FR3110410A1 - Anti-aging cosmetic compositions comprising NMN - Google Patents

Abstract

The invention relates to the cosmetic use of NMN, one of its precursors, one of its derivatives as well as an anti-aging cosmetic composition comprising nicotinamide mononucleotide, one of its derivatives, one of its precursors and / or one of its. salts and their cosmetic use against skin aging.

Description

Anti-aging cosmetic compositions comprising NMN

FIELD OF THE INVENTION

The present invention relates to cosmetic compositions the use of nicotinamide mononucleotide (NMN), one of its derivatives or one of its salts, for cosmetic purposes as well as for the formulation of cosmetic compositions comprising it for dry skin.

TECHNICAL BACKGROUND

The skin is an organ covering the entire human body. Its role is to constitute a barrier between the body and the external environment, and therefore in particular to protect the body from external aggressions, to maintain body temperature. The skin is made up of several layers, the outermost of which is the epidermis.

From the innermost layer to the outermost, the epidermis includes the germinal layer, then the prickly layer, then the granular layer composed of 3 to 5 layers of flattened cells, then the stratum lucidum or clear layer which is a very thin and finally the stratum corneum or stratum corneum composed of flat keratinized and anucleate cells. The stratum corneum consists of rows of flattened cells primarily composed of keratin. These are squamous cells. These cells are shed in layers every day.

Skin aging alters several parameters of the skin such as its firmness, its elasticity, and its density. Wrinkles may form on the surface of the skin. The eye contour can also show dark circles or swelling of the lower eyelid. All these elements can seem unattractive.

Skin aging can affect people's skin differently, depending on their skin type. There are different types of skin: normal skin, dry skin, oily skin and combination skin which can have areas of normal skin and areas of oily skin, or a combination of dry and oily skin.

Healthy skin is naturally protected on the surface by a hydrolipidic film, formed mainly of water and lipids (sebum). Waterproof, it protects the skin from external aggressions and prevents water loss. When the upper layer of the epidermis is not balanced in water and lipids, it can no longer effectively play its role as a barrier and becomes uncomfortable to varying degrees. The subject sometimes feels tightness, burning or itching sensations when his skin becomes dry. The origins of dry skin are diverse. Unlike dehydrated skin, dry or very dry skin is a chronic condition generally due to a genetic dysfunction. In addition to the genetic origin, there are also states of skin dryness triggered by external factors such as climatic or environmental factors (pollution, air conditioning, heating of a room). Dry skin can also be caused by skin pathologies, diseases affecting the whole body such as thyroid dysfunction, diabetes, nutritional deficiencies and/or medical treatments such as anti-acne treatments.

Dry skin is characterized by the following symptoms: a dull appearance, specific epidermal clinical signs of desquamation, cracking, sometimes inflammation and loss of elasticity. The surface irregularities of the skin are all the more important as it is dry. Dry skin provides favorable ground for the appearance of eczema, in particular in the form of achromic eczematids. There are different types of dry skin: (i) dry skin which is characterized by temporary discomfort, slight tightness and/or slight desquamation; (ii) very dry skin showing marked discomfort and tightness, intense scaling, cracking and cracking; and (iii) pre-atopic xerosis characterized by rough, rough skin and mild irritation.

Oily skin is characterized by hypersecretion of sebum by the seborrheic glands of the epidermis. Oily skin may in particular have imperfections such as pimples and/or blackheads, a dull complexion, a shiny appearance of the skin. The causes of oily skin are primarily genetic. However, sebum hypersecretion can also be caused by hormonal influence, the sex of the subject, environmental pollution, high outside temperature, too fatty food, stress and other factors.

Normal skin is characterized by normal sebum production and lacks the characteristics of dry skin.

Combination skin is characterized by oily skin limited to certain areas of the face, and in particular the forehead, nose and/or chin.

The cosmetics industry offers many cosmetic compositions to solve this problem. However, subjects may develop allergies to conventional compositions, in particular to compositions comprising retinol, a cosmetic ingredient which makes it possible to treat skin ageing.

There is therefore a need to develop new cosmetic compositions to prevent or treat the signs of aging, reducing the risk of reaction.

These objectives are achieved thanks to nicotinamide mononucleotide (NMN) and cosmetic compositions comprising it for their cosmetic use as described below.

The present invention relates to nicotinamide mononucleotide (NMN), one of its derivatives, one of its precursors or one of its salts, for its cosmetic use to prevent and/or treat at least one sign of aging.

Preferably, the use of NMN, one of its derivatives, one of its precursors or one of its salts, is not therapeutic.

Advantageously, the cosmetic use of NMN, one of its precursors, one of its derivatives or one of its salts, can prevent or treat at least one sign of aging of dry skin.

Advantageously, the cosmetic use of NMN, one of its precursors, one of its derivatives or one of its salts, can prevent or treat at least one sign of aging for normal skin.

Advantageously, the at least one sign of aging can be chosen from wrinkles, increased roughness of the skin, reduction in the thickness of the epidermis, reduction in the firmness of the epidermis, reduced elasticity of the epidermis, reduced luster of the skin, swelling of the lower eyelid and dark circles.

• X’₁et X’₂sont indépendamment choisis parmi O, CH₂, S, Se, CHF, CF₂, et C=CH₂;
• R’₁et R’13 sont indépendamment choisis parmi H, azido, cyano, un alkyl en C1-C8, un thio-alkyl en C1-C8, un hétéroalkyl en C1-C8, et OR, dans lequel R est choisi parmi H et un alkyl en C1-C8,
• R’₂, R’₃, R’₄, R’₅, R’₉, R’₁₀, R’₁₁, R’₁₂sont indépendamment choisis parmi H, un halogène, un azido, un cyano, un hydroxyl, un alkyl en C₁-C₁₂, un thioalkyl en C₁-C₁₂, un hétéro-alkyl en C₁-C₁₂, un haloalkyl en C₁-C₁₂ et OR, dans lequel R peut être choisi parmi H, un alkyl en C₁-C₁₂, un C(O)( C₁-C₁₂) alkyle, un C(O)NH(C₁-C₁₂) alkyle, un C(O)O(C₁-C₁₂) alkyle, un C(O) aryle, un C(O)( C₁-C₁₂) aryle, un C(O)NH(C₁-C₁₂) alkyle aryle, un C(O)O(C₁-C₁₂) alkyle aryle ou un groupe C(O)CHR_AANH2 dans lequel R_AA est une chaine latérale choisi parmi un acide aminé protéogène ;
• R’₆et R’₈sont indépendamment choisis parmi H, un azido, un cyano, un alkyl en C₁-C₈et OR, dans lequel R est choisi parmi H et un alkyl en C₁-C₈;
• R’₇et R’₁₄sont indépendamment choisis parmi H, OR, NHR, NRR’, NH-NHR, SH, CN, N₃et un halogène, dans lequel R et R’ sont indépendamment choisit parmi H et un (C₁-C₈) alkyle aryle ;
• Y’₁et Y’₂sont indépendamment choisis parmi CH, CH₂, C(CH₃)₂ou CCH³;
• M’ est choisi parmi H ou un contre-ion adapté ;
• représente une liaison simple ou double en fonction de Y’₁et Y’₂; etreprésente un anomère alpha ou béta en fonction de la position de R’1 et R’13 ;

et leurs combinaisons.In one embodiment, the NMN derivative can be chosen from alpha nicotinamide mononucleotide (α-NMN), dihydronicotinamide mononucleotide (denoted NMN-H), the compound of formula (I): (I)
or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its pharmaceutically acceptable crystals thereof, in which:
- X is chosen from O, CH₂, S, Se, CHF, CF₂and C=CH₂;
-R₁is selected from H, azido, cyano, C-alkyl₁-VS₈, thio-C-alkyl₁-VS₈, C-heteroalkyl₁-VS₈and OR; wherein R is selected from H and C-alkyl₁-VS₈;
-R₂, R₃, R₄and R₅are chosen independently of one another from H, halogen, azido, cyano, hydroxyl, C-alkyl₁-VS₁₂, thio-C-alkyl₁-VS₁₂, C-heteroalkyl₁-VS₁₂, C-haloalkyl₁-VS₁₂and OR; wherein R is selected from H, C-alkyl₁-VS₁₂, C(O)(C)₁-VS₁₂)alkyl, C(O)NH(C₁-VS₁₂)alkyl, C(O)O(C₁-VS₁₂)alkyl, C(O)aryl, C(O)(C₁-VS₁₂)alkyl aryl, C(O)NH(C₁-VS₁₂)alkyl aryl, C(O)O(C₁-VS₁₂)alkyl aryl and C(O)CHR_AANH₂; in which R_AAis a side chain selected from a proteinogenic amino acid;
-R₆is selected from H, azido, cyano, C₁-VS₈ alkyl, C₁-VS₈ thio-alkyl, C₁-VS₈ heteroalkyl and OR; wherein R is selected from H and C₁-VS₈ alkyl;
-R₇is selected from H, P(O)R₉R₁₀and P(S)R₉R₁₀; in which
-R₉and R₁₀are chosen independently of each other from OH, OR₁₁, NHR₁₃, NR₁₃R₁₄, C-alkyl₁-VS₈, a C-alkenyl₂-VS₈, a C-alkynyl₂-VS₈, a C-cycloalkyl₃-VS₁₀, an aryl at C₅-VS_{12 ,}(VS₁-VS₈)alkyl aryl, (C₁-VS₈)aryl alkyl, (C₁-VS₈) heteroalkyl, (C₁-VS₈) heterocycloalkyl, a heteroaryl and NHCHR_ATR_{AT '}HORN₁₂; in which :
-R₁₁is selected from a group C₁-VS₁₀alkyl, C₃-VS₁₀cycloalkyl, C₅-VS_{1 8}aryl, C₁-VS₁₀alkylaryl, C₅-VS₁₂substituted aryl, C₁-VS₁₀heteroalkyl, C_3-VS₁₀heterocycloalkyl, C₁-VS₁₀haloalkyl, a heteroaryl, -(CH₂)_notC(O)(C)₁-VS₁₅)alkyl, -(CH₂)_notOC(O)(C)₁-VS₁₅)alkyl, -(CH₂)_notOC(O)O(C)₁-VS₁₅)alkyl, -(CH₂)_notSC(O)(C)₁-VS₁₅)alkyl, -(CH₂)_notC(O)O(C₁-VS₁₅)alkyl and -(CH₂)_notC(O)O(C₁-VS₁₅)alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH)₂;
-R₁₂is selected from H, C_1-VS₁₀alkyl, C₂-VS₈alkenyl, C₂-VS₈alkynyl, C_1-VS₁₀haloalkyl, C_3-VS₁₀cycloalkyl, C_3-VS₁₀heterocycloalkyl, C₅-VS_{1 8} aryl, C₁-VS₄alkylaryl and C₅-VS₁₂heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted from one or two groups selected from halogen, trifluoromethyl, C₁-VS₆alkyl, C₁-VS₆alkoxy and cyano; And
-R_ATAnd R_AT'are independently selected from H, A C_1-VS₁₀alkyl, C₂-VS₁₀alkenyl, C₂-VS₁₀alkynyl, C_3-VS₁₀cycloalkyl, C₁-VS₁₀thio-alkyl, C_1-VS₁₀hydroxylalkyl, C₁-VS₁₀alkylaryl and C₅-VS₁₂aryl, C_3-VS₁₀heterocycloalkyl, heteroaryl, -(CH₂)₃NHC(=NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl and a side chain selected from a proteinogenic amino acid or a non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C_1-VS₁₀alkyl, C_1-VS₆alkoxy, halogen, nitro and cyano; Or
-R₉and R₁₀form together with the phosphorus atoms to which they are attached a 6-membered ring in which –R₉−R₁₀− represents
–CH₂-CH₂-CHR−; wherein R is selected from H, a group (C₅-VS₆) aryl and (C₅-VS₆) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C₁-VS₆alkyl, a C₁-VS₆alkoxy and cyano; Or
R₉and R₁₀form together with the phosphorus atoms to which they are attached a 6-membered ring in which –R₉−R₁₀− represents –O-CH₂-CH₂-CHR-O-; wherein R is selected from H, a group (C₅-VS₆) aryl and (C₅-VS₆) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by halogen, trifluoromethyl, a (C₁-VS₆) alkyl, a (C₁-VS₆) alkoxy and cyano;
-R₈is selected from H, OR, NHR₁₃, NR₁₃R₁₄, NH-NHR₁₃, SH, CN, N₃and halogen; in which R₁₃and R₁₄are chosen independently from one another among H, (C₁-VS₈) alkyl and (C₁-VS₈) alkyl aryl;
- Y is selected from CH, CH₂, C(CH₃)₂and CCH₃;
-
represents a single or a double bond along Y; And
-
represents the alpha or beta anomer depending on the position of R₁
or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its crystals
Or
the compound of formula (II): (II)
or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its crystals, in which

