TOFA analogs, sebum-reducing preparations containing said analogs, and cosmetic and / or therapeutic uses of said analogs as active principles for sebum reduction or sebum suppression - Patents.com

Abstract

A compound of general formula (1).

Description

[Technical field]

[0001] The present invention relates to a novel substance and its use as an active ingredient which is effective against oily and / or dirty skin and mild forms of acne and / or in oily hair, as well as to formulations containing said active ingredient.

[0002] Seborrhea is a predisposing condition characterized by hyperactivity of the sebaceous glands. In addition to the scalp, the skin of the face also appears greasy. The composition of seborrheic sebum differs from normal sebum. Seborrhea can be divided into three stages of development: 1. Simple seborrhea: In mild cases, the skin becomes sticky after 8 days.

[0003] 2. Oily seborrhea: After 2-3 days, the skin becomes sticky.

[0004] 3. Irreversible form: no recovery. Seborrhea: after one day already the hair looks oily.

[0005] The overproduction of the sebaceous glands can be caused, among other things, by androgen disorders (male hormone disorders) and has a negative aesthetic effect on the overall appearance of the hair. This disease can also lead to hair loss. Its precursor is always a seborrheic state of the scalp. Autonomic nervous system disorders and improper care further worsen the appearance of the skin and the condition of the hair. Even with seborrheic conditions, the hair itself can dry out due to a disturbance in the keratin structure. Dryness and damage of hair are often caused by external stresses, for example sunlight or chemical treatments. Too hot a blow dryer or not taking proper care of damaged hair can lead to damage.

[0006] The cause of oily hair is in the human body and is hormonal. Each hair has a sebaceous gland that produces fat (also called sebum). Sebum production is controlled by hormones and can be overproduced or underproduced depending on the hormone sensitivity of the sebaceous gland. Sebum itself keeps the scalp supple. From the sebaceous gland, sebum travels to the scalp and only then does it reach the hairline. There, it is generally absorbed by the hair shaft and is invisible to the eye. When there is too much sebum, the hair shaft can no longer absorb it. The sebum becomes visible as a greasy film on the hair. The result is streaky, sticky and shiny hair.

[0007] The fact that sebaceous glands are constantly producing oil and that their production is dependent on hormonal balance means that the root cause of oily hair problems cannot be addressed. Consistent care and a high-quality regimen remains the best way to combat oily hair.

[0008] Unfortunately, oily hair has a very troublesome consequence: the hair becomes streaky again already a short time after washing, making it difficult to keep the hairstyle in place.

[0009] Contrary to popular belief, washing your hair too frequently makes it get greasy faster is just a myth. A mild shampoo for oily hair will ensure that excess oil is removed. The hair and scalp will be provided with sufficient moisture, which will balance the overproduction of sebum glands.

[0010] Oily hair and dandruff are among the most common hair problems. These disorders are caused by the disturbance of the activity of the sebaceous glands. When the activity of the sebaceous glands becomes too active, it becomes seborrhea. Here, it is divided into two types: oily type (seborrhea oleosa) and dry type (seborrhea sicca).

[0011] Oily seborrhea: In this case, the sebaceous glands become overactive, producing too much sebum, making the skin oily, and the hair ends become sticky and streaky again 2-3 days after washing.

[0012] Dry seborrhea: This is also due to an overactivity of the sebaceous glands, but the sebum becomes drier and has a thicker consistency. Large flakes of sebum that rub off easily appear along with scales on the epidermis. The scalp acquires a waxy, shiny appearance, and the hair becomes oily only at the roots, dry and brittle in the lengths and especially the ends.

[0013] The first step in treating seborrhea is to wash the hair regularly and thoroughly, as necessary, with a special shampoo. It is advisable to simultaneously carry out the washing and massage of the connective tissue, as this will help to empty the sebaceous glands more and delay the re-oiling of the hair.

[0014] In the case of dirty skin and mild forms of acne, in addition to increased sebum production, other influences, such as secondary bacterial infections, are of etiological importance. One of the most important microorganisms associated with dirty skin is Propionibacterium acnes.

[0015] Dirty skin and / or comedones, even in mild cases, are detrimental to the health of the person affected. Virtually all young people suffer from some form of dirty skin, so many need to improve this condition. In this case, excessive sebum production is the essential factor, so in many cases the skin condition can be improved simply by using active ingredients that reduce sebum.

