EP4054575A1

EP4054575A1 - Novel method

Info

Publication number: EP4054575A1
Application number: EP20803454.6A
Authority: EP
Inventors: Remo CAMPICHE; Dominik Imfeld
Original assignee: DSM IP Assets BV
Current assignee: DSM IP Assets BV
Priority date: 2019-11-06
Filing date: 2020-11-03
Publication date: 2022-09-14
Also published as: WO2021089501A1; CN114615969B; CN114615969A

Abstract

The present invention relates to a method for preventing and/or treating dry skin and loss of natural oiliness by the external application of a topical composition comprising certain amides.

Description

NOVEL METHOD

Almost all menopausal and post-menopausal women, many women over thirty-five, and most women over forty years of age, and some older men frequently complain that the natural oiliness of their skin is markedly diminished resulting in dry skin, which is e.g. supported by Pochi et al, who describes the reduction in mean sebum (oil) secretion in males and females in relation to advancing age. (Advances in Biology of skin, Vol VI: Aging, edited by Montagna, W., Pergamon Press, N.Y. (1965)).

Xeroderma, i.e., dry skin, however, can also be caused by various other factors.

Dry skin problems generally affect the entire body. The face and head, however, have the highest population of sebaceous glands and therefore those areas are the most vulnerable to these problems

Dry skin can be treated by increasing the endogenous production and secretion of natural sebum which in turn enhances the water protective barrier of the skin, thus acting as a natural moisturizer.

Oral testosterone therapy increases skin oil production in menopausal and post-menopausal women. However, it produces unwanted superfluous facial and body hair and other systemic masculinizing side effects and is therefore rarely used. Thus, there is an ongoing need for topical treatment to treat dry skin, which allow to overcome the unwanted effects on a localized basis, only at the places where such treatments are desired or necessary.

Surprisingly it has been found that certain amides are able to increase the sebum production in sebaceous glands and are thus able to counteract dry skin problems.

Thus, in a first embodiment, the present invention relates to a method of preventing and/or treating dry skin in a person in need thereof, said method comprising topically administering to the area of dry skin a composition comprising an effective amount of an amide of formula (I) wherein X is CH or N,

Y is CHR⁸ or O, n is 0, 1 or 2,

R¹, R² and R³ are independently of each other selected from the group consisting of H, OH, a halogen atom, a carbamoyl group and Ci-C₆alkyl group, and

R⁴, R⁵, R⁶, R⁷and, R⁸ are independently of each other selected from H or a Ci- C₆alkyl group.

In all embodiments of the present invention particularly advantageous compounds according to formula (I) contain only one residue selected from the group consisting of OH, a halogen atom and a carbamoyl group (C=ONH ).

Examples of Ci-C₆alkyl groups according to the present invention are unbranched Ci-C₆alkyl or branched C3-C6alkyl 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. In all embodiments of the present invention particularly preferred Ci-C₆alkyl groups are unbranched Ci-C₃alkyl groups, more preferably Ci-C2alkyl groups, most preferably methyl groups.

Suitable halogen atoms encompass F, Cl, Br and I. Preferably in all embodiments of the present invention the halogen atoms are either F or Cl.

It is well understood, that the present invention encompasses (if applicable) the compounds of formula (I) as optically pure isomers such as e.g. as pure enantiomers or as mixture of different isomers such as e.g. as racemates.

Particularly suitable compounds of formula (I) according to the present invention are compounds of formula (II) wherein X is CH or N,

R¹, R² and R³ are independently of each other selected from the group consisting of H, OH, a halogen atom, a carbamoyl group and a Ci-C₆alkyl group, and

R⁴, R⁵ and R⁸ are independently of each other H or a Ci-C₆alkyl group.

Further particularly suitable compounds of formula (I) according to the present invention are compounds of formula (III) wherein R¹ and R³ are independently of each other selected from the group consisting of H, OH, a halogen atom (preferably F) and a Ci-C₆alkyl group,

R² is a Ci-C₆alkyl group, and

R⁴, R⁵, R⁶ and R⁷ are independently of each H or a Ci-C₆alkyl group.

