Use of at least one pyrimidine 3-oxide derivative to prevent and / or treat skin signs of aging

Abstract

Use of at least one pyrimidine 3-oxide derivative to prevent and / or treat skin signs of aging The present invention relates to the cosmetic use, in particular non-therapeutic, of at least one pyrimidine 3-oxide derivative of formula (I): (I)- and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and mixtures thereof, as an active agent to prevent and / or treat skin signs of aging, such as signs of aging of the scalp.

Description

Title of the invention: Use of at least one pyrimidine 3-oxide derivative for preventing and / or treating the cutaneous signs of aging

[0001] The present invention relates to the field of active ingredients used to prevent and / or treat the signs of cutaneous aging.

[0002] Human skin is mainly made up of two main layers which are the dermis and the epidermis which covers the dermis superficially.

[0003] The dermis provides the epidermis with a solid support. It is also its nourishing element. It is mainly made up of fibroblasts and an extracellular matrix composed mainly of collagen, elastin and a substance called ground substance. These components are synthesized by fibroblasts.

[0004] The human epidermis is mainly composed of three types of cells: keratinocytes, which are the vast majority, melanocytes and Langerhans cells. Each of these cell types contributes, through its own functions, to the essential role played in the body by the skin.

[0005] Cohesion between the epidermis and the dermis is ensured by the dermo-epidermal junction. This is a complex region with a thickness of approximately 100 nm which includes the basal pole of the basal keratinocytes, the epidermal membrane and the sub-basal zone of the superficial dermis.

[0006] The dermo-epidermal junction is a structure that conditions the surface condition of the skin. Thus, a dermo-epidermal junction having integral anchoring structures is kept pleated, thus making it possible to increase the surface area of ​​the contact zone between the dermis and the epidermis, to promote the exchange of diffusible factors, in particular between these two tissues, to strengthen their cohesion and to improve the appearance of the epidermis.

[0007] In cases where the anchoring structures are altered, in particular due to a deficiency in collagen synthesis and / or due to aging, this causes a flattening of the dermo-epidermal junction. Exchanges are reduced, the two tissues are less united, the epidermis folds and the skin being less firm and less taut, wrinkles appear and the fragility of the skin to mechanical aggression is increased.

[0008] With aging, collagen thins and becomes disorganized, skin cell renewal is reduced, wrinkles appear on the surface of the skin, the skin is less firm, duller. Skin aging is conditioned by genetic characteristics. In addition, certain environmental factors such as Smoking and especially exposure to sunlight accelerate it. The skin therefore looks much older in sun-exposed areas such as the backs of the hands or the face. These other factors also have a negative impact on the skin's natural collagen.

[0009] Consequently, given the important role of collagen in the integrity of the skin and its resistance to external mechanical attacks, the stimulation of the synthesis of these collagens appears to be an effective means of alleviating the signs of skin aging.

[0010] To date, 20 types of collagen have been identified and graded from I to XX. Collagens are not all synthesized by the same cell types, the regulation of their expression differs from one collagen to another, and all collagen molecules are variants of a common precursor which is the alpha chain of procollagen.

[0011] In the skin and dermis, the preferentially expressed collagens are collagen I and, to a lesser extent, collagen III. Collagen I is the predominant fibrillar collagen in the human body, or it can account for 80-90% of all skin collagen (Reilly DM and Lozano J. Skin collagen through the life stages: importance for skin health and beauty. Plast Aesth Res (2021)). Collagen III is also another fibrillar collagen classically highly expressed in the skin. Beyond its importance for the skin, it is also a key collagen for the formation of the matrix layers of blood vessels. It is a collagen mainly induced during the phases of tissue repair and healing (Ristelli et al; Advances in clinical Chemistry (2014)).

[0012] Collagen XV, which is one of the least expressed collagens in human tissues, is predominantly located in the basement membranes of the epidermis (Aranitidis A and Kersdal MA. Type XV collagen. Biochemistry of Collagens, Laminins and Elastin (2016)). Unlike other fibrillar collagens, it plays the role of connector of other fibrillar collagens of the extracellular matrix of the dermis to the basement membrane of the epidermis. This very specific function stabilizes the attachment and increases the resistance of tissues to compression and extension forces (Bachinger HS et al. Comprehensive natural products II (2010)).

[0013] Collagen VI is also another non-fibrillar collagen, expressed mainly in connective tissues, and involved in the organization of the extracellular matrix of the dermis (Theocharidis et al. Type VI collagen regulates dermal matrix assembly and fibroblast motility. J. Invest. Dermatol (2016)).

[0014] Other important junctional proteins (because they interact with collagens for their anchoring at the dermo-epidermal junction) are also known as Dermatopontin (DPN) which serves to assemble collagen fibers together for the reinforcement of connective tissues (Okamoto et al. Dermatopontin, a novel player in the biology of the extracellular matrix. Connect tissue Res (2006)) and facilitate re-epithelialization and adhesion of keratinocytes during healing processes (Okamoto et al. Dermatopontin promotes epidermal keratinocyte adhesion via alpha3betal integrin and a proteoglycan receptor. Biochemistry (2010)).

