Use of at least one pyrimidine 3-oxide derivative for preventing and / or treating the signs of skin ageing

Abstract

The present invention relates to the cosmetic, in particular non-therapeutic, use of at least one pyrimidine 3-oxide derivative of formula (I) - and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, as an active agent for preventing and / or treating the signs of skin ageing, such as the signs of scalp ageing.

Description

[0001] Description

[0002] Use of at least one pyrimidine 3-oxide derivative for preventing and / or treating the signs of skin ageing

[0003] The present invention relates to the field of active agents used for preventing and / or treating the signs of skin ageing.

[0004] Human skin is constituted mainly of two main layers, which are the dermis and the epidermis that superficially covers the dermis.

[0005] The dermis provides the epidermis with a solid support. It is also its nourishing element. It is constituted mainly of fibroblasts and an extracellular matrix composed predominantly of collagen, elastin and a substance known as ground substance. These components are synthesized by the fibroblasts.

[0006] The human epidermis is mainly composed of three types of cells, keratinocytes, which form the vast majority, melanocytes and Langerhans cells. Each of these cell types contributes, by virtue of its intrinsic functions, toward the essential role played in the body by the skin.

[0007] The cohesion between the epidermis and the dermis is provided by the dermal-epidermal junction. This is a complex region about 100 nm thick, which comprises the basal pole of the basal keratinocytes, the epidermal membrane and the sub-basal zone of the superficial dermis.

[0008] The dermal-epidermal junction is a structure that conditions the surface state of the skin. Thus, a dermal-epidermal junction having integral anchoring structures is kept folded, thus making it possible to increase the area of the contact zone between the dermis and the epidermis, to promote exchanges of diffusible factors, in particular between these two tissues, to reinforce their cohesion and to improve the appearance of the epidermis.

[0009] In cases where the anchoring structures are detrimentally modified, in particular because of a deficiency in collagen synthesis and / or because of ageing, this causes a flattening of the dermal-epidermal junction. Exchanges are reduced, the two tissues are less joined together, the epidermis folds up and, since the skin is less firm and less tense, wrinkles appear.

[0010] With ageing, collagen thins and becomes disorganized, the renewal of skin cells is decreased, wrinkles appear on the surface of the skin, and the skin is less firm, more dull. Skin ageing is conditioned by genetic characteristics. Moreover, certain environmental factors such as smoking and especially exposure to sunlight accelerate it. The skin thus has a much older appearance on the areas exposed to sunlight, such as the back of the hands or the face. Thus, these other factors also have a negative impact on the natural collagen of the skin.

[0011] Consequently, given the important role of collagen in the integrity of the skin and in its resistance to external attacking factors of mechanical type, stimulation of the synthesis of these collagens appears to be an effective means for overcoming the signs of skin ageing.

[0012] To date, 20 types of collagen have been identified, and are noted from I to XX. Not all collagens are 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.

[0013] In the skin and the dermis, the collagens preferentially expressed are collagen I and, to a lesser extent, collagen III. Collagen I is the predominant fibrillar collagen of the human body, where it can total 80-90% of the total collagen of the skin (Reilly DM and Lozano J. Skin collagen through the life stages: importance for skin health and beauty. Plast Aesth Res (2021)) Collagen III is, in addition, another fibrillar collagen conventionally strongly expressed in the skin. Beyond its importance for the skin, it is also a key collagen for the formation of 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)).

[0014] Collagen XV, which is one of the collagens least expressed 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 the other fibrillary collagens, it acts as a connector for other fibrillary collagens from the extracellular matrix of the dermis to the basement membrane of the epidermis. This very particular function stabilizes the attachment and increases the resistance of the tissues to compressive and stretch forces (Bachinger HS et al. Comprehensive natural products II (2010)).

[0015] Collagen VI is also another collagen, which is non-fibrillar, 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)).

[0016] Other important junctional proteins (important because they interact with collagens to anchor them to the dermal-epidermal junction) are also known as dermatopontin (DPN), which is used to assemble collagen fibres together to strengthen connective tissues (Okamoto et al. Dermatopontin, a novel player in the biology of the extracellular matrix. Connect tissue Res (2006)) and to facilitate re-epithelialization and adhesion of keratinocytes during healing processes (Okamoto et al. Dermatopontin promotes epidermal keratinocyte adhesion via alpha3beta1 integrin and a proteoglycan receptor. Biochemistry (2010)).

