RS49973B - REZORCINOLA DERIVATIVES - Google Patents

Abstract

A topical pharmaceutical composition for skin whitening - or reducing skin pigmentation - containing a certain amount of a compound of formula I, wherein X is hydrogen; OR 1, wherein R 1 represents hydrogen, (C 1 -C 6) alkyl or aryl- (C 1 -C 6) alkyl; OCOR2 wherein R2 represents (C1-C6) alkyl, aryl- (C1-C6) alkyl or phenyl; halogen; (C1-C6) alkyl; aryl- (C 1 -C 6) alkyl; SR3 wherein R3 is hydrogen, (C1-C6) alkyl or aryl- (C1-C6) alkyl; or NHR1 where R1 is as defined above; n is 0 to 3; and the dashed line represents a double bond of choice; or a pharmaceutically acceptable salt thereof, which is effective for skin whitening or reduction of skin pigmentation; and a pharmaceutically acceptable carrier. The application contains 34 requests.

Description

The present invention relates to the use of certain resorcinol derivatives as skin whitening agents.

The terms "whitening agent" and "depigmentation agent" are used interchangeably throughout this text.

Skin color in humans comes from a series of complex cellular processes that take place within a unique group of cells called melanocytes. Melanocytes are located in the lower layer of the epidermis, and have the function of synthesizing the pigment, meianin, which protects the body from the harmful effects of ultraviolet radiation.

When the skin is exposed to ultraviolet radiation, such as that found in sunlight, melanocytes increase melanin synthesis. Melanin is stored in melanosomes, vesicles found in the cell. Melanosomes are detached from the cells and transported to the surface of the skin by keratinocytes, which release meianin in the melanosomes. The end result is that the visible part of the skin takes on a brown color commonly known as "tan". The skin acquires a dark color in proportion to the amount of meianin synthesized in meianocytes and transferred to keratinocytes.

The mechanism of formation of skin pigmentation, melanogenesis, is particularly complex and schematically includes the following main stages: Tyrosine—>-L - Dopa —»Dopachinone —>Dopachrome —> Melanins. The first two reactions in the series are catalyzed by the enzyme tyrosinase. The activity of tyrosinase is caused by the action of a-melanocyte stimulating hormone or UV rays to eventually form meianin as abnormal pain or pigmentation in the skin. It is generally known that substances that have a whitening effect act either directly on the vitality of epidermal melanocytes in which melanogenesis normally takes place and/or interfere with one of the phases in melanin biosynthesis. The active compounds used in the various methods and formulations of the present invention inhibit tyrosinase and thus inhibit or reduce biomelanin biosynthesis.

There is a great need for agents that allow places where meianine has been removed, such as spots or freckles, to return to normal skin color. For this purpose, various means (agents) and procedures have been developed and brought to the market. Examples of such drugs are (a) a procedure in which vitamin C (L-ascorbic acid), which has good reducing abilities, is administered orally in large quantities, (b) a procedure in which glutathione is administered parenterally, (c) a procedure in which a peroxide, such as hydrogen peroxide, zinc peroxide, sodium peroxide and the like, is believed to have the ability to bleach melamine, and (d) a procedure in which vitamin C or cysteine is administered locally (topically) in the form of ointments, creams, lotion or similar. The problem with vitamin C is stability and it becomes so unstable in water containing systems that it causes changes in smell and color. Thiol compounds, such as glutathione and cysteine, do not show a satisfactory depigmentation effect since the whitening process is very slow.

The substances that are most used nowadays as depigmentation agents are, in particular, hydroquinone and its derivatives, especially ethers such as hydroquinone monomethyl ether. These compounds, while working, are known to cause side effects, which can be dangerous. Hydroquinone, whose use is limited to a concentration of 2%, is both irritating and cytotoxic to melanocytes.

U, S. Patent 4,526,179 relates to certain hydroquinone esters with fats, which have good action, greater stability, and are less irritating than hydroquinone.

Japanese Patent Application No. 27909/86 relates to other hydroquinone derivatives which do not have the disadvantages of hydroquinone but exhibit relatively weak activity.

U.S. Patent 5,449,518 relates to 2,5-dihydroxyphenyl carboxylic acid derivatives as skin depigmentation agents.

European patent application EP 341,664A1 relates to certain resorcinol derivatives as tyrosinase inhibitors and skin depigmentation agents.

