FR2946347A1 - New 2-fluoro-2-(tetrahydro-pyran-2-yl)-malonic acid compounds are glucose transporter 1 inducers, useful to fight against the signs of skin aging and/or appendage, prevent wrinkles and fine lines and reduce and/or prevent hair loss - Google Patents

Abstract

2-Fluoro-2-(tetrahydro-pyran-2-yl)-malonic acid compounds (I) and their organic salts and/or minerals, or their solvates, are new. 2-Fluoro-2-(tetrahydro-pyran-2-yl)-malonic acid compounds of formula (I) and their organic salts and/or minerals, or their solvates are new. R1a : H (preferred) or optionally saturated 2-18C acyl. [Image] ACTIVITY : Dermatological; Endocrine-Gen.; Keratolytic. MECHANISM OF ACTION : Glucose transporter 1 inducer.

Description

The invention relates to novel compounds inducing the expression of GLUT-1, as well as to their use in a composition, in particular for reducing and / or delaying the signs of aging of the skin and / or its appendages, while especially the hair. The invention also relates to a composition comprising at least one of said compounds, as well as a cosmetic treatment method for reducing and / or delaying the signs of aging of the skin and / or its appendices.

The present invention relates to the field of aging and signs associated with it, on the skin and / or its annexes. It relates in particular to the modulation of the equilibrium between the proliferation and the differentiation of the epidermal cells and the improvement of the signs related to the phenomenon of thinning of the epidermis due to a decrease in the number of keratinocytes in the proliferation phase.

Women - and men - tend to want to look young for as long as possible and therefore seek to reduce the marks of aging skin, which result in particular in wrinkles and fine lines, a thinning of the epidermis and / or a soft and withered skin appearance. In this regard, advertising and fashion mention products intended to keep as long as possible a glowing skin without wrinkles, marks of a young skin, especially as the physical aspect acts on the psyche and / or on morale.

The skin consists of two compartments, one superficial, the epidermis, and the other deeper, the dermis, which interact. The natural human epidermis is composed mainly of three types of cells which are the keratinocytes, a very large majority, melanocytes, and Langerhans cells. Each of these cell types contributes, by its own functions, to the essential role played in the body by the skin, in particular the role of protecting the body from external aggressions called barrier function.

The epidermis is conventionally divided into a basal layer of keratinocytes constituting the germinal layer of the epidermis, a so-called spinous layer consisting of several layers of polyhedral cells arranged on the germinal layers, one to three so-called granular layers consisting of flattened cells containing distinct cytoplasmic inclusions, the grains of keratohyalin, and finally the stratum corneum, consisting of a set of layers of keratinocytes at the end stage of their differentiation and called corneocytes. Corneocytes are anucleate cells consisting primarily of a fibrous material containing cytokeratins, surrounded by a horny envelope.

The dermis provides the epidermis with a solid support. It is also its nurturing element. It consists mainly of fibroblasts and an extracellular matrix mainly composed of collagen, elastin and a substance called the fundamental substance. These components are synthesized by fibroblasts. There are also leucocytes, mast cells or tissue macrophages. Finally, the dermis is crossed by blood vessels and nerve fibers. The cohesion between the epidermis and the dermis is ensured by the dermal-epidermal junction.

There is constantly in the epidermis production of new keratinocytes to compensate for the continuous loss of epidermal cells in the stratum corneum. However, during aging, it is possible to physiologically observe a decrease in the number of cells in the proliferation phase, and consequently a decrease in the living epidermal layers. By limiting and / or delaying the passage of the cells in the differentiation phase, the pool of young cells is maintained.

It is therefore important to preserve this pool of proliferative cells, avoiding or delaying their differentiation, in order to help delay the appearance of signs of aging.

Retinoids, and especially retinol, are thus conventionally used to combat the signs of aging and promote epidermal renewal.

Glucose transport in most mammalian cells is regulated by a family of membrane proteins called glucose transporters, also known as GLUT. At least 13 proteins are encoded by a family of related genes, these proteins having different transmembrane domains.

The expression of the different isoforms of GLUT varies according to the tissue and the hormonal and environmental conditions.

