WO2007039821A2

WO2007039821A2 - Novel inhibitors of tyrosinase, their method of preparation and their use in human medicine and in cosmetics

Info

Publication number: WO2007039821A2
Application number: PCT/IB2006/003208
Authority: WO
Inventors: Jean-Claude Yadan; Irène ERDELMEIER; Itaru Suzuki; Philippe Diaz
Original assignee: Galderma Research & Development
Priority date: 2005-08-31
Filing date: 2006-08-29
Publication date: 2007-04-12
Also published as: WO2007039821A3

Abstract

The present invention relates to novel compounds corresponding to the following general formula (I): to compositions containing them, and to their use in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.

Description

Novel inhibitors of tyrosinase, their method of preparation and their use in human medicine and in cosmetics

The invention relates to novel compounds that are inhibitors of tyrosinase, for use in the area of pigmentation. It also relates to their method of preparation and their use in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions and the nontherapeutic use of the latter.

The pigmentation of the human skin results from the synthesis of melanin by dendritic cells, the melanocytes. The latter contain organelles called melanosomes, in which the biosynthesis of melanin takes place. It is the melanosomes which, after migration along the dendrites, are transferred from the melanocytes to the keratinocytes. The keratinocytes are then transported to the surface of the skin in the course of the process of differentiation of the epidermis (Gilchrest BA, Park HY, Eller MS, Yaar M, Mechanisms of ultraviolet light-induced pigmentation. Photochem Photobiol 1996; 63: 1-10; Hearing VJ, Tsukamoto K, Enzymatic control of pigmentation in mammals. FASEB J 1991 ; 5: 2902-2909).

Among the enzymes of melanogenesis, tyrosinase is a key enzyme which catalyses the first two stages of melanin synthesis. Homozygous mutations of tyrosinase cause type I oculocutaneous albinism characterized by complete absence of melanin synthesis (Toyofuku K, Wada I, Spritz RA, Hearing VJ, The molecular basis of oculocutaneous albinism type 1 (OCA1): sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. Biochem J 2001; 355: 259-269).

Since hyperpigmentation disorders result from increased production of melanin, it is proving to be important to develop new therapeutic approaches whose rationale is based on inhibition of tyrosinase activity.

Most of the skin lightening compounds already known are phenols/catechols. These compounds inhibit tyrosinase but the majority of these compounds are cytotoxic to melanocytes, which might cause permanent depigmentation of the skin.

For application in humans it would therefore be useful to have at our disposal novel tyrosinase-inhibiting compounds possessing both good efficacy and good tolerance.

Application FR0504444 discloses tyrosinase-inhibiting compounds having a thioimidazole monomeric structure. The publication of Hauser et al ("1-hydroxyimidazole derivatives Il Synthesis and Reactions of 1-benzyloxy-2,3-dihydroimidazole-2-thione. Preparation of 1-benzyloxy-1H- imidazoles" Scientia Pharmaceutica 56, 235-241, 1988) describes the synthesis of 1- aralkyloxyimidazole compounds; bis-(1-benzyloxy-1H-2-imidazolyl)disulphide is mentioned.

The applicant discovered, surprisingly and unexpectedly, novel dimeric compounds possessing tyrosinase-inhibiting activity and low toxicity. These compounds find applications in human medicine, notably in dermatology, and in the cosmetics area.

Thus, the present invention relates to compounds corresponding to the following general formula (I):

in which:

R1 represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, an aryl radical or an aralkyl radical.

R2 and R3, which may be identical or different, represent a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms or an aryl radical,

With the exception of bis-(1-benzyloxy-1H-2-imidazolyl)disulphide, i.e. when R2 and R3 are identical and represent a hydrogen atom, and R1 is a non substituted benzyl radical.

According to the present invention, alkyl having from 1 to 6 carbon atoms means a linear or branched alkyl radical having from 1 to 6 carbon atoms, preferably the methyl, ethyl, propyl (such as n-propyl, i-propyl, c-propyl), butyl (such as n-butyl, i-butyl, t-butyl), pentyl (such as n-pentyl) or hexyl (such as n-hexyl) radicals. By aryl radical, we mean an aromatic radical such as phenyl, biphenyl, or naphthyl, or heteroaromatic such as notably thiophenyl, pyridinyl, pyrimidyl, imidazole, triazole, optionally fused with one or more other rings and optionally mono- or di-substituted with one or more atoms, groups, functions or radicals selected from a halogen atom, a CF₃ radical, an alkyl radical, an alkoxyl radical, a nitro function, an alkyl ester group, a nitrile function, an amide function, a carboxyl function, a hydroxyl radical, an amino function optionally substituted with at least one alkyl radical.

Preferably, the aryl radical is selected from the unsubstituted phenyl radical and the phenyl radical substituted with at least one halogen atom or a nitro function. Preferably, the aryl radical is phenyl, 3,5-difluorophenyl, 4-fluorophenyl, 3-nitrophenyl or 4- nitrophenyl.

By aralkyl radical, we mean a -(CH₂)n-aryl radical such as benzyl, phenethyl or naphthalen-2-ylmethyl or heteroaromatic radical such as notably thiophene-methyl, pyridine-methyl, pyrimidyl-methyl, optionally mono or di-substituted with one or more atoms, groups, functions or radicals selected from a halogen atom, a CF₃ radical, an alkyl radical, an alkoxyl radical, a nitro function, an alkyl ester group, a nitrile function, an amide function, a carboxyl function, a hydroxyl radical, an amino function optionally substituted with at least one alkyl radical.

Preferably, the aralkyl radical is selected from the unsubstituted benzyl radical, the benzyl radical substituted with at least one halogen atom, and the unsubstituted 3-pyridine- methyl radical. Preferably, the aralkyl radical is benzyl, 3,5-difluorobenzyl or 3-pyridine- methyl.

By alkoxyl radical, we mean preferably a radical containing from one to seven carbon atoms such as the methoxy, ethoxy, isopropyloxy, tert-butoxy, hexyloxy, benzyloxy or phenoxy radicals, which can optionally be substituted with an alkyl radical having from 1 to 12 carbon atoms.

By halogen atom, we mean preferably an atom of fluorine, bromine or chlorine.

According to the present invention, compounds of formula (I) that are more particularly preferred are those for which at least one, and preferably all of the following conditions are met: - R1 represents a hydrogen atom,

- R2 represents a hydrogen atom or an aryl radical, notably phenyl, substituted or unsubstituted,

- R3 represents a hydrogen atom or an aryl radical, notably phenyl, substituted or unsubstituted.

