FR2913686A1 - NOVEL CARBAMATE COMPOUNDS OF VITAMIN C, COMPOSITIONS COMPRISING THE SAME, AND USES THEREOF - Google Patents

Abstract

The present invention relates to novel carbamate compounds of vitamin C, the cosmetic and pharmaceutical compositions comprising them, and their use for preventing and cosmetically treating the cutaneous signs of aging.

Description

The present invention relates to novel carbamate derivatives of vitamin

  C, the compositions including cosmetic including them, and their use to fight against skin aging.

  Women and men currently tend to want to appear young as long as possible and therefore seek to fade the marks of aging skin, which result in particular in the form of wrinkles and fine lines. 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. Up to now, wrinkles and fine lines have been treated with cosmetic products containing active agents acting on the skin, for example by improving its cell renewal or by promoting the synthesis or preventing the degradation of elastic fibers. which make up the cutaneous tissue.

  It is known that human skin consists of two superficial tissues, the epi-dermis, the other deep, the dermis. The natural human epidermis is composed mainly of three types of cells, which are the keratinocytes, the majority of which are melanocytes and Langerhans cells. Each of these cell types contributes, through its specific functions, to the essential role played in the body by the skin, in particular the protection role of the body against external aggressions (climate, ultraviolet rays, tobacco, etc.), called "barrier function".

  The dermis provides the epidermis with a solid support. It is also its nurturing element. It consists mainly of fibroblasts and an extra-cellular matrix composed mainly of collagen, elastin and a substance called the fundamental substance. These components are synthesized by fibroblasts. There are also leucocytes, mast cells or even tissue acacrophages. 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. It is a complex region with a thickness of approximately 100 nm which includes the basal pole of the basal keratinocytes, the epidermal membrane and the sub-basal area of the superficial dermis. From a structural point of view, hemidesmosomes, into which keratin filaments (hemismosome-tonofilament complex) are inserted, are distributed on the plasma membrane of basal keratinocytes. With regard to these hemide-tonofilament complexes, there are anchoring filaments which cross the epidermal basal membrane. The anchoring filaments are bonded to laminin on the epidermal side. Finally, anchoring fibrils constitute the sub-basal network. These are curvilinear structures which originate and terminate on the deep surface of the basement membrane and in which are engaged collagen fibers I, III and V. It has been shown that these anchoring fibrils, perfectly visualizable by electron microscopy, are composed of collagen type VII (hereinafter collagen VII). Collagen VII is synthesized by keratinocytes and fibroblasts but more importantly by keratinocytes (Aumailley et al., Laminins of the Dermal Epidermal Junction, Matrix Biology, 1999, 18, 19-28, Nievers et al., Biology and function of hemidesmosomes, Matrix Biology, 1999, 18, 5-17). Collagens are the major proteins of extracellular matrices. To date, 20 types of collagens are identified and noted from I to XX. In the skin, the collagens mainly present in the whole dermis are the type I and III collagens that form the extracellular matrix of the entire dermis (these are those collagens which constitute 70-80% of the dry weight of the dermis) . Collagens are a family of great diversity; indeed, each type of collagen, and the chains that constitute it, is derived from different genes. For example, type I collagens are composed of two chains COL1A1 and COLIA2 whose genes are located respectively on chromosomes 17q and 7q. Type VII collagen is composed of a single chain and its gene is located on chromosome 3p. Moreover, not all collagens are synthesized by the same cell types, type I and III collagens are essentially produced by the dermal fibroblast whereas type VII collagen is produced by the epidermal keratinocyte. Finally, the regulation of their expression differs from one collagen to another, for example, collagens I and VII are not regulated in the same way by certain cytokines; in fact, TNF alpha and leukoregulin stimulate collagen VII and negatively regulate collagen I.

  The cohesion between the two tissues, epidermis and dermis, is essential for the integrity of the skin as a whole and allows resistance to mechanical external aggression (friction, blows, etc.). The dermal-epidermal junction (DEJ) is also a structure that conditions the surface condition of the skin. Thus, a dermal-epidermal junction presaging intact anchoring structures is maintained folded, thus making it possible to increase the surface area of the contact zone between the dermis and the epidermis, to promote exchanges between these two tissues, to reinforce their cohesion and to improve the appearance of the epidermis. In cases where the anchoring structures are altered (deficiency of collagen VII synthesis, aging, etc.), this causes a flattening of the dermo-epidermal junction. The exchanges are lessened, the two tissues are less supportive, the epidermis creases 40 and the skin being less firm and less tight, wrinkles appear and the fragility of the skin to mechanical aggression is increased. The main role of JDE is thus to ensure a good adhesion between the dermis and the epidermis, but it also has significant biological functions because it constitutes a zone of exchanges between these two compartments (transmission of various signals and nutrients). As a result, this junction plays a significant role in maintaining the firmness and thickness of the skin to combat wrinkles and sagging tissue. During aging, especially at the level of the JDE, there is therefore a flattening and a gradual loss of undulations (deletion of the dermal papillae). The expression of collagen Vil declines, especially at the bottom of wrinkles. This loss of collagen VII is accelerated on a photo-damaged skin and can induce a "sliding" of the different layers of the skin. There is also a decrease in IV collagen content from age 35 which is inversely proportional to the increase in basement membrane thickness. Communication and nutrient exchanges between the dermis and dermis are also reduced, altering cutaneous homeostasis and the mechanical properties of the skin.

