WO2001072767A1 - Dehydroepiandrosterone derivatives, preparation method and uses thereof, in particular for cosmetics - Google Patents

Abstract

The invention concerns novel DHEA derivatives of formula (I) and their preparation method. The invention also concerns cosmetic or dermatological compositions containing said compositions and their uses, in particular for preventing or treating skin ageing and/or for regulating skin and hair pigmentation.

Description

 Dehydroepiandrosterone derivatives, process for their preparation and their uses, in particular cosmetics

The present invention relates to new DHEA derivatives, to cosmetic or dermatological compositions containing them, as well as to their uses.

DHEA, or dehydroepiandrosterone, is a natural steroid produced essentially by the adrenal cortexes Exogenous DHEA, administered topically or orally, is known for its ability to promote keratinization of the epidermis (JP-07 196 467) dry skin by increasing ^* endogenous production and sebum secretion and thereby strengthening the barrier effect of the skin (US-4,496,556) DHEA is also described in the treatment of menopausal symptoms (US-5,854,671) and in the prevention and treatment of osteoporosis (US-5,776,923) It has also been suggested to use DHEA in the treatment of obesity and diabetes (WO 97/13500), of cardiovascular diseases (US- 5,854,671) and in the treatment of certain cancers, such as ovarian (US-5, 798,347), uterine (US-5,872.1 14) or breast (US-5,824,671) cancer

However, DHEA dissolves only with difficulty in aqueous and hydroalcoholic media, which limits its formulation in cosmetic or dermatological compositions applied topically or per os

A certain number of derivatives and / or precursors of DHEA are described in the literature. However, all these products themselves have limited solubility. It follows that the compositions of the prior art contain only a small amount of DHEA or its derivatives, which limits their effectiveness or requires, in any case, to extend their application over long periods of time, for example of the order of four months, to obtain the desired cosmetic or therapeutic effect

The aim of the present invention is therefore to have new DHEA derivatives which are more soluble than DHEA itself and its known derivatives, in particular in aqueous and hydro-alcoholic media.

This object is achieved, according to the invention, by new DHEA derivatives having the general formula (I) below

in which R is chosen from

(a) a group -NR ^, where

R-, is chosen from a hydrogen atom and a hydrocarbon radical, linear, cyclic or branched, Cι-C ₆ , optionally substituted by one or more groups -OH and / or COOH and / or -NH ₂ and R ₂ represents a linear, cyclic or branched Cι-C ₆ hydrocarbon radical, optionally mono- or polyhydroxylated, substituted by one or more COOH and / or -NH _{2 groups} ,

(b) a group

ou .

or .

X represents an oxygen atom or an amino group, and

R ₃ , R, identical or different, represent a hydrogen atom or a group -COR ₅ ,

R ₅ representing a hydrocarbon radical, linear, cyclic or branched at dC ₆ , optionally substituted by one or more groups -OH -COOH or -NH ₂

(c) a group -CH (R ₆ ) -NH-R ₇ or R ₆ represents a hydrogen atom or a hydrocarbon radical, cyclic or branched linear, C C- ₆ , substituted by one or more -OH groups, -COOH and / or NH ₂ and R ₇ represents a hydrogen atom or a group -COR ₈ , Rs representing a hydrocarbon radical, linear, cyclic or branched, in CrC ₆ or an alkoxy radical in CC ₆ , (d) a group -CH (R ₉ ) -NH-COR ₁₀ where

R ₉ represents a linear, cyclic or branched hydrocarbon radical in d-Cβ, and

R ₁₀ represents a linear, cyclic or branched hydrocarbon radical in d'-C ₅

and their cosmetically acceptable salts and complexes

According to a preferred embodiment of the invention, the DHEA derivative is such that, in formula (I) above, R is a group -NRιR ₂ or Ri is a hydrogen atom and R ₂ represents a linear, cyclic or branched, Cι-C ₆ hydrocarbon radical, optionally mono- or polyhydroxylated, substituted by one or more COOH and / or -NH _{2 groups}

According to another preferred embodiment of the invention, the DHEA derivative is such that, in formula (I) above, R is a group

où R₃ = R₄ = H et X représente un atome d'oxygène

where R ₃ = R ₄ = H and X represents an oxygen atom

According to another preferred embodiment of the invention, the DHEA derivative is such that, in formula (I) above R is a group -CH (R ₆ ) -NH (R ₇ ) where R ₆ is a linear hydrocarbon group at dC ₆ the end of the chain of which carries a group -OH or -COOH or -NH ₂ and R ₇ is a hydrogen atom

