FR3136660A1 - ACTIVE COMPOUND DELIVERY COMPOSITION - Google Patents

Abstract

ACTIVE COMPOUND DELIVERY COMPOSITION A composition comprising A) a thiopyridinone compound; B) a C12-20 fatty compound, preferably a C12-C18 fatty compound, or preferably a C12-C16 fatty compound, having at most one C=C bond. Figure for the abstract: None

Description

ACTIVE COMPOUND DELIVERY COMPOSITION

The present invention relates to a composition intended to stimulate the delivery of active compounds into the skin.

CONTEXT

Skin care, for example skin lightening, always attracts great interest among consumers. As a result, the ultimate goal of the cosmetics industry has always been to deliver highly effective products to consumers with skin benefits such as hydrating, brightening, cleansing, and others.

For effective delivery, different forms of products are used. To date, it is still sometimes difficult to deliver hydrophilic active ingredients into the deep skin (round dermal junction). In particular, it is known that certain thiopyridinone compounds exhibit good depigmenting activity, even at low concentrations, see for example documents WO2012080075 and WO2017/102349. The compound thiopyridinone may show strong depigmenting or lightening effects by reducing melanin production.

There is therefore a need for a composition to stimulate the delivery of active compounds, for example thiopyridinone compounds, into the skin.

The inventors have unexpectedly discovered that a composition comprising the components: A) a compound of formula (I) or (I'), which can be considered as a thiopyridinone compound, or their salts, their optical isomers, their racemates, and/or their solvates such as hydrates and their derivatives, alone or in mixture; B) a C12-20 fatty compound having at most one C=C bond can satisfy the requirement. (I) (I')

Formulas (I) and (I’) in which:

R ₁ designates a radical chosen from:

a) a hydrogen atom;

b) a linear saturated 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

ii) -SR _3;

R ₂ designates a radical chosen from:

a) a hydrogen atom;

b) a linear C ₁ -C ₁₂ or branched C ₃ -C ₁₂ or cyclic C ₃ -C ₈ saturated 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 ;

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;

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

R ₃ designates a radical chosen from:

a) a hydrogen atom;

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

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

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

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

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

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

DESCRIPTION OF DRAWINGS

There shows the distribution of compound 20 in the test samples of Ex.1 and some others;

There shows the distribution of TXA in the test samples of Ex.2 and some others;

There shows the distribution of compound 20 in the test samples of Ex.10-11 and EC.3 by confocal Raman microscope; And

There shows the distribution of TXA in the test samples of Ex.10-11 and EC.3 via a confocal Raman microscope.

MODES OF CARRYING OUT THE INVENTION

Throughout the description, including the claims, the term “comprising one” must, unless otherwise stated, be understood as being synonymous with “comprising at least one”. Furthermore, the expression “at least one” used in the present description is equivalent to the expression “one or more”.

For the purposes of the present invention, and unless otherwise indicated:

a “linear C ₁ -C ₁₂ or branched C ₃ -C _12” saturated hydrocarbon group is equivalent to a “linear (C ₁ -C ₁₂ ) alkyl or branched (C ₃ -C ₁₂ ) alkyl group ” which corresponds to a linear or branched C ₁ -C ₁₂ saturated hydrocarbon group in C ₃ -C ₁₂ , and preferably a linear C ₁ -C ₁₀ hydrocarbon group or branched C ₃ -C ₁₀ hydrocarbon group, more preferably a hydrocarbon group in linear C ₁ -C ₆ or branched C ₃ -C ₆ ; 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.

More preferably, the linear or branched saturated alkyl groups 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 C ₃ -C ₈ hydrocarbon cyclic group is a mono or bicyclic cycloalkyl group containing from 3 to 8 carbon atoms, in particular a monocyclic C5 to C7 cycloalkyl group such as the cyclohexyl group,

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

- 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 term “ at least one ” is equivalent to the term “ 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 here include the conventional non-toxic salts of said compounds, such as those formed from an organic or inorganic acid or of an organic or inorganic base.

As salts of the 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 therefore comprise, for example, one or more alcohol functions; we can cite in particular 2-amino-2-methylpropanol, ethanolamine, triethanolamine, 2-dimethylaminopropanol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, 3-(dimethylamino)propylamine.

Mention may also be made of amino acid salts, 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 the 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 present invention 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.