  It is known, in particular by EP1334714 ;, that vitamin C can be used, in particular in cosmetics, to increase the synthesis of collagen VII and / or to reinforce the cohesion of the dermal-epidermal junction. Vitamin C is a great cosmetic reference to fight against skin aging. However, the bioavailability of vitamin C can become problematic. In addition, this molecule may have stability problems: under the action of light, heat and even in the presence of water, vitamin C can decompose in a few days and take an orange color. It is possible to stabilize it, for example by combining it with stabilizers, such as certain polymers; this does not prevent the formation of orange coloration.

  There remains therefore the need for new compounds likely to find an interesting application in the prevention and / or treatment, including topically, the signs of skin aging, whether chrobiobiological or photoinduced.

  The Applicant has surprisingly demonstrated that certain derivative carbamates of L-ascorbic acid (or vitamin C) could make it possible to increase the synthesis of collagen VII, and have a beneficial effect on the structure of the dermal junction. Epidermal, especially on the cohesion between dermis and epidermis. These novel compounds therefore find particular application in cosmetic or pharmaceutical compositions, in particular dermatological compositions, intended to prevent and / or cosmetically treat cutaneous aging; in particular to prevent and / or treat, especially topically, the cutaneous signs of aging, and particularly the cutaneous signs related to wrinkled skin, skin with an alteration of its viscoelastic or biomechanical properties, skin presenting an alteration in the cohesion of its tissues, thinned skin and / or skin with an alteration of its surface appearance.

  The compositions according to the invention may more particularly make it possible to maintain and / or restore the properties of extensibility, tonicity, firmness, flexibility, density and / or elasticity of the skin.

  By "biomechanical properties of the skin" is meant here the properties of extensibility, tonicity, firmness, suppleness and / or elasticity of the skin. By "cutaneous signs of aging" is meant here any modification of the external appearance of the skin due to aging, be it chronobiological or extrinsic, in particular photoinduced or hormonal; Among these signs, we can distinguish: - It wrinkled skin, which is reflected in particular by the appearance of wrinkles and / or fine lines, - the skin with an alteration of its viscoelastic or biomé-conical properties, or skin with a lack of elasticity and / or extensibility and / or firmness and / or flexibility and / or tonicity, which results in particular in skin withered, soft, slackened or sagging, the skin exhibiting an alteration of the cohesion of its tissues; - Thinner skin, - the skin having an alteration of its surface appearance, which results in particular in an alteration of the grain of the skin, for example a roughness.

  The subject of the present invention is therefore new carbamate compounds of vitamin C, of formula as defined below.

  The invention also relates to a cosmetic or pharmaceutical composition comprising, in a physiologically acceptable medium, at least one such compound.

  The compounds according to the invention advantageously have an increased stability and bioavailability compared with vitamin C.

  The compounds according to the invention therefore correspond to the following formula (I): embedded image in which R represents: a linear C 1 -C 10 alkyl radical, optionally substituted by a phenyl group, C3-C10 cyclic alkyl radical, optionally substituted by a phenyl group; - a branched C3-C10 alkyl radical, optionally substituted with a phenyl group, or - a radical -CHRI-000R2 in which: R1 represents H or a C1-C6 linear, C3-C6 or branched C3-C6 alkyl radical, said radical possibly being (i) substituted by at least one group selected from = NH, -NH2, -NHR ', -NR'2 , = O, -OH, -OR ', - SH, -SR', COOR ', phenyl, phenyl substituted with OH or OR', and also: ~ r- N ~~ / NH COR '--COR' and / or (ii) interrupted by a group -NH-, -N (COR ') - or -S-; with R '= C1-C6 linear, C3-C6 cyclic, or branched C3-C6 alkyl radical; R2 represents a C1-C6 linear, C3-C6 or branched C3-C6 alkyl radical; as well as their salts and their optical isomers.

  The term alkyl, in the context of the present invention, means a saturated or unsaturated hydrocarbon chain. Among the alkyl groups which are suitable for the implementation of the invention, mention may especially be made of methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, isobutyl, sec-butyl, pentyl and hexyl groups. heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

  Preferably R is: -. a linear C1-C8, in particular C2-C6, alkyl radical optionally substituted by a phenyl group, a C3-C6 cyclic alkyl radical, optionally substituted by a phenyl group, a branched C3-C6 alkyl radical; optionally substituted with a phenyl group, or - a radical -CHR1-COOR2.

  Preferably, R1 represents H or a C1-C4 linear or C3-C4 branched alkyl radical, optionally substituted by a phenyl group, phenyl substituted with OH, SH, SR ', OH, = O, NH2 or COOR'. .

  Preferably, R 'represents a linear C1-C4 alkyl radical, in particular methyl or ethyl. Preferably, R2 represents a linear C1-C4 alkyl radical, in particular methyl or ethyl.

  In another preferred embodiment, R1 represents the residue of an amino acid of formula NH2-CHRI-000H, in particular of an amino acid chosen by-mi: L-Alanine L-Arginine OH L-Asparagine L-aspartic acid H2 H2N; O! -1 Glycine L-Glutamic Acid L-Glutamine 0 L-Lysine L-Leucine L-Histidine OH H2N

  0 L-Isoleucine L-Methionine O L-Valine L-Serine L-Phenylalanine O 112N L-Threonine L-Tryptophan L-Tyrosine More particularly, the amino acid may be phenylalanine, so R1 may represent -CH2-phenyl.

