FR2935380A1 - NOVEL HEXAFLUORO-2-BIPHENYL-ISOPROPANOL COMPOUNDS, MODULATORS OF LXRS-TYPE RECEPTORS, PROCESS FOR PREPARING THEM AND THEIR APPLICATION AS MEDICAMENTS IN HUMAN OR VETERINARY MEDICINE AS WELL AS IN COSMETICS. - Google Patents

Abstract

The present invention relates to novel compounds hexafluoro-2-biphenyl-isopropanol corresponding to the following general formula (I): ## EQU1 ## where: ## EQU3 ## wherein R1, R2, R3, R4 and R5 are as defined in the description and their method of preparation, and their application as medicaments in human or veterinary medicine, as well as in cosmetics.

Description

The present invention relates to novel compounds hexafluoro-2-biphenyl-isopropanol modulators LXRs receptors, their method of preparation and their application as drugs in human or veterinary as well as in cosmetics.

LXRs (Liver X Receptor) receptors belong to the steroid / thyroid receptor superfamily. In 1995, P.Willy and J.Mangelsdorf cloned a novel receptor belonging to the steroid / thyroid receptor superfamily, referred to as LXRa (Liver X Receptor), by low-stringency screening of a human liver complement DNA library. a pool of degenerate oligonucleotides corresponding to the DNA binding domain of the RARα nuclear receptors. Comparison of the nucleotide sequence of human LXRα with other previously known receptors revealed strong similarities with two orphan receptor sequences: 77% homology to the human NER-1 receptor or Ubiquitous Receptor UR, thus described as the second subtype of LXR and referenced LXR13 and 92% with the rat receptor RLD-1 which appears to be the murine homologue of hLXRa.

The LXR13 isoform has very large homologies with an orphan receptor cloned in 1993 in the rat: OR-1.

The in situ hybridization and northen blot analysis of the messenger RNAs of the two human LXRs subtypes identified and described: LXRa and LXR13, demonstrates an increased tissue distribution in organs with intense metabolic activity such as kidneys, the liver, the intestines as well as more weakly in the spleen, the adrenal glands and the skin. The hLXR13 isoform is much more ubiquitous and is also present in the brain, testes and 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 (called RXRs), LXRs receptors activate transcription by binding to specific DNA sequence elements, called the LXREs, located in the promoter. target gene whose transcription they regulate.

Identification of ligands specific for LXRs has been performed by Janowski et al (Curr, Opin Genet Dev, 1998, Oct; 8 (5), 571-5). It has thus been shown that only a specific group of oxysterol having a backbone and cholesterol structure is capable of activating LXR receptors. The structure / activity relationship study revealed the commitment of a 13-hydroxy cholesterol group and an additional hydroxyl group preferentially localized on a side chain of the molecule. These compounds have been 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 potent activator. A controlled proteolytic digestion experiment established that this compound is a potential LXRa ligand. Indeed, the skin has a structure conferring many properties and a major role in the barrier function. This regulation of the barrier function is particularly ensured by the epidermis.

The natural human epidermis is composed mainly of three types of cells which are the keratinocytes, a very large majority, the melanocytes and the Langerhans cells. Each of these cell types contributes by its own functions to the essential role played in the body by the skin. The epidermis is continuously formed by proliferation of the basal cells of the epidermis. The keratinocytes formed in the deepest part of the epidermis will migrate to the surface of the skin. During this migration, the keratinocytes are differentiated by profound biochemical and structural modifications to result in the formation of cells lacking their nucleus and cytoplasmic organelles, but having synthesized a horny envelope, these are the corneocytes. The horny envelope confers a great rigidity to the corneocytes and ensures the mechanical resistance of the stratum corneum. The set of corneocytes constitutes the horny layer or stratum corneum, the outermost layer of the epidermis and the main regulator of the cutaneous barrier function. The cells constituting the epidermis are delimited by a lipid domain. Epidermal lipids are synthesized mainly in the living epidermis. They consist essentially of phospholipids, sphingolipids, cholesterol, free fatty acids, triglycerides, cholesterol esters and alkanes. During cell differentiation, the phospholipids, whose role is to elaborate the fluid structure of the cell membranes of the living layers of the epidermis, are gradually replaced by a mixture consisting for the most part of fatty acids, cholesterol and of sphingolipids, essential components of the horny layer of the epidermis (stratum corneum). As such, the intercellular cholesterol level has been described by Schmidt et al .; The Journal of Investigative Dermatology, 5, 771-775; as a preponderant element in the spontaneous formation of the horny envelope.

For example, the increase in the level of phosphorylation and messenger RNA levels of enzymes related to the de novo synthesis of the three key lipid types of cell maturation: serine palmitoyl transferase for the formation of ceramides. HMGCoA reductase involved in the synthesis of cholesterol and 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 related to the regulation of key lipid synthesis. Deregulation of the barrier function, whether generalized or localized, is known to be an important component of many disorders and diseases of the skin and mucous membranes. This disruption of the barrier function may lead to the entry of pathogenic elements on the part of the skin affected, but also proves to be an aggravating factor of many cutaneous pathologies correlated with disorders of differentiation and / or proliferation of cells. epidermal.

To treat these imbalances of the barrier function, as well as skin disorders related to insufficient epidermal differentiation and / or an excess of proliferation of epidermal cells, various pharmaceutical approaches have been envisaged.

However, it has been described in the patent application WO 98/32444 that the activators of FXR receptors, PPARy and LXRI3 are likely to restore the barrier function of the skin. These activators are also shown to increase differentiation by inhibiting epidermal proliferation.

In addition, modulators of LXRs have been shown to be able to modulate the inflammatory response and are immunomodulatory. In macrophages, oxysterols are capable of inhibiting the secretion of pro-inflammatory cytokines and lymphocyte activation (Ohlsson et al., J Clin Invest 1996, 98: 78-89). This activity has been confirmed by repression of genes involved in pro-inflammatory mechanisms such as COX-2, IL-6 and IL-13 after bacterial stimulation or 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 oxazolone-induced contact allergy, LXR agonists are able to inhibit inflammation (Fowler AJ, J Invest Dermatol, 2003). , 120: 246-255).

However, many cutaneous pathologies are pro-inflammatory. Some such as atopic dermatitis involve disturbance of the barrier function and inflammation as a result of the penetration of proteins that act as superantigens (Cardona et al., Am J Clin Dermatol, 2006, 7-5: 273-279). LXR modulators therefore seem particularly recommended for this type of pathology since they combine an action on the barrier function and inflammation.

Compounds of the hexafluoro-2-phenyl isopropanol family have been described for modulating LXRs receptors in patent application WO06000323.

N- (2,2,2-Trifluoroethyl) -N- [4- [2,2,2-trifluoro-1-hydroxy-1 (trifluoromethyl) ethyl] phenyl] is also known in the prior art. -benzenesulfonamide: FF 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 putting its role in the modulation of LXR receptors and its potential in many therapeutic indications (Luis A. J. Atherosclerosis, Nature 2000, 407, 233-241). However, the impact of known LXR compounds on lipid metabolism makes these compounds difficult to develop given the potential adverse effects that this pharmacological activity can generate by disrupting metabolism, and in particular on lipid metabolism. Thus, there is a real need for LXR modulators that retain therapeutic efficacy while limiting the peripheral undesirable effects related to lipid metabolism.