[0015] COMP (cartilage oligomeric matrix protein) or Trombospondin 5 represents another protein present in the dermo-epidermal junction and interacts with collagens to reinforce its biomechanical properties.

[0016] Finally, Fibronectin 1 (FN1), another protein of the extracellular matrix constituting the dermo-epidermal junction and which interacts with collagens.

[0017] Thus, the induction of expression of fibrillar dermal collagens, junctional epidermal collagens and the bridging proteins that assemble them play a predominant role in the general physiology of the skin, particularly in the junctional structures that provide both the barrier function and resistance to physical and mechanical attacks of the skin, as well as the strong and organized connection between the epidermis and the deeper fibrillar dermal structures at the level of the dermo-epidermal junction (DEJ), responsible for firmer skin with fewer wrinkles.

[0018] The present invention therefore aims to meet these needs.

[0019] Surprisingly, the inventors have indeed demonstrated the particular properties of 2,4-diaminopyrimidine-3-N-oxide which is a pyrimidine 3-oxide derivative, to modify the abundance of production of a messenger RNA precursor of the synthesis of fibrillar dermal and epidermal matrix collagens, in particular COL1A1, COL12A1, COL10A1, COL3A1, COL14A1, COL13A1, COL5A2, COL6A6, COL1A1, COL15A1, COL1A2, COL3A1, COL6A1, COL6A2, COL6A3, as well as bridging proteins which assemble them such as COMP (cartilage oligomeric matrix protein) or Trombospondin 5 and Fibronectin 1 (FN1).

[0020] All of these properties therefore advantageously make it possible to envisage the use of pyrimidine 3-oxide derivatives, in particular 2,4-diaminopyrimidine-3-N-oxide and / or one of its salts and / or one of its solvates, and / or one of its isomers, and / or one of its tautomers or a composition comprising it or them to prevent and / or treat the cutaneous signs of aging.

[0021] 2,4-Diaminopyrimidine-3-N-oxide is known from patent EP540629B1 as an active ingredient for the cosmetic treatment of hair loss by topical application. 2,4-Diaminopyrimidine-3-N-oxide monohydrate has also already been shown to modulate dermal biomarkers via modulation of lysyl hydroxylase activities suggesting a protective role against perifollicular hair fibrosis and collagen crosslinking (WO96090048 and Mahé YF et al. A Minoxidil-related compound lacking a C6 substitution still exhibits strong anti- Lysyl Hydroxylase activity in vitro. Skin Pharmacol. (1996), Mahe YF Inflammatory perifollicular fibrosis and alopecia Int J Dermatol (1998)).

[0022] However, to the inventors' knowledge, it has never been described as an active ingredient for preventing and / or treating the signs of cutaneous aging, and even less so as an active ingredient for inducing collagen synthesis in the skin.

[0023] Thus, the present invention has as its first object the cosmetic use, in particular non-therapeutic, of at least one pyrimidine 3-oxide derivative of formula (I): in which: - RI denotes a methyl group or NHR4 in which R4 denotes a C1-C4 alkyl group or a hydrogen atom; - R2 denotes a methyl or NHR4 group in which R4 is as defined above, R2 can also denote methyl when RI denotes methyl;

[0024] - R3 denotes a hydrogen atom, a halogen atom or a nitro group or amino, or a C1-C4 alkyl group which may optionally carry: - an OR5 group in which R5 denotes a C1-C4 alkyl group, a benzene nucleus optionally substituted by one or more C1-C4 alkoxy groups; - a benzene nucleus optionally substituted by one or more C1-C4 alkoxy groups; - and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and their mixtures, as an anti-aging active agent.

[0025] The present invention also relates to the cosmetic use, in particular non-therapeutic use, of at least one pyrimidine 3-oxide derivative of formula (I), or of a cosmetic composition comprising it:

[0026] [Chem.l] O (i) in which: - RI denotes a methyl group or NHR4 in which R4 denotes a C1-C4 alkyl group or a hydrogen atom; - R2 denotes a methyl or NHR4 group in which R4 is as defined above, R2 can also denote methyl when RI denotes methyl; - R3 denotes a hydrogen atom, a halogen atom or a nitro or amino group, or a C1-C4 alkyl group which may optionally carry: - an OR5 group in which R5 denotes a C1-C4 alkyl group, a benzene nucleus optionally substituted by one or more C1-C4 alkoxy groups; - a benzene nucleus optionally substituted by one or more C1-C4 alkoxy groups; - and / or at least one of its salts, and / or at least one of its isomers, and / or tautomers and / or at least one of its solvates, and their mixtures, as an active agent to prevent and / or treat the signs of aging of the skin, such as the signs of aging of the scalp.