Additional advantageous compounds of formula (I) are compounds of formula (IV) wherein X is CH or N, and

R¹, R² and R³are independently of each other selected from the group consisting of H, OH, a halogen atom and a Ci-C₆alkyl group.

Most preferred compounds of formula (I) in all embodiments of the present invention are

Such compounds as well as methods for their preparation are e.g. disclosed in WO2017012890.

The most preferred compound in all embodiments of the present invention is [1 ,1'-biphenyl]-3- yl(hexahydro-1H-azepin-1-yl)-methanone (INCI name: Biphenyl Azepanyl Methanone, CAS No: 1910069-14-5), which is e.g. commercially available under the tradename BEL-EVEN™ from DSM Nutritional Products Ltd.

As dry skin is often associated with redness, flakiness and itchiness, the methods according to the present invention also encompass a method to prevent skin to become dry, red, flaky and/ or itchy respectively to minimize the symptoms of dry skin such as in particular red, flaky and itchy skin. This method can in particular be of use in the application of skin cleansing products, as the application thereof generally leads to sebum and fat removal and often leads, in particular after repeated use, to dry skin. Thus, the addition of a compound of formula (I) according to the present invention into skin cleansing products such as e.g. shampoos, skin cleansers, soaps such as soap bars, skin detergent compositions is particularly suitable as it can mitigate the adverse effects associated with a (frequent) use thereof i.e. is able to prevent and/or treat dry skin and loss of natural oiliness caused by the use of skin cleansing products.

In all embodiments of the present invention, the amount of the compound of formula (I) is preferably selected in the range of about 0.00001 to 0.5 wt.-%, more preferably in the range of 0.0001 to 0.25 wt.-%, most preferably in the range of 0.0001 to 0.1 wt.-% based on the total weight of the composition.

Conventional over-the-counter preparations for treating acne generally act as drying agents and exfoliators, which are generally irritating to the skin and counterproductive to the general treatment of dry skin. According, a further embodiment of the present invention relates to the mitigation of the effects of such preparations. Thus, in one preferred embodiment, the present invention relates to a method according to the present invention wherein the composition further comprises a keratolytic agent.

In a further preferred embodiment, the present invention relates to a method according to the present invention for the prevention and/ or treatment of dry skin in persons suffering from and/ or with a tendency for acne, said method encompassing the step of topically applying to said persons a composition comprising next to the compound of formula (I) a keratolytic-agent.

Advantageously, the amide of formula (I) is present in the compositions comprising a keratolytic agent in an amount which is effective to increase sebum production, while the keratolytic agent is present in an amount sufficient to counteract the formation of acne-like skin lesions without diminishing the effectiveness of the amide of formula (I).

Preferred keratolytic agents according to the present invention are selected from hydroxybenzoic acids, alpha-hydroxycarboxylic acids and urea. Ortho-hydroxybenzoic acid (salicylic acid) is particularly preferred. The vehicle may be any of a wide variety of preferably non-drying preparations such as tinctures, creams, ointments, gels and lotions.

Particularly advantageous keratolytic agent are selected from the group of salicylic acid and/ or alpha-hydroxycarboxylic acid.

If present, salicylic acid is preferably used in an amount of 0.1 to 2 wt.-%, based on the total weight of the composition. flf present, the alpha-hydroxycarboxylic acid is preferably used in an amount of 0.1 to 10 wt.- %, based on the total weight of the composition

The compositions according to the present invention are preferably cosmetic or pharmaceutical compositions which are topically applied to mammalian keratinous tissue such as in particular to human skin or the human scalp.

