substances, as well as water and an emulsifier, as commonly used for such a type of formulation.

Gels according to the invention usually contain low C number alcohols, e.g. Ethanol, Propyleglycol, and water or an above-mentioned oil in the presence of a thickening agent, the preferred oily-alcoholic gels, preferably silica or an aluminum silicate, in aqueous-alcoholic or alcoholic gels

Polyacrylate is.

Suitable propellants for preparations which can be sprayed from aerosol containers according to the invention are the customary known highly volatile, liquefied propellants, for example hydrocarbons (propane, butane, isobutane), which can be used alone or mixed with one another. Also, compressed air is advantageous to use.

Compositions according to the invention can also advantageously contain substances which absorb UV radiation in the UVB range, the total amount of the filter substances being, for example, from 0.1% by weight to 30% by weight, preferably from 0.5 to 10% by weight, in particular 1.0 to 6.0% by weight, based on the total weight of the preparations, of providing cosmetic preparations which protect the hair or the skin from the entire range of ultraviolet radiation. They can also serve as a sunscreen for hair or skin. In addition, preparations according to the invention may furthermore advantageously contain substances which serve for preserving, the total amount of the preservatives eg being from 0.001% by weight to 30% by weight, preferably from 0.05 to 10% by weight, in particular from 0.1 to 5, 0% by weight, based on the total weight of the preparations, in order to provide cosmetic preparations.

The following examples are intended to illustrate the present invention without limiting it. Unless indicated otherwise, all amounts, proportions and percentages are based on the weight and the total amount or on the total weight of the preparations.

