EP1802569A1

EP1802569A1 - Bi-aromatic compounds for therapeutic or cosmetic use

Info

Publication number: EP1802569A1
Application number: EP05809265A
Authority: EP
Inventors: Anne-Pascale Luzy
Original assignee: Galderma Research and Development SNC
Current assignee: Galderma Research and Development SNC
Priority date: 2004-10-12
Filing date: 2005-10-10
Publication date: 2007-07-04
Also published as: FR2876376B1; WO2006040462A1; FR2876376A1; JP2008515958A; CA2582248A1; US20070249710A1

Abstract

The invention relates to ester compounds of 2-hydroxy-4-[2-hydroxyimino-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-yl)-ethoxy]-benzoic acid, to the synthesis method thereof and to the uses of same in the medical and cosmetic fields.

Description

Bi-aromatic compounds for therapeutic or cosmetic use

The present invention relates to novel bi-aromatic compounds derived from a salicylic unit, their preparation process and their use in human and veterinary medicine and in cosmetics.

A family of bi-aromatic compounds derived from a salicylic unit has been described in patent EP 0 514 264. These compounds are described as having an application in the topical and systemic treatment of dermatological disorders related to a disorder of keratinization and disorders. ophthalmological conditions, in particular.

The activity of these compounds has been demonstrated in particular by differentiation tests of mouse embryonic teratocarcinoma F9 cells and keratinocyte differentiation tests in humans.

On the other hand, this document makes no mention of any specific activity of the compounds with respect to the gamma subtype of RAR receptors.

Surprisingly, it has now been shown that 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl) -5,6,7,8-tetrahydronaphthalene-2-ene (2-yl) -ethoxy] -benzoic acid exhibits a selective agonist activity for the gamma subtype of the RAR receptor family of great interest.

There is therefore an increased interest in having compounds prodrugs of this acid, possibly themselves having a selective activity vis-à-vis the RARγ receptor.

The invention provides such compounds, which further have the advantage of having a very short hepatic half-life time, advantageously of the order of 3 minutes, and of being perfectly compatible with topical application.

According to a first aspect, the subject of the present invention is the compounds of general formula (I)

(I) in which :

R ₁ represents: an alkyl radical having from 2 to 20 carbon atoms,

an alkenyl radical having from 2 to 20 carbon atoms,

a mono- or polyhydroxyalkyl radical having from 1 to 6 carbon atoms,

- a sugar residue, or

an amino acid residue,

R ₂ represents a hydrogen atom or an alkyl having 1 to 3 carbon atoms, and the salts of the compounds of formula (I), when R ₁ represents an amino acid residue and the isomers of the compounds of formula (I) .

Compounds of the invention of formula (I) defined as above having a sufficiently acid function or a sufficiently basic function or both, may include the corresponding salts of organic or inorganic acid or organic or inorganic base pharmaceutically acceptable.

The invention also relates to tautomeric forms, enantiomers, diastereoisomers, epimers and organic or inorganic salts of the compounds of general formula (I). As used above and throughout the description of the invention, the following terms, unless otherwise stated, are to be understood as having the following meanings:

By "alkyl radical" is meant an aliphatic hydrocarbon group which may be linear or branched having from 2 to 20 carbon atoms in the chain. Preferred alkyl groups have from 2 to 12 carbon atoms in the chain, and especially from 4 to 12 carbon aromas.

"Branched alkyl" means that one or more lower alkyl group (s), such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" refers to a radical having 1 to 4 carbon atoms in the chain which may be linear or branched.

As examples of alkyl radicals, mention may especially be made of ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, n-pentyl, n-hexyl and n-heptyl. and n-octyl.

By "alkenyl" is meant an aliphatic hydrocarbon group which contains a carbon-carbon double bond and which may be linear or branched, having 2 to 15 atoms of carbon in the chain. Preferred alkenyl groups have 2 to 12 carbon atoms in the chain and more preferably 2 to 4 carbon atoms in the chain.

By "branched" is meant that one or more lower alkyl group (s), such as methyl, ethyl or propyl, are bonded to the linear alkenyl chain.

Examples of alkenyl radicals that may especially be mentioned are vinyl, allyl, 2-butenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, hexenyl and heptenyl radicals. octenyl, cyclohexylbutenyl and decenyl.

By "monohydroxyalkyl radical" is meant an alkyl radical as defined herein, substituted with a hydroxy group.

As examples of monohydroxyalkyl radicals, mention may especially be made of the hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyhexyl radicals.

By "polyhydroxyalkyl radical" is meant an alkyl radical as defined herein, preferably comprising from 2 to 6 carbon atoms, substituted with 2 to 5 hydroxyl groups. Examples of polyhydroxyalkyl radicals include 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4,5-tetrahydroxypentyl radicals.