Keratinocytes express at least 4 types of glucose transporters, GLUT-1, 2, 3 and 5. In the prior art, a number of applications are described with GLUT inducers. Thus, US 2003/0187036 proposes the use of biguanide derivatives to promote the healing of cutaneous lesions such as ulcers occurring in diabetics, or other wounds. US 2005/0037440 relates to the identification of mammalian longevity factors, and the role of the cJUN factor and the modulation of the JNK signal. He suggests using agents that reduce the activity of an indicator such as DAF-14, superoxide dismutase, GLUT-1 or GLUT-4 to fight the signs of aging caused mainly by oxidative stress. DE 10259966 discloses cosmetic or pharmaceutical compositions containing amino acids of mycosporin type and improving the uptake of oxygen; these compounds induce in particular a reduction in the expression of GLUT-1. The compositions may in particular be applied for the treatment of aging of the skin. FR2901133 discloses the use in a composition containing a physiologically acceptable medium of at least one epidermal glycolysis inducing compound (excluding IGF-1) as an agent for decreasing and / or delaying the signs of aging of the skin and / or its annexes. Advantageously, the glycolysis inducing compound is an activator of glucose transporter peptides (GLUT). However, there is still a need to find new useful anti-aging agents.

This is why the present invention firstly relates to a compound corresponding to formula (I): R 'O ("OR' OR '(I) in which R' represents: - a hydrogen atom, or - a group linear or branched, saturated or unsaturated acyl having from 2 to 18 carbon atoms.

The present invention also covers the physiologically acceptable solvates of this compound, its physiologically acceptable organic and / or inorganic salts, as well as the physiologically acceptable solvates of these salts.

The patent application EP1466590 describes derivatives related to those disclosed by the present application, compositions containing them and adapted for topical application to the skin and / or the scalp, and a cosmetic treatment method involving these compositions. The quality of the compounds mainly highlighted in this application is their quality of desquamating agents.

Unexpectedly, it has been found in the context of the invention that the compounds of formula (I) limit the differentiation of epidermal cells by induction of the expression of GLUT-1 (active glucose transporter). A basal pool of keratinocytes at the stage of proliferation is thus maintained. The activity of glucose transporters, in particular GLUT-1, varies according to the state of proliferation / differentiation of keratinocytes. They are thus involved in epidermal homeostasis. The modification of their activity, in particular by the compounds of the present invention, can therefore influence the control of the balance proliferation / differentiation during aging.

According to the present invention, the term acyl refers to an alkyl radical bound to the remainder of the compound by a ketone function (C = O). According to the present invention, the term alkyl denotes a linear saturated hydrocarbon radical having more particularly from 1 to 17, preferably 1 to 10, carbon atoms or branched having more particularly from 3 to 17, preferably 3 to 10, carbon atoms. or a linear unsaturated hydrocarbon radical having more particularly from 2 to 17, preferably 2 to 10, carbon atoms or branched, more particularly having from 3 to 17, preferably 3 to 10, carbon atoms. Among the saturated alkyl radicals, mention may especially be made of the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, neopentyl, n-hexyl, n-heptyl and octyl radicals. Radicals having 1 to 7 carbon atoms are particularly preferred. The methyl and ethyl groups are very particularly preferred. Among the unsaturated alkyl radicals, there may be mentioned ethylenic radicals, such as, for example, vinyl and 1,1-dimethylallyl radicals.

The organic and / or inorganic salts of the compounds of formula (I) may be chosen from metal salts, for example aluminum (A13 +), zinc (Zn2 +), manganese (Mn2 +) or copper (Cu2 +), alkaline salts, for example lithium (Li +), sodium (Na +) or potassium (K +), or alkaline earth, for example calcium (Ca2 +) or magnesium (Mg2 +). It may also be ammonium derivatives of formula NH4 + or organic salts such as ammoniums of formula NHX3 +, NX3 denoting an organic amine, the radicals X being identical or different, two or three radicals X may form two by two a ring with the nitrogen atom which carries them or NX3 can designate an aromatic amine. The organic amines are, for example, alkylamines, for example methylamine, dimethylamine, trimethylamine, triethylamine or ethylamine, or hydroxyalkylamines, for example 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, or cycloalkylamines, such as for example bicyclohexylamine or glucamine, piperidine, or pyridines and the like, for example collidine, quinine or quinoline, or amino acids of basic character such as lysine or arginine.

In the case where the compounds according to the invention are in salt form, the cations are of course in an amount ensuring the electroneutrality of the compounds of formula (I). The inorganic salts of the compounds of formula (I) according to the invention may advantageously be chosen from the Cui +, Mn 'and Zn2 + metal salts, the alkaline salts Li +, Na + and K + and the alkaline earth salts Cal + and Mg2 +. According to another variant, the organic salts of the compounds of formula (I) according to the invention may advantageously be chosen from ammoniums, preferably from basic amino acid salts, for example lysine or arginine or from the diethanolamine or triethanolamine salts.