• X' ₁ and X' ₂ are independently chosen from O, CH ₂ , S, Se, CHF, CF ₂ , and C=CH ₂ ;
• R' ₁ and R'13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio-alkyl, C1-C8 heteroalkyl, and OR, wherein R is selected from H and a C1-C8 alkyl,
• R'₂, R'₃, R'₄, R'₅, R'₉, R'₁₀, R'₁₁, R'₁₂are independently selected from H, halogen, azido, cyano, hydroxyl, C-alkyl₁-VS₁₂, a C thioalkyl₁-VS₁₂, a hetero-C-alkyl₁-VS₁₂, a C haloalkyl₁-VS₁₂ and OR, wherein R may be selected from H, C-alkyl₁-VS₁₂, a C(O)( C₁-VS₁₂) alkyl, a C(O)NH(C₁-VS₁₂) alkyl, a C(O)O(C₁-VS₁₂) alkyl, a C(O) aryl, a C(O)( C₁-VS₁₂) aryl, a C(O)NH(C₁-VS₁₂) alkyl aryl, a C(O)O(C₁-VS₁₂) alkyl aryl or a C(O)CHR group_AANH2 in which R_AA is a side chain selected from a proteogenic amino acid;
• R' ₆ and R' ₈ are independently selected from H, azido, cyano, C ₁ -C ₈ alkyl and OR, wherein R is selected from H and C ₁ -C ₈ alkyl;
• R' ₇ and R' ₁₄ are independently selected from H, OR, NHR, NRR', NH-NHR, SH, CN, N ₃ and halogen, wherein R and R' are independently selected from H and un (C ₁ -C ₈ ) alkyl aryl;
• Y' ₁ and Y' ₂ are independently chosen from CH, CH ₂ , C(CH ₃ ) ₂ or CCH ³ ;
• M' is chosen from H or a suitable counterion;
• represents a single or double bond depending on Y' ₁ and Y'₂; And represents an alpha or beta anomer depending on the position of R'1 and R'13;

and their combinations.

In a first preferred embodiment, the derivative is the compound of formula (I).

In a variant of the first embodiment, X represents an oxygen.

In a variant of the first embodiment, R ₁ and R ₆ each independently represent hydrogen.

In a variant of the first embodiment, R ₂ , R ₃ , R ₄ and R ₅ each independently represent a hydrogen or an OH.

In a variant of the first embodiment, Y represents a CH.

In a variant of the first embodiment, Y represents a CH ₂ .

In a variant of the first embodiment, R ₇ represents a hydrogen.

In a variant of the first embodiment, R ₇ represents P(O)(OH) ₂ .

In a variant of the first embodiment,
X represents oxygen; and or
R ₁ and R ₆ each independently represent hydrogen; and or
R ₂ , R ₃ , R ₄ and R ₅ each independently represent hydrogen or R ₂ , R ₃ , R ₄ and R ₅ independently represent OH; and or
Y represents a CH or a CH ₂ ; and or
R ₇ represents P(O)R ₉ R ₁₀ , in which R ₉ and R ₁₀ are independently chosen from OH, OR ₁₁ , NHR ₁₃ , NR ₁₃ R ₁₄ , C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C _3- C ₁₀ cycloalkyl, C ₅ -C ₁₂ aryl, C ₁ -C ₈ aryl alkyl, C ₁ -C ₈ alkyl aryl, C 1 -C ₈ heteroalkyl, C _{1 -} C ₈ heterocycloalkyl , heteroaryl and NHCR _A R _{A '} C(O)R ₁₂ .

In a particularly preferred variant of the first embodiment, the compound of the invention is chosen from the compounds of formula I-A to I-H:

In a second preferred embodiment, the derivative is the compound of formula (II).

In a variant of the second embodiment, X'1 and X'2 each independently represent an oxygen.

In a variant of the second embodiment, R′7 and R′14 each independently represent an NH ₂ .

In a variant of the second embodiment, R′1 and/or R′13 each independently represent a hydrogen.

In a variant of the second embodiment, R′6 and/or R′8 each independently represent a hydrogen.

In a variant of the second embodiment, R′2, R′3, R′4, R′5 _, R′9, R′10, R′11 and R′12 each independently represent a hydrogen.

In a variant of the second embodiment, R'2, R'3, R'4, R'5 _, R'9, R'10, R'11 and R'12 each independently represent an OH.

In a variant of the second embodiment, Y'1 and Y'2 each independently represent a CH.

In a variant of the second embodiment, Y'1 and Y'2 each independently represent a CH2.

In a variant of the second embodiment, the compound according to the invention is chosen from the compounds of formula II-A to II-F:

In a variant of the first particularly preferred embodiment, the derivative is alpha-NMN of formula:

In a fourth preferred embodiment, the derivative is NMN-H:

Advantageously, the precursor is nicotinamide riboside:

or dihydronicotinamide riboside (denoted -NR-H) of formula:

The subject of the present invention is a cosmetic composition comprising nicotinamide mononucleotide (NMN), one of its derivatives, one of its precursors or one of its salts, for preventing or treating at least one sign of aging.

Preferably, the composition according to the invention is not a therapeutic composition.

Advantageously, the NMN derivative can be chosen from alpha nicotinamide mononucleotide (α-NMN), dihydronicotinamide mononucleotide (denoted NMN-H), the compound of formula (I) as defined above, the compound of formula ( II) as defined above and combinations thereof.

Advantageously, the NMN precursor is nicotinamide riboside (NR) and/or dihydronicotinamide riboside (NR-H).

Advantageously, the composition according to the invention can treat the signs of aging of dry skin.

Advantageously, the composition according to the invention can treat the signs of aging of normal skin.

Advantageously, the composition according to the invention can treat at least one of the signs of aging chosen from wrinkles, skin roughness, swelling of the lower eyelid, dark circles, skin thickness and their combinations.

The composition according to the invention can reduce wrinkles and/or increase the firmness of the skin and/or increase the elasticity of dry skin, normal skin and combination skin.

In one embodiment, the composition according to the invention can reduce the roughness of the epidermis of dry skin and/or increase the smoothness of the epidermis of dry skin and/or increase the thickness of the epidermis, especially dry skin.

The composition according to the invention can reduce the swelling of the lower eyelid, preferably of normal skin.

In one embodiment, the composition according to the invention makes it possible to reduce dark circles.

Advantageously, the composition according to the invention may comprise between 0.01% by weight and 30% by weight, preferably between 0.1% and 10% by weight, more preferably between 1% and 5% by weight and even more preferably approximately 2% by weight of NMN, one of its derivatives, one of its precursors or one of its salts, relative to the total weight of the composition.

Advantageously, the composition according to the invention may also comprise at least one cosmetically acceptable adjuvant chosen from the group consisting of thickeners, humectants, emollients, surfactants, preservatives, anti-foams, preservatives, pH regulators, gelling agents, thinners, waxes, vegetable oils, animal oils, butters, emulsifiers, vitamins, vitamin precursors, natural plant extracts, active peptides, anti-pigment active ingredients and/or colorants and combinations thereof.

In a preferred embodiment, the composition according to the invention may also comprise hyaluronic acid, glycolic acid, fruit acids, anti-UVA filters, anti-UVB filters, vitamins, vitamin precursors, natural plant extracts, active peptides and combinations thereof.

Advantageously, the composition according to the invention may be in the form of a gel, a solution, a water-in-oil emulsion, an oil-in-water emulsion, an oil, a cream, ointment, blister dispersion or liniment.

Advantageously, the composition according to the invention may be intended to be applied to the skin of the face and/or of the body, preferably to the face.

Advantageously, the composition according to the invention can be a serum, a universal cream, a day cream, a night cream, an eye contour cream, a make-up remover lotion, a make-up remover milk, a make-up remover oil, a make-up remover balm, a cosmetic mask, a tonic lotion, an exfoliating product, a cleansing gel, a cleansing foam, a cleansing milk, a cleansing lotion.

Advantageously, the pH of the composition according to the invention can be between 4 and 9, preferably between 5 and 7.

A subject of the present invention is also a non-therapeutic cosmetic process for treating the signs of aging comprising the application to the surface of the skin of a composition according to the invention as defined above.

Another object of the invention is the cosmetic use of nicotinamide mononucleotide (NMN), one of its derivatives, one of its precursors or one of its salts or combinations thereof, to prevent or treat at least one sign of aging such as defined above.

DEFINITIONS

In the present invention, the following terms have the following meaning.

Unless otherwise indicated, the nomenclature of substituents which are not explicitly defined in the present invention is obtained by naming the terminal part of the functionality followed by the adjacent functionality towards the point of attachment.

"Alkyl" by itself or as part of another substituent means a hydrocarbyl radical of the formula CnH2n+1 wherein n is a number greater than or equal to 1. In general, the alkyl groups of this invention include from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, even more preferably from 1 to 2 carbon atoms. Alkyl groups can be linear or branched and can be substituted as indicated in the present invention. The alkyls suitable for the implementation of the invention can be chosen from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers such as n-pentyl and iso-pentyl, and hexyl and its isomers such as n-hexyl and iso-hexyl, heptyl and its isomers (e.g. n-heptyl, iso-heptyl), octyl and its isomers (e.g. n-octyl, iso-octyl), nonyl and its isomers (eg n-nonyl, iso-nonyl), decyl and its isomers (eg n-decyl, iso-decyl), undecyl and its isomers, dodecyl and its isomers. Preferably, the alkyl groups can be chosen from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. The saturated and branched alkyl groups can be chosen, without limitation, from isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl,
3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2, 4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2- ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl. Preferred alkyl groups are: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. Cx-Cy-alkyls refer to alkyl groups which contain from x to y carbon atoms.

When the suffix "ene" ("alkylene") is used in conjunction with an alkyl group, it means that the alkyl group as defined herein has two single bonds as points of attachment to other groups. The term "alkylene" includes methylene, ethylene, methylmethylene, propylene, ethylethylene and 1,2-dimethylethylene.

The term "alkenyl" as used herein refers to an unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 12 carbon atoms, preferably between 2 and 8 carbon atoms, and even more preferably between 2 and 6 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the groups similar.

0067] The term "alkynyl", as used herein, refers to a class of monovalent unsaturated hydrocarbyl groups, in which the unsaturation results from the presence of one or more carbon-carbon triple bond(s). . Alkynyl groups generally, and preferably, have the same number of carbon atoms as described above for alkenyl groups. Non-limiting examples of alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers, etc.

"Alkoxy" means an alkyl group as defined above, which is attached to another moiety through an oxygen atom. Examples of alkoxy groups include methoxy, isopropoxy, ethoxy, tert-butoxy, and others. The alkoxy groups can be optionally substituted by one or more substituents. The alkoxy groups included in the compounds of this invention may be optionally substituted with a solubilizing group.