According to another preferred embodiment of the invention, the DHEA derivative is such that, in formula (I) above, R is a group -CH (R ₆ ) -NH-R ₇ where R ₆ and R ₇ each represents a hydrogen atom

As linear, cyclic or branched hydrocarbon radicals, in dC _6l there may be mentioned the methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, n-pentyl, act radicals. -amyl, dry-amyl. tert-amyl, n-hexyl and cyclohexyl

The derivatives according to the invention can be prepared according to acylation techniques well known to those skilled in the art which are conventionally used for obtaining derived from steroidal alcohols from commercial raw materials These techniques are described in particular in Lapatsanis et al J Chem Enq, Data (1980), 25 (3), 287-9

These preparation methods will now be described in more detail.

DHEA carbamate synthesis procedure

A solution of DHEA is prepared in an anhydrous aprotic solvent such as anhydrous toluene (benzene) or anhydrous THF. 1 molar equivalent of isocyanate R ^ NCO and 2 molar equivalents of pyπdiπe are added under an inert atmosphere. The solution is heated to 80 ° C. (or at THF reflux, 70 ° C) for 1 to 12 hours The reaction medium is evaporated to dryness, then taken up in a solvent such as ethyl acetate or dichloromethane After several basic and neutral acid washes, the organic solution is dried then evaporated to dryness The residue is purified by chromatography or by recrystallization to yield DHEA carbamate

General procedure for the synthesis of DHEA 2-hvdroxy malonate esters

A solution of DHEA is prepared in an anhydrous aprotic solvent such as dichloromethane or THF at 0 ° C. 1 molar equivalent of diimidazoy carbonyl and 2-hydroxy-malonate suitably protected is added. The solution is stirred at 0 ° C. for approximately A h then 0 9 equivalent of DHEA is then added in solution in the same solvent. The mixture is stirred at 0 ° C. for approximately 1 h and then at room temperature overnight The reaction medium is evaporated to dryness and then taken up in a solvent such as ethyl acetate After several acidic, basic and neutral washes, the organic solution is dried and then evaporated to dryness "The residue is purified by chromatography or by recnstalling to lead to the protected DHEA ester

The deprotection is then carried out according to conventional techniques depending on the protective groups. Thus, in the case of a BOC group, it is carried out by treatment with an excess of CF ₃ COOH in a solvent such as dichloromethane at room temperature for Vi h at 1. h The solvent is then evaporated to dryness and the residue is recrystallized, for example from a mixture of ethyl acetate and methanol to yield the expected DHEA ester

General procedure for the synthesis of amino acid esters of DHEA

(R = -CH ₂ -NH-R ₆ or -CH (R ₈ ) -NH-COR ₉ or -CH (R ₁₀ ) -NH ₂ )

An amino acid solution protected on the amino group, for example by a BOC group (fert-butoxy carbonyl), is prepared in an anhydrous aprotic solvent such as dichloromethane or THF at 0 ° C. 1 molar equivalent of dnmidazole carbonyl is added The solution is stirred at 0 ° C for about 1 h and then 0.9 equivalent of DHEA is then added in solution in the same solvent The mixture is stirred at 0 ° C for about 1 h then at room temperature overnight The medium reaction mixture is evaporated to dryness and then taken up in a solvent such as ethyl acetate After several acidic, basic and neutral washes, the organic solution is dried and then evaporated to dryness The residue is purified by chromatography or by re-installation to yield the ester of protected DHEA The deprotection is then carried out according to conventional techniques The DHEA derivatives according to the invention can be included in a composition intended to be administered either topically to the skin or the hair, or orally.

When the composition is for topical use, it contains a physiologically acceptable medium, that is to say compatible with the skin and its appendages such as body hair and hair, and it may contain from 0.01 to 10% by weight, advantageously from 1 to 5% by weight of DHEA derivative, relative to the total weight of the composition

This composition can be in all galéπique forms normally used for a topical application, in particular in the form of an aqueous, hydroalcoholic solution, of an oil-in-water or water-in-oil or multiple emulsion, of a gel aqueous or hydro-alcoholic, or an anhydrous liquid, pasty or solid product

This composition can 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 foam. It can optionally be applied to the skin or the hair in the form of an aerosol. It can also be presented in solid form, and for example in the form of a stick. It can be used as a care product and / or as a makeup product. it can also be used as a shampoo or conditioner

In a known manner, the composition according to the invention can also contain the adjuvants usual in the cosmetic and dermatological fields, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, antioxidant preservatives, solvents, perfumes, fillers , filters, pigments, odor absorbers and coloring materials The amounts of these various adjuvants are those conventionally used in the fields under consideration and for example from 0.01 to 20% of the total weight of the composition These adjuvants according to their in nature, can be introduced in the fatty phase into the aqueous phase in lipid vesicles and / or in nanoparticles