  Even more preferably, the compounds of formula (I) may be chosen from those for which R represents: a linear C 2 -C 6 alkyl radical, optionally substituted with a phenyl group, a C 3 -C 6 cyclic alkyl radical, a radical -CHR1-0OOR2 in which: R1 represents H or a C1-C4 linear alkyl radical, optionally substituted by a phenyl group, phenyl substituted by OH, NH2, = O, OH, SH, SR 'or COOR' with R; '= methyl or ethyl; and R2 represents a methyl or ethyl radical.

  In particular, mention may be made of the following compounds: ## STR1 ## denomination -C 2 H 5 - - 5- (1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-di-fluoren-3-yl ethyl carbamate CHR1 COOR 2 - (C1-C2H) diethyl 2 - [({[5- (1,2-dihydroxyethyl) -4-hydroxyoxy-2-oxo-2,5-dihydro-4-yl] oxy} oxy} ca rbo) amino] pentanedioate CHRCOOR2 -CH3 -C2H5 ethyl 2 - [({[5- (1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran 3-yl] oxy} carbonyl) amino] propanoate CHRICOR2 -CH2CH2-SMe-C2H5 ethyl 2 - [({[5- (1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydro furan-3-yl] oxy} carbonyl) amino] -4- (methylsulfanyl) butanoate CHR1COOR2 _C2H5 ethyl [({[5- (1,2-dihydroxyethyl) -H4-hydroxy-2-oxo-2,5 CH 2 CH 2 Ph -5- (1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl (2-phenyl) -dihydro-furan-3-yl] oxy} carbonyl) amino] acetate Cyclohexyl carbamate - (5R) -5 - [(1S) -1,2-dihydroxyethyl] -4-hydroxy-2-oxo-2,5-dihydro furan-3-ylcyclohexylcarbamate CHR1 COOR2 -secButyl -C2H5 ethyl 2 - {[({(5R) -5 - [(1 S) -1,2-di Hydroxyethyl] -4-hydroxy-2-oxo-2,5-dihydro-4-yl} oxy) carbonyl] amino} -4-methyl pentanoate CHR1COOR2 -CH2Ph-C2H5 ethyl 2- { [({(5R) -5 - [(1S) -1,2-dihydroxyethyl] -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl} oxy) car-bonyl] amino} -3- phenyl propanoate C6H13 - - (5R) -5 - [(1S) -1,2-dihydroxyethyl] -4-hydroxy-2-oxo-2,5-dihydro furan-3-yl hexylcarbamate The compounds of Formula (I) may also be in the form of salts or optical isomers. As salts of the compounds of formula (I), mention may be made of salts of mineral acids, such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, boric; as well as salts of organic acids, such as propionic acid, acetic acid, succinic acid, fumaric acid, lactic acid, glycolic acid, citric acid and tartaric acid .

  The compounds of formula (I) can be prepared according to scheme 1 below: ## STR1 ## based on reaction of vitamin C with an isocyanate of formula RNCO, especially at a temperature between 15 and 50 C, preferably at 20-25 C, in an aprotic polar solvent such as DMSO, DMF, pyridine and preferably dioxane; preferably in the presence of an organic base (for example triethylamine) or mineral (for example NaOH), for 1 to 18 hours. The reaction can be stopped by adding a protic solvent (for example water and / or ethanol) and then concentrated under reduced pressure. The residue can then be taken up in water and washed with an organic solvent (for example ethyl acetate). The aqueous phase may be treated with an acidic resin (eg Amberlyst 15) until an acidic pH is obtained. The resin can then be filtered and the aqueous phase concentrated under reduced pressure. The residue can be purified on silica gel.

  The compounds of formula (I) may also be prepared according to Scheme II below: ## STR1 ## Compound (I) HO by neutralization of vitamin C 5,6-isopropylidene in an aprotic polar solvent such as DMSO, DMF, pyridine and preferably dioxane; with an organic base (for example triethylamine) or a mineral base (for example NaOH). An isocyanate of formula RNCO can then be added, and the reaction medium is reacted at a temperature of between 25 and 70 ° C. for 1 to 18 hours. The reaction can then be concentrated under reduced pressure, the residue taken up in a concentrated hydrochloric acid solution and stirred for 1 to 4 hours. Finally, it is possible to concentrate under reduced pressure and purify for example on silica gel, so as to obtain the desired product.

  The compounds according to the invention find a very particular application in the cosmetic or pharmaceutical field, in particular dermatological, They may be present, alone or as a mixture, in cosmetic or pharmaceutical compositions, in an amount which may be between 0.01 and 10% by weight, preferably between 0.1 to 5% by weight, in particular between 0.5 and 3% by weight, relative to the total weight of the composition, The composition further comprises a physiologically acceptable medium, which will be preferably a medium that is cosmetically or pharmaceutically, in particular dermatologically acceptable, that is to say without odor, color or unpleasant appearance, and that does not generate tingling, tightness or redness that is unacceptable to the user. topical application to the skin Physiologically acceptable medium includes a medium compatible with the keratinous substances of human beings human, such as body skin or skin, lips, mucous membranes, eyelashes, nails, scalp and / or hair.