According to the present invention, the compounds of formula (I) more particularly preferred are those for which at least one, and preferably all of the following conditions are met:

- R1 represents an aralkyl radical,

- R2 represents a hydrogen atom,

According to the present invention, compounds of formula (I) that are more particularly preferred are those for which at least one, and preferably all of the following conditions are met:

- R1 represents an alkyl radical having from 1 to 6 carbon atoms,

- R2 represents a hydrogen atom or an aryl radical, notably phenyl, substituted or unsubstituted, or an alkyl radical having from 1 to 6 carbon atoms,

- R3 represents a hydrogen atom or an aryl radical, notably phenyl, substituted or unsubstituted, or an alkyl radical having from 1 to 6 carbon atoms.

- R1 represents an aryl radical,

- R2 represents a hydrogen atom,

- R3 represents a hydrogen atom.

Among the compounds of formula (I) falling within the scope of the present invention, the following may notably be mentioned:

2-1(1 -Hydroxy-5-phenyM H-imidazol-2-yi)-dithio]-5-phenyl-1 H-imidazol-1 -ol

2-[(1-Hydroxy-4-phenyl-1H-imidazol-2-yl)-dithio]-4-phenyl-1 H-imidazol-1-ol

2-[(1-Hydroxy-4-(3',5'-difluorophenyl)-1H-imidazol-2-yl)-dithio]-4-(3^I,5'-difluorophenyl)-1H- imidazol-1-ol

2-[(1 -Hydroxy-5-(4'-fluorophenyl)-1 H-imidazol-2-yl)-dithio]-5-(4'-fluorophenyl)-1 H- imidazol-1-ol

2-[(1 -Hydroxy-4-(4'-nitrophenyl)-1 H-imidazol-2-yl)-dithio]-4-(4'-nitrophenyl)-1 H-imidazol-1 - ol

2-[(1 -Benzy!oxy-1 H-imidazol-2-yl)-dithio]-1 -benzyloxy-1 H-imidazole

2-[(1-Methoxy-1H-imidazol-2-yl)-dithio]-1-methoxy-1H-imidazole

2-[(1-((3'-Pyridine)methyloxy)-1H-imidazol-2-yl)dithio]-1-((3'-pyridine)methyloxy-1H- imidazole

2-[(1 -Benzyloxy-4-phenyl-1 H-imidazol-2-yl)-dithio]-1 -benzyloxy-4-phenyl-1 H-imidazole

2-[(1 -Methoxy-5~phenyl-1 H-imidazol-2-yl)-dithio]-1 -methoxy-5-phenyl-1 H-imidazole

2-[(1 -Methoxy-4-phenyl-1 H-imidazol-2-yl)-dithio]-1 -methoxy-4-phenyl-1 H-imidazole

2-[(1 -Methoxy-4(5)-phenyl-1 H-imidazol-2-yl)-dithio]-1-methoxy-4(5)-phenyl-1 H-imidazole

2-[(1-Ethoxy-5-phenyl-1 H-imidazol-2-yl)-dithio]-1-ethoxy-5-phenyl-1 H-imidazole

2-[(1 -Ethoxy-4(5)-phenyl-1 H-imidazol-2-yl)-dithio]-1 -ethoxy-4(5)-phenyl-1 H-imidazole

2-[(1 -Ethoxy-4(5)-methyl-1 H-imidazol-2-yl)-dithio]-1 -ethoxy-4(5)-methyl-1 H-imidazole

2-[(1-Ethoxy-5-methyl-1H-imidazol-2-yl)-dithio]-1-ethoxy-5-methyl-1 H-imidazole

2-[(1-Hydroxy-4(5)-phenyl-1H-imidazol-2-yl)-dithio]-4(5)-phenyl-1 H-imidazol-1 -ol

2-[(1 -(3',5'-Difluorobenzyloxy)-1 H-imidazol-2-yl)-dithio]-3',5'-difluorobenzyloxy-1 H- imidazole

2-[(1 -Hydroxy-4-(3'-nitrophenyl)-1 H-imidazol-2-yl)-dithio]-4-(3'-nitrophenyl)-1 H-imidazol-1 - ol

2-[(1 -Hydroxy-5-(3'-nitrophenyl)-1 H-imidazol-2-yl)-dithio]-5-(3'-nitrophenyl)-1 H-imidazol-1 - ol

The present invention also relates to the method of preparation of the dimeric compounds of formula (I); this method comprises the dimerization, to disulphide, of thiol monomers (N-hydroxyimidazolethiol derivatives) by an oxidative route.

The N-hydroxyimidazolethiol derivatives (called monomers) are obtained according to the method described in application FR0504444, comprising the following main stages: A. When R1 is equal to H: 1. A 37% aqueous formaldehyde solution and then an aqueous solution of hydroxylamine hydrochloride are added successively, dropwise, at low temperature to an arylglyoxal derivative, commercially available or obtained according to known methods, in a polar solvent. A solution of hydrochloric acid is added dropwise, at this temperature. After leaving the reaction mixture to return to room temperature and to react for 2-72 h, the suspension obtained is filtered. The dried precipitate corresponds to the mixture of the two tautomers of 4(5)-aryl-3-oxy-imidazol-1-ol;

2. The compound obtained previously is treated at low temperature with an α,α'- disubstituted alkylthione such as tetramethyl-1 ,3-cyclobutadithione, tetramethyl-1,3-cyclobutan-2-one-4-thione or adamantyl thione. After stirring for some hours, the reaction mixture is filtered. The precipitate comprises the 4- and 5-aryl isomers. The desired compound is obtained by liquid chromatography on silica gel or by recrystallization of the aforementioned precipitate.

B. When R1 is different from H:

1. A 37% aqueous formaldehyde solution and then an aqueous solution of hydroxylamine hydrochloride are added successively, dropwise, at low temperature to an arylglyoxal derivative, commercially available or obtained according to known methods, in a polar solvent. A solution of hydrochloric acid is added dropwise, at this temperature. After leaving the reaction mixture to return to room temperature and to react for 2-72 h, the suspension obtained is filtered. The dried precipitate corresponds to the mixture of the two tautomers of the desired product;

2. The derivative obtained in the preceding stage is alkylated in the presence of a base and an alkylating agent;

3. The aforementioned derivative is reduced using a reducing agent such as titanium chloride in the presence of a mineral acid such as hydrochloric acid or a hydride such as sodium borohydride in an organic solvent at low temperature;

4. The aforementioned derivative is treated with butyl lithium in an organic solvent at very low temperature then reacted with sulphur S8. The final product is obtained after purification.

By polar solvent, we mean any solvent with polarity greater than that of acetone. By organic solvent, we mean any solvent other than water. By alkylating agent we mean notably the trialkyloxonium derivatives, alkyl sulphate, alkyl halide.

By low temperature, we mean a temperature between -30 and 15°C.