Of course, a person skilled in the art will take care to choose these possible additional compounds, active or non-active, and / or their quantity, in such a way that the advantageous properties of the DHEA derivatives according to the invention are not or not substantially altered by the proposed addition When the composition according to the invention is an emulsion, the proportion of the fatty phase can range from 0.5 to 80% by weight, and preferably from 5 to 50% - by weight relative to the total weight of the composition. emulsifiers and co-emulsifiers used in the composition in the form of an emulsion are chosen from those conventionally used in the field under consideration The emulsifier and the co-emulsifier are present in the composition in a proportion ranging from 0.3 to 30% by weight , and preferably from 0.5 to 20% by weight relative to the total weight of the composition

As oils which can be used in the invention, there may be mentioned mineral oils (petroleum jelly oil), oils of vegetable origin (avocado oil soybean oil), oils of animal origin (lanolin), synthetic oils (perhydrosqualene), silicone oils (cyclomethicone) and fluorinated oils (perfluoropolyethers) Fatty alcohols (cetyl alcohol), fatty acids, waxes (carnauba wax, ozokerite) can also be used.

As emulsifiers and coemulsifiers which can be used in the invention, there may be mentioned, for example, fatty acid esters of polyethylene glycol such as PEG-20 stearate, and fatty acid and glycerin esters such as glyceryl stearate

As hydrophilic gelling agents, mention may be made in particular of carboxyvinyl polymers (carbomers), acrylic copolymers such as acrylate / alkyl acrylate copolymers, polyacrylamides, polysaccharides, natural gums and clays, and, as lipophilic gelling agents, mention may be made of modified clays such as bentones, metal salts of fatty acids, hydrophobic silica and polyethylenes.

As active agents, depigmentants, keratolytic agents and mixtures thereof can be used in particular. In the event of incompatibility, at least some of these active agents and / or the DHEA derivative according to the invention can be incorporated into spherules, in particular ionic vesicles or non-ionic and / or nanoparticles (nanocapsules and / or naπospheres), so that the active ingredients which are incompatible with each other are isolated from one another in the composition According to a preferred embodiment of the invention, the composition containing the DHEA derivative additionally contains at least one UV filter and / or a depigmenting agent and / or a keratolytic agent

As UV filters, we can mention ^:

(1) dibenzoylmethane derivatives and in particular 4- (ter -butyl) 4'-methoxy dibenzoylmethane, in particular that offered for sale under the trade name "PARSOL 1789" by the company GIVAUDAN, and 4-ιsopropyl- dibenzoylméthaπe, filter sold under the name of "EUSOLEX 8020" by the company MERCK,

(2) active filters in UVA derived from beπzy camphor dene, of which a particularly preferred example is benzene 1 4- acid [dι (3-methylιdènecampho 10-sulfonique)] such as the product sold under the name MEXORYL SX by the company CHIMEX, described in particular in patent applications FR-A-2,528,420 and FR-A- 2,639,347,

(3) filters active in UVB derived from benzylidene camphor, and in particular 4-methyl benzylidene camphor, available from the company MERCK under the trade name EUSOLEX 6300,

(4) active filters in UV-B of the benzimidazole or benzoxazole type, such as 2-pheπyl benzimidazole 5-sulfonιque acid, available from the company MERCK under the trade name EUSOLEX 232,

(5) the benzophenone derivatives which can be advantageously chosen from the group consisting of 2-hydroxy-4-methoxy-benzophenedone also called oxybenzone (benzophenone-3) as the product sold under the name UVINUL M40 by BASF, and 2-hydroxy-4-methoxy-benzophenone-5-sulfonic acid, also called sulisobenzone (benzophenone-4) as the product sold under the name UVINUL MS 40 by BASF, as well as its sodium sulfonate form (beπzophenone-5),

(6) silane derivatives or polyorganosiloxanes containing a benzophenone group, such as those described in documents EP-A-0389 377, FR-A-2 657 351 and EP-A-0 655 453,

(7) benzotnazoles and benzotnazole silicones, preferably those described in patents US-4316033, US-4328346 EP-B-0354145, EP-B-0392883 and EP-B-0660701,

(8) the derivatives of magazines described in particular in patent US4617390 and patent applications EP-A-087098, EP-A-0517104, EP-A-0570838 and EP-A-0796851, in particular 2,4,6-very [p- (2'-ethylhexyl-1'-oxy-carbonyl) anιlιno] -1, 3 5-tπazιne sold in particular under the trade name of UVINUL T 150 by BASF