However, the Applicant has unexpectedly and surprisingly found that certain compounds of structure hexafluoro-2-biphenyl isopropanol, object of the present invention, have a very significant activity on the LXR receptors while having a lower impact than the compounds of the invention. prior art on the variations of the main lipid factors in the blood as well as on weight loss. Thus, the present invention relates to compounds of the following general formula (I): in which, R 1, R 2, R 3, R 4 and R 5, which are 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 carboxy radical, an unsubstituted or substituted alkoxycarbonyl radical or a halogen atom; 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: knowing that when R3 is ortho to R4 then R3 and R4 may form a 5- or 6-membered hydrocarbon ring, with the proviso that 1 or 2 carbon atoms may optionally be replaced by 1 or 2 atoms (s) oxygen, nitrogen or sulfur, their optical isomers, or in the form of hydrates or solvates, and their salts with a pharmaceutically acceptable acid or base. (I) 5

Among the addition salts of the compounds of general formula (I) with a pharmaceutically acceptable acid, there may be mentioned preferably 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, sulfuric acid, and nitric acid. Suitable organic acids are, for example, acetic acid, ethanedioic acid, (Z) -2-butene-dioic acid, (E) -2-butene-dioic acid, acid 2, 3-dihydroxy-butanedioic acid, methanesulfonic acid, ethanesulphonic acid, trifluoro-methanesulphonic acid. Among the salts of the compounds of general formula (I) with a pharmaceutically acceptable base, they are salts of an alkali metal, in particular a sodium or potassium salt, or an alkaline earth salt (magnesium or calcium) or organic amine salts, more particularly, amino acids such as arginine or lysine.

The invention also relates to the compounds of general formula (I) in the form of hydrates or solvates with water or with a solvent. Suitable solvents for forming solvates are, for example, alcohols such as ethanol or iso-propanol. According to the present invention, the term "unsubstituted or substituted alkyl" denotes a saturated hydrocarbon chain, linear or branched, comprising from 1 to 7 carbon atoms, unsubstituted or substituted by one or more halogen atoms or hydroxyl groups.

According to the present invention, cycloalkyl means a cyclic saturated hydrocarbon chain comprising from 3 to 7 carbon atoms. According to the present invention, the term "unsubstituted or substituted alkoxy" denotes an oxygen atom substituted by a linear or branched, saturated hydrocarbon-based chain comprising from 1 to 6 carbon atoms, itself unsubstituted or substituted by one or more halogen atoms or hydroxy groups.

According to the present invention, unsubstituted or substituted alkoxycarbonyl means a carboxy substituted with an unsubstituted or substituted alkoxy radical.

According to the present invention, halogen is a bromine, chlorine, iodine or fluorine atom.

The invention relates in particular to the compounds of formula (I) as defined previously 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 previously in which one of the radicals R 3, R 4 and R 5 is chosen from a cyano radical, a carboxamide, N-alkyl carboxamide or N, N-dialkyl group. carboxamide and a sulfonamide, N-alkyl sulfonamide or N, N-dialkyl sulfonamide group,

The invention relates in particular to the compounds of formula (I) as defined above in which one of the radicals R, or R2 represents a hydrogen and the other of the radicals R, or R2 represents an alkyl radical, or alkoxy.

The present invention also relates to the compounds of general formula (I) for which, independently or in combination: - R, 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 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 R1 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 R1 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 R1 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 R1 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 R 1 represents a hydrogen atom, R 2 represents a hydrogen atom or an alkoxy radical, Ar represents a phenyl group, R 3 and R 4 represent a hydrogen atom and R5 represents a carboxamide, N-alkyl carboxamide or N, N-dialkyl carboxamide group or a sulfonamide, N-alkyl sulfonamide, N, N-dialkyl sulfonamide or morpholinosulfonyl group in the 3-position.

The present invention relates more particularly to the compounds of general formula (I) as defined above for which R1 represents a hydrogen atom, R2 represents a hydrogen atom or an alkoxy radical, Ar represents a phenyl group, R3 and / or or R4 represents a hydrogen atom and R5 represents a group at the 3-position.

Among the compounds of formula (I) falling within the scope of the present invention, mention may be made especially of the following compounds:

1) 1,1,1,3,3,3-Hexafluoro-2- [1,1 ', 2', 1 "] terphenyl-4-yl-propan-2-ol 2) 1,1,1,3 3,3-Hexafluoro-2- (4 "-trifluoromethoxy- [1,1 ', 2', 1"] terphenyl-4-yl) propan-2-ol 3) 1,1,1,3,3 3-Hexafluoro-2- (3 "-hydroxymethyl- [1,1 ', 2', 1"] terphenyl-4-yl) -propan-2-ol 4) 1,1,1,3,3,3 Hexafluoro-2- (3 "-methoxy- [1,1 ', 2', 1"] terphenyl-4-yl) -propan-2-ol 5) 2- (3 "-Chloro- [1,1 '] 2 ', 1 "] terphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropan-2-ol 6) 2- (3" -Chloro-4 "-fluoro- [1] 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-yl-biphenyl-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-yl) biphenyl -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) 1,1,1,3,3,3-Hexafluoro-2- (4 "-trifluoromethyl) [1,1 ', 2', 1 "] terphenyl-4-yl) -propan-2-ol 12) 2- (3", 5 "-Bis-trifluoromethyl- [1,1 ', 2', 1"] ] terphenyl-4-yl) -1,1,1,3,3,3-hexafluo 2-propan-2-ol 13) 2- (3 ", 4" -Dichloro- [1,1 ', 2', 1 "] terphenyl-4-yl) -1,1,1,3,3,3 hexafluoro-propan-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) 1,1,1,3,3,3-Hexafluoro-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-yl-biphenyl-4-yl) -propan-2-ol 17) 4- (2,2,2-Trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1 "] terphenyl-3" -N, N-dimethyl sulfonamide 18) 1 1,1,3,3,3-Hexafluoro-2- [3 "- (morpholine-4-sulfonyl) - [1,1 ', 2', 1"] terphenyl-4-yl] propan-2- ol 19) 4- (2,2,2-Trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1 "] terphenyl-3" -sulfonamide 20) 4- (2, 2,2-Trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1 "] terphenyl-3" -N-methyl sulfonamide 21) 4- (2,2,2-Trifluoro) -1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1 "] terphenyl-3" -carbonitrile 22) 4- (2,2,2-Trifluoro-1-hydroxy-1-trifluoromethyl) methyl) - [1,1 ', 2', 1 "] methyl terphenyl-3" -carboxylate 23) 4- (2,2,2-Trifluoro-1-hydrox) y-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1 "] terphenyl-3" -carboxamide 24) 2- (2'-Benzo [1,3] dioxol-5-yl-5'-yl) methoxy-biphenyl-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- 1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 '; 2 ', 1 "] terphenyl-3-carbonitrile 27) 4'-Methoxy-4" - (2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1'; 2 ', 1 "] terphenyl-3-carboxylic acid 28) 4'-Methoxy-4" - (2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [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 of preparation of the compounds of formula (I) as described above as well as to new synthesis intermediates used in this preparation.

The compounds of general formula (I) are prepared according to the general reaction schemes presented in FIG.