By very low temperature, we mean a temperature between -80 and -30°C.

The dimerization, to disulphide, of the thiol monomers thus obtained comprises the following main stages: a) suspending the N-hydroxyimidazolethiol derivative (monomer) in an aqueous solution of acid.

This solution of acid is notably a solution of nitric acid (HNO₃), or of sulphuric or hydrochloric acid, preferably at concentration of 3N. Preferably, the solution of acid is a solution of nitric acid. Preferably, the solution of monomer obtained has a concentration equal to 0.5M; b) adding, to the suspension obtained in a), preferably dropwise, a solution of oxidizing agent preferably selected from sodium nitrite, a hydroperoxide, a peroxide such as hydrogen peroxide, and sodium hypochlorite, in the same acid as used in a). This solution is preferably a solution of sodium nitrite in HNO₃, of concentration equal to that of the monomer in the acid, preferably 0.5M; c) stirring the mixture, until a precipitate is obtained. Preferably, mixing is carried out at room temperature and for a time between 5 and 22 hours; d) the precipitate obtained in c) is filtered and then rinsed with water; e) in order to increase the purity, the precipitate obtained in d) is optionally recrystallized from a polar solvent of the alcohol type, such as ethanol, methanol, isopropanol, preferably methanol, and filtered again to obtain the corresponding dimer of formula (I).

By room temperature, we mean a temperature between 20 and 25°C.

The compounds according to the invention as well as bis-(1-benzyloxy-1H-2- imidazolyl)disulphide display tyrosinase inhibiting properties. This activity is measured in an enzymatic test by the inhibition constant IC50 (dose inhibiting 50% of enzyme activity). By tyrosinase inhibitor, we mean according to the invention any compound displaying an inhibition constant with respect to the enzymes tyrosine hydroxylase and DOPA oxidase less than or equal to 500 μM, in an enzymatic test such as described in Example 6. The preferred compounds of the present invention display an inhibition constant less than or equal to 100 μM, and advantageously less than or equal to 10 μM. The present invention also relates to the compounds of formula (I) as described above or bis-(1-benzyloxy-1 H-2-imidazolyl)disulphide as a medicinal product. The compounds of formula (I) as described above or bis-(1-benzyloxy-1H-2-imidazolyl)disulphide can notably be used as depigmenting agents.

The compounds used according to the invention as well as bis-(1-benzyloxy-1H-2- imidazolyl)disulphide are particularly suitable for the treatment and for the prevention of hyperpigmentation disorders such as melasma, chloasma, lentigo, lentigo senilis, vitiligo, freckles, post-inflammatory hyperpigmentations due to an abrasion and/or a burn and/or a scar and/or a dermatosis and/or a contact allergy; nevi, genetically determined hyperpigmentations, hyperpigmentations of metabolic origin or drug-induced, melanomas or all other hyperpigmentation lesions.

The present invention also relates to a pharmaceutical composition containing, in a physiologically acceptable carrier, at least one compound chosen from compounds of formula (I) as defined above and bis-(1-benzyloxy-1 H-2-imidazolyI)disulphide.

By physiologically acceptable carrier, we mean a medium that is compatible with the skin and optionally with its appendages (eyelashes, nails, hair) and/or the mucosae.

The present invention also relates to a novel medicinal composition intended notably for the treatment of the aforementioned disorders, and which is characterized in that it contains, in a pharmaceutically acceptable carrier, compatible with the method of administration adopted for the latter, at least one compound chosen from compounds of formula (I) and bis-(1-benzyloxy-1H-2-imidazolyl)disulphide.

The composition according to the invention can be administered by the oral, enteral, parenteral, topical or ocular route. Preferably, the pharmaceutical composition is packaged in a form suitable for topical application.

For the oral route, the composition can be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, suspensions of microspheres or nanospheres or lipid or polymer vesicles permitting controlled release. For the parenteral route, the composition can be in the form of solutions or suspensions for perfusion or for injection.

The compounds according to the invention are generally administered at a daily dose of about 0.01 mg/kg to 100 mg/kg of body weight, in 1 to 3 doses.

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

For the topical route, the pharmaceutical composition according to the invention is more particularly intended for the treatment of the skin and of the mucosae and can be in the form of liquid, paste, or solid, and more particularly in the form of salves, creams, milks, ointments, powders, moistened tampons, syndets, solutions, gels, sprays, mousses, suspensions, sticks, shampoos, or washing bases. It can also be in the form of suspensions of microspheres or nanospheres or of lipid or polymer vesicles or of polymeric or gelled patches for controlled release.

The compounds are used topically at a concentration generally between 0.001 and 10 wt.%, preferably between 0.01 and 3 wt.% relative to the total weight of the composition.

The compounds of formula (I) according to the invention as well as bis-(1 -benzyloxy-1 H- 2-imidazolyl)disulphide also find application in cosmetics, in particular for protection against the harmful effects of the sun, for preventing and/or combating photo-induced or chronological aging of the skin and its appendages.

The invention therefore also relates to a composition containing, in a cosmetically acceptable carrier, at least one compound chosen from compounds of formula (I) and bis- (1 -benzyloxy-1 H-2-imidazolyl)disulphide.

By cosmetically acceptable carrier, we mean a medium that is compatible with the skin and optionally with its appendages (eyelashes, nails, hair) and/or the mucosae.

The invention also relates to the cosmetic use of a composition containing at least one compound chosen from compounds of formula (I) and bis-(1 -benzyloxy-1 H-2- imidazolyl)disulphide for preventing and/or treating the signs of aging. The invention also relates to the use, notably cosmetic, of a compound of formula (I) or of bis-(1-benzyloxy-1 H-2-imidazolyl)disulphide for the preparation of a depigmenting composition.

The invention also relates to the cosmetic use of a composition containing at least one compound chosen from compounds of formula (I) and bis-(1-benzyloxy-1H-2- imidazolyl)disulphide for the care of the body or hair.

The cosmetic composition according to the invention containing, in a cosmetically acceptable carrier, at least one compound chosen from compounds of formula (I) and bis- (1-benzyloxy-1 H-2-imidazolyl)disulphide, can notably be in the form of a cream, a milk, a gel, suspensions of microspheres or nanospheres or lipid or polymer vesicles, moistened tampons, solutions, sprays, mousses, sticks, soaps, washing bases or shampoos or washing bases.

The concentration of compound of formula (I) or bis-(1-benzyloxy-1H-2- imidazolyl)disulphide in the cosmetic composition is preferably between 0.001 and 3 wt.% relative to the total weight of the composition.

