FR3143345A1 - Use of at least one Thiopyridinone compound or compositions comprising it to improve the barrier function of the skin - Google Patents

Abstract

Use of at least one Thiopyridinone compound or compositions comprising it to improve the barrier function of the skin The present invention relates to the use of at least one Thiopyridinone compound or compositions comprising it/them to improve the barrier function of the skin . It also relates to a cosmetic treatment process comprising the application to the skin of said thiopyridinone compound(s) or compositions comprising them to improve the barrier function of the skin.

Description

Use of at least one Thiopyridinone compound or compositions comprising it to improve the barrier function of the skin

The present invention relates to the field of active ingredients capable of improving the barrier function of the skin, for a cosmetic application and in particular a cosmetic treatment process comprising the application of a thiopyridinone compound or a composition comprising it, as well as their use cosmetic in improving the barrier function of the skin.

The skin is the body's first barrier to the external environment. Human skin is made up of several compartments, namely a superficial compartment, the epidermis, the dermis, and a deep compartment, the hypodermis.

The human epidermis is mainly composed of three types of cells which are keratinocytes, the vast majority of which, melanocytes and Langerhans cells. Each of these cell types contributes through its own functions to the essential role played in the body by the skin, in particular the role of protecting the body from external attacks, which is called "barrier function".

The epidermis is conventionally divided into a basal layer of keratinocytes constituting the germinative layer of the epidermis, a so-called spiny layer consisting of several layers of polyhedral cells arranged on the germinative layers, one to three so-called granular layers and finally the stratum corneum ( or stratum corneum), made up of a set of layers of keratinocytes at the terminal stage of their differentiation called corneocytes. Corneocytes are anucleate cells mainly composed of a fibrous matrix containing cytokeratins, surrounded by a very resistant structure 15 nm thick, called the corneal envelope. The stack of these corneocytes constitutes the stratum corneum which is responsible for the function barrier of the epidermis.

The stratum corneum constitutes a real protective barrier against exogenous factors and endogenous water loss. Its good renewal as well as the quality of its structure are essential to ensure an effective barrier to the outside world and limit water loss due to dehydration and dry skin (Velarde MC. J. Invest. Dermatol., 2017, 137, 1206). Among the players involved in the proper regulation of the stratum corneum is the enzyme transglutaminase-1 (TGM-1). Its role is perfectly illustrated in ichthyosis, a cornification defect, associated with TGM-1 mutations (Vega VL and Mehta RC, Clin. Insights, 2016, 1-2; Herman ML et al, Human Mutat., 2009, 30, 537).

The cohesion of the epidermis as a water barrier is ensured thanks to the tight junctions between keratinocytes. These tight junctions are made up of transmembrane proteins such as occludin (OCL), claudin (CLDN-1) and are located in the granular layer. Other structures, such as Zonula occludens (ZO) proteins, connect these transmembrane proteins to the cytoskeleton to enable granular cytoplasmic scaffolding (Jin SP et al, J. Dermatol. Sci., 2016, 84, 97; Velarde MC , J. Invest. Dermatol., 2017, 137, 1206, Brandner JM et al, Tissue Barrier, 2015, 3, 1).

Strengthening the quality of the epidermis by favoring intracellular junctions and the cohesion of the stratum corneum contributes to maintaining the functions of the epidermis and ensuring good hydration.

There therefore remains a need to strengthen the quality of the epidermis by favoring intracellular junctions and the cohesion of the stratum corneum, which are a basic element making it possible to maintain the functions of the epidermis and good hydration.

Certain thiopyridinone compounds have already been proposed in the prior art, in particular in documents WO2012/080075 and WO2017/102349, as active ingredients for the skin, for the purposes of depigmentation and/or whitening thereof, and therefore for an effect quite distinct from that considered according to the invention.

Surprisingly, the inventors have in fact demonstrated the particular properties of thiopyridinone compounds or compositions comprising them to modify the abundance of the CLDN-1 and OCLN markers on a model of normal human keratinocytes in monolayer.

All of these properties therefore make it possible, advantageously, to consider the use of at least one thiopyridinone compound, or of a composition comprising said compound(s) to improve the barrier function of the skin.

Thus, the subject of the present invention is the cosmetic use of at least one compound selected from the compounds of formula (I) below, the tautomers of formula (I') below, their salts, their solvates, such as their hydrates, their optical isomers, their racemates, and their mixtures

in which

R ₁ designates a radical chosen from

a) a hydrogen atom, and

b) a saturated linear C ₁ -C ₁₀ or branched C ₃ -C ₁₀ alkyl group optionally substituted by one or more groups, which may be identical or different, chosen from

i) -OR ₃ , and

ii) -SR ₃ ,

And

R ₂ designates a radical chosen from

a) a hydrogen atom,

b) a saturated linear C ₁ -C ₁₂ or branched C ₃ -C ₁₂ or cyclic C ₃ -C ₈ hydrocarbon group, optionally substituted by one or more groups, which may be identical or different, chosen from

i) -OR ₃ ,

ii) -SR ₃ ,

iii) -C(O)-OR ₃ , and

iv) a C ₅ -C ₁₂ aryl group, optionally substituted by one or more hydroxyls and/or by one or more C ₁ -C ₈ alkoxy radicals and

c) a C ₅ -C ₁₂ aryl group, optionally substituted by one or more hydroxyls and/or by one or more C ₁ -C ₈ alkoxy radicals

And

R ₃ designates a radical chosen from

a) a hydrogen atom, and

b) a saturated linear C ₁ -C ₁₀ or branched C ₃ -C ₁₀ alkyl group;

or a composition comprising at least one such compound, to improve the barrier function of the skin.

It may be preferable that:

R ₁ of formula (I) and (I') represents a hydrogen atom;

Or

R ₁ of formula (I) and (I') represents a linear alkyl group (in C ₁ -C ₁₀ ) or a branched alkyl group (in C ₃ -C ₁₀ ), in particular a linear alkyl group (in C ₁ -C ₆ ) or a branched alkyl group (C ₃ -C ₆ ), such as methyl, ethyl, n-pentyl, n-nonyl, isobutyl, more preferably ethyl, in particular said alkyl group of R ₁ is not substituted .

It may be preferable that:

R ₂ of formula (I) and (I') represents a hydrogen atom;

Or

R ₂ of formula (I) and (I') represents a linear alkyl group (in C ₁ -C ₁₀ ) or a branched alkyl group (in C ₃ -C ₁₀ ), in particular a linear alkyl group (in C ₁ -C ₆ ) or a branched alkyl group (C ₃ -C ₆ ), such as methyl, ethyl, n-pentyl, n-nonyl, isobutyl, more preferably, a methyl or ethyl group; said alkyl group of R ₂ not being substituted.

It may be preferable that:

R ₂ of formula (I) and (I') represents a linear alkyl group (in C ₁ -C ₁₀ ) or a branched alkyl group (in C ₃ -C ₁₀ ), in particular a linear alkyl group (in C ₁ -C ₆ ) or a branched alkyl group (C ₃ -C ₆ ), such as methyl, ethyl, n-pentyl, n-nonyl, isobutyl, more preferably, methyl or ethyl; said alkyl group being substituted by one or more groups selected from i), ii), iii) and iv) as defined above, preferably said alkyl group being substituted by one or two groups selected from i), ii) and iii), more preferably by one or two groups chosen from i) and iii), better substituted by a group iii) such as carboxy.