1 2

INCI name% by weight% by weight

Glyceryl stearate citrate 1, 5 1, 5

Cetyl stearyl alcohol 1 1

Octyldodecanol 1 1

Myristyl myristate 1, 5 1, 5

Cyclomethicone 2 2

Glycerol 5 5

Butylene glycol 15 15

Distarch phosphate 2 2

W630 0, 1 0, 1

Hydroxypropyl-beta-cyclodextrin 1, 0

Ethylhexyl methoxycinnamate + BHT 6 6

Butyl Methoxydibenzoylmethane 1 1

Benzophenone-3 2 2

Methylisothiazolinone 0.09 0.09

Phenoxyethanol 0.5 0.5

Alcohol, denatured 3 3

Water + trisodium EDTA 1 1

Carbomer 0.4 0.4

Sodium polyacrylate 0.2 0.2

Sodium hydroxide 0, 15 0, 15

Perfume 0.3 0.3

Water 56,26 55,26

Formulation example 1 2 3 4

INCI name weight% weight% weight% weight%

Stearic acid 2.5 2.0 2.0 2.5

Glyceryl Stearate 1.0 1.0 1.0 1.0

C12-15 alkyl benzoate 3.0 5.00 3.0 2.0

Caprylic Acid / Capric Acid Triglycerides 2.5 2.50 2.0 2.5

Isopropyl Palmitate 2.0 2.0

Cetyl Stearyl Alcohol 3.0 2.0 3.0

Cetyl Alcohol 2.00 -

Stearyl Alcohol 2.00 1.0

Cyclomethicone 1.0 1.0 0.5

Dicaprylyl Carbonate 2.0 2.00 2.00 2.0

Dimethicone 1.0 0.5 1.0

Glycerin 5, 7.0 5.0 9.0

Methyl paraben 0.2

Phenoxyethanol 0.4 0.50 0.5 0.4

Propylparaben 0.1-0.1

1,2-hexanediol - 0.1 0.1

Ethylhexylglycerol - 0.2 -

Methylisothiazolinone 0.05

Butylene glycol 2.0

Carbomer 0.15 0.10 0.15 0.1

Carrageenan 0.10 0.10

Xanthan gum 0.10

Acrylates / C10-30 alkyl acrylates

Crosspolymer 0.10 - 0.1

Trisodium EDTA 0.20 0.20 0.2 0.2

Tapioca starch 1.5 1.0

Nylon 12 - 0.2 0.5

Polymethylsissesquioxane 1.0 1.0

Aluminum starch octenylsuccinate 1.0

Distarch phosphate 1.0 1.0

Butyl Methoxydibenzoylmethane 1.00 2.00 1.00 1.00

Phenylbenzimidazole sulfonic acid 1.00 2.00 -

Octocrylene 2.00 1.00 - Ethyl hexyl salicylates 1, 00 - 1, 00

Phospholipids (90% lecithin) [1] 0, 15 - 0.10 1, 00

N- (4- (2,4-Dihydroxyphenyl) thiazol-2-yl) pivalamide 0.05 0.01 0.06 0.05

N- (4- (2,4-Dihydroxyphenyl) thiazol-2-yl) isobutyramide 0.10-0.10 0.05 0.20

Hydroxypropyl-gamma-cyclodextrin - 0.75 - -

Sodium hydroxide q.s. q.s. q.s. q.s.

Perfume 0.3 0.2 0.2 0.2

Sodium hydroxide q.s. q.s. q.s. q.s.

Water ad 100 ad 100 ad 100 ad 100

¹ film method:

The lecithin was weighed into three round bottom flasks and then dissolved with a little ethanol. The solvent was then removed on a rotary evaporator at a slightly elevated temperature (40 ° C) so that the lecithin left a thin film on the inner glass wall. By means of compressed air flushing last solvent residues were removed. The drug solution of the alkylamidothiazole was then also distributed to the flasks and the flasks were panned until the film had completely peeled off, but at least 15 minutes. Two different homogenization procedures were used: 5 minutes of medium-stage Ultraturrax or a 20-minute ultrasonic bath.

Recipe example 5 6 7 8

INCI name weight% weight% weight% weight%

Glyceryl Stearate Citrate 2.0 1, 5 2.0 2.0

Behenyl Alcohol 1, 5 1, 0 1, 0 1, 0

C12-15 alkyl benzoate 2.0 2.5 2.0 2.5

Caprylic Acid / Capric Acid Triglycerides 2.0 2.0 2.5 2.5

Cetyl Alcohol 2.0 2.0 2.0

Cetylstearyl alcohol 2.0

Cyclomethicone 1.0 1.0 2.0 2.0

Dicaprylyl carbonate - 2.0 2.5 2.5

Paraffin Liquidum 0.5 -

Octyldodecanol 2.0

Dimethicone 0.5 1, 00 1.00

Glycerine 3.00 5.00 7.00 9.00

Methyl paraben 0,20 0, 15

Phenoxyethanol 0.40 0.60 0.5 0.50

Propylparaben 0, 10 -

Methylisothiazolinone - - 0.05

Piroctone Olamine - 0.15

Glyceryl caprylates 0.2

Carbomer 0.20 0.15 0, 15

Sodium polyacrylate 0.4

Xanthan gum 0.10 0.10

Acrylates / C10-30 alkyl acrylates

Crosspolymer 0.1 0.1

Tapioca starch 0.50 0.50

Nylon 12 1, 0 1.0

Polymethylsissesquioxane 1.0 1.0

Aluminum starch octenylsuccinate 1, 0 1.00

N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) isobutyramide 0.10 0.05 0.15 0.15

N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) pivalamide 0.05 0.01 0.30 0.05

Hydroxypropyl-beta-cyclodextrin 0.75

Hydroxypropyl gamma cyclodextrin 1.25 1.00

Gamma-cyclodextrin 1.00 Glycyrrhiza Inflata Root Extract 0.03 0.05 0.05 0.03

Titanium dioxide - 1, 0

Octocrylene - 1, 0 2.0

Until Ethylhexyloxyphenol

Methoxyphenyl Triazines - 1, 0 1.0 -

2-ethylhexyl methoxycinnamate - 1, 0 2.0 2.0

Homosalate (3,3,5-trimethylcyclohexylsalicylate) - - 1, 0 1, 0

Sodium hydroxide q.s. q.s. q.s. q.s.