  The composition according to the invention can then comprise all the adjuvants 15 usually employed in the intended field of application. We can notably mention water; organic solvents, especially C1-C6 alcohols and C2-C10 carboxylic acid esters; carbonaceous and / or silicone oils, of mineral, animal and / or vegetable origin; waxes, pigments, fillers, dyes, surfactants, emulsifiers, co-emulsifiers; cosmetic or dermatological active agents, UV filters, polymers, hydrophilic or lipophilic gelling agents, thickeners, preservatives, perfumes, bactericides, odor absorbers, antioxidants. These optional adjuvants may be present in the composition in a proportion of 0.001 to 80% by weight, especially 0.1 to 40% by weight, relative to the total weight of the composition. These adjuvants, depending on their nature, can be introduced into the fatty phase or into the aqueous phase of the composition, or into lipid vesicles. In any case, these adjuvants, as well as their proportions, will be chosen by those skilled in the art in such a way that the advantageous properties of the compounds according to the invention are not, or not substantially, impaired by the addition envisaged. .

  As oils which can be used in the invention, mention may be made of mineral oils (liquid petroleum jelly), oils of vegetable origin (avocado oil, soya oil), oils of animal origin (lanolin), oils synthetic (perhydrosqualene), silicone oils (cyclomethicone) and fluorinated oils (perfluoropolyethers). Fatty alcohols (al-cool cetyl), fatty acids, waxes (carnauba wax, ozokerite) can also be used as fats. Examples of emulsifiers and co-emulsifiers which may be used in the invention include, for example, polyethylene glycol fatty acid esters such as PEG-100 stearate, and fatty acid and glycerin esters such as glyceryl stearate.

  As hydrophilic gelling agents or thickeners, mention may be made of carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate / alkylacrylate copolymers, polyacrylamides, polysaccharides, natural gums and clays; lipophilic gelling agents or thickeners include modified clays such as bentones, metal salts of fatty acids, and hydrophobic silica.

  As active agents, it will be advantageous to introduce into the composition used according to the invention at least one compound chosen from: desquamating agents; moisturizing agents; depigmenting or propigmenting agents; anti-glycation agents; NO-synthase inhibitors; agents stimulating the synthesis of dermal or epidermal macromolecules and / or preventing their degradation; agents stimulating the proliferation of fibroblasts and / or keratinocytes or stimulating the differentiation of keratinocytes; muscle relaxants and / or dermo-decontracting agents; tensors; anti-pollution and / or anti-radical agents; agents acting on microcirculation; agents acting on the energetic metabolism of cells; and their mixtures. Examples of such additional compounds are: retinol and its derivatives such as retinyl palmitate; ascorbic acid and its derivatives such as magnesium ascorbyl phosphate and ascorbyl glucoside; tocopherol and its derivatives such as tocopheryl acetate; nicotinic acid and its precursors such as nicotinamicle; ubiquinone; glutathione and its precursors such as L-2-oxothiazolidine-4-carboxylic acid; plant extracts and especially vegetable proteins and their hydrolysates, as well as phytohormones; marine extracts such as seaweed extracts; bacterial extracts; sapogenins such as diosgenin and Wild Yam extracts containing it; ceramides; hydroxy acids such as salicylic acid and noctanoyl-5-salicylic acid; resveratrol; oligopeptides and pseudodipeptides and their acyl derivatives; manganese and magnesium salts, in particular gluconates; and their mixtures.

  As indicated above, the composition according to the invention may also contain UV filters or active photoprotective agents in the UVA and / or UVB, in the form of organic or inorganic compounds, the latter being optionally coated to make them hydrophobic. .

  The organic photoprotective agents may in particular be chosen from: anthranilates, in particular menthyl anthranilate; benzophenones, in particular benzophenone-1, benzophenone-3, benzophenone-5, benzophenone-6, benzophenone-8, benzophenone-9, benzophenone-12, and preferentially benzophenone-3 (oxybenzone), or Benzophenone-4 (Uvinul MS40 from BASF); benzylidenecamphers, in particular 3-benzylidenecamphor, benzylidenecamphosulfonic acid, camphor benzalkonium methosulphate, polyacrylamidomethylbenzylidene camphor, terephthalylidene di-camphorsulfonic acid, and preferentially 4-methylbenzylidene carnphre (Eusolex). 6300 from Merck); benzimidazoles, in particular benzimidazilate (Neo Heliopan AP from Haarmann and Reimer), or phenylbenzimidazole sulfonic acid (Eusolex 232 from Merck); benzotria-zoles, in particular trisiloxane drometzol, or methylenebisbenzotriazolyltetramethylbutylphenol (Ciba Tinosorb M); cinnamates, in particular cinoxate, DEA methoxycinnamate, diisopropyl methylcinnamate, dimethoxycinnamate glyceryl ethylhexanoate, isopropyl methoxycinnamate, isoamyl cinnamate, and preferably ethocrylene (Uvinul N35 from BASF), octylmethoxycinnamate (Hoffmann La Roche's Parsol MCX), or octocrylery (Uvinul 539 from BASF); dibenzoylmethanes, especially butyl methoxydibenzoylmethane (Parsol 1789); imidazolines, in particular ethylhexyl dimethoxybenzylidene dioxoimidazoline; PABAs, in particular ethyl dihydroxypropyl PABA, ethylhexyldimethyl PABA, glyceryl PABA, PABA, PEG-25 PABA, and preferentially diethylhexylbutamido-triazone (Uvasorb HEB 3V Sigma), ethylhexyltriazone (Uvinul T150 from BASF), or ethyl PABA (benzocaine); salicylates, especially dipropylene glycol salicylate, ethylhexyl salicylate, homosalate, or TEA salicylate; triazines, in particular anisotriazine (Tinosorb S from Ciba); drometrizole trisiloxane. The inorganic photoprotective agents are preferably made of zinc oxide and / or titanium dioxide, preferably of nanometric size, optionally coated with alumina and / or stearic acid.