It may be preferable that:

R ₂ of formula (I) and (I') represents a cycloalkyl group (C ₃ -C ₈ ), preferably a cycloalkyl group (C ₅ -C ₇ ) such as cyclohexyl;

Or

R ₂ of formula (I) and (I') represents a C ₅ -C ₁₂ aryl group optionally substituted by one or more hydroxyls and/or by one or more C ₁ -C ₈ alkoxy radicals, preferably a phenyl group in particular unsubstituted.

It may be preferable that:

R ₃ of formula (I) and (I') represents a hydrogen atom;

Or

R ₃ of formula (I) and (I') represents a saturated linear C ₁ -C ₁₀ or branched C ₃ -C ₁₀ alkyl group; in particular a linear alkyl group (in C ₁ -C ₆ ) or a branched alkyl group (in C ₃ -C ₆ ), preferably an alkyl group (in C ₁ -C ₄ ) such as a methyl group.

It may be more preferable that:

R ₁ of formula (I) and (I') represents a radical chosen from

a) a hydrogen atom, and

b) a saturated linear C ₁ -C ₆ or branched C ₃ -C ₆ alkyl group optionally substituted by one or more groups, which may be identical or different, chosen from

i) -OR ₃ , and

ii) -SR ₃ ,

preferably optionally substituted with one or more groups i);

R ₂ of formula (I) and (I') represents a radical chosen from

a) a hydrogen atom, and

b) a linear saturated hydrocarbon group in C₁-VS₁₀or branched in C₃-VS₁₀or cyclic in C₃-VS₈as in C₅-VS₆, optionally substituted by one or more groups, which may be identical or different, chosen from:

i) -OR ₃ ,

ii) -SR ₃ ,

iii) -C(O)-OR ₃ , and

iv) a phenyl group optionally substituted by one or more hydroxyls and/or by one or more C ₁ -C ₄ alkoxy radicals such as methoxy,

preferably substituted by one or more groups selected from i) and iii), preferably iii) such as carboxy; And

R ₃ of formula (I) and (I') represents a radical chosen from

a) a hydrogen atom, and

b) a saturated linear C ₁ -C ₆ or branched C ₃ -C ₆ alkyl group,

preferentially, the compounds of formula (I) and the tautomer (I’), their salts, solvates, such as their hydrates, their optical isomers, their racemates, and their mixtures, have the following meanings:

R ₁ of formula (I) and (I') represents a radical chosen from:

a) a hydrogen atom, and

b) a saturated linear C ₁ -C ₄ or branched C ₃ -C ₄ alkyl group optionally substituted by one or more groups, which may be identical or different, chosen from i) -OR _3, more preferably unsubstituted;

R ₂ of formula (I) and (I') represents a radical chosen from

a) a hydrogen atom, and

b) a linear saturated hydrocarbon group in C₁-VS₁₀or branched in C₃-VS₁₀or cyclic in C₃-VS₈as in C₅-C6, optionally substituted by one or more groups, which may be the same or different, chosen from

i) -OR ₃ ,

iii) -C(O)-OR ₃ , and

iv) a C ₅ -C ₁₂ aryl group, optionally substituted by one or more hydroxyls and/or by one or more C ₁ -C ₄ alkoxy radicals; And

R ₃ of formula (I) and (I') represents a radical chosen from:

a) a hydrogen atom;

b) a saturated linear C ₁ -C ₄ or branched C ₃ -C ₄ alkyl group such as methyl or ethyl.

The thiopyridinone compound can be selected from compounds 1 to 24 below, their tautomers, their salts, their solvates, such as their hydrates, their optical isomers, their racemates, and their mixtures, in particular compounds 1, 2, 4 , 6, 7, 9, 11, 12, 14, 15, 16, 17, 18, 19, 20 or 21, more particularly, 1, 9, 16, 18, 19, 20 or 21, preferably, 18, 19 , 20 or 21, and more preferably, 20:

No. Structure Chemical name 1 N-ethyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 2 N-methyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 3 N-octyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 4 N-benzyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 5 N-phenyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 6 N-cyclohexyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 7 N-[2-(4-methoxyphenyl)ethyl]-2-thioxo-1,2-dihydropyridine-3-carboxamide 8 N-(2-methylpropyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 9 N-pentyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 10 N-nonyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 11 N-(2-hydroxyethyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 12 N,N-diethyl 2-mercaptonicotinamide 13 N-ethyl-N-(2-hydroxyethyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 14 N-(2,3-dihydroxypropyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 15 N-(1,3-dihydroxypropan-2-yl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 16 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]alaninate 17 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]phenyl alaninate 18 Ethyl N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate 19 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate 20 N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine 21 N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine 22 N,N-bis(2-hydroxyethyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 23 N-(3-methoxypropyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 24 N-butyl-2-thioxo-1,2-dihydropyridine-3-carboxamide

The quantity of the thiopyridinone compound(s) in the composition according to the invention can range from 0.01% to 10% by weight, preferably from 0.05% to 5% by weight, more preferably from 0.1%. at 3% by weight, relative to the total weight of the composition.

Another object of the present invention is the cosmetic use of a thiopyridinone compound of formula (I) or (I') as described above or of a cosmetic composition comprising it to prevent and/or treat cosmetic signs associated with sensitive or dry skin.

According to another of its objects, the present invention also relates to a cosmetic treatment process comprising a step of applying to the skin a cosmetic composition comprising at least one thiopyridinone compound of formula (I) or (I') as described above to improve the barrier function of the skin.

The present invention also relates to a cosmetic treatment process comprising a step of applying to the skin a cosmetic composition comprising at least one thiopyridinone compound of formula (I) or (I') as described above to prevent and/or treat cosmetic signs associated with sensitive or dry skin.

Definitions

By “physiologically acceptable environment” is meant an environment compatible with the skin, that is to say when it does not generate tingling, tightness or unacceptable discomfort for the user.

By “the skin”, we mean the entire skin of the body, and the scalp and preferably, the skin of the face, neckline, neck, arms and forearms, hands or even more. still preferred, the skin of the face (especially the forehead, nose, cheeks, lips, chin), décolleté and neck.

By “prevent” or “prevention” is meant according to the invention the fact of reducing the risk of occurrence or slowing down the occurrence of a given phenomenon, namely, reducing the risk of appearance of cosmetic signs associated with sensitive skin or dry.

By “treat” or “treatment” we mean any action aimed at improving the comfort and well-being of an individual, this term therefore covers both attenuation, relief and cure.

By “intended to be administered topically” is meant an application to the surface of the skin in question.

Detailed description of the invention

The subject of the present invention is the cosmetic use of at least one thiopyridinone compound of formula (I) or (I'), their salts, their solvates, such as their hydrates, their optical isomers, their racemates and/or their mixtures, or a composition comprising it or them to improve the barrier function of the skin.

(Thiopyridinone compound)

The composition according to the present invention comprises at least one thiopyridinone compound. Two or more distinct thiopyridinone compounds of formula (I) or (I’) may be used in combination. Thus, a single thiopyridinone compound of formula (I) or (I') or a combination of different thiopyridinone compounds of formula (I) or (I') can be used.