In particular, proceed as follows: Using the reaction scheme of FIG. 1: (1) Step a, anilines of general formula (1) in which R 1 is as defined above, can be reacted with sodium nitrite in the presence of hydrochloric acid and potassium iodide to yield iodinated compounds of the general formula (2) wherein R 1 is as previously defined (Carey Sundberg - Advanced Organic Chemistry, Part A and B - Plenum, New York, 1990) "HFFF (2) Step b The compounds of general formula (3) in which R 1 and R 2 are as defined above and X represents a halogen chosen from bromine, chlorine and iodine can be obtained from acids 2 -halogeno arylboronic commercial or prepared by conventional methods and compounds of general formula (2) by a Suzuki type reaction using a palladium catalyst such as tetrakistriphenylphosphine palladium p For example, N. Miyaura, K. Yamada, K. Suzuki, Tetrahedron Lett., 1979, 3437-3440.

Step c: The compounds of general formula (I) in which R 1, R 2, R 3, R 4 and R 5 are as defined above are obtained from the compounds of general formula (3) and commercial boronic acids or prepared according to methods by a Suzuki type reaction using a palladium catalyst such as tetrakistriphenylphosphine palladium for example. N. Miyaura, K. Yamada, K. Suzuki, Tetrahedron Lett., 1979, 3437-3440.

Another embodiment of the invention relates to the following process for the preparation of the compounds of the invention: Step d: The compounds of general formula (I) in which R 1, R 2, R 3, R 4 and R 5 are as defined previously are obtained from the boronic acids of general formula (5) in which R 2, R 3, R 4 and R 5 are as defined previously R 4 (5) and aryl halides of general formula (2) are commercially prepared or prepared according to conventional methods by a Suzuki type reaction using a palladium catalyst such as tetrakistriphenylphosphine palladium for example. N. Miyaura, K. Yamada, K. Suzuki, Tetrahedron Lett., 1979, 3437-3440.

Step 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 halides of aryl of general formula (6) wherein R3, R4 and R5 are as defined above and X 'represents a halogen selected from bromine, chlorine and iodine and 2-halogen phenylboronic acids commercial or prepared according to conventional methods by a Suzuki type reaction using a catalyst palladium X '20 as tetrakistriphenylphosphine palladium for example. N. Miyaura, K. Yamada, K. Suzuki, Tetrahedron Lett., 1979, 3437-3440. (7) Another embodiment of the invention also relates to the following process for the preparation of the compounds of the invention: Step f: The boronates of general formulas (8) in which R 1 is as defined above are obtained at from alkyl halides of general formula (2) as defined above by reaction with bispinacolato diborane in the presence of a palladium catalyst such as dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium for example. lshiyama, T., Murata, M .; Miyaura, N .; J Org Chem 1995, 60 (23), 7508-7510. (G) The compounds of general formula (I) in which R 2, R 3, R 4 and R 5 are as defined above are obtained from the boronates of general formula (8) as defined above and the halides of aryl of general formula (7), as defined above, commercial or prepared according to conventional methods by a Suzuki type reaction using a palladium catalyst such as tetrakistriphenylphosphine palladium for example. N. Miyaura, K. Yamada, K. Suzuki, Tetrahedron Lett., 1979, 3437-3440.

The compounds according to the invention exhibit LXRI3 receptor modulating properties. Modulating properties are understood to mean agonist or antagonist properties of LXR receptors (3). LXR 3 receptors are generally understood to mean LXRI3 receptors taken alone and / or in the form of homodimers and / or in the form of heterodimers such as, and without limitation, LXR / RAR (Retinoid Acid Receptor) heterodimers; LXR / LXR; LXR / PPAR (Peroxisome Proliferator-Activated receptor); LXR / VDR (Vitamin D Nuclear Receptor) whatever the subtypes involved for each of the mentioned receivers.

This activity on LXR receptors (3 is measured in a transactivation test and quantified by the dissociation constant Kdapp (apparent), as described in Example 30. The subject of the present invention is also a compound of formula (I) as defined above for its application as a medicament in human or veterinary medicine In particular, the subject of the present invention is the use of a compound of formula (I) as defined above for its application as a medicinal product: 1) in the treatment of dermatological conditions and in particular: dermatological disorders related to a disorder of keratinization relating to differentiation and proliferation, in particular vulgar, comedonal, polymorphic, rosacea acne, nodulocystic acne, conglobata, senile acnes, secondary acnes such as solar acne, medicated or professional, - ichthyosis, ichtyosiform conditions es, Darrier's disease, palmoplantar keratodermias, leukoplasias and leucoplasiform states, cutaneous or mucosal lichen (buccal), - dermatological conditions with an inflammatory immunoallergic component, with or without a cell proliferation disorder, in particular cutaneous, mucous or nail psoriasis, psoriatic arthritis, cutaneous atopy, such as eczema, respiratory atopy or gingival hypertrophy, - benign or malignant dermal or epidermal proliferations, of viral origin or not, in particular, common warts, flat warts, verruciform epidermodysplasia, oral or florid papillomatoses, T lymphoma, ultraviolet-induced proliferations, in particular baso and squamous cell carcinoma, precancerous skin lesions, especially keratoacanthomas, - immune dermatoses including lupus erythematosus, - bullous immune diseases, - m collagen diseases, in particular scleroderma, dermatological or general disorders with an immunological component, cutaneous disorders due to exposure to UV radiation, photo-induced or chronological aging of the skin, or actinic pigmentations and keratoses, or all pathologies associated with chronological or actinic aging, in particular xerosis, - disorders of the sebaceous function, in particular hyperseborrhea of acne, simple seborrhea or seborrheic dermatitis, - disorders of cicatrization or stretch marks, - disorders of the pigmentation, such as hyperpigmentation, melasma, hypopigmentation or vitiligo, and 2) in the treatment of: - disorders of lipid metabolism, such as obesity, hyperlipidemia, noninsulin-dependent diabetes mellitus or syndrome X, - inflammatory conditions such as arthritis, - cancerous or precancerous states, - alopecia of diffe origins, including alopecia due to chemotherapy or radiation, - disorders of the immune system, such as asthma, type I diabetes mellitus, multiple sclerosis, or other selective dysfunctions of the immune system, or - and disorders of the cardiovascular system such as arteriosclerosis or hypertension.

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

The present invention also relates to 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 about 0.001 mg / kg to 100 mg / kg of body weight, in 1 to 3 doses. The administration of the composition according to the invention may be carried out enterally, parenterally, topically or ocularly. Preferably, the pharmaceutical composition is packaged in a form suitable for topical application.

Enterally, the composition, more particularly the pharmaceutical composition, may be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres. or nanospheres or lipid or polymeric vesicles for controlled release. Parenterally, the composition may be in the form of solutions or suspensions for infusion or injection. 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.

