Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
  • C07H7/02—Acyclic radicals
• • 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
• • 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
  • A61K8/60—Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D309/10—Oxygen atoms

Definitions

• the present invention relates to novel amino C-xyloside derivatives, the compositions including cosmetic comprising them, and their use to fight against skin aging.
• wrinkles and fine lines have been treated with cosmetics containing active agents acting on the skin, for example by improving its cell renewal or by promoting the synthesis or preventing the degradation of the skin. elastic fibers that make up the skin tissue.
• human skin consists of two superficial tissues, the epidermis, the other deep, the dermis.
• 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, through its own functions, to the essential role played in the body by the skin, in particular the protective role of the body against external aggressions (climate, ultraviolet rays, tobacco, etc.), called "function fence".
• the dermis provides the epidermis with a solid support. It is also its nurturing element. It consists mainly of fibroblasts and an extracellular 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 tissue macrophages. Finally, the dermis is crossed by blood vessels and nerve fibers.
• the extracellular matrix of the dermis is composed of proteins belonging to several large families: collagens, matrix glycoproteins other than collagens (fibronectin, laminin), elastin and proteoglycans. Also found in the extracellular matrix of the dermis are glycosaminoglycans in free form (ie not bound to a protein). It is now well established that specific interactions exist between these different classes of proteins to give rise to a functional tissue. An extracellular space (microarray) also exists in the epidermis. This space plays an extremely important functional role in the renewal and maintenance of the cellular tissue.
• Proteoglycans are complex macromolecules consisting of a branched central protein trunk, or protein lattice, to which are attached a large number of polysaccharide side chains called glycosaminoglycans.
• proteoglycans will be designated by the abbreviation PGs and the glycosaminoglycans by the abbreviation GAGs.
• GAGs have long been referred to as acidic mucopolysaccharides because of their high water retention capacity, carbohydrate nature, and acidity from their multiple negative charges.
• the polarity of GAGs makes them implicitly participate in certain biological functions such as the hydration of tissues, the fixation of cations or the role of ionic filtration barrier.
• PGs and GAGs are synthesized by different cells in the dermis and epidermis: fibroblasts, keratinocytes and melanocytes.
• the fibroblasts mainly synthesize collagens, matrix glycoproteins other than collagens (fibronectin, laminin), GAGs, proteoglycans and elastin.
• Keratinocytes mainly synthesize sulfated GAGs and hyaluronic acid whereas melanocytes do not appear to produce hyaluronic acid.
• the GAGs When incorporated into a PG, the GAGs are in the form of linear chains composed of the repetition of a basic diholoside always containing a hexosamine (glucosamine or galactosamine) and another ose (glucuronic acid, iduronic acid or galactose).
• Glucosamine is either N-sulfated or N-acetylated.
• galactosamine is still N-acetylated.
• the strong anionic character of GAGs is explained by the presence of carboxyl groups in hexuronic acids (glucuronic acid and iduronic acid) and O- and N-linked sulfate groups.
• the main GAGs are hyaluronic acid or hyaluronan (HA), heparan sulfate (HS), heparin (HP), chondroitin, chondroitin sulfate (CS), chondroitin 4-sulfate or chondroitin sulfate A (CSA), chondroitin 6-sulfate or chondroitin sulfate C (CSC), dermatan sulfate or chondroitin sulphate B (CSB) and keratin tane sulfate (KS) which differs from other glycosaminoglycans by the presence of galactose in place of uronic acid.
• HA hyaluronic acid or hyaluronan
• HS heparan sulfate
• HP heparin
• CS chondroitin 4-sulfate or chondroitin sulfate A
• CSC chondroitin 6-sulfate or
• Proteoglycans are formed by anchoring several chains of GAGs on a polypeptide chain (so-called carrier protein or "core” protein).
• GAGs may also exist in the extracellular matrix in free form, ie not bound to a matrix protein: this is particularly the case of hyaluronic acid.
• the GAGs are polymerized from these anchoring structures.
• GAGs The synthesis of GAGs requires the coordinated and concerted action of very specific enzymes (transferases, epimerases, sulfotransferases) adjacent to the endoplasmic reticulum membrane and the golgi apparatus. Then a multitude of biochemical reactions (N-deacetylation, N- and O-sulfation, epimerization) modify the two components constituting the base unit and this heterogeneously along the chain.