The thiopyridinone compound(s) are selected from the compounds of formula (I) below, the tautomers of formula (I') below, their salts, their solvates, such as their hydrates, their isomers optics, their racemates and their mixtures:

in which

R ₁ designates a radical chosen from

a) a hydrogen atom, and

b) a saturated linear C ₁ -C ₁₀ or branched C ₃ -C ₁₀ alkyl group optionally substituted by one or more groups, which may be identical or different, chosen from

i) -OR ₃ , and

ii) -SR ₃ ,

And

R ₂ designates a radical chosen from

a) a hydrogen atom,

b) a saturated linear C ₁ -C ₁₂ or branched C ₃ -C ₁₂ or cyclic C ₃ -C ₈ hydrocarbon group, optionally substituted by one or more groups, which may be identical or different, chosen from

i) -OR ₃ ,

ii) -SR ₃ ,

iii) -C(O)-OR ₃ , and

iv) a C ₅ -C ₁₂ aryl group, optionally substituted by one or more hydroxyls and/or by one or more C ₁ -C ₈ alkoxy radicals and

c) a C ₅ -C ₁₂ aryl group, optionally substituted by one or more hydroxyls and/or by one or more C ₁ -C ₈ alkoxy radicals

And

R ₃ designates a radical chosen from

a) a hydrogen atom, and

b) a saturated linear C ₁ -C ₁₀ or branched C ₃ -C ₁₀ alkyl group.

Hereinafter, within the meaning of the present invention and unless otherwise indicated:

- a "saturated, linear C ₁ -C ₁₂ or branched C ₃ -C ₁₂ " hydrocarbon group is equivalent to a "linear (C ₁ -C ₁₂ ) or branched (C ₃ -C ₁₂ ) alkyl group" which corresponds to a saturated hydrocarbon group, linear in C ₁ -C ₁₂ or branched in C ₃ -C ₁₂ , preferably a linear hydrocarbon group in C ₁ -C ₁₀ or branched in C ₃ -C ₁₀ , and more preferably a group linear C ₁ -C ₆ or branched C ₃ -C ₆ hydrocarbon; preferably, the linear or branched groups can be chosen from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl groups; more preferably, the saturated alkyl groups, linear or branched, can be chosen from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, pentyl, hexyl, heptyl and octyl groups, such as methyl, ethyl, n- pentyl, n-nonyl, isobutyl;

- a saturated hydrocarbon group “cyclic in C₃-VS₈» is a group mono or bicyclic cycloalkyl containing 3 to 8 carbon atoms, and in particular is a C monocyclic cycloalkyl group₅to C₇such as a cyclohexyl group,

- an “alkoxy radical” is an alkyl-oxy radical for which the alkyl radical is a linear or branched C ₁ -C ₁₆ hydrocarbon radical, and preferably a C ₁ -C ₈ hydrocarbon radical;

- when the alkoxy group is optionally substituted, this implies that the alkyl group is optionally substituted as defined above;

- an “aryl” group represents a carbon-based group, monocyclic or bicyclic, fused or not, comprising from 5 to 12 carbon atoms, preferably from 6 to 10 carbon atoms, and in which at least one cycle is aromatic ; preferably, the aryl radical is a phenyl, biphenyl, naphthyl group, more preferably a phenyl group:

- the expression “at least one” is equivalent to the expression “one or more”; And

- the term “inclusive” for a concentration range means that the limits of this range are included in the defined range.

The salts of the compounds of formula (I), (I'), (II), or (II') as defined below include conventional non-toxic salts of said compounds, such as those formed from an organic acid or inorganic or of an organic or inorganic base.

As salts of compounds of formula (I), (I’), (II) or (II’), we can cite:

- the salts obtained by addition of the compound of formula (I) or (II) to:

- a mineral base, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, magnesium hydroxide, lithium hydroxide, and carbonate or hydrogen carbonate sodium, potassium or calcium for example; Or

- an organic base such as a primary, secondary or tertiary alkylamine, for example triethylamine or butylamine. This primary, secondary or tertiary alkylamine may comprise one or more nitrogen and/or oxygen atoms and may thus comprise, for example, one or more alcohol functions. Mention may be made in particular of 2-amino-2-methylpropanol, ethanolamine, triethanolamine, 2-dimethylaminopropanol, 2-amino-2-(hydroxymethyl)-1,3-propanediol and 3-(dimethylamino)propylamine. .

We can also cite salts of amino acids, for example lysine, arginine, guanidine, glutamic acid and aspartic acid. Advantageously, the salts of the compounds of formula (I) or (II) (when they comprise a carboxy group) can be chosen from alkali or alkaline earth metal salts such as sodium, potassium, calcium or magnesium salts and ammonium salts.

An “organic or inorganic acid salt” is more particularly chosen from salts chosen from a salt derived from i) hydrochloric acid HCl, ii) hydrobromic acid HBr, iii) sulfuric acid H ₂ SO ₄ , iv) alkylsulfonic acids: Alk -S(O) ₂ OH such as methanesulfonic acid and ethanesulfonic acid; v) arylsulfonic acids: Ar-S(O) ₂ OH such as benzenesulfonic acid and toluenesulfonic acid; vi) citric acid; vii) succinic acid; viii) tartaric acid; ix) lactic acid; x) alkoxysulfinic acids: Alk-OS(O)OH such as methoxysulfinic acid and ethoxysulfinic acid; xi) aryloxysulfinic acids such as tolueneoxysulfinic acid and phenoxysulfinic acid; xii) phosphoric acid H ₃ PO ₄ ; xiii) acetic acid CH ₃ C(O)OH; xiv) triflic acid CF ₃ SO ₃ H; and xv) tetrafluoroboric acid HBF ₄ .

Acceptable solvates of the compounds described in the specification include conventional solvates such as those formed during the preparation of said compounds due to the presence of solvents. We can cite, by way of example, solvates due to the presence of water or linear or branched alcohols, such as ethanol or isopropanol.

Optical isomers are in particular enantiomers and diastereoisomers.

Compound (I’) is the tautomeric form of compound (I) when a tautomeric equilibrium exists according to the following diagram:

According to one embodiment of the present invention, R ₁ represents a hydrogen atom.

According to one embodiment of the present invention, R ₁ of formula (I) and (I') represents a linear (C ₁ -C ₁₀ ) or branched (C ₃ -C ₁₀₎ alkyl group, in particular a linear alkyl group (in C ₁ -C ₆ ) or branched (in C ₃ -C ₆ ), such as methyl, ethyl, n-pentyl, n-nonyl, isobutyl, more preferably, ethyl. In particular, said alkyl group of R ₁ n. is not substituted.

According to one embodiment of the present invention, R ₂ represents a hydrogen atom.

According to one embodiment of the present invention, R ₂ represents a linear (C ₁ -C ₁₀ ) or branched (C ₃ -C ₁₀₎ alkyl group, in particular a linear (C ₁ -C ₆ ) or branched alkyl group (C ₃ -C ₆ ), such as methyl, ethyl, n-pentyl, n-nonyl, isobutyl, more preferably methyl or ethyl; said alkyl group of R ₂ not being substituted.