Topically, the pharmaceutical composition according to the invention is more particularly intended for the treatment of the skin and the mucous membranes and may be in the form of ointments, creams, milks, ointments, powders, soaked swabs, of syndets, solutions, gels, sprays, foams, suspensions, stick lotions, shampoos, or washing bases. It can also be in the form of suspensions of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels allowing controlled release. This topical composition 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 use in the cosmetics field, especially as a cosmetic product, in particular in body and hair hygiene and in particular for the treatment of acne-prone skin, to combat the oily appearance of the skin. skin and hair, in the protection against the harmful effects of the sun or in the treatment of physiologically dry skin, to prevent and / or fight against aging of the skin, in particular photo-induced and / or chronological. The invention therefore also relates to the cosmetic use of a composition comprising, in a physiologically acceptable carrier, at least one of the compounds of formula (I) for preventing and / or treating the signs of aging of the skin 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 one of its optical or geometrical isomers or one of its salts, can be in particular in the form of a cream, a milk, a lotion, ointment, a gel, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, soaked swabs, solutions, sprays, foams, sticks, soaps, shampoos or washing bases.

The compositions as defined above in the form of cream may in particular be creams water in nonionic oil or oil cream in nonionic water. The compositions as defined above in the form of ointment may especially be in the form of 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 further contain additives or combinations of these additives, and in particular: wetting agents; - flavor enhancers; preserving agents such as esters of parahydroxybenzoic acid; stabilizing agents; humidity regulating agents; pH regulating agents; osmotic pressure modifying agents; emulsifying agents; UV-A and UV-B filters; antioxidants, such as α-tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase, ubiquinol or certain metal chelators; - emollients; moisturizing agents such as glycerol, PEG 400, thiamorpholinone and its derivatives or urea.

Of course, those skilled in the art will take care to choose the optional compound (s) to be added to these compositions in such a way that the advantageous properties intrinsically attached to the present invention are not or not substantially impaired by the envisaged addition. Several examples of obtaining compounds of general formula (I) according to the invention, the results of biological activity of these compounds as well as various formulations based on these compounds will now be given by way of illustration and without any limiting character. such compounds. Example 1: 1,1,1,3,3,3-Hexafluoro-2- [1,1 ', 2', 7'-phenphen-4-yl-propan-2-ol

1, 1, 1,3,3,3-Hexafluoro-2- (4-iodo-phenyl) propan-2-ol To a solution of 2- (4-Amino-phenyl) -1,1,1 , 3,3,3-hexafluoropropan-2-ol (15.0 g, 57.9 mmol) in 75 ml of dimethyl formamide, are added dropwise a solution of 6M hydrochloric acid (30.4 ml, 173.6 mmol) and a solution of of sodium nitrite (4.2 g, 60.8 mmol) in 23 ml of water while maintaining the temperature at 5 ° C. The reaction medium is stirred for 30 minutes. At 5 ° C., portion of the potassium iodide (9.6 g, 57.9 mmol) is added. 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 thiosulfate and then dried over magnesium sulfate. After concentration, an oil is obtained which is chromatographed on silica gel: eluent pentane / diethyl ether 90/10). 20.5 g of 1,1,1,3,3,3-Hexafluoro-2- (4-iodo-phenyl) -propan-2-ol are obtained. Yield = 95%.

1H NMR (CDCl3, 400MHz): 3.83 (s, 1H); 7.37-7.41 (m, 3H); 7.72-7.75 (m, 2H). 1,1,1,3,3,3-Hexafluoro-2- [1,1 ', 2; 7-phenphen-4-yl-propan-2-ol

500 mg (1.35 mmol) of 1,1,1,3,3,3-hexafluoro-2- (4-iodo-phenyl) -propan-2-ol, 346 mg (1.75 mmol) of 2-phenylbenzene boronic acid 6 mg (2 mol per 100 mol) of palladium acetate, 19 mg (4 mol per 100 mol) of biphenyldicyclohexyl phosphine are dissolved in 7 ml of dimethylformamide in the presence of 0.5 ml of 2M potassium phosphate solution. . The reaction mixture is stirred for 18 hours at 80 ° C. The reaction mixture is extracted with ethyl acetate. The organic phases are washed with a sodium chloride solution and dried over sodium sulphate. The residual oil is chromatographed on silica gel (Heptane / Ethyl acetate 8/2). 260 mg of 1,1,1,3,3,3-hexafluoro-2- [1,1 ', 2', 1 "] terphenyl-4-yl-propan-2-ol are obtained, yield = 48% 1H NMR (CDCl3, 400MHz): 3.42 (s, 1H), 7.12 (m, 2H), 7.22 (m, 5H), 7.47 (m, 4H), 7.58 (d, J = 8Hz, 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 "-trifluoromethoxy- [1,1 ', 2,1'] terphenyl-4-yl) -propan-2-ol

2- (2 = Bromo-biphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropan-2-ol. 1 g of 1,1,1,3,3,3-hexafluoro-2- (4-iodo-phenyl) -propan-2-ol (2.7 mmol), 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 80 ° C. The reaction mixture is extracted with ethyl acetate and then the residue is chromatographed on silica gel: eluent Heptane / ethyl acetate 95/5. 0.75 g of 2- (2'-Bromo-biphenyl-4-yl) -1,1,1,3,3,3-hexafluoro-propan-2-ol are obtained. Yield = 64%

1H NMR (CDCl3, 400MHz): 3.43 (s, 1H); 7.16-7.19 (m, 2H); 2.26-7.31 (m, 2H); 7.43-7.45 (m, 2H); 7.60-7.63 (m, 1H); 7.70 (d, J = 8.3 Hz, 2H) 1,1,1,3,3,3-Hexafluoro-2- (4'-trifluoromethoxy- [1,1,2] tertphenyl-4-yl) propan-2-ol 200 mg of 2- (2'-bromo-biphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropan-2-ol (0.50 mmol) and 155 mg 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 2.3 mg of Palladium (II) acetate (0.010 mmol) are added. The reaction mixture is stirred for 16 hours at 80 ° C. The mixture is extracted with ethyl acetate, the residue is chromatographed on silica gel: eluent Heptane / ethyl acetate 95/5). 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, 400MHz): 3.38 (s, 1H); 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 = 8.3Hz, 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 In a similar manner to Example 2, 1,1,1,3,3,3-hexafluoro-2- (3 "-hydroxymethyl) is obtained. [1,1 ', 2', 1 "] terphenyl-4-yl) -propan-2-ol

1H NMR (CDCl3, 400MHz): 1.36 (t, J = 6Hz, 1H); 3.69 (s, 1H); 4.40 (d, J = 6Hz, 2H); 6.91 (s, 1H); 7.05 (d, J = 8Hz, 1H); 7.10-7.19 (m, 4H); 7.39 (m, 4H); 7.49 (d, J = 8Hz, 1H) 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 '= methoxy- [1,1', 2 ', 1'] terphenyl-4-yl) propan-2-ol Analogously to Example 2, 1,1,1,3,3,3-hexafluoro-2- (3 "-methoxy- [1,1 ', 2', 1"] terphenyl-4-yl) is obtained. propan-2-ol

1H NMR (CDCl3, 400MHz): 3.44 (2s, 4H, CH3 + OH); 6.46 (s, 1H); 6.70 (m, 2H); 7.08 (t, J = 8Hz, 1H); 7.16 (d, J = 8 Hz, 2H); 7.17 (s, 1H); 7.38 (m, 4H); 7.51 (d, J = 8Hz, 1H) 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 Analogously in example 2 there is obtained 2- (3 "-chloro [1,1 ', 2', 1"] terphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropane -2-ol