"Aryl", as used herein, means a polyunsaturated aromatic hydrocarbyl group having a single ring (e.g. phenyl) or multiple aromatic rings fused together (e.g. naphthyl) or covalently bonded, usually containing 5 to 18 atoms, preferably 5 to 12, more preferably 6 to 10, of which at least one ring is aromatic. The aromatic ring may optionally include one or two additional rings (cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic systems listed herein. Examples of aryl include phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalene-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphthylenyl, 3-, 4- or 5-acenaphthenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl , 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl.

When at least one carbon atom in an aryl group is replaced by a heteroatom, the resulting ring is referred to herein as a "heteroaryl" ring.

"Alkylaryl" means an aryl group substituted by an alkyl group.

"Amino acid" means an alpha-amino carboxylic acid, i.e. a molecule comprising a carboxylic acid functional group and an amino functional group in the alpha position of the carboxylic acid group, for example a proteinogenic amino acid or an amino acid not proteinogenic.

"Proteinogenic Amino Acid" means an amino acid that is incorporated into proteins during the translation of messenger RNA by ribosomes in living organisms, i.e. Alanine (ALA), Arginine (ARG), Asparagine (ASN), Aspartate (ASP), Cysteine (CYS), Glutamate (glutamic acid) (GLU), Glutamine (GLN), Glycine (GLY), Histidine (HIS), Isoleucine (ILE), Leucine (LEU), Lysine ( LYS), Methionine (MET), Phenylalanine (PHE), Proline (PRO), Pyrrolysine (PYL), Selenocysteine (SEL), Serine (SER), Threonine (THR), Tryptophan (TRP), Tyrosine (TYR) or Valine ( VAL).

"Non-proteinogenic amino acid" as used herein refers to an amino acid that is not naturally encoded or found in the genetic code of a living organism. Non-limiting examples of non-proteinogenic amino acid are ornithine, citrulline, argininosuccinate, homoserine, homocysteine, cysteine-sulfinic acid, 2-aminomuconic acid, δ-aminolevulinic acid, β -alanine, cystathionine, γ-aminobutyrate, DOPA, 5-hydroxytryptophan, D-serine, ibotenic acid, α-aminobutyrate, 2-aminoisobutyrate, D-leucine, D-valine, D-alanine or D-glutamate

The term "cycloalkyl" as used herein is a cyclic alkyl group, i.e. a monovalent, saturated or unsaturated hydrocarbyl group, having 1 or 2 ring structures. The term "cycloalkyl" includes monocyclic or bicyclic hydrocarbyl groups. The cycloalkyl groups can comprise 3 or more carbon atoms in the ring and generally, according to the present invention, comprise from 3 to 10, more preferably from 3 to 8 carbon atoms and even more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.

"Halogen" or "halo" means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro and chloro.

"Haloalkyl" alone or in combination means an alkyl radical having the meaning as defined above, in which one or more hydrogen atoms are replaced by a halogen as defined above. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and similar radicals. Cx-Cy-haloalkyl and Cx-Cy-alkyl refer to alkyl groups which contain from x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl and trifluoromethyl.

"Heteroalkyl" means an alkyl group as defined above, in which one or more carbon atoms are replaced by a heteroatom chosen from oxygen, nitrogen and sulfur atoms. In heteroalkyl groups, the heteroatoms are bonded along the alkyl chain only to carbon atoms, i.e. each heteroatom is separated from every other heteroatom by at least one carbon atom. However, the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatoms can optionally be quaternized. A heteroalkyl is bonded to another group or molecule only through a carbon atom, i.e. the bonding atom is not selected from the heteroatoms included in the heteroalkyl group.

The term "heteroaryl" as used herein, alone or as part of another group, includes, but is not limited to, aromatic rings of 5 to 12 carbon atoms or ring systems containing 1 or 2 rings that are fused or covalently bonded, usually containing 5 or 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings are replaced by oxygen, nitrogen and/or sulfur atoms, the nitrogen and sulfur heteroatoms optionally possibly be oxidized and the nitrogen heteroatoms possibly being quaternized. These rings can be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryls include furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, dioxinyl, thiazinyl, triazinyl, imidazo [2,1-b] [1,3] thiazolyl, thieno [3,2-b] furanyl, thieno [3,2-b] thiophenyl, thieno [2,3-d] [ l,3] thiazolyl, thieno [2,3-d] imidazolyl, tetrazolo [l,5-a] pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2- benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3- benzoxadiazolyl, 1, 2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2-a]pyridinyl, 6-oxo-pyridazin-l(6H)-yl, 2 - oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

When at least one carbon atom in a cycloalkyl group is replaced by a heteroatom, the resulting ring is referred to herein as "heterocycloalkyl" or "heterocyclyl".

The terms "heterocyclyl", "heterocycloalkyl" or "heterocyclo", as used herein by themselves or as part of another group, refer to non-aromatic, fully saturated or partially unsaturated (for example, 3 to 7 membered monocyclic, 7 to 11 membered bicyclic or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one ring containing a carbon atom. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms can optionally be quaternized. Any of the carbon atoms of the heterocyclic group can be substituted by an oxo (eg piperidone, pyrrolidinone). The heterocyclic group can be attached to any heteroatom or carbon atom in the ring or ring system, valence permitting. The rings of multi-ring heterocycles can be fused, bridged and/or joined by one or more spiro atoms. Exemplary non-limiting heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, homopiperazinyl, , 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2, 5-dioximidazolidinyl, 2 -oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholine-4-yl, thiomorpholine-4 oxide -ylsulf, thiomorpholine-4-ylsulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl and morpholine-4-yl.

The term "precursor" as used herein means pharmacologically acceptable derivatives of compounds of formula (I) or (II) such as esters whose in vivo biotransformation product is the active drug. Precursors are characterized by increased bioavailability and are readily metabolized to active compounds in vivo. The precursors suitable for the purposes of the invention include in particular the carboxylic esters, in particular the alkyl esters, the aryl esters, the acyloxyalkyl esters and the carboxylic esters of dioxolene; ascorbic acid esters.

The term "active agent" means a molecule or substance whose administration to a subject slows or stops the progression, aggravation or deterioration of one or more symptoms of a condition; relieves symptoms of a condition; cures a condition.

"Salts" include acid and base addition salts of these salts. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples are acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate , esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and salts of xinofoate. Suitable basic salts are formed from bases which form non-toxic salts. Mention may be made, as examples, of the salts of aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc. Hemisalts of acids and bases can also be formed, for example, hemisulfates and chemical calcium salts. Preferred salts are hydrochloride/chloride, bromide/hydrobromide, bisulfate/sulfate, nitrate, citrate and acetate.

1. en faisant réagir le composé avec l'acide souhaité ;
2. en faisant réagir le composé avec la base souhaitée ;
3. en éliminant un groupe protecteur labile en milieu acide ou basique d'un précurseur approprié du composé ou en ouvrant le cycle d'un précurseur cyclique approprié, par exemple une lactone ou un lactame, en utilisant l'acide désiré ; ou
4. en transformant un sel du composé en un autre par réaction avec un acide approprié ou au moyen d'une colonne d'échange d'ions appropriée.

Acceptable salts can be prepared by one or more of these methods:

1. reacting the compound with the desired acid;
2. reacting the compound with the desired base;
3. by removing an acid or base labile protecting group from a suitable precursor of the compound or by opening the cycle of a suitable cyclic precursor, for example a lactone or a lactam, using the desired acid; Or
4. by converting a salt of the compound into another by reaction with an appropriate acid or by means of an appropriate ion exchange column.

All of these reactions are usually carried out in solution. The salt can precipitate out of solution and be collected by filtration or can be recovered by solvent evaporation. The degree of ionization of salt can vary from completely ionized to almost non-ionized.

"Solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more acceptable solvent molecules, for example, ethanol.

The term "substituent" or "substituted" means that a hydrogen radical on a compound or group is replaced by any desired group which is substantially stable under the reaction conditions in an unprotected form or when protected by a protecting group. Examples of preferred substituents include, but are not limited to, halogen (chloro, iodo, bromo or fluoro); an alkyl; an alkenyl; alkynyl, as described above; a hydroxy; an alkoxy; a nitro; a thiol; a thioether; an imine; a cyano; an amido; a phosphonato; a phosphine; a carboxyl; a thiocarbonyl; a sulfonyl; a sulfonamide; a ketone; an aldehyde; an ester; an oxygen (-O); haloalkyl (eg, trifluoromethyl); cycloalkyl, which may be fused or unfused monocyclic or polycyclic (eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocycloalkyl, which may be fused or unfused monocyclic or polycyclic (eg, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), fused or unfused monocyclic or polycyclic, aryl or heteroaryl (e.g., aryl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), fused or unfused monocyclic or polycyclic (e.g., aryl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazidinyl, pyridaziminyl, pyridaziminyl , benzimidazolyl, benzothiophenyl or benzofuranyl); amino (primary, secondary or tertiary); CO ₂ CH ₃ ; CONH2; OCH ₂ CONH ₂ ; _NH2 ; SO ₂ NH ₂ ; OCHF ₂ ; FC ₃ ; OCF ₃ ; and these groups can also be optionally substituted by a fused ring structure or bridge, for example -OCH ₂ O-. These substituents may optionally be further substituted by a substituent selected from these groups. In some representations, the term "substituent" or the adjective "substituted" denotes a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, -C(O)NR ₁₁ R ₁₂ , -NR ₁₃ C(O)R ₁₄ , halo, -OR ₁₃ , cyano, nitro, haloalkoxy, -C(O)R ₁₃ , -NR ₁₁ R ₁₂ , -SR ₁₃ , -C(O)OR ₁₃ , -OC(O)R ₁₃ , -NR ₁₃ C(O)NR ₁₁ R ₁₂ , -OC(O)NR ₁₁ R ₁₂ , -NR ₁₃ C(O)OR ₁₄ , -S(O)rR13 , -NR ₁₃ S(O)rR ₁₄ , -OS(O)rR ₁₄ , S(O)rNR ₁₁ R ₁₂ , -O, -S, and - NR ₁₃ , where r is 1 or 2; R ₁₁ and R ₁₂ , for each occurrence, are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl , optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or R ₁₁ and R ₁₂ taken together with the nitrogen to which they are attached are optionally substituted heterocycloalkyl or optionally substituted heteroaryl; and R ₁₃ and R ₁₄ for each occurrence are, independently, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl. In certain variations, the term "substituent" or the adjective "substituted" denotes a solubilizing group.

The term "administration", or a variation of this term (e.g., "administer"), means to supply the active ingredient, alone or as part of a cosmetic composition, to the subject in whom/to whom the state of the skin should be treated or prevented.

"Treating", "curing" and "curing", as used herein, are meant to include the alleviation, alleviation or ablation of a condition and/or its associated symptoms.

“Prevent”, “prevent” and “prevention”, as used in the present invention, refer to a method of delaying or preventing the onset of a condition and/or its related symptoms, to prevent a subject from contracting a condition, or to reduce the risk of a subject contracting a condition.

The term "cosmetic composition" means any mixture intended to be brought into contact with the superficial parts of the human body (epidermis, hair and capillary systems, nails, lips and external genital organs) or with the teeth and oral mucous membranes in view, exclusively or mainly, to clean them, to perfume them, to modify their appearance, to protect them, to keep them in good condition or to correct body odors.

The term "cosmetic substance" means a chemical element and its compounds in the natural state or obtained by a manufacturing process, including any additive necessary to preserve its stability and any impurity resulting from the process implemented, but exclusion of any solvent which can be separated without affecting the stability of the substance or modifying its composition.

“Mixture” means a mixture or solution composed of two or more substances.

By “ring” is meant, known in anatomy as the jugo-palpebral furrow, is a variation in the coloring of the skin under the eye. Dark circles make your eyes look tired and aged.