According to one embodiment of the present invention, R ₂ of formula (I) and (I') represents a linear (C ₁ -C ₁₀ ) or branched (C ₃ -C ₁₀ ) alkyl group, in particular an alkyl group linear (in C ₁ -C ₆ ) or branched (in C ₃ -C ₆ ), such as methyl, ethyl, n-pentyl, n-nonyl, isobutyl, more preferably methyl or ethyl; said alkyl group being substituted by one or more groups selected from i), ii), iii) and iv) as defined above. Preferably, said alkyl group being substituted by one or two groups selected from i), ii) and iii), more preferably by one or two groups chosen from i) and iii), better substituted by a group iii) such as carboxy.

Another variant for the radical R ₂ is that said alkyl group is substituted by a group iv) in particular substituted by a phenyl group.

According to another embodiment of the present invention, R ₂ represents a cycloalkyl group (C ₃ -C ₈ ), preferably a cycloalkyl group (C ₅ -C ₇ ) such as cyclohexyl.

According to another embodiment of the present invention, R ₂ represents a C ₅ -C ₁₂ aryl group optionally substituted by one or more hydroxyls and/or by one or more C ₁ -C ₈ alkoxy radicals, preferably a group phenyl in particular unsubstituted.

According to one embodiment, R ₃ represents a hydrogen atom.

According to another embodiment, R ₃ represents a saturated alkyl group, linear at C ₁ -C ₁₀ or branched at C ₃ -C ₁₀ ; in particular a linear (C ₁ -C ₆ ) or branched (C ₃ -C ₆ ) alkyl group, preferably an alkyl group (C ₁ -C ₄ ) such as the methyl group.

Preferably, the compounds of formula (I) and the tautomer (I') or their salts, their optical isomers, racemates, and/or solvates such as their hydrates and their derivatives, alone or in mixture

have the following meanings:

R ₁ designates a radical chosen from

a) a hydrogen atom, and

b) a saturated linear C ₁ -C ₆ or branched C ₃ -C ₆ alkyl group optionally substituted by one or more groups, which may be identical or different, chosen from

i) -OR ₃ , and

ii) -SR ₃ ,

preferably optionally substituted with one or more groups i);

R ₂ designates a radical chosen from

a) a hydrogen atom;

b) a linear saturated hydrocarbon group in C₁-VS₁₀or branched in C₃-VS₁₀or cyclic in C₃-VS₈such than in C₅-VS₆optionally substituted by one or more groups, which may be identical or different, chosen from:

i) -OR ₃ ,

ii) -SR ₃ ,

iii) -C(O)-OR ₃ , and

iv) a phenyl group optionally substituted by one or more hydroxyls and/or by one or more C ₁ -C ₄ alkoxy radicals such as methoxy,

preferably substituted by one or more groups selected from i) and iii), preferably iii) such as carboxy; And

R ₃ designates a radical chosen from

a) a hydrogen atom, and

b) a saturated linear C ₁ -C ₆ or branched C ₃ -C ₆ alkyl group

Preferably, the compounds of formula (I) and the tautomer (I’) or their salts, their optical isomers, racemates, and/or their solvates such as their hydrates, alone or in mixture

have the following meanings:

R ₁ designates a radical chosen from

a) a hydrogen atom, and

b) a saturated linear C ₁ -C ₄ or branched C ₃ -C ₄ alkyl group optionally substituted by one or more groups, which may be identical or different, chosen from i) -OR _3, more preferably unsubstituted;

R ₂ designates a radical chosen from

a) a hydrogen atom; And

b) a linear saturated hydrocarbon group in C₁-VS₁₀or branched in C₃-VS₁₀or cyclic in C₃-VS₈as in C₅-VS₆, optionally substituted by one or more groups, which may be identical or different, chosen from:

i) -OR ₃ ,

iii) -C(O)-OR ₃ ,

iv) a C ₅ -C ₁₂ aryl group, optionally substituted by one or more hydroxyls and/or by one or more C ₁ -C ₄ alkoxy radicals; And

R ₃ designates a radical chosen from

a) a hydrogen atom, and

b) a saturated linear C ₁ -C ₄ or branched C ₃ -C ₄ alkyl group such as methyl or ethyl.

Preferably, the compounds of formula (I) and the tautomer (I') or their salts, their optical isomers, racemates, and/or solvates such as hydrates and their derivatives, alone or in mixture

have the following meanings:

R ₁ is a hydrogen atom; And

R ₂ designates a radical chosen from

a) a hydrogen atom, and

b) a saturated hydrocarbon group, linear in C ₁ -C ₅ or branched in C ₃ -C ₅ or cyclic in C ₃ -C ₈ such that C ₅ -C ₆ can be identical or different, chosen from v) -C( O)-OR ₃ , preferably substituted by a group iii) -C(O)-OR ₃ ; R ₂ is even more preferably a saturated hydrocarbon group, linear in C ₁ -C ₄ or branched in C ₃ -C ₄ substituted by a group iii) -C(O)-OR ₃ ; And

R ₃ designates a radical chosen from

a) a hydrogen atom, and

b) a saturated linear C ₁ -C ₄ or branched C ₃ -C ₄ alkyl group such as methyl or ethyl.

According to another preferred embodiment, the compounds of formula (I) and the tautomer (I') are selected from the compounds of formula (II) below and also their tautomers of formula (II') below, their salts, their solvates and their optical isomers, and their racemates, alone or in mixture:

(II) (II’)

In formula (II) and (II'), R ₁ and R ₃ have the same meaning as R ₁ and R ₃ for the compounds of formula (I) and (I'), and ₂ ) _n - with n being an integer ranging from 1 to 10 inclusive, preferably ranging from 1 to 6, more preferably ranging from 1 to 4, such that 1, preferably, R ₃ represents a hydrogen atom .

Among the compounds of formula (I), the following compounds are preferably used, and their tautomer (I') or their salts, their optical isomers, racemates, and/or solvates such as hydrates and their derivatives, alone or in mixture :

No. Structure Chemical name CAS No. 1 N-ethyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 91859-75-5 2 N-methyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 91859-74-4 3 N-octyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 91859-77-7 4 N-benzyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 91859-79-9 5 N-phenyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 104857-16-1 6 N-cyclohexyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 91859-78-8 7 N-[2-(4-methoxyphenyl)ethyl]-2-thioxo-1,2-dihydropyridine-3-carboxamide 923682-88-6 8 N-(2-methylpropyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 1100027-79-9 9 N-pentyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 330667-57-7 10 N-nonyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 1031149-44-6 11 N-(2-hydroxyethyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 12 N,N-diethyl 2-mercaptonicotinamide 13 N-ethyl-N-(2-hydroxyethyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 14 N-(2,3-dihydroxypropyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 15 N-(1,3-dihydroxypropan-2-yl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 16 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]alaninate 17 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]phenyl alaninate 18 Ethyl N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate 19 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate 20 N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine 21 N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine 22 N,N-bis(2-hydroxyethyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 23 N-(3-methoxypropyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 24 N-butyl-2-thioxo-1,2-dihydropyridine-3-carboxamide

