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WO2025003211A1 - Utilisation d'au moins un dérivé de pyrimidine 3-oxide pour la prévention et/ou le traitement des signes du vieillissement de la peau - Google Patents

Utilisation d'au moins un dérivé de pyrimidine 3-oxide pour la prévention et/ou le traitement des signes du vieillissement de la peau Download PDF

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Publication number
WO2025003211A1
WO2025003211A1 PCT/EP2024/067933 EP2024067933W WO2025003211A1 WO 2025003211 A1 WO2025003211 A1 WO 2025003211A1 EP 2024067933 W EP2024067933 W EP 2024067933W WO 2025003211 A1 WO2025003211 A1 WO 2025003211A1
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Prior art keywords
skin
denotes
composition
signs
ageing
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Olivier PERIN
Kahina Abed
Yann Mahe
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LOreal SA
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LOreal SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations

Definitions

  • the present invention relates to the field of active agents used for preventing and/or treating the signs of skin ageing.
  • Human skin is constituted mainly of two main layers, which are the dermis and the epidermis that superficially covers the dermis.
  • 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.
  • 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.
  • 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.
  • the dermal-epidermal junction is a structure that conditions the surface state of the skin.
  • 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.
  • 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)).
  • 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)).
  • 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)).
  • dermatopontin DPN
  • DPN dermatopontin
  • Other important junctional proteins 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)).
  • COMP cartilage oligomeric matrix protein
  • thrombospondin 5 represents another protein present in the dermal-epidermal junction and interacts with collagens to reinforce the biomechanical properties thereof.
  • fibronectin 1 (FN1), another constituent extracellular matrix protein of the dermal-epidermal junction that interacts with collagens.
  • the object of the present invention is therefore to meet these needs.
  • 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).
  • COMP cartilage oligomeric matrix protein
  • FN fibronectin 1
  • 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)).
  • 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:
  • 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;
  • 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:
  • 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 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.
  • the present invention concerns the 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 active agent for preventing and/or treating the signs of skin ageing in subject with aged skin.
  • 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.
  • 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.
  • 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.
  • treating 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.
  • intended to be administered topically means application to the surface of the skin under consideration.
  • aged skin is intended to mean a skin presenting signs of skin ageing.
  • 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.
  • signals 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.
  • signals 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • anti-ageing active agent means an active agent having the effect of preventing and/or treating the abovementioned signs of skin ageing.
  • the pyrimidine 3-oxide derivative corresponds to the following 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.
  • isomers is understood to mean, equally, optical, geometric and tautomeric isomers.
  • solvent when the solvent is water, reference will be made to hydrates.
  • the non-salified product in monohydrate form will be used.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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,
  • the 2,4-diaminopyrimidine 3-N-oxide of formula (III) has in particular the INCI name diaminopyrimidine oxide.
  • the 2,4-diaminopyrimidine 3-N-oxide of formula (III) has in particular the trade name Aminexil®.
  • said compound of formula (III) can be synthesized according to the process described in EP0540629 in Example 1.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • physiologically acceptable medium means a medium that is compatible with the skin.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • composition according to the invention may therefore comprise water and/or any adjuvant normally used in the envisaged field of application.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition according to the invention is a water-in-oil (W/O) or oil-in-water (O/W) emulsion.
  • W/O water-in-oil
  • O/W oil-in-water
  • 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.
  • emulsifiers examples of emulsifiers that may be mentioned are non-ionic emulsifiers.
  • 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.
  • 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.
  • composition may optionally be rinsed off after having been applied to the skin.
  • 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.
  • 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.
  • 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
  • Example 1 Evaluation of the effect of 2,4-diaminopyrimidine 3-N-oxide monohydrate on ageing of the skin.
  • 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.
  • NHDF Human dermal fibroblasts
  • NHEK human epidermal keratinocytes
  • 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.
  • 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.
  • medium KSFM, 1.5 mM CaCh
  • 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.
  • 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)).
  • 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.
  • the NEBNext Ultra II directional RNA library prep library preparation kit for Illumina 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).
  • 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.
  • 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
  • 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 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.
  • 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
  • the above lotion was then applied to the skin of the scalp to promote improvement of the signs of skin ageing.

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Abstract

La présente invention concerne l'utilisation cosmétique, notamment non thérapeutique, d'au moins un dérivé de pyrimidine 3-oxyde de formule (I)-et/ou d'au moins un sel de celui-ci, et/ou d'au moins un isomère de celui-ci, et/ou d'au moins un tautomère de celui-ci et/ou d'au moins un solvate de celui-ci, et de mélanges de ceux-ci, en tant qu'agent actif pour prévenir et/ou traiter les signes du vieillissement de la peau, tels que les signes du vieillissement du cuir chevelu.
PCT/EP2024/067933 2023-06-30 2024-06-26 Utilisation d'au moins un dérivé de pyrimidine 3-oxide pour la prévention et/ou le traitement des signes du vieillissement de la peau Pending WO2025003211A1 (fr)

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FR2307010A FR3150431A1 (fr) 2023-06-30 2023-06-30 Utilisation d’au moins un dérivé de pyrimidine 3-oxyde pour prévenir et/ou traiter les signes cutanés du vieillissement
FRFR2307010 2023-06-30

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WO1996009048A1 (fr) * 1994-09-19 1996-03-28 L'oreal Utilisation du 2,4-diamino pyrimidine 3-oxyde ou de l'un de ses sels dans le traitement des desordres de la maturation et de la structuration du collagene
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JPS62145007A (ja) * 1985-12-18 1987-06-29 Kanebo Ltd 皮膚老化防止用化粧料
EP0540629A1 (fr) 1990-07-20 1993-05-12 Oreal Utilisation de derives de pyrimidine 3-oxyde pour freiner la chute des cheveux et compositions topiques mises en oeuvre.
EP0540629B1 (fr) 1990-07-20 1994-05-04 L'oreal Utilisation de derives de pyrimidine 3-oxyde pour freiner la chute des cheveux et compositions topiques mises en oeuvre
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EP1475376A1 (fr) * 2003-05-06 2004-11-10 L'oreal Composition capillaire contenant un dérivé de pyrimidine N-oxyde, son utilisation pour stimuler la pousse des fibres kératiniques et/ou freiner leur chute
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