[0017] COMP (cartilage oligomeric matrix protein) or thrombospondin 5 represents another protein present in the dermal-epidermal junction and interacts with collagens to reinforce the biomechanical properties thereof.

[0018] Finally, there is fibronectin 1 (FN1), another constituent extracellular matrix protein of the dermal-epidermal junction that interacts with collagens.

[0019] Thus, the induction of expression of fibrillar dermal collagens, junctional epidermal collagens and bridging proteins which assemble them plays a predominant role in the general physiology of the skin, particularly in the junction structures which ensure the strong and organized bond between the epidermis and the deeper fibrillar dermal structures at the dermal-epidermal junction (DEJ) responsible for firmer skin with fewer wrinkles.

[0020] The object of the present invention is therefore to meet these needs.

[0021] Surprisingly, the inventors have in fact demonstrated the particular properties of 2,4- diaminopyrimidine 3-N-oxide, which is a pyrimidine 3-oxide derivative, for modifying the abundance of production of a messenger RNA that is a precursor for the synthesis of fibrillar dermal collagens and epidermal matrix collagens, in particular COL1A1 , COL12A1 , COL10A1 , COL3A1 , COL14A1 , COL13A1 , COL5A2, COL6A6, COL1A1 , COL15A1 , COL1A2, COL3A1 , COL6A1 , COL6A2 and COL6A3, and also the bridging proteins that assemble them, such as COMP (cartilage oligomeric matrix protein) or thrombospondin 5, and fibronectin 1 (FN1).

[0022] All 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 a salt thereof and / or a solvate thereof, and / or an isomer thereof, and / or a tautomer thereof, or of a composition comprising it or them, for preventing and / or treating the signs of skin ageing.

[0023] 2,4-Diaminopyrimidine 3-N-oxide is known from patent EP 540629B1 as an active agent intended for the cosmetic treatment, by topical application, of hair loss. It has also already been demonstrated that 2,4-diaminopyrimidine 3-N-oxide monohydrate modulates dermal biomarkers via modulation of lysyl hydroxylase activities, suggesting a protective role against perifollicular fibrosis of the hair and collagen crosslinking (W096090048 and Mahe 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)).

[0024] However, to the knowledge of the inventors, it has never been described as an active agent making it possible to prevent and / or treat the signs of skin ageing, and even less as an active agent making it possible to induce collagen synthesis in the skin.

[0025] Thus, a first subject of the present invention is the cosmetic, in particular non-therapeutic, use of at least one pyrimidine 3-oxide derivative of formula (I): in which:

[0026] R1 denotes a methyl group or NHR4 in which R4 denotes a C1-C4 alkyl group or a hydrogen atom;

[0027] R2 denotes a methyl group or NHR4 in which R4 is as defined above; R2 may also denote methyl when R1 denotes methyl;

[0028] R3 denotes a hydrogen atom, a halogen atom or a nitro or amino group, or a C1-C4 alkyl group which may optionally bear: an OR5 group in which R5 denotes a C1-C4 alkyl group or a benzene ring optionally substituted with one or more C1-C4 alkoxy groups; a benzene ring optionally substituted with one or more C1-C4 alkoxy groups; and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, as an anti-ageing active agent.

[0029] A subject of the present invention is also the cosmetic, in particular non-therapeutic, use of at least one pyrimidine 3-oxide derivative of formula (I), or of a cosmetic composition comprising same: in which:

[0030] R1 denotes a methyl group or NHR4 in which R4 denotes a C1-C4 alkyl group or a hydrogen atom;

[0031] R2 denotes a methyl group or NHR4 in which R4 is as defined above; R2 may also denote methyl when R1 denotes methyl;

[0032] R3 denotes a hydrogen atom, a halogen atom or a nitro or amino group, or a Ci- 04 alkyl group which may optionally bear: an OR5 group in which R5 denotes a C1-C4 alkyl group or a benzene ring optionally substituted with one or more C1-C4 alkoxy groups; a benzene ring optionally substituted with one or more C1-C4 alkoxy groups; and / or at least one salt thereof, and / or at least one isomer thereof, and / or tautomers and / or at least one solvate thereof, and mixtures thereof, as an active agent for preventing and / or treating the signs of skin ageing, such as the signs of scalp ageing.

