2-Fluoro-4-[ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoate derivatives; compositions containing same; cosmetic uses

FIELD OF THE INVENTION

The invention relates to novel 2-fluoro-4- [ (3, 3, 3- trifluoro-2-hydroxy-2-methylpropanoyl) amino] benzoate derivatives of particular formula (I) that will be defined below.

The present invention also relates to compositions comprising, in a physiologically acceptable medium, at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoate derivative of formula (I) that will be defined in detail below, and also to the salts and/or solvates thereof.

The present invention also relates to the cosmetic use of at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy- 2-methylpropanoyl) amino] benzoate derivative of formula (I) that will be defined in detail below, and also the salts and/or solvates thereof, in a composition comprising a physiologically acceptable medium, with the aim of reinforcing and/or preserving the natural antioxidant protection of the skin, in particular the endogenous antioxidant defence system in the face of oxidative stress, in particular induced by UV radiation .

BACKGROUND OF THE INVENTION

The human keratin fibres to which the invention applies are in particular the hair, the eyebrows, the eyelashes, beard hair, moustache hair and pubic hair. More especially, the invention applies to human hair and/or human eyelashes.

Hair growth and hair renewal are mainly determined by the activity of the hair follicles and of their matrix

environment. Their activity is cyclic and comprises essentially three phases, namely the anagenic phase, the catagenic phase and the telogenic phase.

The anagenic phase (active phase or growth phase) , which lasts several years and during which the hair gets longer, is followed by a very short and transient catagenic phase which lasts a few weeks. During this phase, the hair undergoes a change, the follicle becomes atrophied and its dermal implantation appears higher and higher.

The terminal phase or telogenic phase, which lasts a few months, corresponds to a resting phase of the follicle and the hair ends up falling out. At the end of this resting period, a new follicle is generated, in situ, and another cycle begins again.

The head of hair is thus under permanent renewal and, out of the approximately 150 000 hairs that make up a head of hair, approximately 10% are at rest and will be replaced within a few months.

The natural loss or falling-out of the hair may be estimated, on average, as being a few hundred hairs per day for a normal physiological state. This process of permanent physical renewal undergoes a natural change during ageing; the hairs become finer and their cycles shorter .

Furthermore, various causes may result in a substantial, temporary or permanent loss of hair. This may be loss and impairment of hair at the end stage of pregnancy (post-partum) , during states of dietary malnutrition or imbalance, during physiological stress or else during states of asthenia or of hormonal dysfunction, as may be the case during or at the end state of the menopause. It may also be a case of loss or impairment of the hair related to seasonal phenomena .

It may also be a question of alopecia, which is essentially due to a disturbance in hair renewal, resulting, in a first stage, in acceleration of the frequency of the cycles to the detriment of the quality of the hair, and then of their quantity. The successive growth cycles result in hairs that are finer and finer and shorter and shorter, gradually transforming into an unpigmented down. Certain areas are preferentially affected, in particular the temporal or frontal lobes in men, and a diffuse alopecia of the crown of the head is observed in women.

The term alopecia also covers an entire family of afflictions of the hair follicle whose final consequence is the permanent, partial or general loss of the hair. This more particularly involves androgenic alopecia. In a large number of cases, early loss of hair occurs in genetically predisposed individuals; this is then androchronogenetic alopecia; this form of alopecia especially affects men.

In certain forms of dermatosis of the scalp with an inflammatory characteristic, such as, for example, psoriasis or seborrhoeic dermatitis, hair loss may be greatly accentuated or lead to highly disturbed follicle cycles.

The colour of the hair and of human skin depends on various factors, and in particular on the seasons of the year, on race, on gender and on age. It is mainly determined by the concentration of melanin produced by melanocytes. The latter are specialized cells which, by means of particular organelles, melanosomes, synthesize melanin.

The synthesis of melanin (or melanogenesis) is complex and involves schematically the following main steps:

tyrosine —> dopa --> dopaquinone --> dopachrome —> melanin

Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxidoreductase EC 1.14.18.1) intervenes in this series of reactions by catalyzing in particular the reaction for conversion of tyrosine to dopa (dihydroxyphenyl- alanine) and the reaction for conversion of dopa to dopaquinone .

The upper part of the hair follicle appears as a tubular invagination of the epidermis, which extends down to the deep layers of the dermis. The lower part, or hair bulb, itself comprises an invagination in which the dermal papilla is found. Around the dermal papilla, in the lower part of the bulb, is an area populated with cells that have a high degree of proliferation

(matrix cells) . These cells are the precursors of the keratinized cells which will constitute the hair. The cells that result from the proliferation of these precursors migrate vertically in the bulb and gradually become keratinized in the upper part of the bulb; this assembly of keratinized cells will form the hair stem. Pigmentation of the hair and of body hairs requires the presence of melanocytes in the bulb of the hair follicle. These melanocytes are in an active state, i.e. they synthesize melanins (or melanin pigments) . These pigments are transferred to the keratinocytes intended to form the hair stem, which will give rise to the growth of a pigmented head hair or pigmented body hair. This structure is known as a "follicular pigmentation unit".

It is known that, in most populations, a brown skin coloration and maintenance of a constant coloration of the hair are important aspirations.

It is accepted that the appearance of grey or white body hairs and/or head hairs, or canities, is associated with a decrease in melanin in the hair stem.

This phenomenon occurs naturally during the life of an individual. However, people are seeking to have a younger appearance and, for aesthetic purposes, they are often tempted to combat this phenomenon, especially when it occurs at a relatively early age.

One of the causes of hair loss and/or of the appearance of grey or white body hairs and/or head hairs, or canities, is oxidative stress, in particular induced by ultraviolet radiation. While ultraviolet rays (UVs) are known to transiently improve certain skin conditions, many data from the literature establish their role in oxidative stress and their involvement in the acceleration of skin ageing (photoageing) . Ultraviolet radiation generates, in the skin, reactive oxygen species which weaken the cells by affecting the molecular and enzymatic antioxidant systems and result in degradation of the extracellular matrix and also in DNA damage in various cells (see Buechner et al . , 2008. Exp Gerontol, 43:7:633-637; Wlasteck et al . , 2001. J. Photochem Photobiol B, 63 (1-3) : 41-51; Kadekaro A. L. et al., 2003. Pig Cell Res, 16:434-447) .

The skin, the scalp and the hair are the outermost organs of our body and are therefore the first targets of environmental stress, represented in particular by

UVB and UVA ultraviolet radiation from sunlight. In fact, acute or chronic exposure to the sun is known to induce biological and clinical effects that are harmful to the organism.

Cutaneous damage associated with chronic (repeated irradiation) or acute (strong irradiation) exposure to UV-A or UV-B rays has been extensively studied; it is in particular known that:

- UV-B rays (290-300 nm; 5% of total UV range), which have the highest-energy wavelengths, above all affect the epidermal cells (keratinocytes) , by acting on DNA;

- UV-A rays (320-400 nm; 95% of the total UV range), which are more penetrating, reach the dermal cells such as the fibroblasts and act indirectly via the generation of free radicals; - furthermore, prolonged exposure to ultraviolet radiation has the effect of stimulating the expression of collagenases, particularly matrix metalloproteinase type 1 (MMP-I) .

At the cellular and molecular levels, the impact of UVB and UVA radiation induces various reactions, including direct and indirect induction of DNA lesions.

Among the types of direct induction of DNA lesions, some are specific for UV radiation, for instance pyrimidine dimers and 6,4 photoproducts . In the event of an error during repair by the specialized enzymatic systems (nucleotide excision repair NER, or global excision repair GER) , they may be responsible for mutations, which are themselves the cause of tumoural processes resulting in the development of skin cancers. A very high incidence of mutations characteristic of the impact of solar UV rays is, moreover, found in the cells derived from these tumours. These DNA lesions are also the cause of apoptotic processes inducing the formation of characteristic cells in the epidermis, namely the "sunburn cells". It will also be noted that UV rays are responsible at the cellular level for the generation of reactive oxygen species, which are themselves the cause of many biological effects, for instance the induction of oxidative damage to DNA (8-oxoguanine) or numerous genes.

Finally, in addition to the effects described mainly on the two major cell types of the skin, namely the keratinocytes that form the stratified and differentiated epidermis, and the fibroblasts responsible for the synthesis and renewal of the dermal extracellular matrix, UV rays also have an impact on

Langerhans cells, which have an antigen-presenting immune function.

The harmful effects of UV rays on the skin (erythema, photocarcinogenesis, photoageing, photoimmuno- suppression, etc.) are induced by a direct action of UV rays on certain cellular chromophores such as DNA, but also by an indirect action. The reason for this is that the energy transported by the UV rays is capable of triggering the formation of activated oxygen species

(AOS) , such as singlet oxygen and the superoxide anion, via a photosensitization reaction involving endogenous photosensitizers, such as riboflavins, bilirubins, phaeomelanin and porphyrin derivatives. Singlet oxygen and the superoxide anion undergo a cascade of reactions leading to the production of other AOSs, such as hydrogen peroxide and hydroxyl radicals. The AOSs thus generated damage DNA, cell membranes and certain proteins (enzymes, transcription factors, etc.) .

Cells are equipped with an enzymatic antioxidant defence (Cu-Zn and Mn superoxide dismutases, catalases, glutathione peroxidases, etc.) and non-enzymatic antioxidant defence (vitamins E and C, thiols, including glutathione, β-carotene, trace elements, etc.), the role of which is to maintain the intracellular redox potential, but this defence capacity may be exceeded during an intense oxidative stress .

All the cutaneous appendages which are in contact with the extracellular matrix will thus be subjected at least indirectly to oxidative stress.

