HK1160801A - Novel 4-(heterocycloalkyl)benzene-1,3-diol compounds as tyrosinase inhibitors, process for the preparation thereof and use thereof in human medicine and also in cosmetics - Google Patents

Description

Novel 4- (heterocycloalkyl) benzene-1, 3-diol compounds as tyrosinase inhibitors, process for their preparation and their use in human medicine and cosmetics

The present invention relates to novel 4- (heterocycloalkyl) benzene-1, 3-diol compounds as industrial and useful products. Also relates to a method for the production thereof and to the use thereof as tyrosinase inhibitors in pharmaceutical or cosmetic compositions for the treatment or prevention of pigmentary pathologies.

Skin pigmentation, particularly human skin pigmentation, is the result of melanin synthesis by dendritic cells, melanocytes. Melanocytes contain organelles called melanosomes, which transfer melanin to the upper layers of keratinocytes, which are subsequently transported to the surface of the skin by epidermal differentiation (GilchestBA, Park HY, Eller MS, Yaar M, mechanics of ultravitamin light-induced differentiation. Photochem Photobiol 1996; 63: 1-10; Hearing VJ, Tsukamoto K, enzymic control of differentiation in mammals. FASEB J1991; 5: 2902-.

Tyrosinase is a key enzyme in melanogenesis, catalyzing the first two steps of melanin synthesis. Homozygous mutations in tyrosinase cause type I ocular skin albinism, which is characterized by a complete lack of melanin synthesis (Toyofuku K, Wada I, Spritz RA, Hearing VJ, The molecular basis of oculococcoeous album type 1 (OCA1): lubricating failure and grading of mutant types of lipids in a lack of registration. Biochem J2001; 355: 259-269).

For pigmentation disorders caused by increased melanin production, there is currently no treatment that meets all the expectations of patients and dermatologists. In order to treat pigmentation disorders, it is important to develop new therapeutic approaches.

Most known skin lightening compounds are phenolic or hydroquinone derivatives. These compounds inhibit tyrosinase, but most of them are cytotoxic to melanocytes because of quinone formation. This toxic effect risks permanent depigmentation of the skin. It would be particularly desirable to have compounds that inhibit melanogenesis while being less or not toxic to melanocytes.

Among the compounds already described in the literature, patent application WO 99/15148 discloses the use of 4-cycloalkyl-resorcinols as depigmenting agents.

Patent FR 2704428 discloses the use of 4-halo-resorcinol as a depigmenting agent.

Patent applications WO 2006/097224 and WO 2006/097223 disclose the use of 4-cycloalkylmethylresorcinol as a depigmenting agent.

Patent application WO 2005/085169 discloses the use of alkyl 3- (2, 4-dihydroxyphenyl) propionates as depigmenting agents.

Patent application WO 2004/017936 discloses the use of 3- (2, 4-dihydroxyphenyl) acrylamide as depigmenting agent.

Patent application WO 2004/052330 discloses the use of 4- [1,3] dithian-2-yl resorcinol as a depigmenting agent.

In particular, patent EP 0341664 discloses the use of 4-alkylresorcinols, also known as rucinol, as depigmenting agents, in which 4-n-butylresorcinols are IKLen^®Part of the ingredients of the decolorizing cream sold under the name of (1).

The applicants have now unexpectedly and surprisingly found that novel compounds having the structure of 4- (heterocycloalkyl) benzene-1, 3-diol possess very good tyrosinase inhibitory activity and very low cytotoxicity. In addition, these compounds have greater tyrosinase inhibitory activity than rucinol, while being less cytotoxic to melanocytes than rucinol.

These compounds are useful in the fields of human medicine, in particular dermatological medicine, and cosmetics.

The present invention therefore relates to the following compounds of general formula (I), and to the salts of the compounds of general formula (I), and to the isomeric and enantiomeric forms thereof:

wherein:

r1, R2, R3 and R4, which may be the same or different, represent:

-hydrogen, and (C) hydrogen,

- C₁-C₄an alkyl group, a carboxyl group,

-a hydroxymethyl group, a hydroxyethyl group,

- (C₁-C₄alkoxy) carbonyl groups, in which the carbonyl groups are bonded,

- C₁-C₄an alkoxy group,

-a hydroxyl group,

or

R1 and R2 are linked to each other to form, together with the carbon atoms to which they are linked, a carbocyclic ring containing 5 or 6 carbon atoms, and R3 and R4, which may be identical or different, represent:

-hydrogen, and (C) hydrogen,

- C₁-C₄alkyl radical

Or

R1 and R4 are linked to each other to form a- (CH)₂)₂-or- (CH)₂)₃-a chain, while R2 and R3, which may be identical or different, represent:

-hydrogen, and (C) hydrogen,

- C₁-C₄an alkyl group;

x represents an oxygen atom or a sulfur atom;

y represents a hydrogen, chlorine or fluorine atom;

m may be 1 or 2, n may be 0 or 1, and m is 1 or 2 when n =0, and m =1 when n = 1.

Among the salts of the compounds of formula (I) with pharmaceutically acceptable bases, preference is given to salts with organic bases or with inorganic bases.

Suitable inorganic bases are, for example, potassium hydroxide, sodium hydroxide or calcium hydroxide.

Suitable organic bases are, for example, morpholine, piperazine or lysine.

The compounds of formula (I) may also exist in the form of hydrates or solvates.

Suitable solvents for forming solvates are, for example, alcohols, such as ethanol or isopropanol.

According to the invention, the term "C₁-C₄Alkyl "represents a straight or branched saturated hydrocarbyl chain containing 1 to 4 carbon atoms.

According to the invention, the term "(C)₁-C₄Alkoxy) carbonyl "represents a carboxyl group substituted with an alkyl group having 1 to 4 carbon atoms.

According to the invention, the term "C₁-C₄Alkoxy "represents an oxygen atom substituted by a straight or branched chain saturated hydrocarbon group containing 1 to 4 carbon atoms.

According to the invention, the term "isomers" denotes the cis and trans forms based on the substituents on the heterocycloalkyl radical in position 4 of the benzene-1, 3-diol.

Particularly preferred compounds of the general formula (I) according to the invention are those in which:

-R1 represents hydrogen, C₁-C₄An alkyl group or a hydroxymethyl group, in the form of a linear or branched alkyl group,

-R2 represents hydrogen,

-R3 represents hydrogen,

-R4 represents hydrogen,

-X represents an oxygen atom,

-Y represents a hydrogen or fluorine atom,

-m =1 and n =1,

and also the salts of these compounds of the general formula (I), and the isomers and enantiomeric forms thereof.