[0016] The problem of the present invention was therefore to find a formulation which is effective against oily and / or dirty skin, mild forms of acne and oily hair.

[0017] Some attempts to solve this problem are already known in the prior art, but not all of the advantages of the advances presented herein are known.

[0018] WO 2011 / 005660 discloses analogues of 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA) and their antiseborrheic effects.

[0019] WO 2018 / 022797 discloses analogues of 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA) and their effect on acne vulgaris.

[0020] WO 2019 / 115405 discloses analogues of pyrrole derivatives and their antiseborrheic effects.

[0021] However, the general formula (1) [ka] [In the formula, R represents n-tetradecyl; R 1 , R 2 and R 3 are each independently -H, a hydroxyl group, -C1 to -C2 substituted with one or more hydroxyl groups 24 Represents an alkyl group, However, the group R 1 , R 2 and R 3 of which a maximum of two represent H atoms or hydroxyl groups, and topical pharmaceutical or cosmetic preparations containing one or more of said compounds in effective concentrations. and the cosmetic use of one or more of said compounds for reducing sebum production in human skin. and the use of topical preparations containing one or more of said compounds for the treatment of oily and / or dirty skin and / or mild forms of acne and / or oily hair and / or oily scalp and / or seborrhea. However, it has surprisingly been found to improve upon the shortcomings of the prior art and this is a solution to the problem.

[0022] The sebaceous glands of the scalp and the face have the same structure and the same mechanism of sebum production, so the use according to the invention follows the same principle. Thus, by applying a sebum-reducing active ingredient to the scalp area, sebum production can be reduced, and as a result, the cosmetically undesirable condition of oily hair can be prevented.

[0023] According to the invention, the formulation is particularly advantageously characterized in that one or more compounds of general formula (1) are advantageously present in the aqueous phase and / or in the oily phase, respectively, in a concentration ranging from 0.0001 to 40.00% by weight, preferably from 0.005 to 20.00% by weight and particularly preferably from 0.001 to 6.00% by weight relative to the total weight of the composition.

[0024] Preferred compounds of formula (1) are as follows: [ka]

[0025] Synthesis of TOFA(3) [ka]

[0026] Compound 3 (TOFA) To a suspension of alcohol (2) (25.3 g, 117.8 mM) in 400 ml of o-xylene, NaH (60% in mineral oil, 7.85 g, 196.3 mM) was added at ambient temperature and the mixture was stirred under reflux cooling for 2 h. The mixture was cooled to about 70° C. and acid (1) was added as a solid in one portion (15.0 g, 78.5 mM). The mixture was stirred under reflux cooling for 48 h and cooled to ambient temperature. The mixture was quenched with aqueous KHSO4, extracted with EtOAc, and the organic layer was further washed with H2O, dried over Na2SO4, and evaporated. The residue was triturated with hexane to give compound (3) (7.1 g, 28%). The synthesis was repeated several times to obtain the required amount of TOFA (about 100 g).

[0027] ZE33-0116(T113e) [ka]

[0028] Compound (63) To a solution of TOFA (3) (13.1 g, 40 mM) in 500 ml of CH2Cl2, glycidol (62) (3.78 g, 51 mM) was added, followed by EDCI (10.5 g, 55 mM) and DMAP (0.97 g, 8 mM), and the mixture was stirred at ambient temperature for 20 h. The solvent was evaporated, the residue was dissolved again in EtOAc, washed with H2O, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel, eluted with 15% EtOAc in hexane to give compound (63) (9.43 g, 61%).

[0029] Compound (64) To a solution of 9.43 g (25 mM) of compound (63) in 120 ml of CH2Cl2 was added trifluoroacetic anhydride (26.4 g, 126 mM) in 40 ml of CH2Cl2 at −30° C. The mixture was stirred at ambient temperature for 4 h, evaporated and the residue was coevaporated with CCl4 to give compound (64) (14.5 g, 99%).

[0030] Compound (65)(ZE33-0116) To a solution of compound (64) (14.5 g, 25 mM) in 120 ml of CH2Cl2 at -55°C was added a solution of pyridine (22 g) and MeOH (13 g) in 100 ml of CH2Cl2 in small portions. The mixture was stirred at -30°C for 0.5 h and then at ambient temperature for 3 h. The mixture was evaporated and the residue was washed with hexane to give compound (65) (ZE33-0116) (9.85 g, 100%).