• enzymes transferases, epimerases, sulfotransferases
• the glucuronic acid / iduronic acid ratio From one heparan sulfate chain to another, for example, the glucuronic acid / iduronic acid ratio, the nature, the number and the position of the O-sulfations, as well as the N-sulfate / O-sulfate ratio can vary, which, potentially, offers immense structural diversity.
• PGs In general, the biological roles of PGs are very diverse, ranging from a passive function of mechanical support (for example serglycines) or a role of ionic barrier of molecular filtration (for example perlecan and bamacan of the glomerular basement membrane). , to more specific effects in adhesion, spreading, proliferation, cell differentiation or morphogenesis, or, to very specific effects of PG-protein interactions, such as betaglycan receptor function or interaction of decorin with collagen. They also play a fundamental role in the controlled release of different growth factors.
• mechanical support for example serglycines
• ionic barrier of molecular filtration for example perlecan and bamacan of the glomerular basement membrane
• the dermal connective tissue One of the roles of the dermal connective tissue is to protect the body against external aggressions by forming at the same time an informative interface. To do this, the dermis has a strong mechanical strength while maintaining, however, great flexibility.
• the dense network of collagen fibers is the PGs and the hyaluronic acid, ensuring the hydration, the distribution and the flexibility of the fibers which make the difference between the skin and, for example, the leather.
• the PGs constitute 0.5 to 2% of the dry weight of the dermis, the collagen alone representing up to 80%.
• Hyaluronic acid or hyaluronan is the main GAG of the dermis, the latter containing half of HA of the body.
• HA HA-like substance
• fibroblasts near the inner face of the plasma membrane. It is carried out continuously.
• This gigantic polysaccharide (several million daltons) has a very high intrinsic viscosity, ensuring the hydration and assembly of the various elements of the connective tissue by formation of supramolecular complexes.
• Dermatan sulfate initially isolated from the dermis, is also very abundant in the skin. It constitutes 40 to 50% of dermal GAGs.
• PGs and GAGs are also altered. Indeed, during aging, fibroblasts and keratinocytes produce less and less PGs and GAGs and their synthesis is imperfect. This results in significant disorganization: the deposit of GAGs on the protein skeleton forming the PG is abnormal, which results in less avidity for the water of these PGs and therefore a decrease in hydration and tonicity fabrics.
• Restoring a normal production of PGs and GAGs by fibroblasts and keratinocytes helps, in part, to compensate for loss of skin hydration.
• C-glycoside compounds already known. They are more effective for improving epidermal renewal and firmness of the skin and to fight more effectively against the signs of skin aging. They also have a beneficial effect on the structure of the dermal-epidermal junction, especially on the cohesion between dermis and epidermis.
• novel compounds therefore find particular application in cosmetic or 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 a wrinkled skin, a skin with an alteration of its viscoelastic or biomechanical properties, a skin with an alteration in the skin. cohesion of its tissues, thinned skin and / or skin with an alteration of its surface appearance.
• compositions according to the invention may more particularly make it possible to maintain and / or restore the properties of extensibility, tonicity, firmness, suppleness, density and / or elasticity of the skin.
• biomechanical properties of the skin is meant here the properties of extensibility, tonicity, firmness, suppleness and / or elasticity of the skin.
• cutaneous signs of aging is meant here any modification of the external appearance of the skin due to aging whether chronobiological and / or extrinsic, in particular photoinduced or hormonal; among these signs, we can distinguish:
• the skin having an alteration of its viscoelastic or biomechanical properties, or skin having a lack of elasticity and / or of extensibility and / or firmness and / or of flexibility and / or tonicity, which is reflected in particular by a skin wilted, soft, loose or sagging, the skin exhibiting an alteration of the cohesion of its tissues;
• the skin exhibiting an alteration of its surface appearance, which results in particular in an alteration of the skin's grain, for example a roughness.
• the invention also relates to a cosmetic or dermatological composition
• a cosmetic or dermatological composition comprising, in a physiologically acceptable medium, at least one such compound.
• R2 represents a C3-C6, C3-C6 or branched C3-C6 linear alkyl radical; as well as their salts, solvates and optical isomers.
• alkyl in the context of the present invention, means a saturated or unsaturated hydrocarbon chain.
• 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, hexyl and heptyl groups. , octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
• R represents:
• R represents:
• a C2-C16 linear alkyl radical or a -CHR-1-COOR2 radical in which R-
• R 1 represents the radical R '1 of an amino acid of formula NH 2 -CHR'-COOH, in particular of an amino acid chosen from:
• the amino acid may be phenylalanine (hence R 1 may represent -CH 2 -phenyl), threonine, valine, aspartic acid, tyrosine.