The pharmaceutical compositions and cosmetics as described previously can additionally contain inert additives, or even pharmacodynamically active additives in the case of pharmaceutical compositions, or combinations of these additives, and notably:

- wetting agents;

- flavour improving agents;

- preservatives such as the esters of parahydroxybenzoic acid;

- stabilizers;

- moisture regulators;

- pH regulators;

- agents that modify osmotic pressure;

- emulsifiers;

- UV-A and UV-B filters;

- antioxidants, such as α-tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase, Ubiquinol;

- emollients; - moisturizing agents such as glycerol, PEG 400, thiamorpholinone, and its derivatives or urea;

- antiseborrheic or anti-acne agents, such as S-carboxymethylcysteine, S-benzyl- cysteamine, their salts or their derivatives, or benzoyl peroxide;

- antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, tetracyclines;

- antifungal agents such as ketoconazole or polymethylene-4,5 isothiazolidones-3;

- non-steroidal anti-inflammatory agents;

- carotenoids and, notably, β-carotene;

- antipsoriatic agents such as anthralin and its derivatives;

- eicosa-5,8,11 ,14-tetraynoic and eicosa-5,8,11-triynoic acids, their esters and amides;

- retinoids, i.e. RXR receptor ligands, natural or synthetic;

- corticosteroids or oestrogens;

- α-hydroxy acids and α-keto acids or their derivatives, such as lactic, malic, citric, glycolic, mandelic, tartaric, glyceric, and ascorbic acids, as well as their salts, amides or esters, or β-hydroxy acids or their derivatives, such as salicylic acid as well as its salts, amides or esters;

- blockers of ion channels such as potassium channels;

- or, more particularly for pharmaceutical compositions, in combination with medicinal products that are known to interfere with the immune system (for example, ciclosporin, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors etc.).

Of course, a person skilled in the art will take care to choose any compound or compounds to be added to these compositions so that the advantageous properties intrinsic to the present invention are not or not substantially altered by the addition envisaged.

We shall now give, for purposes of illustration and without limiting the invention in any way, several examples of production of active compounds of formula (I) according to the invention, results for biological activity as well as various actual formulations based on such compounds.

Example 1 : Preparation of 2-r(1-hvdroxy-5-phenyl-1H-imιdazol-2-yl)-dithio1-5- phenyl-1 H-imidazol-1 -ol a) Preparation of 1-hvdroxy-5-phenyl-1.3-dihvdroimidazole-2-thione

This compound is obtained in accordance with Example 17 of application FR0504444: 78.3 g (0.444 mol) of the compound 3-hydroxy-5-phenyl-imidazole-N-oxide is suspended in 1.5 I of ethyl acetate. A solution of 201.8 g (1.111 mol) of tetramethyl-1 ,3-cyclobutan-2- one-4-thione in 47O mL of ethyl acetate is added while cold (1O⁰C), and the heterogeneous reddish reaction mixture is left to return to room temperature. After stirring for 3 days at room temperature, the reaction mixture is filtered and washed with 2x200 ml of ethyl acetate. 37 g of the yellow powder thus obtained (77.67 g, 91%, mixture of the two isomers 73/27).

By repeated trituration in methanol, 39 mg (3.9%) of the compound 1-hydroxy-5-phenyl- 1 ,3-dihydroimidazole-2-thione with a purity of about 95% (¹H-NMR, DMSO-d₆, 300 MHz, isomerically pure) is obtained from 1.O g of a mixture of isomers (50/50) in the form of yellow powder.

b) Preparation of 2-f(1-hvdroxy-5-phenyl-1H-imidazol-2-yl)-dithio1-5-phenyl-1H-imidazol-1- ol

In a 100-ml flask, 1.2 g (6.24 mmol) of compound 1-hydroxy-5-phenyl-1 ,3-dihydro- imidazole-2-thione is suspended in 12.5 ml of HNO₃ (3N). Sodium nitrite solution is added. The reaction mixture, which has become yellow and opaque, is stirred for 6 h

30 min at room temperature to give 1.15 g (91%) of the expected product. m.p. (⁰C): 178 (decomposition). ¹H-NMR (DMSOd₆, 300 MHz): δ (ppm) = 7.45 (t, 2H,

J=6Hz); 7.55 (t, 4H, J=6Hz); 7.9 (d, 2H, J=6Hz); 8.05 (s, 2H).

MS (electrospray): m/z (%) = 383 (MH⁺).

R_f (SiO₂, ethyl acetate/cyclohexane, 8/2+1% trifluoroacetic acid (TFA): 0.29.

Example 2: Preparation of 2-r(1-hvdroxy-4-phenyl-1H-imiclazol-2-vπ-dithio1-4- phenyl-1 H-imidazol-1 -ol

a) Preparation of 1-hvdroxy-4-phenyl-1,3-dihvdroimidazole-2-thione

This compound is obtained in accordance with Example 16 of application FR0504444: The mixture of the two isomers obtained in Example 1a) is recrystallized from a mixture of THF (500 mL) and heptane (150 ml_). 17.06 g of the pure isomer 1-hydroxy-4-phenyl-1 ,3- dihydroimidazole-2-thione and 15.53 g of a 1-hydroxy-4(5)-phenyl-1 ,3-dihydroimidazole- 2-thione mixture (50/50) are obtained after evaporation of the filtrate.

b) Preparation of 2-K1 -hvdroxy-4-phenyl-1 H-imidazol-2-yl)-dithio1-4-phenyl-1 H-imidazol-1 -

Si

In a flask, 0.482 g (2.51 mmol) of compound 1-hydroxy-4-phenyl-1 ,3-dihydroimidazole-2- thione is suspended in 5 ml of an aqueous solution of HNO₃ (3N) so as to obtain a concentration of 0.5M. 2.5 ml of a 0.5M solution of sodium nitrite (1eq) in HNO₃ (3N) is added dropwise. The reaction mixture is stirred for 6 h at room temperature to give the dimer (60%) in the form of a yellow solid. m.p. (⁰C): 180 (decomposition). ¹H-NMR (DMSO, 400 MHz): δ (ppm) = 7.3 (t, 2H, J=8Hz);

7.4 (t, 4H, J=8Hz); 7.8 (d, 4H, J=8Hz); 8.3 (s, 2H).

MS (electrospray): m/z (%) = 381 (M-H)^".

R_f (SiO₂, ethyl acetate/cyclohexane/TFA, 80/19/1): 0.43.

R_f (SiO₂, ethyl acetate/TFA, 99/1): 0.54.

Example 3: Preparation of 2-r(1-hvdroxy-4-(3'.5'-difluorophenyl)-1H-imidazol-2-yl)- dithio1-4-(3',5'-difluorophenyl)-1 H-imidazol-1 -ol a) Preparation of 1-hvdroxy-4-(3\5'-difluorophenyl)-1 ,3-dihvdroimidazole-2-thione

1) Preparation of 3,5-difluorophenyl glyoxal

8.954 g (80.21 mmol) of selenium dioxide and 4.88 g of Fontainebleau sand are suspended in 32 ml of THF and 3,5-difluoroacetophenone is added in portions. The mixture is refluxed for 2 days.