  This composition may be in any galenical form normally used in the cosmetics or pharmaceutical field, and especially in the form of an aqueous or aqueous-alcoholic solution, optionally gelled, of an optionally biphasic lotion-type dispersion, of an emulsion obtained by dispersion of a fatty phase in an aqueous phase (O / W) or conversely (W / O), or a triple emulsion (W / O / W or W / O / H) or a vesicular dispersion of the type ionic and / or nonionic; aqueous or oily gel. These compositions are prepared according to the usual methods. It is preferred to use according to this invention a composition in the form of an emulsion, especially oil-in-water.

  The 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 gel , a foam. It can optionally be applied in the form of an aerosol. It can also be in solid form, in particular in the form of a stick. When the composition is an emulsion, the proportion of the fatty phase can range from 5 to 80% by weight, preferably from 8 to 50% by weight relative to the total weight of the composition. The emulsifier and the co-emulsifier may be present 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.

  The composition according to the invention may constitute a makeup composition, or preferentially skin care, and in particular a cream for cleaning, protecting, treating or caring for the face, for the hands, for the feet, for the skin. large anatomic or body folds (eg day creams, night creams, make-up removers, foundation creams, sunscreen creams); a fluid foundation, a make-up removal milk, a body care or protection milk, an anti-sun milk; a lotion, gel or mousse for the care of the skin, such as a cleaning lotion.

  The composition according to the invention is advantageously an anti-aging composition, in particular a care composition, intended to treat and / or fight, cosmetically, the external signs of cutaneous aging; the composition is more particularly a skincare composition for mature skin.

  The invention also relates to a process for the cosmetic treatment of keratin materials, comprising the application to said keratin materials of a cosmetic composition as defined above. This method finds an advantageous application in the treatment of the skin, in particular mature skin and / or wrinkled skin, in particular the face, in particular the forehead, the neck and / or the hands. The invention also relates to the cosmetic use of a composition as defined above, to improve the structure of the dermo-epidermal junction and / or to reinforce the cohesion between the dermis and the epidermis. The invention also relates to the use of a cosmetic composition as defined above, for preventing and / or cosmetically treating the cutaneous signs of aging, in particular the cutaneous signs chosen from the wrinkled skin, the skin having a deterioration of its viscoelastic or biomechanical properties, the skin having an alteration in the cohesion of its tissues, the thinned skin, and the skin having an alteration of its surface appearance.

  The invention is further illustrated by the following non-limiting examples. EXAMPLE 1 Synthesis of (5R) -5-F (IS) -1,2-dihydroxyethyll-4-hydroxy-2-oxo-2,5-dihydrofuran-3-ylethylcarbamate 1 g of vitamin C are neutralized 1 g of vitamin C are neutralized 5,6-isopropylidene with 191 mg of NaOH in 30 ml of dioxane. 0.372 ml of ethyl isocyanate is then added, and the medium is heated at 50 ° C. for 6 hours. The reaction is concentrated under reduced pressure and the residue is taken up in a concentrated hydrochloric acid solution and stirred for 2 hours. It is concentrated under reduced pressure and purified on silica gel. 300 mg of product (beige powder) is obtained, ie a yield of 26%. The mass and NMR spectra are in accordance with the expected structures.

  Example 2 Synthesis of diethyl (2S) -2- {f ({(5R) -5-1 '(1S) -1,2-dihydroxyethyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3 (1-yl) oxy) carbonylamino} pentane dioate 1 g of vitamin C 5,6-isopropylidene is neutralized with 191 mg of NaOH in 30 ml of dioxane. 1.09 g of (S) - (-) - isocyanoglutaric acid diethyl ester is then added and the medium is heated at 50 ° C. for 6 hours. The reaction is concentrated under reduced pressure and the residue is taken up in a concentrated hydrochloric acid solution and stirred for 2 hours. It is concentrated under reduced pressure and purified on silica gel. 360 mg of product (brown powder) is obtained, ie a yield of 20%. The mass and NMR spectra are consistent with the expected structures.