1H NMR (CDCl3, 400MHz): 3.44 (s, 1H); 6.79 (d, J = 8 Hz, 1H); 6.98 (m, 2H); 7.08 (m, 3H); 7.31 (m, 4H); 7.45 (d, J = 8Hz, 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 '= fluoro- [1,1', 2 '1'] terphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropane 2-ol In a manner similar to Example 2, 2- (3 "-Chloro-4" -fluoro- [1,1 ', 2', 1 "] terphenyl-4-yl) -1 is obtained. 1,1,3,3,3-hexafluoro-propan-2-ol

1H NMR (CDCl3, 400MHz): 3.40 (br, 1H); 6.85 (m, 2H); 7.08 (d, J = 7 Hz, 1H); 7.13 (d, J = 7 Hz, 2H); 7.32-7.38 (m, 4H); 7.52 (d, J = 8Hz, 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-yl-biphenyl-4-yl) -propan-2-ol In a manner analogous to Example 2, 1,1,1,3,3,3-Hexafluoro-2- (2'-thiophen-3-ylbiphenyl-4-yl) propan-2-ol

1H NMR (CDCl3, 400MHz): 3.49 (s, 1H); 6.59 (d, J = 7 Hz, 1H); 6.91 (d, J = 3 Hz, 1H); 7.04 (m, 1H); 7.19 (d, J = 7 Hz, 2H); 7.34 (m, 3H); 7.42 (m, 1H); 7.52 (d, J = 8Hz, 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 In a similar manner to Example 2, 1,1,1,3,3,3-hexafluoro-2- (5'-fluoro-2 "-methyl- [1,1 '; 2', 1 "] terphenyl-4-yl) -propan-2-ol

1H NMR (CDCl3, 400MHz): 1.73 (s, 3H); 3.52 (if, 1H); 6.76 (m, 2H); 6.92 (m, 1H); 7.11 (d, J = 8 Hz, 2H); 7.22 (d, J = 7Hz, 1H); 7.37 (m, 3H); 7.45 (d, J = 7Hz, 2H) 13C NMR (CDCl3, 100MHz): 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] dioxol-5-yl-biphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropan-2-ol In a manner similar to Example 2 gives 2- (2'-benzo [1,3] dioxol-5-yl-biphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropan-2-one. 1 H NMR (CDCl3, 400 MHz): 3.52 (s, 1H); 5.83 (s, 2H); 6.45-6.60 (m, 4H); 7.17 (d, J = 8Hz, 2H); 7.33 (s, 3H); 7.52 (d, J = 8Hz, 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-f1,1; 2; 1 '] terphenyl-4-yl) -1,1 1,3,3,3-hexafluoropropan-2-ol In a similar manner to Example 2, 2- (3 ", 4" -dimethoxy- [1,1 ', 2', 1 "] is obtained. terphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropan-2-ol 1 H NMR (CDCl3, 400 MHz): 3.35 (s, 3H); 3.55 (s, 1H); 3.79 (s, 3H), 6.33 (d, J = 2.0Hz, 1H), 6.731-6.81 (m, 2H), 7.17-7.20 (m, 2H), 7.34-7.40 (m, 4H), , J = 8.3Hz, 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 "-trifluoromethyl- [1,1 ', 2,1'] terphenyl-4-yl) -propan-2-ol Analogously to Example 2, 1,1,1,3,3,3-hexafluoro-2- (4 "-trifluoromethyl- [1,1 ', 2', 1"] terphenyl-4-yl) is obtained. propan-2-ol 1 H NMR (CDCl3, 400 MHz): 3.39 (s, 1H), 7.12-7.16 (m, 4H), 7.36-7.42 (m, 6H), 7.51 (d, j = 8.3Hz, 2H); 13C NMR (CDCl3, 100 MHz): 122.8 (q); 124.2; 124.6; 124.7; 124.8; 128.5; 129.2; 129.7; 130.3; 144.9 Example 12 2- (3 ', 5'-Bis-trifluoromethyl- [1,1,2'-1-yl] terphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropane -2-ol In a manner analogous to Example 2, 2- (3 ", 5" -bis-trifluoromethyl- [1,1 ', 2', 1 "] terphenyl-4-yl) -1,1 is obtained. 1,3,3,3-hexafluoropropan-2-ol 1H NMR (CDCl3, 400MHz): 3.40 (s, 1H); 7.10 (d, J = 8.3Hz, 2H); 7.41-7.47 (m, 6H); 7.55 (d, J = 8.2Hz, 2H); 7.63 (s, 1H)