The mixture is filtered on celite, rinsed with ethyl acetate and the filtrate is evaporated.

The raw product is recrystallized from water to give 4.79 g of the corresponding glyoxal

(31.7%).

2) Preparation ofN-oxide imidazole

A solution of 3.82 g (0.0549 mol) of hydroxylamine hydrochloride in 4.6 ml of water is added dropwise at 5-10⁰C to a solution of 4.70 g (0.025 mol) of 3,5-difluorophenyl glyoxal in 12 ml of methanol and 2.80 ml (1.5eq.) of a 37% formaldehyde solution in water. At the end of addition, 0.49 ml of cone. HCI is then added dropwise, then the reaction mixture is left to return to room temperature. After stirring for 4 days, the heterogeneous reaction mixture is placed on an ice bath, then filtered on Celite, rinsing with 100 ml of methanol. Concentrated soda is added at 5⁰C, until pH = 5. After stirring for 30 min in the cold, the precipitate that formed is filtered and rinsed first with 20 ml of cold water, then with 20 ml of cold methanol and 20 ml of ethyl ether. After drying under vacuum, 3.78 g (71.3%) of the cyclic compound is obtained, in the form of a white solid.

3) Preparation of 1-hydroxy-4-(3',5'-difluorophenyl)-1,3-dihydroimidazole-2-thione According to the general procedure, described in application FR0504444, the compound obtained previously is treated at low temperature with an α,α'-disubstituted alkylthione such as tetramethyl-1 ,3-cyclobutadithione, tetramethyl-1 ,3-cyclobutan-2-one-4-thione or adamantyl thione. After stirring for some hours, the reaction mixture is filtered. The precipitate comprises the isomers 4- and 5-(3',5'-difluorophenyl).

Thus, a precipitate is obtained from 3.78 g (17.8 mmol) of the compound obtained in 2) in

78 ml_ of methanol, after stirring for 21 hours. Dry extraction (white solid) of a sample shows, by NMR, that it is a pure mixture of isomers (50/50).

The yield of the reaction is 97%.

The precipitate that formed in the reaction mixture is filtered to give 1.23 g of the desired compound in the form of a white solid. m.p. (°C): 209-210. 2 C ft 15 °

¹H-NMR (DMSO-d₆, 300 MHz) δ (ppm) 7.15 (tt, 1H₁ J=9Hz, J=2Hz); 7.45 (dd, 2H₁ J=9Hz,

J=2Hz); 8.0 (s, 1H); 11.7-12.0 (small mound which could be -NH or -OH); 12.8 (sb, 1H, -

NH or -OH).

¹³C-NMR (DMSO-d₆, 100 MHz) δ (ppm) 102.6; 107.1 ; 116.2; 122.1 ; 131.5; 158.6; 163.1.

MS (electrospray): m/z (%) = 229 (MH⁺).

R_f (SiO₂, ethyl acetate/cyclohexane, 80/20 + 1% TFA): 0.64.

R_f (SiO₂, dichloromethane/methanol, 90/10): 0.47.

b) Preparation of 2-fπ-hvdroxy-4-(3',5'-difluorophenyl)-1 H-imidazol-2-yl)-dithio1-4-(3'.5'- difluorophenvO-1 H-imidazol-1 -ol

In a flask, 0.994 g (4.36 mmol) of 1-hydroxy-4-(3'_I5'-difluorophenyI)-1 ,3-dihydroimidazole-

2-thione is suspended in 8.70 ml of an aqueous solution of HNO₃ (3N) so as to obtain a concentration of 0.5M. 4.35 ml of a 0.5M solution of sodium nitrite (1eq) in HNO₃ (3N) is added dropwise. The reaction mixture is stirred for 5 h at room temperature to give

0.950 mg (96%) of the expected dimer in the form of a yellow solid. m.p. (⁰C): 190 (decomposition). ¹H-NMR (DMSO, 400 MHz): δ (ppm) = 7.1 (m, 2H); 7.4

(d, 4H, J=7Hz); 8.37 (s, 2H).

¹⁹F-NMR (DMSO, 376 MHz): δ (ppm) -110 (s)

MS (electrospray): m/z (%) = 453 (M-H)-.

R_f (SiO₂, ethyl acetate/cyclohexane/TFA, 50/49/1): 0.38.

R_f (SiO₂, ethyl acetate/cyclohexane/TFA, 40/59/1): 0.33.

Example 4: Preparation of 2-fH-hvdroxy-5-(4'-fluorophenylMH-imidazol-2-yl)- dithio1-5-(4'-f luorophenylH H-imidazol-1 -ol

a) Preparation of 1-hvdroxy-5-(4'-fluorophenyl)-1 ,3-dihydroimidazole-2-thione

1) Preparation of 4-fluorophenylglyoxal

47.60 g (0.4290 mol) of selenium dioxide and 30 g of Fontainebleau sand are suspended in 158 ml of dioxan and 52 ml of water. The mixture is heated to 4O⁰C until the reagent dissolves. 56.44 g (0.4086 mol) of 4-fluoroacetophenone is added dropwise. The mixture is refluxed for 6 h, then stirred overnight at room temperature.

The mixture is filtered on celite, rinsed with ethyl acetate and the filtrate is evaporated. The raw product is recrystallized from water. The solid obtained is washed with cyclohexane to give 54.79 g of the corresponding glyoxal (79%).

2) Preparation of N-oxide imidazole

A solution of 41.69 g (0.6 mol) of hydroxylamine hydrochloride in 51 ml of water is added dropwise at 5-1O⁰C, to a solution of 51.05 g (0.3 mol) of 4-fluorophenyl glyoxal in 75 ml of methanol and 33.5 ml (1.5eq.) of a 37% formaldehyde solution in water. At the end of addition, 5.9 ml of cone. HCI is then added dropwise, then the reaction mixture is left to return to room temperature. After stirring for 20 h, the heterogeneous reaction mixture is dissolved in 120 ml of methanol and filtered on Celite. 66 ml of concentrated soda is added, at 5⁰C, until pH = 5. After stirring for 30 min in the cold, the precipitate formed is filtered and rinsed first with 70 ml of cold water, then with 50 ml of cold methanol and 100 ml of ethyl ether. After drying under vacuum, 56.09 g (96%) of the desired compound is obtained.