[0033] Preferably, the present invention concerns the cosmetic, in particular non-therapeutic, use of at least one pyrimidine 3-oxide derivative of formula (I): in which:

[0034] R1 denotes a methyl group or NHR4 in which R4 denotes a C1-C4 alkyl group or a hydrogen atom;

[0035] R2 denotes a methyl group or NHR4 in which R4 is as defined above; R2 may also denote methyl when R1 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 bear: an OR5 group in which R5 denotes a C1-C4 alkyl group or a benzene ring optionally substituted with one or more C1-C4 alkoxy groups; a benzene ring optionally substituted with one or more C1-C4 alkoxy groups; and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, as an active agent for preventing and / or treating the signs of skin ageing in subject with aged skin.

[0036] The present invention also relates to a cosmetic skin treatment process for preventing and / or treating the signs of skin ageing, comprising at least one step of topical application to skin, in particular scalp skin, exhibiting signs of skin ageing, of at least one compound of formula (I) and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, as defined above, or of a cosmetic composition comprising it or them in a physiologically acceptable medium.

[0037] The present invention also relates to a cosmetic composition for skin care comprising, in a physiologically acceptable medium: at least one pyrimidine 3-oxide derivative of formula (I), and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, as defined above, and at least one anti-ageing active agent.

[0038] Definitions

[0039] The term "skin" is understood to mean the whole of the skin of the human body, in particular the skin of the neckline, of the neck, of the arms and forearms, of the feet, the skin of the face (in particular of the forehead, nose, cheeks, lips, chin), and also the skin of the scalp, preferably the skin of the scalp.

[0040] According to the invention, the term “preventing” or “prevention” means 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 ageing.

[0041] The term “treating” or “treatment” means any action that aims to improve the comfort or the well-being of an individual; this term thus equally covers attenuating, relieving and curing. The term “intended to be administered topically” means application to the surface of the skin under consideration.

[0042] The term “aged skin” is intended to mean a skin presenting signs of skin ageing. Preferably, the term “aged skin” is intended to be different from a dry skin, a fragile skin, a weakened skin, a skin with an impaired skin barrier function or a damaged skin.

[0043] The term "signs of skin ageing" is intended to mean all the modifications of the external appearance of the skin due to ageing, whether the latter is of chronological and / or photoinduced origin. Preferably, "signs of skin ageing” is intended to be different from signs of a dry skin, signs of a fragile skin, signs of a weakened skin, sign of an impaired skin barrier function, or signs of a damaged skin.

[0044] A dry skin is very different from an aged skin, indeed, physiologically, dry skin is often associated with a decrease in skin hydration levels as well as a change in the maturation process of the stratum corneum. Sensorially, dry skin can be characterized by a feeling of tightness and / or tightness in the skin. Regardless of the cause, skin with dry skin can usually show the following signs: rough to the touch and scaly, as well as decreased suppleness and elasticity.

[0045] On the contrary, an aged skin is a skin presenting signs of skin ageing, in particular all the modifications of the external appearance of the skin due to ageing, whether the latter is of chronological and / or photoinduced origin, preferably chronological origin.

[0046] By way of example of these modifications considered in the invention, mention may be made of a thinned epidermis, wrinkles and fine lines, withered skin, and / or of tonicity of the skin, thinning of the dermis and / or the degradation of collagen fibres, which leads to the appearance of flaccid, wrinkled skin.

[0047] Preferably, the signs of skin ageing targeted by the invention are chosen from a thinning of the skin, a loss of firmness, a loss of density or a loss of tonicity of the skin, the formation and / or presence of fine lines and / or of wrinkles, a deterioration of the radiance of the skin complexion, a papery appearance of the skin, a sagging of the skin, or a withering of the skin.

[0048] More preferentially, the signs of skin ageing targeted by the invention are chosen from a loss of firmness, a loss of tonicity of the skin, the formation and / or presence of fine lines and / or of wrinkles, a deterioration of the radiance of the skin complexion, a papery appearance of the skin, a withering of the skin.

[0049] Even more preferably, the signs of skin ageing targeted by the invention are chosen from the formation and / or presence of fine lines and / or of wrinkles, a deterioration of the radiance of the skin complexion.

[0050] For the purposes of the present invention, the expression "anti-ageing active agent" means an active agent having the effect of preventing and / or treating the abovementioned signs of skin ageing.