1- (1,2,3,4,5,6,7,8-octahydro-2,3,8,8-tetramethyl-2-naphthyl) ethane-1-one 0, 1 q.s. q.s.

Geraniol 0.05

Hexyl cinnamal 0.05

Perfume 0.1 0.2 0.3 0.2

Water ad 100 ad 100 ad 100 ad 100

Formulation Examples 9 10 11 12

INCI name weight% weight% weight% weight%

Polyglyceryl-3 methylglucose

Distearate 2.00 2.50 2.50 2.50

Sorbitan Stearate 1, 50 3.00 1, 50 3.00

C12-15 alkyl benzoate 2.50 2.50 2.50 2.50

Caprylic acid / capric acid triglycerides 2.50 2.50 2.50 2.50

Stearyl Alcohol 1, 00 1, 50 1, 00 1, 50

Cyclomethicone 3.00 1, 00 2.00 1, 00

Isopropyl myristate 2.50 2.0 2.50

Isopropyl Palmitate 2.0 1, 0

Dimethicone 1.00 1.00

Glycerine 5.00 7.50 3.00 7.50

Butyrospermum Parkii Butter 2.0

Methyl paraben 0.20 0.20 0.1

Phenoxyethanol 0.40 0.40 0.40 0.40

Propylparaben 0, 10 -

Benzethonium chloride - 0.1

Caprylyl glycol 0.2

Ethylhexylglycerol 0.2 0.2

Carbomer 0.15 0, 10 0.15 0, 10

Ammonium acryloyldimethyltaurate / VP

Copolymer - 0.2 0.2

Carrageenan 0, 1 0.15

Trisodium EDTA - 1.00 1.00

Tapioca Strength 1, 00 1.0

Distarch phosphate 1, 00 1.0

Acrylonitrile-methacrylonitrile-methyl-methacrylate copolymer + isopentane

+ Magnesium hydroxides 1.0 1, 0

N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) isobutyramide 0.1 0.30 0.01 0.05

N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) butyramide 0.01 0.01 0.25 0.15

Hydroxypropyl-beta-cyclodextrin 1, 25 1, 00 Silica microparticles (sol-gel microcapsule) with encapsulated N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) isobutyramide [1] 0.50

N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) butyramide,

Acrylates / ammoniummethacrylate

copolymer microcapsules [2] 0.75

Diethylamino Hydroxybenzoyl Hexyl

Benzoates - 1, 00

Ethylhexyl methoxycinnamate - 1.00 2.00

Butyl Methoxydibenzoylmethane - 2.00 2.00

Octocrylene - 1, 00 2.0 1, 00

Titanium dioxide - - 1, 0 -

Sodium hydroxide q.s. q.s. q.s. q.s.

Sodium Metabisulfite 0, 15 -

BHT (tert-butylhydroxytoluene) 0.05 -

Linalyl acetate 0.05 -

Hexyl salicylate - 0.05 -

Benzyl salicylate - - 0.01 -

Perfume q.s. q.s. q.s. q.s.

Water ad 100 ad 100 ad 100 ad 100

[1] prepared by sol-gel method. For example. with alkyloxysilanes; as exemplified in EP 1 104287 B1

