WO2010023317A1 - Novel hexafluoro-2-biphenylisopropanol compounds that modulate lxr-type receptors, process for the preparation thereof and use thereof as medicaments in human and veterinary medicine and also in cosmetics - Google Patents

Abstract

The present invention relates to novel hexafluoro-2-biphenylisopropanol compounds corresponding to general formula (I) below, in which R₁, R₂, R₃, R₄ and R₅ are as defined in the description, and also to the method for the preparation thereof and to the use thereof as medicaments in human or veterinary medicine and also in cosmetics.

Description

HOVEL HKKAFLUORO-2-EIPHEHYI-ISOPROPAUOL COMPOUNDS THAT MODUIATE LXR-TYPE RECEPTORS, PROCESS FOR THE PREPARRTION THEREOF AND USE THEREOF AS MEDICAMEMTS IN HUMAN AND VETERIHARY MEDICIME AMD ALSO IN COSMETICS

The present invention relates, to novel ϊiexafluoro- 2-biphenylisopropanol compounds that modulate LXR receptors, to the process for the preparation thereof and also to the use thereof as medicaments in human or veterinary medicine and in cosmetics .

The LXR receptors {liver X receptors) belong to the superfamily of steroid/thyroid receptors. In 1995, P. Willy and J. Mangelsdorf cloned a novel receptor belonging to the superfamily of steroid/thyroid receptors, referred to as LXRct (liver X receptor) , by low-stringency screening of a library of complementary DNA from human liver with a pool of degenerate oligonucleotides corresponding to the DNA-binding domain of RARα nuclear receptors . Comparison of the nucleotide sequence . of human LXRα with other receptors already known showed strong similarities between two sequences of orphan receptors: 77% homology with the human receptor NER-I or ubiquitous receptor UR, consequently described as the second LXR subtype and referred to as LXRβ, and 92% homology with the rat receptor RLD-I, which appears to be the murine homologue of hLXRα. The LXRβ isoforπt shows very great homology with an orphan receptor cloned in 1993 in rats: OR-I.

Analysis by in situ hybridization and Northern blotting of the messenger RNAs of the two human LXR subtypes identified and described, LXRα and LXRβ, demonstrates increased tissue distribution in organs with intense metabolic activity, for instance the kidneys, the liver, the intestines and, to a lesser extent, in the spleen, the adrenal glands and the skin. The hLXRβ isoform is much more ubiquitous and is also present in the brain, the testicles and the ovaries . These receptors have the ability to form functional heterodimers with retinoid X receptors (RXRs) . In the form of a heterodimer with retinoid X receptors (known ' as RXRs) , the LXR receptors activate transcription by binding to specific DNA sequence elements, known as the response elements (LXRE) , located in the promoter of the target gene of which they regulate the transcription.

The identification of specific LXR ligands was performed by Janowski et al . (Curr. Opin. Genet. Dev., 1998, Oct; 8(5), 571-5) . It has thus been shown that only one specific oxysterol group having a cholesterol backbone and structure is capable of activating LXR receptors. The study of the structure/activity relationships revealed the involvement of a 3 β-hydroxy group of cholesterol and an additional hydroxyl group preferably located on a side chain of the molecule. These compounds were shown to be active at their physiological concentration and more particularly a compound synthesized by the body: 22 (R) - hydroxycholesterol, which is described as the most powerful activator.

A controlled proteolytic digestion experiment established that this compound is a potential LXRα ligand. The skin has a structure which confers on it numerous properties and a major role in the barrier function. This regulation of the barrier function is particularly provided by the epidermis.

The natural human epidermis is mainly composed of three types of cells, namely the keratinocytes, which are in the vast majority, the melanocytes and the Langerhans cells. Each of these cell types contributes via its own functions to the essential role played in the body by the skin. The epidermis is continually being formed by proliferation of the basal cells of the epidermis. The keratinocytes formed in the deepest part of the epidermis migrate towards the surface of the skin. During this migration, the keratinocytes differentiate by means of profound biochemical and structural changes so as to result in the formation of cells lacking their nucleus and their cytoplasmic organelles, but which have synthesized a horny envelope: these are the corneocytes. The horny envelope gives the corneocytes great rigidity and provides the stratum corneum with mechanical strength. The corneocytes together constitute the horny layer or stratum corneum, which is the outermost layer of the epidermis and the main regulator of the barrier function of the skin.

The cells constituting the epidermis are delimited by a lipid domain. The epidermal lipids are mainly synthesized in the live epidermis. They are essentially constituted of phospholipids, sphingolipids, cholesterol, free fatty acids, triglycerides, cholesterol esters and alkanes. During cell differentiation, the phospholipids, the role of which consists in developing the fluid structure of the cell membranes of the live layers of the epidermis, are gradually replaced with a mixture predominantly composed of fatty acids, cholesterol and sphingolipids, which are the essential constituents of the horny layer of the epidermis (stratum corneum) .

In this respect, the intercellular level of cholesterol was described by Schmidt et al . , The Journal of Investigative Dermatology, No. 5, Ill-lib , as a predominant factor in the spontaneous formation of the horny envelope.

It is observed, for example, that there is an increase in the level of phosphorylation and the level of messenger RNAs of the enzymes associated with the de novo synthesis of the three key types of lipids of cell maturation: serine palmitoyl transferase for the formation of ceramides, HMGCoA reductase involved in the synthesis of cholesterol and of its derivatives, and acetyl CoA carboxylase and fatty acid synthases involved in the formation of cutaneous fatty acids. It appears that the ability to modify cell maturation, and more particularly to restore an effective barrier function, is directly linked to the regulation of the synthesis of the key lipids.

Dysregulation of the barrier function, whether generalized or localized, is known to be an important component of many disorders and diseases of the skin and of the mucous membranes. This disruption of the barrier function can result in the entry of pathogenic elements across the affected part of the skin, but it is also found to be a factor aggravating numerous skin pathologies correlated with disorders of epidermal cell differentiation and/or proliferation.

To treat these imbalances in barrier function, and also the skin disorders associated with insufficient epidermal differentiation and/or excess epidermal cell proliferation, various pharmaceutical approaches have been envisaged.

Now, it was described, in patent application WO 98/32444, that activators of FXR, PPARγ and LXRβ receptors are capable of restoring the barrier function of the skin. These activators are also described as increasing differentiation by inhibiting epidermal proliferation .

Furthermore, it has been shown that LXR modulators are capable of modulating the inflammatory response and are immunomodulators . In macrophages, oxysterols are capable of inhibiting the secretion of pro-inflammatory cytokines and the activation of lymphocytes (Ohlsson et al., J Clin. Invest. 1996, 98:78-89) . This activity was confirmed by the repression of genes involved in pro- inflammatory mechanisms, such as COX-2, IL- 6 and ILl-β, after bacterial stimulation or stimulation with other inflammatory stimuli (Joseph SB et al . , Nat. Med, 2006, Vol. 9, No. 2:213-219) .

It has also been shown that, in animal models of TPA-induced irritation or of oxazolone-induced contact allergy, LXR agonists are capable of inhibiting inflammation (Fowler AJ, J Invest. Dermatol. 2003, 120:246-255) .

Now, many skin pathologies are pro-inflammatory. In some, such as atopic dermatitis, there is a combination of a disruption of the barrier function and an inflammation subsequent to the penetration of proteins that act as superantigens (Cardona et al . , Am J Clin Dermatol, 2006, 7-5:273-279) . The LXR modulators therefore appear to be most particularly recommended for this type of pathology since they combine an action on the barrier function and on inflammation.

Compounds of the hexafluoro-2-phenyl isopropanol family have been described for modulating LXR receptors in patent application WO 06/000323.

Also known in the prior art is the compound N- (2,2,2-trifluoroethyl) -N- [4- [2, 2, 2-trifluoro-1- hydroxy-1- (trifluoromethyl) ethyl] phenyl] benzene- sulphonamide :

hereinafter referenced T0901317, which is a reference compound for the modulation of LXR receptors. It has been the subject of a large number of biological studies revealing its role in the modulation of LXR receptors and its potential in numerous therapeutic indications (Luis A.J. Atherosclerosis. Nature 2000; 407; 233-241) . However, the impact of the known LXR compounds on lipid metabolism makes these compounds difficult to develop given the potential adverse effects that this pharmacological activity may create by disrupting the metabolism, and in particular on lipid metabolism.

Thus, there exists a real need for LXR modulators that would maintain a therapeutic effectiveness while at the same time limiting the lipid metabolism-related adverse peripheral effects. Now, the applicant has found, unexpectedly and surprisingly, that certain compounds having the structure hexafluoro-2-biphenyl isopropanol, which is the subject of the present invention, have a very significant activity on LXR receptors while at the same time having less of an impact than the prior art compounds on variations in the main lipid factors in the blood and also on weight loss. Thus, the present invention relates to compounds of general formula (I) below:

in which Ri, R₂, R3, R4 and R₅, which may be identical or different, represent:

- a hydrogen,

- an unsubstituted or substituted alkyl radical,

- a cycloalkyl radical,

- a cycloalkylalkyl radical, - an unsubstituted or substituted alkoxy radical,

- a carboxyl radical,

- an unsubstituted or substituted alkoxycarbonyl radical,

- a halogen, - a cyano radical,

- a carboxamide, N-alkyl carboxamide or N,N-dialkyl carboxamide group,

- a sulphonamide, N-alkyl sulphonamide, N,N-dialkyl sulphonamide or morpholinosulphonyl group,

Ar represents a cyclic group chosen from:

given that, when R₃ is in the ortho-position with respect to R₄, then R₃ and R₄ can form a 5- or 6-sided hydrocarbon-based ring, it being understood that 1 or 2 carbon atoms (s) may optionally be replaced with 1 or 2 oxygen, nitrogen or sulphur atom(s), the optical isomers thereof, or in the form of hydrates or of solvates, and also the salts thereof with a pharmaceutically acceptable acid or base.

Among the addition salts of the compounds of general formula (I) with a pharmaceutically acceptable acid, mention may preferably be made of the salts with an organic acid or with an inorganic acid.