The use of topical depigmentation agents that are effective (effective) and harmless is especially desirable in the treatment of the following cases: regional hyperpigmentation caused by melanocyte hyperactivity, such as idiopathic melasma that occurs either during pregnancy (pregnancy mask or chloasma) or as a secondary phenomenon when using estrogen-progesterone contraceptives; local hyperpigmentation resulting from benign melanocyte hyperactivity and proliferation such as age spots or liver spots, accidental hyperpigmentation resulting from photosensitization and scarring; and certain forms of leukoderma such as vitiligo where, if the damaged skin cannot repigment, the remaining areas of normal skin become white

to equalize into a homogeneous white color of the rest of the skin.

The resorcinol dervates of formula I, which are defined below, are used in the various methods and formulations of this invention, are useful in the treatment of the aforementioned dermatological conditions as well as other dermatological conditions, some of which are listed later in this document, in persons who are being treated and wish, for medical or cosmetic reasons, to whiten or reduce skin pigmentation depending on the condition.

Resorcinol derivatives of formula I are also useful in the treatment of inflammatory diseases such as psoriasis and acne.

Description of the invention

The invention relates to the use of 4-cycloalkyl resorcinol having the formula:

where X is hydrogen; OR<1> where R<!> represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6)alkyl; OCOR<2> where R 2 represents (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl or phenyl; halogen; (C 1 -C 6 )alkyl;

aryl-(C 1 -C 6 )alkyl; SR<3> where R<3> represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6)alkyl; or NHR<1> where R<1> is as defined above.

it is Odo 3; and

the dashed line indicates the possibility of a double bond at that position.

The present invention also relates to pharmaceutically acceptable addition salts of acids and bases of compounds of formula I. The acids used to obtain pharmaceutically acceptable acid addition salts of the previously mentioned base compounds of this invention are those which form non-toxic acid addition salts, that is, salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succionate, maleate, fumarate, gluconate, saccharate, benzoate, metalsulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ie: 1,1-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic groups or combinations thereof.

The term "ary!", as used herein, refers to phenyl or naphthyl optionally substituted with one or more substituents, preferably from 0 to 2 substituents, independently selected from halogen, (d-C 6 alkyl, (C 1 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino, di-[(C 1 -C 6 )]amino, nitro,

cyano and trifluoromethyl.

The term "one or more substituents", as used herein, refers to the number of substituents which can be from one to the maximum possible number of substituents depending on the number of vacant binding sites.

The term "halogen" as used herein, unless otherwise indicated, includes chlorine, fluorine, bromine and iodine.

Examples of more specific embodiments of the subject invention are:

(a) compounds of formula I where the dashed line represents a single bond between two carbon atoms; (b) compounds of formula I where n is one; (c) compounds of formula I where X is hydrogen; (d) compounds of formula I where X is hydrogen, methyl or ethyl; (e) compounds of formula I where n is 0;

(0 compounds of formula I where n is 2; i

(g) compounds of formula I where X is benzyloxy.

In a preferred embodiment, the compound of formula 1 is 4-cyclohexylresorcinol or 4-cyclopentylresorcinol.

The subject invention also relates to a topical pharmaceutical composition, for skin whitening or skin pigmentation change in humans, containing an amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, which is effective for skin whitening or skin pigmentation reduction and a pharmaceutically acceptable carrier.

The present invention also relates to a method of skin whitening or skin pigmentation modification in humans, which comprises administering to humans an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, which is effective for skin whitening or skin pigmentation reduction.

The present invention also relates to a topical pharmaceutical formulation for inhibiting tyrosinase in humans, comprising an amount of a compound of formula I that effectively inhibits tyrosinase (tyrosinase-inhibitory effective amount), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of inhibiting tyrosinase in humans, which comprises administering a mammalian thyrosinase-inhibiting effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

The present invention also relates to a topical pharmaceutical composition for topical application for skin whitening or skin pigmentation in humans, comprising a tyrosinase-inhibiting effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention also relates to a method of skin whitening or reduction of skin pigmentation in humans, which comprises administering to humans a tyrosinase-inhibiting effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

The present invention also relates to a topical or transdermal pharmaceutical formulation for the treatment of inflammatory diseases such as acne or psoriasis in humans, comprising a certain amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, which is effective in the treatment of such diseases, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating inflammatory diseases such as psoriasis and acne in humans, which comprises administering to humans a certain amount of a compound of formula I or a pharmaceutically acceptable salt thereof, which is effective in treating such diseases.

The present invention also relates to a topical or transdermal pharmaceutical composition for the treatment of inflammatory diseases such as acne or psoriasis in humans, comprising a tyrosinase-inhibiting effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating inflammatory diseases such as psoriasis and acne in humans, which comprises administering a tyrosinase-inhibiting effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. The compounds of formula I can have chiral centers and therefore can occur in different, enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and all stereoisomers of the compounds of formula I and mixtures thereof, and to all pharmaceutical compositions and methods of treatment as defined above, which contain or include them.

