CN114615969A

CN114615969A - Novel process

Info

Publication number: CN114615969A
Application number: CN202080076046.5A
Authority: CN
Inventors: 里莫·坎皮彻; 多米尼克·伊姆费尔德
Original assignee: DSM IP Assets BV
Current assignee: DSM IP Assets BV
Priority date: 2019-11-06
Filing date: 2020-11-03
Publication date: 2022-06-10
Anticipated expiration: 2040-11-03
Also published as: CN114615969B; EP4054575A1; WO2021089501A1

Abstract

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

Description

Novel process

Almost all menopausal and postmenopausal women, many women over the age of 35, and most women over the age of 40 and some elderly men often complain of a significant reduction in the natural oil quality of their skin, leading to dry skin, supported by, for example, Pochi et al, who describes a decrease in average sebum (oil) secretion in men and women with increasing age. (Advances in Biology of skin, Vol VI: Aging, edge by Montagna, W., Pergamon Press, N.Y. (1965)).

However, xeroderma, i.e., dry skin, may also be caused by a variety of other factors.

Skin dryness problems usually affect the entire body. However, the face and head have the most sebaceous gland populations, and therefore these areas are most vulnerable to these problems.

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

Oral testosterone therapy increases skin oil production in menopausal and post-menopausal women. However, it produces unwanted facial and body hair and other systemic androgenic side effects and is therefore rarely used.

Thus, there is a continuing need for topical treatments to treat dry skin only where such treatment is desired or needed, such topical treatments allowing undesirable effects to be overcome on a topical basis.

Surprisingly, it has been found that certain amides are capable of increasing sebum production in sebaceous glands and thus are capable of combating the problem of skin dryness.

Thus, in a first embodiment, the present invention relates to a method for preventing and/or treating dry skin in a human in need thereof, said method comprising topically applying to the dry skin area a composition comprising an effective amount of an amide of formula (I)

Wherein X is CH or N, and the compound is shown in the specification,

y is CHR⁸Or an oxygen-containing gas,

n is 0, 1 or 2,

R¹、R²and R³Independently of one another, selected from the group consisting ofGroup (2): H. OH, halogen atom, carbamoyl group and C₁-C₆An alkyl group, and

R⁴、R⁵、R⁶、R⁷and R⁸Independently of one another, selected from H or C₁-C₆An alkyl group.

In all embodiments of the present invention, particularly advantageous compounds according to formula (I) contain only one group selected from the group consisting of OH, halogen atom and carbamoyl group (C ═ ONH)₂) Residues of the group consisting.

C according to the invention₁-C₆Examples of alkyl radicals are unbranched C₁-C₆Alkyl or branched C₃-C₆Alkyl radicals, for example methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl groups. In all embodiments of the invention, C is particularly preferred₁-C₆Alkyl radicals being unbranched C₁-C₃Alkyl group, more preferably C₁-C₂Alkyl groups, most preferably methyl groups.

Suitable halogen atoms encompass F, Cl, Br and I. Preferably, in all embodiments of the invention, the halogen atom is F or Cl.

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

Particularly suitable compounds of the formula (I) according to the invention are compounds of the formula (II)

Wherein X is a group selected from the group consisting of CH and N,

R¹、R²and R³Independently of each other selected from the group consisting of: H. OH, halogen atom, carbamoyl group and C₁-C₆An alkyl group, and

R⁴、R⁵and R⁸Independently of one another, H or C₁-C₆An alkyl group.

Further particularly suitable compounds of the formula (I) according to the invention are compounds of the formula (III)

Wherein R is¹And R³Independently of each other selected from the group consisting of: H. OH, halogen atoms (preferably F) and C₁-C₆An alkyl group, a carboxyl group,

R²is C₁-C₆Alkyl radical, and

R⁴、R⁵、R⁶and R⁷Independently of one another, H or C₁-C₆An alkyl group.

Additionally advantageous compounds of the formula (I) are compounds of the formula (IV)

Wherein X is CH or N, and

R¹、R²and R³Independently of each other selected from the group consisting of: H. OH, halogen atom and C₁-C₆An alkyl group.

In all embodiments of the invention, the most preferred compound of formula (I) is

Such compounds and methods for their preparation are disclosed, for example, in WO 2017012890.

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 azepan alkyl methanone, CAS number: 1910069-14-5), which is available, for example, from DSM Nutritional Products Ltd under the trade name BEL-EVEN^TMAre commercially available.