[0031] ZE33-0117(T74e) [ka]

[0032] Compound(67) To a solution of TOFA (3) (7.9 g, 24 mM) in 500 ml of CH2Cl2, the protected glycerol (66) (4.1 g, 31 mM) was added, followed by EDCI (6.3 g, 33 mM) and DMAP (0.61 g, 5 mM) and the mixture was stirred at ambient temperature for 20 h. The solvent was evaporated and the residue was again dissolved in EtOAc, washed with H2O, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel, eluted with 15% EtOAc in hexane to give compound (67) (9.16 g, 86%).

[0033] Compound (68)(ZE33-0117) To a solution of compound (67) (8.78 g, 20 mM) in 400 ml of MeOH was added 0.4 ml of 3M HCl in dioxane and the mixture was stirred at ambient temperature for 0.5 h. The mixture was evaporated and then evaporated with MeOH to a volume of about 20 ml, and the resulting pellet was filtered off and dried to give compound (68) (ZE33-0117) (6.9 g, 87%).

[0034] The compounds according to the invention can be advantageously incorporated into cosmetic or dermatological preparations.

[0035] The preparation or use according to the invention can be in the form of a liquid composition that can be applied by brush or blade, roll-on device or nebulizer, as a stick, and in the form of a system that can be applied from conventional bottles and containers, such as creams, gels or lotions. The preparation or use according to the invention can be, for example, a solution, an emulsion of the water-in-oil (W / O) or oil-in-water (O / W) type, or a multiple emulsion, for example of the water-in-oil-in-water (W / O / W) or oil-in-water-in-oil (O / W / O) type, a gel, an aqueous dispersion, a lamellar phase, an isotropic liquid solution phase, a micellar phase, a solid or dispersed hexagonal phase or phases, a solid or dispersed cubic phase or phases, a lyotropic phase, a crystalline phase, a solid stick, or even an aerosol.

[0036] Furthermore, the preparations or uses according to the invention can advantageously be in the form of washes, tinctures, cleansing formulations, pads, cotton or wipes, as well as in the form of tonics or shampoos.

[0037] Advantageously, the pH value of the preparation or use according to the invention is adjusted to a slightly acidic to neutral range, preferably between 3.0 and 7.0, particularly preferably between 5.0 and 6.5.

[0038] The formulations according to the invention can be formulated in the usual way and can be used for the treatment of the skin and / or hair in the context of skin treatment or treatment in the context of cosmetic care products.However, the formulations according to the invention can also be used in make-up products in decorative cosmetics or in cosmetic or skin cleansing products.

[0039] It is well known to those skilled in the art that cosmetic preparations are usually not conceivable without common auxiliaries and additives.Therefore, the cosmetic and dermatological preparations according to the present invention can further comprise the cosmetic auxiliaries that are generally used in said preparations, such as consistency regulators, preservatives, stabilizers, fillers, fragrances, pigments with coloring effect, thickeners, suspending agents, buffer mixtures, surface-active substances, emulsifiers, emollients, moisturizing substances and / or humectants, anti-inflammatory substances, additional active ingredients, such as vitamins or proteins, sunscreens, insect repellents, bactericides, water, salts, antibacterial substances, proteolytic or keratolytic substances, pharmaceuticals, or other common ingredients of cosmetic or dermatological formulations, such as alcohols, polyols, polymers, foam stabilizers, organic solvents or even electrolytes.

[0040] The amount of carrier material to be used in each case can be easily determined by the skilled artisan by simple trials depending on the respective product type.

[0041] In addition to water, ethanol and isopropanol, glycerin and propylene glycol, skin-protecting fatty or fatty-like substances, such as decyl oleate, cetyl alcohol, cetylstearyl alcohol and 2-octyldodecanol, in the quantitative proportions customary for such preparations, as well as mucus-forming substances and thickeners, such as hydroxyethylcellulose or hydroxypropylcellulose, polyacrylic acid, polyvinylpyrrolidone, but also in addition small amounts of cyclic silicone oils (polydimethylsiloxanes) and low-viscosity liquid polymethylphenylsiloxanes, can be used as typical carrier substances for the production or use of the preparations according to the invention.

