OA22073A - Tofa analogues, sebum reduction preparations containg said type of analogues and the cosmetic and/or therapeutic use if said type of analogues as an effective principle for reducing or preventing sebum. - Google Patents
Tofa analogues, sebum reduction preparations containg said type of analogues and the cosmetic and/or therapeutic use if said type of analogues as an effective principle for reducing or preventing sebum.Info
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- OA22073A OA22073A OA1202400444 OA22073A OA 22073 A OA22073 A OA 22073A OA 1202400444 OA1202400444 OA 1202400444 OA 22073 A OA22073 A OA 22073A
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- sebum
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Abstract
The invention relates to compounds of general formula (I).
<img file="OA22073A_A0001.tif"/>
Description
Beiersdorf Aktiengesellschaft
Description
TOFA ANALOGUES, SEBUM REDUCTION PREPARATIONS CONTAINING SAID TYPE OF ANALOGUES AND THE COSMETIC AND/OR THERAPEUTIC USE OF SAID TYPE OF ANALOGUES AS AN EFFECTIVE PRINCIPLE FOR REDUCING OR PREVENTING
SEBUM
The présent invention relates to novel substances and uses thereof as active ingrédients and préparations containing such active ingrédients which are effective against greasy and/or impure skin, and mild forms of acné and/or in the case of greasy hair.
Seborrhea is a prédisposition to increased function of the sebaceous glands. Both scalp and facial skin appear greasy. The composition of seborrheîc sébum is altered compared to normal sébum. Three stages of development of seborrhea are distinguished:
1. Simple seborrhea: mild cases, greasy after 8 days.
2. Oily seborrhea: already greasy after 2-3 days.
3. Irréversible form: no longer réversible. Seborrhea where the hair looks like it has been bathed in grease after just one day.
The excessive sécrétion of the sebaceous glands can, inter alia, be triggered by androgenetic disorders (male sex hormone disorder) and has a detrimental esthetic effect on the overall appearance of the hair. This disorder can also be the cause of hair loss that occurs. The precursor in each case is the seborrhoeic condition of the scalp. Végétative disorders and improper care can worsen the appearance of the skin and also the condition of the hair. Even with seborrhea, the hair itself can be dry due to disturbances in keratin formation. Dry, weakened hair is often caused by external stress such as sun or Chemical treatments. Excessively hot blow-drying or not properiy caring for weakened hair can lead to damage.
The causes of greasy hair lie in the human body and are hormonal. Each hair has its own sebaceous gland, which produces grease (also called sébum). Sébum production is hormonally controlled, and over- or underproduction can occur, depending on the hormone sensitivity of the sebaceous gland. The sébum itself has the function of keeping the scalp supple. It passes from the sebaceous gland to the scalp and only later the haïr root. There it is normally absorbed by the hair shaft and remains invisible. When sébum is overproduced, the hair shaft is no longer able to absorb it. It becomes visible as a greasy film on the hair. The resuit is stringy hair that is shiny with grease.
Due to the fact that sebaceous gland production is dépendent on the hormone balance, the problem of greasy hair cannot be solved fundamentally since the sebaceous glands continually produce grease. Consistent care and high-quality skin care products are still the best way to combat greasy hair.
Unfortunately, greasy hair has very troublesome effects. The hair becomes stringy again just a short time after washing and the hairstyle does not hold.
Contrary to popular belief, it is only a rumor that the hair becomes greasy more quickly as a resuit of excessively frequent washing. Mild shampoos for greasy hair ensure that excess grease is removed. Hair and scalp are supplied with sufficient moisture and balance the overproduction of the sebaceous glands.
Greasy hair and dandruff are among the most common hair problems. These abnormalities can be attributed to a disorder in the activity of the sebaceous glands. If the sebaceous glands are hyperactive, the term used is seborrhea. Two forms can be distinguished here: the oily form (seborrhea oleosa) and the dry form (seborrhea sicca).
Seborrhea oleosa:
This involves hyperactivity of the sebaceous glands, where the sebaceous glands produce too much, and too oily, sébum. The skin therefore has a greasy sheen, and the hair is greasy and stringy again right down to the tips just 2 to 3 days after washing.
Seborrhea sicca:
This can likewise be attributed to hyperactivity of the sebaceous glands, but the skin sébum is drier and has a firmer consistency. With the small flakes of the epidermis, it forms large, easily friable sébum flakes. The scalp has a waxy sheen, the hair becomes greasy only at the roots, and the lengths and particularly the tips are dry and even brittle.