Preferably, the “keratinous material” according to the present invention is skin. By “skin” we mean all the skin on the body. Always preferably, the keratinous material is the face or the neck, more particularly the face.

In the application, unless specifically stated otherwise, the quantities, contents, parts and percentages are expressed on a weight basis.

In the application, a numerical range is defined with a lower limit and an upper limit if necessary, such that one or more lower limits and one or more upper limits are given to form a range optionally with one or more preferred ranges. A given range can be defined by selecting a lower limit and an upper limit that define the bounds of the given range. All ranges defined in this way are inclusive and combinable, that is, any lower limit can be combined with any upper limit to form a range, provided that both lower and upper limits are provided to modify the same subject . For example, when ranges of 60-110 and 80-120 are stated for a specific subject, it should be understood that ranges 60-120 and 80-110 are also being considered and encompassed. Furthermore, if the lower limits shown are 1 and 2 and the upper limits are 3, 4 and 5, the following ranges are all predictable and fall within the scope of this disclosure: 1-3, 1-4, 1 -5 , 2-3, 2-4 and 2-5.

Apart from the operational examples, or unless otherwise indicated, all numbers expressing quantities of components and/or reaction conditions must be understood as being modified in all cases by the term "approximately", with a meaning conventionally known in the 'art, for example, to within 10% of the number indicated (such as "approximately 10%" means 9% - 11% and "approximately 2%" means 1.8% - 2.2%).

Component A)

The composition according to the invention comprises a compound of formula (I) or (I') below or tautomer (I') below or their salts, their optical isomers, their racemates, and/or their solvates such as hydrates and their derivatives, alone or in mixture, as component A): (I) (I')

Formulas (I) and (I’) in which:

R ₁ designates a radical chosen from:

a) a hydrogen atom;

b) a linear saturated 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

ii) -SR _3;

R ₂ designates a radical chosen from:

a) a hydrogen atom;

b) a linear C ₁ -C ₁₂ or branched C ₃ -C ₁₂ or cyclic C ₃ -C ₈ saturated 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 ;

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;

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

R ₃ designates a radical chosen from:

a) a hydrogen atom;

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

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

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

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

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

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

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, as component A) ;

have the following meanings:

R ₁ designates a radical chosen from:

a) a hydrogen atom;

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

ii) -SR _3;

preferably optionally substituted by one or more groups i)

R ₂ designates a radical chosen from:

a) a hydrogen atom;

b) a linear saturated hydrocarbon group in C ₁ -C ₁₀ or branched in C ₃ -C ₁₀ or cyclic in C ₃ -C ₈ such as in C5 -C6, 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 ;

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 chosen from i) and iii), preferably iii) such as carboxy

R ₃ designates a radical chosen from:

a) a hydrogen atom;

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 solvates such as hydrates and their derivatives, alone or in mixture;

have the following meanings:

R ₁ designates a radical chosen from:

a) a hydrogen atom;

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;

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 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;

R ₃ designates 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.

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;

b) a linear saturated hydrocarbon group in C₁-VS₅or branched in C₃-VS₅or cyclic in C₃-VS₈as in C5 -C6 , optionally substituted by one or more groups, which may be the same or different, chosen from v) -C(O)-O-R₃, preferably substituted by a group iii) -C(O)-O-R₃;

R ₂ is even more preferably a saturated linear C ₁ -C ₄ or branched C ₃ -C ₄ hydrocarbon group substituted by a group iii) -C(O)-OR ₃ .

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

Formulas (II) and (II') without which R1 and R3 have the same meaning as for the compounds of formula (I) and (I') and X designates an alkylene radical -(CH ₂ ) _n - with n an integer ranging from 1 to 10 inclusively, preferably ranging from 1 to 6, more preferably ranging from 1 to 4, such that 1, preferably R ₃ represents a hydrogen atom.

Preferably, 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]
wisteria 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]
wisteria

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]
wisteria

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]
wisteria

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 the compounds can be obtained by a chemical process known to those skilled in the art, from commercially available reagents. For example, the synthesis process disclosed in European patent application EP3 390 363 can be used.

Compound 20, N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine, which may also be named 3-carboxymethylaminocarbonyl-2-thiopyridinone, is a typical representative of the thiopyridinone compounds useful herein. invention.

Solubility of Component A)

Through in-depth study, the inventors believe, without being constrained by any known theory, that the compound of formula (I) or (I'), in particular for example compound 20, can be a typical representative of thiopyridinone compounds useful according to the present invention thanks mainly to a specific log P thereof.