(9) cinnamic acid derivatives such as 2-ethylhexyl para-methoxy cinnamate, sold in particular under the trade name PARSOL MCX by the company GIVAUDAN,

(10) alkyl 2-cyano-33-dιphenylacrylate and, preferably octocrylene sold under the name Uvinul N 539 by the company BASF,

(11) the compound of formula (I) below, or 2- (2H-benzotπazole-2-yl) -4-methyl-6- [2-methyl-3- [1, 3,3,3-tetramethyl-1 - [(trιmethylsιlyl) oxy] dιsιloxanyl] propynyl] phenol described in patent application EP-A-0 392 883

(12) and their mixtures

As depigmenting agent, the compositions according to the invention can for example comprise at least one of the following compounds kojic acid, ellagic acid, arbutin and its derivatives such as those described in applications EP-895 779 and EP-524 109, hydroquinone, aminophenol derivatives such as those described in applications WO 99/10318 and WO 99/32077, and in particular N-cholesteryloxycarbonyl-para-amiπophenol and N-ethyloxycarbonyl-para- aminophenol L-2- oxothιazolιdιne-4-carboxylic acid or procysteine, as well as its salts and esters ascorbic acid and its derivatives, in particular ascorbyl glucoside, and plant extracts, in particular licorice, mulberry and skullcap, without this list being exhaustive

The keratolytic agents capable of being used in the compositions according to the invention notably comprise α-hydroxy acids such as citric acids, lactic, glycolic, malic mandelic and tartnque β-hydroxy acids and in particular salicylic acid and its derivatives described in demanαea FR-A-2 581 542, EP-875 495, WO 98/35973 and EP-756 866, α -ketoacids and β-ketoacids, retinoids and in particular retinol and retinyl esters, HMG-CoA reductase inhibitors, as described in application EP-738 510 and sugar derivatives such as those described in application EP-853 472 and in particular 0-octanoyl-6'-β- D-maltose

As a variant or in addition, the composition according to the invention may also contain at least one compound chosen from

(a) a tightening agent such as a vegetable protein, described for example in application WO 98/29091, or a synthetic polymer, for example a grafted silicone polymer as described in application FR-99 03531, and (b) a lipolytic agent, firming and / or acting on the micro-circulation such as a xanthic base, a plant extract such as an extract of Bupleurum Chinensis, climbing ivy, escin, ruscus, ginseng or gingko biloba , or an extract of marine origin such as an alga extract

When the DHEA derivatives according to the invention are administered orally, the composition containing them can be in any dosage form suitable for this mode of administration, for example in the form of breakable tablets or not of granules, capsules, capsules, solutions of suspensions or solutions comprising an appropriate excipient

In this case, the DHEA derivatives are present in the composition in an amount allowing their administration at a dose of between 1 and 100 mg per day, preferably between 25 and 75 mg per day, this dosage being carried out in one or more doses. daily, for example at a unit dose of 50 mg

The DHEA derivatives according to the invention can advantageously be used for cosmetic purposes, as agents for preventing or correcting intrinsic or extrinsic aging, atrophy of the skin, drying of the skin, the papery appearance of the skin, sagging skin, the formation of wrinkles and fine lines and / or loss of radiance and / or to regulate the pigmentation of the skin or hair Cosmetic compositions containing these DHEA derivatives are particularly well suited to the care of mature skin

As a variant, the DHEA derivatives according to the invention can be used as a medicament, for example for making a dermatological composition intended to be administered topically to the skin or the hair or for making a composition intended to be administered by the route oral These compositions can in particular be intended to prevent or treat the symptoms of menopause, in particular osteoporosis

The invention will now be illustrated with the aid of the following nonlimiting examples. In these examples, the concentrations are expressed in percentage by weight unless otherwise indicated.

Example 1: 3-β-17-oxoandrost-5-en-3-yle α-glutamate

A solution of 0.5 mmol of 5-terf-butyl ester of N-ferf-butoxy carbonyl L-glutamic acid is prepared in 2 ml of dichloromethane at 0 ° C. 0.5 mmol of dnmidazole carbonyl is added in solution in 2 ml of dichloromethane The solution is stirred at 0 ° C for 20 min then 0.45 mmol of dehydroepiandrosterone is added

(DHEA) dissolved in 2 ml of dichloromethane The mixture is stirred at 0 ° C for

1h then at room temperature for 15h The reaction medium is evaporated to dryness and then repπs with 5 ml of ethyl acetate The solution is washed with 5 ml of saturated water