The term "cosmetic composition" as used in the present application refers to cosmetic compositions as defined under the heading "Kosmetika" in Rompp Lexikon Chemie, 10th edition 1997, Georg Thieme Verlag Stuttgart, New York as well as to cosmetic compositions as disclosed in A. Domsch, "Cosmetic Compositions", Verlag fur chemische Industrie (ed. H. Ziolkowsky), 4^th edition, 1992. The cosmetic or pharmaceutical compositions according to the present invention comprise a dermatologically acceptable carrier i.e. a physiologically acceptable medium, that is to say a medium compatible with keratinous substances, such as the skin, mucosa, and keratinous fibers. Preferably, the dermatologically acceptable carrier is a cosmetically or pharmaceutically acceptable carrier.

The term cosmetically or pharmaceutically acceptable carrier refers to all carriers and/or excipients and/ or diluents conventionally used in cosmetic compositions such as in particular oils (cosmetic oils), water, surfactants, emulsifiers, thickeners.

The topical compositions according to the present invention are generally prepared by admixing the compound of formula (I) in the amounts indicated herein with a suitable carrier.

The exact amount from carrier will depend upon the actual level of the compound of formula (I) and any other optional ingredients that one of ordinary skill in the art would classify as distinct from the carrier (e.g., other active ingredients).

In an advantageous embodiment, the cosmetic or pharmaceutical compositions according to the present invention comprise from about 50% to about 99%, preferably from about 60% to about 98%, more preferably from about 70% to about 98%, such as in particular from about 80% to about 95% of a carrier, based on the total weight of the cosmetic composition.

In a particular advantageous embodiment, the carrier consists furthermore of at least 40 wt.-%, more preferably of at least 50 wt.-%, most preferably of at least 55 wt.-% of water, such as in particular of about 55 to about 90 wt.-% of water.

The compositions of the invention (including the carrier) may comprise conventional adjuvants and additives, such as preservatives/antioxidants, fatty substances/oils, organic solvents, silicones, thickeners, softeners, emulsifiers, antifoaming agents, aesthetic components such as fragrances, surfactants, fillers, anionic, cationic, nonionic or amphoteric polymers or mixtures thereof, propellants, acidifying or basifying agents, dyes, colorings/colorants, abrasives, absorbents, chelating agents and/ or sequestering agents, essential oils, skin sensates, astringents, pigments or any other ingredients usually formulated into such compositions.

In accordance with the present invention, the compositions according to the invention may also comprise further cosmetically active ingredients conventionally used in cosmetic or pharmaceutical compositions. Exemplary active ingredients encompass skin lightening agents; UV-filters, agents for the treatment of hyperpigmentation; agents for the prevention or reduction of inflammation; firming, moisturizing, soothing, and/ or energizing agents as well as agents to improve elasticity and skin barrier.

Examples of cosmetic excipients, diluents, adjuvants, additives as well as active ingredients commonly used in the skin care industry which are suitable for use in the cosmetic compositions of the present invention are for example described in the International Cosmetic Ingredient Dictionary & Handbook by Personal Care Product Council (http://www.personalcarecouncil.org/), accessible by the online INFO BASE (http://online.personalcarecouncil.org/jsp/Home.jsp), without being limited thereto.

The necessary amounts of the active ingredients as well as the excipients, diluents, adjuvants, additives etc. can, based on the desired product form and application, easily be determined by the skilled person. The additional ingredients can either be added to the oily phase, the aqueous phase or separately as deemed appropriate.

The cosmetically active ingredients useful herein can in some instances provide more than one benefit or operate via more than one mode of action.

Of course, one skilled in this art will take care to select the above mentioned optional additional ingredients, adjuvants, diluents and additives and/ortheir amounts such that the advantageous properties intrinsically associated with the combination in accordance with the invention are not, or not substantially, detrimentally affected by the envisaged addition or additions.

Preferably, the cosmetic or pharmaceutical compositions according to the invention are in the form of a suspension or dispersion in solvents or fatty substances, or alternatively in the form of an emulsion or micro emulsion (in particular of 0/W- or W/O-type), PIT-emulsion, nano emulsion, multiple emulsion (e. g. O/W/O- or W/O/W-type), pickering emulsion, hydrogel, lipogel, one- or multiphase solution or vesicular dispersion.