For the purposes of the present description, the term "residue of a sugar" means a residue derived for example from glucose, galactose or mannose. Examples include 6-glucosyl, 6-galactosyl and 6-mannosyl radicals.

The term "amino acid" refers to a group containing both an amino group and a carboxyl group of the general formula HOOC-CH (side chain) (NH ₂ ). The amino acids may be in the D, L or racemic configuration. Amino acids include both natural and unnatural amino acids. Natural amino acids include the 20 constituent amino acids of proteins such as serine, threonine and tyrosine.

Non-natural amino acids are known and include naturally occurring amino acid analogues. In this regard, one can in particular refer to Lehninger, AL, Biochemistry, ^2nd ed., Worth Publishers, New York, 1975, 71-77.

Non-naturally occurring amino acids include amino acids in which the side chains are replaced by synthetic derivatives.

In the context of the present invention, amino acids in which the side chain comprises one or more functions are particularly preferred. hydroxyls capable of forming with a carboxylic acid function an ester function. Examples of naturally occurring amino acids bearing a hydroxyl function are serine, threonine and tyrosine.

By "amino acid residue" is meant in the sense of the present description the residue of the amino acid after reaction of a hydroxyl group carried by the side chain thereof with a carboxylic acid function to form an ester function of the type :

OH

- U-O - (side chain) - C ¹¹¹ COOH

NH ₂

The term "pharmaceutically acceptable salts" refers to relatively non-toxic, inorganic or organic acid addition salts, and base addition salts, of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, the acid addition salts can be prepared by separately reacting the purified compound in its purified form with an organic or inorganic acid and isolating the salt thus formed.

Examples of the acid addition salts are the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate and citrate salts. , maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptanate, lactobionate, sulfamates, malonates, salicylates, propionates, methylenebis-b-hydroxynaphthoates, gentisic acid, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and quinateslaurylsulfonate, and the like. (See, for example, SM Berge et al., "Pharmaceutical Salts" J. Pharm Sci, 66: p.1-19 (1977).) The acid addition salts can also be prepared by separately reacting the purified compound in its form. acid with an organic or inorganic base and isolating the salt thus formed.

Acidic addition salts include amine and metal salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum salts. Sodium and potassium salts are preferred.

Suitable basic inorganic addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, sodium hydroxide and the like. potassium, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide.

Suitable base amino acid addition salts are prepared from amines which have sufficient alkalinity to form a stable salt, and preferably include amines which are often used in medicinal chemistry because of their low toxicity and acceptability. for medical use: ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) ) -aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethyl-piperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, for example lysine and arginine and dicyclohexylamine, and the like.

The compounds of the present invention may contain asymmetric centers.

These asymmetric centers can be independently in the R or S configuration.

Some compounds may also exhibit geometric isomerism.

The present invention includes individual geometric isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) above.

These types of isomers can be separated from their mixtures by the application or adaptation of known methods, for example chromatography techniques or recrystallization techniques, or they are prepared separately from the appropriate isomers of their intermediates. It is understood that the tautomeric forms are included in the citation of a given group, for example oxo / hydroxy.

Preferably, R ₁ represents an alkyl radical, and in particular an alkyl radical having 2 to 6 carbon atoms.

According to one embodiment, R ₂ represents an alkyl group as defined above and having from 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, isopropyl.

Preferably, R ₂ represents a hydrogen atom. Among the compounds of formula (I) above, there may be mentioned the following compounds:

I) ethyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) -ethoxy] -benzoic acid; 2) Isopropyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) -ethoxy] -benzoic acid;

3) Isobutyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) -ethoxy] -benzoic acid;

4) Butyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) - ethoxy] benzoic acid;

5) the pentyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) - ethoxy] benzoic acid;

6) The hexyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) -ethoxy] -benzoic acid; 7) the heptyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) -ethoxy] -benzoic acid;

8) the hept-6-enyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl) -5,6,7,8-tetrahydronaphthalene 2-yl) -ethoxy] -benzoic acid;

9) 2,3-Dihydroxypropyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl) -5,6,7,8-tetrahydronaphthalene-2 yl) -ethoxy] -benzoic acid;

10) 4-hydroxybutyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) ) -ethoxy] -benzoic acid;

I 1) 6-Galactosyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl) -5,6,7,8-tetrahydronaphthalene-2- acid yl) -ethoxy] -benzoic acid; 12) ester of 6-glucosyl acid 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8 ₁ 8-tetramethyl- 5,6,7,8-tétrahydronaphthalèn-2-yl ) -ethoxy] -benzoic acid;

13) 6-mannosyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) ) -ethoxy] -benzoic acid;

14) 2-amino-2-carboxyethyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5 ₎ 6,7,8-tetrahydronaphthalene acid -2-yl) -ethoxy-3-benzoic acid;

15) 4- (2-Amino-2-carboxyethyl) -phenyl ester of 2-hydroxy-4- [2-hydroxy-imino-2- (5,5,8,8-tetramethyl) -5,6,7,8-tétrahydronaphthalèn-2-yl) -ethoxy] -benzoic acid;

16) 2-amino-2-carboxypropyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl) -5,6,7,8-tetrahydronaphthalene -2-yl) -ethoxy] -benzoic acid.