[0042] As emulsifiers for the production or use of the preparations according to the invention, which are advantageously applied to the desired skin area as liquid or solid preparations, and which can be used in the preparations in small amounts, for example 1-6% by weight based on the total composition, non-ionic types, such as polyoxyethylene fatty alcohol ethers, for example cetostearyl alcohol polyethylene glycol ethers with 12 or 20 ethylene oxide units per molecule, cetostearyl alcohol, as well as sorbitan esters and sorbitan ester-ethylene oxide compounds (for example sorbitan monostearate and polyoxyethylene sorbitan monostearate), as well as long-chain, higher molecular weight waxy polyglycol ethers have proven suitable. In addition to this, however, any other emulsifier or mixture of emulsifiers commonly used in cosmetic preparations is also suitable. These include, for example, but are not limited to, glyceryl citrate stearate, PEG-40 stearate or polyglyceryl(3)-methylglucose distearate, stearic acid, steareth-2 and steareth-21.

[0043] The oil phase of the preparation according to the 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 unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms, and 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.

[0044] Furthermore, the oil phase may advantageously be selected from the group of branched and unbranched hydrocarbons and waxes, silicone oils, dialkyl ethers, the group of saturated or unsaturated branched or unbranched alcohols and the group of fatty acid triglycerides, in particular the triglycerol esters of saturated and / or unsaturated branched and / or unbranched alkanecarboxylic acids having a chain length of 8 to 24, in particular 12 to 18 C atoms. The compounds of the oil phase may be of synthetic, semi-synthetic or natural origin.

[0045] Any mixture of such oil and wax components may also be used advantageously within the context of the present invention.

[0046] Advantageously, the content of the oily phase ranges from 1 to 50% by weight, preferably from 2 to 30% by weight and particularly preferably less than 10% by weight relative to the total weight of the formulation.

[0047] For use, the cosmetic and / or dermatological formulations according to the invention are applied in sufficient amounts to the skin, scalp and / or hair in the usual manner for cosmetic and dermatological preparations.

[0048] Lipid Assay for Testing the Effectiveness of TOFA Derivatives According to the Invention To measure the lipid-reducing effect of the active ingredients, primary cell lines of sebaceous glands from different human donors are used. The cells are cultured for a total of 7 days. After seeding on day 1, the treatment with the active ingredients is carried out on days 3 and 5. On day 7, the cells are stained with the dye AdipoRed, which allows fluorescent staining and quantification of intracellular lipid droplets. In addition, the dye fluorescein diacetate (FDA), which is converted by live cells, is also used to monitor cell vitality. The resulting fluorescent signal is likewise quantifiable. The effect of the active ingredients can be measured and displayed as the ratio of the fluorescent signal of AdipoRed and FDA to the corresponding solvent ratio. The test substances were dissolved in dimethyl sulfoxide (DMSO), so all results were normalized to the DMSO-treated control. [Brief description of the drawings]

[0049] [Figure 1] FIG. 1 shows the results of an assay of the present invention.

[0050] The following examples are intended to illustrate but not limit the invention. Unless otherwise stated, numerical data relate to % by weight.

[0051] [Table 1-1]

[0052] [Table 1-2]

Claims

1. General formula (1) 【Chemistry 1】 [In the formula, R represents n-tetradecyl; R １ , R ２ and R ３ are each independently -H, a hydroxyl group, or -C substituted with one or more hydroxyl groups. １ ~C ２４ Represents an alkyl group, However, the group R １ , R ２ and R ３ wherein a maximum of two of the groups represent H atoms or hydroxyl groups.

2. The compound is selected from the group consisting of: 【Chemistry 2】 2. The compound according to claim 1, characterized in that it is selected from the group:

3. 3. A topical pharmaceutical or cosmetic preparation containing one or more compounds of formula (1) according to claim 1 or 2 in an effective concentration.

4. 3. A topical pharmaceutical or cosmetic preparation comprising one or more compounds of formula (1) according to claim 1 or 2, each in a concentration of 0.0001 to 40.00% by weight, preferably 0.005 to 20.00% by weight, particularly preferably 0.001 to 6.00% by weight, based on the total weight of the composition.

5. 3. Cosmetic use of one or more compounds of formula (1) according to claim 1 or 2 for reducing sebum production in human skin.

6. 3. One or more compounds of formula (1) according to claim 1 or 2 for the therapeutic treatment of oily and / or dirty skin and / or mild forms of acne and / or oily hair and / or oily scalp and / or seborrhea.

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