The bonds of an asymmetric carbon can be represented here using a filled triangle ( ), a dotted triangle ( ) or a zigzag line ( ).

DETAILED DESCRIPTION OF THE INVENTION

The subject of the present invention is the cosmetic use of nicotinamide mononucleotide (NMN), one of its derivatives, one of its precursors or one of its salts, and the cosmetic compositions comprising them for preventing or treating at least one sign of aging. .

Nicotinamide adenine dinucleotide (NAD) is a coenzyme present in all living cells. NAD exists in the cell either in its oxidized form NAD+, or in its reduced form NADH. The role of NAD is that of an electron transporter involved in the oxidation-reduction reactions of the metabolism. NAD is also involved in many cellular processes such as ADP ribosylation as part of post-translational modifications of proteins.

NAD can be synthesized de novo by the cell from amino acids such as tryptophan or aspartate. However, this synthesis is marginal because the main route of NAD synthesis is the salvage pathway by which the cell, and mainly the cell nucleus, recycles compounds to reform NAD from precursors. NAD precursors include niacin, nicotinamide riboside, nicotinamide mononucleotide, and nicotinamide.

NMN is one of the compounds allowing the synthesis of NAD by the salvage pathway and has the formula:

Within the meaning of the invention, the derivatives, precursors and salts of NMN are cosmetically acceptable, that is to say that they are authorized, or at the very least, the use of which is not prohibited or restricted by European Regulation No. 1223/2009 or by the regulatory authority for American health, cosmetic and food products, i.e. the FDA (for Food and Drug Administration in English).

The salts suitable for the implementation of the invention are non-toxic or slightly toxic and are obtained from organic or inorganic bases or acids of NAD precursors. By way of example of salts, mention may be made of chlorides, bromides, fluorides, iodides, sulfates, of sodium, of potassium, of magnesium, of formate, of acetate, of propionate, of butyrate, of glutamate , aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate. Preferably, the salt is a chloride.

In a preferred embodiment, the NMN is in the form of a zwitterion. By “zwitterion” is meant a molecular chemical species possessing electric charges of opposite sign and located, in general, on non-adjacent atoms of the molecule.

Derivatives and precursors of NMN

According to the invention, the NMN derivative can be chosen from alpha nicotinamide mononucleotide (α-NMN), dihydronicotinamide mononucleotide (denoted NMN-H), the compound of formula (I):

• X’₁et X’₂sont indépendamment choisis parmi O, CH₂, S, Se, CHF, CF₂, et C=CH₂;
• R’₁et R’13 sont indépendamment choisis parmi H, azido, cyano, un alkyl en C1-C8, un thio-alkyl en C1-C8, un hétéroalkyl en C1-C8, et OR, dans lequel R est choisi parmi H et un alkyl en C1-C8,
• R’₂, R’₃, R’₄, R’₅, R’₉, R’₁₀, R’₁₁, R’₁₂sont indépendamment choisis parmi H, un halogène, un azido, un cyano, un hydroxyl, un alkyl en C₁-C₁₂, un thioalkyl en C₁-C₁₂, un hétéro-alkyl en C₁-C₁₂, un haloalkyl en C₁-C₁₂ et OR, dans lequel R peut être choisi parmi H, un alkyl en C₁-C₁₂, un C(O)( C₁-C₁₂) alkyle, un C(O)NH(C₁-C₁₂) alkyle, un C(O)O(C₁-C₁₂) alkyle, un C(O) aryle, un C(O)( C₁-C₁₂) aryle, un C(O)NH(C₁-C₁₂) alkyle aryle, un C(O)O(C₁-C₁₂) alkyle aryle ou un groupe C(O)CHR_AANH2 dans lequel R_AA est une chaine latérale choisi parmi un acide aminé protéogène ;
• R’₆et R’₈sont indépendamment choisis parmi H, un azido, un cyano, un alkyl en C₁-C₈et OR, dans lequel R est choisi parmi H et un alkyl en C₁-C₈;
• R’₇et R’₁₄sont indépendamment choisis parmi H, OR, NHR, NRR’, NH-NHR, SH, CN, N₃et un halogène, dans lequel R et R’ sont indépendamment choisit parmi H et un (C₁-C₈) alkyle aryle ;
• Y’1 et Y’2 sont indépendamment choisis parmi CH, CH₂, C(CH₃)₂ou CCH³;
• M’ est choisi parmi H ou un contre-ion adapté ;
• représente une liaison simple ou double en fonction de Y’1 et Y’2 ; et
• représente un anomère alpha ou béta en fonction de la position de R’₁et R’₁₃;

et leurs combinaisons. (I)
or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its pharmaceutically acceptable crystals thereof, in which:
- X is chosen from O, CH₂, S, Se, CHF, CF₂and C=CH₂;
-R₁is selected from H, azido, cyano, C-alkyl₁-VS₈, thio-C-alkyl₁-VS₈, C-heteroalkyl₁-VS₈and OR; wherein R is selected from H and C-alkyl₁-VS₈;
-R₂, R₃, R₄and R₅are chosen independently of one another from H, halogen, azido, cyano, hydroxyl, C-alkyl₁-VS₁₂, thio-C-alkyl₁-VS₁₂, C-heteroalkyl₁-VS₁₂, C-haloalkyl₁-VS₁₂and OR; wherein R is selected from H, C-alkyl₁-VS₁₂, C(O)(C)₁-VS₁₂)alkyl, C(O)NH(C₁-VS₁₂)alkyl, C(O)O(C₁-VS₁₂)alkyl, C(O)aryl, C(O)(C₁-VS₁₂)alkyl aryl, C(O)NH(C₁-VS₁₂)alkyl aryl, C(O)O(C₁-VS₁₂)alkyl aryl and C(O)CHR_AANH₂; in which R_AAis a side chain selected from a proteinogenic amino acid;
-R₆is selected from H, azido, cyano, C₁-VS₈ alkyl, C₁-VS₈ thio-alkyl, C₁-VS₈ heteroalkyl and OR; wherein R is selected from H and C₁-VS₈ alkyl;
-R₇is selected from H, P(O)R₉R₁₀and P(S)R₉R₁₀; in which
-R₉and R₁₀are chosen independently of each other from OH, OR₁₁, NHR₁₃, NR₁₃R₁₄, C-alkyl₁-VS₈, a C-alkenyl₂-VS₈, a C-alkynyl₂-VS₈, a C-cycloalkyl₃-VS₁₀, an aryl at C₅-VS_{12 ,}(VS₁-VS₈)alkyl aryl, (C₁-VS₈)aryl alkyl, (C₁-VS₈) heteroalkyl, (C₁-VS₈) heterocycloalkyl, a heteroaryl and NHCHR_ATR_{AT '}HORN₁₂; in which :
-R₁₁is selected from a group C₁-VS₁₀alkyl, C₃-VS₁₀cycloalkyl, C₅-VS_{1 8}aryl, C₁-VS₁₀alkylaryl, C₅-VS₁₂substituted aryl, C₁-VS₁₀heteroalkyl, C_3-VS₁₀heterocycloalkyl, C₁-VS₁₀haloalkyl, a heteroaryl, -(CH₂)_notC(O)(C)₁-VS₁₅)alkyl, -(CH₂)_notOC(O)(C)₁-VS₁₅)alkyl, -(CH₂)_notOC(O)O(C)₁-VS₁₅)alkyl, -(CH₂)_notSC(O)(C)₁-VS₁₅)alkyl, -(CH₂)_notC(O)O(C₁-VS₁₅)alkyl and -(CH₂)_notC(O)O(C₁-VS₁₅)alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH)₂;
-R₁₂is selected from H, C_1-VS₁₀alkyl, C₂-VS₈alkenyl, C₂-VS₈alkynyl, C_1-VS₁₀haloalkyl, C_3-VS₁₀cycloalkyl, C_3-VS₁₀heterocycloalkyl, C₅-VS_{1 8} aryl, C₁-VS₄alkylaryl and C₅-VS₁₂heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted from one or two groups selected from halogen, trifluoromethyl, C₁-VS₆alkyl, C₁-VS₆alkoxy and cyano; And
-R_ATAnd R_AT'are independently selected from H, A C_1-VS₁₀alkyl, C₂-VS₁₀alkenyl, C₂-VS₁₀alkynyl, C_3-VS₁₀cycloalkyl, C₁-VS₁₀thio-alkyl, C_1-VS₁₀hydroxylalkyl, C₁-VS₁₀alkylaryl and C₅-VS₁₂aryl, C_3-VS₁₀heterocycloalkyl, heteroaryl, -(CH₂)₃NHC(=NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl and a side chain selected from a proteinogenic amino acid or a non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C_1-VS₁₀alkyl, C_1-VS₆alkoxy, halogen, nitro and cyano; Or
-R₉and R₁₀form together with the phosphorus atoms to which they are attached a 6-membered ring in which –R₉−R₁₀− represents
–CH₂-CH₂-CHR−; wherein R is selected from H, a group (C₅-VS₆) aryl and (C₅-VS₆) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C₁-VS₆alkyl, a C₁-VS₆alkoxy and cyano; Or
R₉and R₁₀form together with the phosphorus atoms to which they are attached a 6-membered ring in which –R₉−R₁₀− represents –O-CH₂-CH₂-CHR-O-; wherein R is selected from H, a group (C₅-VS₆) aryl and (C₅-VS₆) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by halogen, trifluoromethyl, a (C₁-VS₆) alkyl, a (C₁-VS₆) alkoxy and cyano;
-R₈is selected from H, OR, NHR₁₃, NR₁₃R₁₄, NH-NHR₁₃, SH, CN, N₃and halogen; in which R₁₃and R₁₄are chosen independently from one another among H, (C₁-VS₈) alkyl and (C₁-VS₈) alkyl aryl;
- Y is selected from CH, CH₂, C(CH₃)₂and CCH₃;
-
represents a single or a double bond along Y; And
-
represents the alpha or beta anomer depending on the position of R₁
or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its crystals
Or
the compound of formula (II): (II)
or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its crystals, in which

• X' ₁ and X' ₂ are independently chosen from O, CH ₂ , S, Se, CHF, CF ₂ , and C=CH ₂ ;
• R' ₁ and R'13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio-alkyl, C1-C8 heteroalkyl, and OR, wherein R is selected from H and a C1-C8 alkyl,
• R'₂, R'₃, R'₄, R'₅, R'₉, R'₁₀, R'₁₁, R'₁₂are independently selected from H, halogen, azido, cyano, hydroxyl, C-alkyl₁-VS₁₂, a C thioalkyl₁-VS₁₂, a hetero-C-alkyl₁-VS₁₂, a C haloalkyl₁-VS₁₂ and OR, wherein R may be selected from H, C-alkyl₁-VS₁₂, a C(O)( C₁-VS₁₂) alkyl, a C(O)NH(C₁-VS₁₂) alkyl, a C(O)O(C₁-VS₁₂) alkyl, a C(O) aryl, a C(O)( C₁-VS₁₂) aryl, a C(O)NH(C₁-VS₁₂) alkyl aryl, a C(O)O(C₁-VS₁₂) alkyl aryl or a C(O)CHR group_AANH2 in which R_AA is a side chain selected from a proteogenic amino acid;
• R' ₆ and R' ₈ are independently selected from H, azido, cyano, C ₁ -C ₈ alkyl and OR, wherein R is selected from H and C ₁ -C ₈ alkyl;
• R' ₇ and R' ₁₄ are independently selected from H, OR, NHR, NRR', NH-NHR, SH, CN, N ₃ and halogen, wherein R and R' are independently selected from H and un (C ₁ -C ₈ ) alkyl aryl;
• Y'1 and Y'2 are independently chosen from CH, CH ₂ , C(CH ₃ ) ₂ or CCH ³ ;
• M' is chosen from H or a suitable counterion;
• represents a single or double bond depending on Y'1 and Y'2; And
• represents an alpha or beta anomer depending on the position of R' ₁ and R'₁₃;

and their combinations.