• R denotes a C2-C-1 linear alkyl radical.
• R denotes a -CHR 1 -COOR 2 radical in which R 1 represents a linear C 1 -C 4 alkyl radical and R 2 represents a linear C 1 -C 4 alkyl radical, in particular ethyl.
• R denotes a radical -CHR1 -COOR2 in which R 1 represents a branched alkyl radical C3-C4 and R2 represents a linear alkyl radical C-1 -C4, in particular ethyl.
• R denotes a radical -CHR1 -COOR2 in which R 1 represents a benzyl radical and R2 represents a linear C1-C4 alkyl radical, in particular ethyl.
• R denotes a -CHR 1 -COOR 2 radical in which R 1 represents a benzyl radical and R 2 represents a linear C 1 -C 4 alkyl radical, in particular ethyl.
• the compounds of formula (I) described above may also be in the form of salts, solvates or optical isomers.
• salts of the compounds of formula (I) mention may be made of the 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 the like. tartaric acid.
• mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, boric
• organic acids such as propionic acid, acetic acid, succinic acid, fumaric acid, lactic acid, glycolic acid, citric acid and the like. tartaric acid.
• Acceptable solvates of the compounds described in the present invention include conventional solvates such as those formed in the last step of preparing said compounds due to the presence of solvents.
• the sodium cyanoborohydride may be replaced by palladium on carbon followed by a hydrogenation step in the presence of hydrogen under pressure.
• the reaction medium is filtered and then concentrated under reduced pressure and purified for example on silica gel, in order to obtain the desired product.
• the present invention also relates to a composition comprising, in a physiologically acceptable medium, a compound of formula (I) as described above.
• the composition is in particular a cosmetic or dermatological composition.
• the compound of formula (I) may be present in cosmetic or dermatological compositions, in an amount which may be between 0.01 and 10% by weight, preferably between 0.1 and 5% by weight, in particular between 0 and 5 to 3% by weight, relative to the total weight of the composition.
• the composition further comprises a physiologically acceptable medium, which will preferably be a medium cosmetically or pharmaceutically, in particular dermatologically acceptable, that is to say without odor, color or unpleasant appearance, and which does not generate tingling, tugging or redness unacceptable for the user.
• the composition is suitable for topical application to the skin.
• physiologically acceptable medium an environment compatible with the keratin materials of human beings such as the skin of the body or of the face, the lips, the mucous membranes, the eyelashes, the nails, the scalp and / or the hair is understood.
• composition according to the invention can then comprise all the cosmetic adjuvants usually used in the intended field of application.
• cosmetic adjuvants usually used in the intended field of application.
• 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 can be introduced into the fatty phase or into the aqueous phase of the composition, or into lipid vesicles.
• 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.
• mineral oils liquid petroleum jelly
• oils of vegetable origin oils of vegetable origin
• oils of animal origin oils of animal origin
• synthetic oils perhydrosqualine
• silicone oils cyclometh icon
• fluorinated oils perfluoropolyethers
• Fatty alcohols cetyl alcohol
• fatty acids fatty acids
• waxes can also be used as fats.
• Hydrophilic gelling agents or thickeners include carboxyvinyl polymers (carbomer), acrylic copolymers such as copolymers of acrylates / alkylacrylates, 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.
• 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 nicotinamide; 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 WiId Yam extracts containing them; ceramides; hydroxy acids such as salicylic acid and n-octanoyl-5-salicylic acid; resveratrol; oligopeptides and pseudodipeptides and their acyl derivatives; manganese and magnesium salts,
• 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-benzylidene camphor, benzylidenecamphosulfonic acid, camphor benzalkonium methosulphate, polyacrylamidomethylbenzylidene camphor, terephthalylidene di-camphorsulfonic acid, and preferentially 4-
• This composition may be in any galenical form normally used in the cosmetic or dermatological 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 including 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.
• 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 skin care composition, and in particular a cleaning, protective, treatment or care cream for the face, for the hands, for the feet, for the large anatomical folds. or for the body (for example, day creams, night creams, make-up removing creams, foundation creams, sunscreen creams); cleansing milk, protective or caring body milk, anti-sun milk; a lotion, gel or mousse for the care of the skin, such as a cleaning lotion.