The hair follicle is one of its appendages that is particularly sensitive to the state of the extracellular matrix. In fact, over the course of successive hair cycles, the hair follicle is either in the upper part of the dermis (telogenic phase) or in the lower

part of the dermis or hypodermis (anagenic phase) . By way of example, perifollicular fibrosis, which afflicts a disregulation of the extracellular matrix, contributes to excessive hair loss in men (Yoo H. G., et al., 2006. Biol Pharm Bull, 29(6) : 1246-1250) .

The human hair follicle is also directly sensitive to oxidative stress, the studies described in the document by Arck et al . , 2006, FASEB J, 20 ( 9) : 1567-1569 demonstrate that said stress impairs the growth and pigmentation thereof.

Thus, all the cutaneous appendages, and in particular the hair follicle, are therefore directly or indirectly subjected to the effects of oxidative stress. It therefore appears to be important to seek to limit the formation of free-radical species in the skin and the scalp in order to limit excessive hair loss.

New compositions for inducing or stimulating the growth of hair and/or reducing its loss and/or increasing its density by providing antioxidant protection against oxidative stress, in particular induced by UV radiation, are therefore being investigated.

New compositions for promoting and/or inducing and/or stimulating the pigmentation of keratin materials and/or limiting their depigmentation and/or their whitening by providing antioxidant protection against oxidative stress, in particular induced by UV radiation, are also being investigated.

Application EP1169300 describes (fluorohydroxymethyl- propionylamino) benzoic acid ester derivatives which have been recommended in cosmetics with the aim of inducing and/or stimulating the growth of keratin fibres, in particular human keratin fibres, and/or preventing their loss and/or increasing their density.

However, these compounds have the drawback of being difficult to solubilize in aqueous-alcoholic media.

The applicant has found a new family of 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methylpropanoyl) amino] - benzoate derivative compounds of formula (I) which exhibits an effective antioxidant activity against oxidative stress and the formation of free-radical species .

The applicant has discovered that such compounds can in particular be favourable to the stimulation and/or induction of the growth of keratin fibres, in particular human keratin fibres, and/or prevent their loss and/or increase their density and/or improve their appearance. These compounds in addition exhibit better solubility in aqueous-alcoholic media than the (fluorohydroxymethylpropionylamino) benzoic acid ester compounds of application EP1169300.

The applicant has discovered that such compounds can in particular be favourable to the induction and/or stimulation of the pigmentation of keratin materials and/or the limitation of their depigmentation and/or their whitening.

A subject of the present invention is new 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methylpropanoyl) - amino] benzoate derivatives of formula (I) that will be defined in detail below, and also the salts and/or solvates thereof.

A subject of the present invention is also compositions comprising, in a cosmetically acceptable medium, at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoate derivative of formula

(I) that will be defined in detail below, and also the salts and/or solvates thereof.

A subject of the present invention is also the cosmetic use of at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2- hydroxy-2-methylpropanoyl) amino] benzoate derivative of formula (I) that will be defined in detail below, and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, in a composition comprising a physiologically acceptable medium, with the aim of reinforcing and/or preserving the natural antioxidant protection of the skin, in particular the endogenous antioxidant defence system, in the face of oxidative stress, in particular induced by UV radiation.

The invention also relates to the cosmetic use of at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoate derivative of formula

(I), and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, as defined above, in a care and/or treatment composition for keratin fibres, in particular human keratin fibres, with the aim of inducing and/or stimulating the growth of keratin fibres, in particular human keratin fibres, and/or preventing their loss and/or increasing their density.

A subject of the present invention is also the cosmetic use of at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2- hydroxy-2-methylpropanoyl) amino] benzoate derivative of formula (I) that will be defined in detail below, and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, in a care and/or makeup composition for keratin materials, in particular human keratin materials, as an agent for

promoting and/or inducing and/or stimulating the pigmentation of keratin fibres and/or limiting their depigmentation and/or their whitening, and more particularly as an agent for preventing and/or limiting human keratin fibre canities.

The term "skin" is intended to mean any cutaneous surface of the human body, including skin, mucous membrane, semi-mucous membrane, therefore including lips, scalp and also the skin appendages, in particular nails, body hair and head hair.

A "physiologically acceptable medium" is, according to the invention, either a cosmetically or pharmaceutically acceptable medium compatible with the skin, the mucous membranes, the nails and/or the hair, or a medium that can be administered orally.

The term "keratin fibres" is intended to mean those of mammals of the animal species (dog, horse or cat, for example) .

The term "human keratin fibres" is intended to mean, for the purpose of the invention, hair, eyebrows, eyelashes, beard hair and moustache hair.

Other subjects of the invention will be defined below in the subsequent description.

The compounds according to the invention are chosen from those corresponding to formula (I) below and also the salts and/or solvates thereof:

(I)

in which:

- R denotes

(i) a saturated or unsaturated, linear, branched or cyclic Ci-Cβ alkyl radical optionally substituted with one or more hydroxyls, with a methyl or with an NRR' group;

(ii) a phenyl optionally substituted with one or more hydroxyls, with a methyl or with an NRR' group; (iii) a heterocycle comprising 4, 5, 6 or 7 atoms that may contain up to 4 heteroatoms, which may or may not be identical, chosen from N, S or O; it being possible for said heterocycle to be substituted with one or more hydroxyls, with a methyl or with an NRR' group;

- R and R', which may be identical or different, denote hydrogen, or a linear or branched Ci-Cβ alkyl radical.

According to the invention, the compounds of formula (I) are in isolated form, i.e. nonpolymeric form.

According to the invention, the term "at least one" signifies one or more (2, 3 or more) . In particular, the composition may contain one or more compounds of formula (I) . This or these compound (s) may be in tautomeric form. This or these compound (s) may be enantiomers or a mixture of these isomers, in particular a racemic mixture. When the compound comprises one or more double bonds, the various cis/trans isomers, and also mixtures thereof, are included.

According to the invention, the term "salts of a compound of formula (I)" is intended to mean the organic or inorganic salts of a compound of formula (D •

As inorganic salts that can be used according to the invention, mention may be made of the hydroxides, hydrohalides (hydrochlorides, for example) , carbonates,

hydrogen carbonates, sulphates, hydrogen phosphates and phosphates .

The organic salts that can be used according to the invention are those of organic acids, such as the citrates, lactates, glycolates, gluconates, acetates, propionates, fumarates, oxalates and tartrates.

As possible solvates of the compounds of formula (I), mention may be made of the hydrates, alkoxides or hydroalkoxides .

The alkyl radical is preferably a saturated or unsaturated alkyl containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, tert-butyl, isopropyl, pentyl or hexyl . The alkyl may contain at least one carbon-carbon double bond or one carbon- carbon triple bond, for instance -CH=CH ₂ , -CH ₂ -CH=CH- CH ₃ , -CH ₂ -C-DCH.

As an example of heterocycles that can be used in the invention, mention may be made independently of azetidine, pyrrole, dihydropyrrole, pyrrolidine, imidazole, dihydroimidazole, imidazolidine, pyrazole, dihydropyrazole, pyrazolidine, oxazole, dihydrooxazole, oxazolidine, isoxazole, dihydroisoxazole, isoxazol- idine, tetrazole, dihydropyridine, tetrahydropyridine, piperidine, dihydropyran, dihydropyrimidine, tetrahydropyrimidine, piperazine, pyridazine, pyrazine, triazine, morpholine, azepine and diazepine rings.

Among the compounds of formula (I), mention may, by way of example, be made of the following compounds and also the salts and/or solvates thereof:

- ethyl 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoate having the structure

- 3-hydroxypropyl 2-fluoro-4- [ (3, 3, 3-trifluoro-2- hydroxy-2-methylpropanoyl) amino] benzoate having the structure:

- pyridin-3-yl 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy- 2-methylpropanoyl) amino] benzoate having the structure:

- 2-hydroxyethyl 2-fluoro-4- [ (3, 3, 3-trifluoro-2- hydroxy-2-methylpropanoyl) amino] benzoate having the structure :

- 2, 3-dihydroxypropyl 2-fluoro-4- [ (3, 3, 3-trifluoro-2- hydroxy-2-methylpropanoyl) amino] benzoate having the

structure :

- phenyl 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoate having the structure:

- 2- (dimethylamino) ethyl 2-fluoro-4- [ (3, 3, 3-trifluoro- 2-hydroxy-2-methylρropanoyl) amino] benzoate having the structure :

- 4-methylphenyl 2-fluoro-4- [ (3, 3, 3-trifluoro-2- hydroxy-2-methylpropanoyl) amino] benzoate having the structure :

- butyl 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-

methylpropanoyl) amino] benzoate having the structure:

- 2-hydroxypropyl 2-fluoro-4- [ (3, 3, 3-trifluoro-2- hydroxy-2-methylpropanoyl) amino] benzoate having the structure :

- 2-hydroxy-l-methylethyl 2-fluoro-4- [ (3, 3, 3-trifluoro- 2-hydroxy-2-methylpropanoyl) amino] benzoate having the structure :

Among the preferred compounds of formula (I), those chosen will be those of formula (I) for which R denotes a saturated or unsaturated, linear or branched Ci-Cβ alkyl radical optionally substituted with one or more hydroxyls, and more particularly chosen from compounds (1), (2), (5), (10) and (11) as described above, and even more particularly compound (1) having the structure

or the R and S enantiomers thereof, having the following structure, in the form of a mixture or in isolated form:

S enantiomer

R enantiomer

The compounds of formula (I) according to the invention for which R denotes a Ci-Cβ alkyl radical can be obtained by means of a synthetic process according to the following reaction scheme A.