Suitable inorganic acids are, for example, hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulphuric acid and nitric acid. Suitable organic acids are, for example, acetic acid, ethanedioic acid, (Z) -2-butenedioic acid, (E) -2- butenedioic acid, 2, 3-dihydroxybutanedioic acid, methanesulphonic acid, ethanesulphonic acid and trifluoromethanesulphonic acid. Among the salts of the compounds of general formula (I) with a pharmaceutically acceptable base, these are salts of an alkali metal, in particular a sodium or potassium salt, or an alkaline-earth metal

(magnesium or calcium) salt or salts of organic amines, more particularly of amino acids such as arginine or lysine .

The invention also relates to the compounds of general formula (I) in the form of hydrates or of solvates with water or with a solvent. Solvents suitable for forming solvates are, for example, alcohols such as ethanol or isopropanol.

According to the present invention, the term

"unsubstituted or substituted alkyl" denotes a linear or branched, saturated hydrocarbon-based chain containing from 1 to 7 carbon atoms, which is unsubstituted or substituted with one or more halogen atoms or hydroxyl groups . According to the present invention, the term "cycloalkyl" denotes a saturated cyclic hydrocarbon- based chain containing from 3 to 7 carbon atoms .

According to the present invention, the term "cycloalkylalkyl" denotes an alkyl radical substituted with a cycloalkyl radical.

According to the present invention, the term "unsubstituted or substituted alkoxy" denotes an oxygen atom substituted with a linear or branched, saturated hydrocarbon-based chain containing from 1 to 6 carbon atoms, which is itself unsubstituted or substituted with one or more halogen atoms or hydroxyl groups.

According to the present invention, the term "unsubstituted or substituted alkoxy carbonyl" denotes a carboxyl substituted with an unsubstituted or substituted alkoxy radical.

According to the present invention, the term "halogen" denotes a bromine, chlorine, iodine or fluorine atom. The invention relates in particular to the compounds of formula (I) as defined above, in which Ar represents a phenyl group.

The invention relates in particular to the compounds of formula (I) as defined above, in which Ar represents a thiophene group.

The invention relates in particular to the compounds of formula (I) as defined above, in which one of the R3, R4 and R5 radicals is chosen from a cyano radical, a carboxamide, N-alkyl carboxamide or N, N- dialkyl carboxamide group and a sulphonamide, N-alkyl sulphonamide or N,N-dialkyl sulphonamide group, it being understood that the alkyl substituent of said radicals has the same definition as that given above.

The invention relates in particular to the compounds of formula (I) as defined above, in which one of the Ri or R₂ radicals represents a hydrogen and the other of the Ri or R₂ radicals represents an alkyl or alkoxy radical. The present invention also relates to the compounds of general formula (I) for which, independently or in combination:

- Ri represents a hydrogen, - R2 represents a hydrogen or an unsubstituted or substituted alkoxy radical,

- R₃ represents a hydrogen or an unsubstituted or substituted alkoxy radical, an unsubstituted or substituted alkyl radical, a cyano group or a carboxamide group,

- R₄ represents a hydrogen or an unsubstituted or substituted alkyl radical,

- R₅ represents a hydrogen or halogen,

- and Ar represents a phenyl. The present invention relates more particularly to the compounds of general formula (I) as defined above, for which Ri and R2 represent hydrogen atoms, and Ar represents a phenyl group.

The present invention relates more particularly to the compounds of general formula (I) as defined above, for which Ri and R2 represent hydrogen atoms, and Ar represents a thiophene group.

The present invention relates more particularly to the compounds of general formula (I) as defined above, for which Ri represents a hydrogen atom, R₂ represents an alkoxy radical and Ar represents a phenyl group.

The present invention relates more particularly to the compounds of general formula (I) as defined above, for which Ri represents a hydrogen atom, R₂ represents a methoxy radical and Ar represents a phenyl group.

The present invention relates more particularly to the compounds of general formula (I) as defined above, for which Ri represents a hydrogen atom, R₂ represents a hydrogen atom or an alkoxy radical, Ar represents a phenyl group, R3 and R₄ represent a hydrogen atom and R₅ represents a carboxamide, N-alkyl carboxamide or N,N-dialkyl carboxamide group or a sulphonamide, N-alkyl sulphonamide, N,N-dialkyl sulphonamide or morpholinosulphonyl group in the 3-position. The present invention relates more particularly to the compounds of general formula (I) as defined above, for which Ri represents a hydrogen atom, R₂ represents a hydrogen atom or an alkoxy radical, Ar represents a phenyl group, R₃ and/or R₄ represent (s) a hydrogen atom and R₅ represents a group in the 3-position.

Among the compounds of formula (I) which fall within the context of the present invention, mention may in particular be made of the following compounds: 1) l,l,l,3,3,3-Hexafluoro-2-[l,l' ;2' ,1" ] terphenyl-4- ylpropan-2-ol

2) l,l,l,3,3,3-Hexafluoro-2- (A" - trifluoromethoxy [ 1, 1' ; 2' , 1' ' ] terphenyl-4-yl) propan-2-ol

3) l,l,l,3,3,3-Hexafluoro-2- (3"- hydroxymethyl [ 1, 1' ; 2' , 1' ' ] terphenyl-4-yl) propan-2-ol

4) l,l,l,3,3,3-Hexafluoro-2- (3"- methoxy [ 1, 1' ; 2' , 1' ' ] terphenyl-4-yl) propan-2-ol

5) 2- (3' '-Chloro[l,l' ;2' ,1' ' ] terphenyl-4-yl) - 1,1,1,3,3, 3-hexafluoropropan-2-ol 6) 2- (3"-Chloro-4"-fluoro[l, 1' ;2' , 1" ] terphenyl-4- yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol

7) 1,1,1,3,3, 3-Hexafluoro-2- (2' -thiophen-3-ylbiphenyl- 4-yl) propan-2-ol

8) 1,1, 1,3, 3, 3-Hexafluoro-2- (5' ' -fluoro-2' '- methyl [1, 1' ;2' , 1" ] terphenyl-4-yl) propan-2-ol

9) 2- (2' -Benzo [1,3] dioxol-5-ylbiphenyl-4-yl) - 1,1,1,3,3, 3-hexafluoropropan-2-ol

10) 2- (3" , 4" -Dimethoxy [1, 1' ; 2' , 1" ] terphenyl-4-yl) - 1,1,1,3,3, 3-hexafluoropropan-2-ol 11) l,l,l,3,3,3-Hexafluoro-2- (4"- trifluoromethyl [ 1, 1' ; 2' , 1' ' ] terphenyl-4-yl) propan-2-ol

12) 2-(3",5"-

Bistrifluoromethyl [1, 1' ;2' , 1' ' ] terphenyl-4-yl) -

1,1,1,3,3, 3-hexafluoropropan-2-ol 13) 2- (3" ,4" -Dichloro[l, 1' ;-2' , 1" ] terphenyl-4-yl) -

1,1,1,3,3, 3-hexafluoropropan-2-ol

14) 1,1, 1,3, 3, 3-Hexafluoro-2- (3",4",5"- trimethoxy [ 1 , 1 ' ; 2 ' , 1 ' ' ] terphenyl-4-yl) propan-2-ol 15 ) 1 , 1 , l , 3 , 3 , 3 -Hexaf luoro-2 - ( 3 " - trifluoromethyl [ 1, 1' ; 2' , 1' ' ] terphenyl-4-yl) propan-2-ol

16) 1,1,1,3,3, 3-Hexafluoro-2- (2' -thiophen-2-ylbiphenyl- 4-yl) propan-2-ol 17) 4- (2,2,2-Trifluoro-l-hydroxy-l- trifluoromethylethyl) [1, 1' ;2' , 1" ] terphenyl-3' ' -N, N- dimethylsulphonamide

18) 1,1,1,3,3, 3-Hexafluoro-2- [3' ' - (morpholine-4- sulphonyl) [1, 1' ;2' , 1' ' ] terphenyl-4-yl ] propan-2-ol 19) 4- (2,2,2-Trifluoro-l-hydroxy-l- trifluoromethylethyl) [1, 1' ;2' , 1" ] terphenyl-3' ' - sulphonamide

20) 4- (2, 2, 2 -Trifluoro-1 -hydroxy- 1- trifluoromethylethyl) [1, 1' ;2' , 1" ] terphenyl-3' ' -N- methylsulphonamide

21) 4- (2, 2, 2-Trifluoro-1-hydroxy-l-trifluoromethyl- ethyl) [1, 1' ;2' , 1' ' ] terphenyl-3' ' -carbonitrile

22) Methyl 4- (2, 2, 2-trifluoro-1-hydroxy-l-trifluoro- methylethyl) [1, 1' ;2' , 1' ' ] terphenyl-3' ' -carboxylate 23) 4- (2,2,2-Trifluoro-l-hydroxy-l- trifluoromethylethyl) [1, 1' ;2' , 1' ' ] terphenyl-3' ' - carboxamide

24) 2- (2' -Benzo [1,3] dioxol-5-yl-5' -methoxybiphenyl-4- yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol 25) 1, 1, 1,3, 3, 3-Hexafluoro-2- (3-hydroxymethyl-4' - methoxy [1, 1' ;2' , 1' ' ] terphenyl-4' ' -yl) propan-2-ol 26) 4' -Methoxy-4' ' - (2, 2, 2-trifluoro-l-hydroxy-1- trifluoromethylethyl) [1, 1' ;2' , 1' ' ] terphenyl-3- carbonitrile 27) 4' -Methoxy-4' '- (2, 2, 2-trifluoro-l-hydroxy-1- trifluoromethylethyl) [1, 1' ;2' , 1' ' ] terphenyl-3- carboxylic acid

28) 4' -Methoxy-4' ' - (2, 2, 2-trifluoro-1 -hydroxy- 1- trifluoromethylethyl) [1, 1' ;2' , 1' ' ] terphenyl-3- carboxamide and 29) 1, 1, 1, 3, 3, 3-Hexafluoro-2- (3" -hydroxymethyl-4' - methoxy [ 1, 1' ; 2' , 1' ' ] terphenyl-4-yl) propan-2-ol.

The invention also extends to the methods for preparing the compounds of formula (I) as described above, and also to the novel synthesis intermediates used during this preparation.

The compounds of general formula (I) are prepared according to the general reaction schemes given in Figure 1.

