Novel Uses of Proline Derivatives

Abstract

The present invention relates to the novel use of proline-containing dipeptides for evening and lightening skin tone. These proline-containing dipeptides are more particularly suitable for improving skin tone in the malar area under the eyes, cheeks and jawline. [Selection diagram] None

Description

Detailed Description of the Invention

[0001] The present invention relates to the novel use of proline-containing dipeptides for evening and lightening skin tone. These proline-containing dipeptides are more particularly suitable for improving skin tone in the malar area under the eyes, on the cheeks and on the jawline.

[0002] Healthy skin is generally characterized by a uniform and even skin coloration. However, human skin often shows small areas affected by poor skin conditions related to redness, inflammation, discoloration and hyperpigmentation. For example, rosacea, a common chronic disorder, is characterized by flushing and persistent redness (erythema) of the central area of ​​the face. Such skin conditions, especially when occurring on the face, can have a significant psychosocial impact on individuals, causing embarrassment, anxiety and low self-esteem.

[0003] Although approved medications exist for the treatment of skin inflammation and / or redness or for the treatment of hyperpigmented skin, there is a need for gentle agents that reduce the appearance of uneven skin tone and provide an even, uniform skin coloration.

[0004] It has surprisingly been found that certain proline-containing dipeptides are capable of evening out skin tone, thus resulting in a more uniform and even skin coloration.

[0005] Therefore, a first object of the present invention is to provide a compound of formula (I) [ka] (In the formula, n represents 0, 1 or 2; R 1 and R 4 are - independently of each other - selected from the group consisting of H, C1-C6 alkyl, amidino or tetra-C1-C6-alkylamidinium, R 2 is H or C1-C6-alkyl, or R 1 and R2 form a 5- to 7-membered saturated ring together with the residue to which they are attached, R 3 is selected from the group consisting of C1-C6 alkyl, arC1-C6 alkyl, and heteroarylC1-C6 alkyl, and R 5 is H or also NH2 when n is 1, or R 5 and R 1 form a 5- to 7-membered saturated ring together with the residue to which they are attached) or a cosmetically acceptable salt thereof for evening out skin tone, for lightening the skin, for reducing inflammation-related discoloration, erythema and / or pigmentation of the skin and / or for reducing dark circles under the eye area.

[0006] In another object, the present invention relates to a method for evening out skin tone, brightening the skin, reducing inflammation-related discoloration, erythema and / or pigmentation of the skin and / or reducing dark circles under the eyes, said method comprising topically administering to an appropriate skin area of ​​a person in need of such treatment an effective amount of a cosmetic composition comprising at least one compound of formula (I) and optionally noticing the effect.

[0007] The phrase "cosmetically acceptable," as used herein, is intended to mean that a particular ingredient is considered safe and non-toxic for application at usage levels to humans, e.g., particularly to human skin.

[0008] Without wishing to be bound by theory, it is believed that the evening out of skin tone by the compounds of formula (I) is accomplished (at least in particular) by removing redness and small dark spots (also called hidden pigmentation) beneath the skin, resulting in a lighter (more radiant) skin tone.

[0009] Evening out skin tone or reducing redness and / or brightening the skin is determined by three values: L for the black-white component (i.e., lightness); *, a for the green-red component * and b for the blue-yellow component * The CILAB color space (CIE L * a * b * Skin color uniformity, resulting in a visible improvement in skin tone, can be determined using the Lab color space, also known as the Lab color space, or sometimes simply abbreviated as the Lab color space. * Increase in value (increase in brightness) and a * This is reflected in a decrease in value (redness).

[0010] L * a * b * Values ​​are measured using a Chroma Meter directly on the skin or using photographs taken in a standardized manner using a mathematical algorithm to determine relative improvement compared to untreated or placebo-treated skin. * a * b * The value can be determined by calculating:

[0011] In a particularly advantageous embodiment, the present invention relates to the use and method according to the invention, in which the L of the skin is reduced compared to untreated or placebo-treated skin. * The value is increased and * The value is lowered. * The value is increased by at least 0.1, preferably at least 0.13 units, and * The value is reduced by at least 0.1, preferably at least 0.13 units.

[0012] The uses and methods according to the present invention may further comprise identifying a person in need of skin tone evenness.