3) Preparation of 1-hydroxy-5-(4'-fluorophenyl)-1,3-dihydroimidazole-2-thione According to the general procedure, described in application FR0504444, the compound obtained previously is treated at low temperature with an α,α'-disubstituted alkylthione such as tetramethyl-1 ,3-cyclobutadithione, tetramethyl-1 ,3-cyclobutan-2-one-4-thione or adamantyl thione. After stirring for some hours, the reaction mixture is filtered. The precipitate comprises the 4- and 5-(4'-fluorophenyl) isomers.

We thus obtain, from 5 g (25.75 mmol) of the compound obtained in 2) in 110 ml of methanol, 4.56 g (84%) of a mixture of isomers (62/38) in the form of a pink solid. By recrystallization from THF/heptane mixture (8/2), 1.47 g (43%) of the desired compound, in the form of a white solid, is obtained from 3.42 g of the raw product. m.p. (⁰C): 197.0 - 198.0.

¹H-NMR (DMSOd₆, 300 MHz) δ (ppm) 7.15 (d, J = 3 Hz, 1H); 7.25 (td, 2H); 7.7 (m, 2H);

11.6 (sb, 1 H₁ -OH or NH); 12.3 (sb, 1 H₁ -OH or NH).

¹³C-NMR (DMSO-d₆, 75.5 MHz) δ (ppm) 109.0; 115.4; 115.7; 124.0; 127.1 ; 128.4; 128.6;

157.9; 160.0; 163.2.

MS (electrospray): m/z (%) = 233.3 (M+Na)^+; 211.3 (M+H)⁺.

R_f (RP-Nitrile, ethyl acetate/cyclohexane, 50/50): 0.38.

R_f (SiO₂, ethyl acetate/cyclohexane, 50/50): 0.55.

b) Preparation of 2-r(1-hvdroxy-5-(4'-fluorophenyl)-1 H-imidazol-2-yl)-dithio1-5-(4'- fluorophenyl)-1 H-imidazol-1 -ol

In a flask, 0.56 g (2.7 mmol) of compound 1-hydroxy-5-(4'-fluorophenyl)-1 ,3- dihydroimidazole-2-thione is suspended in 5 ml of an aqueous solution of HNO₃ (3N) so as to obtain a concentration of 0.5M. 2.5 ml of a 0.5M solution of sodium nitrite (1eq) in

HNO₃ (3N) is added dropwise. The reaction mixture is stirred for 20 h at room temperature. The yellow precipitate obtained is filtered, rinsed with water, taken up in methanol, filtered again, and finally taken up in a 1/1 mixture of ethyl acetate/ethanol

(AcOEt/EtOH), refluxed for a short while and filtered to obtain 275mg (46%) of the expected dimer in the form of a yellow solid. m.p. (⁰C): 192 (decomposition). ¹H-NMR (DMSO, 400 MHz): δ (ppm) = 7.4 (t, 4H, J=8Hz);

7.9 (t, 4H₁ J=8Hz); 8.0 (s, 2H).

¹⁹F-NMR (DMSO, 376 MHz): δ (ppm) -112 (s)

MS (electrospray): m/z (%) = 417 (M-H)^".

R_f (SiO₂, ethyl acetate/cyclohexane/TFA, 80/19/1): 0.27.

R_f (SiO₂, ethyl acetate/TFA, 99/1): 0.45.

Example 5: Preparation of 2-r(1-hyd!roxy-4-(4'-nitrophenyl)-1H-imidazol-2-yl)-dithio1- 4-(4'-nitrophenvπ-1 H-imidazol-1 -ol

a) Preparation of 1-hvdroxy-4-(4'-nitrophenyl)-1 ,3-dihvdroimidazole-2-thione

The compound is obtained in accordance with Example 21 of application FR0504444:

1) Preparation of 4(5)-4'-nitrophenyl-3-hydroxy-imidazole-1-oxide

A solution of 37.7 g (0.54 mol) of hydroxylamine hydrochloride in 46 ml_ of water is added dropwise at 5-1O⁰C to a solution of 53.53 g (0.27 mol) of 3-nitrophenylglyoxal hydrate in 63 ml_ of methanol and 30 mL (0.407 mol) of 37% formaldehyde solution in water. At the end of addition, 5.35 mL of concentrated hydrochloric acid is then added dropwise, then the reaction mixture is left to return to room temperature. After stirring for 72 h, the heterogeneous reaction mixture is dissolved in 1.2 L of methanol and filtered on celite. 60 mL of concentrated soda NaOH is added at 5°C (→ pH = 5). After stirring for 30 min. while cold, the precipitate formed is filtered and rinsed first with 70 mL of cold water, then with 6O mL of cold methanol and 11O mL of ethyl ether. After drying under vacuum, 48.54 g (81%) of the desired compound is obtained in the form of yellowish-orange powder. ¹H-NMR (DMSO-d₆/DCI, 300 MHz): δ (ppm) = 8.12 (d, J = 9 Hz, 2H); 8.34 (d, J = 9 Hz, 2H); 8.55 (d, J = 2 Hz, H-4/5); 10.01 (d, J = 2 Hz, H-1).

2) Introduction of the sulphur

According to the general procedure, 4.66 g (87%) of a mixture of isomers (50/50[1O]) in the form of an orange solid is obtained from 5 g (22.6 mmol) of the preceding compound in 75 mL of methanol. 3) Preparation of 1-hydroxy-4-(4'-nitrophenyl)- 1,3-dihydroimidazole-2-thione

By repeated recrystallization from methanol, 0.3O g (8%) of the compound 1-hydroxy-4-

(4'-nitrophenyl)-1 ,3-dihydroimidazole-2-thione is obtained from 3.28 g of the raw product in the form of a yellow solid. m.p. (⁰C): 202.5 - 204.0.

¹H-NMR (DMSO-de, 300 MHz): δ (ppm) = 7.91 (d, J = 9 Hz, 2H); 8.14 (s, 1H, H-5); 8.22

(d, J = 9 Hz, 2H); 11.93 (sb, 1H₁ -OH or NH); 12.91 (sb, 1H₁ -OH or NH).

¹³C-NMR (DMSO-d₆, 75.5 MHz): δ (ppm) = 117.2; 121.9; 124.3; 134.2; 145.7; 159.1.

MS (electrospray): m/z (%) = 473 (2M-H)^"; 236 (M-H)-.

R_f (RP-nitrile, ethyl acetate/cyclohexane, 50/50): 0.54.