The compounds of general formula (I) may be prepared by application or adaptation of any method known per se of and / or within the scope of those skilled in the art, especially those described by Larock in Comprehensive Organic Transformations, VCH Pub., 1989, or by application or adaptation of the methods described in the examples which follow, or, more particularly, according to the method described in patent EP 0 514 264. In the As described below, it may be necessary to protect the reactive functional groups, for example the hydroxy, amino, carboxy groups, when desired in the final product, to avoid their undesirable participation in the reactions. Traditional protection groups can be used in accordance with standard practice, for examples see TW Green and PGM Wuts in Protective Groups in Organic Chemistry, John Wiley and Sons, 1991; JFW McOmie in Protective Groups in Organic Chemistry, Plenum Press, 1973.

General synthetic routes for preparing the compounds of formula (I) are shown in the scheme of FIG.

The base products or reagents used are commercially available and / or can be prepared by the application or adaptation of known methods, for example processes as described in the examples or their chemical equivalents.

The compounds of formula (I) may be prepared according to routes A or B as represented in the synthesis scheme of FIG.

Unless otherwise indicated, all the substituents shown in the synthetic schemes of Figures 1 and 2 have the aforementioned meanings.

According to another aspect, the present invention therefore also relates to a process for the preparation of the compounds of formula (I) described above comprising the following steps: i) conversion of the ketone function of the compound of formula 3

in which :

R 1 represents: an alkyl radical having from 2 to 20 carbon atoms,

an alkenyl radical having from 2 to 20 carbon atoms, a mono- or polyhydroxyalkyl radical having from 1 to 6 carbon atoms,

- a sugar residue, or

an amino acid residue,

R ₂ represents a hydrogen atom or an alkyl having 1 to 3 carbon atoms, in oxime function to yield the compound of formula (I);

and eventually

ϋ) recovering the compound of formula (I) obtained.

Step (i)

The conversion of the ketone function to oxime can be carried out according to known methods.

By way of example, the oxime may be prepared by reacting hydroxylamine or a salt thereof, such as a hydroxylamine hydrohalide and in particular hydroxylamine hydrochloride, with ketone.

Hydroxylamine derivatives such as, for example, H ₂ NOSO ₃ H and HON (SO ₃ Na) ₂ can also be used. In this regard, mention may refer to March, Jerry, Advanced Organic Chemistry, ^3rd Ed., John Wiley and Sons.

The ratio of the hydroxylamine, its salts or its derivatives to the ketone compound 3 can vary, for example, in the range from 1 to 20 molar equivalents, more preferably from 1 to 5 molar equivalents. The amount of hydroxylamine hydrochloride and pyridine is, for example, respectively 1 mol to 1 mol of compound 3.

The oxime may also be prepared by reacting compound 3 with a combination of hydroxylamine halohydrate and pyridine.

Preferably, these two reagents are present in proportions (1/1) in molar equivalents respectively.

Step (i) can also be performed in the presence of a suitable base. There is no particular restriction on the nature of the basis in this reaction, and any basis traditionally used in reactions of this type can be used here provided that it has no adverse effect on other parts of the molecule.

Examples of suitable bases include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, amines such as triethylamine, diisopropylethylamine, and the like.

There is no particular restriction on the nature of the solvent to be employed, provided that there is no adverse effect on the reaction or the reagents involved.

Examples of suitable solvents include polar solvents, including aliphatic alcohols such as methanol, ethanol, isopropanol; aliphatic ethers such as tetrahydrofuran (THF), diethyl ether, dibutyl ether, dioxane; and mixtures of these solvents.

The reaction can take place over a wide temperature range, and it is not essential for the invention that the reaction be performed at a precise temperature. The reaction temperature is, for example, between 15 ° C and 150 ° C and, most often, between 20 ⁰ C and 100 ⁰ C.

For example, the reaction may be carried out under reflux of methanol and / or THF.

Lane A

Step ai)

According to a first particular embodiment of the process of the invention, the compound of formula 3 is prepared according to a process comprising an esterification reaction of acid 1, according to a step a 1), in the presence of an alcohol R ₁ Wherein R ₁ is as defined above, whereby a compound of formula 2 is obtained.