[0051] Detailed description of the invention

[0052] Pyrimidine 3-oxide derivative of formula (I)

[0053] The pyrimidine 3-oxide derivative corresponds to the following formula (I): in which:

[0054] R1 denotes a methyl group or NHR4 in which R4 denotes a C1-C4 alkyl group or a hydrogen atom;

[0055] R2 denotes a methyl group or NHR4 in which R4 is as defined above; R2 may also denote methyl when R1 denotes methyl;

[0056] R3 denotes a hydrogen atom, a halogen atom or a nitro or amino group, or a C1-C4 alkyl group which may optionally bear: an OR5 group in which R5 denotes a C1-C4 alkyl group or a benzene ring optionally substituted with one or more C1-C4 alkoxy groups; a benzene ring optionally substituted with one or more C1-C4 alkoxy groups; and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof.

[0057] The term "isomers" is understood to mean, equally, optical, geometric and tautomeric isomers. Among the solvates, when the solvent is water, reference will be made to hydrates.

[0058] As hydrate, mention will be made in particular of the monohydrate.

[0059] Preferably, the non-salified product in monohydrate form will be used.

[0060] An alkyl group preferably denotes, in accordance with the invention, a methyl or ethyl group, the alkoxy group preferably denotes methoxy or ethoxy, and the halogen atoms preferably denote chlorine or bromine.

[0061] The preferred compounds which can be used according to the invention are the compounds of formula (I) in which R1 denotes amino, R2 denotes amino, R3 denotes hydrogen or else R1 denotes amino, R2 denotes amino and R3 denotes chlorine, and also the salts and / or solvates thereof, and a mixture thereof, more preferentially the compounds of formula (I) in which R1 denotes amino, R2 denotes amino, R3 denotes hydrogen, and also the salts and / or solvates thereof.

[0062] 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).

[0063] The reduction is carried out according to the conventional method described in the literature (D. J. 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:

[0064] Among the salts which can be used in the context of the invention, mention may be made in particular of the addition salts with an organic or inorganic acid, such as the salts of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, citric acid, benzoic acid, salicylic acid, glycolic acid, aceturic acid, succinic acid, nicotinic acid, tartaric acid, maleic acid, pamoic acid, methanesulfonic acid, picric acid, lactic acid, salts of amino acids and more particularly of N- acetylated amino acids such as aceturic acid. Preferably, use will be made of the 2,4-diaminopyrimidine 3-N-oxide of formula (III) and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof.

[0065] The 2,4-diaminopyrimidine 3-N-oxide of formula (III) has in particular the INCI name diaminopyrimidine oxide.

[0066] The 2,4-diaminopyrimidine 3-N-oxide of formula (III) has in particular the trade name Aminexil®.

[0067] Preferably, said compound of formula (III) can be synthesized according to the process described in EP0540629 in Example 1.

[0068] Preferably, said at least one pyrimidine 3-oxide derivative of formula (I) and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, is used as an active agent in an effective amount, that is to say in an amount that allows it to have the desired effect.

[0069] Said at least one pyrimidine 3-oxide derivative of formula (I) and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, can 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 preferentially from 0.05% to 10% by weight relative to the total weight of the composition, even better still in an amount ranging from 0.1% to 5% by weight relative to the total weight of the composition.

[0070] Composition

[0071] The present invention also relates to a cosmetic composition for caring for the skin, preferably for caring for the skin of the scalp, comprising, in a physiologically acceptable medium: at least one pyrimidine 3-oxide derivative of formula (I), and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, as defined above, and at least one anti-ageing active agent.

[0072] The compositions, in particular cosmetic compositions, which can be used in the context of the use or of the treatment process according to the invention comprise a physiologically acceptable medium.

[0073] The term “physiologically acceptable medium” means a medium that is compatible with the skin. According to one particular embodiment, the pH of the cosmetic composition is between 4 and 7.5, notably between 4.5 and 7, and in particular between 4.7 and 6.5.

[0074] 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 or 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.

[0075] Preferably, the composition according to the invention has a water content ranging from 20% to 95% by weight, more preferentially from 30% to 60% by weight and even better still from 40% to 50% by weight relative to the total weight of the composition.

[0076] 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 still from 45% to 55% by weight relative to the total weight of the composition. The support may be of diverse nature according to the type of composition considered.