  Example 3 Synthesis of ethyl 2- {f ({(5R) -5-f (IS) -1,2-dihydroxyethyll-4-hydroxy-2-oxo-2,5-dihydrofuran-3-fenoxy) carbonyllam i no} propanoate HO HO -OC) neutralizes 1 g of vitamin C 5,6 isopropylidene with 191 mg of NaOH in 10 ml of dioxane. 0.62 ml of ethyl-2-isocyanatopropionate are then added, and the medium is heated at 50 ° C. for 4 hours. The reaction is concentrated under reduced pressure and the residue is taken up in a concentrated hydrochloric acid solution and stirred for 2 hours. It is concentrated under reduced pressure and purified on silica gel. 500 mg of product (yellow viscous oil) is obtained, ie a yield of 34%. The mass and NMR spectra are in accordance with the expected structures. EXAMPLE 4 Synthesis of 2- {f ({(5R) 5-r (IS) -1,2-dihydroxyethyll-4-hydroxy-2-oxo-2,5-dilhydrofuran-3-yl} oxyethyl ) carbonyllamino} -4- (methylsulfanyl) butanoate 1 g of vitamin C 5,6-isopropylidene is neutralized with 191 mg of NaOH in 25 ml of dioxane. 0.64 ml of ethyl-2-isocyanato-4- (methylthio) butyrate are then added, and the medium is heated at 50 ° C. for 10 hours. The reaction is concentrated under reduced pressure and the residue is taken up in a solution of concentrated hydrochloric acid and stirred for 2 hours. It is concentrated under reduced pressure and purified on silica gel. We obtain 200 mg of pro-duit (brown paste), a yield of 12%. The mass and NMR spectra are in accordance with the expected structures. Example 5 Synthesis of ethyl {(((5R) -5 - (1S) -1,2-dihydroxyethyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl} The reaction mixture is treated with 1 g of vitamin C 5,6-isopropylidene and 191 mg of NaOH in 30 ml of dioxane. 0.54 ml of ethyl isocyanatoacetate is then added, and the medium is heated at 50 ° C. for 7 hours. The reaction is concentrated under reduced pressure and the residue is taken up in a concentrated hydrochloric acid solution and stirred for 2 hours. It is concentrated under reduced pressure and purified on silica gel. 500 mg of product (brown paste) is obtained, ie a yield of 48%. The mass and NMR spectra are in accordance with the expected structures. Example 6 Synthesis of (5R) -5-f (1S) -1,2-dihydroxyethyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl (2-phenylethyl) carbamate 0.5 g of vitamin C 5,6-isopropylidene with 97 mg of NaOH in 15 ml of dioxane. 0.32 ml of 2-phenyl-ethyl isocyanate is then added, and the medium is heated at 50 ° C. for 18 hours. The reaction is concentrated under reduced pressure and the residue is taken up in a concentrated hydrochloric acid solution and stirred for 2 hours. Concentrate under reduced pressure and purify on silica gel. 250 mg of product (brown paste) is obtained, a yield of 53%. The mass and NMR spectra are in accordance with the expected structures.

Example 7 Synthesis of (5R) -5 - [(1S) -1,2-dihydroxyethyll-4-hydroxy-2-oxo-2,5-dihydrofuran-3-ylcyclohexylcarbamate 16 HO HO NH C) n made react 1 g of vitamin C and 0.74 ml of cyclohexyl isocyanate in 10 ml of dioxane in the presence of 1 ml of triethylamine, with stirring, at room temperature for 3 hours.

  The reaction is then stopped by adding water and then concentrated under vacuum. The residue is then taken up in water and washed with ethyl acetate. The aqueous phase is then treated with an acidic resin Amberlyst 15, until an acidic pH. The resin is then filtered and the aqueous phase concentrated in vacuo. The residue is purified on silica gel.

  1.35 g of product (gray wax) is obtained, ie a yield of 79%. The mass and NMR spectra are in accordance with the expected structures.

Example 8 Synthesis of ethyl 2- {f ({(5R) -5-f (1S) -1,2-dihydroxyethyll-4-hydoxy-2-oxo-2,5-dihydropyronitrile 3-yl) oxycarbonylamino} -4-methylpentanoate 1 g of vitamin C and 1.08 g of ethyl-2-isocyanato-4-methylvalerate are reacted in 10 ml of dioxane, in the presence of 1 ml of triethylamine, with stirring, at room temperature for 18 hours. The reaction is then stopped by adding water and then concentrated under vacuum. The residue is then taken up in water and washed with ethyl acetate. The aqueous phase is then treated with an acidic resin Amberlyst 15, until an acidic pH. The resin is then filtered and the aqueous phase concentrated in vacuo. The residue is purified on silica gel. 1.57 g of product (yellow liquid) is obtained, ie a yield of 77%. The mass and NMR spectra are in accordance with the expected structures.

  Example 9 Synthesis of ethyl 2- {f ({(5R) -5-f (IS) -1,2-dihydroxyethyll-4-17-hydroxy-2-oxo-2,5-dihydrofuran 3-yl} oxy) carbonylamino} -3-phenylpropanoate C) n is reacted with 1 g of vitamin C and 1.27 g of ethyl-2-isocyanato-3-phenylpropionate, in 10 ml of dioxane, in the presence of 1 ml of triethylamine, with stirring, at room temperature for 18 hours. The reaction is then stopped by adding water and then concentrated under vacuum. The residue is then taken up in water and washed with ethyl acetate. The aqueous phase is then treated with an acidic resin Amberlyst 15, until an acidic pH. The resin is then filtered and the aqueous phase concentrated in vacuo. The residue is purified on silica gel. 830 mg of product (yellow liquid) is obtained, ie a yield of 37%. The mass and NMR spectra are in accordance with the expected structures. Example 10 Synthesis of (5R) - 5-r (IS) -1,2-dihydroxyethyl-4-hydroxy-2-oxo-2,5-dihydrofuran-3-ylhexylcarbamate 1 g of vitamin C and 0.82 ml of hexyl isocyanate in 10 ml of dioxane in the presence of 1 ml of triethylamine, with stirring, at room temperature for 41 hours. The reaction is then stopped by adding water and then concentrated under vacuum. The residue is then taken up in water and washed with ethyl acetate. The aqueous phase is then treated with an acidic Amberlyst 15 resin until an acidic pH is obtained. The resin is then filtered and the aqueous phase concentrated in vacuo. The residue is purified on silica gel. 912 mg of product (gray wax) is obtained, ie a yield of 53%. The mass and NMR spectra are in accordance with the expected structures. EXAMPLE 11 Activation of the Collagen VII Synthesis Constituting the Dermo-Epidermal Junction

  The studies were performed on normal human dermal fibroblasts. The expression of collagen VII was analyzed at the transcriptional level by RTQ-PCR.