NaCl, then 5 ml of 1N sulfuπque acid, then 5 ml of water then 5 ml of water saturated with sodium bicarbonate then with 5 ml of water The residual organic phase is dried over sodium sulphate and then evaporated to dryness The residue is purified by chromatography on a silica column (eluaπt pentane / ethyl acetate 2 1) to yield 50 mg of protected DHEA ester in the form of a white solid

• ¹ H RM compliant

• F = 175-178 ° C

• single-layer thin layer chromatography Rf # 0 8 (silica eluent pentane / ethyl acetate 1 1) ¹

The deprotection is carried out by treatment with 2 ml of a mixture of dichloromethane / tnfluoroacetic acid 1 1 for 30 min at room temperature The mixture is then evaporated to dryness to yield the expected DHEA ester, in the form of a white solid.

• ¹ H NMR compliant

• F = 150-155 ° C

• single-layer thin layer chromatography Rf # 0 1 (silica, eluent pentane / ethyl acetate 1: 1)

Please indicate the results of the analyzes performed Example 2: 3-β-17-oxoandrost-5-en-3-yle glycinate

This compound is prepared according to a process analogous to that described in Example 1.

Example 3: 3-β-17-oxoandrost-5-en-3-yle α-lysinate

This compound is prepared according to a process analogous to that described in the Example.

Example 4: 3-β-17-oxoandrost-5-en-3-yle serinate

This compound is prepared according to a process analogous to that described in Example 1.

Example 5: 3-β-17-oxo-androst-5-en-3-yl 2-hydroxymalonate

Ce composé est prépare selon le procédé général décrit plus haut

This compound is prepared according to the general process described above

Example 6: 1 (1, 3-dicarboxy propyl) carbamate of 3-β-17-oxoandrost-5-en-3-yle

This compound is prepared according to the general process described above

Example 7: solubility test

The solubility in water, and in an aqueous-alcoholic solvent, of the compound of Example 1 was determined by comparison with DHEA at room temperature.

The results are collated in the table below

It appears from this table that the products according to the invention have a markedly improved solubility in water compared to DHEA

EXAMPLE 8 Composition for Topical Application

The following emulsion is prepared in a conventional manner

Compound of Example 1 5% propylene glycol isostearate 13% Polyethylene glycol (8 EO) 5% Propylene glycol 3% Pentylene glycol 3% Glyceryl stearate and stearate polyethylene glycol (100 EO) 5%

Oxyethylenated sorbitan mono-stearate (20 EO) 0.5%

Cetyl alcohol oxyethylenated (20 EO) oxypropyléπé (5 OP) 1% "

Gelling agents 0.5% C ₁₂ alkyl benzoates. ₁₅ 4%

Ethanol 3%

0.12% sodium hydroxide

Preservatives 0.7%

Water qs 100%

A fluid is obtained which can be used in mono- or bi-daily application on the face, to reduce wrinkles and fine lines and firm the skin.

Example 9: topical composition

A lotion is conventionally prepared by mixing the following constituents:

Compound of Example 2 10%

Propylene glycol 15% Ethanol 70%

Water qs 100%

This lotion can be used to reduce pigment spots on the hands and décolleté.

Example 10: topical composition

A gel is prepared, conventionally, having the following composition

Compound of Example 3 1%

Hydroxypropyl cellulose 1%

PPG-12 buteth-16 2%

Butylene glycol 4%

Ethanol 47% Water 45% This gel can be applied to the face to hydrate the skin and give it radiance

Example 11: topical composition

A hair lotion having the following composition is prepared in the conventional manner

Compound of Example 4 1%

Propylene glycol 25%

Ethanol 50% Water 24%

This lotion can be applied to the scalp to prevent hair growth.

Example 12: Oral Composition

A drinkable suspension is prepared in conventional manner in 10 ml ampoules, having the following composition

Compound of Example 5 0.05 g

Glycerin 1, 000 g

Sorbιtol at 70% 1, 000 g

Sodium shankate 0.010 g

Methyl parahydroxybenzoate 0.080 g Aroma qs

Purified water qs 10 ml

This composition can be prescribed as a preventive measure to pre-menopausal women in order to delay the onset of the symptoms of menopause

Example 13: tablet

0.2 g tablets having the following composition are prepared in a conventional manner