R_f (C₁₈, acetonitrile/water, 90/10): 0.81.

b) Preparation of 2-f(1-hvdroxy-4-(4'-nitrophenvO-1H-imidazol-2-yl)-dithio1-4-(4'- nitrophenvD-1 H-imidazol-1 -ol

In a flask, 0.55 g (2.3 mmol) of compound 1-hydroxy-4-(4'-nitrophenyl)-1 ,3- dihydroimidazole-2-thione is suspended in 6.5 ml of an aqueous solution of HNO₃ (3N) so as to obtain a concentration of 0.5M. 2.5 ml of a 0.5M solution of sodium nitrite (1eq) in

HNO₃ (3N) is added dropwise. The reaction mixture is stirred for 22 h at room temperature. The yellow precipitate obtained is filtered, rinsed with water, taken up in methanol and filtered again to obtain the expected dimer (98%) in the form of a yellow solid. m.p. (⁰C): 151 (decomposition). ¹H-NMR (DMSO, 400 MHz): δ (ppm) = 8.0 (d, 2H,

J=8Hz); 8.2 (d, 4H, J=8Hz); 8.5 (s, 2H).

MS (electrospray): m/z (%) = 471 (M-H)^".

R_f (alumina, ethyl acetate/cyclohexane/TFA, 80/19/1): 0.33.

R_f (alumina, ethyl acetate/cyclohexane/TFA, 60/39/1): 0.18.

EXAMPLE 6: Test of inhibition of tyrosinase activity

The activity of the inhibitors is measured from a lysate of B16F1 cells (murine melanoma line). In the presence of the substrate L-tyrosine, the tyrosinase present in these cells catalyses the hydroxylation of L-tyrosine to L-DOPA then the oxidation of L-DOPA to dopaquinone. In the presence of MBTH (3-Methyl-2-Benzo-Thiazolinone Hydrazone), dopaquinone is trapped, forming a pink complex which absorbs at 520 nm.

The B16F1 cells are cultivated in a medium of DMEM + 10% of fetal calf serum + 10^"9 M of αSMH for 4 days at 37°C under 7% of CO₂. They are trypsinized, washed in PBS, counted and sedimented. The sediment is taken up at 10⁷ cells/ml in lysis buffer (sodium phosphate 10 mM pH 6.8 - lgepal 1%) and the suspension is sonicated for 10 seconds. After centrifugation for 30 minutes at 4000 rpm, the supernatant obtained constitutes the cellular lysate used as source of tyrosinase in the enzyme test.

The assays are performed in duplicate in 384-well plates with a total volume of 50 μl. Each well contains:

- 40 μl of solution containing 1.25 mM L-tyrosine, 6.25 μM L-DOPA (cofactor) and 3.75 mM MBTH in buffer B (sodium phosphate 62.25 mM pH 6.8 - 2.5% dimethylformamide)

- 5 μl of inhibitor diluted in DMSO

- 5μl of cellular lysate diluted to ^ΛA in buffer Tris HCI 50 mM pH 7.5

The plate is incubated at 37⁰C and a spectrophotometric reading is performed at 520 nm after 6 hours of incubation. To eliminate possible absorption of the products, the work is performed with corrected absorbance (absorbance at time 6 h - absorbance at time zero).

The inhibitors are tested for dose/response to calculate the IC50 (dose that inhibits 50% of enzyme activity).

Several internal controls are added in each test:

- control 100% of activity: the 5 μl of inhibitor is replaced with 5μl of DMSO

- control 50% of activity: the 5 μl of inhibitor is replaced with 5μl of phenylthiourea at 300 μM in DMSO

- control 0% of activity: the L-tyrosine substrate is replaced with buffer B.

These results show that the compounds of formulae (I) have good tyrosinase inhibiting activity.

EXAMPLE 7: EXAMPLES OF FORMULATION

This example illustrates various actual formulations based on the compounds according to the invention.

A- ORAL ROUTE

(a) Tablet of 0.2 g

- Compound of Example 1 0.001 g

- Starch 0.114 g

- Dicalcium phosphate 0.020 g

- Silica 0.020 g • Lactose 0.030 g Talc 0.010 g

• Magnesium stearate 0.005 g

(b) Drinkable suspension 5-ml vials

^■ Compound of Example 2 0.001 g

^■ Glycerol 0.500 g

^■ Sorbitol at 70% 0.500 g

^■ Saccharin sodium 0.010 g

• Methyl parahydroxybenzoate 0.040 g

• Flavouring qs

^■ Purified water qsf 5 i Til

B- PARENTERAL ROUTE

(a) Composition Compound of Example 1 0.002 g Ethyl oleate qs 10 g

(b) Composition Compound of Example 5 0.05% Polyethylene glycol 20% NaCI solution at 0.9% qs 100

C- TOPICAL ROUTE

(a) Salve

Compound of Example 4 0.300 g ^■ White Vaseline codex qsf 100 g

(b) Cream, water-in-oil, non-ionic Compound of Example 1 0.100 g Mixture of emulsive lanolin alcohols, waxes and oils ("Anhydrous Eucerin" sold by BDF) 39.900 g - Methyl parahydroxybenzoate 0.075 g

- Propyl parahydroxybenzoate 0.075 g

- Sterile demineralized water qsf 100 g

(c) Lotion

- Compound of Example 4 0.100 g

- Polyethylene glycol (PEG 400) 69.900 g

- Ethanol at 95% 30.000 g

Claims

1. Compounds, characterized in that they correspond to the following formula (I):

in which:

With the exception of bis-(1-benzyloxy-1H-2-imidazoiyl)disulphide.

2. Compounds according to Claim 1 , characterized in that the alkyl radicals having from 1 to 6 carbon atoms are selected from the methyl, ethyl, propyl, butyl, pentyl, and hexyl radicals.

3. Compounds according to one of the Claims 1 to 2, characterized in that the aryl radicals are selected from the phenyl, biphenyl, and naphthyl radicals, heteroaromatic radicals such as thiophenyl, pyridinyl, pyrimidyl, imidazole, triazole, optionally fused with one or more other rings and optionally mono or di-substituted with one or more atoms, groups, functions or radicals selected from a halogen atom, CF₃ radical, an alkyl radical, an alkoxyl radical, a nitro function, an alkyl ester group, a nitrile function, an amide function, a carboxyl function, a hydroxyl radical, an amino function optionally substituted with at least one alkyl radical.

4. Compounds according to one of the Claims 1 to 3, characterized in that the aralkyl radicals are selected from the benzyl, phenethyl, naphthalen-2-ylmethyl radicals or heteroaromatic radicals such as thiophene-methyl, pyridine-methyl, pyrimidyl-methyl optionally mono or di-substituted with one or more atoms, groups, functions or radicals selected from a halogen atom, a CF₃ radical, an alkyl radical, an alkoxyl radical, a nitro function, an alkyl ester group, a nitrile function, an amide function, a carboxyl function, a hydroxyl radical, an amino function optionally substituted with at least one alkyl radical.