  1. Treatments of fibroblasts The fibroblasts were precultured in complete DMEM medium then placed in DMEM medium with 1% FCS. The cells were then treated, or not (control), with the compounds to be tested, and cultured for 24 hours at 37 ° C. and 5% CO 2. Each treatment was performed in triplicate. Culture supernatants were then removed and the cell mats were rinsed with PBS solution (Invitrogen 14190094) and then frozen at -80 ° C in the presence of 300 KI per well of Tri-Reagent (Sigma T9424).

  2. Primers used The expression of the selected markers was evaluated by RT-Q-PCR on the messenger RNAs extracted from the cell mats of each treatment. The couples of primers that were used in this study allow the amplification of the following specific fragment: Gene name: Alpha-1 type VII collagen (COL7A1) mRNA, complete cds. Abbreviation: COL7A1 GenBank n: NM 000094

  3. Reverse Transcription - Extraction of the total RNAs from each sample using Tri-Reagent according to the protocol recommended by the supplier. - Elimination of traces of potentially contaminating DNA by treatment with the DNA-free system (Ambion). - Realization of the reverse transcription reaction of the mRNA in the presence of the primer oligo (dT) and the enzyme Superscript II (Gibco). 4. Quantitative PCR PCR reactions (polymerase chain reactions) were performed by quantitative PCR with the Light Cycler system (Roche Molecular Systems Inc.) and according to the procedures recommended by the supplier. This analysis system makes it possible to carry out fast and efficient PCR reactions, with a prior development of the analysis conditions of the different primers. It consists of two main components: - a thermal cycler: optimized for extremely fast heat transfer. a fluorimeter: for continuously measuring the fluorescence intensity incorporated in the DNA (detection at 521 nm). The reaction mixture (10 KI final) for each sample is as follows: 2.5 KI cDNA diluted 1/10. - primers of the different markers used - Reaction mixture (Roche) containing the enzyme taq DNA polymerase, the SYBR Green I marker (fluorophore which is inserted in the double-stranded DNA, during the elongation step) and the MgCl2. 5. Q-PCR Analysis Fluorescence incorporation into the amplified DNA is measured continuously during PCR cycles. This system makes it possible to obtain fluorescence measurement curves as a function of PCR cycles and thus to evaluate a relative expression value for each marker. The number of cycles is determined from the "exit" points of the fluorescence curves. For the same marker analyzed, the longer a sample leaves (high number of cycles), the lower the initial number of copies of the mRNA. The value of RE (relative expression) is expressed in arbitrary units according to the following formula: (1 / 2number of cycles) x 106

  6. Data Processing - The raw count data has been transferred and processed using the Graph Pad Software (PRISM). - Intergroup comparisons were performed by ANOVA using the Dunnett Multiple Comparison Test.

  7. Results The compounds of Examples 9 and 10 activate the synthesis of a consti-tative marker of JDE. Compound Synthesis of Coli VII / control (concentration in mmol / l) Example 9 + 312% (0.2 mM) Example 10 + 233% (1 mM) Vitamin C (control) __ + 271% (0.2 mM) Example 12

  An oil-in-water emulsion facial cream, comprising (% by weight), is prepared: compound of Example 10 glycerol stearate polysorbate 60 (ICI Tween 60) stearic acid triethanolamine carbomer liquid fraction of butter of shea perhydrosqualene antioxidant perfume, water preservative A similar composition is prepared Example 13 C) n prepares an anti-aging gel for the skin comprising (% by weight): compound of the example 10 hydroxypropylcellulose (Klucel H from Hercules) antioxidant qs perfume preservative qs isopropanol 40% water qs 100% A similar composition is prepared with the compound of Examples 4 and 9. 0.005% 2% 1% 1.4% 0.7% 0.4% 12% 12% qs qs qs 100 % with the compounds of Examples 1 to 9. 2% 1%

Claims (12)