The cosmetic or pharmaceutical compositions in accordance with the invention can be in the form of a liquid, lotion, a thickened lotion, a gel, a cream, a milk, an ointment or a paste.

The cosmetic or pharmaceutical compositions according to the invention have a pH in the range of 3-10, preferably in the range of pH of 3-8, most preferred in the range of pH 3-7.5. The pH is adjusted by methods known to a person skilled in the art, e.g. by using an acid such as a hydroxy acid including glycolic acid, lactic acid, malic acid, citric acid and tartaric acid or a base such as e.g. sodium or potassium hydroxide or ammonium hydroxide as well as mixtures thereof.

Preferably, in the compositions according to the invention the acid, if present, is used in an amount from at least 0.0001 wt.-%, such as e.g. in an amount from 0.01-1 wt.-%, in particular in an amount from 0.01 to 0.5 wt.-%.

The cosmetic compositions according to the present invention advantageously comprise an additional preservative or preservation booster. Particular suitable preservatives or preservation booster in all embodiments of the present invention are benzoic acid, sodium benzoate, sorbic acid, potasssium sorbate, dehydroacetic acid, caprylhydroxamic acid, alcohol, alcohol denat., hydroxyacetophenone, caprylyl glycol, pentylene glycol, 1 ,2-hexanediol, decylene glycol, monoglycerides such as glyceryl laurate, propylene glycol caprylate, propylene glycol heptanoate as well as mixtures thereof. When present, the preservative and/ or preservation booster is preferably used in an amount of 0.01 to 2 wt.-%, more preferably in an amount of 0.05 to 1.5 wt.-%, most preferably in an amount of 0.1 to 1.0 wt.-%, based on the total weight of the composition.

It is furthermore preferred that the topical compositions according to the present invention are free of any parabenes, benzethoniumchlorid, piroctone olamine, lauroylarginat, methylisothiazolinon, chlormethylisothiazolinon, bronopol, benzalkoniumchloride, formaldeh releasing compounds, salicylic acid, triclosan, DMDM hydantoin, chlorphenesin and IPBC (lodopropinylbutyl carbamate).

The cosmetic compositions according to the present invention are in particular skin care preparations and/ or functional preparations such as most in particularly skin care preparations.

Examples of skin care preparations are, in particular, light protective preparations (sunscreen preparations), anti-ageing preparations, preparations for the treatment of photo-ageing, body oils, body lotions, body gels, treatment creams, skin protection ointments, moisturizing preparations such as moisturizing gels or moisturizing sprays, face and/or body moisturizers, as well as skin lightening preparations.

Examples of functional preparations are cosmetic compositions containing active ingredients such as hormone preparations, vitamin preparations, vegetable extract preparations, anti- ageing preparations, and/or antimicrobial (antibacterial or antifungal) preparations without being limited thereto.

The topical cosmetic compositions according to the present invention are advantageously O/W emulsions, W/O emulsions and/ or gels such as shower gels.

Furthermore, the topical compositions in the form of O/W emulsions, W/O emulsions and/ or gels according to the present invention are skin care preparation intended for the treatment of acne, for maintaining a healthy skin and for the treatment of people suffering from dry and/ or irritated skin due to low sebum production after menopause and/or age related low sebaceous gland activity.

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

Examples

In vitro assay on sebum modulation

The immortalized human sebocyte cell line (SEB0662) from Bioalternatives responds to lipogenic stimulators. In this model active androgens e.g. testosterone added to basal non- supplemented medium (Keratinocyte-SFM medium) induce strong specific responses among others the induction of sebocyte differentiation program and lipid synthesis storage. It is possible to use the assay under basal conditions (without testosterone stimulation) to test compounds for androgen like effects such as stimulating sebum lipid synthesis and under testosterone stimulated conditions by adding compounds to see further stimulation of sebum lipid synthesis or inhibition of sebum lipid synthesis.