[0027] The present invention also relates to a method for cosmetic treatment of the skin to prevent and / or treat the cutaneous signs of aging comprising at least one step of topical application to skin, in particular scalp skin, showing cutaneous signs of aging, of at least one compound of formula (I) and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and their mixtures as defined above, or of a cosmetic composition comprising it or them in a physiologically acceptable medium.

[0028] The present invention also relates to a cosmetic composition for skin care comprising in a physiologically acceptable medium: i. at least one pyrimidine 3-oxide derivative of formula (I), and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and their mixtures as defined above, and ii. at least one anti-aging active ingredient.

[0029] Definitions

[0030] By "skin" is meant all of the skin of the human body, in particular the skin of the décolleté, the neck, the arms and forearms, the feet, the skin of the face (in particular the forehead, nose, cheeks, lips, chin), as well as the skin of the scalp, preferably the skin of the scalp.

[0031] According to the invention, by "prevent" or "prevention" is meant the fact of reducing the risk of occurrence or slowing down the occurrence of a given phenomenon, namely, reducing the risk of the appearance of signs of skin aging.

[0032] By "treat" or "treatment" we mean any action aimed at improving the comfort and well-being of an individual; this term therefore covers alleviating, relieving and curing.

[0033] By “intended to be administered topically” is meant an application to the surface of the skin in question.

[0034] By "cutaneous signs of aging" we mean all changes in the external appearance of the skin due to aging, whether chronological and / or photo-induced in origin.

[0035] Examples of such modifications considered in the invention include an uneven and less smooth surface, thinned epidermis, wrinkles and fine lines, sagging skin, lack of elasticity and / or tone of the skin, thinning of the dermis and / or degradation of collagen fibers, which results in the appearance of soft and wrinkled skin.

[0036] Preferably, the cutaneous signs of aging targeted by the invention are chosen from thinning of the skin, loss of firmness, loss of elasticity, loss of density, or loss of tone of the skin, alteration of the surface appearance of the skin, appearance of a marked microrelief of the skin, appearance of roughness, formation and / or presence of fine lines and / or wrinkles, alteration of the radiance of the complexion of the skin, a papery appearance of the skin, sagging of the skin, or wilting of the skin.

[0037] More preferably, the cutaneous signs of aging targeted by the invention are chosen from a loss of firmness, a loss of elasticity, a loss of skin tone, an alteration of the surface appearance of the skin, an appearance of a marked microrelief of the skin, an appearance of roughness, a formation and / or a presence of fine lines and / or wrinkles, an alteration of the radiance of the complexion of the skin, a papery appearance of the skin, a wilting of the skin.

[0038] Even more preferably, the cutaneous signs of aging targeted by the invention are chosen from an alteration of the surface appearance of the skin, an appearance of a marked microrelief of the skin, an appearance of roughness, a formation and / or a presence of fine lines and / or wrinkles, an alteration of the radiance of the complexion of the skin.

[0039] The term "anti-aging active" within the meaning of the present invention means an active having the effect of preventing and / or treating the aforementioned cutaneous signs of aging. Detailed description of the invention

[0040] Pyrimidine 3-oxide derivative of formula (I)

[0041] The pyrimidine 3-oxide derivative corresponds to the following formula (I):

[0042] [Chem.l] (I) in which: - RI denotes a methyl group or NHR4 in which R4 denotes a C1-C4 alkyl group or a hydrogen atom; - R2 denotes a methyl or NHR4 group in which R4 is as defined above, R2 can also denote methyl when RI denotes methyl; - R3 denotes a hydrogen atom, a halogen atom or a nitro or amino group, or a C1-C4 alkyl group which may optionally carry: - an OR5 group in which R5 denotes a C1-C4 alkyl group, a benzene nucleus optionally substituted by one or more C1-C4 alkoxy groups; - a benzene nucleus optionally substituted by one or more C1-C4 alkoxy groups; - and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and their mixtures.

[0043] By “isomers” we mean optical, geometric, and tautomeric isomers.

[0044] Among the solvates, when the solvent is water, we will speak of hydrates.

[0045] As hydrate, mention will in particular be made of monohydrate.

[0046] Preferably, the unsalified product will be used in the form of monohydrate.

[0047] An alkyl group preferably denotes, in accordance with the invention, a methyl or ethyl group, the alkoxy group preferably denotes methoxy or ethoxy, the halogen atoms preferably denote chlorine or bromine.

[0048] The preferred compounds which can be used in accordance with the invention are the compounds of formula (I) in which RI denotes amino, R2 denotes amino, R3 denotes hydrogen or RI denotes amino, R2 denotes amino and R3 denotes chlorine, as well as their salts and / or solvates and their mixture, more preferably the compounds of formula (I) in which RI denotes amino, R2 denotes amino, R3 denotes hydrogen as well as their salts and / or solvates.

[0049] The compounds of formula (I) can be obtained for example, by hydrogenolysis, in the presence of palladium on carbon, of compounds of formula (II) defined below in which Z denotes a halogen atom and preferably chlorine or bromine, and R1, R2 and R3 are as defined above for formula (I).