Among the compounds of formula (I) which fall within the scope of the present invention, mention may in particular be made of the following compounds:

1: 4- (tetrahydropyran-4-yl) benzene-1, 3-diol

2: 4- (tetrahydrothiopyran-4-yl) benzene-1, 3-diol

3: 4- (cis-2, 6-dimethyltetrahydropyran-4-yl) benzene-1, 3-diol

4: trans-4- (2-methyltetrahydropyran-4-yl) benzene-1, 3-diol

5: cis-4- (2-methyltetrahydropyran-4-yl) benzene-1, 3-diol

6: trans-4- (2-ethyltetrahydropyran-4-yl) benzene-1, 3-diol

7: cis-4- (2-ethyltetrahydropyran-4-yl) benzene-1, 3-diol

8: trans-4- (2-hydroxymethyltetrahydropyran-4-yl) benzene-1, 3-diol

9: 4- (2,2,6, 6-tetramethyltetrahydropyran-4-yl) benzene-1, 3-diol

10: 4- (tetrahydrofuran-3-yl) benzene-1, 3-diol

11: 4- (tetrahydrothiophen-3-yl) benzene-1, 3-diol

12: 4- (6-oxaspiro [4.5] decan-9-yl) benzene-1, 3-diol

13: 4-chloro-6- (tetrahydropyran-4-yl) benzene-1, 3-diol

14: 4-fluoro-6- (tetrahydropyran-4-yl) benzene-1, 3-diol

15: 4- (2, 2-diethyltetrahydropyran-4-yl) benzene-1, 3-diol

16: 4- (tetrahydropyran-3-yl) benzene-1, 3-diol

17: trans-4- (5-hydroxymethyl-tetrahydrofuran-3-yl) benzene-1, 3-diol

18: cis-4- (5-hydroxymethyl-tetrahydrofuran-3-yl) benzene-1, 3-diol

19: trans-4-fluoro-6- (5-hydroxymethyltetrahydrofuran-3-yl) benzene-1, 3-diol

20: cis-4-fluoro-6- (5-hydroxymethyltetrahydrofuran-3-yl) benzene-1, 3-diol

21: trans-4-fluoro-6- (2-hydroxymethyltetrahydropyran-4-yl) benzene-1, 3-diol

22: cis-4-fluoro-6- (2-hydroxymethyltetrahydropyran-4-yl) benzene-1, 3-diol

23: cis-4- (8-oxabicyclo [3.2.1] oct-3-yl) benzene-1, 3-diol

24: trans-4- (8-oxabicyclo [3.2.1] oct-3-yl) benzene-1, 3-diol

25: 4-fluoro-6- (tetrahydrothiopyran-4-yl) benzene-1, 3-diol

The compounds of general formula (I) were prepared according to the general reaction schemes 1-4 shown in FIG. 1.

Scheme 1 of fig. 1 corresponds to the preparation of compounds of general formula (I) wherein m = n =1, X = O, R1, R2, R3, R4 and Y have the same definitions as above.

According to this reaction scheme of FIG. 1, 2, 4-dibenzyloxybromobenzene (1) is reacted with a heterocycloalkanone of the general formula (2) in the presence of butyllithium to give a benzyl alcohol of the general formula (3), the heterocycloalkanone of the general formula (2) being commercially available or prepared according to conventional synthetic methods (W.D. Langley, Org, Synth. I, 122 (1932)).

The benzyl alcohol of formula (3) is dehydrated in an aprotic solvent, such as toluene, in the presence of an acid, such as camphorsulfonic acid, to give the compound of formula (4).

A compound of the general formula (5):

starting from a compound of formula (3), or starting from a compound of formula (4), by hydrogenation in a solvent (for example methanol) in the presence of hydrogen and a palladium-based catalyst (for example palladium on carbon):

a compound of the general formula (6):

by halogenating agents, e.g. N-chlorosuccinimide (Y = Cl) or Selectfluor, with compounds of the general formula (5)^®(Y = F) by halogenation.

Scheme 2 of fig. 1 corresponds to the preparation of compounds of general formula (I) wherein m = n =1, X = O or S, R1, R2, R3, R4 and Y have the same definitions as above.

According to scheme 1, 2, 4-bis (methoxymethoxy) bromobenzene (7) is reacted with, for example, a heterocyclic alkanone of the general formula (2) in the presence of a base such as butyllithium to give benzyl alcohol of the general formula (8), wherein the heterocyclic alkanone of the general formula (2) is commercially available or prepared according to conventional methods (w.d. Langley, org. synth. I, 122 (1932)).

The benzyl alcohol of formula (8) is dehydrated in a solvent such as toluene in the presence of an acid such as camphorsulfonic acid to give the compound of formula (9).

The compounds of formula (10) are obtained by hydrogenation of compounds of formula (9) in a solvent, such as methanol, in the presence of hydrogen and a palladium-based catalyst, such as palladium on carbon.

The compounds of the general formula (5) are obtained starting from compounds of the general formula (10) in methanol in the presence of hydrochloric acid.

Scheme 3 of fig. 1 corresponds to the preparation of compounds of general formula (I) wherein m =1, n =0, X = O, R1= R2= H, R3, R4 and Y have the same definitions as above.

Reaction scheme 3, 2, 4-dibenzyloxybromine (1) of FIG. 1 is employed in the presence of butyllithium with a heterocycloalkanone of the general formula (11) to give a compound of the general formula (12), wherein the heterocycloalkanone of the general formula (11) is commercially available or is prepared according to conventional synthetic methods (W.D. Langley, org. Synth. I, 122 (1932)).

The compounds of the general formula (13) are obtained starting from compounds of the general formula (12) by hydrogenation in a solvent, for example methanol, in the presence of hydrogen and a palladium-based catalyst, for example palladium on carbon.

A compound of the general formula (16):

from compounds of the general formula (13) with halogenating agents, e.g. N-chlorosuccinimide (Y = Cl) or Selectfluor^®(Y = F) by halogenation.

Scheme 4 of fig. 1 corresponds to the preparation of compounds of general formula (I) wherein m =1, n =0, X = O or S, R1= R2= H, R3, R4 and Y have the same definitions as above.