[0077] The composition according to the invention may therefore comprise water and / or any adjuvant normally used in the envisaged field of application.

[0078] Mention may notably be made of C2-C10 carboxylic acid esters; carbon-based and / or silicone oils, of mineral, animal and / or plant origin; waxes, pigments, fillers, dyes, surfactants, emulsifiers, coemulsifiers; cosmetic or dermatological active agents other than the 2,4- diaminopyrimidine 3-N-oxide according to the invention, such as minoxidil, UV-screening agents, polymers, hydrophilic or lipophilic gelling agents, thickeners, preserving agents, fragrances, bactericides, odour absorbers and antioxidants.

[0079] These optional adjuvants may be present in the composition in a proportion of from 0.001 % to 80% by weight, preferably 0.01% to 40% by weight, better still from 0.1% to 20%, relative to the total weight of the composition. Depending on their nature, these adjuvants may be introduced into the fatty phase, into the aqueous phase and / or into the lipid vesicles.

[0080] Needless to say, a person skilled in the art will take care to select this or these optional additional ingredients and / or active agents, and / or the amount thereof, such that the advantageous properties of the compounds of formula (1) according to the invention are not, or are not substantially, adversely affected by the envisaged addition. The compositions according to the invention may be in any presentation form conventionally used for topical application and notably in the form of aqueous or aqueous-alcoholic solutions, oil-in-water (O / W), 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 possibly being lipid vesicles of ionic and / or non-ionic type (liposomes, niosomes or oleosomes). These compositions are prepared according to the usual methods.

[0081] Advantageously, the cosmetic compositions suitable for the implementation of the invention may be in the form of a suspension, a gel, an emulsion, a shampoo, a leave-on lotion or a foam.

[0082] The compositions may be in any form suitable for skin care, notably for the skin of the scalp, in particular in the form of a hair care lotion, for example for daily or twice-weekly application, a shampoo or a hair conditioner, in particular for weekly or twice-weekly application, a liquid or solid soap for cleansing the scalp, for daily application, a hairstyle shaping product (lacquer, styling gel), a treatment mask, a cream or a foaming gel for cleansing the hair. A composition according to the invention may comprise an oily phase.

[0083] The term “liquid fatty substance” means a compound with a melting point below approximately 30-35°C, such as oils, as opposed to solid fatty substances, such as waxes, which have a melting point above approximately 50°C.

[0084] As oils which may be used in the composition of the invention, mention may for example be made of: hydrocarbon-based oils of plant origin; synthetic esters and ethers, notably of fatty acids, for instance oils of formulae R’COOR2 and R’COR2 in which R’ represents a fatty acid residue including from 8 to 29 carbon atoms and R2 represents a branched or unbranched hydrocarbon-based chain containing from 3 to 30 carbon atoms; linear or branched hydrocarbons, of mineral or synthetic origin; fatty alcohols containing from 8 to 26 carbon atoms; fluoro oils which are partially hydrocarbon-based and / or silicone-based; silicone oils; mixtures thereof.

[0085] In the list of the abovementioned oils, the term "hydrocarbon-based oil" is understood to mean any oil predominantly comprising carbon and hydrogen atoms, and optionally ester, ether, fluoro, carboxylic acid and / or alcohol groups.

[0086] The other fatty substances that may be present in the oily phase are, for example, fatty acids including from 8 to 30 carbon atoms, waxes, silicone resins and silicone elastomers. These fatty substances may be chosen in a varied manner by a person in the art in order to prepare a composition having the desired properties, for example in terms of consistency or texture. 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, with respect to the total weight of the composition. The emulsions generally contain at least one emulsifier chosen from amphoteric, anionic, cationic and non-ionic emulsifiers, used alone or as a mixture, and optionally a coemulsifier. The emulsifiers are appropriately chosen according to the emulsion to be obtained (W / O or O / W). The emulsifier and the coemulsifier 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.

[0087] For the W / O emulsions, examples of emulsifiers that may be mentioned include dimethicone copolyols. A crosslinked elastomeric solid organopolysiloxane including at least one oxyalkylene group may also be used as W / O emulsion surfactant.

[0088] For the O / W emulsions, examples of emulsifiers that may be mentioned are non-ionic emulsifiers.

[0089] Said at least one pyrimidine 3-oxide derivative of formula (I), and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, or said composition comprising it or them, is used, in the context of the use or of the process according to the invention, topically.