Among these compounds, the following compounds are more particularly preferred:

No. Structure Chemical name CAS No. 1 N-ethyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 91859-75-5 2 N-methyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 91859-74-4 4 N-benzyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 91859-79-9 6 N-cyclohexyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 91859-78-8 7 N-[2-(4-methoxyphenyl)ethyl]-2-thioxo-1,2-dihydropyridine-3-carboxamide 923682-88-6 9 N-pentyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 330667-57-7 11 N-(2-hydroxyethyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 12 N,N-diethyl 2-mercaptonicotinamide 14 N-(2,3-dihydroxypropyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 15 N-(1,3-dihydroxypropan-2-yl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 16 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]alaninate 17 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]phenyl alaninate 18 Ethyl N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate 19 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate 20 N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine 21 N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine

More preferably, among these compounds, the following compounds are more particularly preferred:

No. Structure Chemical name CAS No. 1 N-ethyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 91859-75-5 9 N-pentyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 330667-57-7 16 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]alaninate 18 Ethyl N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate 19 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate 20 N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine 21 N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine

Even more preferably, among these compounds, the following compounds are more particularly preferred:

No. Structure Chemical name CAS No. 18 Ethyl N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate 19 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate 20 N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine 21 N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine

In a most preferred embodiment, the compound according to the present invention is the following:

20 N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine

All of the above compounds can be obtained by a chemical process known to those skilled in the art, using commercially available reagents.

The thiopyridinone compound can be prepared according to the process described, for example, in EP-A-3390363 or WO 2017/102349.

The thiopyridinone compound may be an active ingredient or active compound in cosmetic or dermatological products. The term “active” principle or compound used herein means an ingredient or compound which has an active cosmetic or dermatological property.

Composition

A composition used according to the invention comprises in particular at least one thiopyridinone compound of formula (I) or (I’) described above and can be presented in all the galenic forms normally used in the cosmetic field.

It may in particular be in the form of an aqueous, hydroalcoholic solution, possibly gelled, of a dispersion of the lotion type possibly two-phase, of an oil-in-water or water-in-oil or multiple emulsion, of an aqueous gel , a dispersion of oils in an aqueous phase, in particular using spherules, these spherules being able to be polymeric particles or better, lipid vesicles of ionic and/or non-ionic type, or even in the form a powder, a serum, a paste or a flexible stick or even a stick. It can be solid, pasty, or more or less fluid in consistency. It can optionally be applied to the skin in the form of an aerosol. It can also be in solid form, and for example in stick form.

Thus, the composition can include all the constituents usually used in the application and topical administration envisaged.

A composition according to the invention can advantageously be in the form of an emulsion, in particular obtained by dispersing an aqueous phase in a fatty phase (W/O) or of a fatty phase in an aqueous phase (O/W). , of liquid or semi-liquid consistency of the milk type, or of soft, semi-solid or solid consistency of the cream or gel type, or of multiple emulsion (W/O/W or O/W/O). These compositions are prepared according to the usual methods.

The amount of the thiopyridinone compound(s) of formula (I) or (I') in the composition according to the present invention may be 0.01% by weight or more, preferably 0.05% by weight or more , and more preferably 0.1% by weight or more, relative to the total weight of the composition.

Furthermore, the quantity of the thiopyridinone compound(s) of formula (I) or (I')- in the composition according to the present invention may be 10% by weight or less, preferably 5% by weight or less. , and more preferably 3% by weight or less, relative to the total weight of the composition.

The quantity of the thiopyridinone compound(s) of formula (I) or (I') in the composition according to the present invention can range from 0.01% to 10% by weight, preferably from 0.05% to 5%. by weight, more preferably from 0.1% to 3% by weight, relative to the total weight of the composition.

(pH correction agent)

In a particular embodiment of the invention, the composition according to the present invention may also comprise at least one pH correction agent (pH corrector). Two or more pH correction agents may be used in combination. Thus, a single type of pH correction agent or a combination of different types of pH correction agents can be used.

As a pH correction agent, at least one acidifying agent and/or at least one basifying agent (alkaline agent) can be used.

The acidifying agent may be a monovalent or multivalent acid, such as divalent.

The acidifying agents can be, for example, mineral (inorganic) acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or organic acids such as carboxylic acids, for example tartaric acid, citric acid and lactic acid, as well as sulfonic acids.

The basifying agent may be a monovalent or multivalent base, such as divalent.

Basifying agents can be mineral (inorganic) or organic, or hybrid.

The mineral basifying agents can be chosen from aqueous ammonia; alkali metal carbonates or bicarbonates such as sodium or potassium carbonates and sodium or potassium bicarbonates; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and their mixtures.

The organic basifying agents can be chosen from organic amines whose pKb at 25°C is less than 12, preferably less than 10, and even more advantageously less than 6. It should be noted that this is the corresponding pKb to the function of greater basicity. In addition, organic amines do not include any fatty alkyl or alkenyl chains comprising more than ten carbon atoms.

The organic basifying agent can be chosen, for example, from alkanolamines, oxyethylenated and/or oxypropylenated ethylenediamines, amino acids and amine compounds of formula (III) below:

(III)

in which

W represents a divalent C ₁ -C ₆ alkylene radical optionally substituted by one or more hydroxyl groups or a C ₁ -C ₆ alkyl radical, and optionally interrupted by one or more heteroatoms such as O and N, and

R _x , R _y , R _z and R _t , which may be the same or different, represent a hydrogen atom or a C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, or C ₁ -aminoalkyl radical. _C6 .

Examples of amine compounds of formula (III) which may be cited include 1,3-diaminopropane, 1,3-diamino-2-propanol, spermine and spermidine.

The term “alkanolamine” designates an organic amine comprising a primary, secondary or tertiary amine function, and one or more linear or branched C ₁ -C ₈ alkyl groups carrying one or more hydroxyl radicals.

Alkanolamines such as monoalkanolamines, dialkanolamines or trialkanolamines comprising one to three identical or different C ₁ -C ₄ hydroxyalkyl radicals may be suitable for the present invention. Compounds of this type include monoethanolamine (MEA), diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, N-dimethylaminoethanolamine, 2-amino-2-methyl-1-propanol, triisopropanolamine, 2-amino-2-methyl-1 ,3-propanediol, 3-amino-1,2-propanediol, 3-dimethylamino-1,2-propanediol and tris(hydroxymethylamino)methane.

The amino acids which can be used are of natural or synthetic origin, in their L, D or racemic form, and comprise at least one acid function chosen more particularly from the carboxylic acid, sulfonic acid, phosphonic acid or phosphoric acid functions. Amino acids can be in neutral or ionic form.

As amino acids which can be used in the present invention, mention may in particular be made of aspartic acid, glutamic acid, alanine, arginine, ornithine, citrulline, asparagine, carnitine, cysteine, glutamine, glycine, histidine, lysine, isoleucine, leucine, methionine, N-phenylalanine, proline, serine, taurine, threonine, tryptophan, tyrosine and valine.

It may be preferable that the amino acids are basic amino acids comprising an additional amine function optionally included in a ring or in a ureido function.