The above formula I includes compounds which are identical to the described compounds, but the fact that they are one or. more hydrogen, carbon or other atoms replaced by their isotopes. Such compounds can be used as research and diagnostic tools in pharmacokinetic studies of metabolism and in binding assays.

Detailed description of the invention

Compounds of formula 1 can be prepared as described in the reaction schemes and considerations given below. Unless otherwise indicated, X, n, R<1>, R<2> and R<3> and structural formula I in the reaction schemes and considerations that follow are as previously described.

Reaction Schemes 1 to 4 illustrate various procedures for the synthesis of compounds of formula 1.

Referring to Scheme 1, compounds of formula I can be prepared by heating resorcinol with the corresponding cycloalkanol of formula (1) using polyphosphoric acid (PPA) or other suitable acid catalyst. When PPA is used, the reaction usually takes place with one to three equivalents of alcohol in pure PPA at a temperature between 100°C and 160°C.

Referring to Scheme 2, the starting material of formula (2) can be obtained by protection of commercially available 4-bromoresorcinol. Suitable protecting groups (PG) are methyl (CH 3 ) and benzyl (CH 2 C 6 H 5 ), and may be introduced by conventional procedures well known to one of ordinary skill in the art. For example, methyl and benzyl protected compounds can be obtained by alkylation of 4-bromoresorcinol with two equivalents of methyl iodide or with two equivalents of benzyl bromide, and five equivalents of potassium carbonate in acetone solvent at about room temperature.

Compounds of the general formula (3) are known and can be obtained by conventional procedures well known to a person skilled in the art. Compounds of formula (4) can be obtained by reacting compounds of formula (2) and compounds of formula (3) under Heck's conditions. In more detail, the Heck reaction is performed using palladium(II) acetate (one mole percent), triphenylphosphine (two mole percent) and triethylamine (one equivalent) and heating the reactive mixture in a suitable solvent (eg N,N-dimethylformamide (DMF)) at a temperature of about 80°C to about 130°C. Reduction of the compound having the formula (4) with di(isobutyl)aluminum hydride (DIBAL-H) gives the corresponding allyl alcohols of the formula (5). By hydrogenolysis of alcohols of formula (5), for example, using hydrogen gas and a metal as a catalyst, such as palladium-on-charcoal in ethanol, at a temperature close to room temperature, saturated analogues of formula (6) are obtained, which can then be deprotected under favorable conditions to obtain the corresponding resorcinols of formula I, in which X is a hydroxyl group. Alternatively, similar deprotection of alkyl alcohols of formula (5) gives the corresponding resorcinols of formula 1 in which X is a hydroxyl group.

Referring to Scheme 3, a compound of formula (5) or (6) is esterified with a suitable acyl chloride (R<2>COCl) under conventional conditions well known to one of ordinary skill in the art, then deprotected, to afford the corresponding compounds of formula I wherein X is OCOR<2>. For example, esterification can be performed by reacting an alcohol of formula (5) or (6) with one equivalent of acyl chloride and one equivalent of triethylamine in dichloromethane at a temperature close to room temperature. Alkylation of a compound of formula (5) or (6) with an alkyl iodide (R'1) in the presence of a base (using, for example, one equivalent of sodium hydride and the desired alkylating agent in the form of an alkyl chloride, bromide or iodide, in tetrahydrofuran (THF) at a temperature close to reflux) using procedures well known to one of ordinary skill in the art, is then deprotected to give the corresponding compounds of formula I wherein X, OR<1.>

Referring to Scheme 4, conversion of the alcohol function of compounds of formula (5) or (6) to a suitable leaving group (L), such as a mesylate, affords the corresponding compound of formula (7). The mesylate can be obtained from one equivalent of mesyl chloride and one equivalent of triethylamine in dichloromethane at a temperature close to room temperature. Replacement with a thioalkoxide (for example by reacting a compound of formula (7) with a suitable lithium or sodium thioalkoxide in THF at reflux temperature), and subsequent deprotection of the pore by conventional procedures well known to one of ordinary skill in the art, leads to the corresponding compounds of formula I wherein X, SR<3>. Alternatively, substitution with an amine, for example, reaction of a compound of formula (7) with one equivalent of the corresponding amine of formula R'NFbu in THF at reflux temperature, followed by deprotection, gives the corresponding compounds of formula I where X is NHR<1>.

Compounds of formula I wherein X is halogen may be obtained from the corresponding compounds of formula (7) by replacement with a suitable metal halide and subsequent deprotection by conventional methods well known to one of ordinary skill in the art.