[0090] The compositions according to the invention may be applied directly to the skin or, alternatively, to cosmetic supports of occlusive or non-occlusive type, intended to be applied locally to the skin.

[0091] The composition may optionally be rinsed off after having been applied to the skin.

[0092] According to a particular embodiment of the invention, other agents suitable for making the appearance of the skin, preferably of the scalp, more attractive and / or for improving the texture of the skin, preferably of the scalp, and / or agents intended for keratin fibres, preferably the hair, may also be added to the composition that is suitable for the invention.

[0093] Skin treatment process

[0094] The present invention also relates to a cosmetic skin treatment process for preventing and / or treating the signs of skin ageing, comprising at least one step of topical application to skin, in particular scalp skin, exhibiting signs of skin ageing, of at least one compound of formula (I) and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, as defined above, or of a cosmetic composition comprising it or them in a physiologically acceptable medium.

[0095] Throughout the description, including the claims, the expression “at least one” should be understood as being synonymous with “one or more”, unless otherwise specified. The expressions "more than", "between... and..." and "ranging from... to..." should be understood as being limits inclusive, unless otherwise specified.

[0096] The examples and figures that follow are presented as nonlimiting illustrations of the invention. The compounds are, depending on the case, cited as the chemical names or as the CTFA (International Cosmetic Ingredient Dictionary and Handbook) names.

[0097] The invention is illustrated in greater detail in the examples that follow.

[0098] Examples

[0099] Example 1 - Evaluation of the effect of 2,4-diaminopyrimidine 3-N-oxide monohydrate on ageing of the skin.

[0100] A) Materials and methods

[0101] Preparation of tested samples:

[0102] The stock solution of 100 mM 2,4-diaminopyrimidine 3-N-oxide monohydrate (14.41 mg / ml) in DMSO 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 carried out in PBS from the stock solution (10 pl stock solution of 2,4-diaminopyrimidine 3-N-oxide monohydrate + 0.99 ml PBS). From this dilution, a final concentration of 30 pM of 2,4-diaminopyrimidine 3-N-oxide monohydrate was obtained with 300 pl of the solution of 1000 pM + 0.7 ml PBS.

[0103] Biological samples:

[0104] Adult human dermal fibroblasts (NHDF) were inoculated into a 12-well plate and cultured in a culture medium (MEM, 10% FCS) for 24 hours. The culture medium was replaced with fresh culture medium for a further 24 hours. The culture medium was then replaced with medium (MEM, 2% FCS) for the next 24 h.

[0105] Adult human epidermal keratinocytes (NHEK) were inoculated 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.

[0106] Treatment:

[0107] The culture medium for the monolayer fibroblast cells was removed and replaced with medium (MEM, 2% FCS) containing either the DMSO solvent control or a final concentration of 2,4- diaminopyrimidine 3-N-oxide monohydrate of 30 pM. The cells were incubated for 24 hours.

[0108] The culture medium for the monolayer keratinocyte cells was removed and replaced with medium (KSFM, 1.5 mM CaCh) containing either the DMSO solvent control or a final concentration of 2,4-diaminopyrimidine 3-N-oxide monohydrate of 30 pM. The cells were incubated for 24 hours.

[0109] All the experimental conditions were performed in n = 3.

[0110] RNA extraction:

[0111] The samples were received frozen in dry ice and transmitted to the RT-qPCR platform for the steps of total RNA extraction and quality analysis.

[0112] The samples received are found in the form of lysates in buffer RLT+beta-mercaptoethanol for the NHK and NHF cells in monolayers. The samples were thawed. An additional volume of RLT+beta-mercaptoethanol was added to bring the volume to 600 pl. The continuation of the extraction protocol was carried out with the RNeasy micro kit (Qiagen, Germantown, MD, USA), while including a treatment with DNase 1 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)). The purified RNAs were eluted with 30-40 pl of RNase-free water and assayed in duplicate by spectrophotometry with the NanoDrop ND-1000 device (NanoDrop Technologies, Wilmington, DE, USA). An approximate amount of 5 ng of total RNA was used for verifying the integrity of the total RNA in a Bioanalyzer 2100 (Agilent Technologies, Santa Clara, CA, USA) with RNA 6000 Pico Kit (Agilent). The integrity value (INR), an indicator of RNA quality, ranged from 8.5 to 10 out of 10.