The term "log P" is a measure known in the art to distinguish between a "hydrophilic" and "hydrophobic" compound. The value of log P can be determined by any method conventionally known in the art. For "log P", P is a partition coefficient, representing the ratio between the equilibrium concentration of a compound in an organic phase and that in an aqueous phase. Usually, a P value for a compound between octanol and water is used in the art. Therefore, a hydrophilic compound generally has a log P value less than 3.5, less than 1.0, or typically less than about -0.5, where P is the partition coefficient of the compound between octanol and water; and a hydrophobic compound generally has a log P of 3.5 or greater, or typically 5.0 or greater.

Based on Compound 20, the inventors conduct a broad study and determine that Compound 20 is particularly useful primarily because it has a log P falling in the range of -1.6 to 0.5, preferably -0.5 to 0.2. Therefore, thiopyridinone compounds of formula (I) or (I') having a log P of -1.6 to 0.5 are particularly preferred for use as component A).

Component A), for example compound (I), (I'), (II) and/or (II'), in particular a compound having a log P of -1.6 to 0.5, may be present in a quantity ranging for example from 0.01% to 10% by weight, preferably from 0.1% to 5% by weight, in particular from 0.5% to 3% by weight, relative to the total weight of the composition.

Component A'), additional hydrophilic active compounds

As stated above, compound 20 is particularly useful in particular because it has a log P ranging from -1.6 to 0.5. In other words, various additional cosmetically acceptable hydrophilic active compounds needing to be delivered to the skin can be used as component A') according to the present invention or used in combination with component A); as long as the additional hydrophilic active compound has a log P between -1.6 and 0.5.

According to one embodiment of the invention, component A') preferably carries a carboxyl group, which is in particular a carboxylic acid or an ester/salt thereof, preferably a carboxylic acid.

For example, among others, tranexamic acid (TXA) is a typical example of component A'). According to one embodiment of the invention, TXA is used as component A') together with compound 20 as component A).

Additionally, water-soluble vitamins can be used in the composition as an active compound of component A'). Useful vitamin examples include vitamin C (ascorbic acid), the B group of vitamins (e.g., vitamin B5 (panthenol), vitamin B3 (niacinamide), vitamin B1 and vitamin B2), nicotinic acid , folic acid, pantothenic acid, derivatives of these vitamins (especially esters) and their mixtures.

Component A), that is to say the thiopyridinone compound of formula (I) or (I'), is a niacinamide derivative. Within the meaning of the invention, other derivatives of the latter known to be useful as active compounds for cosmetic use, in particular for the skin, can also be used.

Component A') having a log P of -1.6 to 0.5, may be present in an amount ranging for example from 0.01% to 20% by weight, preferably from 0.05% to 10% by weight. weight, or preferably from 0.1% to 5% by weight, relative to the total weight of the composition.

Component B), a C12-20 fatty compound having at most one C=C bond

The composition according to the invention may comprise a C12-20 fatty compound having at most one C=C double bond, that is to say having a C=C bond or having no C=C bond, provided that when component B) is a fatty acid, it is a C12-C16 fatty acid.

By "fatty compound" is meant organic compounds which are insoluble in water at ordinary temperature (25°C) and atmospheric pressure (760 mmHg) (solubility less than 5%, preferably 1% and even more preferably 0, 1%). Furthermore, fatty compounds are generally soluble in organic solvents under the same temperature and pressure conditions, for example chloroform, ethanol, benzene or decamethylcyclopentasiloxane.

The fatty compounds are in particular chosen from fatty alcohols, fatty acids, fatty acid esters, and/or fatty alcohol esters. According to one embodiment of the invention, the fatty compound of component B) according to the invention does not comprise any additional heteroatom other than the C, H and O atoms.

According to the present invention, it is believed that the use of specific component B) in combination with component A) and/or A') can promote the delivery of component A) and/or A') into the skin. Without being limited to any known theory, it is inferred that appropriate carbon chain length is important for delivery. A carbon chain that is too long may result in a decreased delivery effect, while a carbon chain that is too short may be too volatile to be formulated into a useful product. By studying the matching with component A) and/or A') and through experiments, it is believed that the useful component B) may be a C12-20 fatty compound, preferably a C12-18 fatty compound, or preferably a C12-16 fatty compound.

According to one embodiment of the invention, an exemplary component B) may carry a C1-C6 alkyl branch.