Reaction scheme 4, 2, 4-bis (methoxymethoxy) bromobenzene (7) of FIG. 1 with a heterocyclic alkanone of the general formula (11) in the presence of butyllithium, in order to obtain benzyl alcohol of the general formula (14), wherein the heterocyclic alkanone of (11) is commercially available or prepared according to conventional synthetic methods (W.D. Langley, org. Synth. I, 122 (1932)).

The benzyl alcohol of formula (14) is then dehydrated in a solvent such as methanol in the presence of an acid such as hydrochloric acid to give the compound of formula (15).

The compound of formula (13) is obtained by hydrogenation of a compound of formula (15) in a solvent such as methanol in the presence of hydrogen and a palladium-based catalyst such as palladium on carbon.

The invention therefore relates to the use of at least one compound of general formula (I) as defined above as a medicament.

The invention also relates to the use of at least one compound of general formula (I) as defined above, wherein the compound has tyrosinase inhibitory activity, as a medicament.

The invention also relates to the use of at least one compound of general formula (I) as defined above for preparing a pharmaceutical or cosmetic composition, wherein the compound has tyrosinase inhibitory activity.

Advantageously, the IC of the compounds of the invention for tyrosinase₅₀The value (dose inhibiting 50% of the enzymatic activity) is less than or equal to 10. mu.M, in particular less than or equal to 1. mu.M.

The invention also relates to compounds of general formula (I) for the treatment and/or prevention of pigmentary pathologies.

In fact, the compounds of general formula (I) according to the invention are particularly suitable for the treatment or prevention of pigmentary pathologies such as chloasma, lentigo, age-related irregularities, freckles, post-inflammatory hyperpigmentations caused by bruising, burns, scars, skin diseases, contact allergies; nevi, hereditary hyperpigmentation, hyperpigmentation of metabolic or pharmaceutical origin, melanoma or any other hyperpigmented lesion.

A subject of the present invention is also a pharmaceutical composition, in particular for the treatment of the above-mentioned conditions, characterized in that it comprises, in a pharmaceutically acceptable carrier compatible with the chosen method of administration of the composition, a compound of formula (I), in one of its isomeric and enantiomeric forms, or a salt thereof with a pharmaceutically acceptable base.

The term "pharmaceutically acceptable carrier" refers to a medium compatible with the skin, mucous membranes and skin appendages.

The compositions of the present invention may be administered topically. Preferably, the composition is packaged in a form suitable for topical application.

When applied topically, the pharmaceutical composition of the invention is particularly useful for the treatment of the skin and mucous membranes, and it may be in liquid, paste or solid form, in particular in the form of ointments, creams, solutions or gels.

Compositions for topical application will contain the compounds of the invention in concentrations of generally from 0.001 to 10% by weight, preferably from 0.01 to 5% by weight, based on the total weight of the composition.

The compounds of general formula (I) according to the invention can also be used in the cosmetic field, in particular for protecting against the harmful effects of sunlight, for protecting and/or combating light-induced or chronological ageing of the skin and skin appendages.

Thus, a further subject of the invention is a composition comprising, in a cosmetically acceptable support, at least one compound of formula (I). The term "cosmetically acceptable medium" refers to a medium that is compatible with the skin, mucous membranes, and skin appendages.

Another subject of the invention is the cosmetic use of a composition containing at least one compound of general formula (I) for preventing and/or treating the signs of skin aging.

A further subject of the invention is the cosmetic use of a composition comprising at least one compound of formula (I) for body and hair hygiene.

The cosmetic compositions according to the invention comprise, in a cosmetically acceptable support, the compound of general formula (I), or one of its isomeric and enantiomeric forms, or a salt thereof with a cosmetically acceptable base, and may in particular be in the form of creams, emulsions, gels, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, impregnated pads, solutions, sprays, foams, sticks, soaps, washing bases or shampoos.

The concentration of the compounds of formula (I) in the cosmetic composition is preferably from 0.001 to 10% by weight, based on the total weight of the composition.

The above-mentioned pharmaceutical and cosmetic compositions may also contain inert additives or, in the case of pharmaceutical compositions, also pharmacologically active additives or combinations of these additives, in particular:

a wetting agent;

a flavoring agent;

preservatives, such as parabens;

a stabilizer;

a moisture regulator;

a pH adjusting agent;

an osmotic pressure regulator;

an emulsifier;

UV-A and UV-B screening agents;

antioxidants, such as alpha-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene, superoxide dismutase, dihydroubiquinone, sodium pyrophosphate;

an emollient;

humectants, such as glycerol, PEG 400, thiomorpholine and its derivatives, or urea;

anti-seborrheic or anti-acne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, salts or derivatives thereof, or benzoyl peroxide.

Of course, one skilled in the art will be careful to select the optional compounds to be added to these compositions so that the inherent advantages of the invention are not, or are not substantially, compromised by the additions contemplated.

Several preparation examples of the compounds of general formula (I) according to the invention, the results of the biological activity of these compounds, and the various formulations based on these compounds will now be given by way of illustration and not by way of any limitation.

Examples 1: 4- (tetrahydrofuran-4-yl) benzene-1, 3-diol

a) 4- (2, 4-bis (benzyloxy) phenyl) tetrahydropyran-4-ol

To a solution of 1.85 g of 2, 4-bis (benzyloxy) -1-bromobenzene cooled to-70 deg.C in 20 ml of tetrahydrofuran was added 2.4 ml of a 2.5M solution of n-butyllithium in hexane. The reaction mixture was stirred at-70 ℃ for 1 hour and 555. mu.l of tetrahydro-4H-pyran-4-one was added. The reaction mixture was stirred at-70 ℃ for 1 hour, then left overnight, and returned to ambient temperature. The reaction mixture was poured into a 15 ml saturated solution of ammonium chloride to which 2 ml of 2M hydrochloric acid was added, followed by extraction with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel, eluting with 70:30 heptane, ethyl acetate.

This gave 820 mg of 4- (2, 4-bis (benzyloxy) phenyl) tetrahydropyran-4-ol as a white solid. The yield = 42%.

b) 4- (tetrahydrofuran-4-yl) benzene-1, 3-diol

A mixture of 815 mg of 4- (2, 4-bis (benzyloxy) phenyl) tetrahydrofuran-4-ol in 10 ml of ethyl acetate is stirred in the presence of 244 mg of palladium on carbon (10%) at ambient temperature and under a hydrogen pressure of 5 bar for 17 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue (394 mg) was crystallized from ethyl acetate.