Compounds of formula I, which are basic in nature, can form a large number of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, in practice it is often desirable to initially isolate the compound of formula I from the reactive mixture as a pharmaceutically unacceptable salt and then simply convert it to the free base by reaction with an alkaline reagent, after which the free base is converted to a pharmaceutically acceptable acid addition salt. Acid addition salts of the active base compounds of the present invention are readily obtained by reacting the base compound with an equivalent amount of a selected mineral or organic acid in an aqueous solvent or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired salt is easily obtained in solid form.

Those compounds of formula I which are acidic in nature can form base salts with various pharmaceutically acceptable cations. Examples of such salts are alkali metal salts and alkaline earth metal salts, especially sodium and potassium salts. These salts are obtained by conventional techniques. The chemical bases used as reagents for obtaining the pharmaceutically acceptable base salts of the present invention are those which form non-toxic base salts with the acidic compounds of formula 1. Such non-toxic base salts are those derived from such pharmaceutically acceptable cations as sodium, potassium, calcium, magnesium, etc. These salts are readily obtained by reacting the appropriate acidic compounds with an aqueous solution containing the desired pharmaceutically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, the salts can also be prepared by mixing lower alkanol solutions of the acidic compounds and the desired alkali metal alkoxides, and then evaporating the resulting solution to dryness, as previously described. In both cases, stoichiometric amounts of reagents are preferably used to carry the reaction to completion and to obtain the maximum yield of the desired final product.

The compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to as "active compounds used in this invention") are useful in the treatment of pigmentation disorders in humans, including sunspots and common skin spots (including age/liver spots), inelasma/chloasma and post-inflammatory hyperpigmentation. Such compounds reduce melanin levels in the skin by inhibiting melanin production, whether melanin is produced regularly or as a response to UV radiation (eg exposure to sunlight). Therefore, the active compounds used in the present invention can be used to reduce the melanin content of the skin in non-pathological conditions, by inducing a lighter skin color, as desired by the user. They can also be used in combination with skin exfoliants (including glycolic acid or trichloroacetic acid facial peels) to lighten skin tone and prevent repigmentation.

The active compounds used in the present invention can also be used in combination with sunscreen agents (UVA or UVB blockers) to prevent repigmentation, to protect against sun or UV-induced skin darkening, or to increase their ability to reduce the melanin content of the skin and the skin whitening process. These compounds can also be used in combination with retinoic acid or its derivatives or any compounds that are interactive with retinoic acid receptors and accelerate or enhance the ability of the compounds of the present invention to reduce the level of melanin in the skin and the skin whitening process.

The active compounds used in the present invention can also be used in combination with ascorbic acid, its derivatives and products based on ascorbic acid (such as magnesium ascorbate) or other products with anti-oxidative activity (such as resveratrol) that accelerate or enhance the ability of these compounds to reduce the level of melanin in the skin and the skin whitening process.

The present invention relates both to methods of whitening or reducing skin pigmentation in which the compound of formula I or its pharmaceutically acceptable salts, together with one or more of the above-mentioned active ingredients are administered together, as part of the same pharmaceutical formulation, as well as to psotupkas in which they are administered separately as part of a convenient dosage regimen determined to improve the effect of the combined therapy. The appropriate dosage regimen, the amount of each dose administered, and the specific intervals between doses for each active ingredient will depend on the specific combination of active ingredients used, the condition of the patient being treated, and the nature and severity of the disease or condition being treated. Such additional active ingredients are generally administered in amounts less than or equal to those at which they are effective as a single topical therapeutic agent. FDA-approved dosages for given active agents that have FDA approval for human administration are publicly available.

The active compounds of the present invention are generally administered in the form of pharmaceutical compositions containing at least one compound of formula I, together with a pharmaceutically acceptable carrier or diluent. These compositions are generally formulated in a conventional manner using solid or liquid carriers or diluents suitable for topical application in the form of solutions, gels, creams, jellies, pastes, lotions, ointments, salves and the like.

Examples of carriers for the application of active compounds of the present invention are aqueous or aqueous-alcohol solutions, oil-in-water or water-in-oil emulsions, emulsified gel or two-phase systems. Preferably, the formulations according to the invention are in the form of lotions, creams, milks, gels, masks, microspherical or nanospherical or vesicular dispersions. In the case of vesicular dispersions, the fats that make up the carrier can be of the ionic or non-ionic type or their mixture.

In depigmentation formulations according to the present invention, the concentration of the active compounds of the invention is generally between 0.01 and 10%, preferably between 0.1 and 10%, relative to the total weight of the composition.