The acceptable solvates of the compounds of formula (I) according to the invention and / or of their salts include conventional solvates such as those formed during the last step of preparation of said compounds, because of the presence of solvents. By way of examples, mention may be made of solvates due to the presence of water or of linear or branched alcohols, preferably having from 1 to 4 carbon atoms, such as ethanol or isopropanol.

The compounds of formula (I), their salts and their solvates according to the invention may have an anomeric bond (substitution at the 6-position of glucose), either of the α or P-type. A preferred form of the invention concerns the compounds of formula (I), their salts and their solvates according to the invention which have an anomeric bond of type R.

According to a preferred form of the invention, in the formula (I) above, R 'represents a hydrogen atom or an acyl group having from 2 to 7, preferably 2 to 5, carbon atoms. A still more preferred form of the invention relates to the compounds of formula (I), their salts and their solvates, such that R 'represents a hydrogen atom or a saturated acyl group having from 2 to 5 carbon atoms, in particular a hydrogen atom or an acetyl group.

According to a preferred form of the invention, in the formula (I) above, at least one of, and advantageously all the following conditions are combined: - R 'represents a hydrogen atom, - the compound is in acid form, or in the form of Na + sodium salt. A preferred form of the invention thus relates to the compounds according to formula (I) advantageously chosen from: 2-fluoro 2 - [(2R, 3R, 4S, 5S, 6R) 3,4,5-trihydroxy-6- (Hydroxymethyl) tetrahydro-2H-pyran-2-yl] malonic acid, called Compound 1 in the present invention, 2-fluoro 2 - [(2R, 3R, 4S, 5S, 6R) 3,4,5-trihydroxy-6- (OH) Na + O / O-Na + OH-OH OH (called hydroxymethyl) tetrahydro-2H-pyran-2-yl] malonate, called compound 2 in the present invention, and their solvates.

Another subject of the present invention relates to a composition comprising, preferably in a physiologically acceptable medium, at least one compound of formula (I), a salt thereof and / or one of their solvates according to the invention as described herein. -above.

The compounds of formula (I), their salts and / or their solvates according to the invention therefore have properties of inducers of the expression of GLUT-1. They are particularly useful as agents for combating the signs of aging, in particular chronobiological aging, of the skin and / or its appendages.

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By skin, is meant in this text the skin, mucous membranes and / or the scalp. By appendices of the skin is meant in particular the superficies, that is to say the hair, eyelashes, hair and / or nails.

The present invention also relates to the use of at least one compound of formula (I), a salt thereof or a solvate thereof, for the preparation of a composition intended to combat the signs of aging, in particular aging chronobiological, skin and / or its annexes. It also relates to the use of at least one compound of formula (I) as defined above in a cosmetic composition comprising a physiologically acceptable medium, as an agent for combating the signs of aging of the skin and / or its annexes.

The present invention also relates to the use of a compound or a composition according to the invention for combating the signs of aging, in particular chronobiological aging, of the skin and / or its appendages.

The compounds or compositions according to the invention are especially intended for the correction of all disorders of re-epithelialization of the skin and / or its annexes.

The compounds or compositions according to the invention are particularly suitable for combating the signs of chronobiological aging of the epidermis. During chronobiological aging, the thickness of the epidermis is reduced, cell divisions decreasing in number. By facilitating cell multiplication, especially epidermal cells, regeneration is facilitated and the skin looks younger.

The compounds or compositions according to the invention are especially intended to prevent or reduce wrinkles and fine lines, and / or thinning of the skin and / or the appearance of soft and / or withered skin. The present invention thus also relates to the use of at least one compound according to the invention in a cosmetic composition for preventing or reducing wrinkles and fine lines, and / or thinning of the skin and / or skin appearance. soft and / or withered.

According to another aspect of the invention, the compounds or compositions according to the invention are intended to combat the signs of aging of the integuments. The compounds or compositions according to the invention can thus be used to reduce and / or prevent hair loss, and / or to prevent the heterogeneity of the capillary diameter. The present invention thus also relates to the use of at least one compound according to the invention in a cosmetic composition to prevent hair loss, and / or to prevent the heterogeneity of the capillary diameter. Said compounds or compositions are especially intended for the treatment or prevention of alopecia. Indeed, by promoting, at the level of the hair follicle, the maintenance of keratinocytes in proliferation phase, we contribute to the formation of a hair shaft and its renewal. During the course of alopecia, the aging of the whole epithelial structure of the hair follicle is observed, with in particular a decrease of the growth and the diameter of the hair shaft, that it is directly related to a functional alteration of the renewal of the epithelial cells related to the aging of the structure, or indirectly to a lack of oxygenation or nutrition, or to a degradation of the functionality of the connective structures supporting the organ.