[0050] The reduction is carried out according to the classical method described in the literature (DJ BROWN:, The pyrimidines, supplement II, Vol. 16, chapter X, page 360, Interscience Pub. 1985; COWDEN and WARING, Aust. J. Chem. 34, 1539 (1981) according to the following reaction scheme:

[0051] [Chem.2] W (I)

[0052] Among the salts which can be used in the context of the invention, mention may in particular be made of addition salts with an organic or mineral acid such as the salts of sulfuric, hydrochloric, phosphoric, acetic, citric, benzoic, salicylic, glycolic, succinic, nicotinic, tartaric, maleic, pamoic, methanesulfonic, picric, lactic acid, the salts of amino acids and more particularly of N-acetylated amino acids such as aceturic acid.

[0053] Preferably, 2,4-diaminopyrimidine-3-N-oxide of formula (III) and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and their mixtures, will be used.

[0054] [Chem.3] O (III)

[0055] 2,4-Diaminopyrimidine-3-N-oxide of formula (III) has in particular the INCI name diaminopyrimidine oxide.

[0056] 2,4-Diaminopyrimidine-3-N-oxide of formula (III) has in particular the trade name Aminexil®.

[0057] Preferably, said compound of formula (III) can be synthesized according to the method described in EP0540629 in example 1.

[0058] Preferably, said at least one pyrimidine 3-oxide derivative of formula (I) and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, is used as active agent in an effective amount, that is to say in an amount allowing it to have the desired effect.

[0059] Said at least one pyrimidine 3-oxide derivative of formula (I) and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, may be used, in a composition, in particular for topical application to the skin, in particular to the scalp, in an amount ranging from 0.001% to 20% by weight relative to the total weight of the composition, preferably in an amount ranging from 0.01% to 15% by weight relative to the total weight of the composition, more preferably from 0.05% to 10% by weight relative to the total weight of the composition, even better in an amount ranging from 0.1% to 5% by weight relative to the total weight of the composition.

[0060] The present invention also relates to a cosmetic composition for skin care, preferably for scalp skin care, comprising in a physiologically acceptable medium: i. at least one pyrimidine 3-oxide derivative of formula (I), and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and their mixtures as defined above, and ii. at least one anti-aging active ingredient.

[0061] The compositions, in particular cosmetic compositions, capable of being used in the context of the use or treatment method according to the invention comprise a medium physiologically acceptable.

[0062] The term “physiologically acceptable medium” means a medium compatible with the skin. According to a particular embodiment, the pH of the cosmetic composition is between 4 and 7.5, in particular between 4.5 and 7, and in particular between 4.7 and 6.5.

[0063] More particularly, said physiologically acceptable medium may comprise water and / or one or more water-miscible organic solvents which may be chosen from linear or branched C1-C6 monoalcohols such as ethanol, isopropanol, tert-butanol; polyols such as glycerol, propylene glycol, hexylene glycol (or 2-methyl-2,4-pentanediol), and polyethylene glycols; polyol ethers such as dipropylene glycol monomethyl ether; and mixtures thereof.

[0064] Preferably, the composition according to the invention has a water content ranging from 20% to 95% by weight, more preferably from 30% to 60% by weight, even better from 40% to 50% by weight relative to the total weight of the composition.

[0065] Advantageously, the composition comprises one or more water-miscible organic solvents in a content ranging from 20% to 98% by weight, preferably from 40% to 60% by weight, even better from 45% to 55% by weight relative to the total weight of the composition. The support may be of various natures depending on the type of composition considered.

[0066] The composition according to the invention can then comprise water and / or all the adjuvants usually used in the field of application envisaged.

[0067] Mention may in particular be made of C2-C10 carboxylic acid esters; carbonaceous and / or silicone oils, of mineral, animal and / or vegetable origin; waxes, pigments, fillers, dyes, surfactants, emulsifiers, co-emulsifiers; cosmetic or dermatological active agents other than 2,4-diaminopyrimidine-3-N-oxide according to the invention such as minoxidil, UV filters, polymers, hydrophilic or lipophilic gelling agents, thickeners, preservatives, perfumes, bactericides, odor absorbers, antioxidants.

[0068] These optional adjuvants may be present in the composition in an amount of 0.001% to 80% by weight, preferably 0.01% to 40% by weight, even better 0.1% to 20% relative to the total weight of the composition. These adjuvants, depending on their nature, may be introduced into the fatty phase, into the aqueous phase and / or into the lipid vesicles.

[0069] Of course, those skilled in the art will take care to choose this or these possible additional ingredients and / or active ingredients, and / or their quantity, in such a way that the advantageous properties of the compounds of formula (I) according to the invention are not, or not substantially, altered by the envisaged addition.