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 [1,1 ', 2' 1 '] terphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropan-2 As in Example 2, 2- (3 ", 4" -dichloro- [1,1 ', 2', 1 "] terphenyl-4-yl) -1,1,1,3 is obtained. 1 H NMR, 3,3-hexafluoropropan-2-ol 1H NMR (CDCl3, 400MHz): 3.50 (s, 3H); 6.82 (dd, J = 8.3Hz, 2.1Hz, 1H); 7.14-7.16 (m.p. , 7.18 (d, J = 2.6Hz, 1H), 7.37-7.40 (m, 4H), 7.55 (d, J = 8.3Hz, 2H), 13C NMR (CDCl3, 100MHz): 123.0 (m.p. 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- [1,1,2] 1 '] terphenyl-4-yl) propan -2-ol Analogously to Example 2, 1,1,1,3,3,3-hexafluoro-2- (3 ", 4", 5 "-trimethoxy- [1,1 '; 1H-NMR (1H-CDH) 400H NMR (CDCl3, 400 MHz): 3.48 (s, 3H); 3.51 (s, 6H); 3.75 (s, 3H); 6.23 (s); 7.18-7.20 (m, 2H); 7.37-7.43 (m, 4H); 7.53 (d, j = 8.3Hz, 2H) 13C-NMR (CDCl3, 100MHz): 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 ', 2,1'] terphenyl-4-yl) propan-2-ol Analogously to Example 2, 1,1,3,3,3-hexafluoro-2- (3 "-trifluoromethyl- [1,1 ', 2', 1"] terphenyl-4-yl) was obtained. propan-2-ol 1H NMR (CDCl3, 400 MHz): 3.39 (s, 1H) 7.11 (d, J = 7.3Hz, 2H) 7.19 (d, J = 5.7Hz, 2H) 7.28 (s, 7.41 (m 4H), 7.50 (d, J = 7.8Hz, 2H), 13C NMR (CDCl3, 100MHz): 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-yl-biphenyl-4-yl) -propan-2-ol In a manner analogous to Example 2, 1,1,1,3,3,3-Hexafluoro-2- (2'-thiophen-2-ylbiphenyl-4-yl) -propan-2-ol 1H NMR (CDCl3, 400MHz): 3.43 (s) , 1H); 6.56-6.77 (m, 1H); 6.78-6.79 (m, 1H); 7.11-7.13 (m, 1H); 7.24-7.40 (m, 5H); 7.45-7.50 (m, 1H); 7.56 (d, J = 8.0Hz, 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-trifluoromethyl-ethyl) - [1,1 '] -2'] terphenyl-3 '= N, N-dimethyl sulfonamide analogous to Example 2, 4- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1 "] terphenyl-3" -N is obtained, N-dimethyl sulfonamide 1 H NMR (CDCl3, 400 MHz): 2.30 (s, 6H); 6.56-6.77 (m, 1H); 7.25-7.28 (m, 3H); 7.43-7.75 (m, 9H); 8.64 (s, 1H). 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-sulfonyl) - [1,1; 2; 1 '] terphenyl-4-yl] -pro pan -2-ol In a similar manner to Example 2, 1,1,1,3,3,3-hexafluoro-2- [3 "- (morpholine-4-sulfonyl) - [1,1 '; 1H-NMR (CDCl3, 400MHz): 2.77 (t, J = 4.4Hz, 4H); 3.58 (t, J = 4.4Hz, 4H); 7.20-7.32 (m, 2H), 7.39-7.42 (m, 1H), 7.46-7.60 (m, 9H), 8.64 (s, 1H) .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-trifluoromethyl-ethyl) - [1,1 ', 2'-1'] terphenyl-3 '"-sulfonamide Analogous to Example There is obtained 4- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1 "] terphenyl-3" -sulfonic acid amide 1H NMR (CDCl3) 400 MHz): 7.10 (d, J = 7.8Hz, 1H), 7.25-7.34 (m, 5H), 7.46-7.70 (m, 6H), 7.77 (s, 1H), 8.70 (s, 1H), NMR; 13C (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-trifluoromethyl-ethyl) - [1,1 ', 2'] - terphenyl-3 '= N -methyl sulfonamide Analogously to Example 2 gives 4- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1 "] terphenyl-3" -N-methyl sulfonamide 1H NMR (CDCl3, 400 MHz): 2.11 (d, J = 4.8 Hz, 3H); 7.26-7.79 (m, 13H); 8.69 (s, 2H); 13 C NMR (CDCl 3, 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-trifluoromethyl-ethyl) - [1,1 ', 2-yl] terphenyl-3' = carbonitrile Analogous to Example 2 4- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1 "] terphenyl-3" -carbonitrile 1H NMR (CDCl3, 400) is obtained. MHz): 7.25 (d, J = 8.5Hz, 2H); 7.43-7.47 (m, 3H); 7.51-7.58 (m, 6H); 7.68-7.73 (m, 1H); 8.72 (s, 1H). MN 13C (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-trifluoromethyl-ethyl) - [1,1 ', 2-tert-phenyl] -3-carboxylate Analogous to Example 2 gives methyl 4- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1 "] terphenyl-3" -carboxylate 1H (CDCl3, 400 MHz): 3.78 (s, 3H); 7.01 (m, 2H); 7.14 (m, 5H); 7.42 (d, J = 8 Hz, 1H); 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-trifluoromethyl-ethyl) - [1,1 ', 2; 1'] terphenyl-3 '= carboxamide Analogous to Example 2 4- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1 "] terphenyl-3" -carboxamide 1 H NMR (DMSO, 400) is obtained. MHz): 7.08 (d, J = 8Hz, 1H); 7.23 (m, 3H); 7.34 (si, 1H); 7.49 (m, 7H); 7.71 (d, J = 8 Hz); 7.76 (s, 1H); 7.90 (si, 1H). 13 C 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-methoxy-biphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropan-2-ol 2- (2 = Bromo-5 = methoxy-biphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropan-2-ol 404 mg (0.35 mmol, 2% mol) palladium tetrakistriphenylphosphine 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-iodo-phenyl) -propan-2-ol and 5.0 g ( 0.021 mol, 1.2 eq) of 2-bromo-5-methoxy-phenylboronic 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 hydrogencarbonate and then extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride and dried over sodium sulfate. The solvents are evaporated and the residue is chromatographed on silica gel eluent: heptane / ethyl acetate 90/10. 4.94 g of 2- (2'-bromo-5'-methoxy-biphenyl-4-yl) -1,1,1,3,3,3-hexafluoro-propan-2-ol are obtained. Yield = 66%

1 H NMR (DMSO, 400 MHz): 3.56 (sl, 1H); 3.74 (s, 3H); 6.73 (dd, J = 8Hz, J = 3Hz, 1H); 6.80 (d, J = 3.Hz, 1H); 7.42-7.49 (m, 3H); 7.70 (d, J = 8Hz, 2H) 2- (2 = Benzo [1,3] dioxol-5-yl-5-methoxy-biphenyl-4-yl) -1,1,1,3,3,3- hexafluoro-propan-2-ol 132 mg of 3,4-methylene dioxyphenylboronic acid (0.79 mmol) are added to a solution of 310 mg of 2- (2'-Bromo-5'-methoxy-biph in yl-4 1: 1, 1, 3, 3, 3-hexa-fluoro-propan-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 70 ° C. The reaction medium is poured into a saturated solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride and dried over sodium sulfate. The solvents are evaporated and the residue is chromatographed on silica gel eluent: heptane / ethyl acetate 95/5. 160 mg of 2- (2'-Benzo [1,3] dioxol-5-yl-5'-methoxy-biphenyl-4-yl) -1,1,1,3,3,3-hexafluoropropan-2 -ol are obtained. Yield = 43%.

1H NMR (CDCl3, 400MHz): 3.61 (s, 1H); 3.79 (s, 3H); 5.82 (d, J = 2.5Hz, 2H); 6.41-6.47 (m, 1H); 6.56 (d, J = 8.OHz, 1H); 6.90-6.87 (m, 2H); 7.15-7.18 (m, 2H); 7.25 (d, J = 8.2Hz, 1H); 7.51 (d, J = 8.3Hz, 2H); 13 C 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 1,1,3,3,3,3-Hexafluoro-2- (3-hydroxyethyl) -4-methoxy-1,1 ', 2-yl] terphenyl-4' yl) Propan-2-ol In a similar manner to Example 24, 1,1,1,3,3,3-hexafluoro-2- (3-hydroxymethyl-4'-methoxy- [1,1 '] 2' is obtained. , 1 "] terphenyl-4" -yl) -propan-2-ol

1H NMR (CDCl3, 400MHz): 3.90 (s, 3H); 4.39 (d, J = 5.5Hz, 2H); 5.16 (t, J = 5.6 Hz, 1H); 6.89 (d, J = 7.2Hz, 1H); 7.11 (s, 2H); 7.11-7.20 (m, 3H); 7.32 (d, J = 8.4Hz, 2H); 7.40-7.42 (m, 1H) 7.60 (d, J = 8.1 Hz, 2H); 8.74 (s, 1H); 13 C 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-trifluoromethyl-ethyl) - [1,1', 2 '] -] terphenyl-3-carbonitrile Analogously in Example 24 there is obtained 4'-methoxy-4 "- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1"] terphenyl -3-carbonitrile

1H NMR (CDCl3, 400MHz): 3.59 (s, 3H); 4.2 (if, 1H); 6.56 (m, 2H); 6.72 (d, J = 8Hz, 1H); 7.08 (t, J = 8 Hz, 1H); 7.28 (m, 2H); 7.41 (m, 3H); 7.67 (s, 1H), 7.71, d, J = 8 Hz) 13 C 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: Acid 4 = Methoxy-4 '- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1', 2; 1 '] terphenyl-3-carboxylic acid 200 mg 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 0 ° C. 220 mg of chromium trioxide (2.2 mmol) are added together with 2 ml of a 20% sulfuric acid solution. The reaction is stirred for 30 minutes at 0 ° C. and then for 1 hour 30 minutes at room 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 Heptane / Ethyl acetate 1/1. 120 mg of 4'-Methoxy-4 "- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1"] terphenyl-3-carboxylic acid are obtained. Yield = 58%.