According to another aspect of the invention, the compounds or compositions according to the invention are used to combat cutaneous dehydration and / or dryness of the epidermis. The compounds according to the invention are used as moisturizing agents, in compositions designed to promote the synthesis of NMF (natural moisturizing factor), a constituent element of the barrier function and the hydration of the epidermis. This synthesis is favored through the production of lactate, which is a major constituent of the NMF.

Skin dryness can be related to aging skin, and be one of the signs. However, the compounds or compositions according to the invention are also useful for combating the dry conditions constituting the skin, which may exist physiologically in a subject, regardless of his age. The present invention thus also relates to the use of at least one compound according to the invention in a cosmetic composition for combating cutaneous dehydration and / or dryness of the epidermis.

According to another embodiment, the compounds or compositions according to the invention are intended to treat disorders related to abnormal differentiation of the epidermis, such as hyperkeratosis. Said compounds or compositions may also be intended to treat disorders related to abnormal differentiation of the epidermis, such as hyperkeratosis. The present invention thus also relates to the use of at least one compound according to the invention in a cosmetic composition for treating disorders related to abnormal differentiation of the epidermis.

The compositions according to the invention may be cosmetic or pharmaceutical compositions, in particular dermatological compositions.

By physiologically acceptable medium is meant a medium compatible with the human body and in particular the skin and / or its annexes. It is in particular a cosmetically or pharmaceutically acceptable medium.

The amount of compound according to the invention in the compositions depends on the desired effect and will be adapted by those skilled in the art to obtain a stimulation of the proliferation or a decrease in the differentiation of keratinocytes. By way of example, the amount of compound according to the invention may vary from 0.0001% to 10%, and preferably from 0.001% to 5%, by weight relative to the total weight of the composition.

The composition according to the invention may be administered orally and / or in particular topically to the skin and / or its appendices.

For oral administration, the composition according to the invention may be in any suitable form, particularly in the form of an oral solution, a tablet, a capsule, a capsule or a nutritional food or nutritional supplement. The composition further comprises at least one suitable excipient suitable for oral administration.

For administration by topical application to the skin and / or its annexes, the composition according to the invention comprises a cosmetically acceptable support and may be in any galenical form normally used for topical application, especially in the form of an aqueous solution. , hydroalcoholic or oily, an oil-in-water or water-in-oil or multiple emulsion, an aqueous or oily gel, a liquid anhydrous product, pasty or solid, a suspension or a dispersion, for example an oil dispersion in an aqueous phase using spherules, these spherules may be polymeric nanoparticles such as nanospheres and nanocapsules or, better, lipid vesicles of ionic and / or nonionic type . This composition may be more or less fluid and have the appearance of a white or colored cream, an ointment, a milk, a lotion, a serum, a paste, a mousse . It can optionally be applied to the skin in the form of an aerosol. It can also be in solid form, and for example in the form of a stick. It can be used as a care product, as a cleaning product, or as a make-up product.

In known manner, the composition according to the invention may contain the usual adjuvants in the cosmetic and dermatological fields, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, perfumes, fillers. , filters, pigments, chelating agents, odor absorbers and dyestuffs. The amounts of these various adjuvants are those conventionally used in the fields under consideration, for example from 0.01% to 20% of the total weight of the composition. These adjuvants, depending on their nature, can be introduced into the fatty phase, into the aqueous phase, into the lipid vesicles and / or into the nanoparticles. When the composition according to the invention is an emulsion, the proportion of the fatty phase can range from 5% to 80% by weight, preferably from 5% to 50%, of the total weight of the composition. The oils, emulsifiers and coemulsifiers used in the composition in emulsion form are chosen from those conventionally used in the field under consideration. The emulsifier and the coemulsifier are present in the composition in a proportion ranging from 0.3% to 30% by weight, preferably from 0.5% to 20%, of the total weight of the composition. As oils that may be used in the compositions according to the invention, mention may be made of mineral oils, oils of vegetable origin (apricot oil, sunflower oil), oils of animal origin, synthetic oils and silicone oils. and fluorinated oils (perfluoropolyethers). It is also possible to use fatty alcohols (cetyl alcohol), fatty acids and waxes (beeswax) as fatty substances. As emulsifiers and coemulsifiers that may be used in the compositions according to the invention, mention may be made, for example, of fatty acid and polyethylene glycol esters such as PEG-40 stearate, PEG-100 stearate and fatty acid esters. and polyol such as glyceryl stearate and sorbitan tristearate. As hydrophilic gelling agents, mention may in particular be made of carboxyvinyl polymers (carbomer), acrylic copolymers such as copolymers of acrylates / alkylacrylates, polyacrylamides, polysaccharides, natural gums and clays, and, as lipophilic gelling agents, it is possible to mention mention modified clays such as bentones, metal salts of fatty acids, hydrophobic silica and polyethylenes.