[0070] The compositions according to the invention can be presented in all the galenic forms conventionally used for topical application and in particular in the form aqueous, hydroalcoholic solutions, oil-in-water (O / W) or water-in-oil (W / O) or multiple (triple: W / O / W or O / W / O) emulsions, aqueous gels, or dispersions of a fatty phase in an aqueous phase using spherules, these spherules being able to be lipid vesicles of ionic and / or non-ionic type (liposomes, niosomes, oleosomes). These compositions are prepared according to the usual methods.

[0071] Advantageously, the cosmetic compositions suitable for implementing the invention may be in the form of a suspension, a gel, an emulsion, a shampoo, a leave-in lotion or a mousse.

[0072] The compositions may be in any form suitable for skin care, in particular for the skin of the scalp, in particular in the form of a hair care lotion, for example for daily or bi-weekly application, a hair shampoo or conditioner, in particular for weekly or bi-weekly application, a liquid or solid soap for cleaning the scalp for daily application, a hair styling product (hairspray, styling gel), a treatment mask, a cream or a foaming gel for cleaning the hair. A composition according to the invention may comprise an oily phase.

[0073] By "liquid fatty body" is meant a compound having a melting point below about 30-35°C such as oils, as opposed to solid fatty bodies, such as waxes, which have a melting point above about 50°C.

[0074] As oils which can be used in the composition of the invention, we can cite for example: - hydrocarbon oils of animal origin; - hydrocarbon oils of vegetable origin; - synthetic esters and ethers, in particular of fatty acids, such as oils of formulas R'COOR2 and R'COR2 in which R' represents the residue of a fatty acid containing from 8 to 29 carbon atoms, and R2 represents a hydrocarbon chain, branched or not, containing from 3 to 30 carbon atoms; - linear or branched hydrocarbons, of mineral or synthetic origin; - fatty alcohols having 8 to 26 carbon atoms; - partially hydrocarbon and / or silicone fluorinated oils; - silicone oils; - their mixtures.

[0075] In the list of oils cited above, the term "hydrocarbon oil" means any oil comprising mainly carbon and hydrogen atoms, and possibly ester, ether, fluorine, carboxylic acid and / or alcohol groups.

[0076] Other fatty substances that may be present in the oily phase are, for example, fatty acids containing 8 to 30 carbon atoms; waxes; silicone resins; and silicone elastomers. These fatty substances may be chosen so as to varied by a person skilled in the art in order to prepare a composition having the desired properties, for example consistency or texture.

[0077] According to a particular embodiment of the invention, the composition according to the invention is a water-in-oil (W / O) or oil-in-water (O / W) emulsion. The proportion of the oily phase of the emulsion can range from 5 to 90% by weight, and preferably from 5 to 60% by weight relative to the total weight of the composition. The emulsions generally contain at least one emulsifier chosen from amphoteric, anionic, cationic or non-ionic emulsifiers, used alone or as a mixture, and optionally a co-emulsifier. The emulsifiers are chosen appropriately depending on the emulsion to be obtained (W / O or O / W). The emulsifier and the co-emulsifier are generally present in the composition, in a proportion ranging from 0.3 to 30% by weight, and preferably from 0.5 to 20% by weight relative to the total weight of the composition.

[0078] For W / O emulsions, emulsifiers that may be mentioned include, for example, dimethicone copolyols. A crosslinked solid elastomeric organopolysiloxane comprising at least one oxyalkylene group may also be used as a surfactant for W / O emulsions.

[0079] For O / W emulsions, examples of emulsifiers that may be mentioned are non-ionic emulsifiers.

[0080] Said at least one pyrimidine 3-oxide derivative of formula (I), and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates and their mixtures, or said composition comprising it or them is implemented, in the context of the use or the method according to the invention, by topical route.

[0081] The compositions according to the invention may be applied directly to the skin or, alternatively, to cosmetic supports of the occlusive or non-occlusive type, intended to be applied locally to the skin.

[0082] The composition may or may not be rinsed off after being applied to the skin.

[0083] According to a particular embodiment of the invention, it is also possible to add to the composition suitable for the invention other agents intended to beautify the appearance and / or improve the texture of the skin, preferably the scalp, and / or agents intended for keratin fibers, preferably the hair.

[0084] The present invention also relates to a method for cosmetic treatment of the skin to prevent and / or treat the cutaneous signs of aging comprising at least one step of topical application to skin, in particular scalp skin, showing cutaneous signs of aging, of at least one compound of formula (I) and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and their mixtures such as as defined above, or a cosmetic composition comprising it or them in a physiologically acceptable medium.

[0085] Throughout the description, including the claims, the expression "at least one" must be understood as being synonymous with "one or more" unless otherwise specified.

[0086] The expressions “more than”, “between ... and …” and “ranging from ... to …” must be understood inclusively, unless otherwise specified.

[0087] The following examples and figures are presented for illustrative and non-limiting purposes of the invention. The compounds are, as appropriate, cited by chemical names or CTFA (International Cosmetic Ingredient Dictionary and Handbook) names.