[0113] Library preparation and sequencing:

[0114] The NEBNext Ultra II directional RNA library prep library preparation kit for Illumina (New Englands Biolabs Inc., Ipswich, MA, USA) was used for the preparation of the RNA libraries, 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 the selection of the poly A+ mRNA using oligos dT attached to magnetic beads (NEBNext Poly(A), New Englands Biolabs Inc., Ipswich, MA, USA). The isolated mRNA was used as a template for the synthesis of cDNA by a reverse transcriptase with random primers. Strand specificity was obtained by replacing dTTP with dUTP. After purification with AxyPrep Mag PCR Clean-up kit beads (Axygen, Big Flats, N.Y., USA), this cDNA was converted into double-stranded DNA and the ends were repaired. After excision of the strands containing the dUTPs, a 13-cycle amplification was carried out in order to incorporate the specific indexed adaptors for multiplexing. The quality of the final libraries was verified using TapeStation 2200 (Agilent Technologies, Santa Clara, CA, USA) and the quantification was carried out on a QBit 3.0 fluorimeter (ThermoFisher Scientific, Canada). Subsequently, the mRNA-seq libraries each having 2 unique indexes were grouped, in an equimolar ratio, into 7 pools. Each pool was deposited on one lane of a high-performance S4 flow cell and sequenced on an Illumina NovaSeq 6000 system (Illumina Inc., San Diego, CA, USA). A paired sequencing of 100 bp was carried out. The average coverage / sample obtained was approximately 29M paired readings.

[0115] Bioinformatics analysis:

[0116] The reads were trimmed using the fastp v0.22.0 tool [1], The read quality controls were performed on both raw and trimmed reads using the FastQC vO.11.9 tool [2] and MultiQC v1.11 tool [3], The quantification step was carried out with Kallisto vO.46.1 [4] using as a basis the "coding protein" type transcripts based on the human transcriptome version GRCh38 of the Ensembl database (Release 104). (GRCh38 downloaded from Ensembl release 104). Principal component analyses (PCA) were performed with the FactoMineR v2.6 R package

[0117] [5], The PCA and Volcano Plot visualizations were produced with the R ggplot2 v3.4.0 package

[0118] [6], Differential expression analyses were conducted using the DESeq2 v1.34.0 package [7], All analyses with the R software were performed with version R v4.1.2 [8],

[0119] Literature

[0120] [1] Chen, S., Zhou, Y, Chen, Y, & Gu, J. (2018). Fastp: An ultra-fast all-in-one FASTQ preprocessor. Bioinformatics, 34(17), i884-i890.

[0121] [2] Andrews, Simon. "FastQC: A quality control tool for high throughput sequence data." (2010).

[0122] [3] Ewels, Philip, Mans Magnusson, Sverker Lundin, and Max Kaller. "MultiQC: summarize analysis results for multiple tools and samples in a single report." Bioinformatics 32, no. 19 (2016): 3047-3048.

[0123] [4] Bray, Nicolas L., Harold Pimentel, Pall Melsted, and Lior Pachter. "Near-optimal probabilistic RNA-seq quantification." Nature biotechnology 34, no. 5 (2016): 525.

[0124] [5] Le, S., Josse, J., & Husson, F. (2008). FactoMineR: an R package for multivariate analysis. Journal of statistical software, 25(1), 1-18.

[0125] [6] Wickham, H. (2011). ggplot2. Wiley Interdisciplinary Reviews: Computational Statistics, 3(2), 180-185.

[0126] [7] Love, Michael I., Wolfgang Huber, and Simon Anders. "Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2." Genome biology 15, no. 12 (2014): 550

[0127] [8] R: Team, R. Core. "R: A language and environment for statistical computing." (2013): 201.

[0128] B) Results Table 1 shows the epidermal matrix genes of which the expression is favourably modulated by the treatment of skin keratinocytes with the compound 2,4-diaminopyrimidine 3-N-oxide monohydrate. Table 1

[0129] Table 2 shows the fibrillar dermal collagen genes of which the expression is favourably modulated by the treatment of skin fibroblasts with the compound 2,4-diaminopyrimidine 3-N- oxide monohydrate.