The composition of the present invention may also optionally contain a humectant, surfactants, keratolytics, anti-inflammatory agents, complexing agents, antioxidants, preservatives, fragrances or sunscreens.

The ability of compounds of formula I to inhibit tyrosinase can be determined according to one of the following procedures.

1. Analysis of tyrosinase (POPA oxidase) using cell lysate:

A human melanoma cell line, SKMEL 188 (license from Memorial Sloan-Kettering), was used in the cell lysate for analysis and screening. In the assay, compounds and L-dihydroxyphenylalanine (L-DOPA) (100 µg/ml) are incubated with cell lysate containing human tyrosinase for 8 hours and then read at 405 nm. The potency of the compound in the DOPA oxidase assay correlates very well with the tyrosine hydroxylase assay using 3H-tyrosine as a substrate. When 4-cyclohexylresorcinol is tested in this assay, it exhibits an IC50 of 0.3 µM.

2. Analysis of melanin in primary human melanocytes:

The compounds were incubated with primary human melanocytes in the presence of α-melanocyte stimulating hormone (α-MSH) for 2 to 3 days. Cells are then lysed with sodium hydroxide and sodium dodecyl sulfate (SDS) and melanin signals are read at 405 nm. Alternatively, 14C-DOPA was added to the cells in combination with tyrosinase inhibitors and acid-insoluble<14>C-melanin was quantified using a scintillation counter. The IC50 values reflect the compound's inhibitory potential in the processes of new melanin synthesis stimulated by a-MSH.

3. Determination of tyrosine kinase (TK):

TK assays can be performed using purified tyrosine kinase domains of c-met, erb-B2, or IGF-r. In the analysis, a specific antibody to the dephosphorylated tyrosine residue is used. Colorimetric signals are produced using horseradish peroxidase, which is conjugated to an antibody.

4. Equivalent human skin model:

A mixture of human melanocytes and keratinocytes was grown in an air-liquid interphase. This tissue culture forms a three-dimensional structure that is histologically and microscopically similar to the epidermis of human skin. Test compounds (test compounds) are added to the top of the cells to mimic topical drug application. After incubation with compounds (10 µM) for 3 days, cells were washed thoroughly and lysed for DOPA oxidase analysis.

5. Determination of IL-1 (determination of interleukin-1):

Determination of IL-1 and ELISA (R&D System) can be used to evaluate the effect of compounds on IL-1 secretion in a model equivalent to human skin. IL-1α is a pro-inflammatory cytokine and plays a role in the inflammatory processes in the skin that are induced by UV rays.

6. In vivo testing:

Black or dark brown guinea pigs with homogeneous skin color may be used in this test. A solution of the test compound of formula 1 (5% in ethanoicpropylene glycol, 70:30) and a control solution are administered to the animals 2 times a day, 5 days a week for 4 to 8 weeks. Using these determinations, skin depigmentation was visible in cases where 5% 4-cyclohexyl resorcinol or 5% 4-cyclopentylresorcinol was used as the test compound.

The subject invention is described by the following examples. It is understood, however, that the invention is not limited by the specific details of these examples. Melting points are uncorrected. Proton nuclear magnetic resonance (1H NMR) was measured from solutions in dć-DMSO and peak positions were expressed in parts per million (ppm) lower than tetramethylsilane (TMS). Peak shapes are indicated as follows: s, singlet, d, doublet; t, triplet; q, quartet; m, multiplet; b, broad spectrum line.

EXAMPLE!

Example 1

4-cyclohexyl resorcinol

Resorcinol (2.2g, 20 mmol) and cyclohexanol (6.33 ml, 6g, 60 mmol) were suspended in 85% polyphosphoric acid (8 ml). The mixture was heated at 125°C for 24 hours, after which time it was determined by TLC that complete consumption of the starting material had occurred. After cooling, the mixture was partitioned between water (50 mL) and diethyl ether (50 mL). The aqueous layer was discarded and the organic portion was extracted with sodium hydroxide solution (2 x 50 ml, 2M). The base extract was washed with ether (3 x 50 ml) and then acidified with aqueous hydrochloric acid (120 ml, 2M). The organic components were then extracted into diethyl ether (2 x 50 ml), dried (magnesium sulfate), filtered and the solvent was removed under reduced pressure. The resulting brown oil was then chromatographed on silica gel eluting with ethyl acetate/petroleum ether (b.p. 60 to 80°C) 1 : 2 to give the desired product as an off-white solid (1.7 g, 44%).

