Novel 1-phenylmono- or -polyhydroxypropane compounds, compositions and cosmetic uses thereof

The present invention relates to the use of 1-phenylmono- or -polyhydroxypropane derivatives for combating aging of the skin and also relates to novel 1-phenylmono- or -polyhydroxypropane derivatives, and to compositions, especially cosmetic compositions, comprising them.

Women and men currently have a tendency to wish to appear youthful for as long as possible and consequently seek to tone down the signs of aging of the skin, which are reflected especially by wrinkles and fine lines. In this regard, the advertising and fashion industries mention products for retaining radiant and wrinkle-free skin, which are signs of youthful skin, for as long as possible, all the more so since physical appearance has an effect on the psyche and/or on morale.

Hitherto, wrinkles and fine lines were treated using cosmetic products containing active agents acting on the skin, for example by improving its cell renewal or alternatively by promoting the synthesis, or preventing the degradation, of the elastic fibers which make up skin tissue.

The skin consists of two compartments, a surface compartment, the epidermis, and the other deeper compartment, the dermis, which interact. Natural human epidermis is composed mainly of three types of cells, namely keratinocytes, which form the vast majority, melanocytes and Langerhans cells. Each of these three types of cells contributes, by virtue of its intrinsic functions, to the essential role played in the body by the skin, especially the role of protecting the body against external attacking factors, which is known as the "barrier function".

The epidermis is conventionally divided into a basal layer of keratinocytes that constitutes the germinative layer of the epidermis, a spinous layer consisting of several layers of polyhedral cells positioned on the germinative layers, one to three "granular" layers consisting of flattened cells containing distinct cytoplasmic inclusions, keratohyalin granules, and finally the cornified layer (or stratum corneum), consisting of a set of layers of keratinocytes at the terminal stage of their differentiation, known as corneocytes. Corneocytes are anuclear cells mainly consisting of a fibrous material containing cytokeratins, surrounded by a cornified envelope.

The dermis provides the epidermis with a solid support. It is also its nourishing element. It consists mainly of fibroblasts and of an extracellular matrix predominantly composed of collagen, elastin and a substance, known as ground substance, comprising glycosaminoglycans that are sulfated (e.g. chondroitin sulfate) or not (e.g. hyaluronic acid), proteoglycans and various proteases. These components are synthesized by the fibroblasts. Leukocytes, mast cells or else tissue macrophages are also found therein. Finally, blood vessels and nerve fibers pass through the dermis. The cohesion between the epidermis and the dermis is provided by the dermo-epidermal junction.

The epidermis is constantly engaged in producing new keratinocytes to compensate for the continuous loss of epidermal cells at the cornified layer. However, in the course of aging, a decrease in the number of cells in the proliferation phase, and consequently a decrease of the live epidermal layers, may be observed physiologically.

The homeostasis of the skin, and in particular of the epidermis, results from a finely regulated balance between the processes of proliferation and of differentiation of the skin cells. These processes of proliferation and differentiation are entirely regulated: they participate in the renewal and/or regeneration of the skin and lead to the maintenance of a constant thickness of the skin, and in particular of a constant thickness of the epidermis. This homeostasis of the skin also participates in maintaining the mechanical properties of the skin.

However, this homeostasis of the skin may be impaired by certain physiological factors (age, menopause, hormones, etc.) or environmental factors (UV stress, oxidative stress, irritant stress, etc.).

The proliferative cells are metabolically very active and are sensitive to these deleterious factors (intrinsic or environmental), with, as a consequence on the epidermis, a reduction in their amount. Certain biochemical markers characterize this loss of regenerative capacity of the epidermis such as the Sab galactosidase activity (Dimri GP, et al. Proc Natl Acad Sci U S A. 1995) or markers of impairment of the cell cycle such as pl6(INK4a) (Cordisco S & al, J Invest Dermatol. 2010).

It is thus important to preserve this pool of cells in order to contribute toward delaying the onset of the signs of aging.

The cellular vitality of the keratinocytes may be decreased especially in the context of aging or on account of oxidative stress (for example solar radiation, i.e. UV, visible light, infrared), on account of attack of the epidermis by toxins or metabolites of the microflora, or, more generally, during chronological aging. The capacity for renewal and differentiation of the keratinocytes is reduced and the homeostasis of structures dependent thereon, such as the barrier function of the epidermis, is impaired.

When the regenerative potential of the epidermis becomes smaller: the cells of the basal layer divide less actively, leading especially to a slowing-down and/or decrease in epidermal renewal. Consequently, the cell renewal no longer compensates for the loss of cells removed at the surface, leading to atrophy of the epidermis and/or a reduction in skin thickness. This is likewise the case for the proliferative cells of the epidermal appendages, for example the nails, the consequence of which is a slowing-down of the growth of the nails.