According to an advantageous embodiment, the compositions according to the invention contain at least one other active agent chosen from UV screening agents, moisturizing agents, depigmenting agents, anti-glycation agents, NO synthase inhibitors, synthesis of dermal or epidermal macromolecules and / or preventing their degradation, agents stimulating the proliferation of fibroblasts and / or keratinocytes, muscle-relaxing or dermo-decontracting agents, tensing agents, anti-pollution or anti-radical agents, agents anti-hair loss, soothing agents, desquamating agents and active cells on energy metabolism of cells. The amount of these additional active agents can vary to a large extent and is for example 10-6 to 20% by weight, in particular from 0.001% to 10%, relative to the total weight of the composition. The agents stimulating proliferation of fibroblasts that can be used in the composition according to the invention may for example be chosen from plant proteins or polypeptides, extracted especially from soybeans (for example a soybean extract marketed by LSN under the name Eleseryl SH-VEG). 8 or marketed by SILAB under the trade name Raffermine), and plant hormones such as giberrellins and cytokinins.

The agents stimulating the proliferation of keratinocytes that can be used in the composition according to the invention include retinoids such as retinol and its esters, including retinyl palmitate, adenosine, cinnamic acid and its derivatives, lycopene and its derivatives. , phloroglucinol, walnut cake extracts marketed by Gattefosse, and extracts of Solanum tuberosum marketed by Sederma, certain monosaccharides such as rhamnose, mannose and galactose. By desquamating agent is meant any compound capable of acting: either directly on the desquamation by promoting exfoliation, such as the β-hydroxy acids, in particular salicylic acid and its derivatives (including n-octanoyl 5 -salicylic); α-hydroxy acids, such as glycolic, citric, lactic, tartaric, malic and mandelic acids; urea; gentisic acid; oligofucoses; cinnamic acid; Saphora japonica extract; resveratrol; or on the enzymes involved in desquamation or degradation of corneodesmosomes, glycosidases, stratum corneum chymotryptic enzyme (SCCE), or even other proteases (trypsin, chymotrypsin-like). Mention may be made of chelating agents for mineral salts: EDTA; N-acyl-N, N ', N', ethylene diaminetriacetic acid; aminosulfonic compounds and in particular (N-2-hydroxyethylpiperazine-N-2-ethane) sulfonic acid (HEPES); 2-oxothiazolidine-4-carboxylic acid derivatives (procysteine); glycine-type alpha amino acid derivatives (as described in EP-0 852 949, as well as methylglycine sodium diacetate marketed by BASF under the trade name TRILON M); honey ; sugar derivatives such as O-octanoyl-6-D-maltose and N-acetyl glucosamine.

Other desquamating agents that can be used in the composition according to the invention include oligofructoses, extracts of Laminaria algae, O-linoleyl-6D-glucose, (3-hydroxy-2-pentylcyclopentyl) acetic acid, trilactate and the like. glycerol, (S) carboxymethylcysteine, silicon derivatives of salicylate as in patent EP 0 796 861, salts of 5-acyl salicylic acid, active agents having effects on transglutaminase as in patent EP 0 899 330, jasmonic acid and its derivatives as in patent applications EP 1 333 022 and EP 1 333 021, Exfolactive Silab (ficus opuntia indica flower extract), Soypon O Kawaken fine chemicals (sodium cocoyl sarcosinate).

The present invention finally relates to a method of cosmetic treatment of the skin and / or its appendices for combating the signs of aging of the skin and / or its appendages, characterized in that it comprises the administration of a cosmetic composition comprising at least one compound of formula (I) as defined above, or a salt or solvate thereof. The administration can be carried out for example orally or topically.