Compound of example 6 0.05 g

Starch 0.06 g Lactose 0.06 g

Calcium phosphate 0 02 g

Magnesium stearate 0.01 g

These tablets can be taken to prevent or reduce the signs of skin aging

Claims

1 DHEA derivatives having the following general formula (I)

in which R is chosen from (a) a group -NR., R ₂ or Ri is chosen from a hydrogen atom and a cyclic or branched linear hydrocarbon radical, Cι-C ₆ , optionally substituted by one or more groups -OH and / or COOH and / or -NH ₂ , and R ₂ represents a hydrocarbon radical, linear, cyclic or branched, in dC ₆ , optionally mono- or polyhydroxylated, substituted by one or more COOH and / or -NH _{2 groups} , (b) a group

or X represents an oxygen atom or an amino group, and R ₃ , R ₄ , identical or different, represent a hydrogen atom or a group -COR ₅ , R ₅ representing a hydrocarbon radical, linear cyclic or branched, in dC ₆ , optionally substituted by one or more groups -OH -COOH or -NH ₂ (c) a group -CH (R ₆ ) -NH-R ₇ where R ₆ represents a hydrogen atom or a linear cyclic or branched hydrocarbon radical, at dC ₆ , substituted by one or more groups -OH -COOH and / or NH ₂ and R ₇ represents a hydrogen atom or a group -COR _e R ₈ representing a cyclic or branched linear hydrocarbon radical in dC ₆ or an alkoxy radical in dC ₆ , (d) a -CH (R ₉ ) -NH-COR _{10 group} or R ₉ represents a cyclic linear or branched hydrocarbon radical at dC ₆ , and R ₁₀ represents a hydrocarbon radical, linear cyclic or branched in Ci-Ce and their cosmetically acceptable salts and complexes 2 Derivatives according to claim 1, characterized in that R is a group - NRιR ₂ , where R, is a hydrogen atom and R ₂ represents a hydrocarbon radical, linear, cyclic or branched, in dC ₆ , optionally mono- or polyhydroxylated, substituted by one or more COOH and / or -NH _{2 groups} 3 derivatives according to claim 1, characterized in that R is a group O ° - 4 where R ₃ = R ₄ = H and X represents an oxygen atom 4 Drifts according to claim 1, characterized in that R is a group - CH (R ₆ ) -NH (R ₇ ) where R ₆ is a linear hydrocarbon group in dC ₆ the end of the chain of which carries a group -OH or -COOH or -NH ₂ and R- is a hydrogen atom 5. Derivatives according to claim 1 characterized in that R is a group - CH (R ₆ ) -NH-R ₇ where R ₆ and R ₇ each represent a hydrogen atom 6 Composition comprising in a physiologically acceptable medium at least one DHEA derivative as defined in any one of claims 1 to 5 7. Composition according to claim 6, characterized in that it contains from 0.01 to 10% by weight of DHEA derivative, relative to the total weight of the composition 8 Composition according to Claim 7, characterized in that it contains 1 to 5% by weight of DHEA derivative, relative to the total weight of the composition 9 Composition according to any one of claims 6 to 8, characterized in that it also contains at least at least one UV filter and / or a depigmenting agent and / or a keratolytic agent 10. Composition according to claim 9, characterized in that said UV filter is chosen from dibenzoylmethane derivatives and in particular 4- (ter -butyl) 4'-methoxy dibenzoylmethane and 4-ιsopropyl-dιbenzoylmethane, the active filters in UVA derivatives of benzylidene camphor, such as 1-4 benzene acid [dι (3-methylιdènecampho 10-sulfonιque)}, active filters in UVB derived from benzylidene camphor, and in particular 4-methyl benzylidene camphor , active filters in UV-B of the benzimidazole or benzoxazole type, such as 2-phenyl benzimidazole 5-sulfonιque acid, benzophenone derivatives especially chosen from the group consisting of 2-hydroxy-4-methoxy-benzophenone , 2-hydroxy-4-methoxy-benzophenone-5-sulfonic acid and its sodium sulfonate form, the silane derivatives or the polyorganosiloxanes containing a benzophenone group, the benzotnazoles and benzotnazole sihcones; tnazine derivatives, in particular 2,4,6-tπs [p- (2'-ethylhexyl-1'- oxy-carbonyl) anιlιno] -1, 3,5-tπazιne, cinnamic acid derivatives such that the para-methoxy cinnamate of 2-ethylhexyl, the 2-cyano-33-dιphenylacrylate of alkyl and preferably, octocrylene, the compound of formula (I) below, or 2- (2H- benzotπazole-2- yl) -4-methyl-6- [2-methyl-3- [1, 3,3,3-tetramethyl-1 - [(tπméthylsιlyl) oxy] dιsiloxanyi] propynyl] phenol