Since dry skin is often associated with redness, flaking and itching, the method according to the present invention also encompasses a method of preventing the skin from drying out, redness, flaking and/or itching, respectively, in order to minimize the symptoms of dry skin, such as, in particular, redness, flaking and itching of the skin. This method is particularly useful for application of skin cleansing products, as application of skin cleansing products often results in the removal of sebum and fat, and often results in dry skin, particularly after repeated use. Thus, the incorporation of a compound of formula (I) according to the invention into skin cleansing products (e.g. shampoos, skin cleansers, soaps such as soap bars, skin detergent compositions) is particularly suitable as it may alleviate the side effects associated with (frequent) use of skin cleansing products, i.e. enable the prevention and/or treatment of skin dryness and loss of natural oils caused by the use of skin cleansing products.

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

Traditional over-the-counter preparations for the treatment of acne generally act as drying agents and exfoliants, which are generally irritating to the skin and counterproductive to the general treatment of dry skin. Thus, another embodiment of the invention relates to mitigating the effects of such preparations.

Thus, in a 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 invention for preventing and/or treating dry skin in a person suffering from acne and/or having a predisposition to acne, said method comprising the step of topically applying to said person a composition comprising a keratolytic agent in addition to the compound of formula (I).

Advantageously, the amide of formula (I) is present in the composition comprising the keratolytic agent in an amount effective to increase sebum production, while the keratolytic agent is present in an amount sufficient to combat acne-like skin lesion formation without reducing the effectiveness of the amide of formula (I).

Preferred keratolytic agents according to the present invention are selected from the group consisting of hydroxybenzoic acid, alpha-hydroxycarboxylic acid and urea. Ortho-hydroxybenzoic acid (salicylic acid) is particularly preferred. The vehicle can be any of a number of preferred non-dry preparations (e.g., tinctures, creams, ointments, gels, and lotions).

Particularly advantageous keratolytic agents are selected from the group consisting of: salicylic acid and/or alpha-hydroxycarboxylic acids.

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

If 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 composition according to the invention is preferably a cosmetic or pharmaceutical composition for topical application to mammalian keratinous tissue, such as in particular to human skin or human scalp.

The term "cosmetic composition" as used in the present application refers to compositions as described in "Kosmetika" in

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 für chemische Industrie(ed.H.Ziolkowsky),4^thCosmetic compositions as disclosed in edition, 1992.

The cosmetic or pharmaceutical composition according to the invention comprises a dermatologically acceptable carrier, i.e. a physiologically acceptable medium, i.e. a medium compatible with keratin materials such as the skin, mucous membranes and keratin fibres. 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 of the present invention are typically prepared by blending the amount of the compound of formula (I) described herein with a suitable carrier.

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

In an advantageous embodiment, the cosmetic or pharmaceutical composition according to the invention comprises from about 50% to about 99%, preferably from about 60% to about 98%, more preferably from about 70% to about 98%, for example in particular from about 80% to about 95%, of the carrier, based on the total weight of the cosmetic composition.

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

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

According to the invention, the composition according to the invention may also comprise other cosmetically active ingredients conventionally used in cosmetic or pharmaceutical compositions. Exemplary active ingredients include skin lightening agents; ultraviolet filters, agents for treating hyperpigmentation; agents for preventing or reducing inflammation; firming, moisturizing, soothing and/or energizing agents (energizing agents), and agents for improving elasticity and skin barrier.

Examples of Cosmetic excipients, diluents, adjuvants, additives and active ingredients commonly used in the skin Care industry, which are suitable for use in the Cosmetic composition of the present invention, are described, for example, but not limited to, in International Dictionary and Handbook of Cosmetic ingredients (http:// www.personalcarecouncil.org /) provided by the Personal Care products committee, accessible via an online INFO BASE (http:// online.

The necessary amounts of the active ingredients as well as excipients, diluents, adjuvants, additives and the like can be readily determined by the skilled person on the basis of the desired product form and application. Additional ingredients may be added to the oil phase, the aqueous phase, or separately as appropriate.

In some instances, the cosmetically active ingredient useful in this invention may provide more than one benefit or work through more than one mode of action.

Of course, the person skilled in the art will take care to select the above-mentioned optional additional ingredients, adjuvants, diluents and additives and/or their amounts such that the advantageous properties intrinsically associated with the combination according to the invention are not or substantially not adversely affected by the addition or additions which are envisaged.

Preferably, the cosmetic or pharmaceutical composition according to the invention is in the form of a suspension or dispersion in a solvent or fatty substance, or alternatively in the form of an emulsion or microemulsion (in particular of the O/W or W/O type), PIT emulsion, nanoemulsion, multiple emulsion (for example of the O/W/O or W/O/W type), pickering emulsion, hydrogel, lipogel, single-phase or multiphase solution or vesicular dispersion.

The cosmetic or pharmaceutical composition according to the invention may be in the form of a liquid, lotion, thickened lotion, gel, cream, emulsion, ointment or paste.

The cosmetic or pharmaceutical composition according to the invention has a pH in the range of 3 to 10, preferably a pH in the range of 3 to 8, most preferably a pH in the range of 3 to 7.5. The pH is adjusted by methods known to those skilled in the art, for example by using acids (e.g., hydroxy acids including glycolic, lactic, malic, citric and tartaric acids) or bases (e.g., sodium or potassium or ammonium hydroxide and mixtures thereof).