The impairments in epidermal homeostasis are also reflected by a dull and/or off-color appearance of the skin complexion.

Impairment of the barrier function is manifested by various signs depending on the localization: dry skin, hyperkeratosis, thin epidermis, thin lips, surface wrinkles.

The disorders associated with impairment of the cellular vitality of the epidermis thus concern not only its structure, but also its homeostasis. The resistance to stress of the epidermis and its capacity for regeneration are reduced. If the skin barrier of an elderly person is compared with that of a young adult, the differences do not appear at first sight: the thickness of the cornified layer and the composition of its lipids are not necessarily altered, and the barrier function expressed by the transepidermal water loss is conserved. The deficiencies of the elderly skin barrier appear under mechanical stress or during exposure to irritant factors: the barrier of an elderly epidermis degrades more rapidly and its function recovers less quickly. On a daily basis, alcoholic disinfection, contact with lemon juice or other irritants then cause stinging and burning, and dry air is poorly tolerated, whereas a young skin tolerates this without any problem. An impaired skin barrier also facilitates the contact of allergens with the immune system of the epidermis, thus increasing the risk of allergic sensitization.

At the present time, there is not sufficient evidence to prove that senescent cells accumulate with age in the body. Senescence-associated β-galactosidase is a marker of senescent cells and its accumulation has been shown in vivo in the skin (Dimai GP et al Proc Nat Acad. SCI U S A. 1995; 92(20): 9363-7).

Another marker of senescence is the impairment of mitochondrial functioning. The role of the mitochondrion is to produce cellular energy.

The clinical signs of the phenomenon of photoaging have been widely described (Photodermatol Photoimmunol Photomed. 2008 (4) Fourtanier A, Moyal D, Seite S.).

Intrinsic aging, also known as chronological aging, of the skin is described as a result of an impairment in cellular vitality similar to what takes place in the other organs. Intrinsic or chronological aging is manifested by other clinical markers and signs, in particular the impairment of the barrier function as described above (Farage MA et al. 2009; 10(2): 73-86).

These esthetic disorders such as dry skin, wrinkles, fine lines, etc. are such that there is a need in cosmetics for compounds acting on the skin to improve the cellular vitality when it is impaired.

AMPK is present in all the cells of the body and plays an energy gauge role therein. AMPK (or 5 '-adenosine monophosphate activated protein kinase) is a heterotrimeric enzyme composed of a catalytic subunit a with kinase activity and two regulatory subunits β and γ. The activity of AMPK depends on the variation of the AMP/ATP ratio which characterizes the energy level of the cell (ATP being hydrolyzed into AMP to "deliver" the energy required for the various biochemical processes of the cell). It is present in two forms, phosphorylated or non-phosphorylated, the phosphorylated form being the active form.

When it is activated in response to an energy demand or a stress of the cell, AMPK increases the energy-generating processes such as glycolysis and it inhibits the nonessential consuming processes, thus enabling cell survival. Preservation of the cellular energy status is involved in maintaining the longevity of the species and combating the signs of aging. Thus, compounds that are capable of increasing the activity of AMPK are at the present time the object of great interest in the treatment of age-related clinical manifestations. The value in transposing this approach, validated for the whole organism, to the skin in the context of preventing its age-related impairment may be understood.

The AMPK activity corresponds to the cellular concentration of phosphorylated AMPK. Thus, it is worthwhile having the highest possible levels of phosphorylated protein in order to have this high activity.

The role of AMPK in controlling the energy metabolism of the keratinocyte is suspected at the present time (Prahl et al, Biofactors. 2008;32(l-4):245-55), its involvement in the proliferation and differentiation of the keratinocyte has been established (Saha AK et al. Biochem Biophys Res Commun. 2006 Oct 20; 349(2): 519-24).

WO 2004/05098 proposes to modulate the lifetime of any cell or of an organism by controlling the activity of AMPK, and to treat age-related disorders by administering modulators of the AMPK metabolic pathway, without stating whether it involves an activator or an inhibitor.

Saha et al. (Biochem. Biophys. Res. Commun 2006, 349:519-524) studied the AMPK-regulated growth of keratinocytes and conclude that AMPK activators such as AICAR promote the in vitro differentiation of keratinocytes.

It has been found, unexpectedly, in the context of the present invention, that certain 1-phenylmono- or -polyhydroxypropane derivatives described below are capable of stimulating the activity of AMPK, in particular the production of phosphorylated AMPK by normal human keratinocytes. These compounds will thus be particularly useful for combating the decrease in the vitality of skin cells during aging, and retarding the onset of the signs associated therewith.