[2] Preparation described by way of example in US Pat. No. 6,932,984 B1

Formulation Examples 17 18 19 20

INCI name weight% weight% weight% weight%

Glyceryl Stearate Citrate 2.0 2.0 2.0 2.0

Isopropyl palmitate 3.0 2.0 3.0 1, 0

Cetyl stearyl alcohol 4.0 3.0 3.0

Cetyl alcohol 4.0

Caprylic Acid / Capric Acid Triglycerides 3.0 2.5 2.0 3.0

C12-15 alkyl benzoate 3.0 2.5 2.0 2.0

Cyclomethicone 1, 0 1, 0 -

Dicaprylyl carbonate - 2.5 -

Dimethicone 0.50

Octyldodecyl myristate 1, 0

Glycerine 4.00 6.00 5.00 6.00

Methyl paraben 0.20-0.10

Phenoxyethanol 0.40 0.40 0.40 0.40

Piroctone Olamine - - 0, 10

Ethylhexylglycerol - 0.3 -

Glyceryl Caprylate 0.3

2-methyl-1,3-propanediol 2.0 2.0

Carbomer 0.20 0, 10 0.15

Sodium polyacrylate 0.40

Xanthan gum 0.10 0.15

Acrylates / C10-30 alkyl acrylates

Crosspolymer 0.1 0.2

Acrylonitrile-methacrylonitrile-methyl-methacrylate copolymer + Isopentane +

Magnesium hydroxides 0.50 0.50

Aluminum Starch Octenylsuccinate 1.00 1, 00

Methyl Methacrylate Crosspolymer 1.0 1, 0

N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) isobutyramide 0.01 0, 1 0.15 0.05

N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl)

cyclohexanecarboxamide 0, 10 0.05 0.30 0.01

Gamma cyclodextrin 0.5 0.75 -

Hydroxypropyl-beta-cyclodextrin 1.10 - Hydroxypropyl gamma cyclodextrin - - - 0.65

Bis-Ethylhexyloxyphenol Methoxyphenyl

Triazines - 1, 0

Titanium dioxide - 1, 00 1, 00

Octocrylene - 1, 00 1.0 1, 00

Butyl methoxydibenzoylmethane 1, 00 1, 00

Ethyl hexyl salicylate 1.0

Citronellol 0.05 0.05

Coumarin 0.05 0.05 0.05

Triethyl citrate - - 0.05 0.05

Sodium hydroxide q.s. q.s. q.s. q.s.

Water ad 100 ad 100 ad 100 ad 100

Recipe examples 21 22 23 24

INCI name weight% weight% weight% weight%

Sucrose Polystearate + Hydrogynated

Polyisobutenes 1, 00 1, 00 2.00 2.00

Sodium stearoyl glutamate 0.20 0.20 0.30 0.30

C12-15 alkyl benzoates 1, 50 1, 50

Cetyl Alcohol 0.50 0.50

Cyclomethicone 10.00 10.00 5.00 5.00

Dimethicone 3.00 3.00 2.50 2.50

Glycerine 7.50 7.50 5.00 5.00

Isopropyl Stearate 1, 00 1, 00 2.00 2.00

Paraffinum Liquidum 3.00 3.00 1, 00 1, 00

Methyl paraben 0, 10 - 0, 10

Ethylhexylglycerol 0.3 0, 10

Propylparaben 0.1

Methylisothiazolinone 0.05

Phenoxyethanol 0.40 0.50 0.40 0.40

N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) isobutyramide 0.10-0.10 0.05 0.01

N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) -6-hydroxyheptanamide 0.30 0.05 0.01 0.10

Beta cyclodextrin 0.50

Alpha cyclodextrin 0.50 0.50

Hydroxypropyl-beta-cyclodextrin 0.75

Ethylhexyl Methoxycinnamate 3.00 2.00 3.00 3.0

Butyl Methoxydibenzoylmethane 2.00 2.00 1, 00 1, 0

Phenylbenzimidazole sulfonic acid - 1, 5 1, 0

Butylene Glycol - 3.0

Polymethylsissesquioxanes - 1, 0 1.0

Nylon 12 1.0 1, 0

Distarch phosphate 1, 0 - 1.0

Methyl Methacrylate Crosspolymer 1.0 -

Aluminum Starch Octenylsuccinate 1, 0 -

Ammonium acryloyldimethyltaurate / VP

Copolymer 0.25 0.25

Xanthan gum 0.10 0, 1 Acrylates / C10-30 alkyl acrylates

Crosspolymer 0.25 0, 1 -

Carbomer 0, 1 0.1

Hexyl cinnamal 0.05 0, 1 0.1

1- (1,2,3,4,5,6,7,8-octahydro-2,3,8,8, -tetramethyl-2-naphthyl) ethan-1-one 0.1, 0.1

Linalool 0.05 0.05

Perfume 0.2 0.2 0.2 0.2

Sodium hydroxide q.s. q.s. q.s. q.s.