The treatment of seborrhea includes, first of ail, regular and thorough washing of the head with spécial shampoos, which can be carried out as often as seems necessary. The washing
should be combined with massage in the connective tissue because this empties the sebaceous glands more, which delays the regreasing.
In the case of impure skin and mild forms of acné, in addition to increased sébum production, 5 other influences such as secondary bacterial infections are also of etiological importance.
One of the most important microorganisms associated with impure skin is Propionibacterium acnés.
Impure skin and/or comedones adversely affect the well-being of those affected, even in mild 10 cases. Since practically every adolescent is affected by impure skin to some degree, for many people there is a need to remedy this condition. Since a major factor here is the excessive production of sébum, in many cases it is possible to improve the condition of the skin just through the use of sebum-reducing active ingrédients.
It was thus the object of the présent invention to find préparations that are effective against greasy and/or impure skin, mild forms of acné and against greasy hair.
The prior art already discloses some attempts to solve this problem, but they do not disclose ail the advantages of the development presented herein.
WO 2011/005660 discloses analogs of 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA) and their antiseborrheic effect.
Document WO 2018/022797 discloses analogs of 5-(tetradecyloxy)-2-furancarboxylic acid 25 (TOFA) and their effect against acné vulgaris.
Document WO 2019/115405 discloses analogs of pyrrole dérivatives and their antiseborrheic effect.
However, it has surprisingly been found, and therein lies the achievement of the object, that novel compounds of the general formula (1 )
O in which R = n-tetradecyl, and R’t R2 and R3 independently are -H, a hydroxyi group, a -C1-C24 alkyl substituted by one or more hydroxyi groups with the proviso that at most two of the groups R1, R2 and R3 represent an H atom or a hydroxyi group, and médicinal or cosmetic topical préparations containing one or more such compounds at an effective concentration, and the cosmetic use of one or more such compounds for reducing sébum production in human skin, and the use of topical préparations containing one or more such compounds for the treatment of greasy and/or impure skin and/or mild forms of acné and/or greasy hair and/or greasy scalp and/or seborrhea, remedy the disadvantages of the prior art
The uses according to the invention follow a similar principle, since the sebaceous glands on the scalp and on the face hâve an identical structure and the sébum production proceeds according to the same mechanism. The application of the sebum-reducing active ingrédients on the scalp région thus makes it possible to reduce sébum production and therefore prevent the cosmetically undesirable condition of greasy hair.
Préparations that are particularly advantageous according to the invention are those that are characterized in that one or more compounds ofthe general formula (1), advantageously in a water and/or oil phase, are présent at concentrations of 0.0001 - 40.00% by weight.
preferably 0.005 - 20.00% by weight, particularly preferably 0.001 - 6.00% by weight, in each case based on the total weight of the composition.
Preferred compounds of formula (1) are:
T74e
T113e
Synthesis of TOFA (3)
Compound 3 (TOFA)
NaH (60% in minerai oïl, 7.85 g, 196.3 mM) was added at ambient température to a suspension of alcohol (2) (25.3 g, 117.8 mM) in 400 ml of o-xylene and the mixture was stirred for 2 hours under reflux cooling. The mixture was cooled down to approx. 70°C, and acid (1) was added in solid form in one portion (15.0 g, 78.5 mM). The mixture was stirred for 10 48 h under reflux cooling and cooled to ambient température. The mixture was quenched with aqueous KHSO4, extracted with EtOAc, the organic layer was additionally washed with H2O, dried with Na2SO4 and evaporated. The residue was triturated with hexane, which gave Compound (3) (7.1 g, 28%). The synthesis was repeated several times in order to obtain the required amount of TOFA (approx. 100 g).
ZE33-0116 (T113e)
Compound (63)
Giycidol (62) (3.78 g, 51 mM) was added to a solution of TOFA (3) (13.1 g, 40 mM) in 500 ml 5 of CH2CI2, foflowed by the addition of EDCI (10.5 g, 55 mM) and DMAP (0.97 g, 8 mM) and the mixture was stirred at ambient température for 20 h. The solvent was evaporated, the residue was dissolved again in EtOAc, washed with H2O and dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel, elution being performed with 15% EtOAc in hexane, which gave Compound (63) (9.43 g, 61%).