Other routes of action are possible in order to prevent or limit the consequences of aging of the skin, including in particular the stimulation of the synthesis of the structural molecules of the skin, such as collagen, and in particular collagen I, and also filaggrin.

The use according to the invention is a non-therapeutic use and advantageously a cosmetic use; the term "cosmetic" means intended to improve the esthetic appearance of the skin or its appendages such as the nails, especially to retard or reduce physiological modifications in the appearance, arising with age, of individuals in good health. These modifications may appear from the age of 30 or 35, but are generally more pronounced after the age of 40, and become accentuated at 50 and over.

The compounds according to the invention are effective for improving epidermal renewal and for more efficiently combating the signs of aging of the skin.

These compounds therefore find a particular application in cosmetic compositions intended for preventing and/or cosmetically treating aging of the skin; especially preventing and/or treating, in particular topically, the signs of aging of the skin, and most particularly the signs on the skin related to wrinkled skin, skin exhibiting impairment of its viscoelastic or biomechanical properties, skin exhibiting impairment in the cohesion of its tissues, thinned skin and/or skin exhibiting impairment of its surface appearance.

Specifically, it has now been found that 1-phenylmono- or -polyhydroxypropane derivatives are capable of stimulating the activation of AMPK by the keratinocytes.

As explained above, the activation of AMPK, in particular the increase of its phosphorylated form, corresponds to stimulation of the metabolic functions of keratinocytes: these cells are then in a state similar to those of young keratinocytes, and will contribute toward regulating the physiological mechanisms of cutaneous homeostasis.

The use of the compounds according to the invention may make it possible more particularly to maintain and/or restore the biomechanical properties of the skin.

The term "biomechanical properties of the skin" means herein the stretchability, tonicity, firmness, suppleness and/or elasticity properties of the skin.

The term "signs of aging of the skin" means herein any modification of the outer appearance of the skin due to aging, whether it is chronobiological and/or extrinsic aging, in particular photoinduced or hormonal aging; among these signs, it is possible to distinguish:

- wrinkled skin, which is reflected especially by the appearance of wrinkles and/or fine lines;

- skin exhibiting impairment of its viscoelastic or biomechanical properties, or skin exhibiting a lack of elasticity and/or of stretchability and/or of firmness and/or of suppleness and/or of tonicity, which is reflected in particular by wizened, flaccid, slack or saggy skin;

- skin exhibiting impairment of the cohesion of its tissues;

- thinned skin; and

- skin exhibiting impairment of its surface appearance, which is especially reflected by impairment of the grain of the skin, for example roughness.

The invention relates to the non-thera eutic use of a compound of formula (I) as an agent for preventing and/or reducing the signs of aging of the skin, especially the signs on the skin chosen from wrinkled skin, skin exhibiting impairment of its viscoelastic or biomechanical properties, skin exhibiting impairment in the cohesion of its tissues, thinned skin, and skin exhibiting impairment of its surface appearance.

Particularly the invention relates to the use, preferably non-therapeutic, of a compound of formula (I)

in which

- n = 0; 1; 2 or 3

- m = 0; 1; 2 or 3

with 1 < m + n < 3

- Rl independently denotes a linear C1-C6 alkyl radical or a branched C3-C6 alkyl radical or a linear C 1 -C6 acyl radical,

- R2 and R3 independently denote a hydrogen atom or an OH radical,

and also an optical isomer, stereoisomer and/or diastereoisomer thereof and/or salts thereof, provided that when Rl denotes methyl, R2 denotes a OH radical, and R3 denotes an hydrogen atom then 2 < m + n < 3,

as an agent for preventing and/or reducing the signs of aging of the skin, especially the signs on the skin chosen from wrinkled skin, skin exhibiting impairment of its viscoelastic or biomechanical properties, skin exhibiting impairment in the cohesion of its tissues, thinned skin, and skin exhibiting impairment of its surface appearance

The invention also relates to a composition, especially a cosmetic composition,

comprising, in a physiologically acceptable medium, at least one compound of formula (I) according to the invention.

Particularly the invention relates to a composition, especially a cosmetic composition, comprising, in a physiologically acceptable medium, at least one compound of formula (I) according to the invention, with the exception of the following compound;

The invention also relates to the non-therapeutic use of a composition, especially a cosmetic composition, comprising, in a physiologically acceptable medium, at least one compound of formula (I).