• a skin care composition and in particular a cleaning, protective, treatment or care cream for the face, for the hands, for the feet, for the large anatomical folds. or for the body (for example, day creams, night creams, make-up removing creams, foundation creams, sunscreen creams); cleansing milk, protective or caring body milk, anti-sun milk; a lotion, gel or mousse for the care of the skin, such as a cleaning lotion.
• composition according to the invention is advantageously an anti-aging composition, especially of care, intended to treat and / or fight against, cosmetically, the external signs of skin aging; the composition is more particularly a skincare composition for mature skin.
• the composition may also be a make-up composition, especially a foundation.
• the invention also relates to a method for cosmetic treatment of the skin, comprising the application to the skin 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 use of a cosmetic composition as defined above or a compound of formula (I) as described above, for preventing and / or cosmetically treating the cutaneous signs of aging, in particular the signs selected from the wrinkled skin, the skin having an alteration of its viscoelastic or biomechanical properties, the skin showing an alteration in the cohesion of its tissues, the thinned skin, and the skin having an alteration of its surface appearance.
• the invention also relates to the cosmetic use of a composition as defined above or of a compound of formula (I) as described above, to improve the firmness of the skin and / or to improve the structure of the skin. dermal-epidermal junction and / or to reinforce the cohesion between the dermis and the epidermis.
• This compound comprises a group R which is the residue of a serine residue.
• 2 g (1 1, 8 mmol, 1 eq) of the hydrochloride salt of the ethyl ester of serine was reacted with 2.98 g (15.7 mmol, 1.33 eq) of C- ⁇ -D-xylopyranoside-n-propan-2-one, 0.99 g of NaBh 3 CN (15.7 mmol, 1.33 eq),
• reaction mixture was filtered, concentrated under vacuum and then purified on silica gel (dichloromethane / methanol)
• This compound comprises a group R which is the residue of a valine residue.
• the compound was prepared according to the synthesis method described in Example 1 using 2 g of valine ethyl ester hydrochloride, 2.79 g of C- ⁇ -D-xylopyranoside-n-propan-2-one 0.917 g of NaBH 4 CN, 0.65 ml of acetic acid, and 2 spatulas of sodium sulfate in 25 ml of ethanol. 800 mg (23% yield) of product was obtained as a light yellow oil.
• This compound comprises a group R which is the residue of an aspartic acid residue.
• the compound was prepared according to the synthesis method described in Example 1 using 2 g of aspartic acid ethyl diester hydrochloride, 2.24 g of C- ⁇ -D-xylopyranoside-n-propan-2-one 0.741 g of NaBH3CN, 0.53 ml of acetic acid, and 2 spatulas of sodium sulfate in 20 ml of ethanol.
• This compound comprises a group R which is the residue of a threonine residue.
• the compound was prepared according to the synthesis method described in Example 1 using 0.5 g of threonine methyl ester hydrochloride, 0.75 g of C- ⁇ -D-xylopyranoside-n-propane-2 -one, 0.25 g of NaBH 4 CN, 70 ⁇ l of acetic acid, and 1 spatula of sodium sulfate in 7 ml of ethanol. 199 mg (22% yield) of product was obtained as a white powder.
• This compound comprises a group R which is the residue of a phenylalanine residue.
• the compound was prepared according to the synthesis method described in Example 1 using 3.5 g of phenylalanine ethyl ester hydrochloride, 2.65 g of C- ⁇ -D-xylopyranoside-n-propane-2 -one, 1.02 g of NaBH 4 CN, 0.73 ml of acetic acid, and 2 spatulas of sodium sulfate in 30 ml of ethanol. 3.9 g (69% yield) of product was obtained as a white powder.
• the 1 H NMR and mass spectra are in accordance with the structure of the expected product.
• the compound was prepared according to the synthesis method described in Example 1 using 2.97 g of dodecylamine, 2.70 g of C- ⁇ -D-xylopyranoside-n-propan-2-one, 1.02 g NaBH ⁇ CN, 0.9 ml of acetic acid, and 2 spatulas of sodium sulfate in 30 ml of ethanol.
• This compound comprises a group R which is the residue of a tyrosine residue.
• the compound was prepared according to the synthesis method described in Example 1 using 2 g of tyrosine ethyl ester hydrochloride, 2.06 g of C- ⁇ -D-xylopyranoside-n-propan-2-one 0.68 g of NaBH 4 CN, 0.48 ml of acetic acid and 2 spatulas of sodium sulfate in 25 ml of ethanol. 800 mg (23% yield) of product was obtained as an orange oil.