5. Compounds according to Claim 3 or 4, characterized in that the alkoxyl radicals are selected from the radicals containing from one to seven carbon atoms such as the methoxy, ethoxy, isopropyloxy, tert-butoxy, hexyloxy, benzyloxy or phenoxy radicals, which can optionally be substituted with an alkyl radical having from 1 to 12 carbon atoms.

6. Compounds according to Claim 3 or 4, characterized in that the halogen atom is an atom of fluorine, of bromine or of chlorine.

7. Compounds according to Claim 1 , characterized in that they have at least one of the following characteristics:

- R1 represents a hydrogen atom,

- R2 represents a hydrogen atom or a substituted or unsubstituted aryl radical,

- R3 represents a hydrogen atom or a substituted or unsubstituted aryl radical.

8. Compounds according to Claim 1 , characterized in that they have at least one of the following characteristics:

- R1 represents an aralkyl radical,

- R2 represents a hydrogen atom,

- R3 represents a hydrogen atom or a substituted or unsubstituted aryl radical.

9. Compounds according to Claim 1 , characterized in that they have at least one of the following characteristics:

- R1 represents an alkyl radical having from 1 to 6 carbon atoms,

- R2 represents a hydrogen atom or a substituted or unsubstituted aryl radical or an alkyl radical having from 1 to 6 carbon atoms, - R3 represents a hydrogen atom or a substituted or unsubstituted aryl radical or an alkyl radical having from 1 to 6 carbon atoms.

10. Compounds according to Claim 1 , characterized in that they have at least one of the following characteristics:

- R1 represents an aryl radical,

- R2 represents a hydrogen atom,

- R3 represents a hydrogen atom.

11. Compounds according to Claim 1 , characterized in that they are taken, alone or as a mixture, from the group comprising:

2-[(1 -Hydroxy-5-phenyl-1 H-imidazol-2-yl)-dithio]-5-phenyl-1 H-imidazol-1 -ol

2-[(1 -Hydroxy-4-phenyl-1 H-imidazol-2-yl)-dithio]-4-phenyl-1 H-imidazol-1 -ol

2-[(1-Hydroxy-4-(4'-nitrophenyl)-1H-imidazol-2-yl)-dithio]-4-(4'-nitrophenyl)-1 H-imidazol-1 - ol

2-[(1-Benzyloxy-1H-imidazol-2-yl)-dithio]-1-benzyloxy-1H-imidazole

2-[(1-Methoxy-1 H-imidazol-2-yl)-dithio]-1-methoxy-1 H-imidazole

2-[(1-((3'-Pyridine)methyloxy)-1H-imidazol-2-yl)-dithio]-1-((3'-pyridine)methyloxy-1H- imidazole

2-[(1 -BenzyIoxy-4-phenyl-1 H-imidazol-2-yl)-dithio]-1 -benzyloxy-4-phenyl-1 H-imidazole

2-[(1 -Methoxy-5-phenyl-1 H-imidazol-2-yl)-dithio]-1 -methoxy-5-phenyl-1 H-imidazole

2-[(1-Methoxy-4-phenyl-1 H-imidazol-2-yl)-dithio]-1-methoxy-4-phenyl-1 H-imidazole

2-[(1 -Methoxy-4(5)-phenyl-1 H-imidazol-2-yl)-dithio]-1 -methoxy-4(5)-phenyl-1 H-imidazole

2-[(1-Ethoxy-4(5)-phenyl-1H-imidazol-2-yl)-dithio]-1-ethoxy-4(5)-phenyl-1 H-imidazole

2-[(1 -Ethoxy-5-methyl-1 H-imidazol-2-y l)-dithio]-1 -ethoxy-5-methyl-1 H-imidazole

2-[(1 -Hydroxy-4(5)-phenyl-1 H-imidazol-2-yl)-dithio]-4(5)-phenyl-1 H-imidazol-1 -ol

2-[(1-(3',5'-Difluorobenzyloxy)-1H-imidazol-2-yl)-dithio]-3',5^l-difluorobenzyloxy-1H- imidazole

2-[(1-Hydroxy-4-(3'-nitrophenyl)-1H-imidazol-2-yl)-dithio]-4-(3'-nitrophenyl)-1 H-imidazol-1- Ol

12. Compounds selected from the compounds according to any one of the Claims 1 to 11 and bis-(1-benzyloxy-1H-2-imidazolyl)disulphide as a medicinal product.

13. Compounds selected from the compounds according to any one of the Claims 1 to 11 and bis-(1-benzyloxy-1H-2-imidazolyl)disulphide as depigmenting agents.

14. Method of preparation of the compounds of formula (I) according to one of the Claims 1 to 11 , characterized in that it comprises the following stages: a) suspending the N-hydroxyimidazolethiol derivative in an aqueous solution of acid; b) adding, to the suspension obtained in a), a solution of oxidizing agent in the same acid as used in a); c) stirring the mixture, until a precipitate is obtained; d) the precipitate obtained in c) is filtered and then rinsed with water, e) optionally, the precipitate obtained in d) is recrystallized from a polar solvent and filtered again to obtain the corresponding dimer of formula (I).

15. Use of a compound according to any one of the claims 1 to 11 or of bis-(1-benzyloxy- 1 H-2-imidazolyl)disulphide for the preparation of a composition intended for the treatment of at least one disorder selected from melasma, chloasma, lentigo, lentigo senilis, vitiligo, freckles, post-inflammatory hyperpigmentations due to an abrasion and/or a burn and/or a scar and/or a dermatosis and/or a contact allergy; nevi, genetically determined hyperpigmentations, hyperpigmentations of metabolic origin or drug-induced, or melanomas.

16. Use of a compound according to any one of the claims 1 to 11 or of bis-(1-benzyloxy- 1H-2-imidazolyl)disulphide for the preparation of a depigmenting composition.

17. Pharmaceutical composition, characterized in that it comprises, in a physiologically acceptable carrier, at least one of the compounds as defined in any one of the Claims 1 to 11 or of bis-(1-benzyloxy-1H-2-imidazolyl)disulphide.

18. Composition according to Claim 17, characterized in that the concentration of compound(s) is between 0.001 and 10 wt% relative to the total weight of the composition.

19. Composition according to Claim 17 or 18, characterized in that the concentration of compound(s) is between 0. 01 and 3 wt% relative to the total weight of the composition.

20. Cosmetic composition, characterized in that it comprises, in a cosmetically acceptable carrier, at least one of the compounds as defined in any one of the Claims 1 to 11 or of bis-(1 -benzyloxy-1 H-2-imidazolyl)disulphide.

21. Composition according to Claim 20, characterized in that the concentration of compound(s) is between 0.001 and 3 wt% relative to the total weight of the composition.

22. Cosmetic use of a composition as defined in one of the Claims 20 or 21 for preventing and/or treating the signs of aging.