In a first preferred embodiment, the acceptable derivative is the compound of formula (I).

In a variant of the first embodiment, X represents an oxygen.

In a variant of the first embodiment, R ₁ and R ₆ each independently represent hydrogen.

In a variant of the first embodiment, R ₂ , R ₃ , R ₄ and R ₅ each independently represent a hydrogen or an OH.

In a variant of the first embodiment, Y represents a CH.

In a variant of the first embodiment, Y represents a CH ₂ .

In a variant of the first embodiment, R ₇ represents a hydrogen.

In a variant of the first embodiment, R ₇ represents P(O)(OH) ₂ .

In a variant of the first embodiment, the compound of the invention is chosen from the compounds of formula I-A to I-H:

In a second preferred embodiment, the acceptable derivative is the compound of formula (II).

In a variant of the second embodiment, X'1 and X'2 each independently represent an oxygen.

In a variant of the second embodiment, R′7 and R′14 each independently represent an NH ₂ .

In a variant of the second embodiment, R′1 and/or R′13 each independently represent a hydrogen.

In a variant of the second embodiment, R′6 and/or R′8 each independently represent a hydrogen.

In a variant of the second embodiment, R′2, R′3, R′4, R′5 _, R′9, R′10, R′11 and R′12 each independently represent a hydrogen.

In a variant of the second embodiment, R'2, R'3, R'4, R'5 _, R'9, R'10, R'11 and R'12 each independently represent an OH.

In a variant of the second embodiment, Y'1 and Y'2 each independently represent a CH.

In a variant of the second embodiment, Y'1 and Y'2 each independently represent a CH2.

In a variant of the second embodiment, the compound according to the invention is chosen from the compounds of formula II-A to II-F:

In a preferred variant of the first embodiment, the derivative is alpha-NMN of formula:

In a fourth preferred embodiment, the derivative is NMN-H:

Advantageously, the precursor is nicotinamide riboside (denoted NR):

or dihydronicotinamide riboside (denoted -NR-H) of formula: or their combination.

Preferably, the NMN derivative is dihydronicotinamide mononucleotide (NMN-H) and/or alpha-NMN.

Uses

The inventors have demonstrated that the cosmetic use of NMN, one of its derivatives, one of its precursors or one of its salts, and the cosmetic compositions comprising them make it possible to treat dry skin. More specifically, the inventors have demonstrated that the cosmetic use of NMN, one of its derivatives, one of its precursors or one of its salts, and the compositions comprising it make it possible to prevent or treat at least one sign of aging.

The sign of aging can be chosen from wrinkles, increased skin roughness, reduction in epidermis thickness, reduction in epidermis firmness, reduction in elasticity of the epidermis, reduction of the luster of the skin, swelling of the lower eyelid and dark circles and combinations thereof.

By reducing the roughness or increasing the smoothness of the skin is meant by reducing the parameter Ra. The “Ra” parameter corresponds to the average roughness. Ra (in µm) is the arithmetic mean of the absolute values, not differentiating between peaks and troughs, of the heights over the length of the profile (see ):

This parameter can be measured by any method well known to those skilled in the art and in particular by fringe projection by a three-dimensional scanner (see ). Briefly, the measurement principle is based on triangulation, similar to laser profiling, but the entire surface of the sample is acquired at once by projecting a striped pattern onto the surface, typically at a 30° angle. , and recording the resulting image by a camera oriented perpendicular to the analyzed surface. An algorithm will then calculate the measured reliefs.

The reduction of wrinkles can be measured by measuring the parameters carried out by projection of fringes with a three-dimensional scanner as mentioned above. The parameters studied on each profile are as follows: the roughness Ra, the reduction of which characterizes a smoothing effect, the average relief Rz and the amplitude Rt, the reductions of which reflect tensor and anti-wrinkle effects (see ).

The Rz parameter is the average of the 5 maxima over the profile length. A maximum is the difference between the highest peak and the deepest trough within an lr measurement section (see ). The Rz parameter can be calculated as follows: Rz (µm) = (Rz1 + Rz2 + Rz3 + Rz4 + Rz5)/5.

The parameter Rt (µm) is the difference in height between the highest peak and the deepest trough inside the total measurement section (ln) (see ).

The increase in the elasticity of the epidermis can be measured by any method well known to those skilled in the art, and in particular by using the Cutometer® MPA580 (Courage & Khazaka). This device measures the deformation of a skin area subjected to mechanical suction stress and its recovery power. Cutometry is used to measure the elasticity and firmness of the skin. The device measures different parameters, and the combination of these different parameters makes it possible to establish measurements of firmness or elasticity. The principle of the device is based on the application of a depression on an area of skin which can vary from 20 to 500 mbar. The area of skin to be measured is aspirated into the standard probe opening of 2 mm in diameter. The depth of penetration of the skin inside the probe is determined without contact, by an optical measurement system consisting of a light emitter and a light receiver. The amount of light received is proportional to the depth of penetration of the skin. A spring inside the Probe provides constant pressure on the skin.

The firmness of the skin can be measured by the parameter R0, which measures the maximum amplitude of the depression. The R0 parameter corresponds to the Uf value (see ). The elasticity of the skin can be measured by the combination of the following three parameters: the parameter R2 representing the biological elasticity of the skin, that is to say the ability of the skin to return to its normal state and calculated by doing the ratio of the Ua/Uf value, the parameter R5 representing the net elasticity, that is to say the immediate extension of the skin calculated by calculating the Ur/Ue ratio; and the parameter R7 representing the raw elasticity of the skin, that is to say the immediate retractability of the skin calculated by taking the ratio Ur/Uf. Increasing the R0 parameter means that the skin is firmer. The increase in the R2, R5 and R7 parameters means that the skin is more elastic. These parameters are measured by cutometry, as defined above.

The increase in the reduction in the density of the epidermis can be measured by ultrasound, in particular using the DermaScan automaton. Ultrasound is performed using a probe equipped with a transmitter and an ultrasound wave receiver (transducer). In order to visualize the different layers of the skin (epidermis, dermis, hypodermis), it is possible to use probes with a high frequency (10 to 50 MHz), preferably 20 MHz. This technique allows a two-dimensional visualization of the skin with a depth of 13 mm. The measurement of the thickness of the skin is done by a ratio of surface area of the non-echogenic tissues to the total measured surface.

The reduction of swelling of the lower eyelid, dark circles under the eye and/or wrinkles can be achieved by clinical scoring carried out by a trained clinician or by self-assessment by the subject. The technique, also known as the Bazin scale, involves providing photographs to the assessor or subject showing different stages of eye wrinkles and fine lines (see ), swelling of the lower eyelid (see ).and rings (see ). Each photograph is associated with a numerical value. The subject chooses the numerical value corresponding to his estimation of the aspect of the age sign in question.

Skin radiance can be measured by self-assessment or using the Glossymeter automaton (Courage & Khazaka). The GL200® Glossymeter (Courage & Khazaka) is used to measure the luster (or luster) of the surface measured by quantification of the reflected light.

As shown in , when the probe is in contact with the measurement zone, a white light is projected at an angle of 0° and reflected, by mirrors, at an angle of 60° (arrow 1). Part of this light is directly reflected (brightness) at the same angle of 60° (arrow 2 = angle of reflection). Another part of this light is absorbed by the surface of the sample and then scattered and reflected diffusely (arrows 3). Diffuse reflected light is measured at 0° (i.e. vertical to the measured surface). The 2.5 x 5 mm probe is particularly suitable for measurements on small surfaces. Unlike other gloss measuring devices which can only compare surfaces that are almost similar in structure, color and gloss, the GL200® Glossometer is equipped with DSC (Diffuse Scattering Correction) technology which reduces the influence of the diffuse reflection affected by the color of the measurement area, which makes it possible to compare different types of skin/hair/nails/lips. The values are expressed in "Glossymeter unit", a unit of measurement correlated to standard industrial units (GU: gloss unit) based on DIN and ISO standards.

Within the meaning of the invention, the use of NMN is not a therapeutic use and the composition according to the invention is not a therapeutic composition.

Thus, the cosmetic compositions according to the invention make it possible to prevent or treat at least one sign of aging in the subject, preferably humans. The NMN and the cosmetic composition according to the invention are therefore well tolerated and do not induce, or at the very least reduce, the risks of allergy linked to the use of anti-aging cosmetic ingredients such as retinol for example .

Compositions

The composition according to the invention may comprise between 0.01% by weight and 30% by weight, preferably between 0.1% and 10% by weight, more preferably between 1% and 5% by weight and even more more preferably approximately 2% by weight of NMN, one of its derivatives, one of its precursors or one of its salts, relative to the total weight of the composition.

The composition according to the invention may also comprise at least one cosmetically acceptable adjuvant chosen from the group consisting of thickeners, humectants, emollients, surfactants, preservatives, anti-foams, preservatives, pH, gelling agents, thinners, waxes, vegetable oils, animal oils, butters, emulsifiers, vitamins and their precursors, natural plant extracts, active peptides, anti-pigment active agents and/or pigments and their combinations. A person skilled in the art knows which cosmetic adjuvants to use to formulate the cosmetic composition according to the invention.

Mention may be made, by way of thickener, of gums such as guar gum, carrageenan gum, acacia gum, agar-agar gum, xanthan gum and combinations thereof.

Examples of humectants include glycerol, glycerin, urea, amino acids, lactates and lactic acids, butylene glycol, simple sugars such as glucose, hyaluronic acid and combinations thereof. Humectants help retain water inside the skin and therefore reduce skin dehydration.

Mention may be made, as emollients, of squalane, vegetable oils, fatty acids and their derivatives, glycerin, glyceryl stearate, glycine from soybean oil, lecithin and combinations thereof. Mention may be made, by way of surfactant, of anionic surfactants such as sodium lauryl sulphate, cationic surfactants, such as quaternary ammoniums, amphoteric, such as phospholipids and nonionic, such as glycol or glycerol esters and combinations thereof.

Mention may be made, by way of antifoaming agent, of di- and tri-methicones, siloxanes, polysilicones, isopropyl alcohol and propyl alcohol and their combinations.

Examples of preservatives include salicylic acid, vitamin E, sodium benzoate, parabens, antioxidants, phenoxyethanol and combinations thereof.

Mention may be made, as pH regulators, of calcium carbonate, citric acid, lactic acid, sodium hydroxide and combinations thereof.

Mention may be made, as gelling agents, of aloe vera gel, hyaluronic acid, and all forms of hydrogels and their combinations.

Mention may be made, as diluents, of water, oils, C1-C16 alcohols and their combinations.

Mention may be made, as waxes, of carnauba wax, beeswax, ozokerite, candelilla wax and microcrystalline waxes or silicone oils, for example dimethylpolysiloxane or alternatively acids fatty alcohols, C12-C18 fatty alcohols and combinations thereof.

Mention may be made, as vegetable or animal oils, modified or not, such as sweet almond oil, avocado oil, calophyllum oil, castor oil, olive oil, lanolin and its derivatives, perhydrosqualene, peanut oil, wheat germ oil, linseed oil, jojoba oil, apricot kernel oil, nuts, palm oil, pistachio oil, sesame oil, rapeseed oil, cade oil, corn germ oil, peach kernel oil, poppyseed oil, pine oil, soybean oil, safflower oil, coconut oil, hazelnut oil, grapeseed oil or sunflower oil , esters of saturated or unsaturated fatty acids or synthetic oils such as ethyl or isopropyl palmitate, alkyl myristates such as those of isopropyl, butyl and cetyl, hexyl stearate, C8-C18 fatty acid triglycerides, cetyl ricinoleate, stearyl octanoate (hu ile de Purcellin), cetostearyl 2-ethyl hexanoate, esters of fatty acids and glycerol, hydrogenated polyisobutene, and their combinations.