The compounds of formula (I) according to the invention may be synthesized by treating the compounds of formula (II) with a basic aqueous solution, for example sodium hydroxide. In this case, the products are obtained in the form of sodium salts from which it is easy for one skilled in the art to obtain the compounds of formula (I) in their acid form. H + OO-Na + / OO-Na + FII O OR NaOH / H2O R'O (I)

The synthesis of the compounds of formula (II) is described in the patent application FR2899464 of L'Oréal as well as in a publication by M.A. Gonzales et al. (Carbohydrate Res 1986, 158, p53-66).

Other features and advantages of the invention will appear on reading the examples which follow. In these examples, reference will be made to the figures described below. In the present application, the percentages are by weight unless otherwise stated.

DESCRIPTION OF THE FIGURES

Figure 1: Fluorescence immunodetection of the GLUT-1 transporter on the cell wall of cultured keratinocytes (pink fluorescence). The presence of the compound according to the invention significantly increases the immunofluorescence, which indicates a significantly greater expression of GLUT-1 type glucose transporters.

FIG. 2: Western blot immunodetection of the presence of the GLUT-1 protein in keratinocyte extracts in culture in the presence of the compound according to the invention; the intensity of the black band shows that the expression of GLUT-1 is greater than that obtained under the control conditions.

EXAMPLES Example 1: Activity test

Description of the biological model: - Cell type: normal human epidermal keratinocytes (NHEK) K074, used at the third passage 20 - Culture conditions: 37 ° C, 5% CO2 - Culture medium: Keratinocyte-SFM (Invitrogen 17005-034) supplemented with Epidermal Growth Factor (EGF) 0.25 ng / mL, pituitary extract (PE) 25 g / mL (Invitrogen 3700015), Gentamycin 25 g / mL (Sigma G1397). Test medium: Keratinocyte-SFM (Invitrogen 17005-034) supplemented with Gentamycin 25 g / ml (Sigma G1397).

Description of the test: The keratinocytes were seeded in two series of high-density 96-well plates (confluent cells, in differentiation). After 24 hours of incubation, the culture medium was removed and replaced with test medium or non-test medium (control) test compounds or references and the cells were incubated for 48h. All the experimental conditions were realized in n = 3. After treatment, the culture medium was removed and the cells were rinsed and then fixed with a solution of PBS containing 4% paraformaldehyde for 30 minutes at room temperature. After removing the fixing solution and rinsing the cells, the cells were permeabilized for 10 minutes at room temperature using a solution of PBS containing 0.1% Triton X-100. After removal of the permeabilization solution, non-specific binding sites were saturated by incubation for 30 minutes at room temperature in PBS / Tween / milk buffer. After washing, the GLUT-1 glucose transporters were localized using anti-GLUT-1 antibodies (rabbit polyclonal antibody, AbCam 15309), for 1 h at room temperature.

The anti-GLUT-1 antibody was then revealed using a rabbit anti-immunoglobulin conjugate (GAR-alexa 568, invitrogen A11011). Images were acquired using the InCell AnalyzerTm 1000 (GE Healthcare). Controls without primary antibody (secondary antibody alone) were performed to adjust the acquisition parameters of the camera. For each well, 5 captures of digitized images were made.

Test Results: Treatment Concentration Mean esm n% p Control Control 53177 1688 12 100 - 30000 cells / well - (differentiating cells) Control 83208 1620 6 156 p <0.001 cells / well - (cells in the process of proliferation) Retinoic acid 10-7 M 64329 1075 3 121 p <0.01 CaCl 2 1.5 mM 36968 4832 3 70 p <0.01 Reference: Metformin 0.4 mM 61417 4160 3 115 p> 0.05 2 mM 82195 6591 3 155 p <o, ol 2-fluoro 2- 0.08 mil 49762 2616 3 94 p> 0.05 [(2R, 3R, 4S, 5S, 6R) 3,4,5-trihydroxy-6- (hydroxymethyl) sodium tetrahydro 211-pyran-2-yl] sodium malonate .mu..sub.2 O.sub.2 O.sub.2 O.sub.4 OH.sub.2 O.sub.4 OH.sub.4 In the presence of a compound according to the invention Detection in immunofluorescence of the expression of GLUT-1: Keratinocytes were cultured in monolayer in the presence of a compound chosen from compounds 1 and 2 according to the invention (acid 2-fluoro 2 - [(2R, 3R, 4S, 5S, 6R) 3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro 2H-pyran-2-yl] malonic acid and sodium 2-fluoro 2 - [(2R, 3R, 4S, 5S, 6R) 3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl] malonate) at concentrations of 0.5 mM and 1 mM respectively. The results are shown in Figure 1 in the appendix. The compound according to the invention increases the glucose transport in keratinocytes. This increase is related to an increase in the expression of GLUT-1. The presence of the compound according to the invention significantly increases immunofluorescence, indicating a significantly greater expression of GLUT-1 type glucose transporters.