Such basic amino acids can preferably be chosen from those corresponding to formula (IV) below:

(IV)

in which

R represents a group chosen from:

,

-(CH ₂ ) ₃ -NH ₂ ,

-(CH ₂ ) ₂ -NH ₂ ,

-(CH ₂ ) ₂ -NH-CO-NH ₂ , and

.

Compounds corresponding to formula (IV) include histidine, lysine, arginine, ornithine and citrulline.

The organic basifying agent can be chosen from organic amines of heterocyclic type. In addition to histidine which has already been mentioned in the amino acids, we can cite in particular pyridine, piperidine, imidazole, triazole, tetrazole and benzimidazole.

The organic basifying agent can also be chosen from amino acid dipeptides. As amino acid dipeptides which can be used in the present invention, mention may in particular be made of carnosine, anserine and whalebone.

The organic basifying agent can also be chosen from compounds comprising a guanidine function. As amines of this type which can be used in the present invention, in addition to arginine, which has already been mentioned as an amino acid, mention may in particular be made of creatine, creatinine, 1,1-dimethylguanidine, 1,1-diethyl-guanidine, glycocyamine. , metformin, agmatine, N-amidinoalanine, 3-guanidino-propionic acid, 4-guanidinobutyric acid and 2-([amino(imino)methyl]amino)ethane-1-sulfonic acid.

In a preferred embodiment of the present invention, the organic basifying agent can be selected from amino acids, preferably basic amino acids, and more preferably arginine, lysine, histidine or mixtures thereof. Even more preferably, the organic basifying agent may be arginine.

Hybrid compounds that may be cited include salts of the aforementioned amines with acids such as carbonic acid or hydrochloric acid. Guanidine carbonate or monoethanolamine hydrochloride can in particular be used.

The pH correction agent may be present in an amount of 0.01% by weight or more, preferably 0.05% by weight or more, and more preferably 0.1% by weight or more, relative to to the total weight of the composition.

The pH correction agent may be present in an amount of 15 weight percent or less, preferably 10 weight percent or less, and more preferably 5 weight percent or less, based on the total weight of the composition. .

The pH correction agent may be present in an amount ranging from 0.01% to 15% by weight, preferably from 0.05% to 10% by weight, and more preferably from 0.1% to 5% by weight. weight or less, relative to the total weight of the composition.

It is preferable that the composition according to the present invention has a pH of 4.5 or more, and more preferably 5 or more.

It is preferable that the composition according to the present invention has a pH of 6.5 or less, and more preferably 6 or less.

It is preferable that the composition according to the present invention has a pH of 4.5 to 6.5, and more preferably of 5 to 6.

The pH of the composition means the pH of the aqueous phase of the composition according to the present invention.

It may be preferable that at least one buffer or buffering agent is also used, such as the pH correction agent, in combination with the acidifying agent and/or the basifying agent, in order to stabilize the pH of the composition according to the present invention.

As a buffer, any of the commonly known buffers can be used. For example, salts of acids or bases, preferably salts of weak acids or bases, may be used. For example, sodium citrate or sodium lactate can be used as a buffer, if citric acid or lactic acid is used as an acidifying agent.

(Other optional additives)

The composition according to the present invention may also comprise any other optional additive(s) usually used in the field of cosmetics, chosen, for example, from solvents, chelating agents, cosmetic active agents other than the thiopyridinone compound, such as oils, preservatives, and mixtures thereof.

It is part of the ordinary operations for those skilled in the art to adjust the nature and quantity of the above optional additives which may be present in the composition according to the present invention in such a way that the desired cosmetic properties are not affected by these.

As solvents, mention may be made of one or more cosmetically acceptable organic solvents, which may be alcohols: in particular monovalent alcohols such as ethyl alcohol, isopropyl alcohol, benzyl alcohol and phenylethyl alcohol; diols such as ethylene glycol, propylene glycol and butylene glycol; and ethers such as ethylene glycol monomethyl, monoethyl and monobutyl ethers, propylene glycol monomethyl, monoethyl and monobutyl ether, and butylene glycol monomethyl, monoethyl and monobutyl ethers.

The organic solvent(s) may be present in a concentration of 0.01% to 30% by weight, preferably 0.1% to 20% by weight and more preferably, from 1% to 10% by weight, relative to the total weight of the composition.

The compositions, in particular cosmetics, capable of being used in the context of the invention generally comprise a physiologically acceptable medium.

Preferably, the composition according to the invention has a water content ranging from 20% to 95% by weight, even better from 40% to 90% by weight relative to the total weight of the composition.

Of course, those skilled in the art will take care to choose this or these possible complementary ingredients and/or active ingredients, and/or their quantity, in such a way that the advantageous properties of the thiopyridinone compound according to the invention are not, or substantially not , altered by the planned addition.

Said thiopyridinone compound(s) of formula (I) or (I'), or said composition containing them are used, in the context of a use or a process according to the invention, topically.

The compositions according to the invention may be applied directly to the skin or, alternatively, to cosmetic supports of the occlusive or non-occlusive type, intended to be applied locally to the skin. As examples of non-limiting cosmetic supports, we can in particular cite a patch, a wipe, a roll-on and a pen.

The composition may or may not be rinsed after being applied to the skin.

Uses and cosmetic treatment process

The present invention also relates to a cosmetic treatment process comprising a step of applying to the skin at least one thiopyridinone compound according to the invention or a composition comprising it or them, to improve the barrier function of the skin. .

Furthermore, another object of the present invention relates to the cosmetic use of at least one thiopyridinone compound as defined according to the invention or of a composition comprising it or them, to prevent and/or treat the cosmetic signs associated with sensitive or dry skin as well as a cosmetic treatment process comprising a step of applying to the skin at least one thiopyridinone compound according to the invention or a composition comprising it or them, to prevent and/or treat the signs cosmetics associated with sensitive or dry skin.

Thus, according to the invention, the use of at least one thiopyridinone compound of formula (I) or (I') or of a composition comprising it or them makes it possible to exert beneficial effects for treating or preventing the signs cosmetics associated with sensitive or dry skin, such as alteration of microrelief.

A cosmetic implementation of the invention therefore only addresses aesthetic defects of the skin, and therefore does not exert a therapeutic effect.

The present invention aims at a non-therapeutic cosmetic skin care implementation of at least one thiopyridinone compound of formula (I) or (I'), or of a particularly cosmetic composition comprising said or said thiopyridinone compounds.

By “treatment”, we mean a non-therapeutic treatment capable of producing an aesthetic effect without preventing or correcting a pathological dysfunction of the skin.

Skin surface

The surface of human skin is not smooth. It presents a relief resulting in fine lines, distinct from wrinkles, observable with a magnifying glass in children and with the naked eye in the elderly. These fine lines or furrows intersect to form polygonal structures, namely the microrelief of the skin.

The number and depth of furrows constituting the microrelief of the skin can be affected by numerous external or internal factors.

Advantageously, a thiopyridinone compound according to the invention, or a composition comprising said thioyridinone compound, can be used to prevent and/or treat an alteration of the surface condition of the skin, in particular following an alteration of the barrier function of the skin.