[0013] In certain embodiments, the present invention relates to a method for treating skin with a compound of formula (I) that reduces the L * Increase the value (i.e., brightness) and *The present invention also relates to the use of a compound of formula (I), with all the priorities and definitions given herein, for reducing the level of, and optionally realizing the effect of,

[0014] In another embodiment, the present invention relates to a method for reducing the appearance of uneven skin tone, comprising topically applying any one of the compositions of the present invention to skin. Uneven skin tone can appear as discolored skin. The composition can be applied selectively to discolored skin (e.g., facial skin, arm skin, leg skin, scalp, neck skin, chest skin, abdominal skin, hand skin, etc.) or to a larger skin area that includes discolored skin. Discolored skin can be age spots, blemished skin, freckles, hyperpigmented skin, skin suffering from melasma, skin overexposed to sunlight, etc. The method can also be used to prevent the appearance of uneven skin tone by topically applying the composition disclosed throughout this specification to skin at risk of developing uneven skin tone. Skins at risk for developing uneven skin tone include skin overexposed to sunlight, the skin of pregnant women, individuals who have or are at risk for developing melasma, and post-inflammatory hyperpigmentation (e.g., darkening of the skin following acne lesions or skin injury such as burns).The compositions of the present invention can also be used to lighten the skin by topically applying the compositions disclosed herein to the skin (area) that the user desires to lighten.

[0015] The cosmetic compositions according to the invention are preferably intended for topical application, which should be understood as external application to the skin, in particular the face.

[0016] The (total) amount of at least one compound of formula (I) in the cosmetic composition according to the present invention is preferably chosen in the range of 0.5 ppm to 5,000 ppm, preferably in the range of 2.5 ppm to 250 ppm, most preferably in the range of 25 ppm to 100 ppm, based on the total weight of the composition.

[0017] The term "effective amount" refers to the amount necessary to obtain a physiological effect. The physiological effect may be achieved by application in a single dose or by repeated applications. The dose administered may, of course, vary depending on known factors such as the physiological characteristics of the particular composition comprising at least one compound of formula (I) and its method and route of administration; the age, health and weight of the recipient; the nature and extent of the condition; the type of concomitant treatment; the frequency of treatment; and the desired effect, and can be adjusted by the skilled artisan. Preferably, the amount of cosmetic composition applied to the skin is between 0.1 and 3 mg / cm of skin. 2 In the range of, for example, preferably 0.1 to 2 mg / cm of skin 2 in the range of 0.5-2 mg / cm of skin, most preferably 2 In a preferred embodiment, the cosmetic composition is applied once or twice daily.

[0018] In a preferred embodiment of the present invention, the cosmetic composition is applied once or twice daily for at least 10 days, even more preferably for at least 20 days, such as most preferably for at least 25 days, such as at least 28 days.

[0019] In a preferred embodiment of the present invention, the cosmetic composition is applied to the face. Particularly suitable application areas of the face include the forehead, the cheek area under the eyes (dark circles under the eyes), the cheeks and the jawline. The most preferred is the cheek area under the eyes, since the effect is particularly pronounced in the cheek area under the eyes.

[0020] The term "C1-C6 alkyl" as used herein refers to unbranched C1-C6 alkyl or branched C3-C6 alkyl groups, such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl groups.

[0021] The term "arC1-C6 alkyl" as used herein refers to -C1-C6 alkyl-aryl, where the term "aryl" is, for example, a phenyl, indanyl or naphthyl group.

[0022] The term "heteroaryl C1-C6 alkyl" as used herein refers to -C1-C6 alkyl-heteroaryl, where the term "heteroaryl" refers to a 5- or 6-membered aromatic ring containing one or more heteroatoms, i.e., N, O, or S, which may be fused to other aromatic systems.

[0023] R 1 and R 2 or R 1 and R 5 However, examples of 5- to 7-membered saturated rings which they may each form together with the residue to which they are attached are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, oxazolidinyl, thiazolidinyl and 1,2,3,4-tetrahydroquinolinyl.

[0024] It will be appreciated that the present invention encompasses compounds of formula (I) as optically pure isomers, e.g., pure enantiomers or stereoisomers, and as mixtures of different isomers, e.g., racemates or mixtures of diastereoisomers.

[0025] The term "cosmetically acceptable salt" refers to a non-toxic acid addition salt, i.e., a physiologically acceptable salt, and is fully understood to be usable in contact with skin, lips, hair or gums without causing undesirable or harmful effects.Preferably, the term "or its cosmetically acceptable salt" refers to the compound of formula (I) in the form of an acid addition salt, such as in the form of a chloride, acetate, mesylate or trifluoroacetate.Alternatively, the salt may be formed by reaction with an alkali base or alkaline earth base, resulting in the alkali salt or alkaline earth salt, respectively, such as, in particular, the lithium, sodium, potassium, magnesium or calcium salt, respectively.