• the 1 H NMR and mass spectra are in accordance with the structure of the expected product.
• the compound was prepared according to the synthesis method described in Example 1 using 1.3 g of hexadecylamine, 1 g of C- ⁇ -D-xylopyranoside-n-propan-2-one, 0.36 g of NaBH 4 CN, 0.3 ml of acetic acid, and 1 spatula of sodium sulfate in 11 ml of ethanol.
• the compound was prepared according to the synthesis method described in Example 1 using 0.81 g of octylamine, 1 g of C- ⁇ -D-xylopyranoside-n-propan-2-one, 0.36 g of NaBH 3 CN, 0.3 ml of acetic acid, and 1 spatula of sodium sulfate in 1 ml of ethanol.
• reaction mixture was filtered, concentrated under vacuum and then purified on silica gel (dichloromethane / methanol)
• the compound was prepared according to the synthesis method described in Example 10 using 1, 2 eq of propylamine, 1 eq of C- ⁇ -D-xylopyranoside-n-propan-2-one, 0.1 eq of catalyst palladium supported 10% on charcoal, 1, 2 eq of acetic acid, in ethanol.
• the study is done by measuring the incorporation of radioactive glucosamine into the neosynthesized matrix by normal human dermal fibroblast cultures or by keratinocytes.
• the incorporation of radioactive glucosamine indicates a specific neosynthesis of glycosaminoglycans via incorporation of the acetylated form of this glucosamine.
• the fibroblast cultures are carried out according to the standard cell culture methods, namely in a DMEM medium sold by Gibco, in the presence of L-glutamine (2 mM), penicillin (50 IU / ml) and 10% of serum. fetal calf (Gibco).
• the keratinocyte cultures are carried out in a Keratinocyte-SFM medium sold by Gibco in the presence of EGF (Epidermal Growth Factor) (0.25 ng / ml), pituitary extract (25 ⁇ g / ml) and gentamicin ( 25 ⁇ g / ml).
• EGF Epidermal Growth Factor
• pituitary extract 25 ⁇ g / ml
• gentamicin 25 ⁇ g / ml
• Fibroblasts and keratinocytes were cultured in 96-well plates. At confluence, the culture medium was replaced with suitable culture medium containing or not (control) the test compound or reference, and then the cells were incubated for 48 hours. The 35 S-sulfate radioactive label was added (40 ⁇ Ci final) and the cells were incubated for an additional 24 hours. All conditions were realized 3 times.
• glycosaminoglycans of the extracellular matrix were extracted with a chaotropic buffer volume (50 mM Tris / HCl, 4 M guanidine, 5 mM EDTA, pH
• the sulphated GAGs were purified by ion exchange chromatography: absorption of anionic molecules on Q-Sepahrosis beads under conditions of high stringency, desorption of the weakly and moderately anionic molecules with a 6 M NaCl 0.2 mM NaCl solution. , then washings.
• the radioactivity incorporated in the highly cationic molecules remaining on the support was measured by liquid scintillation.
• the results are evaluated by providing a control consisting of cells that have not been treated with a compound of formula (I).
• a positive control TGF ⁇ at 10 ng / ml
• a positive control TGF ⁇ at 10 ng / ml
• a positive control (CaCl 2 at 1.4 mM) known to stimulate the synthesis of GAGs is introduced into the test performed on keratinocytes as a positive reference. The results are expressed as a percentage of variation of glycosaminoglycan synthesis relative to the control.
• esm standard deviation / (n) 1/2 where n is the number of tests performed.
• An oil-in-water emulsion facial cream comprising (% by weight): compound of Example 5 0.005% is prepared glycerol stearate 2% polysorbate 60 (ICI Tween 60) 1% stearic acid 1, 4% triethanolamine 0.7% carbomer 0.4% liquid fraction of shea butter 12% perhydrosqualene 12% antioxidant qs perfume, preservative qs water qs 100%
• composition applied to the face helps strengthen the firmness of the skin and thus fade the signs of skin aging.
• An anti-aging gel for the skin comprising (% by weight): compound of the example 2% hydroxypropylcellulose (Klucel H from Hercules) 1% antioxidant qs perfume, preservative qs isopropanol 40% water qs 100%
• composition applied to the face helps strengthen the firmness of the skin and thus fade the signs of skin aging.

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