Water ad 100 ad 100 ad 100 ad 100

Formulation Examples 25 26 27 28

INCI name weight% weight% weight% weight%

Sodium Cetearyl Sulfates 0, 15 0, 15 0.15 0, 15

Glyceryl Stearate SE 2.00 2.00 1, 50 1, 50

C12-15 alkyl benzoate 2.50 2.50 2.50 2.50

Octyldodecanol 1, 00 1, 00

Caprylic Acid / Capric Acid Triglycerides 2.00 2.00 2.00 2.00

Cetylstearyl alcohol 2.00 2.00 3.00 1.00

Cyclomethicone 1, 50 1, 50 2.50 2.50

Dimethicone 0.50 0.50 0.50 0.50

Glycerin 5.00 5.00 7.50 7.50

Isopropyl Stearate 3.00 3.00 2.00 2.00

Paraffinum Liquidum 2.00 2.00 1, 00 1, 00

Methylisothiazolinone 0.05

Phenoxyethanol 0.4 0.5 0.40 0.30

Methyl paraben 0, 15 - -

Propylparaben 0, 1 -

Piroctone Olamine 0.15

Benzethonium chloride 0.10

N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) pivalamide 0.10 0.20 0.05 0.10

^*** Active1 ^*** W630 N- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) isobutyramide 0.02 0.05 0.30 0.10

Gamma cyclodextrin 0.75 0.50

Hydroxypropyl gamma cyclodextrin 0.50 1.00

Ethylhexyl methoxycinnamate 3.00 3.00 5.00 5.00

Butyl Methoxydibenzoylmethane 1, 00 1, 00 2.00 2.00

Pentylene glycol 1, 0 1, 0

Butylene glycol 1.0 1, 5 3.0 3.0

2-methyl-1,3-propanediol

1, 2-hexanediol 1.0

Nylon-12 1.0 1.0 1.0 1, 0

Carbomer 0.10 0.15

Ammonium acryloyldimethyltaurate / VP

Copolymer 0.20 - Chondrus Crispus 0, 10 0, 10

Xanthan gum - 0.10

Acrylates / C10-30 alkyl acrylates

Crosspolymer - 0.2 0.1 0.1

Coumarin 0, 1 0.05 0.05

Hydroxyisohexyl 3-cyclohexenecarboxaldehydes 0.05 0.05 0.05 0, 1.

1- (1,2,3,4,5,6,7,8-octahydro-2,3,8,8, -tetramethyl-2-naphthyl) ethane-1-one - 0.05 0.1 -

Perfume 0.2 0.3 0.4. 0.2.

Sodium hydroxide q.s. q.s. q.s. q.s.

Water ad 100 ad 100 ad 100 ad 100

Claims

claims

Active ingredient combinations of one or more alkylamidothiazoles and one or more cyclodextrins.

Active substance combinations according to claim 1, characterized in that as cyclodextrin one or more substances from the group α-cyclodextrin, ß-

Cyclodextrin, γ-cyclodextrin, δ-cyclodextrin, methyl, ethyl and hydroxypropyl

Cyclodextrin is or will be chosen.