and their mixtures 11 Composition according to Claim 9, characterized in that the said depigmenting agent is chosen from kojic acid, ellagic acid, arbutin and its derivatives, hydroquinone, aminophenol derivatives such as N-cholesteryloxycarbonyl- para-aminophenol and N-ethyloxycarbonyl-para-aminophenol L-2-oxothιazolιdιne-4-carboxylic acid or procysteine, as well as its salts and esters ascorbic acid and its derivatives, in particular ascorbyl glucoside, and extracts plants especially mulberry licorice and skullcap 12 Composition according to Claim 9, characterized in that the said keratolytic agent is chosen from α-hydroxy acids such as citric, lactic, glycolic, mandelic, malic and tartaric acids, β-hydroxy acids and in particular salicylic acid and its derivatives , α-keto acids and β-keto acids, retinoids and in particular retinol and retinyl esters; HMG-CoA reductase inhibitors, and sugar derivatives such as 0-octanoyl-6'-β-D-maltose 13 Composition according to any one of claims 9 to 12, characterized in that it also contains at least one compound chosen from (a) a tightening agent such as a vegetable protein or a synthetic polymer, in particular a grafted silicone polymer , and (b) a lipolytic agent, firming and / or acting on the micro-circulation, such as an xanthic base, a plant extract such as an extract of Bupleurum Chinensis, climbing ivy, escin, ruscus, ginseπg or gingko biloba, or an extract of marine origin such as an alga extract 14 DHEA derivative according to any one of claims 1 to 5 as a medicament. 15 Use of a DHEA derivative according to any one of claims 1 to 5 for the manufacture of a dermatological composition intended to be administered topically to the skin or the hair 16 Use of a DHEA derivative according to any one of claims 1 to 5 for the manufacture of a composition intended to be administered orally 17 Cosmetic use of a derivative according to any one of Claims 1 to 5 as an agent for preventing or correcting intrinsic or extrinsic aging, atrophy of the skin, dryness of the skin, papery appearance of the skin, sagging skin, the formation of wrinkles and fine lines and / or loss of radiance and / or to regulate the pigmentation of the skin or hair 18 Use of a derivative according to any one of claims 1 to 5 for the manufacture of a composition intended to prevent or treat the symptoms of menopause AMENDED CLAIMS [received by the International Bureau on September 17, 2001 (17.09.01); claims 1, 4 amended; claim 5 deleted; claims 6-18 renumbered as claims 5-17; other claims unchanged (5 pages)] 1. DHEA derivatives having the following general formula (I)

in which R is chosen from (a) a group -NR ^, WHERE Ri is chosen from a hydrogen atom and a linear, cyclic or branched, Cι-C ₆ hydrocarbon radical, optionally substituted by one or more groups -OH and / or COOH and / or -NH ₂ , and R ₂ represents a linear, cyclic or branched, Cι-C ₆ hydrocarbon radical, optionally mono- or polyhydroxylated, substituted by one or more COOH and / or -NH _{2 groups} , (b) a group

OR X represents an oxygen atom or an amino group, and R ₃ , R, identical or different, represent a hydrogen atom or a group -COR ₅ , R5 representing a hydrocarbon radical, linear, cyclic or branched, in dC ₆ , optionally substituted by one or more groups -OH -COOH or -NH ₂ , (c) a group -CH (R ₆ ) -NH-R ₇ where R ₆ represents a hydrogen atom or a hydrocarbon radical, linear, cyclic or branched, C -Ce, substituted by one or more groups -OH, -COOH and / or NH _2. And R ₇ represents a hydrogen atom or a group -COR ₈ , R ₈ representing a hydrocarbon radical, linear, cyclic or branched, C -Ce or an alkoxy radical dC ₆ ; it being understood that when R ₇ represents a hydrogen atom, then R ₆ is different from a hydrogen atom and from a CH ₂ -COOH group; (d) a group -CH (R ₉ ) -NH-CORι ₀ where: R ₉ represents a linear, cyclic or branched hydrocarbon radical at dC ₆ , and Rio represents a linear, cyclic or branched hydrocarbon radical at Ci-Ce and their cosmetically acceptable salts and complexes. 2. Derivatives according to claim 1, characterized in that R is a group - R ^, where Ri is a hydrogen atom and R ₂ represents a hydrocarbon radical, linear, cyclic or branched, Ci-Ce, optionally mono- or polyhydroxylated, substituted by one or more COOH and / or -NH _{2 groups} . 3. Derivatives according to claim 1, characterized in that R is a group