[0088] The invention is illustrated in more detail in the following examples. Examples

[0089] Example 1 - Evaluation of the effect of 2,4-diaminopyrimidine-3-N-oxide monohydrate on skin aging.

[0090] A) Material and Method

[0091] Preparation of tested samples:

[0092] The stock solution of 2,4-diaminopyrimidine-3-N-oxide monohydrate 100 mM in DMSO (14.41 mg / mL) was prepared with 5 mg of 2,4-diaminopyrimidine-3-N-oxide monohydrate diluted in 0.34 ml of DMSO solvent. An additional dilution to 1000 pM was made in PBS from the stock solution (10 pL of 2,4-diaminopyrimidine-3-N-oxide monohydrate stock solution + 0.99 ml PBS). From this dilution, a final concentration of 30 pM of 2,4-diaminopyrimidine-3-N-oxide monohydrate was made with 300 pL of the 1000 pM solution + 0.7 ml PBS.

[0093] Biological samples:

[0094] Human adult dermal fibroblasts (NHDF) were seeded into a 12-well plate and cultured in culture medium (MEM 10% FCS) for 24 hours. The culture medium was replaced with fresh culture medium for another 24 hours. The culture medium was then replaced with medium (MEM 2% FCS) for the next 24 hours.

[0095] Adult human epidermal keratinocytes (NHEK) were seeded into a 24-well plate and cultured in culture medium (KSFM, Gibco) for 24 hours. The culture medium was replaced with fresh culture medium for the next 48 hours.

[0096] Treatment:

[0097] The culture medium of the fibroblast monolayer cells was removed and replaced with medium (MEM 2% FCS) containing either the solvent control DMSO or a final concentration of 2,4-diaminopyrimidine-3-N-oxide monohydrate of 30 pM. cells were incubated for 24 hours.

[0098] The culture medium of the keratinocyte monolayer cells was removed and replaced with medium (KSFM 1.5 mM CaCl2) containing either the solvent control DMSO or a final concentration of 2,4-diaminopyrimidine-3-N-oxide monohydrate of 30 pM. The cells were incubated for 24 hours.

[0099] All experimental conditions were carried out in n=3.

[0100] RNA extraction:

[0101] Samples were received frozen in dry ice and transmitted to the RT-qPCR platform for total RNA extraction and quality analysis steps.

[0102] The samples received were found in the form of lysates in RLT+b-mercaptoethanol buffer for KHN and FHN monolayer cells. The samples were thawed. An additional volume of RLT+b-mercaptoethanol was added to bring the volume to 600 μl. The rest of the extraction protocol was carried out with the RNeasy micro kit (Qiagen, Germantown, MD, USA) including a DNase 1 treatment and modifying the addition to 1.5 volumes of 100% ethanol to the lysate in order to preserve the small RNA (Qiagen Supplementary Protocol: Purification of miRNA from animal cells (RY26 Jun-06)). Purified RNAs were eluted with 30-40 μl of RNase-free water and assayed in duplicate spectrophotometrically using the NanoDrop ND-1000 (NanoDrop Technologies, Wilmington, DE, USA). Approximately 5 ng of total RNA was used for total RNA integrity verification using the Bioanalyzer 2100 (Agilent Technologies, Santa Clara, CA, USA) with the RNA 6000 Pico Kit (Agilent).The integrity value (RIN), an indicator of RNA quality, ranged from 8.5 to 10 out of 10.

[0103] Library preparation and sequencing:

[0104] The NEBNext Ultra II directional RNA library prep kit for Illumina (New Englands Biolabs Inc., Ipswich, MA, USA) was used for RNA library preparation according to the manufacturer's instructions. Briefly, 100 ng of total RNA, to which an external RNA control (Ambion® ERCC Spike-In Control Mixes; ThermoFisher, Canada) diluted 1 / 300 was added, was used for poly A+ mRNA selection using dT oligos attached to magnetic beads (NEBNext poly(A), New Englands Biolabs Inc., Ipswich, MA, USA). The isolated mRNA was used as a template for cDNA synthesis by reverse transcriptase with random primers. Strand specificity was achieved by replacing dTTP with dUTP. After purification with AxyPrep Mag PCR Clean-up kit beads (Axygen, Big Flats, NY, USA), this cDNA was converted to double-stranded DNA and the ends were repaired.After excision of the dUTP-containing strands, a 13-cycle amplification was performed to incorporate the specific indexed adapters. for multiplexing. The quality of the final libraries was checked using a TapeStation 2200 (Agilent Technologies, Santa Clara, CA, USA) and quantification was performed using a QBit 3.0 fluorometer (ThermoFisher Scientific, Canada). Subsequently, the mRNA-seq libraries, each with 2 unique indexes, were pooled in an equimolar ratio into 7 pools. Each pool was loaded onto a high-performance fowcell S4 lane and sequenced on an Illumina NovaSeq 6000 system (Illumina Inc., San Diego, CA, USA). Paired-end sequencing of 100 bp was performed. The average coverage / sample obtained was approximately 29M paired-end reads.