275 mg of 4- (tetrahydrofuran-4-yl) benzene-1, 3-diol are obtained in the form of a white crystalline solid. The yield = 68%.

Examples 2: 4- (tetrahydrothiopyran-4-yl) benzene-1, 13-diol

a) 1-bromo-2, 4-di (methoxymethoxy) benzene

42.56 g of potassium carbonate are added to a solution of 20.0 g of 4-bromoresorcinol (97%) in 200 ml of acetone. The reaction mixture was stirred at 5 ℃ for 10 minutes, and then 23.4 ml of chloromethyl methyl ether was added dropwise. The reaction mixture was stirred at ambient temperature for 3 hours. The solvent was evaporated and the residue was dissolved in a water-ethyl acetate mixture. The aqueous phase is extracted with ethyl acetate and the organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on silica gel eluting with 90:10 heptane, ethyl acetate.

27.94 g of 1-bromo-2, 4-di (methoxymethoxy) benzene were obtained as a colorless oil. The yield = 99%.

b) 4- (2, 4-bis (methoxymethoxy) phenyl) tetrahydrothiopyran-4-ol

To a solution of 5.54 g of 1-bromo-2, 4-bis (methoxymethoxy) benzene in 80 ml of tetrahydrofuran was added 6.35 ml of tetramethylethylenediamine. The mixture was cooled to-70 ℃ and 16.8 ml of a 2.5M solution of n-butyllithium in hexane were added. The reaction mixture was stirred at-70 ℃ for 1 hour and a solution of 2.79 g of tetrahydrothiopyran-4-one in 30 ml of tetrahydrofuran was added. The reaction mixture was stirred at-70 ℃ for 1 hour and then left at ambient temperature overnight. 50 ml of 2M hydrochloric acid was added, and the reaction mixture was stirred vigorously for 15 minutes, followed by extraction with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with a 75:25 mixture of heptane to ethyl acetate.

2.97 g of 4- (2, 4-bis (methoxymethoxy) phenyl) tetrahydrothiopyran-4-ol are obtained in the form of a yellow oil. The yield = 47%.

C) 5- (2, 4-bis (methoxymethoxy) phenyl) -3, 6-dihydro-2H-thiopyran

To a solution of 2.96 g of 4- (2, 4-bis (methoxymethoxy) phenyl) tetrahydrothiopyran-4-ol in 60 ml of toluene was added 22 mg of camphorsulfonic acid. The mixture was refluxed for 1 hour, the solvent was evaporated and the residue was chromatographed on silica gel eluting with 80:20 heptane ethyl acetate.

1.90 g of 5- (2, 4-bis (methoxymethoxy) phenyl) -3, 6-dihydro-2H-thiopyran were obtained as a yellow oil. The yield = 68%.

d) 4- (2, 4-bis (methoxymethoxy) phenyl) tetrahydrothiopyran

A mixture of 1.89 g of 4- (2, 4-bis (methoxymethoxy) phenyl) -3, 6-dihydro-2H-thiopyran in 20 ml of ethyl acetate was stirred in the presence of 1.89 g of palladium on carbon (10%) at 50 ℃ and a hydrogen pressure of 80 bar for 8 hours. The reaction mixture was filtered through celite and the filtrate was evaporated.

This gave 1.48 g of 4- (2, 4-bis (methoxymethoxy) phenyl) tetrahydrothiopyran as an oil. The yield = 77%.

e) 4- (tetrahydrothiopyran-4-yl) benzene-1, 3-diol

To a solution of 1.47 g 4- (2, 4-bis (methoxymethoxy) phenyl) tetrahydrothiopyran in 18 ml methanol and 3 ml ethyl acetate was added 18 ml 1M hydrochloric acid. The mixture was stirred at ambient temperature for 3 hours and heated at 50 ℃ for 17 hours. To the reaction mixture was added 12.0 ml of a saturated solution of sodium hydrogencarbonate, which was vigorously stirred for 20 minutes, followed by separation by settling. The aqueous phase is extracted with ethyl acetate, the organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel, eluting with 70:30 heptane, ethyl acetate. The resulting solid was dissolved in diethyl ether and heptane, filtered and dried.

The resulting solid was crystallized from diethyl ether, filtered and dried.

30 mg of 4- (tetrahydrothiopyran-4-yl) benzene-1, 3-diol are obtained in the form of a white powder. The yield = 3%.

Examples 3: cis-4- (2, 6-dimethyltetrahydropyran-4-yl) benzene-1, 3-diol

a) Cis-2, 6-dimethyltetrahydropyran-4-one

10 g of 2, 6-dimethyl-gamma-pyrone are dissolved in 200 ml of methanol, and then 0.8 g of palladium on carbon (10%) are added. The reaction mixture was stirred under 25 atmospheres of hydrogen for 24 hours. The reaction mixture was filtered, and the solvent was distilled off to recover 8.81 g of cis-2, 6-dimethyltetrahydropyran-4-one. The yield = 88%.

b) 4- (2, 4-bis (methoxymethoxy) phenyl) -2, 6-dimethyltetrahydrofuran-4-ol

To a solution of 2.65 g of 1-bromo-2, 4-bis (methoxymethoxy) benzene in 40 ml of tetrahydrofuran was added 3.0 ml of tetramethylethylenediamine. The mixture was cooled to-70 ℃ and 8.0 ml of 2.5M n-butyllithium/hexane were added. The reaction mixture was stirred at-70 ℃ for 1 hour and a solution of 1.47 g cis-2, 6-dimethyltetrahydropyran-4-one in 15 ml tetrahydrofuran was added. The reaction mixture was stirred at-70 ℃ for 1 hour and then left at ambient temperature overnight. 25 ml of 2M hydrochloric acid were added, and the reaction mixture was stirred vigorously for 15 minutes, followed by extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel, eluting with 75:25 heptane, ethyl acetate.

562 mg of 4- (2, 4-bis (methoxymethoxy) phenyl) -2, 6-dimethyltetrahydropyran-4-ol are obtained as a yellow oil. The yield = 18%.

c) 4- (2, 4-bis (methoxymethoxy) phenyl) -2, 6-dimethyl-3, 6-dihydro-2H-pyran

To a solution of 247 mg of 4- (2, 4-bis (methoxymethoxy) phenyl) -2, 6-dimethyltetrahydropyran-4-ol in 5 ml of toluene was added 2 mg of camphorsulfonic acid. The mixture was refluxed for 2 hours. The solvent was evaporated and the residue was chromatographed on silica gel, eluting with an 80:20 heptane to ethyl acetate mixture.