The process will in particular be carried out in the following way:

Using the reaction scheme of Figure 1:

Stage a: Commercially available anilines of general formula (I) in which Ri is as defined above can react with sodium nitrite in the presence of hydrochloric acid and of potassium iodide so as to give the iodinated compounds of general formula (2) in which Ri is as defined above (Carey Sundberg - Advanced Organic Chemistry, Part A and B - Plenum, New York, 1990)

Stage b: The compounds of general formula (3) in which Ri and R2 are as defined above and X represents a halogen chosen from bromine, chlorine and iodine can be obtained from 2-haloarylboronic acids which are commercially available or prepared according to conventional methods and from the compounds of general formula (2) by means of a Suzuki reaction using a palladium-based catalyst such as tetrakis (triphenyl- phosphine) palladium, for example (N. Miyaura, K. Yamada, K. Suzuki, Tetrahedron Lett., 1979, 3437-3440) .

Stage c: The compounds of general formula (I) in which Ri, R2, R3, R4 and R₅ are as defined above are obtained from the compounds of general formula (3) and from boronic acids which are commercially available or prepared according to conventional methods, by means of a Suzuki reaction using a palladium-based catalyst such as tetrakis (triphenylphosphine) palladium, for example (N. Miyaura, K. Yamada, K. Suzuki, Tetrahedron Lett., 1979, 3437-3440) .

Another embodiment ooff tthhee iinnvveennttiioonn relates to the following process for preparing the compounds of the invention : Stage d: The compounds of general formula (I) in which Ri, R2, R3, R4 and R₅ are as defined above are obtained from the boronic acids of general formula (5) in which R2, R3, R4 and R₅ are as defined above

(5)

and from the aryl halides of general formula (2) which are commercially available or prepared according to conventional methods, by means of a Suzuki reaction using a palladium-based catalyst such as tetrakis (triphenylphosphine) palladium, for example (N. Miyaura, K. Yamada, K. Suzuki, Tetrahedron Lett., 1979, 3437-3440) .

Stage e: The aryl halides of general formula (7) in which R2, R3, R4 and R5 are as defined above and X represents a halogen chosen from bromine, chlorine and iodine are obtained from the aryl halides of general formula (6) in which R₃, R₄ and R₅ are as defined above and X' represents a halogen chosen from bromine, chlorine and iodine

(6)

and from 2-halophenylboronic acid which are commercially available or prepared according to conventional methods, by means of a Suzuki reaction using a palladium-based catalyst such as tetrakis (triphenylphosphine) palladium, for example (N. Miyaura, K. Yamada, K. Suzuki, Tetrahedron Lett., 1979, 3437-3440) .

Another embodiment of the invention also relates to the following process for preparing the compounds of the invention:

Stage f: The boronates of general formula (8) in which

Ri is as defined above are obtained from the alkyl halides of general formula (2) as defined above by reaction with bis (pinacolato) diborane in the presence of a palladium catalyst such as dichloro [1, 1' - bis (diphenylphosphino) ferrocene] palladium, for example

(Ishiyama, T.; Murata, M.; Miyaura, N.; J Org Chem

1995, 60 (23) , 7508-7510) .

Stage g: The compounds of general formula (I) in which R2, R3, R4 and R₅ are as defined above are obtained from the boronates of general formula (8) as defined above and from the aryl halides of general formula (7), as defined above, which are commercially available or prepared according to conventional methods, by means of a Suzuki reaction using a palladium-based catalyst such as tetrakis (triphenylphosphine) palladium, for example (N. Miyaura, K. Yamada, K. Suzuki, Tetrahedron Lett., 1979, 3437-3440) .

The compounds according to the invention have modulatory properties on LXRβ-type receptors.

The term "modulatory properties" is intended to mean LXRβ-type receptor agonist or antagonist properties .

The term "LXRβ receptors" is generally intended to mean LXRβ receptors taken individually and/or in the form of homodimers and/or in the form of heterodimers such as, without limitation, the LXR/RAR (Retinoid Acid Receptor) ; LXR/LXR; LXR/PPAR (Peroxisome Proliferator- Activated receptor) ; LXR/VDR (Vitamin D Nuclear Receptor) heterodimers, irrespective of the subtypes involved for each of the receptors mentioned. This activity on LXRβ receptors is measured in a transactivation test and quantified by means of the dissociation constant Kdapp (apparent) , as described in Example 30.

A subject of the present invention is also a compound of formula (I) as defined above, for use thereof as a medicament in human or veterinary medicine .

In particular, a subject of the present invention is the use of a compound of formula (I) as defined above, for use thereof as a medicament:

1) in the treatment of dermatological conditions, and in particular: dermatological conditions associated with a keratinization disorder relating to differentiation and proliferation, in particular common acne, comedonal acne, polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata, senile acne, secondary acne such as solar acne, acne medicamentosa or occupational acne, ichthyosis, ichthyosiform conditions, Darier' s disease, palmoplantar keratoderma, leukoplakia and leukoplakiform conditions, and cutaneous or mucosal (oral) lichen, - dermatological conditions with an inflammatory immunoallergic component, with or without a cell proliferation disorder, in particular cutaneous, mucosal or ungual psoriasis, psoriatic arthritis, cutaneous atopy, such as eczema, respiratory atopy or gingival hypertrophy, benign or malignant dermal or epidermal proliferations, whether or not of viral origin, in particular common warts, flat warts, epidermodysplasia verruciformis, oral or florid papillomatoses, and T lymphome, proliferations that may be induced by ultraviolet radiation, in particular basocellular and spinocellular epithelioma, precancerous skin lesions, in particular keratoacanthomas, immune dermatoses, in particular lupus erythematosus, - bullous immune diseases, collagen diseases, in particular sclerodermia, dermatological or systemic conditions with an immunological component, skin disorders due to exposure to UV radiation, photo-induced or chronological ageing of the skin or actinic pigmentations and keratosis, or any pathologies associated with chronological or actinic ageing, in particular xerosis, sebaceous function disorders, in particular hyperseborrhoea of acne, simple seborrhoea or seborrhoeic dermatitis, cicatrization disorders or stretchmarks, pigmentation disorders, such as hyperpigmentation, melasma, hypopigmentation or vitiligo, and also 2) in the treatment of:

- lipid metabolism conditions, such as obesity, hyperlipidaemia, non-insulin-dependent diabetes or syndrome X, - inflammatory conditions such as arthritis, cancerous or precancerous states, alopecia of various origins, in particular alopecia caused by chemotherapy or radiation, immune system disorders, such as asthma, type I sugar diabetes, multiple sclerosis, or other selective dysfunctions of the immune system, or cardiovascular system conditions, such as arteriosclerosis or hypertension.

For example, the invention relates to the compounds of the invention for their application as medicaments in the treatment of acne, psoriasis and cutaneous atopy.

The subject of the present invention is also a pharmaceutical or cosmetic composition comprising at least one compound of formula (I) as defined above.

The compounds according to the invention are generally administered at a daily dose of approximately 0.001 mg/kg to 100 mg/kg of body weight, in 1 to 3 intakes .

The composition according to the invention may be administered enterally, parenterally, topically or ocularly. Preferably, the pharmaceutical composition is packaged in a form which is suitable for topical application .

For enteral administration, the composition, more particularly the pharmaceutical composition, may be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, or lipid or polymer vesicles or nanospheres or microspheres for controlled release. For parenteral administration, the composition may be in the form of solutions or suspensions for a drip or for inj ection .

The compounds are used systemically at a concentration generally of between 0.001% and 10% by weight, preferably between 0.01% and 1% by weight, relative to the weight of the composition.

Administered topically, the pharmaceutical composition according to the invention is more particularly for use in treating the skin and the mucous membranes and may be in the form of ointments, creams, milks, salves, powders, impregnated pads, syndets, solutions, gels, sprays, foams, suspensions, lotions, sticks, shampoos or washing bases. It may also be in the form of suspensions of lipid or polymer vesicles or nanospheres or microspheres or polymer patches and hydrogels for controlled release. This composition for topical administration may be in anhydrous form, in aqueous form or in the form of an emulsion . The compounds are used topically at a concentration generally of between 0.001% and 10% by weight, preferably between 0.01% and 1% by weight, relative to the total weight of the composition.

The compounds according to the invention also find a use in the cosmetics field, especially as a cosmetic product, in particular in body and hair hygiene and especially for treating acne-prone skin, for combating the greasy appearance of the skin and the hair, in protecting against the harmful effects of sunlight or in treating physiologically dry skin, and for preventing and/or combating skin ageing, in particular photo-induced and/or chronological skin ageing.

A subject of the invention is therefore also the cosmetic use of a composition comprising, in a physiologically acceptable support, at least one of the compounds of formula (I), for preventing and/or treating the signs of skin ageing or for body or hair hygiene .

The cosmetic composition according to the invention containing, in a cosmetically acceptable support, at least one compound of formula (I) or an optical or geometric isomer thereof or a salt thereof, may in particular be in the form of a cream, a milk, a lotion, an ointment, a gel, suspensions of lipid or polymer vesicles or nanospheres or microspheres, impregnated pads, solutions, sprays, foams, sticks, soaps, shampoos or washing bases.

The compositions as defined above in the form of a cream may in particular be non-ionic water-in-oil creams or non-ionic oil-in-water creams.

The compositions as defined above in the form of an ointment may in particular be in the form of a hydrophobic ointment. The concentration of compound of formula (I) in the cosmetic composition is advantageously between 0.001% and 3% by weight, relative to the total weight of the composition.

The pharmaceutical and cosmetic compositions as described above may also contain additives or combinations of these additives, and in particular:

- wetting agents;

- flavour enhancers;

- preservatives such as para-hydroxybenzoic acid esters;

- stabilizers;

- moisture regulators;

- pH regulators;

- osmotic pressure modifiers; - emulsifiers;

UV-A and UV-B screens;

- antioxidants, such as α-tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase, ubiquinol or certain metal-chelating agents;

- emollients;

- hydrating agents such as glycerol, PEG 400, thiamorpholinone and derivatives thereof, or urea .

Of course those skilled in the art will take care to select the possible compound (s) to be added to these compositions in such a way that the advantageous properties intrinsically associated with the present invention are not, or are not substantially, adversely affected by the envisaged addition.