Preferably, in the composition according to the invention, the acid (if present) is used in an amount of at least 0.0001 wt.%, for example in an amount of 0.01 wt.% to 1 wt.%, in particular in an amount of 0.01 wt.% to 0.5 wt.%.

The cosmetic compositions according to the invention advantageously comprise an additional preservative or preservative synergist. In all embodiments of the present invention, particularly suitable preservatives or preservative synergists are benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, dehydroacetic acid, caprylhydroxamic acid, alcohols, denatured alcohols, hydroxyacetophenone, caprylyl glycol, pentanediol, 1, 2-hexanediol, decanediol, monoglycerides such as glyceryl laurate, propylene glycol caprylate, propylene glycol heptanoate, and mixtures thereof. The preservative and/or preservative synergist, when present, is preferably used in an amount of 0.01 to 2 wt%, more preferably 0.05 to 1.5 wt%, most preferably 0.1 to 1.0 wt%, based on the total weight of the composition.

Furthermore, it is preferred that the topical composition according to the present invention is free of any parabens, benzethonium chloride, piroctone olamine, lauroyl arginine, methylisothiazolinone, chloromethylisothiazolinone, bronopol, benzalkonium chloride, formaldehyde-releasing compounds, salicylic acid, triclosan, DMDM hydantoin, chlorphenesin and IPBC (iodopropynyl butylcarbamate).

The cosmetic compositions according to the invention are in particular skin care articles and/or functional articles, for example most particularly skin care articles.

Examples of skin care products are in particular light protection products (sun protection products), anti-ageing products, products for the treatment of photoaging, body oils, body milks, body gels, care creams, skin care ointments, moisturizing products (e.g. moisturizing gels or moisturizing sprays), facial and/or body moisturizers, and skin lightening products.

Examples of functional articles are cosmetic compositions containing active ingredients such as, but not limited to, hormone articles, vitamin articles, plant extract articles, anti-aging articles, and/or antimicrobial (antibacterial or antifungal) articles.

The topical cosmetic composition according to the invention is advantageously an oil-in-water (O/W) emulsion, a water-in-oil (W/O) emulsion, and/or a gel such as a shower gel.

Furthermore, the topical compositions in the form of O/W emulsions, W/O emulsions and/or gels according to the invention are skin care preparations intended for the treatment of acne, for maintaining healthy skin, and for the treatment of persons suffering from dry and/or sensitive 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 present invention in any way.

Examples

In vitro assay for sebum regulation

An immortalized human sebaceous gland cell line (SEBO662) from a biosubstituent responds to adipogenic stimuli. In this model, active androgens (e.g. testosterone) added to basal non-supplemented medium (keratinocyte-SFM medium) induce strong specific responses, especially induction of sebaceous gland cell differentiation programs and lipid synthesis stores. Assays can be used that test compounds for their androgenic effects under basal conditions (testonone stimulation), e.g. stimulation of sebum lipid synthesis, and observe further stimulation of sebum lipid synthesis or inhibition of sebum lipid synthesis by addition of compounds under testosterone stimulated conditions.

Example 1: modulation of adipogenesis in human sebaceous gland cell lines under basal conditions

For this test, the immortalized sebaceous gland cell line SEBO662AR established at bioalternates (Gencay, France) was used:

cell culture:sebaceous gland cells were seeded in 96-well plates and cultured in sebaceous gland cell culture medium for 24 hours. The medium was replaced with assay medium (keratinocyte-SFM supplemented with 25ug/ml gentamicin) with or without (control) 1nM of test compound or testosterone. Cells were incubated for 7 days. Within a seven day period, after 3 days, half of the medium was removed and the treatment (including testosterone stimulation) was repeated. All experimental conditions were performed when n is 3.

Lipid content analysis (Biodipy marker):at the end of the incubation time, the cells were washed, fixed and permeabilized. The lipid droplets contained in the cells were then labeled with a specific Bodipy fluorescent lipid probe (molecular probe reference D-3922) that predominantly labels neutral lipids. In parallel, nuclei were stained with Hoechst 33258 solution. Image acquisition was performed using the INCell Analyzer 2200(GE Healthcare). The labeling was quantified by normalization to a measurement of fluorescence intensity over the total number of cells. Fluorescence intensity was only analyzed in lipid droplets (image analysis program based on object segmentation).

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

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

And (4) conclusion: like testosterone, compounds IV-f stimulated sebum lipid accumulation as seen by a dose-dependent increase in lipid fluorescence units.

Example 2: modulation of adipogenesis in androgen-stimulated human sebaceous gland cell lines

For this test, the immortalized sebaceous gland cell line SEPO 662AR established in bioalternates (Gencay, France) was used.