[0130] Table 2

[0131] Conclusion: 2,4-diaminopyrimidine 3-N-oxide monohydrate significantly stimulates the expression of mRNA encoding the matrix epidermal collagen genes COL15A1 , COL1A2, COL3A1 , COL6A1 , COL6A2 and COL6A3, the fibrillar dermal collagen genes COL1A1 , COL12A1 , COL10A1 , COL3A1 , COL14A1 , COL13A1 , COL5A2, COL6A6 and COL1A1 , and also the COMP, DPT and FN1 genes encoding the bridging proteins, thus demonstrating a favourable effect of this compound on the induction of the expression of the junctional epidermal and fibrillar dermal collagens and of the bridging proteins which assemble them, thus making it possible to reinforce the strong and organized bond between the epidermis and the fibrillar dermal structures at the dermal-epidermal junction (DEJ) responsible for firmer skin with fewer wrinkles.

[0132] Example 2 - Cosmetic composition - Scalp lotion

[0133] The following composition was prepared:

[0134] Table 3

[0135] The above lotion was then applied to the skin of the scalp to promote improvement of the signs of skin ageing.

Claims

Claims1. Cosmetic, in particular non-therapeutic, use of at least one pyrimidine 3-oxide derivative of formula (I):in which:R1 denotes a methyl group or NHR4 in which R4 denotes a C1-C4 alkyl group or a hydrogen atom;R2 denotes a methyl group or NHR4 in which R4 is as defined above; R2 may also denote methyl when R1 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 bear: an OR5 group in which R5 denotes a C1-C4 alkyl group or a benzene ring optionally substituted with one or more C1-C4 alkoxy groups; a benzene ring optionally substituted with one or more C1-C4 alkoxy groups; and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, as an anti-ageing active agent.

2. Cosmetic, in particular non-therapeutic, use of at least one pyrimidine 3-oxide derivative of formula (I), or of a composition comprising same:in which:R1 denotes a methyl group or NHR4 in which R4 denotes a C1-C4 alkyl group or a hydrogen atom;R2 denotes a methyl group or NHR4 in which R4 is as defined above; R2 may also denote methyl when R1 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 bear: an OR5 group in which R5 denotes a C1-C4 alkyl group or a benzene ring optionally substituted with one or more C1-C4 alkoxy groups; a benzene ring optionally substituted with one or more C1-C4 alkoxy groups; and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, as an active agent for preventing and / or treating the signs of skin ageing.

3. Cosmetic use according to Claim 1 or 2, in which said pyrimidine 3-oxide derivative is 2,4-diaminopyrimidine 3-N-oxide of formula (III) below:salts thereof, isomers thereof, tautomers thereof, solvates thereof, and mixtures thereof.

4. Cosmetic use according to any one of the preceding claims, in which said pyrimidine 3-oxide derivative of formula (I), and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, 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 preferentially from 0.05% to 10% by weight relative to the total weight of the composition, even better still 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 salt thereof, and / or at least oneisomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, 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 signs of skin ageing are chosen from a thinning of the skin, a loss of firmness, a loss of density or a loss of tonicity of the skin, the formation and / or presence of fine lines and / or of wrinkles, a deterioration of the radiance of the skin complexion, a papery appearance of the skin, a sagging of the skin, or a withering of the skin.

7. Cosmetic use according to any one of Claims 2 to 5, characterized in that the signs of skin ageing are chosen from loss of firmness, loss of skin tone, the formation and / or the presence of fine lines and / or of wrinkles, a deterioration of the radiance of the skin complexion, a papery appearance of the skin, a withering of the skin.

8. Cosmetic use according to any one of Claims 2 to 5, characterized in that the signs of skin ageing are chosen from the formation and / or presence of fine lines and / or of wrinkles, a deterioration of the radiance of the skin complexion.

9. Cosmetic composition for caring for the skin, preferably for caring for the skin of the scalp, comprising, in a physiologically acceptable medium: at least one pyrimidine 3-oxide derivative of formula (I), and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, as defined according to any one of Claims 1 to 4, and at least one anti-ageing active agent.

10. Cosmetic skin treatment process for preventing and / or treating the signs of skin ageing, comprising at least one step of topical application to skin, in particular scalp skin, exhibiting signs of skin ageing, of at least one compound of formula (I) and / or at least one salt thereof, and / or at least one isomer thereof, and / or at least one tautomer thereof and / or at least one solvate thereof, and mixtures thereof, 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.

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