Several examples of the production of compounds of general formula (I) according to the invention, biological activity results of these compounds and also various formulations based on such compounds will now be given by way of illustration which is in no way limiting in nature.

Example 1: 1 ,1 ,1 ,3,3,3-Hexafluoro-2- [1 ,1' ;2' ,1' ' ]- terphenyl-4-ylpropan-2-ol

1,1,1 , 3, 3, 3-Hexafluoro-2- (4-iodophenyl)propan-2-ol

A 6M solution of hydrochloric acid (30.4 ml, 173.6 mmol) and a solution of sodium nitrite (4.2 g, 60.8 mmol) in 23 ml of water are added, dropwise, to a solution of 2- (4-aminophenyl) -1, 1, 1, 3, 3, 3- hexafluoropropan-2-ol (15.0 g, 57.9 mmol) in 75 ml of dimethylformamide, while maintaining the temperature at 5°C. The reaction medium is stirred for 30 minutes. Potassium iodide (9.6 g, 57.9 mmol) is added portionwise at 5°C. The medium returns to ambient temperature and is stirred for 16 hours. The organic phase is extracted with diethyl ether, washed with a saturated aqueous solution of sodium thiosulphate and then dried over magnesium sulphate. After concentration, an oil is obtained, which is chromatographed on silica gel: eluent 90/10 pentane/diethyl ether. 20.5 g of 1,1,1,3,3,3- hexafluoro-2- (4-iodophenyl) propan-2-ol are obtained. Yield = 95%.

¹H NMR (CDCl₃, 400 MHz) : 3.83 (s, IH); 7.37-7.41 (m, 3H) ; 7.72-7.75 (m, 2H) .

1,1,1 , 3, 3, 3-Hexafluoro-2- [1,1' ; 2' ,1' '] terphenyl-4- ylpropan-2-ol

500 mg (1.35 mmol) of 1, 1, 1, 3, 3, 3-hexafluoro-2- (4- iodophenyl) propan-2-ol, 346 mg (1.75 mmol) of 2-phenylbenzeneboronic acid, 6 mg (2 mol per 100 mol) of palladium acetate and 19 mg (4 mol per 100 mol) of biphenyldicyclohexylphosphine are dissolved in 7 ml of dimethylformamide in the presence of 0.5 ml of a 2M potassium phosphate solution. The reaction mixture is stirred for 18 hours at 80⁰C. The reaction mixture is extracted with ethyl acetate. The organic phases are washed with a solution of sodium chloride and dried over sodium sulphate. The residual oil is chromatographed on silica gel (8/2 heptane/ethyl acetate) . 260 mg of 1, 1, 1, 3, 3, 3-hexafluoro-2- [ 1, 1' ; 2' , 1' ' ] terphenyl-4-ylpropan-2-ol are obtained. Yield = 48%.

¹H NMR (CDCl₃, 400 MHz) : 3.42 (s, IH); 7.12 (m, 2H); 7.22 (m, 5H); 7.47 (m, 4 H); 7.58 (d, J = 8 Hz, 2H) . ¹³C NMR (CDCl₃, 100 MHz) : 126.0, 126.7, 127.6, 127.9, 128.0, 129.8, 130.0, 130.4, 130.6, 139.7, 141.0, 141.3, 144.0.

Example 2: 1 ,1 ,1 ,3,3,3-Hexafluoro-2- (4^r ' - trifluoromethoxy- [1 ,1' ;2' ,1' ' ] terphenyl-4-yl)propan-2- ol

2- (2 ' -Bromobiphenyl-4-yl) -1,1,1 ,3,3,3-hexafluoropropan- 2-ol

1 g of 1, 1, 1, 3, 3, 3-hexafluoro-2- (4-iodophenyl) propan-2- ol (2.7 mmol) and 600 mg of 2-bromophenylboronic acid (2.97 mmol) are dissolved in 10 ml of dimethylformamide, in the presence of 1.8 ml of a 2M aqueous solution of potassium phosphate (3.51 mmol) . 38 mg of 2- (dicyclohexylphosphino) biphenyl (0.108 mmol) and 12 mg of palladium (II) acetate (0.054 mmol) are then added. The reaction mixture is stirred for 16 hours at 80⁰C. The reaction mixture is extracted with ethyl acetate and then the residue is chromatographed on silica gel: eluent 95/5 heptane/ethyl acetate. 0.75 g of 2- (2' -bromobiphenyl-4- yl) -1, 1, 1, 3, 3, 3-hexafluoropropan-2-ol is obtained. Yield = 64%. ¹H NMR (CDCl₃, 400 MHz) : 3.43 (S, IH) ; 7.16-7.19 (m, 2H) ; 2.26-7.31 (m, 2H) ; 7.43-7.45 (m, 2H) ; 7.60-7.63 (m, IH) ; 7.70 (d, J = 8.3 Hz, 2H) .

1,1,1 , 3, 3, 3-Hexafluoro-2- (4 ' ' -trifluoromethoxy- [1,1' ;2' ,1' ' ] terphenyl-4-yl)propan-2-ol

200 mg of 2- (2' -bromobiphenyl-4-yl) -1, 1, 1, 3, 3, 3- hexafluoropropan-2-ol (0.50 mmol) and 155 mg of

4- (trifluoromethoxy) phenylboronic acid (0.75 mmol) are dissolved in 2.0 ml of dimethylformamide in the presence of 0.45 ml of a 2M aqueous solution of potassium phosphate (0.90 mmol) . 7 mg of 2- (dicyclohexylphosphino) biphenyl (0.020 mmol) and also

2.3 mg of palladium (II) acetate (0.010 mmol) are added.

The reaction mixture is stirred for 16 hours at 80⁰C.

The mixture is extracted with ethyl acetate and the residue is chromatographed on silica gel: eluent 95/5 heptane/ethyl acetate. 197 mg of 1,1,1,3,3,3- hexafluoro-2- (4' ' -trifluoromethoxy [ 1, 1' ; 2' , 1" ] - terphenyl-4-yl) propan-2-ol are obtained. Yield = 55%.

¹H NMR (CDCl₃, 400 MHz) : 3.38 (s, IH); 6.97 (d, J = 8.1 Hz, 2H); 7.02-7.05 (m, 2H); 7.11-7.13 (m, 2H);

7.37-7.40 (m, 4H); 7.49 (d, J = 8.3 Hz, 2H) .

¹³C NMR (CDCl₃, 100 MHz) : 120.0 (q) ; 120.4; 122.8 (q) ;

126.4; 128.1; 128.2; 129.0; 129.1; 129.7; 130.2; 130.3;

131.3; 138.7; 139.1; 140.0; 142.5; 147.1; 147.2.

Example 3: 1,1,1 , 3, 3, 3-Hexafluoro-2- (3 ' ' -hydroxymethyl-

[1,1' ;2' ,1' '] terphenyl-4-yl)propan-2-ol

1,1,1,3,3, 3-hexafluoro-2- (3' ' -hydroxymethyl-

[ 1, 1' ; 2' , 1' '] terphenyl-4-yl) propan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 1.36 (t, J = 6 Hz, IH); 3.69 (s, IH); 4.40 (d, J = 6 Hz, 2H); 6.91 (s, IH); 7.05 (d, J = 8 Hz, IH) ; 7.10-7.19 (m, 4H) ; 7.39 (m, 4H) ; 7.49 (d, J = 8 Hz, IH) .

¹³C NMR (CDCl₃, 100 MHz) : 63.1, 120.5, 123.3, 124.0, 125.6, 126.0, 126.3, 127.1, 128.0, 128.2, 128.3, 137.3, 138.1, 138.2, 139.1, 141.5.

Example 4: 1 ,1 ,1 ,3,3,3-Hexafluoro-2- (3^r ' - methoxy[l ,1' ;2^r ,1' '] terphenyl-4-yl)propan-2-ol

1,1, l,3,3,3-hexafluoro-2- (3' ' -methoxy [1, 1' ;2' , 1" ] - terphenyl-4-yl) propan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 3.44 (2s, 4H, CH3 +OH); 6.46 (s, IH); 6.70 (m, 2H); 7.08 (t, J = 8 Hz, IH); 7.16 (d, J = 8 Hz, 2H); 7.17 (s, IH); 7.38 (m, 4H); 7.51 (d, J = 8 Hz, IH) .

¹³C NMR (CDCl₃, 100 MHz) : 55.3, 113.3, 115.4, 122.6, 122.8 (q) , 126.4, 127.8, 128.1, 128.4, 129.4, 130.4, 130.8, 130.9, 139.7, 140.8, 142.6, 144.1, 159.4.

Example 5: 2- (3' ' -Chloro [1 ,1' ;2' ,1' ' ] terphenyl -4- yl) 1,1,1 , 3 , 3 , 3-hexafluoropropan-2-ol

2- (3' ' -chloro [1, 1' ;2' , 1" ] terphenyl-4-yl) -1, 1,1, 3,3,3- hexafluoropropan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 3.44 (si, IH); 6.79 (d, J = 8 Hz, IH); 6.98 (m, 2H); 7.08 (m, 3H); 7.31 (m, 4H); 7.45 (d, J = 8 Hz, 2H) . 1³C NMR (CDCl₃, 100 MHz) : 126.2, 126.2, 126.8, 127.4, 128.1, 128.7, 129.0, 129.8, 130.0, 130.4, 133.8, 139.2, 139.4, 142.8, 143.1.

Example 6: 2- (3' ' -Chloro-4' ' -fluoroζl,l' ;2' ,1"]- terphenyl-4-yl) -1,1,1 , 3, 3, 3-hexafluoropropan-2-ol

2- (3' ' -Chloro-4' ' -fluoro- [1, 1' ;2' , 1" ] terphenyl-4-yl) - 1, 1, 1, 3, 3, 3-hexafluoropropan-2-ol is obtained in a manner analogous to Example 2. ¹H NMR (CDCl₃, 400 MHz) : 3.40 (si, IH) ; 6.85 (m, 2H) ; 7.08 (d, J = I Hz, IH) ; 7.13 (d, J = I Hz, 2H) ; 7.32- 7.38 (m, 4H) ; 7.52 (d, J = 8 Hz, 2H) .