Scheme A

The 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methyl- propanoyl) amino] benzoic acid of formula (II) is reacted

with the alcohol ROH in the presence of sulphuric acid. The reaction medium is refluxed for 5 hours. After cooling, the mixture is poured into ice-cold water. The precipitate is filtered off, rinsed with water, and then dried under vacuum.

The compounds of formula (I) according to the invention for which R denotes a Ci-C ₆ alkyl radical substituted with a hydroxyl can be obtained by means of a synthetic process according to the following reaction scheme B.

H ₂ SO ₄ reflux

Scheme B

The 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methyl- propanoyl) amino] benzoic acid of formula (II) is reacted with a diol HO-R-OH in the presence of sulphuric acid, and the reaction medium is refluxed overnight. After cooling, the mixture is diluted with water and then extracted 3 times with ethyl acetate. The organic phase is dried with sodium sulphate, filtered and concentrated to the maximum extent. The yellow residue is chromatographed on silica gel (eluent: dichloro- methane/methanol (98/2)) . The slightly yellow oil is triturated in diethyl ether. The solid formed is filtered off and dried under vacuum.

The compounds of formula (I) according to the invention for which R denotes a Ci-C ₆ alkyl radical substituted with a hydroxyl can also be obtained by means of a synthetic process according to the following reaction scheme C:

65 ⁰ C

Scheme C

Under a nitrogen stream, the 2-fluoro-4- [ (3, 3, 3-tri- fluoro-2-hydroxy-2-methylpropanoyl) amino] benzoic acid is dissolved in anhydrous tetrahydrofuran and then the carbonyldiimidazole is added. The reaction medium is heated at 65°C for 2 hours. The diol HO-R-OH is introduced into the reaction mixture, which is heated at 65°C for 2 hours and then maintained at ambient temperature with magnetic stirring overnight. The reaction mixture is concentrated to the maximum degree and the residue is then diluted with ethyl acetate. The organic phase is washed successively 3 times with a IN solution of hydrochloric acid, 3 times with water, 3 times with a saturated solution of sodium hydrogen carbonate and then 3 times with a saturated solution of sodium chloride. The organic phase is dried over sodium sulphate, filtered and concentrated to the maximum degree. The residue is triturated with dichloromethane and the solid formed is then filtered off and dried under vacuum.

The compounds of formula (I) according to the invention for which R denotes a Ci-Cβ alkyl radical substituted with a hydroxyl can also be obtained by means of a synthetic process according to the following reaction scheme D:

Scheme D

The 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methyl- propanoyl) amino] benzoic acid of formula (II) is reacted with a mixture of methanesulphonic acid and acidic alumina prepared beforehand. The diol is introduced into the reaction medium, which is subsequently heated at 80°C for Ihl5. After cooling, the mixture is run into a mixture of water and ice, and then extracted with ethyl acetate. The organic phase is washed successively with water, twice with a 5% aqueous solution of sodium hydrogen carbonate and, finally, with water. It is dried over sodium sulphate, filtered and concentrated to the maximum degree. The oil is purified by silica gel chromatography (gradient: dichloromethane to dichloromethane/methanol (98/2)) . The solid obtained is dissolved in the minimum amount of acetone, to which water and also a small amount of vegetable charcoal are added. The mixture is kept stirring for 10 minutes and then filtered through celite. The acetone is removed by evaporation and the product precipitates from water. The solid is filtered off, rinsed with water and then dried under vacuum.

The compounds of formula (I) according to the invention for which R denotes a Ci-Cβ alkyl radical substituted with two adjacent hydroxyls can also be obtained by means of a synthetic process according to the following reaction scheme E:

Scheme E

In a first step, the 2-fluoro-4- [ (3, 3, 3-trifluoro-2- hydroxy-2-methylpropanoyl) amino] benzoic acid of formula (II) is dissolved in a 2, 2 -dimethyl- 1, 3-dioxolane- alkanol compound, to which 97% sulphuric acid is added. The reaction medium is heated at 85% for 8 hours. After cooling, the mixture is concentrated to the maximum degree. The residue is diluted with water and then extracted 3 times with dichloromethane . The organic phase is dried with sodium sulphate, filtered and concentrated to the maximum degree. The oil is chromatographed on silica gel (gradient: dichloromethane to dichloromethane/methanol (98/2)) . The oil is dissolved in ethanol and a few milligrams of vegetable charcoal are added, and the mixture is then refluxed for 3 hours and filtered through celite. The filtrate is concentrated to the maximum degree and then chromatographed on silica gel (gradient: dichloromethane to dichloromethane/methanol (99/1)) . A (2,2- dimethyl-1, 3-dioxolan-4-yl) alkyl 2-fluoro-4- [ (3, 3, 3- trifluoro-2-hydroxy-2-methylpropanoyl) amino] benzoate compound of formula (III) is obtained.

In a second step, the (2, 2-dimethyl-l, 3-dioxolan-4- yl) alkyl 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoate of formula (III) is dissolved in tetrahydrofuran, and a 4N solution of hydrochloric acid is slowly added to this solution. The reaction mixture is concentrated to the maximum degree. The residue is diluted in water and then extracted

3 times with ethyl acetate. The organic phase is washed twice with a saturated solution of sodium chloride and then dried over sodium sulphate, filtered and concentrated to the maximum degree. The oil obtained is triturated with diethyl ether and the precipitate is filtered off and then dried under vacuum.

The compounds of formula (I) according to the invention for which R denotes a heterocycle can be obtained by means of a synthetic process according to the following reaction scheme F.

(H)

Scheme F

Under a nitrogen stream, the 2-fluoro-4- [ (3, 3, 3-tri- fluoro-2-hydroxy-2-methylpropanoyl) amino] benzoic acid of formula (II) is dissolved in the anhydrous tetrahydrofuran and then the carbonyldiimidazole is added. The reaction medium is heated at 65°C for lh30. The heterocycle ROH predissolved in anhydrous tetrahydro- furan is introduced into the reaction mixture, which is maintained at ambient temperature with magnetic stirring overnight. The reaction medium is again heated at 65°C for 3 hours, and then, after cooling, it is concentrated to the maximum degree. The residue is diluted with ethyl acetate and is then washed successively 3 times with a saturated solution of sodium hydrogen carbonate, once with water, twice with a IN solution of hydrochloric acid and then 3 times with a saturated solution of sodium chloride. The organic phase is dried over sodium sulphate, filtered and concentrated to the maximum degree. The residue is triturated with diisopropyl ether and then filtered.

The solid obtained is suspended in a minimum amount of dichloromethane/methanol mixture (98/2) . The solid obtained is filtered off and then dried under vacuum.

The compounds of formula (I) according to the invention for which R denotes a phenyl can be obtained by means of a synthetic process according to the following reaction scheme G.

Scheme G

Under an inert atmosphere, the 2-fluoro-4- [ (3, 3, 3-tri- fluoro-2-hydroxy-2-methylpropanoyl) amino] benzoic acid of formula (I) is dissolved in anhydrous dichloro- methane, to which the compound O-benzotriazole-1-yl- N, N, N' ,N' -tetramethyluronium tetrafluoroborate (TBTU) and N-hydroxybenzotriazole (HOBt) are added. Triethyl- amine is added to the heterogeneous medium and the reaction is stirred for 30 minutes at ambient temperature. The mixture becomes homogeneous and the phenol is introduced. The reaction is stirred overnight at ambient temperature and then treated with 50 ml of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase is dried over magnesium sulphate, filtered and concentrated to the maximum degree. The residue is purified by silica gel chromatography (gradient of 80/20 to 50/50 petroleum ether/ethyl acetate) .

The compounds of formula (I) according to the invention for which R denotes a phenyl substituted with an alkyl can be obtained by means of a synthetic process according to the following reaction scheme H.

(H) Scheme H (I)

Under a nitrogen stream, the 2-fluoro-4- [ (3, 3, 3-tri- fluoro-2-hydroxy-2-methylpropanoyl) amino] benzoic acid of formula (II) is dissolved in anhydrous tetrahydrofuran and then the carbonyldiimidazole is added. The reaction medium is heated at 65°C for 2 hours. The phenol substituted with an alkyl is introduced into the reaction mixture, which is kept at ambient temperature overnight with magnetic stirring. The reaction mixture is concentrated to the maximum degree. The residue is diluted with water and then extracted 3 times with ethyl acetate. The organic phase is washed successively 3 times with a saturated solution of sodium hydrogen carbonate, twice with water and twice with a saturated solution of sodium chloride, and then dried over sodium sulphate, filtered and concentrated to the maximum degree. The oil obtained is purified by silica gel chromatography (gradient of 100% dichloromethane to 98/2 dichloromethane/methanol) .

The compounds of formula (I) according to the invention for which R denotes a Ci-Cβ alkyl radical substituted with an NRR' group can also be obtained by means of a synthetic process according to the following reaction scheme I :

(N) (I)

Scheme I

Under a nitrogen stream, the 2-fluoro-4- [ (3, 3, 3-tri- fluoro-2-hydroxy-2-methylpropanoyl) amino] benzoic acid is dissolved in anhydrous tetrahydrofuran and then the carbonyldiimidazole is added. The reaction medium is heated at 65 ⁰ C for 2 hours. The RR 'N-ROH compound is introduced dropwise into the reaction mixture, which is maintained at ambient temperature overnight with magnetic stirring. The reaction mixture is concentrated to the maximum degree; the residue is diluted with a IN solution of hydrochloric acid and then washed twice with ethyl acetate. The acidic aqueous phase is brought to pH 8 with a IN solution of sodium hydroxide and then extracted twice with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride and then dried over sodium sulphate, filtered and concentrated to the maximum degree. The powder obtained is triturated with diethyl ether and then filtered and dried under vacuum.