Active substance combinations according to claim 1 or 2, characterized in that the one or more alkylamidothiazoles substances of the general formula

are at which

Ri = -Ci-C ₂ 4-alkyl (linear and branched), -Ci-C ₂ 4-alkenyl (linear and branched), -d-C ₈ -cycloalkyl, -CrC ₈ -cycloalkyl-alkylhydroxy, -C1-C24 Alkylhydroxy (linear and branched), -C1-C24 alkylamine (linear and branched), -Ci-C ₂ -4-alkylaryl (linear and branched), -Ci-C ₂ -4-alkylaryl-alkyl-hydroxy (linear and branched), -Ci-C ₂₄ -alkyl heteroaryl (linear and branched),

(linear and branched), -C- | -C ₂₄ -alky-morpholino, -C- | -C ₂₄ -alky-piperidino, -C- | -C ₂₄ -alky-piperazino, -C- | -C ₂₄ -alky- piperazino- N-alkyl means

R ₂ = H, _-C-C24 alkyl (linear and branched), -C-C ₂₄ alkenyl (linear and branched), - -C ₈ cycloalkyl, -C-C ₂₄ hydroxyalkyl (linear and branched), -Ci-C ₂₄ -alkylaryl (linear and branched), -Ci-C ₂₄ -alkyl heteroaryl (linear and branched), X = -H, -Ci-C ₂ 4-alkyl (linear and branched), -Ci-C ₂ 4-alkenyl (linear and branched), --CrC ₈ -cycloalkyl, -Ci-C ₂ 4-aryl (if necessary. singly or multiply substituted with -OH, -F, - Cl, -Br, -I, -OMe, -NH _2, -CN) -C-C ₂₄ heteroaryl (optionally mono- or poly-substituted with -OH. - F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN), -Ci-C ₂₄ -alkylaryl (linear and branched), -Ci-C ₂₄ -alkyl heteroaryl (linear and branched), -aryl (optionally mono- or polysubstituted by -OH, -F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN), -phenyl, -2,4-dihydroxyphenyl, -2,3-dihydroxyphenyl , 2,4-dimethoxyphenyl, -2,3-dimethoxyphenyl,

Y is H, C 1 -C ₂₄ -alkyl (linear and branched), C 1 -C ₂₄ -alkenyl (linear and branched), C 1 -C ₈ -cycloalkyl, -Ci-C ₂₄ -aryl, -Ci-C ₂₄ -heteroaryl, -Ci-C ₂₄ -alkylaryl (linear and branched), -Ci-C ₂₄ -alkyl heteroaryl (linear and branched), -aryl, -phenyl, -2,4-dihydroxyphenyl, -2,3-dihydroxyphenyl, -2,4-dimethoxyphenyl, -2,3-dimethoxyphenyl, -COO-alkyl, -COO-alkenyl, -COO-Cylcloalkyl, -COO-aryl, -COO-heteroaryl, and X, Y optionally also = condensed aromatic where X and Y can form aromatic or aliphatic homo- or heterocyclic ring systems with up to n ring-forming atoms, and where the number n can assume values of 5 to 8, and the respective ring systems in turn contain up to n-1 alkyl groups, Hydroxyl groups, carboxyl groups, amino groups, nitrile functions, sulfur-containing substituents, ester groups and / or ether groups may be substituted, wherein the alkylamidothiazole or both as the free base as well may be present as cosmetically and dermatologically usable salts.

Active compound combinations according to claim 3, characterized in that X is selected from the group of substituted phenyl groups and Y, R ¹ and R ² may have the properties defined in claim 3.

Active substance combinations according to claim 3, characterized in that X is selected from the group of substituted phenyl groups, in particular selected from the group of substances having the following structure:

where the substituents (Z) can be selected from the group -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN, acetyl and may be identical or different and Y, R ¹ and R ² may have the properties defined in claim 3.

Active substance combinations according to one of the preceding claims, characterized in that the alkylamidothiazole (s) have the structure:

wherein the substituent (Z) can be selected from the group -H, -OH, -F, -Cl, -Br, - I, -OMe, -NH ₂ , -CN and Y, R ¹ and R ² as claimed in 3 defined properties can have.