¹³C NMR (CDCl₃, 100 MHz) : 116.4, 120.9, 122.9 (q) , 126.7, 127.2, 128.6, 129.6, 130.4, 130.7, 130.8, 130.9, 132.2, 138.4, 138.6, 139.7, 143.3, 157.5.

Example 7: 1,1,1 , 3, 3, 3-Hexafluoro-2- (2 ' -thiophen-3- ylbiphenyl-4-yl)propan-2-ol 1,1,1,3,3, 3-hexafluoro-2- (2' -thiophen-3-ylbiphenyl-4- yl) propan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 3.49 (si, IH); 6.59 (d, J = 7 Hz, IH); 6.91 (d, J = 3 Hz, IH); 7.04 (m, IH); 7.19

(d, J = I Hz, 2H); 7.34 (m, 3H); 7.42 (m, IH); 7.52 (d,

J = 8 Hz, 2H) .

¹³C NMR (CDCl₃, 100 MHz) : 122.6 (q) , 123.1, 124.7,

126.1, 127.5, 127.7, 128.0, 128, 128.9, 129.7, 130.2, 130.3, 135.3, 139.3, 141.5, 143.7.

Example 8: 1,1,1 , 3, 3, 3-Hexafluoro-2- (5 ' ' -fluoro-2 ' ' - methyl [1 ,1' ;2' ,1' ' ] terphenyl-4-yl)propan-2-ol

1,1, 1,3, 3, 3-hexafluoro-2- (5' ' -fluoro-2' '- methyl [1, 1' ;2' , 1' '] terphenyl-4-yl) propan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 1.73 (s, 3H); 3.52 (si, IH);

6.76 (m, 2H); 6.92 (m, IH); 7.11 (d, J = 8 Hz, 2H); 7.22 (d, J = I Hz, IH); 7.37 (m, 3H); 7.45 (d, J =

1 Hz, 2H) .

¹³C NMR (CDCl₃, 100 MHz) : 19.5, 114.4, 117.4, 122.9 (q) ,

126.4, 127.2, 128.0, 128.4, 129.8, 130.5, 131.4, 131.8,

139.7, 139.9, 142.7, 143.4, 161.0.

Example 9: 2- (2 ' -Benzo [1 , 3]d±oxol-5-ylbiphenyl-4-yl) -

1,1,1 ,3,3,3-hexafluoropropan-2-ol

2- (2'-benzo[l,3]dioxol-5-ylbiphenyl-4-yl) -1, 1,1, 3,3,3- hexafluoropropan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 3.52 (s, lH) ; 5.83 (s, 2H) ; 6.45-6.60 (m, 4H) ; 7.17 (d, J = 8 Hz, 2H) ; 7.33 (s, 3H) ; 7.52 (d, J = 8 Hz, 2H) .

¹³C NMR (CDCl₃, 100 MHz) : 101.6; 108.3; 110.7; 123.0; 123.9; 126.5; 127.9; 128.3; 130.8; 131.0; 132.1; 135.4; 139.7; 140.7; 144.1; 146.2; 146.8; 147.7.

Example 10: 2- (3' ' ,4' ' -Dimethoxy[l ,1' ; 2' ,1' ' Jterphenyl- 4-yl) -1,1,1 , 3 , 3 , 3-hexafluoropropan-2-ol

2- (3' ' , 4" -dimethoxy [1, 1' ;2' , 1" ] terphenyl-4-yl) -

1, 1, 1, 3, 3, 3-hexafluoropropan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 3.35 (s, 3H); 3.55 (s, IH);

3.79 (s, 3H); 6.33 (d, J = 2.0 Hz, IH); 6.731-6.81 (m,

2H); 7.17-7.20 (m, 2H); 7.34-7.40 (m, 4H); 7.52 (d, J =

8.3 Hz, 2H) . 1³C NMR (CDCl₃, 100 MHz) : 55.7, 56.2, 111.2, 114.1,

121.6, 122.1, 124.4, 126.6, 127.8; 127.8; 128.5; 130.0;

130.4; 130.8; 130.9; 133.8; 139.5; 140.5; 144;3; 148.3;

148.4; 171.7.

Example 11: 1 ,1 ,1 ,3,3,3-Hexafluoro-2- (4' ' - tr±fluoromethyl [1 ,1' ;2^r ,1' ' ] terphenyl-4-yl)propan-2-ol

1,1,1,3,3, 3-hexafluoro-2- (4' ' -trifluoromethyl-

[ 1, 1' ; 2' , 1' '] terphenyl-4-yl) propan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 3.39 (s,lH); 7.12-7.16 (m, 4H);

7.36-7.42 (m, 6H); 7.51 (d, j = 8.3 Hz, 2H) .

¹³C NMR (CDCl₃, 100 MHz) : 122.8 (q) ; 124.2; 124.6;

124.7; 124.8; 125.6; 126.5; 127.1; 127.4; 127.7; 128.3; 128.5; 129.2; 129.7; 130.3; 130.5; 138.6; 139.0; 142.3;

144.9.

Example 12: 2- (3' ' ,5' ' -Bistrifluoromethyl [1 ,1' ;2' ,1' ' ]- terphenyl-4-yl) -1,1,1 , 3, 3, 3-hexafluoropropan-2-ol 2- (3' ' , 5" -bistrifluoromethyl [1, 1' ;2' , 1" ] terphenyl-4- yl) -1, 1, 1, 3, 3, 3-hexafluoropropan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 3.40 (s,lH); 7.10 (d, J = 8.3 Hz, 2H); 7.41-7.47 (m, 6H); 7.55 (d, J = 8.2 Hz, 2H) ; 7.63 (s, IH) .

¹³C NMR (CDCl₃, 100 MHz) : 120.8, 121.4, 122.1, 124.8, 126.9, 128.6, 129.0, 129.4, 130.4, 130.6, 131.1, 131.2, 131.5, 131.8, 137.8, 140.0, 142.7, 143.2.

Example 13: 2- (3' ' ,4' ' -Dichloro[l ,1' ;2' ,1' '] terphenyl- 4-yl) -1,1,1 , 3, 3, 3-hexafluoropropan-2-ol

2- (3' ' , 4" -dichloro [1, 1' ;2' , 1" ] terphenyl-4-yl) - 1, 1, 1, 3, 3, 3-hexafluoropropan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 3.50 (s, 3H); 6.82 (dd, J = 8.3 Hz, 2.1 Hz, IH); 7.14-7.16 (m, 3H); 7.18 (d, J = 2.6 Hz, IH); 7.37-7.40 (m, 4H); 7.55 (d, J = 8.3 Hz, 2H) .

¹³C NMR (CDCl₃, 100 MHz) : 123.0 (q) ; 126.7; 127.2; 128.5; 128.7; 129.4; 129.7; 129.8; 129.9; 130.2; 130.5; 130.6; 130.8; 131.5; 137.4; 139.0; 141.3; 142.3; 156.8.

Example 14: 1,1,1 , 3, 3, 3-Hexafluoro-2- (3 ' ' , 4 ' ' , 5 ' ' - trimethoxy[1 ,l';2',l'^f] terphenyl-4-yl)propan-2-ol

1,1, 1, 3, 3, 3-hexafluoro-2- (3" , 4" , 5" -trimethoxy-

[ 1, 1' ; 2' , 1' '] terphenyl-4-yl) propan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 3.48 (s, 3H); 3.51 (s, 6H); 3.75 (s, 3H); 6.23 (s, 2H); 7.18-7.20 (m, 2H); 7.37- 7.43 (m, 4H); 7.53 (d, j = 8.3 Hz, 2H) . 1³C NMR (CDCl₃, 100 MHz) : 56.1, 61.3, 107.7, 124.4, 126.5, 127.8, 128.0, 128.5, 130.3, 130.5, 130.8, 136.5, 137.2, 139.7, 140.8, 144.2, 153.1.

Example 15: 1 ,1 ,1 ,3,3,3-Hexafluoro-2- (3' ' - trifluoromethyl [1 ,1' ;2^r ,1' ' ] terphenyl-4-yl)propan-2-ol

1,1,1,3,3, 3-hexafluoro-2- (3' ' -trifluoromethyl- [1, 1' ; 2' , 1' '] terphenyl-4-yl) propan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 3.39 (s, IH); 7.11 (d, J = 7.3 Hz, 2H); 7.19 (d, J = 5.7 Hz, 2H); 7.28 (s, 2H); 7.41 (m, 4H); 7.50 (d, J = 7.8 Hz, 2H) .

¹³C NMR (CDCl₃, 100 MHz) : 122.8 (q) ; 123.3; 123.4; 123.8(q); 126.29; 126.3; 126.5; 128.44; 128.45; 128.7; 129.2; 129.4; 129.7; 130.3; 130.4; 133.3; 138.3; 139.1; 141.3; 142.3.

Example 16: 1,1,1 , 3, 3, 3-Hexafluoro-2- (2 ' -thiophen-2- ylbiphenyl-4-yl)propan-2-ol

1,1,1,3,3, 3-hexafluoro-2- (2' -thiophen-2-ylbiphenyl-4- yl) propan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 3.43 (s, IH); 6.56-6.77 (m, IH); 6.78-6.79 (m, IH); 7.11-7.13 (m, IH); 7.24-7.40 (m, 5H); 7.45-7.50 (m, IH); 7.56 (d, J = 8.0 Hz, 2H) . ¹³C NMR (CDCl₃, 100 MHz) : 122.9 (q) ; 126.5; 126.7; 127.0; 127.1; 128.1; 128.3; 129.5; 129.5; 130.4; 130.6; 132.5; 139.1; 142.0; 142.7.

Example 17 : 4- (2,2, 2-Trifluoro-1 -hydroxy-1- trifluoromethylethyl) [1 ,1' ;2' ,1' ' ] terphenyl-3' '-N,N- dimethylsulphonamide 4- (2, 2, 2-trifluoro-1-hydroxy-l-trifluoromethylethyl) -

[ 1, 1' ; 2' , 1' ' ] terphenyl-3' ' -N, N-dimethylsulphonamide is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 2.30 (s, 6H); 6.56-6.77 (m, IH); 7.25-7.28 (m, 3H); 7.43-7.75 (m, 9H); 8.64 (s, IH) .