Compound (64)
Trifluoroacetic anhydride (26.4 g, 126 mM) in 40 ml of CH2CI2 was added at -30°C to a solution of 9.43 g (25 mM) of Compound (63) in 120 ml of CH2CI2. The mixture was stirred at ambient température for 4 hours and evaporated, the residue was coevaporated with CCL, 15 which gave Compound (64) (14.5 g, 99%).
Compound (65) (ZE33-0116)
A solution of pyridine (22 g) and MeOH (13 g) in 100 ml of CH2CI2 was added dropwise at 55°C to a solution of Compound (64) (14.5 g, 25 mM) in 120 ml of CH2CI2. The mixture was 20 stirred at -30°C for 0.5 h and then at ambient température for 3 h. The mixture was evaporated and the residue was washed with hexane, which gave Compound (65) (ZE330116) (9.85 g, 100%).
ZE33-0117 (T74e)
Compound (67)
Protected glycerol (66) (4.1 g, 31 mM) was added to a solution of TOFA (3) (7.9 g, 24 mM) in 500 ml of CH2CI2, followed by the addition of EDCI (6.3 g, 33 mM) and DMAP (0.61 g, 5 mM) and the mixture was stirred at ambient température for 20 h. The solvent was evaporated, the residue was dissolved again in EtOAc, washed with H2O and dried over Na2SO« and evaporated. The residue was purified by coiumn chromatography on silica gel, elution being performed with 15% EtOAc in hexane, which gave Compound (67) (9.16 g, 86%).
Compound (68) (ZE33-0117)
0.4 ml of 3 M HCl in dioxane was added to a solution of Compound (67) (8.78 g, 20 mM) in 400 ml of MeOH and the mixture was stirred at ambient température for 0.5 hours. The mixture was evaporated and subsequently coevaporated with MeOH to a volume of approx. 20 ml, the pellet formed was isoîated by filtration and dried, which gave Compound (68) (ZE33-0117) (6.9 g, 87%).
The compounds according to the invention can advantageously be incorporated into cosmetic or dermatological préparations.
The préparations or uses according to the invention may be in the form of liquid compositions that can be applied using brushes or spreaders, roll-on devices or atomizers, as sticks and in the form of Systems that can be applied from normal bottles and containers, for example creams, gels or lotions. For example, they may thus constitute a solution, an émulsion of water-in-oil (W/O) type or of oil-in-water (O/W) type, or a multiple émulsion, for example of water-in-oil-in-water (W/O/W) type, oil-in-water-in-oil (O/W/O) type, a gel, a hydrodispersion, a lamellar phase, a liquid isotropie solution phase, a micellar phase, a solid or dispersed mono- or polyhexagonal phase, a solid or dispersed mono- or polycubic phase, a lyotropic phase, a crystalline phase, a solid stick or else an aérosol.
Furthermore, the préparations or uses according to the invention may advantageously be in the form of facial toners, tinctures, cleansing formulations, pads, cotton balls or wipes, and in the form of tonies or shampoos.
Advantageously, the pH of the préparations or uses according to the invention is set in the weakly acidic to neutral range, preferably from 3.0 - 7.0, particularly preferably from 5.0 - 6 5.
The formulations according to the invention may hâve the customary composition and be used for the treatment of the skin and/or the hair in the sense of a dermatological treatment 10 or a treatment in the sense of care cosmetics. They may alternatively be used in makeup
Products in décorative cosmetics or in the cosmetic and dermatological cleansing products.
It is of course known to those skilled in the art that cosmetic préparations are usually not conceivable without the customary auxiliaries and additives. The cosmetic and dermatological préparations according to the invention may accordingly further comprise cosmetic auxiliaries, such as those usually used in such préparations; for example consistency regulators, preservatives, stabilizers, fillers, perfumes, pigments that hâve a coloring effect, thickeners, suspending agents, buffer mixtures, surface-active substances, emulsifiers, softening, moistening and/or moisturizing substances, anti-inflammatory substances, additional active ingrédients such as vitamins or proteins, light stabilizers, insect repeilents, bactéricides, water, salts, antimicrobial, proteolytic or keratolytic substances, médicaments or other customary constituents of a cosmetic or dermatological formulation such as alcohols, polyols, polymers, foam stabilizers, organic solvents or else electrolytes.