132 mg of 4- (2, 4-bis (methoxymethoxy) phenyl) -2, 6-dimethyl-3, 6-dihydro-pyran are obtained in the form of a yellow oil. The yield = 57%.

d) Cis-4- (2, 4-bis (methoxymethoxy) phenyl) -2, 6-dimethyltetrahydropyran

A mixture of 132 mg of cis-4- (2, 4-bis (methoxymethoxy) phenyl) -2, 6-dimethyl-3, 6-dihydro-2H-pyran in 10 ml of methanol was stirred in the presence of 28 mg of palladium on carbon (10%) at ambient temperature and 3 bar of hydrogen pressure for 5 hours. The reaction mixture was filtered and the filtrate was evaporated.

125 mg of cis-4- (2, 4-bis (methoxymethoxy) phenyl) -2, 6-dimethyltetrahydropyran are obtained in the form of a white powder. The yield = 94%.

e) Cis-4- (2, 6-dimethyltetrahydropyran-4-yl) benzene-1, 3-diol

To a solution of 120 mg of cis-4- (2, 4-bis (methoxymethoxy) phenyl) -2, 6-dimethyltetrahydropyran in 2.5 ml of methanol was added 1.9 ml of 1N hydrochloric acid. The mixture was stirred at ambient temperature overnight and then refluxed for 1 hour. 1.5 ml of a saturated solution of sodium hydrogencarbonate was added, and the reaction mixture was vigorously stirred for 20 minutes and then separated by settling. The aqueous phase is extracted with ethyl acetate and the organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on silica gel, eluting with 95:5 dichloromethane: methanol. This gave 40 mg of cis-4- (2, 6-dimethyltetrahydropyran-4-yl) benzene-1, 3-diol as a white powder with a yield = 46%.

Examples 4: trans-4- (2-methyltetrahydropyran-4-yl) benzene-1, 3-diol

a) 2-methyl-2, 3-dihydropyran-4-one

To a solution of 2.07 g Danishefsky diene (((E) -3-methoxy-1-methyleneallyloxy) trimethylsilane) and 581 mg acetaldehyde in 25 ml diethyl ether cooled to-70 deg.C was added 1.7 ml BF₃·Et₂And O. The mixture was stirred at-70 ℃ for 1 hour. 10 ml of a saturated solution of sodium hydrogencarbonate were added and the reaction mixture was extracted with diethyl ether. The organic phases are combined and washed with magnesium sulphateDrying, filtering and cold evaporation.

1.35 g of 2-methyl-2, 3-dihydropyran-4-one are obtained as an orange oil. The yield = 100%.

b) 2-Methyltetrahydropyran-4-one

1.35 g 2-methyl-2, 3-dihydropyran-4-one are stirred in 15 ml ethyl acetate in the presence of 270 mg palladium on carbon (10%) for 3 days at ambient temperature under a hydrogen atmosphere. The reaction mixture was filtered through filter paper and the filtrate was evaporated. The residue was chromatographed on silica gel eluting with 60:40 pentane/ether.

787 mg of 2-methyltetrahydrofuran-4-one were obtained as a yellow oil. The yield = 57%.

c) 4- (2, 4-bis (benzyloxy) phenyl) -2-methyltetrahydropyran-4-ol

To a solution of 2.06 g 2, 4-bis (benzyloxy) -1-bromobenzene in 20 ml tetrahydrofuran cooled to-70 ℃ was added 2.7 ml of a 2.5M solution of n-butyllithium in hexane. The reaction mixture was stirred at-70 ℃ for 10 minutes and a solution of 766 mg of 2-methyltetrahydropyran-4-one in 7 ml of tetrahydrofuran was added. The reaction mixture was stirred at-70 ℃ for 1 hour and then allowed to stand for 3 hours to return to ambient temperature. It is poured into a saturated solution of 20 ml of sodium chloride to which 3 ml of 2M hydrochloric acid have been added and extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel, eluting with 70:30 heptane, ethyl acetate.

838 mg of 4- (2, 4-bis (benzyloxy) phenyl) -2-methyltetrahydropyran-4-ol are obtained as a yellow oil. The yield = 37%.

d) Trans-4- (2-methyltetrahydropyran-4-yl) benzene-1, 3-diol

830 mg of 4- (2, 4-bis (benzyloxy) phenyl) -2-methyltetrahydropyran-4-ol are stirred in 12 ml of ethyl acetate in the presence of 415 mg of palladium on carbon (10%) for 3 hours at ambient temperature and under a hydrogen pressure of 5 bar. The reaction mixture was filtered and the filtrate was evaporated. The residue (516 mg) was chromatographed on silica gel, eluting with 80:20 heptane: ethyl acetate.

37 mg of trans-4- (2-methyltetrahydropyran-4-yl) benzene-1, 3-diol are obtained in the form of a white powder. The yield = 8%.

Examples 5: cis-4- (2-methyltetrahydropyran-4-yl) benzene-1, 3-diol

In the previous purification step, a further polar fraction is separated: 57 mg of cis-4- (2-methyltetrahydropyran-4-yl) benzene-1, 3-diol are obtained in the form of a white powder. The yield = 13%.

Examples 6: trans-4- (2-ethyltetrahydrofuran-4-yl) benzene-1, 3-diol

In a similar manner to example 4, but using propionaldehyde at step 4a, then repeating steps 4b, 4c, and 4d in a similar manner yields trans-4- (2-ethyltetrahydropyran-4-yl) benzene-1, 3-diol.

Examples 7: cis-4- (2-ethyltetrahydropyran-4-yl)) Benzene-1, 3-diol

In a similar manner to example 5, by purifying the product obtained in the synthesis of example 6, a further polar fraction cis-4- (2-ethyltetrahydropyran-4-yl) benzene-1, 3-diol was obtained.

Examples 8: trans-4- (2-hydroxymethyltetrahydropyran-4-yl) benzene-1, 3-diol

In a similar manner to example 4, but using benzyloxyacetaldehyde at step 4a, then repeating steps 4b, 4c and 4d in a similar manner to give trans-4- (2-hydroxymethyltetrahydropyran-4-yl) benzene-1, 3-diol.