¹³C NMR (CDCl₃, 100 MHz) : 37.6, 77.0, 123.0, 126.4, 127.1, 128.6, 128.7, 128.9, 129.0, 129.7, 129.9, 130.2, 131.1, 131.2, 134.3, 134.9, 138.8, 139.3, 142.4, 142.7. Example 18: 1 ,1 ,1 ,3,3,3-Hexafluoro-2- [3' ' - (morpholine- 4-sulphonyl) [1 ,1' ;2^r ,1' ' ] terphenyl-4-yl]propan-2-ol

1,1,1,3,3, 3-hexafluoro-2- [3' ' - (morpholine-4- sulphonyl) [1, 1' ; 2' , 1' '] terphenyl-4-yl] propan-2-ol is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 2.77 (t, J = 4.4 Hz, 4H); 3.58 (t, J = 4.4 Hz, 4H); 7.20-7.32 (m, 2H); 7.39-7.42 (m, IH); 7.46-7.60 (m, 9H); 8.64 (s, IH) .

¹³C NMR (CDCl₃, 100 MHz) : 45.9, 65.3, 125.9, 126.5, 127.6, 128.2, 128.4, 128.6, 129.2, 129.2, 129.5, 129.7, 130.6, 130.6, 133.4, 134.4, 134.7, 138.3, 139.0, 141.9, 142.2.

Example 19: 4- (2,2,2-TrIfluoro-1 -hydroxy-1- tr±fluoromethylethyl) [1 ,1' ;2' ,1' '] terphenyl-3" - sulphonami.de

4- (2, 2,2-trifluoro-1 -hydroxy- 1- trifluoromethylethyl) [1, 1' ; 2' , 1" ] terphenyl-3" - sulphonic acid amide is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 7.10 (d, J = 7.8 Hz, IH); 7.25- 7.34 (m, 5H); 7.46-7.70 (m, 6H); 7.77 (s, IH); 8.70 (s,

IH) .

¹³C NMR (CDCl₃, 100 MHz) : 77.0, 125.9, 126.7, 126.8,

126.9, 127.2, 128.6, 128.7, 128.8, 129.3, 129.5, 130.0,

130.8, 131.0, 133.2, 138.9, 139.2, 141.6, 142.6, 144.6.

Example 20: 4- (2,2,2-Trifluoro-1 -hydroxy-1- trifluoromethylethyl) [1 ,1' ;2' ,1' ' ] terphenyl-3 ' ' -N- methylsulphonamide

4- (2,2, 2 -trifluoro-1 -hydroxy- 1- trifluoromethylethyl) [1, 1' ; 2' , 1" ] terphenyl-3" -N- methylsulphonamide is obtained in a manner analogous to

Example 2.

¹H NMR (CDCl₃, 400 MHz) : 2.11 (d, J = 4.8 Hz, 3H); 7.26- 7.79 (m, 13H) ; 8.69 (s, 2H) .

¹³C NMR (CDCl₃, 100 MHz) : 28.6, 125.4, 126.9, 128.0,

128.7, 128.8, 129.1, 129.5, 129.6, 129.6, 130.1, 130.9,

131.1, 133.6, 138.9, 139.2, 139.2, 141.9, 142.6.

Example 21: 4- (2,2,2-TrIfluoro-1 -hydroxy-1- tr±fluoromethylethyl) [1 ,1' ;2' ,1' '] terphenyl-3 ' ' - carbon!trile

4- (2, 2, 2-trifluoro-1-hydroxy-l-trifluoromethylethyl) - [ 1 , 1 ' ; 2 ' , 1 ' ' ] terphenyl-3' ' -carbonitrile is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 7.25 (d, J = 8.5 Hz, 2H); 7.43- 7.47 (m, 3H); 7.51-7.58 (m, 6H); 7.68-7.73 (m, IH); 8.72 (s, IH) .

¹³C NMR (CDCl₃, 100 MHz) : 75.0, 109.5, 116.7, 121.2,

126.8, 126.9, 127.5, 127.6, 128.2, 128.8, 128.9, 131.3, 132.8, 136.3, 137.4, 140.1, 140.5.

Example 22: Methyl 4- (2,2, 2-Trifluoro-1 -hydroxy-1- tr±fluoromethylethyl) [1 ,1' ;2' ,1' ' ] terphenyl-3 ' ' - carboxylate

Methyl 4- (2, 2, 2-trifluoro-1-hydroxy-l-trifluoromethylethyl) [1, 1' ;2' , 1" ] terphenyl-3" -carboxylate is obtained in a manner analogous to Example 2.

¹H NMR (CDCl₃, 400 MHz) : 3.78 (s, 3H); 7.01 (m, 2H); 7.14 (m, 5H); 7.42 (d, J = 8 Hz, IH); 7.71 (m, 2H); 7.84 (m, 2H) . 1³C NMR (CDCl₃, 100 MHz) : 52.6, 123.1 (q) , 125.7, 126.4, 127.5, 128.4, 128.5, 128.6, 129.1, 129.4, 130.1, 130.5,

131.2, 131.2, 135.0, 140.2, 140.3, 141.5, 142.9, 167.6.

Example 23: 4- (2,2,2-Trifluoro-1 -hydroxy-1- trifluoromethylethyl) [1 ,1' ;2' ,1' '] terphenyl-3 ' ' - carboxamide

4- (2, 2, 2-trifluoro-1-hydroxy-l-trifluoromethylethyl) - [ 1, 1' ; 2' , 1" ] terphenyl-3" -carboxamide is obtained in a manner analogous to Example 2. ¹H NMR (DMSO, 400 MHz) : 7.08 (d, J = 8 Hz, IH); 7.23 (m, 3 H); 7.34 (si, IH); 7.49 (m, 7H); 7.71 (d, J = 8 Hz); 7.76 (s, IH) ; 7.90 (si, IH) . 1³C NMR (DMSO, 100 MHz) : 122.9 (q) , 126.0, 126.5, 127.7, 128.1, 128.3, 128.6, 129.0, 129.8, 130.5, 130.7, 132.4, 134.4, 139.0, 139.6, 140.7, 142.7, 167.6.

Example 24 : 2- (2' -Benzo [1 ,3]dioxol-5-yl-5' - methoxybiphenyl-4-yl) -1,1,1 , 3, 3, 3-hexafluoropropan-2-ol 2- (2 ' -Bromo-5 ' -methoxybiphenyl-4-yl) -1,1,1,3,3,3- hexafluoropropan-2-ol

404 mg (0.35 mmol, 2 mol%) of tetrakis (triphenylphosphine) palladium are added to a solution of 6.47 g (0.0175 mol, 1.0 eq) of 1,1,1,3,3,3- hexafluoro-2- (4-iodophenyl) propan-2-ol and of 5.0 g

(0.021 mol, 1.2 eq) of 2-bromo-5-methoxyphenylboronic acid in 65 ml of toluene in the presence of 17.5 ml of a 2M potassium carbonate solution. The reaction mixture is refluxed for 1 hour 50. The reaction medium is poured into a saturated solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride and dried over sodium sulphate. The solvents are evaporated off and the residue is then chromatographed on silica gel: eluent: 90/10 heptane/ethyl acetate.

4.94 g of 2- (2 ' -bromo-5' -methoxybiphenyl-4-yl) - 1, 1, 1, 3, 3, 3-hexafluoropropan-2-ol are obtained. Yield = 66%.

¹H NMR (DMSO, 400 MHz) : 3.56 (si, IH); 3.74 (s, 3H); 6.73 (dd, J = 8 Hz, J = 3 Hz, IH); 6.80 (d, J = 3. Hz, IH); 7.42-7.49 (m, 3H); 7.70 (d, J = 8 Hz, 2H) .

2- (2 ' -Benzo [1 , 3]dioxol-5-yl-5 ' -methoxybiphenyl-4-yl) - 1,1,1 , 3, 3, 3-hexafluoropropan-2-ol

132 mg of 3, 4-methylenedioxyphenylboronic acid (0.79 mmol) are added to a solution of 310 mg of 2-(2'- bromo-5' -methoxybiphenyl-4-yl) -1,1,1,3,3,3- hexafluoropropan-2-ol (0.72 mmol) in 3 ml of dimethylformamide in the presence of 0.47 ml of a 2M aqueous solution of potassium phosphate (0.94 mmol) . 10 mg of 2- (dicyclohexylphosphino) biphenyl (0.029 mmol) and 3 mg of palladium (II) acetate (0.014 mmol) are added. The reaction mixture is stirred for 16 hours at 70⁰C. The reaction medium is poured into a saturated solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride and dried over sodium sulphate. The solvents are evaporated off and the residue is then chromatographed on silica gel: eluent: 95/5 heptane/ethyl acetate. 160 mg of 2-(2'- benzo [ 1, 3] dioxol-5-yl-5' -methoxybiphenyl-4-yl) - 1, 1, 1, 3, 3, 3-hexafluoropropan-2-ol are obtained. Yield = 43%.

¹H NMR (CDCl₃, 400 MHz) : 3.61 (s, IH); 3.79 (s, 3H); 5.82 (d, J = 2.5 Hz, 2H); 6.41-6.47 (m, IH); 6.56 (d, J = 8.0 Hz, IH); 6.90-6.87 (m, 2H); 7.15-7.18 (m, 2H); 7.25 (d, J = 8.2 Hz, IH); 7.51 (d, J = 8.3 Hz, 2H) . 1³C NMR (CDCl₃, 100 MHz) : 55.8, 101.2, 108.2, 110.7, 113.9, 116.0, 123.8, 126.5, 128.0, 130.2, 132.0, 133.3, 135.1, 140.7, 143.9, 146.5, 147.6, 159.2.

Example 25: 1,1,1 , 3, 3, 3-Hexafluoro-2- (3-hydroxymethyl- 4 ' -methoxy[l ,1' ;2' ,1"] terphenyl-4 ' ' -yl)propan-2-ol

1,1,1,3,3, 3-hexafluoro-2- (3-hydroxymethyl-4' -methoxy- [ 1 , 1 ' ; 2 ' , 1 ' ' ] terphenyl-4 ' ' -yl) propan-2-ol is obtained in a manner analogous to Example 24.