Example 1: Modulation lipogenesis in human sebocyte cell line at basal conditions

For this testing the immortalized sebocyte cell line SEB0662AR established at Bioalternatives

(Gencay, France) was used:

Cell Culture: The sebocytes were seeded in 96 well plates and cultured for 24 hours in sebocytes culture medium. The medium was replaced by assay medium (Keratinocyte-SFM supplemented with Gentamycin 25ug/ml) containing or not (control) the test compounds or testosterone at 1nM. The cells were incubated for 7 days. Within the seven-day period after 3 days half of the medium was removed, and the treatments were renewed (including testosterone stimulation). All experimental conditions were performed at n = 3. Lipid content analysis (Biodipy labelling^'): At the end of the incubation time, the cells were rinsed, fixed and permeabilized. The lipid droplets contained in the cells were then labeled using a specific Bodipy fluorescent lipid probe labeling mainly neutral lipids (molecular probes ref. D-3922) In parallel the cell nuclei were stained using a Hoechst 33258 solution. The acquisition of the images was performed using INCell Analyzer 2200 (GE Healthcare). The labeling was quantified by fluorescence intensity measurement normalized to the total number of cells. The fluorescence intensity was analyzed exclusively in the lipid droplets (image analysis program based on object segmentation)

The results after stimulation from basal conditions are shown in the table below:

*1 ,1 '-biphenyl]-3-yl(azepan-1 -yl) methanone

Conclusion: Similar as testosterone the compound IV-f stimulated sebum lipid accumulation as can be seen by the dose dependent increase of lipid fluorescence units.

Example 2: Modulation lioogenesis in androgen stimulated human sebocvte cell line

(Gencay, France) was used.

Cell Culture: The sebocytes were seeded in 96 well plates and cultured for 24 hours in sebocytes culture medium. The medium was replaced by assay medium (Keratinocyte-SFM supplemented with Gentamycin 25ug/ml) containing or not (control) the test compounds or the reference inhibitor compound (1uM dutasteride) and the cells were pre-incubated for 4 hours. Then, 1nM of testosterone was added to all conditions except to the non-stimulated control and the cells were incubated for 7 days. Within the seven-day period after 3 days half of the medium was removed, and the treatments were renewed (including testosterone stimulation). All experimental conditions were performed at n = 3.

Lipid content analysis (Biodipy labelling): same procedure as described in example 1

The results are shown in the table below:

*[1 ,1'-biphenyl]-3-yl(azepan-1-yl) methanone

Conclusion: Also, in combination with testosterone the compound IV-f further stimulated sebum lipid accumulation as can be seen by the dose dependent increase of lipid fluorescence units. Dutasteride inhibited sebum production as expected and served as control compound.

Example 3: Formulation with eratolytic agent

All-day cream with light and smooth texture to improve the appearance of acne flare ups and to even the skin tone of leftover acne discoloration.

¹Containing 0.2% of [1 ,1'-biphenyl]-3-yl(azepan-1 -yl) methanone (i.e. compound IV-f)

Procedure

1 Heat up phase A and B separately to 80° C while stirring.

2 When everything is dissolved, add phase A to B while stirring and homogenize the emulsion.

3 Cool down the emulsion to 30-35 °C then add phase C.

4 Adjust the pH to about 7.0 with D

Claims

1. A method of preventing and/or treating dry skin and loss of natural oiliness in a person in need thereof, said method comprising topically administering to the area of dry skin a composition comprising an effective amount of an amide of formula (I)

X is CH or N,

Y is CHR⁸ or O, n is 0, 1 or 2, preferably 1 or 2,

R¹, R² and R³are independently of each other selected from the group consisting of H, OH, a halogen atom, a carbamoyl group and Ci-C₆alkyl group, and R⁴, R⁵, R⁶, R⁷ and R⁸ are independently of each other H or a Ci-C₆alkyl group.

2. The method according to claim 1 , characterized in that the compound of formula (I) contains only one residue selected from the group consisting of OH, a halogen atom and a carbamoyl group.