Examples of butter include shea butter, cocoa butter, avocado butter, mango butter, olive butter, almond butter and combinations thereof.

Mention may be made, as mineral oils, of petroleum jelly and paraffin and their combinations.

Butters, waxes as well as vegetable and mineral oils can act as emollients by providing lipids to the skin.

Mention may be made, as emulsifiers, of cetearyl alcohol, cetyl alcohol, soy lecithin, sugar ester and combinations thereof.

Mention may be made, as vitamins, of vitamin C, vitamin E, vitamin A and combinations thereof.

Mention may be made, as vitamin A, of retinol, retinoic acid or retinaldehyde.

Mention may be made, as vitamin precursors, of provitamin A.

Mention may be made, as natural plant extracts, of extracts chosen from rosemary, avocado, pumpkin, sweet almond, Swiss alpine mallow, alpine flax, castor bean, wild acanthus, samphire , edelweiss, Indian jasmine, mangosteen, chaste tree and their combinations.

Mention may be made, as active peptides, of palmitoyl pentapeptide-4, acetyl hexapeptide-3, mu-conotoxin CnIIIc, copper tripeptide-3 and their combinations.

Mention may be made, as anti-stain active agents, of resorcinol, phe-resorcinol, ginko, ferulic acid and their combinations.

Mention may be made, as anti-UVA filters, of terephthalyidene dicaphor sulfonic acid, butyl methoxydibenzoylmethane and their combinations.

Mention may be made, as anti-UVB filters, of homosalate, benzophenones, phenylbenzimidazole sulfonic acid, octocrylene, ethylhexyl methoxicinnamate, ethylhexine triazone, 4-methylbenzylidene camphor, salicilates, ethylhexyl or octyl dimethyl, titanium dioxide, zync oxide, polysilicones and their combinations.

In a preferred embodiment, the composition according to the invention may also comprise hyaluronic acid, glycolic acid, fruit acids, anti-UVA filters, anti-UVB filters, vitamins, vitamin precursors, natural plant extracts, active peptides and combinations thereof.

The composition according to the invention may be in the form of a gel, a solution, a water-in-oil emulsion, an oil-in-water emulsion, an oil, a cream, a balm, an ointment, a dispersion of vesicles or a liniment.

The composition according to the invention may be intended to be applied to dry skin. Preferably, the composition according to the invention may be intended to be applied to the face or the body, more preferably to the face.

The composition according to the invention for its application to the face can be a serum, a universal cream, a day cream, a night cream, an eye contour cream, a make-up remover lotion, a make-up remover milk, a make-up remover oil , a make-up remover balm, a cosmetic mask, a tonic lotion, an exfoliating product, a cleansing gel, a cleansing foam, a cleansing milk, a cleansing lotion.

The composition according to the invention for its application to the face can be a body milk, a body balm, a body cream, a soap, a shower gel, a shower oil, a body scrub.

Advantageously, the pH of the composition according to the invention can be between 4 and 9, preferably between 5 and 7. Thus, the composition according to the invention has a pH compatible with the pH of the epidermis.

A subject of the present invention is also a non-therapeutic cosmetic process for treating the signs of aging comprising the application to the surface of the skin of a composition according to the invention as defined above.

The cosmetic composition according to the invention can be produced using any technique well known to those skilled in the art.

Process for the preparation of derivatives

The derivatives of formula (I) or of formula (II) can be prepared according to any method well known to those skilled in the art.

Process for the preparation of the compounds of formula (I)

The derivatives of formula (I) can be prepared according to the process described in international application WO 2017/024255A1.

In particular, the derivatives of formula (I) as well as alpha-NMN can be prepared according to the method described below.

In particular, compounds of formula (I) disclosed herein may be prepared as described below from substrates A-E. It will be understood by one skilled in the art that these reaction schemes are in no way limiting and that variations may be made without departing from the spirit and scope of the present invention.

According to one embodiment, the invention relates to a method for preparing the compounds of formula (I) as described above.

The method involves in a first step the mono-phosphorylation of a compound of formula (A), in the presence of phosphoryl chloride and a trialkyl phosphate, to lead to the phosphorodichloridate of formula (B),

Wherein X, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₈ , Y, And are as defined above for the compounds of formula (I).

In a second step, the phosphorodichloridate of formula (B) is hydrolyzed to yield the phosphate of formula (C),

wherein X, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₈ , Y, And are as defined above for the compounds of formula (I).

According to one embodiment, the compound of formula (A) is synthesized using various methods known to those skilled in the art.

According to one embodiment, the compound of formula (A) is synthesized by reaction of the pentose of formula (D) with a nitrogenous derivative of formula (E), in which R, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , Y are as described above for the compounds of formula I, leading to the compound of formula (A-1) which is then selectively deprotected to give the compound of formula (A),

wherein X, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₈ , Y,
And
are as defined above for the compounds of formula (I).

According to one embodiment, R is a suitable protecting group known to those skilled in the art. In one embodiment, the protective group is chosen from triarylmethyls and/or silyls. Non-limiting examples of triarylmethyl include trityl, monomethoxytrityl, 4,4'-dimethoxytrityl and 4,4',4"-trimethoxytrityl groups. Non-limiting examples of silyl groups include trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert- butyldiphenylsilyl, tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl.

According to one embodiment, any hydroxyl group attached to the pentose is protected by an appropriate protective group known to those skilled in the art.

The choice and exchange of protecting groups is within the skill of the art. Protecting groups can also be removed by methods well known to those skilled in the art, for example, with an acid (eg, mineral or organic acid), base or fluoride source.

In a preferred embodiment, the nitrogenous derivative of formula (E) is coupled to the pentose of formula (D) by a reaction in the presence of a Lewis acid leading to the compound of formula (A-1). Non-limiting examples of Lewis acids include TMSOTf, BF ₃ .OEt ₂ , TiCl ₄ and FeCl ₃ .

In one embodiment, the method of the present invention further comprises a step of reducing the compound of formula (A) by various methods well known to those skilled in the art leading to the compound of formula (A') in which is CH ₂ and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₈ , Y, And are as defined above for the compounds of formula (I).

In a particular embodiment, the present invention relates to a method for the preparation of the compounds of formula I-A, I-C, I-E, I-G.

In a first step, the nicotinamide of formula E is coupled to the ribose tetraacetate of formula D by a coupling reaction in the presence of a Lewis acid, leading to the compound of formula A-1:

In a second step, an ammoniacal treatment of the compound of formula A-1 is carried out, leading to the compound of formula I-A:

In a third step, the mono-phosphorylation of the compound of formula I-A, in the presence of phosphoryl chloride and a trialkyl phosphate, leads to the phosphorodichloridate of formula I-A':

In a fourth step, the phosphorodichloridate of formula B is hydrolyzed to yield the compound of formula I-C:

[Chem.14] .

In one embodiment, a step of reducing the compound of formula I-A is carried out, resulting in the compound of formula I-E.

The compound of formula I-E is then mono-phosphorylated as described in the fourth step and hydrolyzed to yield the compound of formula I-G.

According to one embodiment, the compounds of formula (I) are selected from compounds I-A to I-H in the table below:

In a preferred embodiment, the compounds of the invention are the compounds of formula IA, IC, IE and IG from the table above or a pharmaceutically acceptable salt and/or solvate thereof. In an even more preferred embodiment, the compound is the compound of formula IC or ID a pharmaceutically acceptable salt and/or solvate thereof .

Process for the preparation of the derivatives of formula (II)

In particular, compounds of formula II shown herein can be prepared as described below from substrates X-XIII. It will be understood by one of ordinary skill in the art that these diagrams are in no way limiting and that variations in detail may be made without departing from the spirit and scope of the present invention.

According to one embodiment, the invention relates to a method of preparing the compound of formula I described above.

The method consists first of mono-phosphorylating a compound of formula X, in the presence of phosphoryl chloride in a trialkyl phosphate, to obtain the phosphorodichloridate compound XI,

in which X'₁, R'₁, R'₂, R'₃, R'₄, R'₅, R'₆, R'₇, Y'₁,Andare as defined above.

In a second step, the hydrolysis of the phosphorodichloridate XI obtained in the first step gives the phosphate compound of formula XII,

(XI)
in which X'₁, R'₁, R'₂, R'₃, R'₄, R'₅, R'₆, R'₇, Y'₁,M’,
And
are as defined above.

The phosphate compound of formula XII obtained in the second step is then reacted with a phosphorodichloridate compound of formula XIII obtained as described in the first step,

wherein X' ₂ , R' ₈ , R' ₉ , R' ₁₀ , R' ₁₁ , R' ₁₂ , R' ₁₃ , R' ₁₄ , Y' ₂ ,
And
are as described herein for formula II, to give the compound of formula II as described herein.

According to one embodiment, the method further comprises a step of reducing the compound of formula II, using various methods known to specialists, to give the compound of formula II, where Y'₁and Y'₂are identical and represent each CH₂and where X'₁, X'₂, R'₁, R'₂, R'₃, R'₄, R'₅, R'₆, R'₇, R'₈, R'₉, R'₁₀, R'₁₁, R'₁₂, R'₁₃, R'₁₄, Y'₁, Y'₂ And are as described herein for Formula II.

Alternatively, R is a suitable protecting group known to those skilled in the art. Triarylmethyl and/or silyl groups are examples of suitable protecting groups. Non-limiting examples of triarylmethyl include trityl, monomethoxytrityl, 4,4'-dimethoxytrityl and 4,4',4"-trimethoxytrityl. Non-limiting examples of silyl groups include trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl , tert-butyldiphenylsilyl, tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl.

According to one embodiment, any hydroxy group attached to the pentose ring is protected by an appropriate protecting group known to those skilled in the art.

The selection and exchange of protection groups is within the competence of those skilled in the art. Any protecting group can also be removed by methods known in the art, for example, with an acid (eg, mineral or organic acid), base or fluoride source.

According to a preferred embodiment, the nitrogenous derivatives of formula XV are added to pentose XIV by a coupling reaction in the presence of a Lewis acid to give the compound of formula X-1. Non-limiting examples of suitable Lewis acids include TMSOTf, BF3.OEt2, TiCl4 and FeCl3.

According to a specific embodiment, the invention relates to a method of preparing the compound of formula VIII,

or their pharmaceutically acceptable salts and/or solvates.

In a first step, the nicotinamide of formula XV is added to ribose XIV tetraacetate, by a coupling reaction in the presence of a Lewis acid, to give the compound of formula X-1:

.

In a second step, an ammoniacal treatment of the compound of formula X-1 gives the compound of formula X:

.

In a third step, the mono-phosphorylation of a compound of formula X, in the presence of phosphoryl chloride in a trialkyl phosphate, gives the compound phophorodichloridate XI:

.

In a fourth step, the phosphorodichloridate compound XI obtained in the third step is partially hydrolyzed to give the phosphate compound of formula XII:

.

In a fifth step, the phosphate compound of formula XII obtained in the fourth step is then reacted with the phosphorodichloridate compound of formula XI obtained as described in the third step, to obtain the compound of formula VIII.

According to another specific embodiment, the invention relates to a method of preparing the compound of formula IX,

or their pharmaceutically acceptable salts and/or solvates.

According to a variant, the compound of formula IX is obtained from the compound of formula VIII, synthesized beforehand as described above.

In this embodiment, the compound of formula IX is obtained by reducing the compound of formula VIII, using a suitable reducing agent known to those skilled in the art, to give the compound of formula IX.

According to one embodiment, the preferred compounds of the invention are compounds II-A to II-F, listed in Table 2:

FIGURES

is a graph showing the evolution of the Ra, Rz and Rt parameters as a function of the type of dry, normal or oily skin as a function of the treatment with the composition comprising NMN according to the invention or the same cream without NMN as negative control.

is a graph showing the improvement in the thickness of the skin as a function of the type of dry, normal or oily skin as a function of the treatment with the composition comprising NMN according to the invention or the same cream without NMN as a negative control.