Furthermore, it is surprising to see that for the purposes of the present invention, the useful fatty compound can preferentially have at most one C=C double bond, for example, have no C=C bond. Therefore, a C12-20 fatty compound, preferably a C12-18 fatty compound, or preferably a C12-16 fatty compound, having a saturated carbon chain may be particularly useful.

The fatty alcohols which can be used in the composition of the invention are not oxyalkylenated. They are saturated or unsaturated, linear or branched and include 12 to 20 carbon atoms. We can cite lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol and their mixture (cetyl stearyl alcohol), octyldodecanol, butyloctanol, or hexyldecanol.

The fatty acid which may be used in the composition of the invention includes a C12 to C16 fatty acid, such as lauric acid or lauroleic acid (C12), myristic acid or myristelaidic acid (C14 ), palmitic acid or palmitoleic acid (C16).

The useful esters are the esters of aliphatic mono- or polyacids, saturated or unsaturated, linear or branched, and of aliphatic mono- or polyalcohols, saturated or unsaturated, linear or branched, provided that the total carbon number of the esters is between 12 and 20.

Among the monoesters, we can cite cetyl lactate; C ₁₂ -C ₁₅ alkyl lactate; lauryl lactate; oleyl lactate; octyl octanoate; isononyl isononanoate; octyl isononanoate; 2-ethylhexyl isononate; octyl pelargonate; ethyl and isopropyl palmitates, alkyl myristates such as butyl myristate, ethyl laurate or oleate.

Among the polyesters, we can cite: diethyl sebacate; diisopropyl sebacate; diisopropyl adipate; di-n-propyl adipate; dioctyl maleate; glyceryl undecylenate; propylene glycol dicaprylate; triisopropyl citrate; glyceryl trilactate.

Preferably, no C18 or higher fatty acid is included in the composition of the present invention.

Advantageously, the content of fatty compound(s) ranges from 0.01% to 30% by weight, preferably from 0.1% to 10% by weight, or from 0.5% to 5% by weight relative to the total weight. of the composition.

Component C), surfactant

The composition according to the present invention may comprise a surfactant as optional component C), for example a nonionic surfactant, or a mixture thereof. According to the present invention, any conventional surfactant can be used, as long as it is compatible with the other components of the composition, in particular with components A), A') and/or B), in particular those benefiting, or at least not negatively affecting the delivery effect of component A) and/or A') in the skin.

Among the useful nonionic surfactants, mention may be made of esters of polyols and fatty acids with a saturated or unsaturated chain, as well as their oxyalkylenated derivatives, that is to say derivatives containing oxyethylenated and/or oxypropylenated units, such as as glyceryl esters and their oxyalkylenated derivatives; polyethylene glycol esters and their oxyalkylenated derivatives; sorbitol esters and their oxyalkylenated derivatives; sugar esters (sucrose, glucose or alkylglucose) and their oxyalkylenated derivatives; fatty alcohol ethers; sugar ethers and their mixtures.

The glyceryl esters of fatty acids which may in particular be mentioned include glyceryl stearate (glyceryl monostearate, distearate and/or sadearate).

Polyethylene glycol esters of fatty acids which may in particular be mentioned include polyethylene glycol 40 EO monostearate (CTFA name: PEG-40 stearate).

Mixtures of these surfactants can also be used.

In accordance with the solubility of component A) and the nature of component B), as well as with the medium/solvent to be used, component C), when used, can preferably have an HLB value of 2-20, of preferably 8-20, or preferably 10-18.

The nonionic surfactant may be present in the composition according to the present invention in an amount of 0.1% to 15% by weight, such as 0.15% to 10% by weight, relative to the total weight of the composition.

Component D), Medium/Solvent

The composition according to the invention may advantageously comprise at least one medium/solvent, in particular water and/or an organic medium/solvent, for use as optional component D).

Water

The composition according to the invention may advantageously comprise water in various quantities. For low viscosity applications of the composition, for example in the form of a leave-on lotion, a relatively large amount of water may be used. For example, water is used in a content greater than or equal to 40% by weight relative to the total weight of the composition. The water content in the low viscosity composition according to the invention preferably ranges from 40% to 99% by weight, more preferably from 50% to 90% by weight, or from 60% to 80% by weight, relative to the weight. total composition.