[0026] Most preferred in all embodiments of the present invention are compounds of formula (I) in the form of their acetate or trifluoroacetate salts, such salts being readily prepared by those skilled in the art.

[0027] In all embodiments of the present invention, R 1 , R 4 and R 5 is preferably H.

[0028] In all embodiments of the present invention, R 2 is preferably H and methyl, most preferably H.

[0029] In all embodiments of the present invention, R 3 is preferably arC1-C6 alkyl, and most preferably benzyl.

[0030] In all embodiments of the present invention, n is preferably 0 or 1, most preferably 1.

[0031] Most preferred in all embodiments of the present invention are 1 , R 2 , R 4 and R 5 is H and R 3 is benzyl and n is 1.

[0032] Compounds of formula (I) can be prepared, for example, as disclosed in US Patent Application Publication No. 2009 / 0111731.

[0033] Particularly advantageous in all embodiments of the invention is the dipeptide having the sequence H-(beta-Ala)-Pro-Dab-NH-benzyl, especially as the diacetate salt, which is also known as dipeptide diaminobutyroylbenzylamide diacetate (INCI) [CAS 823202-99-9] and is commercially available as SYN®-AKE from DSM Nutritional products Ltd.

[0034] As used herein, the term "cosmetic composition" refers to a composition used to treat, care for, or improve the appearance of the skin and / or scalp. Particularly advantageous cosmetic compositions are skin care preparations.

[0035] Since the compositions according to the invention are intended for topical application, they comprise a physiologically acceptable medium, i.e. a medium that is compatible with the skin. In particular, a physiologically acceptable medium is a cosmetically acceptable carrier.

[0036] The term "cosmetically acceptable carrier" as used herein refers to a physiologically acceptable medium that is compatible with keratinous materials, particularly skin. Suitable carriers are well known in the art and are selected based on the end use application. Preferably, the carrier of the present invention is suitable for application to the skin (e.g., sunscreen, cream, milk, lotion, mask, serum, aqueous dispersion, foundation, cream, cream gel or gel, etc.). Such carriers are well known to those skilled in the art and may include one or more compatible liquid or solid fillers, diluents, excipients, additives or vehicles that are suitable for application to the skin. The exact amount of carrier may depend on the level of the compound of formula (I) and any other optional ingredients (e.g., other active ingredients) that may be classified as different from carriers by those skilled in the art. The compositions of the present invention preferably include about 75% to about 99.999% by weight of the composition, more preferably about 85% to about 99.99% by weight, even more preferably 90% to about 99% by weight, and most preferably about 93% to about 98% by weight of the carrier.

[0037] The cosmetic composition of the present invention can be formulated into various kinds of product types, including cream, wax, paste, lotion, milk, mousse, gel, oil, tonic and spray.Preferably, the compound of formula (I) is formulated into lotion, cream, gel and tonic.These product forms can be used for several applications, including, but not limited to, hand and body lotion, facial moisturizer, anti-aging preparation, makeup including foundation, etc.Any additional ingredients required to formulate such products vary depending on the product type, and can be routinely selected by those skilled in the art.

[0038] When the compositions of the present invention are formulated as an aerosol and applied to the skin as a spray-on product, a propellant is added to the composition.

[0039] The cosmetic composition according to the present invention can be prepared by conventional methods in the art, for example by mixing the compound of formula (I), with all the definitions and priorities as set forth herein, with a cosmetically acceptable carrier.The cosmetic composition of the present invention (including the carrier) can contain further conventional cosmetic adjuvants and additives, such as preservatives / antioxidants, fatty substances / oils, water, organic solvents, silicones, thickeners, emollients, emulsifiers, defoamers, aesthetic ingredients such as fragrances, surfactants, fillers, anionic, cationic, nonionic or amphoteric polymers or mixtures thereof, propellants, acidifying or basifying agents, dyes, colorants / coloring agents, abrasives, absorbents, chelating agents and / or sequestering agents, essential oils, skin sensates, astringents, pigments or any other ingredients that are usually incorporated into such compositions.

[0040] According to the present invention, the cosmetic composition according to the present invention may also contain other cosmetically active ingredients that are conventionally used in cosmetic compositions.Exemplary active ingredients include skin whitening agents; UV filters, agents for treating hyperpigmentation; agents for preventing or reducing inflammation; firming, moisturizing, soothing and / or revitalizing agents and agents for improving elasticity and skin barrier.