. Is a graph showing the improvement in skin firmness and elasticity as a function of dry, normal or oily skin type as a function of treatment with the composition comprising NMN according to the invention or the same cream without NMN as negative control.

is a graph showing the evolution of wrinkles, fine lines, swelling of the eyelid, dark circles under the eye and tired appearance of the skin for all skin types, as a function of treatment with the composition comprising NMN according to the invention or the same cream without NMN as negative control.

is a diagram showing the principle of fringe projection

is a diagram showing the calculation principle of the parameter Ra

is a diagram showing the principle of calculation of the parameters Rz and Rt

shows the photographs of the Bazin scale to assess crow's feet wrinkles and wrinkles and fine lines under the eyes.

shows the skin deformation curve obtained with the Cutometer.

shows the photographs of the Bazin scale for assessing swelling of the lower eyelid.

shows the photographs of the Bazin scale to assess the dark circle.

is a diagram showing the principle of analysis by the Glossymeter.

EXAMPLE

In the remainder of this description, the examples are provided by way of illustration of the present invention and are in no way intended to limit its scope.

Example 1

An example of a cosmetic composition according to the invention was tested on two groups of healthy volunteers composed of women between the ages of 45 and 65, having dry (denoted S), normal (denoted N) or combination (denoted M) skin. The phototype of the participants was between phototype II and IV.

The first group applied twice a day to their face a cosmetic composition comprising 2% NMN. The second group applied the same composition without NMN to their face twice a day, as a negative control. The study lasted 28 days. The composition according to the invention was prepared by taking the control composition and mixing NMN therein in the form of a zwitterion at the final mass concentration of 2%. The study lasted 28 days.

EU INCI CASE Ingredient function % mass Aqua 7732-18-5 solvent 70 Caprylic/Capric Triglyceride 73398-61-5 moisturizing / masking / perfuming / humectant / solvent 2.00 Nicotinamide mononucleotide 1094-61-7 emollient 2.00 Glycerine 56-81-5 denaturing / humectant / perfuming / solvent 5.00 Butylene Glycol 107-88-0 humectant / masking / solvent / viscosity control 3.00 Glyceryl Stearate SE 11099-07-3 emulsifier 1.00 Propylene Glycol Dipelargonate 41395-83-9 moisturizer / viscosity control 3.00 Pentylene Glycol 5343-92-0 humectant / solvent 2.00 Dicaprylyl Carbonate 1680-31-5 moisturizer / humectant 2.00 Butyrospermum Parkii Butter (Shea Butter) 194043-92-0 Humectant / Viscosity Control / Emollient 2.00 Hydrogenated Palm Kernel Glycerides 93334-20-4 moisturizer / humectant / viscosity control 2.00 Glyceryl Stearate 31566-31-1 moisturizer / emulsifier 1.00 Sodium Citrate 6132-04-3 Buffer agent 0.30 Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer 111286-86-3 emulsion stabilization / viscosity control 0.40 Polyacrylate Crosspolymer-6 / Emulsion Stabilization / Viscosity Control 0.50 Steareth-21 9005-00-9 (Generic) cleaner / emulsifier / surfactant 0.50 Glyceryl Caprylate 26402-26-6 moisturizer / emulsifier 0.30 Xanthan Gum 11138-66-2 binder / emulsifier / emulsion stabilizer / gelling agent / humectant / surfactant / viscosity control 0.20 Chlorphenesin 104-29-0 conservative <0.1 Tocopherol /
10191-41-0
59-02-9 antioxidant / masking / humectant 0.2 Hydrogenated Palm Glycerides 91744-66-0 moisturizer / emulsifier / humectant / viscosity control 2.00 Ethylhexylglycerin 70445-33-9 humectant 0.2 Citric Acid 77-92-9 Buffer/masking agent <0.1 Glycine Soybean Oil 8001-22-7 moisturizer / perfume / skincare <0.1 Polysorbate 60 9005-67-8 emulsifier / surfactant <0.1 Sorbitan Isostearate 71902-01-7 emulsifier <0.1

The mass percentage of an ingredient is calculated as follows: Ingredient mass percentage (%)=(ingredient mass) x 100 / (total composition mass)

Different signs of aging were assessed in the participants, including skin roughness by projection of fringes, skin firmness and skin elasticity by cutometry, skin density by Dermascan ultrasound, swelling of the lower eyelid, the dark circle under the eye and the tired appearance of the skin by the clinical evaluation of an expert. These parameters were measured in the patients on day 0, at the time of inclusion and before any treatment, and on day 28, at the end of the study. The various parameters measured on day 28 were compared with those measured on day 0 for each group and the parameters measured on day 28 were compared between the NMN-treated and control-treated groups.

The results were evaluated with a Student test on EXCEL (Microsoft) and SAS 9.4 software.

According to , the composition according to the invention has made it possible to significantly reduce the parameters Ra, Rz and Rt in dry skin in particular. The composition according to the invention therefore makes it possible to reduce the roughness and to smooth the skin, in particular in dry skin.

According to , the composition according to the invention makes it possible to increase the thickness of the skin by approximately 5% for all skin types combined. However, the composition gives a statistically significant increase for dry skin. However, one of the signs of aging is the reduction in the thickness of the skin. Consequently, the composition according to the invention makes it possible to prevent or treat a sign of aging, and in particular to increase the thickness of the skin.

According to , the composition according to the invention made it possible to significantly increase the firmness of normal skin.

There shows the evolution of different signs of aging, regardless of skin type. The improvement of wrinkles, fine lines, swelling of the lower eyelid and dark circles is evaluated by the reduction of each of these parameters. The reduction (in %) is noted as %D and is calculated as follows: %D = (value obtained on the area treated by the product on D28 - value obtained on the area treated by the product on D0) x 100 / (value obtained on the area treated with the product on D0).

According to , the composition according to the invention makes it possible to significantly reduce the size and depth of wrinkles and fine lines, as well as the swelling of the lower eyelid, the size of the dark circle under the eye and the tired appearance of the skin.

After 28 days of use, a significant improvement of 11% in the shine of the participants' skin was measured using the Glossymeter after use of the cosmetic composition according to the invention containing NMN (p=0.032). The composition according to the invention comprising NMN therefore leaves the skin brighter and therefore appears less tired, which contributes to the anti-aging effect.

Participants were also asked to complete a self-assessment questionnaire regarding the signs of aging. As can be seen below, the participants are mostly satisfied with the composition according to the invention:

Percentage of participants agreeing with the statement (%) The product is moisturizing 91 My skin is firmer 83 My skin looks denser 83 My skin looks plumper 69 My features are less tired 82 My skin is softer 96 My skin is smoother 86 The skin is comforted and restored 78 The product leaves the skin luminous 91 The product restores radiance to the skin 87 Wrinkles and fine lines of crow's feet are faded 52 Signs of aging are reduced 65

The composition according to the invention therefore makes it possible to significantly reduce the signs of aging.

The use of NMN and of a composition comprising it in accordance with the invention therefore makes it possible to reduce the signs of aging, in particular in dry and normal skin.

Example 2 - Examples of compositions according to the invention

Face cream Ingredients (INCI name) CAS number Role Mass percentage Aqua 7732-18-5 Solvent QSP 100% Glycerine 56-81-5 humectant, solvent 4.5 Squalane 111-01-3 emollient 4.0 Glyceryl Stearate SE 11099-07-3 Emulsifier 3.0 Propanediol 504-63-2 Viscosity control, solvent 3.0 Propylene Glycol Dipelargonate 41395-83-9 Emollient, viscosity control 3.0 Caprylic/Capric Triglyceride
73398-61-5 Emollient, solvent, perfume 2.0 Nicotinamide Mononucleotide 1094-61-7 Cosmetic active agent 2.0 Pentylene Glycol 5343-92-0 Solvent, Emollient 2.0 Dicaprylyl Carbonate 1680-31-5 emollient 1.99 C10-18 Triglycerides 85665-33-4 emollient, solvent 1.5 Butyrospermum Parkii Butter 194043-92-0 Emollient, viscosity control 1.5 Glyceryl Stearate 31566-31-1 emollient, emulsifier 0.75 Polyacrylate Crosspolymer-6 / Emulsion stabilizer, viscosity control 0.5 silica 7631-86-9 Absorbent, viscosity control 0.5 Steareth-21 9005-00-9 (Generic) Surfactant, emulsifier 0.5 Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer 111286-86-3 Emulsion stabilizer, viscosity control 0.4 Isomalt 64519-82-0 Humectant 0.372 Sodium Hyaluronate 9067-32-7 Humectant, Emollient 0.35 Glyceryl Caprylate 26402-26-6 emollient, emulsifier 0.30 Sodium Citrate 6132-04-3 Buffering Agent, Chelating Agent 0.30 Xanthan Gum 6132-04-3 Binder, Emulsifier, Surfactant, Viscosity Control, Emollient 0.20 Ethylhexylglycerin 70445-33-9 lipid-replenishing 0.149850 Tocopherol 10191-41-0
59-02-9 Antioxidant, Emollient 0.140900 Sodium Hydroxide 1310-73-2 Buffer Agent 0.072 Glycine Soybean Oil 8001-22-7 Emollient, Perfume 0.060 Citric Acid 77-92-9 antioxidant 0.055515 Polysorbate 60 9005-67-8 Chelating/Buffering Agent 0.030 Sorbitan Isostearate 71902-01-7 Emulsifier 0.030 Sodium Benzoate 532-32-1 Conservative 0.0060 Lecithin 8002-43-5 Emulsifier 0.00320 Rhododendron Ferrugineum Leaf Cell Culture Extract 90106-21-1 emollient 0.00320

Eye contour serum Ingredients (INCI name) CAS number Role Mass percentage Aqua 7732-18-5 Solvent QSP 100% Glycerine 56-81-5 humectant, solvent 7.658800 Nicotinamide Mononucleotide 1094-61-7 Cosmetic active agent 2.0 Pentylene Glycol 5343-92-0 Solvent, Emollient 2.0 Squalane 111-01-3 emollient 1.5 C14-C22 alcohols / / 1.185000 Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer 111286-86-3 Emulsion stabilizer, viscosity control 0.8 Polyacrylate Crosspolymer-6 / Emulsion stabilizer, viscosity control 0.8 Glyceryl Stearate SE 11099-07-3 Emulsifier, emollient 0.5 Dicaprylyl Carbonate 1680-31-5 Emollient, 0.499813 Fagus Sylvatica Bud Extract 85251-65-6 Toning 0.35 Glyceryl Caprylate 26402-26-6 Emollient, emulsifier 0.30
/ Emulsifier, surfactant 0.285 Allantoin 97-59-6 Lipid-replenishing, skin protector 0.20

skin protector 0.18 Sodium Hydroxide 1310-73-2 buffer 0.13950 Ethylhexylglycerin 70445-33-9 Emollient 0.09990 Benzyl Alcohol 100-51-6 Perfume, preservative, viscosity control, solvent 0.060 Polysorbate 60 9005-67-8 Chelating/buffer 0.060 Sorbitan Isostearate 71902-01-7 emulsifier 0.060 Leontopodium Alpinum Callus Culture Extract / Antioxidant, humectant 0.04 Chlorella Vulgaris Extract 223749-83-5 Emollient 0.0225 Caprylic/Capric Triglyceride
73398-61-5 Emollient, solvent, perfume, lipid-replenishing 2.0 Glucose 50-99-7 Humectant 0.015 Palmaria Palmata Extract 223751-74-4 Skin Protector 0.01 Hydrolyzed Linseed Extract / emollient 0.00950 Sodium Benzoate 532-32-1 Conservative 0.0075 Citric Acid 77-92-9 antioxidant 0.0061 Benzoic Acid 65-85-0 Conservative 0.004 Xanthan Gum 6132-04-3 Binder, emulsifier, surfactant, viscosity control, gelling, replenishing 0.000600 Tocopherol 10191-41-0
59-02-9 Antioxidant, Emollient 0.000288