The starting compound for all these syntheses, namely the 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methyl- propanoyl) amino] benzoic acid of formula (II), can also be obtained by means of a synthetic process according to the following reaction scheme J:

/ -20 ⁰ C Yield: 62%

Scheme J

For example, 2.55 g of 3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoic acid are dissolved in 20 ml of anhydrous dimethylacetamide . The solution is degassed for 10 minutes with a stream of argon. The reaction medium is cooled to -20 ⁰ C, and 1.2 ml of thionyl chloride (1.5 eq.) are added. After 1 h at -20 ⁰ C,

1.67 g of 4-amino-2-fluorobenzoic acid dissolved in 65 ml of anhydrous dimethylacetamide are added. The reaction medium is left at ambient temperature for 5 hours, and then poured into 100 ml of ice-cold water. The mixture is extracted with 2 times 100 ml of dichloromethane . The organic phase is washed with a saturated solution of sodium chloride, and then dried over sodium sulphate, filtered and concentrated. The yellow oil obtained is chromatographed on silica gel (gradient: dichloromethane to dichloromethane/methanol (95/5)) . The oil obtained is solubilized with a 5% solution of sodium hydrogen carbonate and then acidified to pH 1 with a 37% solution of hydrochloric acid. The precipitate is filtered off, rinsed with water and then dried under vacuum. 2 g of white solid are obtained (yield = 62%) . The nuclear magnetic resonance and mass spectrometry spectra are compliant.

The compounds of formula (I) according to the invention make it possible to reinforce and/or preserve the cellular antioxidant defence systems, in particular the antioxidant defence systems of the skin cells. The skin cells are in particular fibroblasts, keratinocytes and Langerhans cells.

According to one advantageous use of the invention, the compounds of general formula (I) are useful as skin photoprotective agents.

This use may be useful whether the skin has undergone exposure to daylight of an intensity lower than the minimum erythemal dose and the effects of which do not produce any visible signs on the skin, or whether the UV-ray damage is visible, for example through the appearance of redness on the skin.

Consequently, the impairments range from simple discomfort, such as a uniquely perceptible sensation of heating of the skin, to redness, or even irritation.

Thus, the compounds of general formula (I) are useful for preventing and/or treating UV stress and/or heating sensations caused by solar radiation, in particular UVA and/or UVB radiation.

The compounds of general formula (I) are also useful for the preparation of a composition comprising a physiologically acceptable medium, for use in the prevention and/or treatment of skin impairments, such as skin redness and irritation, caused by solar radiation .

The compounds of general formula (I) are also useful for the preparation of a composition comprising a physiologically acceptable medium, for use in the treatment of skin and/or mucous membrane disorders induced by irradiation with UVA and/or UVB radiation.

Solar irradiation or exposure is characterized by an exposure to sunlight, and may in particular be an intense irradiation corresponding to exposure to zenithal sunlight or to solar radiation varying by an angle of 30° around this zenithal position and/or when the skin is subjected to UV radiation capable of inducing solar erythema (redness commonly known as "sunburn"), and defined by a minimum erythemal dose (MED) . This dose varies as a function of the phototype of the individual and of the UVA/UVB ratio.

The invention is in particular directed towards preventing or reducing the damage induced in the skin, mucous membranes and/or integuments of a mammal, in particular of a human being, by short exposure to erythemal doses of solar radiation.

These solar exposure conditions comprise UVA and/or UVB radiation, at doses around the MED, in particular at a dose of greater than or equal to 1 MED.

Thus, the cosmetic use according to the invention of at least one compound of formula (I) in a composition containing a physiologically acceptable medium is particularly suitable for preparing the skin for exposure to sunlight.

In particular, preparation of the skin for exposure to sunlight may be performed by the daily application to the skin of said cosmetic composition for one week before the exposure to sunlight, and preferably for two weeks, up to at least one night (between 6 and 18 hours) before the exposure to sunlight.

Whether they are of endogenous or exogenous origin, free radicals cause substantial oxidative damage, in particular in cell membranes (lipid peroxidation causing degradation of membrane permeability) , cell nuclei (destruction of DNA) and tissues, in particular connective tissue (degradation of elastin and collagen fibres, depolymerization of polyuronic fibres) . This damage in particular leads to drying-out and loss of firmness and elasticity of the skin (Grinwald et al . 1980, Agren et al . 1997) .

Specialists currently consider that one of the causes of cellular ageing is the weakening of the defence capacities against free radicals and against oxidation phenomena (in particular the formation of superoxide ions) that they initiate.

Thus, more generally, the compounds of general formula (I) according to the invention are useful as indirect antioxidant compounds for preventing and/or limiting the formation of free radicals and/or for removing the free radicals present in cells, and can be used for any skin disorder caused by oxidative stress.

Thus, the use of the compounds according to the invention makes it possible to prevent and/or treat certain clinical signs of skin ageing.

Ageing is a natural physiological phenomenon, the clinical signs of which can generally be reflected on the skin by the appearance of wrinkles and fine lines, by slackening of the cutaneous and subcutaneous tissues, by loss of skin elasticity and by atony of the texture of the skin. The loss of firmness and tonicity of the skin, for instance wrinkles and fine lines, is at least partly accounted for by dermal atrophy and also by flattening of the dermo-epidermal junction; the skin is less firm and more flaccid, and the thickness of the epidermis decreases.

Another clinical sign of ageing is the dry and rough appearance of the skin, which is essentially due to greater desquamation; by diffracting light rays, these squames also contribute to the slightly grey appearance of the complexion.

Some of these signs are more particularly associated with intrinsic or physiological ageing, i.e. age- related ageing, whereas others are more specific to extrinsic ageing, i.e. ageing caused in general by the environment; this is more particularly a case of photoageing due to exposure to sunlight, light or any other radiation, or alternatively pollutants.

Thus, the subject of the invention is particularly suited to the cosmetic use of at least one compound of general formula (I), and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof according to the invention, in a composition containing a physiologically acceptable medium, for preventing and/or treating loss of firmness and/or of

elasticity of the skin. Such a use in particular allows the skin to regain a uniformly smooth appearance.

The invention is also suited to the cosmetic use of at least one compound of general formula (I) according to the invention, and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, in a composition containing a physiologically acceptable medium, for preventing and/or treating skin dehydration .

More generally, the subject of the invention is also suited to the cosmetic use of at least one compound chosen from those of general formula (I) according to the invention, and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, in a composition containing a physiologically acceptable medium, for preventing and/or treating epidermal atrophy and/or roughness of the skin and/or dryness of the skin.

Another subject of the invention relates to the cosmetic use of at least one compound of general formula (I), and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, in a composition containing a cosmetically acceptable medium, for preventing and/or treating the harmful effects of pollution on the skin.

It is known that the toxicity of atmospheric pollutants, in particular gaseous pollutants such as sulphur dioxide, ozone and nitrogen oxides, on the constituents of the skin (fibres, cells, enzymes) and

on the sebum secreted by the skin is in particular linked to their activity as free-radical initiators, which are a source of oxidation phenomena that cause cell damage in living beings.

The live cells, which are in direct and constant contact with the external environment (in particular the skin, the scalp and certain mucous membranes) , are particularly sensitive to these effects of gaseous pollutants, which are in particular reflected by accelerated ageing of the skin, with an early formation of wrinkles or fine lines, and also by a decrease in vigour and a dull appearance of the hair.

As explained previously, an adverse effect of the presence of free radicals in the skin is that they cause lipid peroxidation. With age (more particularly from the age of forty) , the accumulation of these peroxidized lipids is responsible for unpleasant body odour such as a rancid odour (Haze S. et al. J. Invest. Dermatol. 2001, 116(4) : 520-4) .

The subject of the invention is suited to the cosmetic use of at least one compound of general formula (I) according to the invention, and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, in a composition containing a physiologically acceptable medium, for preventing and/or limiting and/or eliminating the peroxidation of skin lipids .

Thus, the subject of the invention is also useful for preventing and/or limiting and/or eliminating unpleasant body odour.

The compositions according to the invention may be for cosmetic and/or dermatological use. They may be

compositions suitable for topical application, in particular external topical application to the skin, the mucous membranes and/or the integuments.

The invention also relates to the cosmetic use of at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoate derivative of formula

(I), and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, as defined above, in a care and/or treatment composition for keratin fibres, in particular human keratin fibres, with the aim of inducing and/or stimulating the growth of keratin fibres, in particular human keratin fibres, and/or preventing their loss and/or increasing their density.

Thus, the invention also relates to the cosmetic use of at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoate derivative of formula

(I), and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or solvate thereof as defined above, in a human cosmetic haircare composition, with the aim of treating alopecia of natural origin, and in particular androgenic alopecia. Thus, this composition makes it possible to maintain the head of hair in good condition and/or to combat natural hair loss, and more especially natural hair loss in men. This composition thus makes it possible to maintain the hair in good condition and/or to improve its condition and/or its appearance.

A subject of the invention is also the cosmetic use of at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoate derivative of formula

(I), and also a tautomeric form thereof and/or an

enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof as defined above, in a cosmetic care and/or makeup composition for human eyelashes, for inducing and/or stimulating the growth of the eyelashes and/or increasing their density. This composition thus makes it possible to maintain the eyelashes in good condition and/or to improve their condition and/or their appearance.

A subject of the present invention is also a cosmetic treatment process for human keratin fibres (especially hair or eyelashes) and/or for the skin from which said fibres emerge, including the scalp and the eyelids, characterized in that it consists in applying, to said keratin fibres and/or said skin, a cosmetic composition comprising at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2- hydroxy-2-methylpropanoyl) amino] benzoate derivative of formula (I), and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, as defined above, in leaving said composition in contact with the keratin fibres and/or the skin from which said fibres emerge, and optionally in rinsing said fibres and/or said skin.