Western blot analysis of the expression of GLUTs in keratinocytes in culture: The keratinocytes are cultured according to the protocol described in Example 1. The proliferating keratinocytes are removed at 1 day of autocrine culture; the differentiating keratinocytes are removed at 6 days of autocrine culture. The keratinocytes are lysed in triton buffer (20 mM Hepes, pH 7.6, 20 mM NaF, 30 mM KCl, 1 mM EDTA, protease inhibitors and phosphatases, 1% triton). Proteins (15 g / lane) are separated by SDS-10 gel and transferred to PVDF membrane. The saturation of the sites is carried out for 1 hour in TBS / 0.1% Tween / 5% milk. The primary antibody is incubated for 1 hour in the saturation buffer (Anti-Glucose Transporter-1, Human (rabbit) Calbiochem, ref 400060, 1/1000). The secondary antibody is incubated for 1 h (anti-rabbit / peroxidase antibody Sigma A-0545, 1/20000) in 0.1% TBS / Tween. The revelation is carried out using the ECL kit (Roche). The results are shown in Figure 2 in the appendix. The intensity of the black band shows that the expression of GLUT-1 is greater than that obtained under the control conditions.

Example 3 Synthesis of the compounds according to the invention

The compounds whose synthesis is described below were analyzed by NMR and mass spectrometry, the spectra obtained are consistent with those expected for the compounds.

Synthesis of compound 1: 2-fluoro 2 - [(2R, 3R, 4S, 5S, 6R) 3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-ylmalonic acid In a 250 ml monocolumn are introduced 5 g of glucose, solubilized in 56 ml of water. 4.33 g of 1,3-dimethylbarbituric acid are introduced and placed under stirring.

NaHCO3 is added until pH = 7. After neutralization, the flask is equipped with a refrigerant and the reaction medium is heated at T = 80 ° C. for 5 hours. The reaction is monitored by TLC in eluent CH2Cl2 (1) / MeOH (1). The reaction medium is concentrated on a rotary evaporator and then taken up in water before being reprecipitated in acetone. The precipitate (powder) takes on a white / beige color. After one night in the desiccator, 9.3 g of product are obtained, ie a yield of 98%. 2 g of the product obtained above are introduced into a 100 ml monocol and solubilized in 30 ml of anhydrous DMF. The flask is placed under nitrogen circulation, with stirring, and is cooled to 0 ° C. by means of an ice bath (probably exothermic reaction). The selectfluor is then added. The solution becomes clear after 2/3 minutes. The reaction is monitored by TLC in eluent (CH 2 Cl 2 (8) / MeOH (2)). The reaction medium is left stirring and at ambient temperature overnight. 20 ml of water are added to neutralize excess Sélectfluor. The reaction medium is then evaporated at the paddle pump and a sintered silica partition is carried out in the eluent (CH 2 Cl 2 (9) / MeOH (1) at Rf = 0.57). 1.77 g of product are recovered, ie a molar yield of 83%. 890 mg of product obtained previously are introduced into a 100 ml flask and solubilized in water. 5.3 ml of 1 M sodium hydroxide solution is then carefully added to the syringe. Stirring is maintained at ambient temperature until the starting material disappears (approximately 45 minutes). Then the mixture is acidified with 1M HCl to pH = 1, and is concentrated in vacuo until the reaction crude is in a minimum of water. The product is then obtained by precipitation by adding acetone. 960 mg of the product are obtained in the presence of urea (molar purity = 73% (NMR)).

Synthesis of the compound 2: 2-fluoro 2 - [(2R, 3R, 4S, 5S, 6R) 3,4,5-trihydroxy 6-25 (hydroxymethyl) tetrahydro 2H-pyran 2-ylmalonate sodium In a 250 ml monocolumn 5 g of Glucose are introduced, solubilized in 56 ml of water. 4.33 g of 1,3-dimethylbarbituric acid are introduced and placed under stirring. NaHCO3 is added until pH = 7. After neutralization, the flask is equipped with a refrigerant and the reaction medium is heated at T = 80 ° C. for 5 hours. The reaction is monitored by TLC in eluent CH2Cl2 (1) / MeOH (1). The reaction medium is concentrated on a rotary evaporator and then taken up in water before being reprecipitated in acetone. The precipitate (powder) takes on a white / beige color. After one night in a desiccator, 9.3 g of product are obtained, ie a molar yield of 98%.