Particularly the invention relates to the non-therapeutic use of a composition, especially a cosmetic composition, comprising, in a physiologically acceptable medium, at least one compound of formula (I) in which when Rl denotes methyl, R2 denotes a OH radical, and R3 denotes an hydrogen atom then 2 < m + n < 3.

The invention also relates to a non-therapeutic cosmetic process for treating the skin, comprising the application to the skin of at least one compound of formula (I) and/or of a cosmetic composition containing at least one compound of formula (I) according to the invention. This process finds an advantageous application in the treatment of the skin, especially of mature skin (skin of individuals with age at least 40) and/or wrinkled skin, in particular of the face, especially of the forehead, the neck, the neckline and/or the hands. A subject of the invention is also a cosmetic treatment process, characterized in that it is intended for promoting the renewal of the keratinocytes and for reducing or preventing signs chosen from thinning of the epidermis, surface wrinkles and impairment of the barrier function.

Particularly the invention relates to a non-therapeutic cosmetic process for treating the skin, comprising the application to the skin of at least one compound of formula (I) in which when Rl denotes methyl, R2 denotes a OH radical, and R3 denotes an hydrogen atom then 2 < m + n < 3.

Particularly the invention relates a cosmetic composition containing at least one compound of formula (I) according to the invention with the exception of the following compound;

A subject of the present invention is also novel 1-phenylmono- or -polyhydroxypropane compounds of formulae (V) to (IX) as defined below.

A subject of the present invention is also compositions, especially cosmetic compositions, comprising, in a physiologically acceptable medium, at least one compound of formulae (V) to (IX).

The invention also relates to the non-therapeutic use of the novel compounds of formulae (V) to (IX) or of a composition, especially a cosmetic composition, of a novel compound of formulae (V) to (IX), in particular as an agent for preventing and/or reducing the signs of aging of the skin, especially the signs on the skin chosen from wrinkled skin, skin exhibiting impairment of its viscoelastic or biomechanical properties, skin exhibiting impairment in the cohesion of its tissues, thinned skin, and skin exhibiting impairment of its surface appearance.

The invention finally relates to a non-therapeutic cosmetic process for treating the skin, comprising the application to the skin of at least one novel compound of formulae (V) to (IX) and/or of a cosmetic composition containing at least one novel compound of formulae (V) to (IX) according to the invention. This process finds an advantageous application in the treatment of the skin, especially of mature skin and/or wrinkled skin, in particular of the face, especially of the forehead, the neck and/or the hands.

The compounds according to the invention thus correspond to formula (I) below:

in which

- n = 0; 1; 2 or 3

- m = 0; l; 2 or 3

with 1 < m + n < 3

- Rl independently denotes a linear C1-C6 alkyl radical or a branched C3-C6 alkyl radical or a linear C1-C6 acyl radical,

- R2 and R3 independently denote a hydrogen atom or a hydroxyl radical,

and also an optical isomer, stereoisomer and/or diastereoisomer thereof and/or salts thereof.

In an embodiment of the invention, .the compounds correspond to formula (I) below:

in which

- n = 0; 1; 2 or 3

- m = 0; 1; 2 or 3

with 1 < m + n < 3

- Rl independently denotes a linear C1-C6 alkyl radical or a branched C3-C6 alkyl radical or a linear C1-C6 acyl radical,

- R2 and R3 independently denote a hydrogen atom or an OH radical,

and also an optical isomer, stereoisomer and/or diastereoisomer thereof and/or salts thereof, provided that when Rl denotes methyl, R2 denotes a OH radical, and R3 denotes a hydrogen atom then 2 < m + n < 3.

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

Preferably salts compounds of formula (I) are calcium salts.

Preferably:

- n = 0; l; 2 or 3

- m = 0; 1; 2 or 3

with 2 < m + n < 3

- Rl independently denotes a linear C1-C6 alkyl radical or a branched C3-C6 alkyl radical or a linear C1-C6 acyl radical,

- R2 and R3 independently denote a hydrogen atom or an OH radical.

Preferably:

n = 0; 1; 2 or 3

m = 0; 1; 2 or 3

with 1 < m + n < 3

Each of the substituents Rl independently denotes a linear C1-C4 alkyl radical

R2 and R3 independently denote a hydrogen atom or a hydroxyl radical,

and also an optical isomer, stereoisomer and/or diastereoisomer thereof.

Preferentially, the linear saturated or branched alkyl groups may be chosen from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, more preferentially methyl.

Preferably:

n = 0; l; 2 or 3

m = 0; 1; 2 or 3

with 2 < m + n < 3

each of the substituents Rl independently denotes a linear C1-C4 alkyl radical; preferably denotes methyl;

R2 and R3 independently denote a hydrogen atom or a hydroxyl radical.