This treatment process indeed has the characteristics of a cosmetic process insofar as it makes it possible to improve the aesthetics of human keratin fibres, and in particular of the hair and the eyelashes, by giving them greater vigour and an improved appearance. In addition, it may be used daily for several months, without medical prescription.

More especially, a subject of the present invention is a cosmetic care process for human hair and/or the human scalp, for the purpose of improving their condition

and/or their appearance, characterized in that it consists in applying, to the hair and/or the scalp, a cosmetic composition comprising an effective amount of at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoate derivative of formula

(I), and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, as defined above, in leaving said composition in contact with the hair and/or the scalp, and optionally in rinsing the hair and/or the scalp.

A subject of the invention is also a cosmetic care and/or makeup process for human eyelashes, for the purpose of improving their condition and/or their appearance, characterized in that it consists in applying, to the eyelashes and/or the eyelids, a mascara composition comprising at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methylpropanoyl) amino] - benzoate derivative of formula (I), and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, as defined above, and in leaving said composition in contact with the eyelashes and/or the eyelids. This mascara composition may be applied alone or as a basecoat for a standard pigmented mascara, and may be removed like a standard pigmented mascara.

A subject of the present invention is therefore the cosmetic use of at least one 2-fluoro-4- [ (3, 3, 3- trifluoro-2-hydroxy-2-methylpropanoyl) amino] benzoate derivative of formula (I), and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof as defined above, as an agent for

promoting and/or inducing and/or stimulating the pigmentation of keratin materials and/or as an agent for preventing and/or limiting the depigmentation and/or the whitening of keratin materials, and more particularly human keratin fibres such as human hair, beard hair, moustache hair, eyelashes and eyebrows.

The present invention relates more particularly to the cosmetic use of at least one 2-fluoro-4- [ (3, 3, 3- trifluoro-2-hydroxy-2-methylpropanoyl) amino] benzoate derivative of formula (I), and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, as defined above, as an agent for preventing and/or limiting human keratin fibre canities .

The present invention also relates to a cosmetic process for treating human keratin fibre canities, in particular canities of the hair, beard hair, moustache hair, eyelashes and/or eyebrows, characterized in that it consists in applying, to said fibres, an effective amount of at least one 2-fluoro-4- [ (3, 3, 3-trifluoro-2- hydroxy-2-methylpropanoyl) amino] benzoate derivative of formula (I), and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate thereof, as defined above.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE

INVENTION

In the subsequent text, and unless expressly mentioned, the use of the term "compound of formula (I)" should be understood to mean both the compound of formula (I) and also a tautomeric form thereof and/or an enantiomer thereof in isolated form or as a mixture and/or a

cis/trans isomer thereof in isolated form or as a mixture and/or a salt and/or a solvate, in particular hydrate, thereof or a solvated (in particular hydrated) salt thereof.

The effective amount of a compound of formula (I) (salified or nonsalified, solvated or nonsolvated) corresponds to the amount necessary to obtain the desired result (namely, increasing the density of the keratin fibres, and in particular of the hair and of the eyelashes, or promoting their growth) . Those skilled in the art are therefore in a position to evaluate this effective amount which depends on the nature of the compound used, on the individual to whom it is applied, and on the time for this application.

In the subsequent text, and unless otherwise indicated, the amounts of the various ingredients of the composition are given as percentage by weight relative to the total weight of the composition.

To give an order of magnitude, according to the invention, the compound of formula (I) (salified or nonsalified, solvated or nonsolvated) or a mixture of compounds of formula (I) and/or of salts thereof may be used in an amount representing from 10 ^~3 % to 10% of the total weight of the composition, and preferably in an amount representing from 10 ^~3 % to 5%, and better still from 10 ^~2 % to 2% of the total weight of the composition, for example from 0.5% to 2%.

The composition of the invention may be for cosmetic or pharmaceutical use. Preferably, the composition of the invention is for cosmetic use. Thus, the composition should contain a physiologically acceptable medium which is nontoxic and which can be applied to the skin, including the scalp and the eyelids, and to the keratin fibres of humans. For the purpose of the invention, the

term "cosmetic" is intended to mean a composition having a pleasant appearance, odour and feel.

The compound of formula (I), which may be salified or nonsalified and solvated or nonsolvated, may be used in a composition which must be ingested, injected or applied to the skin or to the keratin fibres (to any cutaneous area or fibres to be treated) .

According to the invention, the compound of formula (I) or a mixture of compounds of formula (I) may be used orally in an amount of from 0.1 to 300 mg per day, in particular from 5 to 10 mg/d.

A preferred composition of the invention is a composition for cosmetic use, and in particular for topical application to the skin and the keratin fibres, and more especially to the scalp, the hair and the eyelashes .

This composition may be in any of the known galenical forms suitable for the method of use.

For topical application to the skin or the keratin fibres, the composition may be in the form of an aqueous, alcoholic or aqueous-alcoholic solution or suspension or of an oily suspension or solution, an emulsion or dispersion of more or less fluid consistency, and especially liquid or semi-liquid consistency, obtained by dispersion of a fatty phase in an aqueous phase (O/W) or vice versa (W/O) , a solid

(O/W) or (W/O) emulsion or dispersion, an aqueous, aqueous-alcoholic or oily gel which is more or less fluid or solid, a loose or compacted powder to be used as it is or to be incorporated into a physiologically acceptable medium, or else microcapsules or microparticles, or vesicular dispersions of ionic and/or non-ionic type.

A composition in the form of a mousse or else in the form of a spray or an aerosol, which then comprises a pressurized propellant, may also be envisaged.

It may thus be in the form of a lotion, serum, milk, 0/W or W/0 cream, gel, salve, ointment, powder, balm, patch, impregnated pad, bar or mousse.

In particular, the composition for application to the scalp or the hair may be in the form of a haircare lotion, for example for daily or twice-weekly application, a shampoo or a hair conditioner, in particular for twice-weekly or weekly application, a liquid or solid scalp cleansing soap for daily application, a hairstyle shaping product (lacquer, hairsetting product, styling gel) , a treatment mask, or a foaming gel or cream for cleansing the hair. It may also be in the form of a hair dye or mascara to be applied with a brush or a comb.

Moreover, for application to the eyelashes or body hairs, the composition to which the invention applies may be in the form of a pigmented or unpigmented mascara, to be applied with a brush to the eyelashes or alternatively to beard or moustache hair.

For a composition for use by injection, the composition may be in the form of an aqueous lotion or an oily suspension. For oral use, the composition may be in the form of capsules, granules, oral syrups or tablets.

According to one particular embodiment, the composition according to the invention is in the form of a hair cream or hair lotion, a shampoo or hair conditioner, or a mascara for the hair or for the eyelashes.

The amounts of the various constituents of the composition according to the invention are those generally used in the fields under consideration. In

addition, these compositions are prepared according to the usual methods .

When the composition is an emulsion, the proportion of the fatty phase may range from 2% to 80% by weight, and preferably from 5% to 50% by weight, relative to the total weight of the composition. The aqueous phase is adjusted according to the content of fatty phase and of compound (s) (I) and also to that of the possible additional ingredients, so as to obtain 100% by weight.

In practice, the aqueous phase represents from 5% to

99.9% by weight.

The fatty phase may contain fatty or oily compounds that are liquid at ambient temperature (25°C) and atmospheric pressure (760 mmHg) , which are generally known as oils. These oils may be mutually compatible or incompatible and may form a macroscopically homogeneous liquid fatty phase or a two-phase or three-phase system.

The fatty phase may, in addition to the oils, contain waxes, gums, lipophilic polymers, and viscous or 'pasty' products containing solid parts and liquid parts.

The aqueous phase contains water and optionally an ingredient that is miscible in all proportions with water, for instance Ci to Cs lower alcohols such as ethanol or isopropanol, polyols, for instance propylene glycol, glycerol or sorbitol, or else acetone or ether.

The emulsifiers and coemulsifiers used to obtain a composition in emulsion form are those generally used in the cosmetics and pharmaceutical fields. Their

nature also depends on the direction of the emulsion. In practice, the emulsifier and optionally the coemulsifier are present, in the composition, in a proportion ranging from 0.1% to 30% by weight, preferably from 0.5% to 20% by weight, and better still from 1% to 8%. The emulsion may also contain lipid vesicles, and in particular liposomes.

When the composition is in the form of an oily solution or gel, the fatty phase may represent more than 90% of the total weight of the composition.

Advantageously, for a topical hair application, the composition is an aqueous, alcoholic or aqueous- alcoholic solution or suspension, and better still a water/ethanol solution or suspension. The alcoholic fraction may represent from 5% to 99.9%, and better still from 8% to 80%.

For a topical mascara application, the composition of the invention is in particular in the form of a wax-in- water or wax-in-oil dispersion, a gelled oil or an aqueous gel, which may or may not be pigmented.

The composition of the invention may also comprise other additional ingredients normally used in the fields concerned, chosen from solvents, aqueous-phase or oily-phase thickeners or gelling agents, dyestuffs that are soluble in the medium of the composition, solid particles of the filler or pigment type, antioxidants, preservatives, fragrances, electrolytes, neutralizing agents, film-forming polymers, UV blockers such as sunscreens, cosmetic and pharmaceutical active agents with a beneficial action on the skin or keratin fibres, other than the compounds of formula (I), and

mixtures thereof. These additives may be present in the composition according to the amounts generally used in the cosmetics and dermatological field, and in particular at a ratio of from 0.01% to 50% of the total weight of the composition, and better still from 0.1% to 20% and, for example, from 0.1% to 10%. Depending on their nature, these additives may be introduced into the fatty phase, into the aqueous phase and/or into lipid vesicles, and in particular liposomes. Of course, those skilled in the art will take care to select the possible additional ingredients and/or the amount thereof in such a way that the advantageous properties of the composition according to the invention, namely the inhibition of 15-PGDH type 1 and in particular the increase in density of the keratin fibres, are not or are not substantially impaired by the addition envisaged.