For high viscosity applications of the composition, for example in the form of a leave-in cream, a relatively smaller amount of water may be used. The high viscosity composition according to the invention advantageously comprises water in a content less than or equal to 40% by weight relative to the total weight of the composition. The water content in the high viscosity composition according to the invention preferably ranges from 10% to 40% by weight, more preferably from 15% to 35% by weight, or from 20% to 30% by weight, relative to the weight. total composition.

Organic medium/solvent

The composition according to the invention may also comprise one or more organic media/solvents, preferably water-soluble organic media/solvents (solubility greater than or equal to 5% in water at 25°C and at atmospheric pressure; or having a log P of -3.0 to 3.5, preferably -3.0 to 0.5).

According to a preferred embodiment of the invention, the composition may comprise at least one organic medium/solvent.

Examples of organic media/solvents which may be cited include monoalcohols or diols, linear or branched, and preferably saturated, comprising 2 to 10 carbon atoms, such as propylene glycol; aromatic alcohols; polyols containing more than two hydroxyl functions; polyol ethers, alone or in mixture.

The organic medium(s), when present, are present in an amount ranging from 0.1% to 40% by weight, preferably from 1% to 30% by weight, or from 3% to 20% by weight, for example relative to the total weight of the composition according to the invention.

pH correction agent

The composition according to the present invention may comprise (3) 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 (3) 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, 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 containing 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. -C ₆ .

Examples of amine compounds of formula (III) which may be mentioned 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 be made in particular 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, there may be mentioned in particular 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 chosen 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 which may be mentioned include salts of the previously mentioned amines with acids such as carbonic acid or hydrochloric acid. Guanidine carbonate or monoethanolamine hydrochloride can in particular be used.

The (3) 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 (3) pH correction agent may be present in an amount of 15% by weight or less, preferably 10% by weight or less, and more preferably 5% by weight or less, relative to the total weight of the composition. .

The (3) 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. % by 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 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, as (3) 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 weak bases, can 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.

Admixtures

In known manner, the composition of the present invention may also contain adjuvants which are usual in the cosmetic, pharmaceutical and/or dermatological field depending on the end uses and/or the specific forms of the products, such as hydrophilic or lipophilic gelling agents. , emulsifiers, hydrophilic or lipophilic active agents, preservatives, fragrances, fillers, pH correctors, odor absorbers and dyes. The quantities of these different adjuvants are those conventionally used in the field considered, and for example from 0.01 to 20% by weight of the total weight of the composition.

These adjuvants and their concentrations must be such that they do not modify the property sought for the composition of the invention.

The composition according to the invention is preferably in the form of an aqueous gel.

In a preferred embodiment according to the invention, the composition comprises hydrophilic gelling agents.

The compositions according to the invention can be manufactured by known processes, generally used in the cosmetic or dermatological field.

The composition according to the invention finds its application in a large number of cosmetic treatments of keratinous materials such as the skin, the scalp or the mucous membranes (lips), and more particularly the skin, in particular in skin care, to lighten the skin.

The object of the invention is also a cosmetic process for the care or makeup of keratinous materials, comprising the application to the keratinous materials of a composition as defined above. The object of the invention is also a non-therapeutic cosmetic process for depigmenting, lightening and/or discoloring keratin materials, preferably the skin, comprising the step of applying a composition as defined above to the keratin materials.

The object of the invention is also a non-therapeutic cosmetic process for the care or makeup of keratinous materials, comprising the application to the keratinous materials of a composition as defined above.

The invention also relates to the cosmetic use of a composition as defined above, for the care or makeup of keratinous materials.

More particularly, the object of the invention is the cosmetic use of a composition as defined above, for skin care, preferably for lightening the skin, and/or reducing or lightening darker spots. and/or more colored on the skin.

In a particular embodiment, the composition is suitable for the treatment of darker and/or more colored spots on the skin.

EXAMPLES

The following examples of compositions according to the invention are given by way of illustration and without limitation. Compounds are indicated by chemical name or INCI name.

The quantities/concentrations of ingredients in the compositions/formulas described below are expressed as % by weight, relative to the total weight of each composition/formula, unless otherwise indicated.