7. active substance combinations according to one of the preceding claims, characterized in that the one or more alkylamidothiazoles have the structure:

X =

Y = H

Ri = -Ci-C ₂ 4-alkyl (linear and branched), -Ci-C ₂ 4-alkenyl (linear and branched), -d-C ₈ -cycloalkyl, -CrC ₈ -cycloalkyl-alkylhydroxy, -CrC ₂₄ alkylhydroxy (linear and branched), -C1-C24 alkylamine (linear and branched), -Ci-C ₂ 4-alkylaryl (linear and branched), -Ci-C ₂ 4-alkylaryl-alkyl-hydroxy (linear and branched), -C1-C24 -Alkylheteroaryl (linear and branched), -Ci-C24-alkyl-0-Ci-C ₂ 4-Alkyl (linear and branched), -C1-C24 Alky-Morpholino, -C1-C24 Alky-Piperidino, -C1 -C24 Alky-piperazino, -C1-C24 Alky-piperazino-N-alkyl,

R ₂ = H, -Ci-C ₂ 4-alkyl (linear and branched).

Z = -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH ₂ , -CN, acetyl.

Y = H

R1 = -Ci-C ₂ 4-alkyl (linear and branched), -Ci-C ₂ 4-alkenyl (linear and branched), -d-C ₈ -cycloalkyl, -C- | -C ₈ -cycloalkyl-alkylhydroxy, -C | -C ₂ alkylhydroxy (linear and branched), -C- | -C ₂ alkylamine (linear and branched), -C ₁ -C ₂ alkylaryl (linear and branched), -C ₁ -C ₂ 4-Alkylaryl-alkyl-hydroxy (linear and branched), -C ₁ -C ₂ -alkyl-heteroaryl (linear and branched), -C ₁ -C ₂ -alkyl-0-C ₁ -C ₂ 4- Alkyl (linear and branched), -C- | -C ₂ 4 -alkyl-morpholino, -C- | -C ₂ 4 -alkylpiperidino, -C- | -C ₂ 4 -alkylpiperazino, -C- | -C ₂ 4 Alky-piperazino-N-alkyl,

R ₂ = H.

V- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) Isobutyramide

7V- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) butyramide

A '- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) heptanamide

W (4- (2,4-dihydroxyphenyl) thiazol-2-yl) -6-hydroxyhexanamide

A '- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) -3-hydroxypropanamide

JV (4- (2,4-dihydroxyphenyl) thiazol-2-yl) -2-methoxyacetamides

3-amino-A '- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) propanamides

JV (4- (2,4-dihydroxyphenyl) thiazol-2-yl) acetamide

A '- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) -4- (hydroxymethyl) cyclohexanecarboxamide

jV- (4- (2,4-dihydroxyphenyl) thiazol-2-yl) cyclohexanecarboxamide and

A ⁱ - (4- (2,4-dihydroxyphenyl) tazazol-2-yl) -2- (4- (hydroxymethyl) phenyl) acetamides

10. active compound combinations according to one of the preceding claims, characterized in that the or the Alkylamidothiazole can be present as a halide, carbonate, ascorbate, sulfate, acetate and / or phosphate.

1 1. Cosmetic or dermatological preparations containing active compound combinations according to any one of the preceding claims.

12. Preparations according to claim 1 1, characterized in that they contain 0.000001 to 10 wt .-%, in particular 0.0001 to 3 wt .-%, very particularly 0.001 to 1 wt .-% of one or more Alkylamidothiazolen , relative to the total weight of the preparation.

13. Preparations according to claim 1 1, characterized in that the total amount of one or more Cyclodextrinhen 0.00001 wt .-% to 10 wt .-%, preferably 0.001 wt .-% - 5 wt .-%, in particular 0.005 wt. -% - 3 wt .-%, based on the total weight of the preparations.

14. Cosmetic, non-therapeutic use of preparations or active compound combinations according to any one of the preceding claims for lightening the human skin.

15. Active substance combinations and preparations according to one of the preceding claims for the therapeutic lightening of the human skin.