HNMR (250MHz, de6-DMSO); δ 1.13-1.34 (5H,m); 1.65-1.71 (5H, m); 2.67-2.75 (IH, m); 6.11 (IH, dd J - 8.3, 2.4 Hz); 6.22 (IH, d, J = 2.4 Hz); 6.79 (IH, d, J = 8.3 Hz); 8.90 (IH, s); 9.00 (IH, s).

M/Z (ES's) gives 191.5 (M-H).

The following compounds were obtained in the same way:

Example 2

4-cyclopentyl resorcinol

From cyclopentanol as a white solid.

HNMR (250 MHz, d 6 -DMSO): 51.34-1.75 (6H, m); 1.78-1.88 (2H, m); 3.06 (IH, fifth, J = 9.5Hz); 6.12 (IH, dd, J = 2.4, 8.2 Hz); 6.22 (IH, d, J = 2.4 Hz); 6.83 (IH, d, J = 8.3 Hz); 8.91 (IH, s); 9.01 (IH, s).

M/Z (ES's) gives 177.5 (M-H).

Example 3

4-(1-methyl-1-cyclopentyl) resorcionol

From 1-methylcyclopentanol as a solid.

HNMR (400 MHz, CDCl 3 -MeOH): δ 1.31 (3H, s); 1.74-1.89 (4H, m); 1.94-2.03 (4H, m); 6.33-6.34 (IH, m); 6.39 (IH, dd, J = 2.5, 8.4 Hz); 7.10 (IH, m).

M/Z (ES's) gives 191.6 (M-H).

Example 4

4-(1-methyl-1-cyclohexyl)resorcinol

From 1-methylcyclohexanol in the form of an orange oil. Data given are adjusted for a 1:1 mixture of conformers.

HNMR (250 MHz, d6-DMSO): δ 1.20-1.80 (9H, m); 1.97 (3H, s); 2.60-3.00 (IH, m); 6.10-6.14 (IH, m); 6.22-6.70 (IH, m); 6.67-6.85 (IH, m); 8.89-8.90 (IH, m); 8.98-9.02 (IH, m).

M/Z (ES's) gives 411.6 (2M-H).

Example 5

4-cycloheptyl resorcinol

From cycloheptanol in the form of orange oil. Data given are adjusted for a 1:1 mixture of conformers.

1 H NMR (250 MHz, d6-DMSO): δ 1.30-1.80 (12H, m); 2.60-2.90 (IH, m); 6.08-6.13 (IH, m); 6.20-6.22 (IH, m); 6.78-6.88 (IH, m); 8.86-8.87 (IH, m); 8.89-8.98 (IH, m).

M/Z (ES's) gives 205.5 (M-H).

Example 6

4-cyclooctyl resorcinol

From cyclooctanol in the form of orange oil. Data given are adjusted for a 1:1 mixture of conformers.

HNMR (250 MHz, d6-DMSO): δ 1.20-1.80 (14H, m); 2.68-3.00 (IH, m); 6.09-6.15 (IH, m); 6.21-6.23 (IH, m); 6.73-6.84 (IH, m); 8.80-8.83 (IH, m); 8.90-9.00 (IH, m).

M/Z (ES's) gives 219.6 (M-H).

Example 7

In vivo test data

Experiments were performed in vivo to determine the effects of depigmentation

4-Cyclohexylresorcinol and 4-Cyclopentylresorcinol used in the analyzes as previously described (Tests in vivo). Thus, 5% 4-cyclohexylresorcinol and 5% 4-cyclopentyl-resorcinol, each in a solution of ethanol:propylene glycol (70 : 30), and separately administered in the ears of black guinea pigs. Depigmentation is determined by subtracting light reflectance on untreated ears from light reflectance on treated ears. As can be seen from the data in the table provided, both tested formulations reduce pigmentation in the treated ears 3 weeks after the initial treatment. The effect of depigmentation is reversible and repigmentation partially continues for a week after stopping the treatment.

Claims (35)