The amounts of carrier substances to be used in each case can easily be determined by those skilled in the art by simple trial and error, depending on the type of the product in question.
As customary carrier substances for the production of the préparations or uses according to 30 the invention, it is possible to use not only water, éthanol and isopropanol, glycerol and propylene glycol, but also skincare lipids or lipoids, such as decyl oleate, cetyl alcohol, cetylstearyl alcohol and 2-octyldodecanol, in the proportions customary for such préparations, and mucilaginous substances and thickeners, for example hydroxyethylcellulose or hydroxypropylcellulose, polyacrylie acid, polyvinylpyrrolidone, but 35 additionally also, in small amounts, cyclic silicone oils (polydimethylsiloxanes) and liquid polymethylphenylsiloxanes of low viscosity.
Emulsifiers that can be used in the préparations in a small amount, for exampie 1% to 6% by weight, based on the total composition, and that hâve proved to be suitable for the production of the préparations or uses according to the invention, which are advantageously to be applied as liquid or solid préparations to the desired skin régions, are noniogenic types, 5 such as polyoxyethylene fatty alcohoi ethers, for exampie cetostearyl alcohol potyethylene glycol ether with 12 or 20 added-on ethylene oxide units per molécule, cetostearyl alcohol, and sorbitan esters and sorbitan ester-ethylene oxide compounds (for example sorbitan monostearate and polyoxyethylene sorbitan monostearate), and long-chain higher molecular weight waxy polyglycol ethers. However, a whole range of other emulsifiers or emulsifier 10 mixtures which are usually used in cosmetic préparations are additionally also suitable.
These include for example, but are not restricted to, glyceryl stéarate citrate, PEG-40 stéarate or else polyglyceryl-3 methylglucose distearate, stearic acid, steareth-2 and steareth-21.
The oil phase of the préparations according to the invention is advantageously setected from the group of esters of saturated and/or unsaturated, branched and/or unbranched alkanecarboxylic acids having a chain îength of 3 to 30 carbon atoms and saturated and/or unsaturated, branched and/or unbranched alcohols having a chain Iength 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 Iength of 3 to 30 carbon atoms.
In addition, the oil phase may advantageously be selected from the group of branched and unbranched hydrocarbons and hydrocarbon waxes, silicone oils, dialkyl ethers, the group of 25 saturated or unsaturated, branched or unbranched alcohols, and fatty acid triglycérides, namely the triglyceryI esters of saturated and/or unsaturated, branched and/or unbranched alkanecarboxylic acids having a chain Iength of 8 to 24, in particular 12-18, carbon atoms. The compounds of the oil phase may be of synthetic, semi-synthetic or natural origin.
Any blends of such oil and wax components may also advantageously be used in the context of the présent invention.
The content of the oil phase is advantageously between 1 % and 50% by weight, based on the total weight of the préparations, preferably 2% - 30% by weight, especially preferably 35 below 10% by weight.
The cosmetic and/or dermatological formulations according to the invention are used by applying a suffirent amount to the skin, scalp and/or the hair in the manner customary for cosmetics and dermatological products
Lipid assay for testing the effectiveness of TOFA dérivatives according to the invention
To détermine the lipid-reducîng effect of active ingrédients, primary cell lines from sebaceous glands of different human donors are used. The cells are cuitured for a total of 7 days. After the cells are seeded on day 1, the active ingrédient treatment is effected on day 3 and day 5. On day 7, the cells are stained with the dye AdipoRed. This makes it possible to fluorescently stain and to quantify the lipid droplets inside the cells. The dye fluorescein diacetate (FDA), which is converted by living cells, is also used to monitor the vitality of the cells. The resulting fluorescence signal can likewise be quantified. The effect of an active ingrédient can be measured and presented as the ratio of the AdipoRed and FDA fluorescence signal relative to the ratio of the corresponding solvent. The tested substances were dissolved in dimethyl sulfoxide (DMSO); ail results were accordingly normalized to the DMSO-treated control.