1H NMR (CDCl3, 400MHz): 3.91 (s, 3H), 7.08 (m, 1H), 7.13 (d, J = 8Hz, 1H), 7.33 (m, 4H), 7.46 (d, J = 8Hz). , 1H), 7.60 (d, J = 8 Hz, 2H), 7.66 (s, 1H), 7.81 (d, J = 8Hz, 1H), 8.71 (s, 1H), 12.8 (bs, 1H). 13 C NMR (CDCl 3, 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-trifluoromethyl-ethyl) - [1,1', 2,1'] terphenyl-3-carboxamide Similarly to EXAMPLE 24 4'-methoxy-4 "- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1"] terphenyl-3 is obtained 1H NMR carboxamide (DMSO, 400 MHz): 3.68 (s, 3H); 7.01 (m, 2H); 7.10 (d, J = 8Hz, 1H); 7.19 (t, J = 8Hz, 1H); 7.28 (d, J = 8 Hz, 2H); 7.34 (si, 1H); 7.42 (d, J = 8 Hz, 1H); 7.55 (d, J = 8Hz, 2H); 7.68 (d, J = 8Hz, 1H); 7.73 (s, 1H); 7.90 (s, 1H); 8.7 (s, 1H). 13 C NMR (CDCl 3, 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 1,1,3,3,3,3-Hexafluoro-2- (3'-hydroxymethyl-4-methoxy- [1,1 ', 2,7-phenphen-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 -o1. 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-iodo-phenyl) -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 80 ° C. The reaction medium is poured into a saturated solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride and dried over sodium sulfate. The solvents are evaporated and the residue is chromatographed on silica gel eluent: eluent Heptane / Ethyl acetate 95/5. 8.88 g of 1,1,1,3,3,3-Hexafluoro-2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] - propan-2-ol are obtained. Yield = 84% 1 H NMR (CDCl3, 400 MHz): 1.28 (s, 6H); 3.54 (s, 1H); 7.64 (d, J = 8 Hz, 2H); 7.82 (d, J = 8Hz, 2H); (2-Bromo-5-methoxy-biphenyl-3-yl) -methanol. 0.54 g of 2-bromo-5-methoxy-phenylboronic acid (2.35 mmol) are added to a solution of 0.5 g (3-lodo-phenyl) -methanol (2.14 mmol) in 5 ml of toluene in the presence of 1.4 ml of toluene. aqueous solution of 2M sodium carbonate (1.4 ml, 2.78 mmol). 0.1 g of palladium (0) tetrakis- (triphenylphosphine) (0.085 mmol) are added and the reaction mixture is then stirred for 6 hours under reflux. The reaction medium is poured into a saturated solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride and dried over sodium sulfate. The solvents are evaporated and the residue is chromatographed on silica gel eluent: 80/20 heptane / ethyl acetate eluent. 170 mg of (2'-Bromo-5'-methoxy-biphenyl-3-yl) -methanol are obtained. Yield = 56% 1H NMR (CDCl3, 400 MHz): 3.79 (s, 3H); 4.56 (d, J = 6Hz, 2H); 5.26 (t, J = 6Hz, 1H); 6.90-6.94 (m, 2H); 7.26 (d, J = 7Hz, 1H); 7.32-7.43 (m, 3H); 7.61 (dd, J = 1.5Hz, 7.6Hz, 2H) 1,1,1,3,3,3-Hexafluoro-2- (3'-hydroxymethyl-4 = methoxy- [1,1; 2; 1 '] terphenyl-4-yl) propan-2-ol. 490 mg of 1,1,1,3,3,3-hexafluoro-2- [4- (4,4,5,5-tetramethyl- [1,3,2] 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 an aqueous solution of 2M potassium phosphate (2.36 mmol). 18.5 mg of 2- (dicyclohexyl-phos-phino) 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 70 ° C. The reaction medium is poured into a saturated solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride and dried over sodium sulfate. The solvents are evaporated and the residue is chromatographed on silica gel eluent: 80/20 heptane / ethyl acetate eluent. 170 mg 1,1,1,3,3,3-Hexafluoro-2- (3 "-hydroxymethyl-4'-methoxy- [1,1 ', 2', 1"] terphenyl-4-yl) -propane 2-ol of are obtained. Yield = 31% 1 H NMR (CDCl 3, 400 MHz): 3.90 (s, 3H); 4.41 (d, J = 6Hz, 2H); 5.18 (t, J = 5.7Hz, 1H); 6.97 (d, J = 7Hz, 1H); 7.01 (d, J = 3Hz, 1H); 7.08-7.13 (m, 2H); 7.18-7.25 (m, 4H) 7.44 (d, J = 8Hz, 1H); 7.56 (d, J = 8Hz, 2H); 8.70 (s, 1H). 13 C NMR (CDCl 3, 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 LXRR Receptor: The activity of the LXRI3 receptor is measured in a transactivation test. Activation of the receptor by an agonist (activator) in HeLa cells leads to the expression of a reporter gene, luciferase, which in the presence of a substrate generates light. Receptor activation can thus be measured by quantifying the luminescence produced after incubation of the cells in the presence of a reference agonist. The antagonistic products will displace the agonist from its site thus preventing activation of the receptor: there will therefore be a drop in the light produced which can be quantified. The products are tested alone and their effect is measured by measuring the activation of the luminescence after incubation. Determination of the apparent Kd: In this study, we determine a constant that represents the affinity of the molecule for the receptor. Since this value can fluctuate according to the basal activity and the expression of the receptor, it is called Kd apparent (KdApp). To determine this constant, we carry out in plate 96 crossed curves of the product to be tested against a reference agonist: 10 concentrations of the product to be tested plus a concentration 0 (in line) and 7 concentrations of the agonist plus a concentration 0 (in column). This represents 88 measurement points for 1 product and 1 receiver. The remaining 8 wells are used for 100% (total agonist) and 0% (DMSO) controls.

These cross curves allow us to determine the AC50 (concentration at which 50% activation is observed) of the reference ligand at different concentrations of product to be tested. These AC50s are used to calculate Schild regression by plotting a line corresponding to the Schild equation (Terry P.Kenakin quantitation in receptor pharmacology, Receptors and Channels, 2001, 7, 371-385). In the case of an antagonist, we calculate an IC50 (concentration inhibiting 50% of the activity) by plotting the product curve at the concentration of the reference ligand giving 80% activation.

The cell lines used are HG5LN cells, HeLa cells stably transfected with the reporter (17mer) 5-bGlob-Luc and also stably transfected with plasmid Gal-hLXR13-DEF. These cells are seeded in 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% of delipidated calf serum. The plates are then incubated at 37 ° C., 7% CO 2 for 4 H. The various dilutions of the products to be tested, the reference ligand and the 100% control (N- (2,2,2-trifluoroethyl) -N) - [4- (trifluoro-hydroxy-trifluoromethyl-ethyl) -phenyl] benzenesulfonamide or T0901317) and control 0% (dimethylsulfoxide 0.2%) are added at a rate of 5 μl per well. The plates are then incubated for 18 hours at 37 ° C., 7% CO 2. The culture medium is removed by inversion and 100 μl of a 1: 1 PBS / Luciferine mixture is added to each well. After 5 minutes, the plates are read by the luminescence reader.