[0105] Bioinformatics analysis:

[0106] Reads were trimmed using the fastp v0.22.0 tool [1]. Read quality controls were performed on both raw and trimmed reads using the FastQC vO.11.9 tool [2] and MultiQC vl.ll [3]. The quantification step was performed with Kallisto vO.46.1 [4] using “coding protein” transcripts based on the human transcriptome version GRCh38 from the Ensembl database (Release 104). (GRCh38 downloaded from Ensembl release 104). Principal component analyses (PCA) were performed with the R package FactoMineR v2.6 [5]. PCA and “Volcano Plot” visualizations were produced with the R package ggplot2 v3.4.0 [6]. Differential expression analyses were conducted using the DESeq2 v 1.34.0 package [7]. All analyses with R software were performed using R v4.1.2 [8].

[0107] Bibliography

[0108] [1] Chen, S., Zhou, Y., Chen, Y., & Gu, J. (2018). fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics, 34(17), i884-i890.

[0109] [2] Andrews, Simon. "FastQC: a quality control tool for high throughput sequence data." (2010).

[0110] [3] Ewels, Philip, Mans Magnusson, Sverker Lundin, and Max Kâller. "MultiQC: summarize analysis results for multiple tools and samples in a single [OUI] report." Bioinformatics 32, no. 19 (2016): 3047-3048. j

[0112] [4] Bray, Nicolas L., Harold Pimentel, Pâli Melsted, and Lior Pachter. "Near-optimal probabilistic RNA-seq quantification." Nature biotechnology 34, no. 5 (2016): 525.

[0113] [5] Lê, S., Josse, J., & Husson, F. (2008). FactoMineR: an R package for multivariate analysis. Journal of statistical software, 25(1), 1-18.

[0114] [6] Wickham, H. (2011). ggplot2. Wiley Interdisciplinary Reviews: Computational Statistics, 3(2), 180-185.

[0115] [7] Love, Michael L, Wolfgang Huber, and Simon Anders. "Moderate estimate of fold change and dispersion for RNA-seq data with DESeq2." Genome biology 15, no. 12 (2014): 550

[0116] [8] A: Team, R. Core. "R: A language and environment for statistical computing." (2013): 201.

[0117] B) Results

[0118] Table 1 shows the epidermal matrix genes whose expression is favorably modulated by the treatment of cutaneous keratinocytes with the compound 2,4-diaminopyrimidine-3-N-oxide monohydrate.

[0119] [Tables 1] Tested Compound Genes Fold Change Log 2 Fold Change Adjusted P value 2,4-Diaminopyrimid ine-3-N-oxide monohydrate COL15A1 1.849048217 0.886782846 0.03368614 8 COL1A2 21.23079212 4.408086294 7.57E-64 COL3A1 22.75198255 4.507920359 5.32E-26 COL6A1 1.67455761 0.743780011 0.0010523 92 COL6A2 12.72344763 3.66941774 9.45E-06 COL6A3 14.87087064 3.89441721 1 JOE-11 COMP 1.91148703 0.934695411 0.0320172 73 DPT 3.645750203 1.866215715 0.0108600 77 FN1 1.583353987 0.662983832 5.20E-13

[0120] Table 2 shows the fibrillar dermal collagen genes whose expression is favorably modulated by treatment of skin fibroblasts with the compound 2,4-diaminopyrimidine-3-N-oxide monohydrate.

[0121] [Tables2] Test compound 2,4-Diaminopyrimidin-3-N-oxide monohydrate Genes Fold Change Log 2 Fold Change Adjusted P value COL1A1 1.098055912 0.601996478 9.36E-06 COL12A1 1.75245978 0.809381334 7.03E-15 COL10A1 2.300343035 -1.201849017 0.0045157 27 COL3A1 1.639482043 0.7132401 4.64E-06 COL14A1 2.216020209 1.147971038 l,36E-07 COL13A1 3.580895455 -1.8403204 3.57E-18 COL5A2 1.59377299 0.672446153 3.76E-07 COL6A6 3.136763526 1.649276772 2.53E-06

[0122] Conclusion: 2,4-Diaminopyrimidine-3-N-oxide monohydrate significantly stimulates the expression of mRNA coding for matrix epidermal collagen genes COL15A1, COL1A2, COL3A1, COL6A1, COL6A2, COL6A3, fibrillar dermal collagen genes COL1A1, COL12A1, COL10A1, COL3A1, COL14A1, COL13A1, COL5A2, COL6A6, COL1A1 as well as COMP, DPT and FN1 genes coding for bridging proteins, thus demonstrating a favorable effect of this compound on the induction of the expression of fibrillar dermal and junctional epidermal collagens and the bridging proteins that assemble them, thus strengthening the strong and organized bond between the epidermis and the structures fibrillar dermal cells at the dermoepidermal junction (DEJ) responsible for firmer skin with fewer wrinkles.