[0041] Examples of excipients, diluents, adjuvants, additives and active ingredients for cosmetics suitable for use in the cosmetic compositions of the present invention and commonly used in the skin care industry are described, for example but not limited to, in the International Cosmetic Ingredient Dictionary & Handbook by the Personal Care Product Council (http: / / www.personalcarecouncil.org / ), available online at INFO BASE (http: / / online.personalcarecouncil.org / jsp / Home.jsp).

[0042] The required amounts of active ingredients and cosmetic excipients, diluents, adjuvants, additives, etc. can be readily determined by one skilled in the art based on the desired product form and application. Additional ingredients can be added to the oily phase, the aqueous phase, or separately therefrom as deemed appropriate.

[0043] The cosmetically active ingredients useful herein can optionally provide more than one benefit or act by more than one mechanism of action.

[0044] Naturally, the skilled artisan will carefully select the above-mentioned optional additional components, adjuvants, diluents and additives and / or the amounts thereof, such that the advantageous properties inherently associated with the combination according to the present invention are not adversely affected or are not substantially affected by the envisaged addition.

[0045] The cosmetic compositions according to the invention may be in the form of suspensions or dispersions in solvents or fatty substances or alternatively in the form of emulsions or microemulsions (in particular of the oil-in-water (O / W) or water-in-oil (W / O) type, silicone-in-water (Si / W) or water-in-silicone (W / Si) type), PIT-emulsions, multiple emulsions (for example of the oil-in-water-in-oil (O / W / O) or water-in-oil-in-water (W / O / W) type), Pickering emulsions, hydrogels, alcoholic gels, lipogels, single- or multiphase solutions or vesicular dispersions or other conventional forms, which can also be applied by pen, as a mask or as a spray.

[0046] When the cosmetic composition is an emulsion, in particular an O / W, W / O, Si / W, W / Si, O / W / O, W / O / W multiple or Pickering emulsion, the amount of oily phase present in such cosmetic emulsion is preferably at least 10% by weight, for example in the range of 10 to 60% by weight, preferably in the range of 15 to 50% by weight, most preferably in the range of 15 to 40% by weight, based on the total weight of the cosmetic composition.

[0047] In one embodiment, the cosmetic composition according to the invention is advantageously in the form of an oil-in-water (O / W) emulsion comprising an oily phase dispersed in an aqueous phase in the presence of an O / W emulsifier. The preparation of such O / W emulsions is well known to those skilled in the art.

[0048] The cosmetic composition according to the invention, when it is an O / W emulsion, advantageously contains at least one O / W or Si / W emulsifier selected from the list: glyceryl stearate citrate, glyceryl stearate SE (self-emulsifying), stearic acid, stearates, polyglyceryl-3-methylglycol distearate. Further suitable emulsifiers are phosphoric acid esters and their salts, such as cetyl phosphate (for example as Amphisol® A from DSM Nutritional Products Ltd.), diethanolamine cetyl phosphate (for example as Amphisol® DEA from DSM Nutritional Products Ltd.), potassium cetyl phosphate (for example as Amphisol® K from DSM Nutritional Products Ltd.), sodium cetearyl sulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glyceride phosphates and mixtures thereof. Further suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose polystearate and hydrated polyisobutene.Furthermore, one or more synthetic polymers may be used as emulsifiers, such as PVP eicosene copolymer, acrylates / C10-30 alkyl acrylate crosspolymer and mixtures thereof.

[0049] The at least one O / W or Si / W emulsifier is preferably used in an amount ranging from 0.5 to 10 wt.-%, in particular from 0.5 to 6 wt.-%, such as more particularly in the range from 0.5 to 5 wt.-%, such as most particularly in the range from 1 to 4 wt.-%, based on the total weight of the cosmetic composition.

[0050] Particularly suitable O / W emulsifiers for use in the cosmetic compositions according to the invention include phosphate ester emulsifiers, such as advantageously 8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, ceteareth-2 phosphate, ceteareth-5 phosphate, ceteth-8 phosphate, ceteth-10 phosphate, cetyl phosphate, C6-10 pareth-4 phosphate, C12-15 pareth-2 phosphate, C12-15 pareth-3 phosphate, DEA-ceteareth-2 phosphate, DEA-cetyl phosphate, DEA-oleth-3 phosphate, potassium cetyl phosphate, deceth-4 phosphate, deceth-6 phosphate and trilaureth-4 phosphate.