The esterification reaction according to step a1) can be catalyzed by a suitable acid. Examples of acids include hydrochloric, hydrobromic, nitric or sulfuric acid, the latter being preferred. When R ₂ = H, the compound of formula 3 is thus directly obtained according to step a 1) from 2-hydroxy-4- [2-hydroxyimino-2 - (5,5,8,8-tetramethyl) -5,6,7,8-tetrahydro-naphthalen-2-yl) -ethoxy] -benzoic acid 1. This may be prepared according to the method described in patent EP 0 514 264.

Step a2)

When R ₂ represents an alkyl group, the process for preparing the compound of formula 3 additionally comprises an alkylation reaction of the phenol function of compound 2 in the presence of an alkyl halide of formula R ₂ X, in which R ₂ represents an alkyl having 1 to 3 carbon atoms, and X represents a halogen atom such as Cl or Br.

This alkylation reaction can be carried out according to conventional methods. In this regard, reference may be particularly March, Jerry, Advanced Organic Chemistry, ^3rd Ed., John Wiley and Sons. For example, the alkylation reaction can be carried out in the presence of a suitable base.

Examples of suitable bases include alkali metal carbonates such as potassium carbonate, sodium carbonate or cesium carbonate; alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide.

Track B

Step b2) According to a second embodiment, the compound 3 is prepared by an alkylation reaction of a haloacetophenone 6, in particular bromoacetophenone, with a compound of formula 5.

x = Br, ci

This alkylation reaction can be carried out according to known methods. In this regard, reference may be particularly March, Jerry, Advanced Organic Chemistry, ^3rd Ed., John Wiley and Sons. For example, the alkylation reaction can be carried out in the presence of a suitable base.

Examples of suitable bases are in particular alkali metal carbonates such as potassium carbonate, sodium carbonate or cesium carbonate, alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide or potassium hydroxide. potassium carbonate, the latter being particularly preferred.

Step b1)

The compound 5 can be prepared by an esterification reaction of dihydrobenzoic acid with an alcohol R ₁ OH, followed by an alkylation reaction with an alkyl halide R ₂ X, according to conventional methods.

According to a particularly preferred embodiment, in the case where R ₂ = H, the compounds of formula (I) are prepared according to the following steps: 1) esterification of 2-hydroxy-4- [2-hydroxyimino-2 acid - (5,5,8,8-tetra ~ methyl-

5,6,7,8-tetrahydro-naphthalen-2-yl) -ethoxy] -benzoic acid of formula 1 in the presence of sulfuric acid and an alcohol R ₁ OH; and 2) reacting the ester obtained in step 1) with a mixture of hydroxylamine hydrochloride and pyridine in a polar solvent. This embodiment is illustrated in particular by the synthesis diagram of FIG. 2.

The compound (I) thus prepared and, if appropriate, the intermediates 2 and 5 can be recovered from the reaction mixture by conventional means. For example, the compounds can be recovered by distilling the solvent from the reaction mixture or if necessary after distilling the solvent from the solution mixture, pouring the remainder into water followed by extraction with an organic solvent immiscible in the reaction mixture. water, and distilling the solvent from the extract. In addition, the product may, if desired, be further purified by various techniques, such as recrystallization, reprecipitation or various chromatography techniques, including column chromatography or preparative thin layer chromatography.

The subject of the present invention is also the compounds of formula (I) as described above as a medicament. According to another aspect, the invention relates to a pharmaceutical or cosmetic composition characterized in that it comprises in a pharmaceutically or cosmetically acceptable vehicle at least one compound of formula (I) above.

By "pharmaceutically or cosmetically acceptable vehicle" is meant a suitable vehicle for use in contact with cells of humans and animals, without toxicity, irritation, undue allergic response and the like, and proportionate to a reasonable risk / benefit ratio .

Administration may be topical, enteral or oral, parenteral or ocular.

Among these routes of administration, the topical route is particularly preferred. Topically, the pharmaceutical composition according to the invention is more particularly intended for the treatment of the skin and mucous membranes and may be in liquid, pasty or solid form, and more particularly in the form of ointments, creams, milks , ointments, powders, soaked swabs, syndets, solutions, gels, sprays, mousses, suspensions, sticks, shampoos, or washing bases. It may also be in the form of suspensions of microspheres or nanospheres or lipid or polymeric vesicles or polymeric or gelled patches allowing controlled release.

The compounds are used topically at a concentration generally of between 0.001% and 3% by weight, relative to the total weight of the composition.

For a cosmetic application, the composition is preferably in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or lipid or polymeric vesicles, a soap, a shampoo.

By enteral or oral route, the composition may be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, suspensions of 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 according to the invention are generally administered at a daily dose of about 0.01 mg / kg to 30 mg / kg of body weight, in 1 to 3 doses. The compounds according to the invention can advantageously act as prodrugs.