where R ₃ = R = H and X represents an oxygen atom. 4. Derivatives according to claim 1, characterized in that R is a group -CH (R ₆ ) -NH (R ₇ ) where R ₆ is a linear Ci-Ce hydrocarbon group the end of the chain of which carries a group -OH or -NH ₂ or else a linear C ₂ -C ₆ hydrocarbon group the end of the chain of which carries a group -COOH and R ₇ is a hydrogen atom. 5. Composition comprising, in a physiologically acceptable medium, at least one DHEA derivative as defined in any one of claims 1 to 4. 6. Composition according to claim 5, characterized in that it contains from 0.01 to 10% by weight of DHEA derivative, relative to the total weight of the composition. 7. Composition according to claim 6, characterized in that it contains from 1 to 5% by weight of DHEA derivative, relative to the total weight of the composition. 8. Composition according to any one of claims 5 to 7, characterized in that it also contains at least at least one UV filter and / or a depigmenting agent and / or a keratolytic agent. 9. Composition according to claim 8, characterized in that said UV filter is chosen from: dibenzoylmethane derivatives and in particular 4- (ter.-butyl) 4'-methoxy dibenzoylmethane and 4-isopropyl-dibenzoylmethane; active filters in UVA derived from benzylidene camphor, such as benzene acid 1, 4- [di (3-methylidenecampho 10-sulfonic)]; filters active in UVB derived from benzylidene camphor, and in particular 4-methyl benzylidene camphor; filters active in UV-B of the benzimidazole or benzoxazole type, such as 2-phenyl benzimidazole 5-sulfonic acid; benzophenone derivatives especially chosen from the group consisting of: 2-hydroxy-4-methoxy-benzophenone, 2-hydroxy-4-methoxy-benzophenone-5-sulfonic acid, and its sodium sulfonate form; silane derivatives or polyorganosiloxanes containing a benzophenone group; benzotnazoles and benzotnazoles silicones; triazine derivatives, in particular 2,4,6-tris [p- (2'-ethylhexyl-1'-oxy-carbonyl) anilino] -1, 3,5-triazine; cinnamic acid derivatives such as 2-ethylhexyl para-methoxy cinnamate; alkyl 2-cyano-33-diphenylacrylate and, preferably, octocrylene; the compound of formula (I) below, or 2- (2H-benzotriazole-2-yl) -4-methyl-6- [2-methyl-3- [1, 3,3,3-tetramethyl-1 - [( trimethylsilyl) oxy] disiloxanyl] propynyl] phenol:

and their mixtures 10 Composition according to Claim 8, characterized in that the said depigmenting agent is chosen from kojic acid, ellagic acid, arbutin and its derivatives, hydroquinone, aminophenol derivatives such as N-cholesteryloxycarbonyl- para-aminophenol and N-ethyloxycarbonyl-para-aminophenol, L-2-oxothιazolιdιne-4-carboxylic acid or procysteine, as well as its salts and esters, ascorbic acid and its derivatives, in particular ascorbyl glucoside, and plant extracts, in particular licorice, mulberry and skullcap 11 Composition according to Claim 8, characterized in that the said keratolytic agent is chosen from α-hydroxy acids such as citric, lactic, glycolic, mandelic, mahic and tartaric acids, β-hydroxy acids and in particular sahcyiic acid and its derivatives , α-keto acids and β-keto acids, retinoids and in particular retinol and retinyl esters, HMG-CoA reductase inhibitors, and sugar derivatives such as 0-octanoyl-6'-β- D-maltose 12. Composition according to any one of claims 8 to 11, characterized in that it also contains at least one compound chosen from (a) a tightening agent such as a vegetable protein or a synthetic polymer, in particular a grafted silicone polymer, and (b) a lipolytic agent, firming and / or acting on the micro-circulation, such as an xanthic base, a plant extract such as an extract of Bupleurum Chinensis, climbing ivy, escin, ruscus, ginseng or gingko biloba, or an extract of marine origin such as an alga extract 13. DHEA derivative according to any one of claims 1 to 4 as a medicament. 14. Use of a DHEA derivative according to any one of claims 1 to 4 for the manufacture of a dermatological composition intended to be administered topically to the skin or the hair. 15. Use of a DHEA derivative according to any one of claims 1 to 4 for the manufacture of a composition intended to be administered orally 16. Cosmetic use of a derivative according to any one of claims 1 to 4 as an agent for preventing or correcting intrinsic or external aging, atrophy of the skin, drying of the skin, papery appearance of the skin , sagging skin, the formation of wrinkles and fine lines and / or loss of radiance and / or to regulate the pigmentation of the skin or hair. 17. Use of a derivative according to any one of claims 1 to 4 for the manufacture of a composition intended to prevent or treat the symptoms of menopause.