face serum Ingredients (INCI name) CAS number Role Mass percentage Aqua 7732-18-5 Solvent QSP 100% Glycerine 56-81-5 humectant, solvent 6.588000 Methylpropanediol 2163-42-0 solvent 3.0 Isopropyl Myristate 110-27-0 Binder, emollient, perfume, solvent 2.0 Nicotinamide Mononucleotide 1094-61-7 Cosmetic active agent 2.0 Pentylene Glycol 5343-92-0 Solvent, emollient 2.0 Squalane 111-01-3 emollient 1.5 C14-C22 alcohols / Emulsion stabilizer 1,975 Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer 111286-86-3 Emulsion stabilizer, viscosity control 0.925 Maltodextrin 9050-36-6 Absorbent, binder, emulsion stabilizer, film former, emollient 0.78 PANTHENOL 81-13-0 emollient 0.5
/ Emulsifier, surfactant 0.475 Leontopodium Alpinum Callus Culture Extract / Antioxidant, humectant, skin protectant 0.4 Squalane 111-01-3 emollient, 0.357 Glyceryl Caprylate 26402-26-6 emollient, emulsifier 0.30 Caprylic/Capric Triglyceride
73398-61-5 Emollient, solvent, perfume 0.16 Lecithin 8002-43-5 emollient, emulsifier 0.145 Sodium Hydroxide 1310-73-2 buffer 0.111 Polysorbate 60 9005-67-8 Chelating/buffer 0.107 Sorbitan Isostearate 71902-01-7 Emulsifier 0.051 Biosaccharide Gum-1 194237-89-3 emollient 0.05 Ethylhexylglycerin 70445-33-9 emollient 0.049950 Pistacia Lentiscus Gum 61789-92-2 Filmogenic 0.0400 Glucose 50-99-7 Humectant 0.025000 Citric Acid 77-92-9 antioxidant 0.0115 Sodium Benzoate 532-32-1 Conservative 0.006 Xanthan Gum 6132-04-3 Binder, emulsifier, surfactant, viscosity control, gelling agent, emollient 0.006 Magnolia Officinalis Bark Extract / emollient 0.002250 Tocopherol 10191-41-0
59-02-9 Antioxidant, Emollient 0.001550 Vitis Vinifera Seed Extract 84929-27-1 Antioxidant, Antimicrobial, UV Absorbent, Skin Protector 0.000450

Claims (7)

Cosmetic composition comprising nicotinamide mononucleotide (NMN), one of its derivatives, one of its precursors or one of its salts, for preventing or treating at least one sign of aging chosen from wrinkles, increased roughness of the skin, reduction in the thickness of the epidermis, reduction in the firmness of the epidermis, reduction in the elasticity of the epidermis, reduction in the luster of the skin, swelling of the lower eyelid and the tree ring and their combinations. Cosmetic composition according to Claim 1, in which the precursor is nicotinamide riboside (NR) and/or dihydronicotinamide riboside (NR-H). Cosmetic composition for its use according to one of the preceding claims, in which the NMN derivative is chosen from alpha nicotinamide mononucleotide (α-NMN), dihydronicotinamide mononucleotide (denoted NMN-H), the compound of formula (I):
[Chem. 1](I)
or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its pharmaceutically acceptable crystals thereof, in which:
- X is chosen from O, CH₂, S, Se, CHF, CF₂and C=CH₂;
-R₁is selected from H, azido, cyano, C-alkyl₁-VS₈, thio-C-alkyl₁-VS₈, C-heteroalkyl₁-VS₈and OR; wherein R is selected from H and C-alkyl₁-VS₈;
-R₂, R₃, R₄and R₅are chosen independently of one another from H, halogen, azido, cyano, hydroxyl, C-alkyl₁-VS₁₂, thio-C-alkyl₁-VS₁₂, C-heteroalkyl₁-VS₁₂, C-haloalkyl₁-VS₁₂and OR; wherein R is selected from H, C-alkyl₁-VS₁₂, C(O)(C)₁-VS₁₂)alkyl, C(O)NH(C₁-VS₁₂)alkyl, C(O)O(C₁-VS₁₂)alkyl, C(O)aryl, C(O)(C₁-VS₁₂)alkyl aryl, C(O)NH(C₁-VS₁₂)alkyl aryl, C(O)O(C₁-VS₁₂)alkyl aryl and C(O)CHR_AANH₂; in which R_AAis a side chain selected from a proteinogenic amino acid;
-R₆is selected from H, azido, cyano, C₁-VS₈ alkyl, C₁-VS₈ thio-alkyl, C₁-VS₈ heteroalkyl and OR; wherein R is selected from H and C₁-VS₈ alkyl;
-R₇is selected from H, P(O)R₉R₁₀and P(S)R₉R₁₀; in which
-R₉and R₁₀are chosen independently of each other from OH, OR₁₁, NHR₁₃, NR₁₃R₁₄, C-alkyl₁-VS₈, a C-alkenyl₂-VS₈, a C-alkynyl₂-VS₈, a C-cycloalkyl₃-VS₁₀, an aryl at C₅-VS_{12 ,}(VS₁-VS₈)alkyl aryl, (C₁-VS₈)aryl alkyl, (C₁-VS₈) heteroalkyl, (C₁-VS₈) heterocycloalkyl, a heteroaryl and NHCHR_ATR_{AT '}HORN₁₂; in which :
-R₁₁is selected from a group C₁-VS₁₀alkyl, C₃-VS₁₀cycloalkyl, C₅-VS_{1 8}aryl, C₁-VS₁₀alkylaryl, C₅-VS₁₂substituted aryl, C₁-VS₁₀heteroalkyl, C_3-VS₁₀heterocycloalkyl, C₁-VS₁₀haloalkyl, a heteroaryl, -(CH₂)_notC(O)(C)₁-VS₁₅)alkyl, -(CH₂)_notOC(O)(C)₁-VS₁₅)alkyl, -(CH₂)_notOC(O)O(C)₁-VS₁₅)alkyl, -(CH₂)_notSC(O)(C)₁-VS₁₅)alkyl, -(CH₂)_notC(O)O(C₁-VS₁₅)alkyl and -(CH₂)_notC(O)O(C₁-VS₁₅)alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH)₂;
-R₁₂is selected from H, C_1-VS₁₀alkyl, C₂-VS₈alkenyl, C₂-VS₈alkynyl, C_1-VS₁₀haloalkyl, C_3-VS₁₀cycloalkyl, C_3-VS₁₀heterocycloalkyl, C₅-VS_{1 8} aryl, C₁-VS₄alkylaryl and C₅-VS₁₂heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted from one or two groups selected from halogen, trifluoromethyl, C₁-VS₆alkyl, C₁-VS₆alkoxy and cyano; And
-R_ATAnd R_AT'are independently selected from H, A C_1-VS₁₀alkyl, C₂-VS₁₀alkenyl, C₂-VS₁₀alkynyl, C_3-VS₁₀cycloalkyl, C₁-VS₁₀thio-alkyl, C_1-VS₁₀hydroxylalkyl, C₁-VS₁₀alkylaryl and C₅-VS₁₂aryl, C_3-VS₁₀heterocycloalkyl, heteroaryl, -(CH₂)₃NHC(=NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl and a side chain selected from a proteinogenic amino acid or a non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C_1-VS₁₀alkyl, C_1-VS₆alkoxy, halogen, nitro and cyano; Or
-R₉and R₁₀form together with the phosphorus atoms to which they are attached a 6-membered ring in which –R₉−R₁₀− represents
–CH₂-CH₂-CHR−; wherein R is selected from H, a group (C₅-VS₆) aryl and (C₅-VS₆) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C₁-VS₆alkyl, a C₁-VS₆alkoxy and cyano; Or
R₉and R₁₀form together with the phosphorus atoms to which they are attached a 6-membered ring in which –R₉−R₁₀− represents –O-CH₂-CH₂-CHR-O-; wherein R is selected from H, a group (C₅-VS₆) aryl and (C₅-VS₆) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by halogen, trifluoromethyl, a (C₁-VS₆) alkyl, a (C₁-VS₆) alkoxy and cyano;
-R₈is selected from H, OR, NHR₁₃, NR₁₃R₁₄, NH-NHR₁₃, SH, CN, N₃and halogen; in which R₁₃and R₁₄are chosen independently from one another among H, (C₁-VS₈) alkyl and (C₁-VS₈) alkyl aryl;
- Y is selected from CH, CH₂, C(CH₃)₂and CCH₃;
-represents a single or a double bond along Y; And
-represents the alpha or beta anomer depending on the position of R₁
or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its crystals
Or
the compound of formula (II):
(II)
or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its crystals, in which

• X' ₁ and X' ₂ are independently chosen from O, CH ₂ , S, Se, CHF, CF ₂ , and C=CH ₂ ;
• R' ₁ and R'13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio-alkyl, C1-C8 heteroalkyl, and OR, wherein R is selected from H and a C1-C8 alkyl,
• R'₂, R'₃, R'₄, R'₅, R'₉, R'₁₀, R'₁₁, R'₁₂are independently selected from H, halogen, azido, cyano, hydroxyl, C-alkyl₁-VS₁₂, a C thioalkyl₁-VS₁₂, a hetero-C-alkyl₁-VS₁₂, a C haloalkyl₁-VS₁₂ and OR, wherein R may be selected from H, C-alkyl₁-VS₁₂, a C(O)( C₁-VS₁₂) alkyl, a C(O)NH(C₁-VS₁₂) alkyl, a C(O)O(C₁-VS₁₂) alkyl, a C(O) aryl, a C(O)( C₁-VS₁₂) aryl, a C(O)NH(C₁-VS₁₂) alkyl aryl, a C(O)O(C₁-VS₁₂) alkyl aryl or a C(O)CHR group_AANH2 in which R_AA is a side chain selected from a proteogenic amino acid;
• R' ₆ and R' ₈ are independently selected from H, azido, cyano, C ₁ -C ₈ alkyl and OR, wherein R is selected from H and C ₁ -C ₈ alkyl;
• R' ₇ and R' ₁₄ are independently selected from H, OR, NHR, NRR', NH-NHR, SH, CN, N ₃ and halogen, wherein R and R' are independently selected from H and un (C ₁ -C ₈ ) alkyl aryl;
• Y'1 and Y'2 are independently chosen from CH, CH ₂ , C(CH ₃ ) ₂ or CCH ³ ;
• M' is chosen from H or a suitable counterion;
• represents a single or double bond depending on Y'1 and Y'2; And
• represents an alpha or beta anomer depending on the position of R' ₁ and R'₁₃;

and their combinations. Cosmetic composition according to one of the preceding claims comprising between 0.01% by weight and 30% by weight, preferably between 0.1% and 10% by weight, more preferably between 1% and 5% by weight and even more preferably approximately 2% by weight of NMN, one of its derivatives, one of its precursors or one of its salts, relative to the total weight of the composition. Cosmetic composition according to one of the preceding claims comprising at least one cosmetically acceptable adjuvant chosen from the group consisting of thickeners, humectants, emollients, surfactants, preservatives, antifoams, colorants, preservatives, pH regulators, gelling agents, thinners, waxes, vegetable oils, animal oils, emulsifiers, vitamins, vitamin precursors, natural plant extracts, anti-pigment active agents, active peptides and/ or dyes. Cosmetic composition according to one of the preceding claims, which is in the form of a gel, a solution, a water-in-oil emulsion, an oil-in-water emulsion, an oil, a cream, an ointment, a dispersion of vesicles or a liniment. Cosmetic composition according to one of the preceding claims having a pH of between 4 and 9, preferably between 5 and 7.