The term "prodrugs" means that the compounds are transformed in vivo to give the parent compound, 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7, 8-tetrahydro-naphthalen-2-yl) -ethoxy] -benzoic, by hydrolysis in the human or animal body. (Prodrugs, Drugs and the Pharmaceutical Sciences, Kenneth B. Sloan 53, p

152).

The compounds of the invention are useful, alone or in admixture, for the preparation of a pharmaceutical or cosmetic composition wherein said compound is an agent exerting selective RAR gamma receptor agonist activity.

The invention also relates to a method of therapeutic or cosmetic treatment, comprising the administration of a pharmaceutical or cosmetic composition comprising such a compound, as an agent exerting a selective agonist activity of the RAR gamma receptor.

The pharmaceutical composition may be more particularly intended to treat a pathology for the treatment of which a selective agonist activity of the RAR gamma receptor is desired.

The composition is also useful for the treatment of a pathology related to the disorders of cell differentiation or proliferation, particularly in the field of dermatology.

More particularly, it is useful for the treatment of a pathology related to a disorder of keratinization.

The treatment of acne is thus envisaged, in particular vulgar, comedonal, polymorphic acne, nodulocystic acne, conglobata, senile acnes, secondary acne such as solar acne, medicated, professional acne.

The pharmaceutical composition comprising a compound of the invention is also useful for treating other dermatological conditions related to a disorder of keratinization with an inflammatory and / or immunoallergic component and, in particular, all forms of psoriasis, whether cutaneous , mucous or ungueal. The compounds of the invention are also useful in a cosmetic composition for combating cutaneous aging, whether it is for example photoinduced or chronological.

The pharmaceutical or cosmetic composition also makes it possible to reduce skin pigmentations and to treat actinic keratoses.

In all the envisaged applications, the compound of the invention may be combined with another therapeutic agent useful in the treatment of a pathology related to the disorders of cell differentiation or proliferation.

The following examples illustrate the invention without limiting it. The starting materials used are known products or prepared according to known procedures.

In the examples below, the samples were analyzed by ¹ H NMR and ¹³ C NMR, HPLC / MS.

Example 1 Synthesis of 2-hydroxy-4-hydroxy-2-hydroxy-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -ethoxylbenzoate ethyl

a) Ethyl 2-hydroxy-4- [2-oxo-2- (5, 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -ethoxy] benzoate

5 g (13 mmol) of 2-hydroxy-4- [2-oxo-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) - ethoxy] -benzoic acid are dissolved in 10O mL of absolute ethanol. 1 ml of concentrated sulfuric acid are added, and the reaction mixture is stirred at reflux temperature for 24 hours. After hydrolysis and extraction with ethyl acetate, the organic phase is dried and concentrated, and the residue is purified by chromatography (eluent heptane 95, AcOEt 5). A yellow oil is obtained (3.9 g, R = 73%).

b) ethyl 2-Hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -ethoxy] -benzoate

3.9 g (9.5 mmol) of 2-hydroxy-4- [2-oxo-2- (5,5,8,8-tetramethyl) -5,6,7,8-tetrahydronaphthalen-2-yl) ethoxy) -benzoate are dissolved in 100 mL of THF and 100 mL of methanol. 3.9 mL (47.5 mmol) of pyridine and then 3.3 g (47.5 mmol) of hydroxylamine hydrochloride are added, and the mixture is stirred at reflux temperature for 1h30.

The reaction medium is treated with a 1N hydrochloric acid solution, extracted with ethyl acetate. The residue obtained after drying and concentration is purified by chromatography on a silica column (eluent heptane 95 / EtOAc 5). Two products are obtained: the syn isomer (white solid, mp 130 ^° C., m = 2.4 g, R = 59%), ¹ H NMR (CDCl ₃ ): 1.29 (s, 12H); 1, 39-1, 42 (t, J = 8Hz, 3H); 1.69 (s, 4H); 4.40 (q, J = 8Hz, 2H); 5.29 (s, 2H); 6.48 (dd, J1 = 4Hz, J2 = 8Hz, 1H); 6.57 (s, 1H); 7.30-7.32 (m, 1H); 7.40-7.42 (m, 1M); 7.61 (s, 1H); 7.74-7.76 (d, J = 8Hz, 1H); 8.20 (s, 1H); 11.0 (s, 1H) and the anti isomer (white solid, mp = 155 ° C, m = 0.5 g, R = 12%) ¹ H NMR (CDCl ₃ ): 1.27 (s, 6H); 1, 30 (s, 6H); 1.39-1.43 (t, J = 8Hz, 3H); 1.7 (s, 4H); 4.36-4.42 (q, J = 8Hz, 2H); 4.92 (s, 2H); 6.4-6.52 (m, 1H); 6.55-6.56 (s, 1H); 7.35-7.42 (m, 2H); 7.58 (s, 1H); 7.63 (s, 1H); 7.76-7.78 (d, J = 8Hz, 1H); 11 (s, 1H).