Even more preferably,

n = 0; 1; 2 or 3

m = 0; 1; 2 or 3

with 2 < m + n < 3

Each of the substituents Rl denotes methyl

R2 and R3 independently denote a hydrogen atom or a hydroxyl radical,

and also an optical isomer, stereoisomer and/or diastereoisomer thereof.

In a first preferred variant of the invention, among the compounds of formula (I), or an optical isomer, stereoisomer and/or diastereoisomer thereof and/or salts thereof, the compounds for which R2 denotes a hydrogen atom or a hydroxyl radical and R3 denotes a hydrogen atom will preferably be chosen,

i.e. the compounds corresponding to formula (II) below:

in which:

n = 0; 1; 2 or 3

m = 0; 1; 2 or 3

with 1 < m + n < 3

- each of the substituents Rl independently denotes a linear C1-C6 alkyl radical or a branched C3-C6 alkyl radical or a linear C1-C6 acyl radical,

R2 denotes a hydrogen atom or a hydroxyl radical.

Preferably:

- n = 0; 1; 2 or 3

- m = 0; l; 2 or 3

with 2 < m + n < 3

- Rl independently denotes a linear C1-C6 alkyl radical or a branched C3-C6 alkyl radical or a linear C1-C6 acyl radical,

- R2 and R3 independently denote a hydrogen atom or an OH radical.

Preferably:

n = 0; 1; 2 or 3

m = 0; 1; 2 or 3

with 1 < m + n < 3

- each of the substituents Rl independently denotes a linear C1-C4 alkyl radical

- R2 denotes a hydrogen atom or a hydroxyl radical.

Preferably:

n = 0; 1; 2 or 3

m = 0; l; 2 or 3

with 2 < m + n < 3

each of the substituents Rl independently denotes a linear C1-C4 alkyl radical; preferably denotes methyl;

R2 and R3 independently denote a hydrogen atom or a hydroxyl radical.

Even more preferably,

n = 0; 1; 2 or 3

m = 0; 1; 2 or 3

with 2 < m + n < 3

Rl denotes methyl

R2 denotes a hydrogen atom or a hydroxyl radical.

Among the compounds of formula (II), compounds 1 to 4 and 7 below, the optical isomers, stereoisomers and diastereoisomers thereof and/or geometrical isomers thereof and/or salts thereof will be chosen more particularly:

In a second preferred variant of the invention, among the compounds of formula (I), or an optical isomer, stereoisomer and/or diastereoisomer thereof and/or salts thereof, the compounds for which R2 denotes a hydrogen atom and R3 denotes a hydroxyl radical, i.e. the compounds corresponding to formula (III), will preferably be chosen,

in which:

n = 0; 1; 2 or 3

m = 0; 1; 2 or 3

with 1 < m + n < 3

- each of the substituents Rl independently denotes a linear C1-C6 alkyl radical or a branched C3-C6 alkyl radical or a linear C1-C6 acyl radical,

Preferably:

n = 0; 1; 2 or 3

m = 0; 1; 2 or 3

with 1 < m + n < 3

- each of the substituents Rl independently denotes a linear C1-C4 alkyl radical.

Even more preferably,

n = 0; 1; 2 or 3

m = 0; l; 2 or 3

with 2 < m + n < 3

Rl denotes methyl

Among the compounds of formula (III), compounds 5 and 6 below, the optical isomers, stereoisomers and diastereoisomers thereof or geometrical isomers thereof and/or salts thereof will be chosen more particularly preferably, and even more particularly compound 5 :

Preferably among the compounds of formula (III), calcium salts of compounds 5 and 6 above will be chosen more particularly, and even more particularly calcium salt of compound 5.

A subject of the invention is also the novel compounds of formulae (V) to (IX) below:

Formula (V):

(V)

in which:

n = 1 or 2

each of the substituents Rl independently denotes a hydrogen atom or a linear C1-C6 alkyl or a branched C3-C6 alkyl

Formula (VI):

(WE)

in which:

when R2 denotes a hydroxyl radical, then R3 denotes a hydrogen atom,

- when R2 denotes a hydrogen atom, then R3 denotes a hydroxyl radical,

each of the substituents Rl independently denotes a hydrogen atom or a linear C1-C6 alkyl or a branched C3-C6 alkyl

Formula (VII):

in which:

R3 denotes a hydrogen atom or a hydroxyl radical

each of the substituents Rl independently denotes a hydrogen atom or a linear C1-C6 alkyl or a branched C3-C6 alkyl

Formula (VIII):

in which:

when R2 denotes a hydroxyl radical, then R3 denotes a hydrogen atom,

when R2 denotes a hydrogen atom, then R3 denotes a hydroxyl radical,

each of the substituents Rl independently denotes a hydrogen atom or a linear C1-C6 alkyl or a branched C3-C6 alkyl

Formula (IX):

(IX)

in which Rl denotes a hydrogen or a linear C1-C6 alkyl or a branched C3-C6 alkyl.