2 g of the product obtained above are introduced into a 100 ml monocol and solubilized in 30 ml of anhydrous DMF. The flask is placed under nitrogen circulation, with stirring, and is cooled to 0 ° C. by means of an ice bath (probably exothermic reaction). The selectfluor is then added. The solution becomes clear after 2/3 minutes. The reaction is monitored by TLC in eluent (CH 2 Cl 2 (8) / MeOH (2)). The reaction medium is left stirring at room temperature overnight. 20 ml of water are added to neutralize excess Sélectfluor. The reaction medium is then evaporated at the paddle pump and a sintered silica partition is carried out in the eluent (CH 2 Cl 2 (9) / MeOH (1) at Rf = 0.57). 1.77 g of product are recovered, ie a molar yield of 83%.

The product obtained above is introduced into a monocol and solubilized in water. A 1M sodium hydroxide solution is added carefully to the syringe to the reaction medium. Stirring is maintained at ambient temperature until the starting material disappears (approximately 45 minutes). The reaction medium is evaporated to the maximum without going to dryness. The sodium salt is precipitated by addition of ethanol and acetone. The precipitate is filtered and washed with acetone and then with diethyl ether. The monitoring is performed by reverse phase TLC (MeOH (8) / water (2)). The molar yield is 90%.

EXAMPLE 4 Compositions According to the Invention (% by Weight): Compound 1 or 2 of Example 3 0.005% Glycerol Stearate 2% Polysorbate 60 (ICI Tween 60) 1% Stearic Acid 1.4% Triethanolamine 0.7 % Carbomer 0.4% - An oil-in-water emulsion facial cream is prepared comprising 30 Liquid fraction of shea butter 12% Perhydrosqualene 12% Antioxidant qs Perfume, preservative qs Water qs 100%

An anti-aging gel for the skin comprising (% by weight) is prepared: Compound 1 or 2 of Example 3 2% Hydroxypropylcellulose (Klucel H from Hercules) 1% Antioxidant qs Perfume, preservative qs Isopropanol 40% Water qs 100 %

Claims (15)

CLAIMS 1- A compound according to general formula (I): OR '(I) in which R' represents: - a hydrogen atom, or - a linear or branched, saturated or unsaturated acyl group having from 2 to 18 carbon atoms one of its organic and / or inorganic salts, or one of their physiologically acceptable solvates. 2- compound according to claim 1, wherein at least one of, and preferably all the following conditions are met: - R 'represents a hydrogen atom, - the compound is in acid form, or in salt form sodium Na +. 3. Compound according to one of the preceding claims, characterized in that it is selected from 2-fluoro 2 - [(2R, 3R, 4S, 5S, 6R) 3,4,5-trihydroxy-6- ( hydroxymethyl) tetrahydro-2H-pyran-2-yl] malonic acid, 2-fluoro 2 - [(2R, 3R, 4S, 5S, 6R) 3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl] sodium malonate, and their solvates. 4- Composition comprising in a physiologically acceptable medium at least one compound of formula (I) according to one of the preceding claims. 5. The composition as claimed in claim 4, for combating the signs of aging of the skin and / or its appendages. 6. Composition according to claim 4, for preventing or reducing wrinkles and fine lines, and / or thinning of the skin and / or soft and / or withered skin appearance. 7- The composition of claim 4 for reducing and / or preventing hair loss, and / or for preventing heterogeneity of the capillary diameter. 8- Composition according to claim 4, for combating cutaneous dehydration and / or dryness of the epidermis. 9- Composition according to claim 4 for treating disorders related to abnormal differentiation of the epidermis. 10- Composition according to one of claims 4 to 9, said composition being intended for topical application to the skin and / or its annexes. 11- Use of at least one compound of formula (I) according to any one of claims 1 to 3 in a cosmetic composition comprising a physiologically acceptable medium, as an agent for combating the signs of aging of the skin and / or its annexes. 12- Use according to claim 11 or 12, for preventing and / or reducing wrinkles and fine lines, and / or thinning of the skin and / or the appearance of soft and / or withered skin. 25 13- Use according to claim 11 or 12, for reducing and / or preventing hair loss, and / or for preventing heterogeneity of the capillary diameter. 14- Use according to claim 11 or 12 for combating cutaneous dehydration and / or dryness of the epidermis. 15. Cosmetic treatment method for combating the signs of aging of the skin and / or its appendages, comprising the administration of a cosmetics composition comprising at least one compound of formula (I) according to claim 1. at 3.