The main raw materials used, their trade names and suppliers are given below. INCI name Trade name Supplier PEG-40 STEARATE TEGO ACID S40 P EVONIK GOLDSCHMIDT SUCROSE TRISTEARATE SURFHOPE SE COSME C-1803 MITSUBISHI-KAGAKU FOODS TRANEXAMIC ACID SPECWHITE® TA SPECCHEM INDUSTRY NIACINAMIDE NIACINAMIDE PC DSM NUTRITIONAL PRODUCTS OLEIC ACID KORTACID 1811 PACIFIC OLEOCHEMICALS OLEYL ALCOHOL HD-OCENOL® 80/85 V BASF ISOSTEARIC ACID PRISORIN ^TM 3505-LQ-(GD) CRODA HEXYLDECANOL ISOFOL 16 SASOL LAURYL ALCOHOL/MYRISTYL ALCOHOL/CETYL ALCOHOL VEGAROL® 1216 VVF ETHYL OLEATE DUB OE HP DUBOIS STEARINERY ETHYL LINOLEATE VITAMIN F(EE) OLEON PROPYLENE GLYCOL PROPYLENE GLYCOL USP/EP DOW GLYCERIN GLYCERIN 4861 OLEON

Compound 20 is synthesized as indicated in Example 2 of patent EP 3 390 363 .

Example A

The inventive compositions of Ex.1-9, as well as the comparative composition of EC.1-2, were prepared, from the ingredients indicated in Table 1 below (in which the contents are indicated in % by weight of materials relative to the total weight of the composition):

Components Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 THIS. 1 THIS. 2 PEG-40 STEARATE 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 GLYCERYL STEARATE 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 PROPYLENE GLYCOL 20 20 20 20 20 20 20 20 20 20 20 ETHYL OLEATE 3 3 3 3 HEXYLDECANOL 3 3 3 3 OLEYL ALCOHOL 5 3 2 LAURYL ALCOHOL/MYRISTYL ALCOHOL/CETYL ALCOHOL 3 TRANEXAMIC ACID 1 1 1 1 1 1 1 1 1 NIACINAMIDE 4 4 4 4 4 4 COMPOUND 20 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 WATER Qs for 100 Qs for 100 Qs for 100 Qs for 100 Qs for 100 Qs for 100 Qs for 100 Qs for 100 Qs for 100 Qs for 100 Qs for 100

The compositions were prepared according to the following steps, taking Ex.1 as an example:

1). Heat the fatty compounds to 75℃, and mix well until all the solid has melted.

2). Mix the soluble raw materials, and heat to 75℃, mix well until there are no lumps.

3). Transfer the oil phase into the water phase at 75℃, mixing evenly for 15 min.

4). Cool to 30℃.

5). Finally, add compound 20 and correct the pH to be 5.6 ±0.3.

Example B

The inventive compositions of Ex.1-9, as well as the comparative composition of CE.1-2, prepared in Example A were evaluated by Raman spectroscopy and bioavailability study.

Raman spectroscopy:

A LabRam HR Evolution confocal Raman microscope (Horiba Jobin-Yvon, Villeneuve-d'Ascq, France) was used. The Raman spectrum was obtained using a 532 nm DPSS laser with a power of 8 mW on the sample, coupled to a ×50 LM Plan objective (Olympus, AN 0.75, Rungis, France). The confocal hole was set at 100 μm in diameter for all measurements. The system was spectrally calibrated to the 520.7 cm ^-1 silicon spectral line before testing. Detection was facilitated by scattering shifted Raman radiation onto a charge-coupled device (CCD) detector using a 600 line/mm grating.

For pure active ingredients, single-point spectra were acquired with a laser intensity of 25% and an acquisition time of 10 seconds, for the spectral range 400 - 2000 cm ⁻¹ .

For formula testing mapping, the step size was 3 μm in the X and Y directions. The acquisition areas were 18 X 150 μm. For each spot, a laser intensity of 50% and an acquisition time of 5 seconds per spectrum were used. The spectral range was from 400 to 2000cm ⁻¹ .

For the test, skin tissue samples were prepared as follows: for sample preparation, 6μL of formula was applied evenly to 0.8 cm X 0.8 cm porcine skin, corresponding to 9 mg /cm². The porcine skin sample then emerged onto an insert membrane with PBS underneath, followed by incubation at 37℃ at 95% relative humidity for 6 hours. The treated sample was embedded in OCT, then frozen and cryo-sectioned at 20 µm thickness. It was then placed on a CaF ₂ substrate for confocal Raman scanning. Three porcine samples were prepared for each formulation. Confocal Raman mapping was acquired for each processed sample.