Cell culture:sebaceous gland cells were seeded in 96-well plates and cultured in sebaceous gland cell culture medium for 24 hours. The medium was replaced with assay medium (keratinocyte-SFM supplemented with 25ug/ml gentamicin) with or without (control) test compound or reference inhibitor compound (1uM dutasteride) and the cells were preincubated for 4 hours. Then, 1nM testosterone was added to all conditions except the unstimulated control, and the cells were incubated for 7 days. Within a seven day period, after 3 days, half of the medium was removed and the treatment (including testosterone stimulation) was repeated. All experimental conditions were performed when n is 3.

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

The results are shown in the following table:

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

And (4) conclusion: in addition, in combination with testosterone, compounds IV-f further stimulated sebum lipid accumulation as seen by a dose-dependent increase in lipid fluorescence units. Dutasteride inhibited sebum production as expected and served as a control compound.

Example 3: preparation containing keratolytic agent

All-day cream, having a light, smooth texture, for improving the appearance of having acne flares and homogenizing skin tones with residual acne discoloration.

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

The process comprises the following steps:

1 phase A and phase B were heated to 80 ℃ separately while stirring.

2 when all the material dissolved, add phase a to phase B while stirring and homogenize the emulsion.

3 the emulsion is cooled to 30-35 ℃ and then phase C is added.

4 the pH is adjusted to about 7.0 with D.

Claims

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

Wherein

X is a group selected from the group consisting of CH and N,

y is CHR⁸Or an oxygen-containing gas,

n is 0, 1 or 2, preferably 1 or 2,

R¹、R²and R³Independently of each other selected from the group consisting of: H. OH, halogen atom, carbamoyl groupAnd C₁-C₆An alkyl group, and

R⁴、R⁵、R⁶、R⁷and R⁸Independently of one another, H or C₁-C₆An alkyl group.

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

3. The method of claim 1 or 2, wherein C is₁-C₆Alkyl radicals being unbranched C₁-C₃Alkyl group, more preferably C₁-C₂Alkyl groups, most preferably methyl groups.

4. The method according to any one of the preceding claims, wherein the halogen atom is F or Cl.

5. The process according to any of the preceding claims, wherein the compound of formula (I) is (4-methylpiperidin-1-yl) (3- (6-methylpyridin-3-yl) phenyl) methanone (II-a), (4' -hydroxy- [1,1' -biphenyl ] -3-yl) (4-methylpiperidin-1-yl) methanone (II-b), (4' -fluoro- [1,1' -biphenyl ] -3-yl) (4-methylpiperidin-1-yl) methanone (II-c), (3' -fluoro-4 ' -methyl- [1,1' -biphenyl ] -3-yl) (4-methylpiperidin-1-yl) methanone (II-d), (2 '-chloro- [1,1' -biphenyl ] -3-yl) (4-methylpiperidin-1-yl) methanone (II-e), (4 '-methyl- [1,1' -biphenyl ] -3-yl) (4-methylpiperidin-1-yl) methanone (II-f), (4 '-chloro- [1,1' -biphenyl ] -3-yl) (4-methylpiperidin-1-yl) methanone (II-g), (3, 3-dimethylpiperidin-1-yl) (3 '-fluoro-4' -methyl- [1,1 '-biphenyl ] -3-yl) methanone (II-h), 3' - (4-methylpiperidin-1-carbonyl) - [1,1' -biphenyl ] -4-carboxamide (II-i), (3' -hydroxy- [1,1' -biphenyl ] -3-yl) (4-methylpiperidin-1-yl) methanone (II-j), 3' - (4-methylpiperidin-1-carbonyl) - [1,1' -biphenyl ] -3-carboxamide (II-k), (2, 2-dimethylmorpholino) (3' -fluoro-4 ' -methyl- [1,1' -biphenyl ] -3-yl) methanone (III-a), (2, 6-dimethylmorpholino) (3' -fluoro-4 ' -methyl- [1,1' -biphenyl ] -3-yl) methanone (III-b), (2, 6-dimethylmorpholino) (4' -methyl- [1,1' -biphenyl ] -3-yl) methanone (III-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 of the preceding claims, characterized in that the amount of the compound of formula (I) in the composition is selected from the range of 0.00001 to 0.5 wt. -%, preferably from 0.0001 to 0.25 wt. -%, most preferably from 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 of claim 7, wherein the keratolytic agent is at least one of salicylic acid and an alpha hydroxy acid.

9. The method according to any of the preceding claims, wherein the human is a human suffering from acne and/or having a genetic predisposition to acne.

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

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

12. 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 for stimulating sebum production in sebaceous glands.

14. The method according to any of the preceding claims, wherein the human has dry and sensitive skin due to low sebum production after menopause and/or low age-related sebaceous gland activity.