Examples 9: 4- (2,2,6, 6-tetramethyltetrahydropyran-4-yl) benzene-1, 3-diol

a) 2,2,6, 6-tetramethyltetrahydropyran-4-one

Commercial phorone 5 g was dissolved in 36 ml of 1M hydrochloric acid solution and heated at 40 ℃ for 2 days. The reaction mixture was distilled (63-65 ℃ C.) to give 3.0 g of a pale yellow oil. The yield = 53%.

b) 4- (2,2,6, 6-tetramethyltetrahydropyran-4-yl) benzene-1, 3-diol

In a similar manner to example 4, but using 2,2,6, 6-tetramethyltetrahydropyran-4-one in step 4c, then repeating step 4d in a similar manner to give 4- (2,2,6, 6-tetramethyltetrahydropyran-4-yl) benzene-1, 3-diol.

Examples 10: 4- (tetrahydrofuran-3-yl) benzene-1, 3-diol

a) Dihydrofuran-3-one

A solution of 16.8 g of chromium (VI) oxide in 50 ml of water and 15.6 ml of 95% sulfuric acid is added dropwise to a solution of 4.9 g of 3-hydroxytetrahydrofuran in 450 ml of acetone. The reaction mixture was stirred at 0 ℃ for 40 minutes. 450 ml of water was added and extracted with diethyl ether. The organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with 60:40 pentane/ether. 1.78 g of dihydrofuran-3-one are obtained as a colorless oil. The yield = 28%.

b) 3- (2, 4-bis (benzyloxy) phenyl) -2, 5-dihydrofuran

To a solution of 4.74 g 2, 4-bis (benzyloxy) -1-bromobenzene in 50 ml tetrahydrofuran cooled to-70 ℃ was added 2 ml of a 2.5M solution of n-butyllithium in hexane. The reaction mixture was stirred at-70 ℃ for 10 minutes, a solution of 1.77 g of dihydrofuran-3-one in 15 ml of tetrahydrofuran was added and the reaction mixture was stirred at-70 ℃ for 1 hour and then left overnight to return to ambient temperature. The reaction mixture was poured into 35 ml of a saturated solution of ammonium chloride to which 6.5 ml of 2M hydrochloric acid had been added, followed by extraction with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel, eluting with 60:40 heptane, ethyl acetate.

1.57 g of 3- (2, 4-bis (benzyloxy) phenyl) -2, 5-dihydrofuran were obtained as a yellow oil. The yield = 34%.

c) 4- (tetrahydrofuran-3-yl) benzene-1, 3-diol

A mixture of 1.56 g of 3- (2, 4-bis (benzyloxy) phenyl) tetrahydrofuran-3-ol in 25 ml of ethyl acetate was stirred in the presence of 780 mg palladium on carbon (10%) at ambient temperature and 5 bar of hydrogen pressure for 7 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was chromatographed on silica gel, eluting with 50:50 heptane, ethyl acetate. The solid obtained was crystallized from dichloromethane/heptane. 285 mg of 4- (tetrahydrofuran-3-yl) benzene-1, 3-diol are obtained in the form of a white powder. The yield = 36%.

Examples 11: 4- (tetrahydrothiophen-3-yl) benzene-1, 3-diol

a) 3- (2, 4-bis (methoxymethoxy) phenyl) tetrahydrothiophen-3-ol

To a solution of 13.10 g of 1-bromo-2, 4-di (methoxymethoxy) benzene in 200 ml of tetrahydrofuran cooled to-70 ℃ was added 23.0 ml of a 2.5M n-butyllithium/hexane solution. The reaction mixture was stirred at-70 ℃ for 20 minutes, 4.90 ml of tetrahydrothiophen-3-one were added. The reaction mixture was stirred at-70 ℃ for 1 hour and then left overnight to return to ambient temperature. The reaction mixture was poured into 150 ml of a saturated solution of ammonium chloride to which 30 ml of 2M hydrochloric acid had been added, followed by extraction with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel, eluting with 85:15 heptane, ethyl acetate.

4.10 g of 3- (2, 4-bis (methoxymethoxy) phenyl) tetrahydrothiophen-3-ol are obtained as an orange oil. The yield = 29%.

b) 4- (4, 5-dihydrothiophen-3-yl) benzene-1, 3-diol

To a solution of 4.10 g of 3- (2, 4-bis (methoxymethoxy) phenyl) tetrahydrothiophen-3-ol in 50 ml of methanol and 8 ml of ethyl acetate was added 50 ml of 1N hydrochloric acid. The mixture was heated at 50 ℃ for 4 hours. 40 ml of a saturated solution of sodium hydrogencarbonate were added, and the reaction mixture was stirred vigorously for 20 minutes and then separated by settling. The aqueous phase is extracted with ethyl acetate and the organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on silica gel, eluting with 80:20 heptane, ethyl acetate.

400 ml of 4- (4, 5-dihydrothien-3-yl) benzene-1, 3-diol are obtained as yellow oil. The yield = 15%.

c) 4- (tetrahydrothiophen-3-yl) benzene-1, 3-diol

A mixture of 400 mg of 4- (4, 5-dihydrothiophen-3-yl) benzene-1, 3-diol in 10 ml of ethyl acetate is stirred in the presence of 400 mg of palladium on carbon (10%) at ambient temperature and 6 bar of hydrogen pressure for 4 days. The reaction mixture was filtered and the filtrate was evaporated. The residue was chromatographed on silica gel, eluting with 80:20 heptane, ethyl acetate. The solid obtained was crystallized from dichloromethane/heptane.

232 mg of 4- (tetrahydrothiophen-3-yl) benzene-1, 3-diol are obtained in the form of a cream-colored solid. The yield = 57%.

Examples 12: 4- (6-oxaspiro [4.5]]Decan-9-yl) benzene-1, 3-diol

a) 6-oxaspiro [4.5] decan-9-ones

5 g of (E) -3- [ (tert-butyldimethylsilyloxy) but-1, 3-dienyl ] dimethylamine are added at ambient temperature to a solution of 3.9 g of cyclopentanone in 11 ml of 2-butanol. The reaction mixture was stirred at ambient temperature for 18 hours, the solvent was evaporated and the residue was then dissolved in 100 ml of diethyl ether. The mixture was cooled to-78 ℃ and then 1.9 ml of acetyl chloride was slowly added. The mixture was stirred at-78 ℃ for 10 minutes and then 100 ml of saturated ammonium chloride solution was added to stop the reaction. The resulting mixture was extracted with 200 ml of diethyl ether, and the organic phases were combined and dried over anhydrous sodium sulfate. After evaporation the residue is chromatographed on silica gel (heptane: ethyl acetate 8: 2). The residue was dissolved in 50 ml of methanol, and 200 mg of palladium on carbon (10%) were added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours, filtered, and then methanol was distilled off. 600 mg of 6-oxaspiro [4.5] decan-9-one were obtained. The yield = 18%.

b) 4- (6-oxaspiro [4.5] decan-9-yl) benzene-1, 3-diol

In a similar manner to example 1, but using 6-oxaspiro [4.5] decan-9-one in step 1a, then repeating step 1b in a similar manner to give 4- (6-oxaspiro [4.5] decan-9-yl) benzene-1, 3-diol.