Even more particularly, a thiopyridinone compound according to the invention, or a composition comprising said thiopyridinone compound can be used to prevent and/or treat an alteration of the microrelief of the skin, to reduce the number of furrows in the microrelief of the skin, to smooth the surface of the skin, to prevent and/or treat a surface irregularity of the skin, in particular to prevent and/or treat a condition of roughness of the skin, or to reduce the depth of the furrows of the microrelief of the skin.

Dry skin

One of the functions of the Stratum Corneum is to capture and retain the water contained in the epidermis, and any alteration of its structure and/or function, in particular following or associated with an alteration of the barrier function of the skin, may occur. translate into changes in skin hydration. Hydration is provided to the skin by water from deep layers and by sweat. An imbalance in skin hydration can result in profound consequences, both physiological and cosmetic.

Physiologically, dry skin is often associated with a drop in skin hydration levels as well as a change in the maturation process of the Stratum Corneum. On a sensory level, dry skin can be characterized by a feeling of tightness and/or skin tension.

A thiopyridinone compound according to the invention, or a composition comprising said thiopyridinone compound, may be particularly suitable for preventing and/or treating dry skin and/or skin signs associated with dry skin.

Whatever the origin, skin suffering from dry skin can generally present the following signs: rough and scaly appearance, as well as reduced suppleness and elasticity.

According to one embodiment, a cosmetic use of the invention may advantageously be suitable for preventing and/or treating dry or fragile skin, and winter xerosis.

According to one embodiment, a cosmetic use of the invention may advantageously be suitable for preventing and/or treating feelings of tightness associated with dry skin.

Throughout the description, including the claims, the expression "comprising one" should be understood as being synonymous with "comprising at least one", unless the contrary is specified.

Furthermore, the expression “at least one” must be understood as being synonymous with “one or more” unless the contrary is specified.

The expressions “more than”, “between… and…” and “ranging from… to…” must be understood inclusive, unless otherwise specified.

The examples which follow are presented by way of illustration and not limitation of the invention. The compounds are, depending on the case, cited in chemical names or in CTFA names (International Cosmetic Ingredient Dictionary and Handbook).

The invention is illustrated in more detail in the following examples.

Examples

Example 1 – Evaluation of the effect of N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine (compound 20) on strengthening the barrier function.

A) Principle of the test

The study consists of measuring the effect of a treatment of N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine (compound 20) on the properties of the barrier function on human keratinocytes normal in single layer.

The objective of the study is to demonstrate, by immunolabeling, the effects of N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine (compound 20) on the abundance protein of claudin-1 (CLDN-1) and occludin (OCLN) from NHEKs keratinocytes in monolayer treated for 72 hours (Claudin-1) or 144 hours (Occludin).

B) Operating mode

The effect of N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine (compound 20) was compared to the effect of a hypercalcic treatment (1.5 mM CaCl2) used in as a reference condition. A preliminary cytotoxicity study made it possible to define the concentrations tested for N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine (compound 20). The tested thiopyridinone compound can be prepared according to the process described, for example, in EP-A-3390363 or WO 2017/102349.

Treatment of NHEKs keratinocytes

NHEKs keratinocytes were seeded in 96-well culture plates, 24 hours before treatment. They were then treated for 72 hours or 144 hours with N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine (compound 20). A renewal of the culture medium and treatments was carried out after 72 hours.

In parallel, the cells were also cultured in hypercalcic medium (1.5 mM CaCl2) in order to stimulate their differentiation and induce the expression of the 2 target proteins or their cellular relocalization (reference treatment).

The experiments were carried out in culture triplicates (n=3).

Immunofluorescence labeling of CLDN-1 and OCLN

At the end of the treatments, the NHEKs keratinocytes were fixed then placed in the presence of primary antibodies specific for the 2 proteins of interest. Secondary antibodies conjugated to Alexa 488 were then used to enable detection of target proteins. The table below shows the references of the primary and secondary antibodies used for each of the immunomarkings.

Hoechst 33258 (ThermoFisher, H3569), a fluorescent molecule capable of binding to the adenine and thymine bases of DNA, was used to detect the nuclei of NHEKs keratinocytes.

Image acquisition (5 images/culture well) was carried out with an INCell Analyzer ^TM 2200 (automated microscope). The labeling was quantified by measuring the fluorescence intensity relative to the number of cells identified by the Hoechst labeling. The analyzes were carried out using the Developer Toolbox 1.5 software.

C) Results

Protein abundance (% relative to untreated controls) Terms Concentrations Claudine-1 Occludin CaCl ₂ 1.5mM 1084** 730*** N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine (compound 20) 15 μM 472* 169 50 μM 510* 220*

The results (means +/- standard deviations of three independent cultures) are expressed in relation to the respective untreated control conditions. P values between 0.01<p<0.05 are considered significant (*), between 0.001<p<0.01 as highly significant (**) and p<0.001 as very highly significant (***) (t-student statistical analysis carried out to compare the treatments individually compared to untreated controls).

As expected, treatment with CaCl2 (positive control to validate the test) makes it possible to significantly induce the abundance of Claudine-1 and Occludin, which validates the experiment.

N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine (compound 20) according to the invention significantly increases the expression of Claudine-1 at concentrations of 15 and 50 µM. Furthermore, it significantly increases the expression of occludin under the conditions tested at a concentration of 50 µM.

Ref: Furuse M, Hata M, Furuse K, Yoshida Y, Haratake A, Sugitani Y, Noda T, Kubo A, Tsukita S. “Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1- deficient mice”. J Cell Biol. 2002 Mar 18;156(6):1099-111.

Pummi K, Malminen M, Aho H, Karvonen SL, Peltonen J, Peltonen S. “Epidermal tight junctions: ZO-1 and occludin are expressed in mature, developing, and affected skin and in vitro differentiating keratinocytes”. J Invest Dermatol. 2001 Nov;117(5):1050-8.

Example 2 – Cosmetic composition

A composition in gel form for topical application is prepared comprising:

The composition applied to the skin helps improve the barrier function of the skin.

Claims (10)

Cosmetic use of at least one compound selected from the compounds of formula (I) below, the tautomers of formula (I') below, their salts, their solvates, such as their hydrates, their optical isomers, their racemates , and their mixtures:

in which
R₁designates a radical chosen from
a) a hydrogen atom, and
b) a linear saturated C alkyl group₁-VS₁₀or branched in C₃-VS₁₀optionally substituted by one or more groups, which may be the same or different, chosen from
i) -O-R₃, And
ii) -S-R₃,
And
R₂designates a radical chosen from
a) a hydrogen atom,
b) a linear saturated hydrocarbon group in C₁-VS₁₂or branched in C₃-VS₁₂or cyclic in C₃-VS₈optionally substituted by one or more groups, which may be the same or different, chosen from
i) -O-R₃,
ii) -S-R₃,
iii) -C(O)-O-R₃, And
iv) an aryl group in C₅-VS₁₂, optionally substituted by one or more hydroxyls and/or by one or more C-alkoxy radicals₁-VS₈And
c) an aryl group in C₅-VS₁₂, optionally substituted by one or more hydroxyls and/or by one or more C-alkoxy radicals₁-VS₈
And
R₃designates a radical chosen from