1. A topical pharmaceutical composition for whitening the skin or reducing skin pigmentation, indicated by the fact that it contains a certain germ of the compound of formula 1, where X is hydrogen; OR<1>, where R<1> represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6)alkyl; OCOR<2> where R<2> represents (C1-C6)alkyl, aryl-(C1-C6)alkyl or phenyl; halogen; (CrC6)alkyl; aryl-(C 1 -C 6 )alkyl; SR<3> where R<3> represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6)alkyl; or NHR<1>wherein R<1>is defined as previously given; her Odo 3; and dashed line represents optional double bond; or a pharmaceutically acceptable salt thereof, which is effective for skin whitening or reducing skin pigmentation; and a pharmaceutically acceptable carrier. 2. The topical pharmaceutical composition of claim 1, characterized in that the compound of formula 1 is 4-cyclohexylresorcinol. 3. Topical pharmaceutical composition from claim 1, characterized in that the compound of formula 1 is 4-cyclopentylresorcinol. 4. A non-therapeutic method of skin whitening or reduction of skin pigmentation in a human, comprising administering to the human an amount of a compound of formula I where X is hydrogen; OR<1>, where R<1> represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6)alkyl; OCOR<2> where R 2 represents (C 1 -C 6 )alkyl, aryl-(C 1 -C 6 )alkyl or phenyl; halogen; (C 1 -C 6 )alkyl; aryl-(C 1 -C 6 )alkyl; SR<3> where R<3> represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6)alkyl; or NHR<1>wherein R<1>is defined as above; n is 0 to 3; and dashed line represents optional double bond; or a pharmaceutically acceptable salt thereof, which is effective in skin whitening or reducing skin pigmentation. 5. The method of claim 4, characterized in that the compound of formula I is 4-cyclohexylresocinol. 6. The method of claim 4, characterized in that the compound of formula I is 4-cyclopentylresorcinol. 7. A topical pharmaceutical composition for tyrosinase inhibition in humans, characterized in that it contains an effective amount of a compound of formula I, where X is hydrogen; OR<1>, where R<1> represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6)alkyl; OCOR<2> where R<2> represents (C1-C6)alkyl, aryl-(C1-C6)alkyl or phenyl; halogen; (C 1 -C 6 )alkyl; aryl-(C 1 -C 6 )alkyl; SR<3>wherein R<3>represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6alkyl); or NHR<1>wherein R<1>is defined as previously given; her 0 to 3; and dashed line represents optional double bond; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 8. The topical pharmaceutical composition of claim 7, characterized in that it is a compound of the formula 1,4-cyclohexylresorcinol. 9. The topical pharmaceutical composition of claim 7, characterized in that it is a compound of the formula 1,4-cyclopentylresorcinol. 10. A non-therapeutic method of inhibiting human tyrosinase comprising administering to a mammal a tyrosinase-inhibiting effective amount of a compound of the formula 1, where X is hydrogen; OR<1>, where R<1> represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6)alkyl; OCOR<2> where R<2> represents (C1-C6)alkyl, aryl-(C1C6)alkyl or phenyl; halogen; (C 1 -C 6 )alkyl; aryl-(C 1 -C 6 )alkyl; SR<3>where R<3>represents hydrogen; (C 1 -C 6 )alkyl or aryl-(C 1 -C 6 )alkyl; or NHR<1>wherein R<1>is defined as previously given; her 0 to 3; and dashed line represents optional double bond; or pharmaceutically acceptable salts thereof. 11. The method of claim 10, characterized in that the compound of formula I is 4-cyclohexylresorcinol. 12. The method of claim 10, characterized in that the compound of formula 1 is 4-cyclopentylresorcinol. 13. Topical pharmaceutical composition for skin whitening or reduction of skin pigmentation, characterized in that it contains a tyrosinase inhibiting effective amount of the compound of formula I, where X is hydrogen; OR<1>, where R<1> represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6)alkyl; OCOR<2> where R<2> represents (C,-C6)alkyl, or aryl-(C,-C6)alkyl or phenyl; halogen; (C 1 -C 6 )alkyl; aryl-(C 1 -C 6 )alkyl; SR<3>where R<3>represents hydrogen; C 1 -C 6 )alkyl or aryl-(C 1 -C 6 )alkyl; or NH R<1> where R<1> is as defined above; her 0 to 3; and dashed line represents optional double bond; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 14. The topical pharmaceutical composition of claim 13, characterized in that it is a compound of the formula 1,4-cyclohexylresorcinol. 15. Topical pharmaceutical composition according to claim 13, characterized in that the compound of formula I is 4-cyclopentylresorcinol. 