Examples 13: 4-chloro-6- (tetrahydropyran-4-yl) benzene-1, 3-diol

To a solution of 2 g of 4- (tetrahydropyran-4-yl) benzene-1, 3-diol (example 1) in 30 ml of dichloromethane was added 2.4 g N-chlorosuccinimide at 0 ℃. The reaction mixture was stirred at ambient temperature for 16 hours, extracted with dichloromethane and then washed with water. The organic phases were combined and dried over sodium sulfate. After evaporation the residue is chromatographed on silica gel (75: 25 heptane: ethyl acetate). 400 mg of 4-chloro-6- (tetrahydropyran-4-yl) benzene-1, 3-diol are obtained. The yield = 17%.

Examples 14: 4-fluoro-6- (tetrahydropyran-4-yl) benzene-1, 3-diol

To a solution of 2 g of 4- (tetrahydropyran-4-yl) benzene-1, 3-diol (example 1) in 20 ml of acetonitrile was added 3.65 g N-fluoro-N' - (chloromethyl) triethylenediamine bis (tetrafluoroborate) at 0 ℃. The reaction mixture was stirred at ambient temperature for 16 hours, then extracted with ethyl acetate, and the organic phase was washed and dried over sodium sulfate. The residue after evaporation is chromatographed on silica gel (9: 1 heptane: ethyl acetate). 200 mg of 4-fluoro-6- (tetrahydropyran-4-yl) benzene-1, 3-diol are obtained. The yield = 10%.

Examples 15: 4- (2, 2-diethyltetrahydropyran-4-yl) benzene-1, 3-diol

In a similar manner to example 12a, but using diethyl ketone, then step 12b is repeated in a similar manner to give 4- (2, 2-diethyltetrahydropyran-4-yl) benzene-1, 3-diol.

Examples 16: 4- (tetrahydropyran-3-yl) benzene-1, 3-diol

In a similar manner to example 1, but using dihydropyran-3-one, 4- (tetrahydropyran-3-yl) benzene-1, 3-diol is obtained.

Examples 17: tyrosinase activity inhibition assay

The activity of the inhibitors was determined using lysates of B16F1 cells (murine melanoma cell line). Tyrosinase, present in these cells, catalyzes the reaction of L-tyrosine to L-DOPA by hydroxylation and subsequent oxidation of L-DOPA to dopaquinone in the presence of an L-tyrosine substrate. In the presence of MBTH (3-methyl-2-benzothiazolinone hydrazone), dopaquinone was trapped, forming a pink complex that absorbs at 520 nm.

B16F1 cells were cultured in DMEM medium +10% fetal bovine serum +10^-97% CO in M.alpha. -MSH₂The cells were cultured at 37 ℃ for 4 days. It was trypsinized, washed in PBS, counted and pelleted. Mixing the granules with 10⁷Cells/ml were placed in lysis buffer (10 mM sodium phosphate, pH 6.8-1% Igepal) and the suspension was sonicated for 10 seconds. After centrifugation at 4000 rpm for 30 minutes, the resulting supernatant constituted the cell lysate which was the source of tyrosinase in the enzyme-catalyzed assay.

The assay was performed in duplicate in 384 well plates in a total volume of 50. mu.l. Each well contains:

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

5 μ l dilutions of inhibitor in DMSO;

half of 5. mu.l of cell lysate was diluted in 50 mM Tris HCl buffer, pH 7.5.

Plates were incubated at 37 ℃ and after 6 hours spectroscopic readings were taken at 520 nM. To avoid any possible product absorption, the system used corrected absorbance (absorbance after 6 hours-absorbance at time zero).

Inhibitors were tested in a dose-response fashion to calculate IC₅₀(dosage to inhibit 50% enzyme activity).

Several internal controls were added for each experiment:

controls for 100% activity: mu.l of inhibitor was replaced by 5. mu.l DMSO,

controls for 50% activity: mu.l of inhibitor was replaced with 5. mu.l of phenylthiourea/DMSO (300. mu.M),

controls for 0% activity: the L-tyrosine substrate was replaced with buffer B.

The results obtained for the compounds of the invention are shown in table a:

watch (A) A

Examples 18: melanogenesis inhibition assay

The inhibition of melanogenesis was determined in MNT1 human melanoma cells according to a protocol modified according to the method of Reigner et al, Cell mol. Biol (1999) 45: 969-980. The basis of this assay is the concomitant incorporation of 2 radiolabeled tracers:¹⁴the incorporation of C-thiouracil into newly synthesized melanogenesis reflects melanogenesis; while³Incorporation of H-leucine into the protein reflects cell survival and thus toxicity of the test compound.

MNT1 cells were seeded into 96-well plates in the presence of test compounds and radioisotopes. After 24 hours incubation at 37 ℃, the cells were washed and the number of 2 radioisotopes was determined. Test compounds were evaluated in a dose-response manner toBased on¹⁴Calculation of the incorporation Rate of C IC for the inhibition of melanogenesis₅₀To do so¹⁴The C doping rate is determined by³The H incorporation rate is normalized. Also according to³H incorporation efficiency the IC for cytotoxicity was calculated₅₀。

This assay therefore makes it possible to distinguish products which specifically inhibit melanogenesis from products which are cytotoxic to melanocytes.

Examples 19: preparation

This example illustrates various formulations based on the compounds of the present invention.