¹H NMR (CDCl₃, 400 MHz) : 3.90 (s, 3H); 4.39 (d,

J = 5.5 Hz, 2H); 5.16 (t, J = 5.6 Hz, IH); 6.89 (d,

J = 7.2 Hz, IH); 7.11 (s, 2H); 7.11-7.20 (m, 3H); 7.32

(d, J = 8.4 Hz, 2H); 7.40-7.42 (m, IH); 7.60 (d, J = 8.1 Hz, 2H); 8.74 (s, IH) . ¹³C NMR (CDCl₃, 100 MHz) : 55.7; 63.0; 114.3; 115.8; 121.9; 124.7; 126.7; 127.9; 128.4; 128.4; 130.9; 132.0; 133.0; 140.4; 140.4; 142.6; 143.3; 159.3.

Example 26: 4 ' -Methoxy-4 '' -(2,2,2-trifluoro-1 -hydroxy- 1-tr±fluoromethylethyl) [1 ,1' ;2' ,1' ' ] terphenyl-3- carbonitrile

4' -methoxy-4' '-(2,2, 2-trifluoro-l-hydroxy-1- trifluoromethylethyl) [1, 1' ;2' , 1' ' ] terphenyl-3- carbonitrile is obtained in a manner analogous to Example 24.

¹H NMR (CDCl₃, 400 MHz) : 3.59 (s, 3H); 4.2 (si, IH); 6.56 (m, 2H); 6.72 (d, J = 8 Hz, IH); 7.08 (t, J = 8 Hz, IH); 7.28 (m, 2H); 7.41 (m, 3H); 7.67 (s, IH) , 7.71, d, J = 8 Hz) .

¹³C NMR (CDCl₃, 100 MHz) : 55.6, 112.7, 113.6, 115.7, 118.9, 122.6, 126.9, 129.3, 129.5, 129.8, 131.0, 131.3, 133.4, 138.9, 141.1, 142.5, 142.8, 159.8.

Example 27 : 4 ' -Methoxy-4 '' -(2,2,2-trifluoro-1 -hydroxy- 1-trifluoromethylethyl) [1 ,1' ;2' ,1' ' ] terphenyl-3- carboxylic acid 200 mg of 1, 1, 1, 3, 3, 3-hexafluoro-2- (3-hydroxymethyl-4' - methoxy [1, 1' ;2' , 1' ' ] terphenyl-4' ' -yl) propan-2-ol

(0.44 mmol) are dissolved in 5 ml of acetone. At 0⁰C, 220 mg of chromium trioxide (2.2 mmol) are added, as are 2 ml of a solution of sulphuric acid at 20%. The reaction is stirred for 30 minutes at 0⁰C and then 1 h 30 at ambient temperature. The reaction mixture is poured into 5 ml of water and then extracted with diethyl ether. The organic phases are dried over sodium sulphate and the residue is then chromatographed on silica gel. Eluent: 1/1 heptane/ethyl acetate. 120 mg of 4' -methoxy-4' '- (2, 2, 2-trifluoro-l-hydroxy-1- trifluoromethylethyl) [1, 1' ;2' , 1' ' ] terphenyl-3- carboxylic acid are obtained. Yield = 58%. ¹H NMR (CDCl₃, 400 MHz) : 3.91 (s, 3H) , 7.08 (m, IH) , 7.13 (d, J = 8 Hz, IH) , 7.33 (m, 4H) , 7.46 (d, J = 8 Hz, IH) , 7.60 (d, J = 8 Hz, 2H) , 7.66 (s, IH) , 7.81 (d, J = 8 Hz, IH) , 8.71 (s, IH) , 12.8 (bs, IH) . 1³C NMR (CDCl₃, 100 MHz) : 55.7, 114.4, 115.9, 126.84, 127.5, 128.5, 129.5, 130.0, 130.7, 130.9, 131.9, 132.0,

140.5, 141.0, 142.8, 159.3, 167.3.

Example 28: 4 ' -Methoxy-4 '' - (2,2,2-trifluoro-1 -hydroxy- 1-tr±fluoromethylethyl) [1 ,1' ;2' ,1' ' ] terphenyl-3- carboxamide

4' -methoxy-4 ' '-(2,2, 2-trifluoro-l-hydroxy-1- trifluoromethylethyl) [1, 1' ;2' , 1' ' ] terphenyl-3- carboxamide is obtained in a manner analogous to Example 24.

¹H NMR (DMSO, 400 MHz) : 3.68 (s, 3H); 7.01 (m, 2H); 7.10 (d, J = 8 Hz, IH); 7.19 (t, J = 8 Hz, IH); 7.28 (d, J = 8 Hz, 2H); 7.34 (si, IH); 7.42 (d, J = 8 Hz, IH); 7.55 (d, J = 8 Hz, 2H); 7.68 (d, J = 8 Hz, IH); 7.73 (s, IH) ; 7.90 (s, IH) ; 8.7 (s, IH) .

¹³C NMR (CDCl₃, 100 MHz) : 55.8, 114.4, 115.9, 126.0, 126.9, 127.9, 129.0, 129.6, 132.3, 132.4, 132.9, 134.7,

140.6, 140.9, 143.0, 159.3, 168.1.

Example 29: 1 ,1 ,1 ,3,3,3-Hexafluoro-2- (3' ' - hydroxymethyl-4 ' -methoxy[l ,1' ;2' ,1' '] terphenyl-4- yl)propan-2-ol 1,1, 1,3,3, 3-Hexafluoro-2- [4- (4,4,5, 5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)phenyl]propan-2-ol

7.43 g of 1, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl- [1,3] dioxolan-2-ylboranyl) [1,3,2] dioxaborolane (29.27 mmol) are added to a solution of 10 g of 1, 1, 1, 3, 3, 3-hexafluoro-2- (4-iodophenyl) propan-2-ol (22.51 mmol) in 80 ml of dimethylformamide . 6.63 g of potassium acetate (67.54 mmol) and 920 mg of bis (triphenylphosphine) palladium (II) chloride

(1.126 mmol) are added to the reaction mixture. The reaction medium is stirred for 16 hours at 80⁰C. The reaction medium is poured into a saturated solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride and dried over sodium sulphate. The solvents are evaporated off and the residue is then chromatographed on silica gel: eluent: 95/5 heptane/ethyl acetate. 8.88 g of 1,1,1,3,3, 3-hexafluoro-2- [4- (4, 4, 5, 5-tetramethyl- [l,3,2]dioxaborolan-2-yl) phenyl] propan-2-ol are obtained.

Yield = 84%.

¹H NMR (CDCl₃, 400 MHz) : 1.28 (s, 6H); 3.54 (s, IH); 7.64 (d, J = 8 Hz, 2H); 7.82 (d, J = 8 Hz, 2H) .

(2 ' -Bromo-5 ' -methoxybiphenyl-3-yl)methanol

0.54 g of 2-bromo-5-methoxyphenylboronic acid (2.35 mmol) are added to a solution of 0.5 g of (3-iodophenyl) methanol (2.14 mmol) in 5 ml of toluene in the presence of 1.4 ml of a 2M aqueous solution of sodium carbonate (1.4 ml, 2.78 mmol) . 0.1 g of tetrakis (triphenylphosphine) palladium (0) (0.085 mmol) is added and the reaction mixture is then stirred for 6 hours at reflux. The reaction medium is poured into a saturated solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride and dried over sodium sulphate. The solvents are evaporated off and the residue is then chromatographed on silica gel: eluent: 80/20 heptane/ethyl acetate. 170 mg of (2' -bromo-5' - methoxybiphenyl-3-yl) methanol are obtained. Yield = 56%.

¹H NMR (CDCl₃, 400 MHz) : 3.79 (s, 3H); 4.56 (d, J = 6 Hz, 2H); 5.26 (t, J = 6 Hz, IH); 6.90-6.94 (m, 2H); 7.26 (d, J = 7 Hz, IH); 7.32-7.43 (m, 3H); 7.61 (dd, J = 1.5 Hz, 7.6 Hz, 2H) . 1,1,1 , 3, 3, 3-Hexafluoro-2- (3 ' ' -hydroxymethyl-4 ' - methoxy[l ,1' ;2^r ,1' '] terphenyl-4-yl)propan-2-ol

490 mg of 1, 1, 1, 3, 3, 3-hexafluoro-2- [4- (4, 4, 5, 5- tetramethyl [l,3,2]dioxaborolan-2-yl) phenyl] propan-2-ol (1.31 mmol) are added to a solution of 350 mg of (2 ' -bromo-5' -methoxybiphenyl-3-yl) methanol (1.19 mmol) in 5 ml of dimethylformamide in the presence of 1.2 ml of a 2M aqueous solution of potassium phosphate (2.36 mmol) . 18.5 mg of 2- (dicyclohexylphosphino) biphenyl (0.053 mmol) and 6 mg of palladium (II) acetate (0.026 mmol) are added. The reaction mixture is stirred for 16 hours at 70⁰C. The reaction medium is poured into a saturated solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride and dried over sodium sulphate. The solvents are evaporated off and the residue is then chromatographed on silica gel: eluent: 80/20 heptane/ethyl acetate. 170 mg of 1,1,1,3,3, 3-hexafluoro-2- (3' ' -hydroxymethyl-4' - methoxy [ 1, 1' ; 2' , 1' ' ] terphenyl-4-yl) propan-2-ol are obtained. Yield = 31%.

¹H NMR (CDCl₃, 400 MHz) : 3.90 (s, 3H); 4.41 (d, J = 6 Hz, 2H); 5.18 (t, J = 5.7 Hz, IH); 6.97 (d,

J = 1 Hz, IH); 7.01 (d, J = 3 Hz, IH); 7.08-7.13 (m,

2H); 7.18-7.25 (m, 4H); 7.44 (d, J = 8 Hz, IH); 7.56

(d, J = 8 Hz, 2H) ; 8.70 (s, IH) .

¹³C NMR (CDCl₃, 100 MHz) : 55.7, 63.0, 114.3, 115.8, 121.9, 124.7, 126.7, 127.9, 128.4, 128.4, 130.9, 132.0,

133.0, 140.4, 140.4, 142.6, 143.3, 159.2.