Bioavailability study:

For the percutaneous absorption study, vertical diffusion cells were used. The study was carried out following the following procedure: the formula containing the active ingredient of interest was applied to skin samples (n=9) at 5 mg/cm ² . After 16 hours of exposure, the unabsorbed residues remaining on the surface of the skin were removed by washing, the stratum corneum was then collected by removal with adhesive tape (20 passes, grouped by 10), the epidermis, the dermis and receptor fluid were collected. The actives were extracted from each of the collected compartments: washing, taping, epidermis, dermis and receiving fluid, and the quantity of actives was quantified by LC MS/MS. The mass balance was checked to see if the amount of T applied to the skin was recovered at the end of the experiment; data were excluded when the mass balance did not meet the criterion of 100 ± 15%.

[Table 2] Table 2 Data on active delivery in the bioavailability assay - corresponding to Table 1 Properties Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 EC. 1 EC. 2 Raman (compound 20) √ √ √ √ √ Δ Δ × Raman (TXA) Δ Δ ○ Δ × Bioavailability (compound 20) 3.15% 1.48% Bioavailability (TXA) 2.3% 2.3% 0.11%

√: the signal can be observed in the stratum corneum, epidermis；Δ: A scattered signal can be found in the epidermis;

○: a weak signal can be found in the epidermis; And

×: no signal can be observed in the skin

The results are also provided in Figures 1 and 2. For compound 20, signals were observed in the stratum corneum and epidermis in Ex.1, Ex.4, Ex.5, Ex.6, Ex. 7, Ex.8 and Ex.9 while no signal was found in EC.2. For active TXA, weak or scattered signals were found in the epidermis in Ex.2, Ex.4, Ex.6 and Ex.7 while no signals were found in EC.1 .

[Table 3] Table 3: Bioavailability data: Formulation Example 1 Example 2 Example 3 EC. 2 EC. 1 N=7, % applied dose (mean ± standard deviation) Stratum corneum 6.36±1.99 7.80±1.50 9.80±1.90 2.61±1.36 0.21±0.08 Epidermis 2.41±1.53 1.30±1.60 1.10±0.90 0.87±0.49 0.048±0.042 Dermis 0.25±0.21 0.66±0.66 0.44±0.25 0.29±0.23 0.018±0.011 Receiving fluid (FR) 0.49±0.74 0.077±0.104 0.13±0.13 0.31±0.38 0.015±0.016 Epidermis+Dermis+FR 3.15±2.08 2.30±2.30 2.30±2.30 1.48±0.73 0.11±0.06

The bioavailability results were shown in Tab.3. For the inventive examples, high % of doses applied to the skin in the formulas of the sample, in particular more than 1% of active ingredient in (Epidermis+dermis+FR) were obtained; while the active was less found in the skin in EC.1 and EC.2.

Example C

The inventive compositions of Ex.10-11, as well as the comparative composition of EC.3, were prepared, from the ingredients indicated in Table 2 below (in which the contents are indicated in % by weight of materials per relative to the total weight of the composition):

[Table 4] Table 4 Components Example 10 Example 11 EC. 3 PEG-40 STEARATE 1.2 1.2 1.2 SUCROSE TRISTEARATE 0.5 0.5 0.5 GLYCERIN 9 9 9 ETHYL OLEATE 1 HEXYLDECANOL 1 ETHYL LINOLEATE 3 TRANEXAMIC ACID 1 1 1 NIACINAMIDE 4 4 4 COMPOUND 20 0.5 0.5 0.5 WATER Qs for 100 Qs for 100 Qs for 100

Example D

The inventive compositions of Ex.10-11, as well as the comparative composition of EC.3, prepared in Example C were evaluated by Raman spectroscopy as set forth in Example B.

The result was shown on the . The three formulations are comparable in signal intensity and depth of compound 20 in pig skin, all signals can be observed in the stratum corneum, epidermis and dermis.

The result was also shown on the . For Ex.10, the TXA signal is uniformly distributed in the stratum corneum, epidermis and dermis. But for Ex.11 & EC.3, no obvious signal can be observed in the epidermis, only in the stratum corneum and dermis.

It is concluded that with the technical solutions of the present invention, using a fatty compound having at most one C=C bond, the formulas can achieve penetration of the active substance comparable to that of classic formulas having 2 C=C bonds or more, but inhibit or even avoid the storage instability defect brought by the more numerous C=C connections.