[0051] A particularly suitable O / W emulsifier to be used in the cosmetic composition according to the invention is cetyl phosphate, such as preferably potassium cetyl phosphate, which is commercially available, for example as Amphisol® K from DSM Nutritional Products Ltd Kaiseraugst.

[0052] Another particularly suitable type of O / W emulsifier is a non-ionic self-emulsifying system derived from olive oil, known for example as Cetearyl and Sorbitan Olivate (INCI name) sold under the trade name OLIVEM 1000 (chemical composition: sorbitan and cetearyl esters of olive oil fatty acids).

[0053] In one particular embodiment, the present invention relates to a cosmetic composition with all the definitions and priorities given herein, in the form of an O / W emulsion comprising an oily phase dispersed in an aqueous phase in the presence of an O / W emulsifier, where the O / W emulsifier is potassium cetyl phosphate. The amount of oily phase in such an O / W emulsion is preferably at least 10% by weight, more preferably in the range of 10-60% by weight, most preferably in the range of 15-50% by weight, for example in the range of 15-40% by weight.

[0054] Cosmetic compositions according to the present invention generally have a pH in the range of 3 to 10, preferably in the range of 4 to 8, and most preferably in the range of 4 to 7.5. The pH can be readily adjusted as required according to standard methods in the art, for example with a suitable acid such as citric acid or a base such as sodium hydroxide (e.g., as an aqueous solution), triethanolamine (TEA Care), tromethamine (Trizma Base) and aminomethylpropanol (AMP-Ultra PC 2000).

[0055] The following examples are provided to further illustrate the compositions and effects of the present invention. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

[0056] [Experimental part] 1. Materials and Methods This was a placebo-controlled, full-face, parallel-group study. Volunteers had to apply the cosmetic formulation twice a day for 29 days. 54 Asian female volunteers participated in the study and were divided into a placebo group and an active agent group (formulation containing 4% SYN®-AKE).

[0057] Volunteers were photographed at a 45° angle from the left and right using cross-polarized illumination with a Visia CR® device (Canfield, Parsippany, US). A prescribed algorithm was used to measure the L * a * b * Values ​​were calculated directly. Differences were calculated and significance was calculated using Student's t-test (if values ​​were normally distributed) or Wilcoxon signed rank test (if values ​​were not normally distributed).

[0058] [2.Clinical research] A double-blind, parallel-group study was conducted with Asian female volunteers aged 41-55 years. Twenty-seven volunteers (mean age 47 years) received the placebo formulation and 27 volunteers (mean age 48 years) received the active formulation containing SYN®-AKE. The placebo or active formulation was applied twice daily to the face for 28 days. At the end of the study, photographs were taken for computerized analysis of skin tone as outlined above.

[0059] [Table 1]

[0060] [Table 2]

[0061] As can be seen from the results, a significant improvement in skin tone was observed compared to the placebo formulation containing no active agent.

Claims

1. 1. A cosmetic composition comprising H-(beta-Ala)-Pro-Dab-NH-benzyl or a cosmetically acceptable salt thereof for evening out skin tone, brightening the skin, reducing inflammation-related discoloration, erythema and / or pigmentation of the skin and / or reducing dark circles under the eyes.

2. The L of the skin compared to untreated skin ＊ The value is increased and ＊ 2. The cosmetic composition of claim 1, wherein the value is reduced to even out skin tone and / or to lighten said skin.

3. 3. The cosmetic composition according to claim 1 or 2, characterized in that the amount of H-(beta-Ala)-Pro-Dab-NH-benzyl or a cosmetically acceptable salt thereof in the cosmetic composition is selected in the range of 0.5 ppm to 5,000 ppm based on the total weight of the composition.

4. The amount of the cosmetic composition applied to the skin is 0.1 to 3 mg / cm of skin. ２ The cosmetic composition according to any one of claims 1 to 3, characterized in that the content is selected in the range of

5. The cosmetic composition according to any one of claims 1 to 4, characterized in that the cosmetic composition is applied once or twice a day.

6. Cosmetic composition according to any one of claims 1 to 5, characterized in that it is a skin care preparation.

7. 7. The cosmetic composition according to claim 1, wherein the composition is an O / W emulsion comprising an oily phase dispersed in an aqueous phase in the presence of an O / W emulsifier.

8. The cosmetic composition according to claim 7, wherein the O / W emulsifier is cetyl phosphate.

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