Topical formulations

(a) Ointment formulation

Compound 10.020 g

81.700 g of isopropyl myristate

Liquid vaseline 9.100 g

Silica gel (Aerosil 200) 9.180 g

(b) Ointment formulation

Compound 60.300 g

White Vaseline, proper amount to 100 g of pharmaceutical grade

(c) Non-ionic water/oil cream

Compound 10.100 g

Of emulsified lanolin alcohols, waxes and oils

39.900 g of mixture (Anhydrous eucerin)

0.075 g of methylparaben

Propyl p-hydroxybenzoate 0.075 g

Proper amount of sterile softened water to 100 g

(d) Lotion formulation

Compound 60.100 g

Polyethylene glycol (PEG 400) 69.900 g

95% ethanol 30.000 g

(e) Hydrophobic ointment

Compound 20.300 g

36.400 g of isopropyl myristate

Silicone oil (Rhodorsil 47V 300) 36.400 g

Beeswax 13.600 g

Proper amount of silicone oil (Abil 300000 cst) to 100 g

(f) Non-ionic oil/water cream

Compound 41.000 g

Cetyl alcohol 4.000 g

Glycerol monostearate 2.500 g

Stearic acid polyethylene glycol (50) ester 2.500 g

Shea butter 9.200 g

Propylene glycol 2.000 g

0.075 g of methylparaben

Propyl p-hydroxybenzoate 0.075 g

Proper amount of sterile softened water to 100 g

Claims (9)

1. A compound of the following general formula (I) and salts of the compounds of the general formula (I), their isomers and enantiomeric forms:

wherein:

r1, R2, R3 and R4, which may be the same or different, represent:

-hydrogen, and (C) hydrogen,

- C₁-C₄alkyl radical，

-a hydroxymethyl group, a hydroxyethyl group,

- (C₁-C₄alkoxy) carbonyl groups, in which the carbonyl groups are bonded,

- C₁-C₄an alkoxy group,

-a hydroxyl group,

or

R1 and R2 are linked to each other to form, together with the carbon atoms to which they are linked, a carbocyclic ring containing 5 or 6 carbon atoms, and R3 and R4, which may be identical or different, represent:

-hydrogen, and (C) hydrogen,

- C₁-C₄alkyl radical

Or

R1 and R4 are linked to each other to form a- (CH)₂)₂-or- (CH)₂)₃-a chain, while R2 and R3, which may be identical or different, represent:

-hydrogen, and (C) hydrogen,

- C₁-C₄an alkyl group;

x represents an oxygen atom or a sulfur atom;

y represents a hydrogen, chlorine or fluorine atom;

m may be 1 or 2, n may be 0 or 1, and m is 1 or 2 when n =0, and m =1 when n = 1.

2. A compound according to claim 1, characterized in that it is in the form of a salt with a base selected from the group consisting of organic and inorganic bases.

3. A compound according to claim 1 or 2, characterized in that it is in the form of a hydrate or solvate.

4. A compound according to any one of claims 1 to 3, characterized in that:

r1 represents hydrogen, C₁-C₄An alkyl group or a hydroxymethyl group, in the form of a linear or branched alkyl group,

r2 represents hydrogen, and R2 represents hydrogen,

r3 represents hydrogen, and R3 represents hydrogen,

r4 represents hydrogen, and R4 represents hydrogen,

x represents an oxygen atom, and X represents an oxygen atom,

y represents a hydrogen or fluorine atom,

m =1 and n =1,

and salts of these compounds, as well as isomers and enantiomeric forms thereof.

5. A compound according to any one of claims 1 to 4, characterized in that it is selected from the following compounds:

1: 4- (tetrahydropyran-4-yl) benzene-1, 3-diol

2: 4- (tetrahydrothiopyran-4-yl) benzene-1, 3-diol

3: 4- (cis-2, 6-dimethyltetrahydropyran-4-yl) benzene-1, 3-diol

4: trans-4- (2-methyltetrahydropyran-4-yl) benzene-1, 3-diol

5: cis-4- (2-methyltetrahydropyran-4-yl) benzene-1, 3-diol

6: trans-4- (2-ethyltetrahydropyran-4-yl) benzene-1, 3-diol

7: cis-4- (2-ethyltetrahydropyran-4-yl) benzene-1, 3-diol

8: trans-4- (2-hydroxymethyltetrahydropyran-4-yl) benzene-1, 3-diol

9: 4- (2,2,6, 6-tetramethyltetrahydropyran-4-yl) benzene-1, 3-diol

10: 4- (tetrahydrofuran-3-yl) benzene-1, 3-diol

11: 4- (tetrahydrothiophen-3-yl) benzene-1, 3-diol

12: 4- (6-oxaspiro [4.5] decan-9-yl) benzene-1, 3-diol

13: 4-chloro-6- (tetrahydropyran-4-yl) benzene-1, 3-diol

14: 4-fluoro-6- (tetrahydropyran-4-yl) benzene-1, 3-diol

15: 4- (2, 2-diethyltetrahydropyran-4-yl) benzene-1, 3-diol

16: 4- (tetrahydropyran-3-yl) benzene-1, 3-diol

17: trans-4- (5-hydroxymethyl-tetrahydrofuran-3-yl) benzene-1, 3-diol

18: cis-4- (5-hydroxymethyl-tetrahydrofuran-3-yl) benzene-1, 3-diol

19: trans-4-fluoro-6- (5-hydroxymethyltetrahydrofuran-3-yl) benzene-1, 3-diol

20: cis-4-fluoro-6- (5-hydroxymethyltetrahydrofuran-3-yl) benzene-1, 3-diol

21: trans-4-fluoro-6- (2-hydroxymethyltetrahydropyran-4-yl) benzene-1, 3-diol

22: cis-4-fluoro-6- (2-hydroxymethyltetrahydropyran-4-yl) benzene-1, 3-diol

23: cis-4- (8-oxabicyclo [3.2.1] oct-3-yl) benzene-1, 3-diol

24: trans-4- (8-oxabicyclo [3.2.1] oct-3-yl) benzene-1, 3-diol

25: 4-fluoro-6- (tetrahydrothiopyran-4-yl) benzene-1, 3-diol.

6. Use of at least one compound according to any one of claims 1 to 5 as a medicament.

7. Use according to claim 6, characterized in that said compound has tyrosinase inhibitory activity.

8. Use according to claim 6 or 7 for the treatment and/or prevention of pigmentary lesions.

9. The use of claim 8, wherein said pigmented lesion is selected from the group consisting of: chloasma, lentigo, age spots, irregular hyperpigmentation associated with photoaging, freckles, post-inflammatory hyperpigmentation caused by abrasion, burns, scars, skin diseases, contact allergies; nevi, hereditary hyperpigmentation, hyperpigmentation of metabolic or pharmaceutical origin, melanoma or any other hyperpigmented lesion.