The examples that follow are intended to elucidate, but not restrict, the invention. Unless stated otherwise, the figures are based on % by weight.
| Example 1 | Example 2 | Example 3 | Example 4 | |
| Caprylic/Capric Triglycéride | ||||
| Propylene Glycol + Aqua | 5.00 | 5.00 | ||
| Citric Acid | 0.00 | 0.00 | 0.00 | |
| Cetearyl Alcohol | 2.00 | |||
| Aqua + Trisodium EDTA | 1.00 | |||
| Phenoxyethanol + Aqua | 0.40 | |||
| Dimeth icône | 3.00 | |||
| Glycerol | 6.00 | 4.00 | 4.00 | 10.00 |
| PEG-40 Hydrogenated Castor Oil | 1.00 | 5.00 | ||
| Butylène Glycol + Aqua | 20.00 | 10.00 | 10.00 | |
| Hydroxyethylcellulose + Disodium Phosphate + Sodium Phosphate | 0.15 | |||
| Alcohol Denat. + Aqua | 8.00 | 50.00 | 40.00 | 40.00 |
| Xanthan Gum | 0.15 | |||
| Acrylates/C 10-30 Alkyl Acrylate Crosspolymer | 0.15 | |||
| PEG-150 Distearate | 0 50 | |||
| Tapioca Starch + Aqua | 1.00 | |||
| Ammonium Acryloyldimethyltaurate/VP Copolymer + Aqua | 0.50 | 0.65 | 0.65 | 0.65 |
| Methylpropanediol | 4.00 | 4.00 | ||
| Sodium Stearoyl Glutamate + Sodium Chloride | 0.30 | |||
| TOFA dérivative T74e | 2.00 | 1.00 | 2.00 | 2.00 |
| Water to | 100.00 | 100.00 | 100.00 | 100.00 |
| Example 5 | Example 6 | Example 7 | |
| Capryiic/Capric T riglyceride | 4.00 | ||
| Propylene Glycol + Aqua | 5.00 | ||
| Citrie Acid | 0.00 | ||
| Cetyl Alcohol | 3.00 | ||
| Aqua + Trisodium EDTA | 1.00 | 1.00 | |
| Diisopropyl Adipate | 10.00 | 10.00 | |
| Phenoxyethanol + Aqua | 0.50 | 0.80 | |
| Hydrogenated Coco-Glycerides | 2.00 | ||
| Glycerol | 10.00 | 3.00 | 9.00 |
| Aqua + Sodium Hydroxide | 0.06 | 0.01 | |
| PEG-40 Hydrogenated Castor Oil | 5.00 | ||
| Butylène Glycol + Aqua | 10.00 | 5.00 | |
| Alcohol Denat. + Aqua | 40.00 | 10.00 | 5.00 |
| Xanthan Gum | 0.30 | 0.30 | |
| Acrylates/C 10-30 Alkyl Acrylate Crosspolymer | 0.20 | ||
| Glyceryl Stéarate Citrate | 2.00 | ||
| Acrylates/C 10-30 Alkyl Acrylate Crosspolymer | 0.20 | ||
| Ammonium Acryloyldimethyltaurate/VP Copolymer + Aqua | 0.65 | ||
| Methylpropanediol | 4.00 | ||
| TOFA dérivative T113e | 0.50 | 0 50 | 1.00 |
| Water to | 100.00 | 100.00 | 100.00 |
Claims (6)
1. Compounds of the general formula (1 )
5 in which R = n-tetradecyl, and R1, Rz and R3 independently are -H, a hydroxyl group, a -Ct-Cz4 alkyl substituted by one or more hydroxyl groups with the proviso that at most two of the groups R1, R2 and R3 represent an H atom or a
10 hydroxyl group.
2. The compounds as claimed in claim 1, characterized in that they are selected from the following group:
3. Médicinal or cosmetic topical préparations containing one or more compounds of formula (1) as claimed in claim 1 or 2 at an effective concentration.
4. Médicinal or cosmetic topical préparations containing one or more compounds of
20 formula (1) as claimed in claim 1 or 2 présent at concentrations of 0.0001 - 40.00% by weight, preferably 0.005 - 20.00% by weight, particularly preferably 0.001 - 6.00% by weight, in each case based on the total weight of the composition.
5. The cosmetic use of one or more compounds of formula (1 ) as claimed in claim 1 or 2 for reducing sébum production in human skin.
6. One or more compounds of formula (1) as claimed in claim 1 or 2 for the therapeutic 5 treatment of greasy and/or impure skin and/or mild forms of acné and/or greasy hair and/or greasy scalp and/or seborrhea.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102022201277.1 | 2022-02-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA22073A true OA22073A (en) | 2025-12-02 |
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