Example 2: Isopropyl 2-hydroxy-4-hydroxy-2-hydroxy-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -ethoxy-benzoate

a) Isopropyl 2-hydroxy-4- [2-oxo-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -ethoxy] benzoate

In a similar manner to Example 1a, by reacting 1.9 g (5 mmol) of 2-hydroxy-4- [2-oxo-2- (5,5,8,8-tetramethyl) -5, 6,7,8-tetrahydro-naphthalen-2-yl) -ethoxy] benzoic acid in 50 mL of isopropanol. A brown oil is obtained (m = 660 mg, R = 32%).

b) Isopropyl 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -ethoxy] -benzoate In a similar manner to Example 1b, by reaction of 660 mg (1.5 mmol) of 2-hydroxy-4- [2-oxo-2- (5,5,8,8-tetramethyl) -5,6,7 Isopropyl 8-tetrahydro-naphthalen-2-yl) -ethoxy-benzoate with 0.54 g (78 mmol) of hydroxylamine hydrochloride and 0.6 ml of pyridine. Two products are obtained: the syn isomer (white solid, mp 130 ° C., m = 600 mg, R = 88%), ¹ H NMR (CDCl ₃ ): 1.28 (s, 12H); 1, 37-1, 38 (d, J = 6.25, 6H), 2.19 (s, 4H); 5.29 (m, 3H); 6.49 (m, 1H); 6.57 (s, 1H); 7.29-7.31 (m, 1H); 7.40 (m, 1H); 7.61 (s, 1H); 7.72-7.75 (d, J = 8Hz, 1H); 8.45 (s, 1H); 11 (s, 1H) and the anti isomer (white solid, mp = 149 ° C, m = 70 mg, R = 5%) ¹ H NMR (CDCl ₃ ): 1.27 (s, 6H); (S, 6H); 1.38-1.39 (d, J = 6.24Hz, 6H); 1.70 (s, 4H); 4.9 (s, 2H); 5.25-5.29 (m, 1H); 6.48-6.51 (m, 1H); 6.55 (s, 1H); 7.35-7.42 (m, 2H); 7.58 (s, 1H); 7.59-7.61 (m, 1H); 7.74-7.77 (d, J = 8Hz, 1H), 11 (s, 1H). EXAMPLE 3 Synthesis of 2-hydroxy-4-hydroxy-2- (5,5,8,8-tetramethyl-5,6J, 8-tetrahydro-naphthalen-2-yl) -ethoxy-benzoate-bis-butyl benzoate

a) Isobutyl 2-hydroxy-4- [2-oxo-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -ethoxy] benzoate

In a similar manner to Example 1a, by reacting 1.9 g (5 mmol) of 2-hydroxy-4- [2-oxo-2- (5,5,8,8-tetramethyl) -5,6-acid, , 7,8-tetrahydro-naphthalen-2-yl) -ethoxy] -benzoic acid in 50 ml of isobutanol. A brown oil is obtained (m = 1.7 g, R = 79%).

b) Isobutyl 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -ethoxy] -benzoate

In a similar manner to Example 1b, by reaction of 1.7 g (3.9 mmol) of 2-hydroxy-4- [2-oxo-2- (5,5,8,8-tetramethyl-5,6) Isobutyl-7,8-tetrahydro-naphthalen-2-yl) -ethoxy-benzoate with 1. 4 g (20 mmol) of hydroxylamine hydrochloride and 1.6 ml of pyridine. Two products are obtained: the syn isomer (white solid, mp 96 ° C., m = 1.2 g, R = 70%), ¹ H NMR (CDCl ₃ ): 1, 02-1, 04 (d, J). = 8Hz, 6H); 1, 29 (s, 12H); 1.69 (s, 4H); 2.1-2.2 (m, 1H); 4.10-4.12 (d, J = 8 Hz, 2H); 5.29 (s, 2H); 6.48-6.50 (dd, J = 8Hz, 1H); 6.58 (s, 1H); 7.30-7.32 (m, 1H); 7.40-7.42 (m, 1H); 7.62 (s, 1H); 7.75-7.77 (d, J = 8 Hz, 1H); 8.21 (s, 1H); 11 (s, 1H) and the anti isomer (white solid, mp = 156 ° C, m = 130 mg, R = 7%) ¹ H NMR (CDCl ₃ ): 1.03-1.05 (d, J = 6.7Hz, 6H); 1, 28 (s, 6H); 1.30 (s, 6H); 1.70 (s, 4H); 2.08-2.11 (m, 1H); 4.11-4.12 (d, J = 6.7 Hz, 2H); 4.9 (s, 2H); 6.5-6.52 (m, 1H); 6.56 (s, 1H); 7.35-7.42 (m, 2H); 7.59 (s, 1H); 7.66 (s, 1H); 7.76-7.78 (d, J = 8Hz, 1H); 11 (s, 1H).