Results: The compounds of the invention show a strong affinity for the LXR 13 receptor as shown in Table 1 Table 1: Affinity for the LXR R receptor: Tested compound KdApp (nM) Compound of Example 21: 15 4- ( 2,2,2-Trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) - [1,1 ', 2', 1 "] terphenyl-3" -carbonitrile Compound of Example 25: 1.11.1 , 3,3,3-Hexafluoro-2- (3-hydroxymethyl-4'-methoxy- [1,1 ', 2', 1 "] terphenyl-4" -yl) -propan-2-ol for comparison the reference ligand of the prior art (T0901317) has a KdApp twice as high, ie 30 nM.

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

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

Systemic effects are assessed 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 of the ethics committee. The product to be tested 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 on a surface of 2 cm × 3 cm. The treatment is repeated every 24 hours for 25 days. Animals are randomized the first day according to body weight.

The systemic effects are evaluated on the one hand by monitoring the weight of animals and on the other hand by the determination of plasma triglycerides. The animals are weighed once a week. To perform the blood sample, the rats are anesthetized with a gas anesthesia system. Blood samples are taken 24 hours after the last treatment. Blood is collected on a heparinized tube. Plasma triglycerides are quantified using the COBAS INTEGRA 400+ and the statistical analysis performed using the Provantis software coupled to the controller.30 Results:

Loss of weight: At a dose of 1%, the compounds of the invention (compounds of Examples 23 and 25) do not cause significant weight loss while the reference compound of the prior art (compound T0901317), in the same conditions, induces a limitation of weight gain of the animal (see Tables 2a, 2b and 2c). Table 2a: Composed of the example Weight gain Student test versus 23 from D1 to D25 (g) vehicle Weight gain Treatment Average Pr = Significance Vehicle 52.4 4.3 1% 43.1 3.0 0.3600 NS Table 2b: Composed of the example Weight gain Student test versus 25 days D1 to D25 (g) vehicle Weight gain Treatment Average Progravity Vehicle 44.2 14.9 1% 47.0 11.3 0.6500 NS Table 2c: T0901317 Weight gain Test of Student vs Weight gain from D1 to D25 (g) Vehicle Median Treatment Value Significance Vehicle 49 6.7 T0901317 1% 30.5 2.5 0.0406 Student's statistical test: (*) = 0.01 P <0.05, (NS) = 0.05 P esm = standard deviation from mean NS = Not Significant

Blood triglyceride level: From the 0.1% dose, the compound of the prior art causes a significant increase in the level of triglycerides in the blood by a factor of 1.77 whereas at this same dose, the compounds of the invention do not lead to a significant increase in this same level of triglycerides (see Table 3). Table 3: Determination of Triglyceride Triglyceride Plasma Treatment Ratio vs Vehicle Statistical Analysis Provantis Compound T0901317 at 1.77 0.1% Compound of Example 3 0.98 NS at 0.1% Compound of Example 21 1.36 NS at 0.1% Compound of Example 23 0.99 NS at 0.1% Compound of Example 25 0.95 NS at 0.1% Statistical test from Provantis software: (*) = 0.01 P <0.05, NS = 0.05 P Example 32: Measurement of the anti-inflammatory activity of Compounds of the invention: The model used is the mouse ear inflammation model induced by a single application of TPA (Phorbol-12-Myristate-13-Acetate). Female Balb / c ByJlco mice are used. The edema is induced by application to the ear of 20 μl of 0.01% TPA dissolved in acetone. The molecule to be evaluated is dissolved in the 0.01% TPA solution and applied at the same time. The edema is evaluated 6 hours after application by measuring the ear thickness using an Oditest micrometer. TPA-induced edema is evaluated relative to the vehicle acetone group. Inhibition of edema by the molecule is expressed as a percentage of reduction of edema induced by TPA alone.

Results: It turns out that the compound of the invention (compound of Example 23) displays a significant anti-inflammatory activity at a dose of 0.1% (see Table 4). Table 4: Model of Ear Edema Inhibition TPA-TPA Student vs. TPA Test Treatment% P Value Significance TPA 0.01% + Compound 44.5 0.0002 *** Example 23 to 0.1 % TPA 0.01% + compound of 52.1 0.0013 ** example 23 to 0.3% TPA 0.01% + compound of 82.9 0.0000 *** example 23 to 1% TPA 0.01% + compound of 96.6 0.0000 *** example 23 to 2% 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 WAY

(a) Ointment - Compound of Example 1 0.020g - Isopropyl Myristate 81.700g - Fluid Vaseline Oil 9.100g - Silica ("Aerosil 200") 9.180g

(b) Ointment - Compound 6 0.300 g - White Vaseline codex qs 100 g

(C) Non-ionic Water-in-Oil Cream - Compound of Example 1 0.100 g - Mixture of emulsifiable lanolin alcohols, waxes and oils ("Anhydrous Eucerin") 39.900 g - Methyl parahydroxybenzoate 0.075 g Propyl parahydroxybenzoate 0.075 g 33 - Sterile demineralized water qs 100 g (d) Lotion - Compound of Example 6 0.100 g - Polyethylene glycol (PEG 400) 69.900 g - 95% ethanol 30.000 g

(e) Hydrophobic Ointment - Compound 2 0.300 g - Isopropyl Miristate 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 100 g 15 (f) Nonionic Oil-in-Water Cream - Compound of Example 4 1.000 g - Cetyl alcohol 4.000 g - Glycerol monostearate 2.500 g 20 - PEG 50 stearate 2.500 g - Shea butter 9,200 g Propylene glycol 2.000 g methyl parahydroxybenzoate 0.075 g propyl parahydroxybenzoate 0.075 g sterile demineralized water qs 100 g

Claims (11)

1. A compound of general formula (I) below: F (I) wherein, R, R2, R3, R4 and R5, identical or different, represent: - a hydrogen - an alkyl radical, unsubstituted or substituted a cycloalkyl radical a cycloalkylalkyl radical an unsubstituted or substituted alkoxy radical, a carboxy radical, an unsubstituted or substituted alkoxycarbonyl radical, a halogen, a cyano radical, a carboxamide group, N- alkyl carboxamide or N, N-dialkyl carboxamide, a sulphonamide, N-alkyl sulphonamide, N, N-dialkyl sulphonamide or morpholinosulphonyl group, Ar represents a cyclic group chosen from: when R3 is in the ortho position with respect to R4 then R3 and R4 can form a hydrocarbon ring with 5 or 6 sides, it being understood that 1 or 2 carbon atom (s) can optionally be replaced by 1 or 2 atom (s) of oxygen, nitrogen or sulfur, their optical isomers, or in the form of hyd or solvates, and their salts 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 grouping 4. Compound according to one of Claims 1 to 3, characterized in that one of the radicals R 3, R 4 and R 5 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 radicals R, or R2 represents a hydrogen and the other of the radicals R, or R2 represents an alkyl radical, or alkoxy. 6. Compound according to any one of claims 1 to 5 for its application as a medicament in human or veterinary medicine. 7. A compound according to any one of claims 1 to 5 for its application 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. 25 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 aging of the skin.