EXAMPLE 30: Activity on the LXRβ receptor:

The activity of the LXRβ receptor is measured in a transactivation test. Activation of the receptor with an agonist (activator) in HeLa cells leads to the expression of a reporter gene, luciferase, which, in the presence of a substrate, generates light. The activation of the receptors can thus be measured by quantifying the luminescence produced after incubation of the cells in the presence of a reference agonist. The antagonist products will displace the agonist from its site, thus preventing activation of the receptor: there will thus be a reduction in the light produced, which can be quantified. The products are tested alone and their effect is measured by measuring the activation of luminescence after incubation.

Determination of the apparent Kd:

In this study, a constant which represents the affinity of the molecule for the receptor is determined. Since this value can fluctuate depending on the basal activity and the expression of the receptor, it is referred to as the apparent Kd (KdApp) .

To determine this constant, "crossover curves" of the test product against a reference agonist are produced in a 96-well plate: 10 concentrations of the test product plus a concentration 0 (along the rows) and 7 concentrations of the agonist plus a concentration 0 (along the columns) . This represents 88 measurement points for one product and one receptor.

The remaining 8 wells are used for the 100% control

(total agonist) and 0% control (DMSO) . These crossover curves make it possible to determine the AC50 values (concentration at which 50% activation is observed) of the reference ligand at various concentrations of the test product. These AC50 values are used to calculate the Schild regression by plotting a straight line corresponding to the Schild equation ("Quantitation in receptor pharmacology" Terry P. Kenakin, Receptors and Channels, 2001, 1_, 371-385) .

In the case of an antagonist, an IC50 value (concentration inhibiting 50% of the activity) is calculated by plotting the curve of the product at the concentration of the reference ligand giving 80% activation .

The cell lines used are HG5LN cells, HeLa cells stably transfected with the (17mer) 5-bGlob-Luc reporter and also stably transfected with the Gal-hLXRβ-DEF plasmid. These cells are seeded into 96-well plates at a rate of 10 000 cells per well in 100 μl of DMEM medium without phenol red and supplemented with 10% defatted calf serum. The plates are then incubated at 37°C, 7% CO₂ for 4 hours.

The various dilutions of the test products, of the reference ligand and of the 100% control (N- (2,2,2- trifluoroethyl) -N- [4- (trifluorohydroxytrifluoromethyl- ethyl) phenyl ] benzenesulphonamide or T0901317) and of the 0% control (0.2% dimethyl sulphoxide) are added at a rate of 5 μl per well. The plates are then incubated for 18 hours at 37°C, 7% CO₂.

The culture medium is removed by turning the plates over and 100 μl of a 1:1 PBS/luciferin mixture are added to each well. After 5 minutes, the plates are read using the luminescence reader.

Results: the compounds of the invention show a strong affinity for the LXRβ receptor as shown in Table 1

Table 1: Affinity for the LXRβ receptor:

By way of comparison, the reference ligand of the prior art (T0901317) has a KdApp which is twice as high, i.e. 30 nM.

Example 31 : Measurement of the risk of adverse effects relating to the use of the compounds of the invention

Given the tropism of the LXR receptor ligands for lipid metabolism, the following measurements were carried out after 4 weeks of topical administration of the compounds of the invention in rats at a daily dose of 0.1%.

The systemic effects are evaluated in 10-week-old male Fuzzy rats (Hsd: Fuzzy-fz) . The studies are carried out in accordance with the European instructions on "the protection of animals used for experimental or scientific purposes" (European instruction 86/609) and after approval by the ethics committee .

The test product is diluted to the desired concentration in acetone so as to obtain the desired final concentration. 100 μl of the test compound are then deposited on the back of the animal over a surface area of 2 cm x 3 cm. The treatment is repeated every 24 hours for 25 days. The animals are randomized on the first day according to body weight.

The systemic effects are evaluated, on the one hand, by monitoring the weight of the animals and, on the other hand, by assaying plasma triglycerides. The animals are weighed once a week. In order to take the blood sample, the rats are anaesthetized using a gas anaesthesia system. The blood samples are taken 24 hours after the final treatment. The blood sample is taken on a heparinized tube. The plasma triglycerides are quantified using the Cobas Integra^® 400+ automated system and the statistical analysis is carried out using the Provantis^® software coupled to the automated system.

Results : Weight loss: At a dose of 1%, the compounds of the invention (compounds of Examples 23 and 25) do not cause significant weight loss, whereas the reference compound of the prior art (compound T0901317), under the same conditions, induces a limitation of the weight gain by the animal (see Tables 2a, 2b and 2c) .

Table 2b: Compound

Weight of Example gain from Student's test versus

25 Dl to D25 carrier

Weight

(g) gain

Treatment Value

Mean sdm Significance of P

Carrier 44.2 14.9

47.0 11.3 0.6500 NS

Table 2c:

Student's statistical test: ( ) = 0.01 < P < 0.05, (NS; = 0.05 < P sdm = standard deviation of the mean NS = not significant Triglyceride level in the blood: From the 0.1% dose onwards, the prior art compound causes a significant increase in the triglyceride level in the blood by a factor of 1.77, whereas, at this same dose, the compounds of the invention do not lead to any significant increase in the same triglyceride level (see Table 3) .

Table 3:

Statistical test derived from the Provantis software (^*) = 0.01 < P < 0.05, NS= 0.05 < P

Example 32: Measurement of the anti-inflammatory activity of the compounds of the invention:

The model used is the model of inflammation of the mouse ear induced by a single application of TPA

(Phorbol-12-Myristate-13-Acetate) . Female Balb/c ByJIco mice are used. The oedema is induced by application to the ear of 20 μl of 0.01% of TPA dissolved in acetone.

The molecule to be evaluated is dissolved in the 0.01%

TPA solution and applied at the same time. The oedema is evaluated 6 hours after application by measuring the thickness of the ear using an Oditest^® micrometer. The oedema induced by the TPA is evaluated relative to the acetone carrier group. The inhibition of the oedema by the molecule is expressed as percentage reduction in the oedema induced by the TPA alone.

Results :

It is found that the compound of the invention (compound of Example 23) displays a significant antiinflammatory activity from the 0.1% dose onwards (see Table 4) .

Table 4:

Student's statistical test: (^***) = P < 0.001, (^**) = 0.001 < P < 0.01, (^*) = 0.01 < P < 0.05, (NS) = 0.05 < P

Example 33 : Formulations In this example, various concrete formulations based on the compounds according to the invention have been illustrated.

TOPICAL ADMINISTRATION

(a) Ointment - Compound of Example 1 0.020g - Isopropyl myristate 81.700 g

- Fluid liquid petroleum jelly 9.100 g

- Silica ("Aerosil 200") 9.180 g

(b) Ointment

- Compound 6 0.300 g

- White petroleum jelly, pharmaceutical grade qs 100 g

(c) Non-ionic water-in-oil cream

- Compound of Example 1 0.100 g

- Mixture of emulsive lanolin alcohols, of waxes and of oils ("anhydrous eucerin") 39.900 g - Methyl para-hydroxybenzoate 0.075 g

- Propyl para-hydroxybenzoate 0.075 g

- Sterile demineralized water qs 100 g

(d) Lotion - Compound of Example 6 0.100 g

- Polyethylene glycol (PEG 400) 69.900 g

- Ethanol at 95% 30.000 g

(e) Hydrophobic ointment - Compound 2 0.300 g

- Isopropyl myristate 36.400 g

- Silicone oil ("Rhodorsil 47 V 300") 36.400 g

- Beeswax 13.600 g

- Silicone oil ("Abil 300 000 cst" sold by Goldschmidt) qs 100 g

(f) Non-ionic oil-in-water cream

- Compound of Example 4 1.000 g

- Cetyl alcohol 4.000 g - Glyceryl monostearate 2.500 g

- PEG 50 stearate 2.500 g

- Shea butter 9.200 g

- Propylene glycol 2.000 g

- Methyl para-hydroxybenzoate 0.075 g - Propyl para-hydroxybenzoate 0.075 g

- Sterile demineralized water qs 100 g

Claims

1. Compound of general formula (I) below:

in which Ri, R₂, R3, R4 and R₅, which may be identical or different, represent:

- a hydrogen,

- an unsubstituted or substituted alkyl radical,

- a cycloalkyl radical,

- a cycloalkylalkyl radical,

- an unsubstituted or substituted alkoxy radical, - a carboxyl radical,

- an unsubstituted or substituted alkoxycarbonyl radical,

- a halogen,

- a cyano radical, - a carboxamide, N-alkyl carboxamide or N,N-dialkyl carboxamide group,

- a sulphonamide, N-alkyl sulphonamide, N,N-dialkyl sulphonamide or morpholinosulphonyl group,

Ar represents a cyclic group chosen from:

given that, when R₃ is in the ortho-position with respect to R₄, then R₃ and R₄ can form a 5- or 6-sided hydrocarbon-based ring, it being understood that 1 or 2 carbon atoms (s) may optionally be replaced with 1 or 2 oxygen, nitrogen or sulphur atom(s), the optical isomers thereof, or in the form of hydrates or of solvates, and also the salts thereof with a pharmaceutically acceptable acid or base.

2. Compound according to Claim 1, characterized in that Ar represents a phenyl group:

3. Compound according to Claim 1, characterized in that Ar represents a thiophene group:

4. Compound according to one of Claims 1 to 3, characterized in that one of the R3, R4 and R5 radicals is chosen from a cyano radical, a carboxamide, N-alkyl carboxamide or N,N-dialkyl carboxamide group and a sulphonamide, N-alkyl sulphonamide or N,N-dialkyl sulphonamide group.

5. Compound according to one of Claims 1 to 4, characterized in that one of the Ri or R2 radicals represents a hydrogen and the other of the Ri or R₂ radicals represents an alkyl or alkoxy radical.

6. Compound according to any one of Claims 1 to 5, for use thereof as a medicament in human or veterinary medicine.

7. Compound according to any one of Claims 1 to 5, for use thereof as a medicament in the treatment of dermatological conditions.

8. Pharmaceutical composition, characterized in that it comprises at least one compound of general formula

(I) as defined in any one of Claims 1 to 5.

9. Use of a compound according to one of Claims 1 to 5, as a cosmetic product.

10. Cosmetic composition, characterized in that it comprises at least one compound of general formula (I) as defined in any one of Claims 1 to 5.

11. Cosmetic use of a composition as defined in Claim 10, for preventing and/or treating the signs of ageing of the skin.