Claims (10)

Composition comprising the following components:
A) at least one compound chosen from the compounds of formula (I) and the tautomer of formula (I') below; and their salts, optical isomers, racemates, and/or solvates such as hydrates, alone or in mixture: (I) (I') formulas(I)And(I')in which :
-R ₁designates a radical chosen from:
a) a hydrogen atom;
b) a linear saturated C alkyl group₁-VS₁₀or in C₃-VS₁₀branched optionally substituted by one or more groups, which may be identical or different, chosen from:
i) -O-R₃
ii) -S-R_3;
-R ₂ designates a radical chosen from:
a) a hydrogen atom;
b) a saturated hydrocarbon group in C₁-VS₁₂linear or C₃-VS₁₂branched or C₃-VS₈cyclic, 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;
iv) an aryl group in C₅-VS₁₂, optionally substituted by one or more hydroxyls and/or by one or more C-alkoxy radicals₁-VS₈;
c) an aryl group in C₅-VS₁₂, optionally substituted by one or more hydroxyls and/or by one or more C-alkoxy radicals₁-VS₈
-R ₃designates a radical chosen from:
a) a hydrogen atom;
b) a linear saturated C alkyl group₁-VS₁₀or branched in C₃-VS₁₀;
B) at least one C12-20 fatty compound, preferably a C12-C18 fatty compound, or preferably a C12-C16 fatty compound, having at most one C=C bond, provided that when component B) is a fatty acid, it is a C12-C16 fatty acid. Composition 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 (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 ethyl; in particular said alkyl group of R ₁ is not substituted. Composition according to any one of the preceding claims, in which:
-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 not being substituted. Composition according to any one of the preceding claims, in which:
-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. Composition according to any one of the preceding claims, in which:
-R ₁ of formula (I) and (I') represents a radical chosen from:
a) a hydrogen atom;
b) a linear saturated C alkyl group₁-VS₆or in C₃-VS₆branched optionally substituted by one or more groups, which may be identical or different, chosen from:
i) -O-R₃
ii) -S-R_3;
preferably optionally substituted by one or more groups i)
-R ₂ of formula (I) and (I') represents a radical chosen from:
a) a hydrogen atom;
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 identical or different, chosen from:
i) -O-R₃
ii) -SR-₃
iii) -C(O)-O-R₃;
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 chosen from i) and iii), preferably iii) such as carboxy
-R₃of formula (I) and (I') represents a radical chosen from:
a) a hydrogen atom;
b) a linear saturated C alkyl group₁-VS₆or branched in C₃-VS₆;
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:
-R₁of formula (I) and (I') represents a radical chosen from:
a) a hydrogen atom;
b) a linear saturated C alkyl group₁-VS₄or in C₃-VS₄branched optionally 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;
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 identical or different, chosen from:
i) -O-R₃
iii) -C(O)-O-R₃;
iv) an aryl group in C₅-VS₁₂, optionally substituted by one or more hydroxyls and/or by one or more C-alkoxy radicals₁-VS₄;
-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. Composition according to any one of the preceding claims, in which:
the compound of formula (I) chosen from the group consisting of compounds 1 to 24 below and their tautomer or their salts, their optical isomers, their racemates and/or their solvates such as hydrates, alone or in mixture, 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, 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-dihydropyridine
-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 . Composition according to any one of the preceding claims, in which component A) is chosen from those having a log P falling in the range of -1.6 to 0.5. Composition according to any one of the preceding claims, wherein an additional hydrophilic active compound having a log P of -1.6 to 0.5 is used as component A') in combination with component A), component A') being preferentially chosen from the group consisting of water-soluble vitamins, cosmetically acceptable niacinamide derivatives, and tranexamic acid, preferably ascorbic acid, niacinamide or tranexamic acid. Using the combination of
component A) an active compound having a log P of -1.6 to 0.5
component B) a C12-20 fatty compound, preferably a C12-C18 fatty compound, or preferably a C12-C16 fatty compound, having at most one C=C bond; And
optionally component C); a surfactant having an HLB value of 2-20, preferably 8-20, or preferably 10-18; And
optionally component D) a glycol having a log P of -3.0 to 3.5, preferably of -3.0 to 0.5,
to stimulate the delivery of component A) into the skin. Non-therapeutic cosmetic process for depigmenting, lightening and/or bleaching keratin materials, preferably the skin, comprising the step of applying a composition according to one of claims 1 to 8 to the keratin materials.