  1. Vitamin C carbamate compound of formula (I): ## STR2 ## in which R represents: a linear C 1 -C 10 alkyl radical, optionally substituted with a phenyl group, a C 3 -C 10 cyclic alkyl radical; optionally substituted by a phenyl group; - a branched C3-C10 alkyl radical, optionally substituted by a phenyl group, or - a -CHR1-000R2 radical in which: R1 represents H or a linear C1-C6 alkyl radical; C6, cyclic C3-C6 or branched C3-C6, said radical may be optionally (i) substituted by at least one group selected from = NH, -NH2, -NHR ', -NR'2, = 0, -OH , -OR ', -SH, -SR', COOR ', phenyl, phenyl substituted with OH or OR', as well as: N 1 COR '--COR' 20 and / or (ii) interrupted by a group -NH- , -N (COR ') - or -S-; with R '= C1-C6 linear, C3-C6 cyclic, or branched C3-C6 alkyl radical; R2 represents a C1-C6 linear, C3-C6 or branched C3-C6 alkyl radical; as well as their salts and their optical isomers.   2. Compound according to claim 1, in which R represents: a linear C 1 -C 8, in particular C 2 -C 6, alkyl radical optionally substituted with a phenyl group, a C 3 -C 6 cyclic alkyl radical, optionally substituted with a phenyl group, - a branched C3-C6 alkyl radical optionally substituted with a phenyl group, or - a radical -CHR1-COOR2.   3. Compound according to one of the preceding claims, wherein there is: - R1 represents H or a C1-C4 linear or branched C3-C4 alkyl radical, optionally substituted with a phenyl group, phenyl substituted by OH, SH, SR ', OH, = O, NH2 or COOR'; and / or - R 'represents a linear C1-C4 alkyl radical, in particular methyl or ethyl; and / or - R2 represents a linear C1-C4 alkyl radical, in particular methyl or ethyl.   4. Compound according to one of the preceding claims, in which R represents a linear C2-C6 alkyl radical, optionally substituted with a phenyl group, a C3-C6 cyclic alkyl radical, or a radical -CHR1-0OOR2 in which R1 represents H or a C1-C4 linear alkyl radical, optionally substituted by a phenyl group, phenyl substituted by OH, NH2, = O, OH, SH, SR 'or COOR' with R '; = methyl or ethyl; and R2 represents a methyl or ethyl radical.   5. Compound according to one of the preceding claims, chosen from the following compounds: - 5- (1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl ethylcarbamate diethyl 2 - [({[5- (1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl] oxy} carbonyl) amino] pentanedioate, ethyl 2 - [({[5- (1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl] oxy} carbonyl) amino] propanoate, ethyl 2- [ ({[5- (1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl] oxy} carbonyl) amino] -4- (methylsulfanyl) butanoate, ethyl [ ({[5- (1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl] oxy} carbonyl) amino] acetate, - 5- (1,2-dihydroxyethyl) 4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl (2-phenylethyl) carbamate, (5R) -5 - [(1S) -1,2-dihydroxyethyl] -4- hydroxy-2-oxo-2,5-dihydrofuran-3-yl cyclohexylcarbamate, 40 - ethyl 2 - {[((5R) -5 - [(1S) -1,2-dihydroxyethyl] -4- hydroxy-2-oxo-2,5-dihydrofuran-3-yl} oxy) carbonyl] amino} -4-methyl pentanoate, ethyl 2 - {[({(5 R) -5 - [(1S) -1,2-dihydroxyethyl] -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl} oxy) carbonyl] amirio} -3-phenylpropanoate, and (5R) -5 - [(1S) -1,2-dihydroxyethyl] -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl hexylcarbamate.   6. A cosmetic or pharmaceutical composition comprising, in a physiologically acceptable medium, at least one compound of formula (I) as defined in any one of claims 1 to 5. 10   7. Composition according to claim 6, wherein the compound of formula (I) is present, alone or as a mixture, in an amount of between 0.01 and 10% by weight, preferably between 0.1 and 5% by weight. , in particular between 0.5 and 3% by weight, relative to the total weight of the composition. 15   8. Composition according to one of claims 6 to 7, wherein the physiologically acceptable medium comprises at least one adjuvant selected from: water; organic solvents, especially C1-C6 alcohols and C2-C10 carboxylic acid esters; carbonaceous and / or silicone oils, of mineral, animal and / or vegetable origin; waxes, pigments, fillers, dyes, surfactants, emulsifiers, co-emulsifiers; cosmetic or dermatological active agents, UV filters, polymers, hydrophilic or lipophilic gelling agents, thickeners, preservatives, perfumes, bactericides, odor absorbers, antioxidants. 25   9. Composition according to one of claims 6 to 8, wherein the physiologically acceptable medium comprises at least one compound selected from: desquamating agents; moisturizing agents; depigmenting or propigmenting agents; anti-glycation agents; NO-synthase inhibitors; agents stimulating the synthesis of dermal or epidermal macromolecules and / or preventing their degradation; agents stimulating the proliferation of fibroblasts and / or keratinocytes or stimulating the differentiation of keratinocytes; muscle relaxants and / or dermo-decontracting agents; tensors; anti-pollution and / or anti-radical agents; agents acting on microcirculation; agents acting on the energetic metabolism of cells; and their mixtures.   10. Composition according to one of claims 6 to 9, in the form of an aqueous solution or aqueous-alcoholic, optionally gelled, a dispersion of the lotion type optionally biphasic, an oil-in-water emulsion, d a water-in-oil emulsion, a triple emulsion (E / H / E or H / E / H), a vesicular dispersion of ionic and / or nonionic type, aqueous or oily gel.   11. Composition according to one of claims 6 to 10, in the form of a makeup composition, or skin care, including a cleansing cream, protection, treatment or care for the face, for the hands, for the feet, for large anatomical folds or for the body (for example, day creams, night creams, make-up removing creams, foundation creams, sunscreen creams); a fluid foundation, a make-up removal milk, a body care or protection milk, an anti-sun milk; a lotion, gel or mousse for the care of the skin, such as a cleaning lotion. 1 2. Composition according to one of claims 6 to 11, being in the form of an anti-aging composition, especially care to fight against the external signs of skin aging. 13. A process for the cosmetic treatment of keratin materials, comprising the application to said keratin materials of a cosmetic composition as defined in one of claims 6 to   12. Process for the cosmetic treatment of the skin, in particular of mature and / or wrinkled skin, in particular the skin of the face, in particular the forehead, neck and / or hands, comprising topical application to said skin. skin of a cosmetic composition as defined in one of claims 6 to 12. 15. Cosmetic use of a cosmetic composition as defined in one of claims 6 to 12, to improve the structure of the dermal junction. -pidermal and / or strengthen the cohesion between the dermis and the epidermis. 16. Use of a cosmetic composition as defined in one of claims 6 to 12, for preventing and / or cosmetically treating the cutaneous signs of aging, in particular the cutaneous signs chosen from the wrinkled skin, the skin having an alteration of its viscoelastic or biomechanical properties, the skin having an alteration in the cohesion of its tissues, the thinned skin, and the skin having an alteration of its surface appearance. 35