The compounds corresponding to formula (I) may be prepared according to four reaction sequences, depending on the substitution unit of the propane unit (values of R2 and R3).

Case where R2 = R3 = H

m, n and Rl having the same meaning as previously.

A solution of m-CPBA (1-5 eq.) in an aprotic solvent such as dichloromethane is added dropwise to the alkene predissolved in the same solvent. The reaction mixture is stirred (0°C- 50°C) for 1-72 hours and then worked up with aqueous Na2S03 solution (cone. 5-20%) to neutralize the excess oxidizing agent. The phases are separated and the organic phase is washed twice with a basic aqueous solution such as aqueous 10%> NaHC03 solution, dried and concentrated. The residue may be purified by column chromatography on silica gel.

Advantageously, when m = 0, compound (I) may be obtained directly by alkylation of the corres onding phenol derivative.

Rl and n having the same meaning as previously.

Propylene oxide (1-10 eq.) is added dropwise to a solution of the phenol derivative (1 eq.) in an organic solvent such as THF at 0-70°C. A solution of n-BuLi in hexane (for example a commercial 1.6 M solution (0.1-2 eq.) is added dropwise and the reaction mixture is then stirred at room temperature for 1-24 hours. The excess base is neutralized by adding saturated aqueous NH4C1 solution and the mixture is extracted with an organic solvent such as ethyl acetate or dichloromethane. The organic phases are combined, dried and concentrated. The residue is purified by column chromatography on silica gel.

Case where R2 = OH, R3 = H

(OH),

Rl, m and n having the same meaning as previously.

When m > 1, Prot denotes a hydroxyl- function protecting group, in particular -CO-CH3 or

a) protection of the free phenol functions according to the standard methods known to those skilled in the art (see, for example, Greene's Protective Groups in Organic Synthesis, P. G. M. Wutz, T. Greene, ed. Wiley-Blackwell), for example by using the acetate group or the benzyl group as protecting group;

b) dihydroxylation of the corresponding protected styrenes:

The reaction may be performed using the commercial Sharpless systems AD-mix-a (available from the supplier Sigma USA under the reference 392758) or AD-mix-β (available from the supplier Sigma USA under the reference 392766).

The oxidizing system AD-mix (1-3 eq.) and the protected styrene derived from the first step are dissolved in an alkanol water two-phase mixture such as the t-BuOH/water mixture in 1/1 proportions and the medium is stirred at 0-50°C until dissolution is complete.

The reaction medium is heated at 0-70°C for 2-96 hours. After cooling to room temperature, it is stirred in contact with sodium sulfite to neutralize the peroxides. The product is extracted with an organic solvent such as ethyl acetate and the organic phases are combined, dried and concentrated. The residue is purified by column chromatography on silica gel.

c) deprotection of the phenol functions, protected beforehand, according to the standard methods known to those skilled in the art (see, for example, Greene's Protective Groups in

Organic Synthesis, P. G. M. Wutz, T. Greene, ed. Wiley-Blackwell)

Case where R2 = OH, R3 = OH

(OH),

Rl, m and n having the same meaning as previously.

When m > 1, Prot denotes a hydroxyl- function protecting group, in particular -CO-CH3 or CH2-Ph.

a) protection of the free phenol functions according to the standard methods known to those skilled in the art (see, for example, Greene's Protective Groups in Organic Synthesis, P. G. M. Wutz, T. Greene, ed. Wiley-Blackwell), for example by using the acetate group or the benzyl group as protecting group;

b) dihydroxylation of the corresponding protected alkenes:

The reaction may be performed using the commercial Sharpless systems AD-mix-a (available from the supplier Sigma USA under the reference 392758) or AD-mix-β (available from the supplier Sigma USA under the reference 392766).

The oxidizing system AD-mix (1-3 eq.) and the protected alkene derived from the first step are dissolved in an alkanol water two-phase mixture such as the t-BuOH/water mixture in 1/1 proportions and the medium is stirred at 0-50°C until dissolution is complete.

The reaction medium is heated at 0-70°C for 2-96 hours. After cooling to room temperature, it is stirred in contact with sodium sulfite to neutralize the peroxides. The product is extracted with an organic solvent such as ethyl acetate and the organic phases are combined, dried and concentrated. The residue is purified by column chromatography on silica gel.