As solvents that can be used in the invention, mention may be made of C2 to Cs lower alcohols such as ethanol or isopropanol, propylene glycol and certain light cosmetic oils such as Ce to C16 alkanes.

As oils that can be used in the invention, mention may be made of oils of mineral origin (liquid petroleum jelly, hydrogenated isoparaffin) , oils of plant origin

(liquid fraction of shea butter, sunflower oil, apricot oil, fatty alcohol or fatty acid) , oils of animal origin (perhydrosqualene) , synthetic oils (fatty acid ester, Purcellin oil), silicone oils (linear or cyclic polydimethylsiloxane, or phenyl trimethicone) and fluoro oils (perfluoropolyethers) . As waxes, mention may be made of silicone waxes, beeswax, rice wax, candelilla wax, carnauba wax, paraffin wax and polyethylene wax.

As emulsifiers that can be used in the invention, mention may, for example, be made of glyceryl stearate, glyceryl laurate, sorbitol stearates, sorbitol oleates, alkyl dimethicone copolyols (with alkyl > 8) and mixtures thereof for a W/0 emulsion. Polyethylene glycol monostearate or monolaurate, polyoxyethylenated sorbitol stearate or oleate, and dimethicone copolyols, and mixtures thereof, may also be used for an 0/W emulsion .

As hydrophilic gelling agents that can be used in the invention, mention may be made of carboxyvinyl polymers (carbomer) , acrylic copolymers such as acrylate/alkyl acrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, natural gums and clays, and as lipophilic gelling agents, mention may be made of modified clays such as bentones, metal salts of fatty acids, for instance aluminium stearates, hydrophobic-treated silica and ethylcellulose, and mixtures thereof.

As a cosmetic or pharmaceutical active agent, other than the compounds of formula (I), that can be used in the invention, mention may be made of hydrophilic active agents, for instance proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, water-soluble vitamins, plant extracts (those from Iridacea plants or from soybean) and hydroxy acids such as fruit acids or salicylic acid; and lipophilic active agents, such as retinol (vitamin A) and its derivatives, in particular esters (retinyl palmitate) , tocopherol (vitamin E) and its derivatives, in particular esters (tocopheryl acetate) , essential fatty acids, ceramides, essential

oils, salicylic acid derivatives, for instance 5- octanoylsalicylic acid, hydroxy acid esters, and phospholipids, for instance lecithin, and mixtures thereof .

According to one particular embodiment of the invention, the compound of formula (I) or a salt and/or a solvate thereof may be combined with additional compounds for promoting the growth of human keratin fibres and/or limiting their loss and/or increasing their density (hair, eyelashes) . These additional compounds are in particular chosen from the lipoxygenase inhibitors as described in EP 648488, the bradykinin inhibitors described in particular in EP 845700, prostaglandins and derivatives thereof, in particular those described in WO 98/33497, WO 95/11003, JP 97-100091 and JP 96-134242, prostaglandin receptor agonists or antagonists, the nonprostanoic prostaglandin analogues as described in EP 1175891 and EP 1175890, WO 01/74307, WO 01/74313, WO 01/74314, WO 01/74315 or WO 01/72268, and mixtures thereof.

As other additional active compounds for promoting the growth of keratin fibres and/or limiting their loss (in particular the hair or the eyelashes) that may be present in the composition according to the invention, mention may be made of vasodilators, antiandrogens, cyclosporins and analogues thereof, antimicrobial and antifungal agents, anti-inflammatories and retinoids, alone or as a mixture.

The vasodilators that can be used are in particular potassium channel agonists, including minoxidil, and also the compounds described in patents US 3 382 247, 5 756 092, 5 772 990, 5 760 043, 5 466 694, 5 438 058 and 4 973 474, cromakalim, nicorandil and diaxozide, alone or in combination.

- A A -

The antiandrogens that can be used include in particular steroidal and non-steroidal 5α-reductase inhibitors, such as finasteride and the compounds described in US 5 516 779, cyprosterone acetate, azelaic acid and the salts and derivatives thereof and the compounds described in US 5 480 913, flutamide, oxendolone, spironolactone, diethylstilbestrol and the compounds described in patents US 5 411 981, 5 565 467 and 4 910 226.

The antimicrobial or antifungal compounds may be chosen from selenium derivatives, octopirox, triclocarban, triclosan, zinc pyrithione, itraconazole, Asiatic acid, hinokitiol, mipirocin, tetracyclines, in particular erythromycin and the compounds described in EP 0680745, clidamycin hydrochloride, benzoyl peroxide or benzyl peroxide, minocycline and the compounds belonging to the imidazole class, such as econazole, ketoconazole or miconazole or their salts, nicotinic acid esters, including in particular tocopheryl nicotinate, benzyl nicotinate and Ci-Cβ alkyl nicotinates, for instance methyl nicotinate or hexyl nicotinate.

The anti-inflammatories may be chosen from steroidal anti-inflammatories, for instance glucocorticoids or corticosteroids (for example: hydrocortisone), and nonsteroidal anti-inflammatories, for instance glycyrrhetinic acid and α-bisabolol, benzydamine, salicylic acid and the compounds described in EP 0770399, WO 94/06434 and FR 2 268 523.

The retinoids may be chosen from isotretinoin, acitretin, tazarotene, retinal and adapalene.

As other additional active compounds for promoting the growth and/or limiting the loss of keratin fibres such as the hair and the eyelashes, that can be used in combination with the compound of formula (I), in salified or nonsalified, and solvated or nonsolvated

form, mention may be made of aminexil, 6-0- [ (9Z, 12Z) - octadeca-9, 12-dienoyl] hexapyranose, benzalkonium chloride, benzethonium chloride, phenol, oestradiol, chlorpheniramine maleate, chlorophyllin derivatives, cholesterol, cysteine, methionine, menthol, peppermint oil, calcium pantothenate, panthenol, resorcinol, protein kinase C activators, glycosidase inhibitors, glycosaminoglycanase inhibitors, pyroglutamic acid esters, hexosaccharide or acylhexosaccharide acids, substituted aryl ethylenes, N-acylamino acids, flavonoids, ascomycin derivatives and analogues, histamine antagonists, saponins, proteoglycanase inhibitors, oestrogen agonists and antagonists, pseudoterines, cytokines and growth factor promoters, IL-I or IL- 6 inhibitors, IL-IO promoters, TNF inhibitors, benzophenones, hydantoin, retinoic acid; vitamins such as vitamin D, vitamin B12 analogues, pantothenol; triterpenes, for instance ursolic acid and the compounds described in US 5 529 769, US 5 468 888 and US 5 631 282; antipruriginous agents, for instance thenaldine, trimeprazine or cyproheptadine; antiparasitic agents, in particular metronidazole, crotamiton or pyrethrinoids; calcium antagonists, for instance cinnarizine, diltiazem, nimodipine, verapamil, alverine and nifedipine; hormones such as oestriol or analogues thereof, thyroxine and salts thereof, progesterone; FP receptor (type F prostaglandin receptor) agonists such as latanoprost, (5E) -7- { (IR, 2R, 3R, 5S) -3, 5-dihydroxy-2-[ (3R) -3-hydroxy-5-phenyl- pentyl]cyclopentyl}hept-5-enoic acid, bimatoprost, travoprost, unoprostone and butaprost; O-acylated derivatives obtained by partial or total esterification of vitamin F with glucose, as described in application EP 1688128; 15-hydroxy prostaglandin dehydrogenase inhibitors; and mixtures thereof.

As other additional active compounds for promoting the growth and/or limiting the loss of keratin fibres such as the hair and the eyelashes, that can be used in

combination with the compound of formula (I), in salified or nonsalified, and solvated or nonsolvated form, mention may be made of pyridine dicarboxylate derivatives or a salt thereof, such as those described in application EP 1352629, and more particularly diethyl pyridine-2, 4 -dicarboxylate .

Advantageously, the composition according to the invention comprises at least one compound of formula (I) as defined above and at least one prostaglandin or one prostaglandin derivative, for instance the prostaglandins of series 2, including in particular PGF2-α and PGE2 in acid, salt or ester form (for example, the isopropyl esters) , derivatives thereof, for instance 16, 16-dimethyl PGE2, 17-phenyl PGE2, 16, 16-dimethyl PGF2-α, 17-phenyl PGF2-α, prostaglandins of series 1, for instance 11-deoxyprostaglandin El, 1- deoxyprostaglandin El in acid, salt or ester form, analogues thereof, in particular latanoprost, (5E) -7- { (IR, 2R, 3R, 5S) -3, 5-dihydroxy-2-[ (3R) -3-hydroxy-5- phenylpentyl]cyclopentyl}hept-5-enoic acid, viprostol, bimatoprost, cloprostenol, travoprost, fluprostenol, cloprostenol, butaprost, unoprostone, misoprostol, and the salts or esters thereof.

Preferably, the composition contains at least one non- prostanoic EP2 and/or EP4 receptor agonist, in particular as described in EP 1175892.

Particularly preferably, the additional active compound will be chosen from aminexil, minoxidil, O-acylated derivatives obtained by partial or total esterification of vitamin F with glucose; latanoprost, (5E) -7- { (IR, 2R, 3R, 5S) -3, 5-dihydroxy-2-[ (3R) -3-hydroxy-5- phenylpentyl]cyclopentyl}hept-5-enoic acid, butaprost, bimatoprost, travoprost, diethyl pyridine-2, 4- dicarboxylate, or mixtures thereof.