3. The method according to claim 1 or 2, characterized in that the Ci-C₆alkyl group is an unbranched Ci-C₃alkyl group, more preferably a Ci-C alkyl group, most preferably a methyl group.

4. The method according to anyone of the preceding claims, characterized in that the halogen atom is F or Cl.

5. The method according to anyone of the preceding claims, characterized in that the compound of formula (I) is (4-methylpiperidin-1-yl) (3-(6-methylpyridin-3- yl)phenyl)methanone (ll-a), (4'-hydroxy-[1,1'-biphenyl]-3-yl)(4-methylpiperidin-1- yl)methanone (ll-b), (4'-fluoro-[1 ,T-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (ll-c), (3'-fluoro-4'-methyl-[1 ,T-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (II- d), (2'-chloro-[1 ,1'-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (ll-e), (4'- methyl-[1 ,1'-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (ll-f), (4'-chloro-[1 ,1 biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone (ll-g), (3,3-dimethylpiperidin-1- yl)(3'-fluoro-4'-methyl-[1 ,1'-biphenyl]-3-yl)methanone (ll-h), 3'-(4-methylpiperidine-1- carbonyl)-[1 ,1'-biphenyl]-4-carboxamide (ll-i), (3'-hydroxy-[1 ,1'-biphenyl]-3-yl)(4- methylpiperidin-1-yl)methanone (ll-j), 3'-(4-methylpiperidine-1-carbonyl)-[1 ,T- biphenyl]-3-carboxamide (ll-k), (2,2-dimethylmorpholino) (3'-fluoro-4'-methyl-[1 ,T- biphenyl]-3-yl)methanone (lll-a), (2,6-dimethylmorpholino) (3'-fluoro-4'-methyl-[1 ,T- biphenyl]-3-yl)methanone (lll-b), (2,6-dimethylmorpholino) (4'-methyl-[1 , 1 biphenyl]-3-yl)methanone (lll-c), azepan-1-yl(3'-fluoro-4'-methyl-[1 ,1'-biphenyl]-3- yl)methanone (IV-a), azepan-1-yl(4'-chloro-[1 ,1'-biphenyl]-3-yl)methanone (IV-b), azepan-1-yl(4'-methyl-[1,1'-biphenyl]-3-yl)methanone (IV-c), azepan-1-yl(4'- hydroxy-[1 ,1'-biphenyl]-3-yl)methanone (IV-d), azepan-1-yl(3-(6-methylpyridin-3- yl)phenyl)methanone (IV-e), [1 ,1'-biphenyl]-3-yl(azepan-1-yl)methanone (IV-f), or azepan-1-yl(3',4'-dimethyl-[1 ,1'-biphenyl]-3-yl)methanone (IV-g).

6. The method according to any one of the preceding claims, characterized in that the amount of the compound of formula (I) in the composition is selected in the range of 0.00001 to 0.5 wt.-%, preferably in the range of 0.0001 to 0.25 wt.-%, most, preferably in the range of 0.0001 to 0.1 wt.-% based on the total weight of the composition.

7. The method according to any one of the preceding claims, characterized in that the composition further comprises a keratolytic agent.

8. The method according to claim 7, characterized in that the keratolytic agent is at least one of salicylic acid and an alpha hydroxy acid.

9. The method according to any one of the preceding claims, characterized in that the person is a person suffering from acne and/ or has a genetic tendency for acne.

10. The method according to any one of the preceding claims, characterized in that the composition is a cosmetic or pharmaceutical composition.

11 . The method according to any one of the preceding claims, characterized in that the composition is an O/W emulsion, a W/O emulsion or a gel.

12. The method according to any one of the preceding claims, characterized in that the composition comprises water and at least one agent selected from the group consisting of surfactants, emulsifiers, thickeners and oils.

13. Use of a compound of formula (I) as defined in claim 1 to stimulate the sebum production in sebaceous glands.

14. The method according to any one of the preceding claims, characterized in that the person is suffering from dry and irritated skin due to low sebum production after menopause and/or age related low sebaceous gland activity.