Alternatively, this dihydroxylation may be performed via an epoxidation/hydrolysis sequence. A solution of m-CPBA (1-5 eq.) in an aprotic solvent such as dichloromethane is added dropwise to the protected alkene derived from the first step (1 eq.), predissolved in the same solvent. The reaction mixture is stirred (0°C-50°C) for 1-72 hours and then worked up with aqueous Na2S03 solution (cone. 5-20%) to neutralize the excess oxidizing agent. The phases are separated and the organic phase is washed twice with a basic aqueous solution such as aqueous 10%> NaHC03 solution, dried and concentrated. The residue is purified by column chromatography on silica gel.

The product thus isolated is dissolved in an aprotic solvent such as dichloromethane and an acidic aqueous solution, such as aqueous 1-20% sulfuric acid solution, is added at 0-30°C. The reaction mixture is stirred at room temperature for 1-96 hours and the solvent is then removed by evaporation. The aqueous solution obtained is extracted three times with an organic solvent, such as ethyl acetate or diethyl ether. The organic phases are combined, dried and then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel.

c) deprotection of the phenol functions, protected beforehand, according to the standard methods known to those skilled in the art (see, for example, Greene's Protective Groups in Organic Synthesis, P. G. M. Wutz, T. Greene, ed. Wiley-Blackwell)

Case where R2 = R3 = OH

The derivatives of formula (I) such that R2 = R3 = OH may be obtained by dihydroxylat the corresponding allylic alcohols, protected beforehand.

CLAIMS

1.Use of a compound of formula (I)

in which

- n = 0; 1; 2 or 3

- m = 0; 1; 2 or 3

with l < m + n < 3

- Rl independently denotes a linear C1-C6 alkyl radical or a branched C3-C6 alkyl radical or a linear C1-C6 acyl radical,

- R2 and R3 independently denote a hydrogen atom or an OH radical,

and also an optical isomer, stereoisomer and/or diastereoisomer thereof and/or salts thereof, provided that when Rl denotes methyl, R2 denotes a OH radical, and R3 denotes a hydrogen atom then 2 < m + n < 3,

as an agent for preventing and/or reducing the signs of aging of the skin, especially the signs on the skin chosen from wrinkled skin, skin exhibiting impairment of its viscoelastic or biomechanical properties, skin exhibiting impairment in the cohesion of its tissues, thinned skin, and skin exhibiting impairment of its surface appearance.

2. Use of a compound of formula (I)

in which

- n = 0; 1; 2 or 3

- m = 0; 1; 2 or 3

with 2 < m + n < 3

- Rl independently denotes a linear C1-C6 alkyl radical or a branched C3-C6 alkyl radical or a linear C1-C6 acyl radical,

- R2 and R3 independently denote a hydrogen atom or an OH radical,

and also an optical isomer, stereoisomer and/or diastereoisomer thereof and/or salts thereof,

as an agent for preventing and/or reducing the signs of aging of the skin, especially the signs on the skin chosen from wrinkled skin, skin exhibiting impairment of its viscoelastic or biomechanical properties, skin exhibiting impairment in the cohesion of its tissues, thinned skin, and skin exhibiting impairment of its surface appearance.

3. The use as claimed in claim 1 or 2, characterized in that, in the compound of formula (I): n = 0; 1; 2 or 3

m = 0; 1; 2 or 3

with 2 < m + n < 3

each of the substituents Rl independently denotes a linear C1-C4 alkyl radical; preferably denotes methyl;

R2 and R3 independently denote a hydrogen atom or a hydroxyl radical.

4. The use as claimed in any one of claims 1 to 3, characterized in that the compound of formula (I) is a compound of formula (II):

in which:

n = 0; 1; 2 or 3

m = 0; 1; 2 or 3

with 2 < m + n < 3

- each of the substituents Rl independently denotes a linear C1-C6 alkyl radical or a branched C3-C6 alkyl radical or a linear C1-C6 acyl radical,

- R2 denotes a hydrogen atom or a hydroxyl radical.

5. The use as claimed in claim 4, in which:

- n = 0; 1; 2 or 3

m = 0; 1; 2 or 3

with 2 < m + n < 3

- each of the substituents Rl independently denotes a linear C1-C4 alkyl radical, preferably denotes methyl;

- R2 denotes a hydrogen atom or a hydroxyl radical.