[0123] Example 2 - Cosmetic composition - Scalp lotion

[0124] The following composition was prepared:

[0125] [Tables3] Ingredients Quantity (% by weight) 2,4-diamino-pyrimidine-3-ox yde monohydrate 1.5 Ethyl alcohol 96° denatured 31.1 Deionized water qsp 100

[0126] The above lotion was then applied to the scalp skin to promote improvement of the skin signs of aging.

Claims

Claims

1. Cosmetic use, in particular non-therapeutic use, of at least one pyrimidine 3-oxide derivative of formula (I): in which: - RI denotes a methyl group or NHR4 in which R4 denotes a C1-C4 alkyl group or a hydrogen atom; - R2 denotes a methyl or NHR4 group in which R4 is as defined above, R2 can also denote methyl when RI denotes methyl; - R3 denotes a hydrogen atom, a halogen atom or a nitro or amino group, or a C1-C4 alkyl group which may optionally carry: - an OR5 group in which R5 denotes a C1-C4 alkyl group, a benzene nucleus optionally substituted by one or more C1-C4 alkoxy groups; - a benzene nucleus optionally substituted by one or more C1-C4 alkoxy groups; - and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and their mixtures, as an anti-aging active agent.

2. Cosmetic use, in particular non-therapeutic use, of at least one pyrimidine 3-oxide derivative of formula (I), or of a composition comprising it: in which: - RI denotes a methyl group or NHR4 in which R4 denotes a C1-C4 alkyl group or a hydrogen atom; - R2 denotes a methyl or NHR4 group in which R4 is as defined above, R2 may also denote methyl when RI denotes methyl; - R3 denotes a hydrogen atom, a halogen atom or a nitro or amino group, or a C1-C4 alkyl group which may optionally carry: - an OR5 group in which R5 denotes a C1-C4 alkyl group, a benzene nucleus optionally substituted by one or more C1-C4 alkoxy groups; - a benzene nucleus optionally substituted by one or more C1-C4 alkoxy groups; - and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and their mixtures, as an active agent to prevent and / or treat the skin signs of aging.

3. Cosmetic use according to claim 1 or 2, wherein said pyrimidine 3-oxide derivative is 2,4-diaminopyrimidine-3-N-oxide of formula (III) as follows: n (In) its salts, its isomers, its tautomers, its solvates, and their mixtures.

4. Cosmetic use according to any one of the preceding claims, wherein said pyrimidine 3-oxide derivative of formula (I), and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and mixtures thereof, is present in a composition, in an amount ranging from 0.001% to 20% by weight relative to the total weight of the composition, preferably in an amount ranging from 0.01% to 15% by weight relative to the total weight of the composition, more preferably from 0.05% to 10% by weight relative to the total weight of the composition, even better in an amount ranging from 0.1% to 5% by weight relative to the total weight of the composition.

5. Cosmetic use according to any one of the preceding claims, characterized in that said compound of formula (I) and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and their mixtures, or said composition comprising it or them is intended for topical administration.

6. Cosmetic use according to any one of claims 2 to 5, characterized in that the cutaneous signs of aging are chosen from thinning of the skin, loss of firmness, loss of elasticity, loss of density, or loss of tone of the skin, alteration of the surface appearance of the skin, appearance of a marked microrelief of the skin, appearance of roughness, formation and / or presence of fine lines and / or wrinkles, alteration of the radiance of the complexion of the skin, a papery appearance of the skin, sagging of the skin, or wilting of the skin.

7. Cosmetic use according to any one of claims 2 to 5, characterized in that the cutaneous signs of aging are chosen from a loss of firmness, a loss of elasticity, a loss of skin tone, an alteration of the surface appearance of the skin, an appearance of a marked microrelief of the skin, an appearance of roughness, a formation and / or a presence of fine lines and / or wrinkles, an alteration of the radiance of the skin complexion, a papery appearance of the skin, a wilting of the skin.

8. Cosmetic use according to any one of claims 2 to 5, characterized in that the cutaneous signs of aging are chosen from an alteration of the surface appearance of the skin, an appearance of a marked microrelief of the skin, an appearance of roughness, a formation and / or a presence of fine lines and / or wrinkles, an alteration of the radiance of the complexion of the skin.

9. Cosmetic composition for skin care, preferably for scalp skin care, comprising in a physiologically acceptable medium: i. at least one pyrimidine 3-oxide derivative of formula (I), and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and their mixtures as defined according to any one of claims 1 to 4, and ii. at least one anti-aging active ingredient.

10. Cosmetic skin treatment process for preventing and / or treating the cutaneous signs of aging comprising at least one step of topical application to skin, in particular scalp skin, showing cutaneous signs of aging, of at least one compound of formula (I) and / or at least one of its salts, and / or at least one of its isomers, and / or at least one of its tautomers and / or at least one of its solvates, and their mixtures as defined according to any one of claims 1 to 4, or of a cosmetic composition comprising it or them in a physiologically acceptable medium.