It may also be envisaged for the composition comprising

- A l - at least the compound of formula (I), in salified or nonsalified, and solvated or nonsolvated form, to be in liposomal form, as described in particular in document WO 94/22468. Thus, the compound encapsulated in the liposomes may be delivered selectively to the hair follicle .

The composition according to the invention may be applied to the alopecic areas of the scalp and to the hair of an individual, and optionally left in contact for several hours and optionally rinsed out.

The composition containing an effective amount of a compound of formula (I), in salified or nonsalified, and solvated or nonsolvated form, may, for example, be applied in the evening, kept in contact throughout the night and optionally shampooed out in the morning. These applications may be repeated daily for one or more months according to the individual .

Advantageously, in the process according to the invention, between 5 and 500 μl of a solution or composition as defined above, comprising from 0.001% to 5% of 15-PGDH inhibitor, is applied to the areas of the scalp to be taken care of or treated.

Exemplary embodiments of the invention, which cannot in any way limit its scope, will now be given by way of illustration .

EXAMPLES

EXAMPLE IA: Preparation of ethyl 2-fluoro-4- [ (3, 3, 3- trifluoro-2-hydroxy-2-methylpropanoyl) amino] benzoate - compound (1) :

1 g of 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methyl- propanoyl) amino] benzoic acid is dissolved in 40 ml of ethanol, to which 1 ml of 97% sulphuric acid is added. The reaction medium is refluxed for 5 hours. After cooling, the mixture is poured into ice-cold water. The precipitate is filtered off, rinsed with water and then dried under vacuum. 0.9 g of a white solid is obtained

(yield = 82%) . The nuclear magnetic resonance and mass spectrometry spectra comply.

EXAMPLE IA: Production and separation of the R and S enantiomers correspponding to compound (1) :

The two enantiomers of Example 1 were obtained by the preparative chiral HPLC separation technique. Their use is particularly advantageous.

S enantiomer R enantiomer

The enantiomers are separated on a Chiralpak IA chiral column and are detected by UV spectrophotometry and polarimetry .

Semi-preparative separation makes it possible to obtain 12 mg of each pure enantiomer per hour. 60 mg of each

enantiomer were thus obtained with the following characteristics :

Enantiomer (-) αD25 = -11.0 (CHCl ₃ , c=l)

The enantiomeric excess is greater than 99.5%.

Enantiomer (+) αD25= +10.9 (CHCl ₃ , c=l)

The enantiomeric excess is greater than 99.5%.

The NMR spectra of the two samples comply, the stereochemistry is not confirmed (the enantiomers are not differentiated by NMR) .

EXAMPLE 2 : Preparation of 3-hydroxypropyl 2-fluoro-4- [(3,3, 3-trifluoro-2-hydroxy-2-methylpropanoyl) amino] - benzoate - compound (2)

550 mg of 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoic acid are dissolved in 5 ml of 1, 3-propanediol, to which 3 to 4 drops of 97% sulphuric acid are added. The reaction medium is refluxed overnight. After cooling, the mixture is diluted with water and then extracted 3 times with ethyl acetate. The organic phase is dried with sodium sulphate, filtered and concentrated to the maximum degree. The yellow residue is chromatographed on silica gel (eluent: dichloromethane/methanol (98/2)) . The slightly yellow oil is triturated in diethyl ether. The solid formed is filtered off and dried under vacuum. 106 mg of a white solid are obtained (yield = 17%) . The nuclear magnetic resonance and mass spectrometry spectra comply.

EXAMPLE 3 : Preparation of pyridin-3-yl 2-fluoro-4- [(3,3, 3-trifluoro-2-hydroxy-2-methylpropanoyl) amino] - benzoate - compound 3

Yield: 44%

Under a nitrogen stream, 1 g of 2-fluoro-4- [ (3, 3, 3-tri- fluoro-2-hydroxy-2-methylpropanoyl) amino] benzoic acid is dissolved in 20 ml of anhydrous tetrahydrofuran and then 659 mg of carbonyldiimidazole are added. The reaction medium is heated at 65°C for lh30. 644 mg of 3-hydroxypyridine dissolved beforehand in 5 ml of anhydrous tetrahydrofuran are introduced into the reaction mixture, which is maintained at ambient temperature overnight with magnetic stirring. The reaction medium is again heated at 65°C for 3 hours, and then, after cooling, it is concentrated to the maximum degree. The residue is diluted with ethyl acetate and is then washed successively 3 times with a saturated solution of sodium hydrogen carbonate, once with water, twice with a IN solution of hydrochloric acid and then 3 times with a saturated solution of sodium chloride. The organic phase is dried over sodium sulphate, filtered and concentrated to the maximum degree. The residue is triturated with diisopropyl ether and then filtered. The solid obtained is suspended in a minimum amount of a mixture of dichloromethane/methanol (98/2) . The white solid is filtered off and then dried under vacuum. 540 mg of a white powder are obtained (yield = 44%) . The nuclear magnetic resonance and mass spectrometry spectra comply.

EXAMPLE 4 : Preparation of 2-hydroxyethyl 2-fluoro-4- [ (3,3, 3-trifluoro-2-hydroxy-2-methylpropanoyl) amino] - benzoate - compound (4)

Yield: 62%

Under a nitrogen stream, 0.5 g of 2-fluoro-4- [ (3, 3, 3- trifluoro-2-hydroxy-2-methylpropanoyl) amino] benzoic acid is dissolved in 7 ml of anhydrous tetrahydrofuran, and then 0.36 g of carbonyldiimidazole is added. The reaction medium is heated at 65°C for 2 hours. 1.5 ml of ethylene glycol are introduced into the reaction medium, which is heated at 65°C for 2 hours and then maintained at ambient temperature overnight with magnetic stirring. The reaction mixture is concentrated to the maximum degree and then the residue is diluted with ethyl acetate. The organic phase is washed successively 3 times with a IN solution of hydrochloric acid, 3 times with water, 3 times with a saturated solution of sodium hydrogen carbonate and then 3 times with a saturated solution of sodium chloride. The organic phase is dried over sodium sulphate, filtered and concentrated to the maximum degree. The residue is triturated with dichloromethane and the solid formed is then filtered off and dried under vacuum. 354 mg of a white powder are obtained (yield = 62%) . The nuclear magnetic resonance and mass spectrometry spectra comply.

EXAMPLE 5: Two-stage preparation of 2 , 3-dihydroxypropyl 2-fluoro-4- [(3,3, 3-trifluoro-2-hydroxy-2-methyl-

a) Synthesis of (2, 2 -dimethyl- 1, 3-dioxolan-4-yl) methyl 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methyl-propa- noyl) amino] benzoate

500 mg of 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoic acid are dissolved in 6 ml of 2, 2-dimethyl-l, 3-dioxolane-4-methanol, to which 3 to 4 drops of 97% sulphuric acid are added. The reaction medium is heated at 85°C for 8 hours. After cooling, the mixture is concentrated to the maximum degree. The residue is diluted with water and then extracted 3 times with dichloromethane . The organic phase is dried with sodium sulphate, filtered and concentrated to the maximum degree. The oil is chromatographed on silica gel (gradient: dichloromethane to dichloromethane/methanol (98/2)) . The oil is dissolved in ethanol and a few milligrams of vegetable charcoal are added, and then the mixture is refluxed for 3 hours and filtered through celite. The filtrate is concentrated to the maximum degree and then chromatographed on silica gel (gradient: dichloromethane to dichloromethane/methanol (99/1)) . 250 mg of a colourless oil are obtained (yield = 40%) . The nuclear magnetic resonance and mass spectrometry spectra comply.

b) Synthesis of 2, 3-dihydroxypropyl 2-fluoro-4- [ (3, 3, 3- trifluoro-2-hydroxy-2-methylpropanoyl) amino] benzoate

200 mg of (2, 2-dimethyl-l, 3-dioxolan-4-yl) methyl 2-flu- oro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methylpropanoyl) - amino] benzoate are dissolved in 2.5 ml of tetra- hydrofuran, to which 2.5 ml of a 4N solution of hydrochloric acid are slowly added. The reaction mixture is concentrated to maximum degree. The residue is diluted in water and then extracted 3 times with ethyl acetate. The organic phase is washed twice with a saturated solution of sodium chloride and then dried over sodium sulphate, filtered and concentrated to the

maximum degree. The yellow oil is triturated with diethyl ether and the precipitate is filtered off and then dried under vacuum. 65 mg of a white powder are obtained (yield = 36%) . The nuclear magnetic resonance and mass spectrometry spectra comply.

EXAMPLE 6: Preparation of phenyl 2-fluoro-4- [ (3, 3, 3- trifluoro-2-hydroxy-2-methylpropanoyl) amino] benzoate - compound ( 6 )

Yield: 56%

Under an inert atmosphere, 23 g of 2-fluoro-4- [ (3, 3, 3- trifluoro-2-hydroxy-2-methylpropanoyl) amino] benzoic acid are dissolved in 150 ml of anhydrous dichloro- methane, to which 30 g of O-benzotriazole-1-yl- N, N, N ' , N ' -tetramethyluronium tetrafluoroborate and 6.3 g of N-hydroxybenzotriazole are added. 18.4 ml of triethylamine are added to the heterogeneous medium and the reaction is stirred for 30 minutes at ambient temperature. The mixture becomes homogeneous and 30.8 g of phenol are introduced. The reaction is stirred overnight at ambient temperature and then treated with 50 ml of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase is dried over magnesium sulphate, filtered and concentrated to the maximum degree. The residue is purified by silica gel chromatography (gradient from 80/20 to 50/50 petroleum ether/ethyl acetate) . 16.3 g of a beige solid are obtained (yield = 56%) . The nuclear magnetic resonance and mass spectrometry spectra comply.