6. The use as claimed in any one of claims 1 to 5, characterized in that the compound of formula (I) or (II) is chosen from compounds 1 to 4 and 7 below, the optical isomers, stereoisomers and diastereoisomers thereof and/or geometrical isomers thereof and/or salts thereof:

7. The use as claimed in either of claims 1, 2 and 3, characterized in that the compound of formula (I) is a compound of formula (III):

in which:

n = 0; 1; 2 or 3

m = 0; 1; 2 or 3

with 1 < m + n < 3

- each of the substituents Rl independently denotes a linear C1-C6 alkyl radical or a branched C3-C6 alkyl radical or a linear C2-C6 acyl radical.

8. The use as claimed in any one of claims 1, 2, 3 or 7, characterized in that the compound of formula (I) or (III) is chosen from compounds 5 and 6 below, the optical isomers, stereoisomers and diastereoisomers thereof or geometrical isomers thereof and/or salts thereof, and even more particularly compound 5:

9. The use as claimed in any one of the preceding claims, characterized in that the compound of formula (I) is present, in a composition containing a physiologically acceptable medium, at a concentration of between 0.0001% and 40% by weight relative to the total weight of the composition.

10. A cosmetic treatment process for reducing or preventing the signs of aging of the skin, characterized in that a compound of formula (I) or a composition containing it, as defined in any one of the preceding claims, is applied to the skin, in particular mature and/or wrinkled skin.

11. The cosmetic treatment process as claimed in the preceding claim, characterized in that it is intended for promoting the renewal of the keratinocytes and for reducing or preventing signs chosen from thinning of the epidermis, surface wrinkles and impairment of the barrier function.

12. A compound of formulae (V) to (IX):

Formula (V):

in which:

n = 1 or 2

each of the substituents Rl independently denotes a hydrogen atom or a linear C1-C6 alkyl or a branched C3-C6 alkyl

Formula (VI):

(VI)

in which:

when R2 denotes a hydroxyl radical, then R3 denotes a hydrogen atom,

when R2 denotes a hydrogen atom, then R3 denotes a hydroxyl radical,

each of the substituents Rl independently denotes a hydrogen atom or a linear C1-C6 alkyl or a branched C3-C6 alkyl

Formula (VII):

in which:

R3 denotes a hydrogen atom or a hydroxyl radical

each of the substituents Rl independently denotes a hydrogen atom or a linear C1-C6 alkyl or a branched C3-C6 alkyl

Formula (VIII):

in which:

when R2 denotes a hydroxyl radical, then R3 denotes a hydrogen atom,

when R2 denotes a hydrogen atom, then R3 denotes a hydroxyl radical,

each of the substituents Rl independently denotes a hydrogen atom or a linear C1-C6 alkyl or a branched C3-C6 alkyl

Formula (IX):

(IX)

in which Rl independently denotes a hydrogen or a linear C1-C6 alkyl or a branched C3-C6 alkyl.

13. A cosmetic composition comprising, in a physiologically acceptable medium, at least one compound of formula (I) as defined in any one of claims 1 to 8, with the exception of the following compound;

14. The composition as claimed in the preceding claim, in which the compound of formula (I) is present, alone or as a mixture, in an amount of between 0.01% and 30% by weight, preferably between 0.1% and 10%> by weight and especially between 0.5%> and 5% by weight, relative to the total weight of the composition.

15. The composition as claimed in either of claims 13 and 14, comprising at least one cosmetic ingredient chosen from water; organic solvents, in particular C1-C6 alcohols and C2-C10 carboxylic acid esters; hydrocarbon-based oils, silicone oils, fluoro oils, waxes, pigments, fillers, dyes, surfactants, emulsifiers, cosmetic or dermato logical active agents, UV-screening agents, film-forming polymers, hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic thickeners, preserving agents, fragrances, odor absorbers and antioxidants.

16. The composition as claimed in one of claims 13 to 15, in which the physiologically acceptable medium comprises at least one cosmetic active agent other than the compounds of formula (I), in particular chosen from: desquamating agents; moisturizers; depigmenting or propigmenting agents; anti-glycation agents; NO-synthase inhibitors; agents for stimulating the synthesis of dermal or epidermal macromolecules and/or for preventing their degradation; agents for stimulating fibroblast and/or keratinocyte proliferation or for stimulating keratinocyte differentiation; dermo-decontracting agents; tensioning agents; agents acting on microcirculation; agents acting on the energy metabolism of cells; and mixtures thereof.

17. A composition, especially a cosmetic composition, comprising, in a physiologically acceptable medium, at least one novel compound of formulae (V) to (IX).

18. A non-therapeutic cosmetic process for treating the skin, comprising the application to the skin of a cosmetic composition as defined in any one of claims 13 to 17.

19. The process as claimed in the preceding claim, in which the composition is applied to mature and/or wrinkled skin.