Example 4 Transactivation Test

a) Principle of the test:

Activation of the receptors 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 therefore be measured by quantifying the luminescence produced after incubation of the cells in the presence of a reference antagonist. The activating products move the antagonist of its site thus allowing the activation of the receptor. The measurement of the activity is done by the quantification of the increase of the light produced. This measurement makes it possible to determine the activating activity of the compound useful in the invention. In this study, a constant is determined which 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 apparent Kd (KdApp).

To determine this constant, "cross-curves" of the test product (2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl) -5,6,7,8- tétrahydronaphthalèn-

2-yl) -ethoxy] -benzoic acid), against a reference antagonist otherwise named reference ligand, 4- (5,5-Dimethyl-8-p-tolyl-5,6-dihydro-naphthalen-2- ylethynyl) -benzoic acid are produced. The test product is used at 10 concentrations and the reference antagonist at 7 concentrations. In each well (of a 96-well plate), the cells are in contact with a concentration of the test product and a concentration of the reference antagonist.

Measurements are also made for total agonist controls otherwise called 100% control (4- [2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) propenyl] - benzoic acid) and reverse agonist otherwise designated 0% control, 4 - {(E) -3- [4- (4-tert-Butyl-phenyl) -5,5,8,8-tetramethyl-5,6, 7,8-tetrahydro-naphthalen-2-yl] -3-oxo-propenyl} -benzoic acid.

These crossed curves make it possible to determine the AC50 (concentration at which one observes 50% activation) of the reference ligand at different concentrations of product to be tested. These AC50s are used to calculate the Schild regression by plotting a line corresponding to the Schild equation ("quantitation in receptor pharmacology").

Terry P.Kenakin, Receptors and Channels, 2001, 7, 371-385).

In the case of an agonist, IΑC50 (concentration giving 50% of the activity) is calculated by plotting the product curve at the concentration of the reference ligand giving 80% activation. The activation percentage corresponding to the maximum level of activity obtained is also measured.

b) Materials and Method:

The HeLa cell lines used are stable transfectants containing the ERE-βGlob-Luc-SV-Neo plasmids (reporter gene) and RAR (α, β, Y) ER-DBD-puro. These cells are inoculated into 96-well plates at the rate of 10,000 cells per well in

100μl of DMEM medium without phenol red and supplemented with 10% delipidated calf serum. The plates are then incubated at 37 ° C, 7% CO ₂ for 4 hours.

The different dilutions of the product to be tested, the reference ligand (4- (5,5-dimethyl-8-p-tolyl-5,6-dihydro-naphthalen-2-ylethynyl) -benzoic acid), of the control 100 % (4- [2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) propenyl] -benzoic acid

100 nM) and control 0% (4 - {(E) -3- [4- (4-tert-butyl-phenyl) -5,5,8,8-tetramethyl) 5,6,7,8-tetrahydro-naphthalen-2-yl] -3-oxo-propenyl} -ben2oic 500 nM) are added at a rate of 5 .mu.l 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 mixture of 1: 1 PBS (phosphate buffer solution) / Luciferine is added to each well. After 5 minutes, the plates are read by the luminescence reader.

c) Results:

The values of the apparent Kd constants are shown in the table below.

The results obtained with 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) -ethoxy] -benzoic acid show a high specificity of this compound for the RARgamma receptor subtype in comparison with the other two subtypes RARaipha and RARbeta.

2-Hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -ethoxy] benzoic acid is a agonist or selective activator of the RARgamma receptor.

Example 5: Irritation test

The irritancy of ethyl ester and isobutyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl) -5,6,7,8- Tetrahydronaphthalen-2-yl) -ethoxy] -benzoic acid (compounds of Examples 1 and 3 respectively) is evaluated by single topical application to the ear in BALB / c mice. The mice (ByJlco) are female mice aged 8 weeks. A batch of 5 mice is tested.

20 μl of the product to be tested, in acetone, is applied to the right ear on D1. The thickness of the ear is measured at Oditest at times J4, J5, J6, J7, J8 and J11.

Neither of the two compounds tested induced irritation at the tested doses of 0.003% to 0.01%.

Claims

1. Compound of formula (I):

in which :

R 1 represents an alkyl radical having from 2 to 20 carbon atoms,

an alkenyl radical having from 2 to 20 carbon atoms,

a mono- or polyhydroxyalkyl radical having from 1 to 6 carbon atoms,

- a sugar residue, or

an amino acid residue,

R ₂ represents a hydrogen atom or an alkyl having 1 to 3 carbon atoms, and the salts of the compounds of formula (I), when R 1 represents an amino acid residue and the isomers of the compounds of formula (I).