EXAMPLE 7: Preparation of 2- (dimethylamino) ethyl 2- fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methyl- propanoyl) amino] benzoate - compound (7)

Under a nitrogen stream, 0.5 g of 2-fluoro-4- [ (3, 3, 3- trifluoro-2-hydroxy-2-methylpropanoyl) amino] benzoic acid are dissolved in 5 ml of anhydrous tetrahydrofuran and then 0.33 g of carbonyldiimidazole is added. The reaction medium is heated at 65°C for 2 hours. 205 μl of N, N-dimethylethanolamine are introduced dropwise into the reaction mixture, which is maintained at ambient temperature overnight with magnetic stirring. The reaction mixture is concentrated to the maximum degree; the residue is diluted with a IN solution of hydrochloric acid and then washed twice with ethyl acetate. The acidic aqueous phase is brought to pH 8 with a IN solution of sodium hydroxide, and then extracted twice with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride and then dried over sodium sulphate, filtered and concentrated to the maximum degree. The light yellow powder is triturated with diethyl ether and then filtered and dried under vacuum. 275 mg of a white powder are obtained (yield = 44%) . The nuclear magnetic resonance and mass spectrometry spectra comply.

EXAMPLE 8 : Preparation of 4-methylphenyl 2-fluoro-4- [(3,3, 3-trifluoro-2-hydroxy-2-methylpropanoyl) amino] - benzoate - compound (8)

Under a nitrogen stream, 0.5 g of 2-fluoro-4- [ (3, 3, 3- trifluoro-2-hydroxy-2-methylpropanoyl) amino] benzoic acid are dissolved in 5 ml of anhydrous tetrahydrofuran and then 0.33 g of carbonyldiimidazole is added. The

reaction medium is heated at 65°C for 2 hours. 167 mg of p-cresol are introduced into the reaction mixture, which is maintained at ambient temperature overnight with magnetic stirring. The reaction mixture is concentrated to the maximum degree. The residue is diluted with water and then extracted 3 times with ethyl acetate. The organic phase is washed successively 3 times with a saturated solution of sodium hydrogen carbonate, twice with water and twice with a saturated solution of sodium chloride, and then dried over sodium sulphate, filtered and concentrated to the maximum degree. The yellow oil is purified by silica gel chromatography (gradient of 100% dichloromethane to 98/2 dichloromethane/methanol) . 65 mg of a white powder are obtained (yield = 11%) . The nuclear magnetic resonance and mass spectrometry spectra comply.

EXAMPLE 9: Preparation of butyl 2-fluoro-4- [ (3, 3, 3- trifluoro-2-hydroxy-2-methylpropanoyl) amino] benzoate - compound ( 9)

Yield: 16%

1 g of 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methyl- propanoyl) amino] benzoic acid are dissolved in 10 ml of butanol, to which 3 to 4 drops of 97% sulphuric acid and four spatulas of sodium sulphate are added. The reaction medium is refluxed overnight. After cooling, the mixture is filtered and then concentrated to the maximum degree (coevaporation with cyclohexane) . The residue is diluted with 100 ml of dichloromethane and then washed successively with 100 ml of a IN solution of sodium hydroxide and with 50 ml of a saturated solution of sodium chloride. The organic phase is dried with sodium sulphate, filtered and concentrated to the maximum degree. The oil is purified by silica gel

chromatography (eluent: dichloromethane/methanol (98/2)) . The oil is diluted in 30 ml of heptane and maintained at ambient temperature overnight with stirring. The precipitate formed is filtered off and then dried under vacuum. 190 mg of a white powder are obtained (yield = 16%) . The nuclear magnetic resonance and mass spectrometry spectra comply.

EXAMPLE 10: Preparation of 2-hydroxypropyl 2-fluoro-4- [(3,3, 3-trifluoro-2-hydroxy-2-methylpropanoyl) amino] - benzoate - compounds (10) and (11)

Yield: 50%

500 mg of 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2- methylpropanoyl) amino] benzoic acid are added to a mixture of 1.7 ml of methanesulphonic acid and 52 mg of acidic alumina prepared beforehand. 130 mg of propylene glycol are introduced into the reaction medium, which is subsequently heated at 80 ⁰ C for Ihl5. After cooling, the mixture is run into a mixture of water and ice, and then extracted with ethyl acetate. The organic phase is washed successively with water, twice with a 5% aqueous solution of sodium hydrogen carbonate and, finally, with water. It is dried over sodium sulphate, filtered and concentrated to the maximum degree. The oil is purified by silica gel chromatography (gradient: dichloromethane to dichloromethane/methanol (98/2)) . The solid obtained is dissolved in the minimum amount of acetone, to which water and also a small amount of vegetable charcoal are added. The mixture is kept

stirring for 10 minutes and then filtered through celite. The acetone is removed by evaporation and the product precipitates from the water. The solid is filtered off, rinsed with water and then dried under vacuum. 300 mg of a white powder are obtained (yield = 50%) . This white powder contains 55% of 2-hydroxypropyl 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methylpropan- oyl) amino] benzoate and 45% of 2-hydroxy-l-methylethyl 2-fluoro-4- [ (3, 3, 3-trifluoro-2-hydroxy-2-methylpropan- oyl) amino] benzoate . The nuclear magnetic resonance and mass spectrometry spectra comply.

EXAMPLE 11: Hair lotion

Compound 1 3.88 g

Propylene glycol 20.00 g

Ethyl alcohol 50.00 g

Water qs 100.00 g

This lotion is applied to the scalp, one to two times a day, at a rate of 1 ml per application, the scalp being gently massaged so as to cause the active agent to penetrate. The head of hair is then dried in the open air. This lotion makes it possible to reduce hair loss. It also makes it possible to improve the appearance of the hair.

EXAMPLE 12 : Wax/water mascara

Beeswax 6.00%

Paraffin wax 13.00%

Hydrogenated jojoba oil 2.00%

Water-soluble film-forming polymer 3.00%

Triethanolamine stearate 8.00%

Compound 1 1.00%

Black pigment 5.00%

Preservative qs

Water qs 100.00%

This mascara is applied to the eyelashes like a conventional mascara, with a mascara brush.

EXAMPLE 13: Hair lotion

Compound 1 3.88 g

Latanoprost 0.10 g

Propylene glycol 20.00 g

Ethyl alcohol 50.00 g

Water qs 100.00 g

This lotion is applied to the scalp one to two times a day, at a rate of 1 ml per application, the scalp being gently massaged so as to cause the active agent to penetrate. The head of hair is then dried in the open air. This lotion makes it possible to reduce hair loss. It also makes it possible to improve the appearance of the hair.

EXAMPLE 14: Hair lotion

Compound 1 3.88 g

Travoprost 0.1 g

Propylene glycol 20.00 g

Ethyl alcohol 50.00 g

Water qs 100.00 g

This lotion is applied to the scalp one to two times a day, at a rate of 1 ml per application, the scalp being gently massaged so as to cause the active agent to penetrate. The head of hair is then dried in the open air. This lotion makes it possible to reduce hair loss.

It also makes it possible to improve the appearance of the hair.

EXAMPLE 15: Hair lotion

Compound 1 3.88 g

Ethyl alcohol 50.00 g

Water qs 100 . 00 g

This lotion is applied to the scalp one to two times a day, at a rate of 1 ml per application, the scalp being gently massaged so as to cause the active agent to penetrate. The head of hair is then dried in the open air. This lotion makes it possible to reduce hair loss. It also makes it possible to improve the appearance of the hair.

EXAMPLE 16: Comparative tests of solubility in an aqueous-alcoholic medium between a compound of the invention and a compound of application EP1169300

The solubility of each of the following compounds, at ambient temperature in an ethanol/propylene glycol/water mixture (50/20/30), is compared.

Compound 6 of the invention having the structure

Example 1 of Application EP1169300

Compound (e) of Application EP1169300

Compound (6) is soluble at 0.12 M, unlike the two prior art compounds .

EXAMPLE 17: EVALUATION OF THE ANTIOXIDANT POTENTIAL: DCFH-DA TEST

Compound (1) of Example IA is used.

The global oxidative stress effect of compound 1 is measured, after oxidation of a fluorescent probe (DCFH- DA) , in a model of human epidermoid keratinocytes in culture (HaCaT) exposed to UV rays.

The use of DCFH-DA as a marker for intracellular global oxidative stress is based on its physicochemical properties. It is an apolar, non-ionic molecule capable of diffusing through cell membranes. Once inside the cell, DCFH-DA will be hydrolysed by intracellular esterases to a nonfluorescent compound: DCFH or 2,7- dichlorofluorescin . In the presence of activated oxygen species (H2O2; OH°), the DCFH is rapidly oxidized to a highly fluorescent compound: DCF or 2,7- dichlorofluorescein .

HaCaT keratinocytes pretreated with the active agents for 24 hours are rinsed with PBS+ and incubated in the presence of DCFH-DA [20 μM] for 30 minutes at 37°C in the dark.

After the probe has been removed, the cells are exposed to 2J/cm ² of UVA (WG335 filter) , in the presence of

1 ml/well of PBS+. The fluorescence of the DCF is evaluated immediately after UVA exposure, by spectro- fluorimetry (excitation 480 nm; emission 530 nm) .

Compound (1) of Example 1 shows antioxidant efficacy, with a dose effect. For the solution at 3 μM, 13% protection against UVA-induced oxidative stress is observed, and 27% protection is observed when the cells are treated with the active agent at 30 μM.