1. a hydrogen atom, and
2. b) a saturated linear C ₁ -C ₁₀ or branched C ₃ -C ₁₀ alkyl group;

or a composition comprising at least such compound, to improve the barrier function of the skin. Use according to claim 1, in which:
R ₁ of formula (I) and (I') represents a hydrogen atom;
Or
R ₁ of formula (I) and (I') represents a linear alkyl group (in C ₁ -C ₁₀ ) or a branched alkyl group (in C ₃ -C ₁₀ ), in particular a linear alkyl group (in C ₁ -C ₆ ) or a branched alkyl group (C ₃ -C ₆ ), such as methyl, ethyl, n-pentyl, n-nonyl, isobutyl, more preferably ethyl, in particular said alkyl group of R ₁ is not substituted;
R ₂ of formula (I) and (I') represents a hydrogen atom;
Or
R ₂ of formula (I) and (I') represents a linear (C ₁ -C ₁₀ ) or branched (C ₃ -C ₁₀ ) alkyl group, in particular a linear alkyl group (C ₁ -C ₆ ) or branched (C ₃ -C ₆ ), such as methyl, ethyl, n-pentyl, n-nonyl, isobutyl, more preferably methyl or ethyl; said alkyl group of R ₂ being unsubstituted; And
R ₃ of formula (I) and (I') represents a hydrogen atom;
Or
R ₃ of formula (I) and (I') represents a saturated linear C ₁ -C ₁₀ or branched C ₃ -C ₁₀ alkyl group; in particular a linear (C ₁ -C ₆ ) alkyl group or a branched (C ₃ -C ₆ ) alkyl group, preferably a (C ₁ -C ₄ ) alkyl group such as the methyl group. Use according to claim 1 or 2, in which:
R ₂ of formula (I) and (I') represents a linear alkyl group (in C ₁ -C ₁₀ ) or a branched alkyl group (in C ₃ -C ₁₀ ), in particular a linear alkyl group (in C ₁ -C ₆ ) or a branched alkyl group (C ₃ -C ₆ ), such as methyl, ethyl, n-pentyl, n-nonyl, isobutyl, more preferably, methyl or ethyl; said alkyl group being substituted by one or more groups selected from i), ii), iii) and iv) as defined above, preferably said alkyl group being substituted by one or two groups selected from i), ii) and iii), more preferably by one or two groups chosen from i) and iii), better substituted by a group iii) such as carboxy. Use according to any one of claims 1 to 3, in which:
R₁of formula (I) and (I’) represents a radical chosen from
a) a hydrogen atom, and
b) a linear saturated C alkyl group₁-VS₆or in C₃-VS₆branched optionally substituted by one or more groups, which may be the same or different, chosen from
i) -O-R₃, And
ii) -S-R₃,
preferably optionally substituted with one or more groups i);
R₂of formula (I) and (I’) represents a radical chosen from
a) a hydrogen atom, and
b) a linear saturated hydrocarbon group in C₁-VS₁₀or branched in C₃-VS₁₀or cyclic in C₃-VS₈as in C₅-VS₆, optionally substituted by one or more groups, which may be identical or different, chosen from:
i) -O-R₃,
ii) -S-R₃,
iii) -C(O)-O-R₃, And
iv) a phenyl group optionally substituted by one or more hydroxyls and/or by one or more C-alkoxy radicals₁-VS₄such as methoxy,
preferably substituted by one or more groups selected from i) and iii), preferably iii) such as carboxy; And
R₃of formula (I) and (I’) represents a radical chosen from
a) a hydrogen atom, and
b) a linear saturated C alkyl group₁-VS₆or branched in C₃-VS₆,
preferentially, the compounds of formula (I) and the tautomer (I’), their salts, solvates, such as their hydrates, their optical isomers, their racemates, and their mixtures, have the following meanings:
R₁of formula (I) and (I’) represents a radical chosen from:
a) a hydrogen atom, and
b) a linear saturated C alkyl group₁-VS₄or branched in C₃-VS₄optionally substituted by one or more groups, which may be the same or different, chosen from i) -OR_3,more preferably unsubstituted;
R₂of formula (I) and (I’) represents a radical chosen from
a) a hydrogen atom, and
b) a linear saturated hydrocarbon group in C₁-VS₁₀or branched in C₃-VS₁₀or cyclic in C₃-VS₈as in C₅-C6, optionally substituted by one or more groups, which may be the same or different, chosen from
i) -O-R₃,
iii) -C(O)-O-R₃, And
iv) an aryl group in C₅-VS₁₂, optionally substituted by one or more hydroxyls and/or by one or more C-alkoxy radicals₁-VS₄; And
R₃of formula (I) and (I’) represents a radical chosen from:
a) a hydrogen atom;
b) a linear saturated C alkyl group₁-VS₄or branched in C₃-VS₄such as methyl or ethyl. Use according to any one of claims 1 to 4, in which:
the compound (1) is selected from compounds 1 to 24 below, their tautomers, their salts, their solvates, such as their hydrates, their optical isomers, their racemates, and their mixtures, in particular compounds 1, 2, 4, 6, 7, 9, 11, 12, 14, 15, 16, 17, 18, 19, 20 or 21, more particularly 1, 9, 16, 18, 19, 20 or 21, preferably 18, 19, 20 or 21, and more preferably 20: No. Structure Chemical name 1 N-ethyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 2 N-methyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 3 N-octyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 4 N-benzyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 5 N-phenyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 6 N-cyclohexyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 7 N-[2-(4-methoxyphenyl)ethyl]-2-thioxo-1,2-dihydropyridine-3-carboxamide 8 N-(2-methylpropyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 9 N-pentyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 10 N-nonyl-2-thioxo-1,2-dihydropyridine-3-carboxamide 11 N-(2-hydroxyethyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 12 N,N-diethyl 2-mercaptonicotinamide 13 N-ethyl-N-(2-hydroxyethyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 14 N-(2,3-dihydroxypropyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 15 N-(1,3-dihydroxypropan-2-yl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 16 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]alaninate 17 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]phenyl alaninate 18 Ethyl N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate 19 Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate 20 N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine 21 N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine 22 N,N-bis(2-hydroxyethyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 23 N-(3-methoxypropyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide 24 N-butyl-2-thioxo-1,2-dihydropyridine-3-carboxamide Use according to one of the preceding claims in which said compound of formula (I) or (I') is present in the cosmetic composition in a content ranging from 0.01% to 10% by weight, preferably 0.05%. at 5% by weight, more preferably from 0.1% to 3% by weight, relative to the total weight of the composition Use according to any one of the preceding claims, in which said compound of formula (I) or (I') is incorporated into a cosmetic composition intended for topical application. Cosmetic use of at least one compound of formula (I) or (I') as defined in any one of claims 1 to 5 or of a composition comprising at least one such compound, to prevent and/or treat cosmetic signs associated with sensitive or dry skin. Cosmetic treatment process comprising a step of applying to the skin at least one compound of formula (I) or (I') as defined in any one of claims 1 to 5 or of a cosmetic composition comprising at least less such a compound, to improve the barrier function of the skin. Cosmetic treatment process comprising a step of applying to the skin at least one compound of formula (I) or (I') as defined in any one of claims 1 to 5 or of a cosmetic composition comprising at least less such a compound, to prevent and/or treat cosmetic signs associated with sensitive or dry skin.