2. Compound according to claim 1, characterized in that the alkyl radical of 2 to 20 carbon atoms is chosen from the group consisting of ethyl, isopropyl, n-propyl, tert-butyl, n-butyl and n-pentyl radicals. , n-hexyl, n-heptyl and n-octyl.

3. Compound according to claim 1, characterized in that the alkenyl radical of 2 to 20 carbon atoms is chosen from the group consisting of vinyl, allyl, 2-butenyl, n-butenyl and 3-methylbut-2-one radicals. enyl, n-pentenyl, hexenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.

4. Compound according to claim 1, characterized in that the monohydroxyalkyl radical is selected from the group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyhexyl radicals. 5. Compound according to claim 1, characterized in that the polyhydroxyalkyl radical is chosen from the group consisting of the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4-radical,

5-tetrahydroxypentyl.

6. Compound according to claim 1, characterized in that the sugar residue is chosen from the group consisting of 6-glycosyl, 6-galactosyl and 6-mannosyl radicals.

7. Compound according to claim 1, characterized in that an amino acid residue is selected from the group consisting of the serine, tyrosine and threonine radicals.

8. Compound according to any one of the preceding claims, characterized in that R ₂ is a hydrogen atom.

9. Compound according to any one of the preceding claims, characterized in that it is one of the following compounds:

1) ethyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) -ethoxy] -benzoic acid; 2) isopropyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl)

5,6,7,8-tetrahydronaphthalen-2-yl) -ethoxy] -benzoic acid; 3) isobutyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl)

5,6,7,8-tetrahydronaphthalen-2-yl) -ethoxy] -benzoic acid;

6) the hexyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) -ethoxy] -benzoic acid;

7) the heptyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) -ethoxy] -benzoic acid; 8) the hept-6-enyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl) -5,6,7,8-tetrahydronaphthalene 2-yl) -ethoxy] -benzoic acid;

9) 2,3-Dihydroxypropyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl) -5,6,7,8-tetrahydronaphthalene-2 -yl) -ethoxy] -benzoic acid;

11) 6-Galactosyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) ) -ethoxy] -benzoic acid; 12) 6-glucosyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) ) -ethoxy] -benzoic acid;

13) 6-mannosyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) ) -ethoxy] -benzoic acid; 14) 2-amino-2-carboxyethyl ester of 2-hydroxy-4- [2-hydroxyimino-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene) -2-yl) -ethoxy] -benzoic acid;

15) 4- (2-Amino-2-carboxyethyl) -phenyl ester of 2-hydroxy-4- [2-hydroxy-imino-2- (5,5,8,8-tetramethyl) -5,6,7,8-tétrahydronapritrιalèn-2-yl) -ethoxy] -benzoic acid;

A compound according to any one of the preceding claims as a medicament.

11. A pharmaceutical or cosmetic composition comprising, in a suitable pharmaceutically or cosmetically acceptable vehicle, at least one compound of formula (I) according to claims 1 to 9.

12. Pharmaceutical or cosmetic composition according to claim 11, characterized in that it is in a form suitable for topical administration.

13. Pharmaceutical or cosmetic composition according to claim 11, for combating cutaneous aging.

14. Use of a compound of formula (I) as defined in one of claims 1 to 9, for the preparation of a pharmaceutical composition for the treatment of which a selective agonist activity of the RAR gamma receptor is desired.

15. The use according to claim 14, for the treatment of a pathology related to the disorders of cell differentiation or proliferation.

16. Use according to claim 14, for the treatment of a pathology related to a disorder of keratinization.

17. Use according to claim 14 for the treatment of acne.

18. Use according to claim 15 for the treatment of psoriasis.

19. Process for preparing a compound of formula (I) according to claims 1 to 9, comprising a step of converting the ketone function of the compound of formula 3

³ wherein: R ₁ represents: - an alkyl radical having from 2 to 20 carbon atoms,

an alkenyl radical having from 2 to 20 carbon atoms,

a mono- or polyhydroxyalkyl radical having from 1 to 6 carbon atoms,

- a sugar residue, or

an amino acid residue,

20. The method of claim 19, characterized in that the oxime is prepared by reaction of the compound 3 with a mixture of hydroxylamine halohydrate and pyridine.

21. Method according to any one of claims 19 or 20, characterized in that the compound 3 is prepared according to a process comprising a step of alkylation of the compound 2 in the presence of a halide R ₂ X, where R ₂ represents an alkyl group having 1 to 3 carbon atoms and X represents a halogen atom.