16. A non-therapeutic method of skin whitening or reducing skin pigmentation in humans, comprising administering to the human a tyrosinase-inhibiting effective amount of a compound of formula I where X is hydrogen; OR<1>, where R<1> represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6)alkyl; OCOR<2> where R<2> represents (C1-C6)alkyl, aryl-(C1-C6)alkyl or phenyl; halogen; (C 1 -C 6 )alkyl; aryl-(C 1 -C 6 )alkyl; SR<3> where R<3> represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6)alkyl; or NH R' where R<1> is as defined above; her 0 to 3; and dashed line represents optional double bond; or pharmaceutically acceptable salts thereof. 17. The method of claim 16, characterized in that the compound of formula I is 4-cyclohexylresorcinol. 18. The method of claim 16, characterized in that the compound of formula I is 4-cyclopentylresorcinol. 19. The composition according to claim 1, characterized in that it also contains a sun protection agent. 20. Composition according to claim 1, characterized in that it also contains resveratrol or another active agent that is an antioxidant. 21. The composition according to claim 1, characterized in that it also contains retinoic acid or a derivative of retinoic acid. 22. The composition according to claim 1, characterized in that it contains glycolic acid, trichloroacetic acid or other skin exfoliating agent. 23. The composition according to claim 1, characterized in that it is in the form of a lotion, cream or ointment. 24. Topical or transdermal pharmaceutical composition for the treatment of inflammatory diseases in humans, indicated by the fact that it contains a certain amount of the compound of formula I, where X is hydrogen; OR<1>, where R<1> represents hydrogen, (C1-C6)alkyl or aryl-(C1-C6)alkyl; OCOR<2> where R<2> represents (C,-C6)alkyl, or aryl-(C,-C6)alkyl or phenyl; halogen; (C 1 -C 6 )alkyl; arylHd-OOalkyl; SR<3> where R<3> represents hydrogen, C1-C6)alkyl or aryl-(C1C6)alkyl; or NHR<1>wherein R<1>is defined as above; her Odo 3; and dashed line represents optional double bond; or a pharmaceutically acceptable salt thereof, which is effective in the treatment of the indicated disorder, and a pharmaceutically acceptable carrier. 25. The composition of claim 24, characterized in that the compound of formula I is 4-cyclohexylresorcinol. 26. the composition of claim 24, characterized in that the compound of formula I is 4-cyclopentylresorcinol. 27. A non-therapeutic method of treating inflammatory diseases in humans, comprising administering to a human a certain amount of a compound of formula I. where X is hydrogen; OR<1>, where R<1>represents hydrogen, (C5-C6)alkyl or aryl-(Ci-C6)alkyl; OCOR<2>where R<2>represents (Ci-C6)alkyl, aryl-(C1-C6)alkyl or phenyl; halogen; (CrC6)alkyl; aryl-(CrC6)alkyl; SR<3>where R<3>represents hydrogen, (Ci-C6)alkyl or aryl-(CrC6) C6)alkyl; or NHR<1> where R<1> is as defined above; her 0 to 3; and dashed line represents optional double bond; or pharmaceutically acceptable salts thereof; which is effective in the treatment of the indicated disease. 28. The method of claim 27, characterized in that the compound of formula I is 4-cyclohexylresorcinol. 29. The method of claim 27, characterized in that the compound formulal, 4-cyclopentylresorcinol, 30. A topical or transdermal pharmaceutical composition for the treatment of an inflammatory disease in humans, characterized in that it contains a tyrosinase-inhibiting effective amount of the compound of formula I where X is hydrogen; OR<1>, where R<1> represents hydrogen, (C1-C6)alkyl or aryl-(C6)alkyl; OCOR<2> where R<2> represents (C 1 -C 6 )alkyl, aryl-(C 1 -C 6 )alkyl or phenyl; halogen; (C 1 -C 6 )alkyl; aryl-(C 1 -C 6 )alkyl; SR<3> where R<3> represents hydrogen, (C 1 -C 6 )alkyl or aryl-(C 1 -C 6 )alkyl; or NH R<1> where R<1> is as defined above; her 0 to 3; and dashed line represents optional double bond; or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier. 31. The method of claim 30, characterized in that the compound of formula I is 4-cyclohexylresorcinol 32. The method of claim 30, characterized in that the compound of formula I is 4-cyclopentylresorcinol. 33. A non-therapeutic method of treating inflammatory diseases in humans, comprising administering to the human a tyrosinase-inhibiting effective amount of a compound of formula I where X is hydrogen; OR<1>, where R<1> represents hydrogen, (C1C6)alkyl or aryl-(C1-C6)alkyl; OCOR<2> where R<2> represents (C 1 -C 6 )alkyl, aryl-(C 1 -C 6 )alkyl or phenyl; halogen; (C 1 -C 6 )alkyl; aryl-(C 1 -C 6 )alkyl; SR<3> where R<3> represents hydrogen, (C1C6)alkyl or aryl-(C1C6)alkyl; or NHR<1>wherein R<l>is defined as previously given; nje0do 3; and dashed line represents optional double bond; or pharmaceutically acceptable salts thereof. 34. The method of claim 33, characterized in that the compound of the formula is 1,4-cyclohexylresorcinol. 35. The method of claim 33, characterized in that the compound of formula I is 4-cyclopentylresorcinol.