WO2003051325A1

WO2003051325A1 - Skin lightening agents, novel compounds, compositions and use

Info

Publication number: WO2003051325A1
Application number: PCT/GB2002/005557
Authority: WO
Inventors: Peter Samuel James Cheetham
Original assignee: Zylepsis Limited
Priority date: 2001-12-14
Filing date: 2002-12-09
Publication date: 2003-06-26
Also published as: WO2003051325A8; EP1455747A1; GB0129987D0; AU2002347372A1

Abstract

The present invention provides novel compound and their use of formula (I) or a cosmetically acceptable salt thereof as a skin lightening agent wherein in formula (I), A is an optionally substituted aryl or heteroaryl group, Z is C=O, C=S, C=CH2 or CH2, Y is NR1, O or S, X is S, SO or SO2, and where R1 is hydrogen, alkyl, alkylaryl or aryl. The invention also relates to the use of a ring opened derivative of formula (I).

Description

SKIN LIGHTENING AGENTS , NOVEL COMPOUNDS, COMPOSITIONS AND USE

The present invention provides the use of compounds as skin lightening agents. The invention further provides a skin composition comprising compounds of the invention for use in the lightening of skin and a method of lightening skin comprising administering a compound of the invention.

There are three main uses for skin lighteners; to lighten age spots (liver spots or senile lentigo), to reduce the brown-black colour of non-Caucasian skin and to prevent the darkening of Caucasian and Asian skins (that is, to maintain a light/fair complexion). It is desirable that a skin lightener should meet a number of targets: it should be permeable through both the cell and melanocyte membranes in order to reach the basal layer of the skin; it should be safe and non-toxic to skin cells; it should have suitable stability for short, medium or long term use; and its cost should be suitable for use in cosmetics.

Commonly used skin lighteners are hydroquinone, arbutin and kojic acid. Hydroquinone is the most effective but has significant adverse effects so that it is no longer registered for use in the European Union. Many other materials have also been used or documented as skin lighteners, including lactic acid, ferulic acid and nicotinamide as well as plant extracts such as Bearberry extract. Other skin lighteners include glycosides and esters of hydroxy salic lic acid, ascorbyl methylsilanol and liquorice extracts. The use of caffeic acid or an ester or amide thereof to depigment the skin is described in US 5164185. Depigmenting compositions containing di- or tri- caffeoylquinic acid are disclosed in US 5445816. PCT/GB 00/00490 describes the use of compounds of the formula

where R¹ is CH=CH₂, COOH or CH₂-CH₃, R³ is OH or OCH₃ and R², R⁵ and R⁶ are hydrogen, as skin lightening agents.

Known skin lighteners, such as hydroquinone and kojic acid may exhibit some cytotoxicity against skin cells. Whilst such cytotoxicity can be tolerated, it may be advantageous to ameliorate it to some extent. The present invention addresses this issue by providing a particular class of compounds that have activity as skin lightening agents, and while exhibiting improvements towards the targets described above.

Accordingly, the first aspect of the invention provides the use of a compound of formula I

I (closed ring structure) or a cosmetically acceptable salt thereof as a skin lightening agent, wherein in formula I:

A is an optionally substituted aryl or heteroaryl group;

Z is C=0, C=S, C=CH₂ or CH₂, preferably C=0 or C=S, most preferably C=0

Y is NR¹, O or S, preferably NR¹ or O,

and X is S, SO or S0₂, preferably S0₂;

and where R¹ is hydrogen, alkyl, alkylaryl or aryl, preferably hydrogen;

or a ring opened derivative of formula I as illustrated below:

I (open ring structure)

Wherein X, Z, A and Y are as defined above,

W is O, NR¹, or S, preferably O, wherein R¹ is as defined above,

9 9

R is any group preferably R is hydrogen, alkyl, aryl or a skin lightening agent, a fatty acid or a lipid; where R² is alkyl, the alkyl group preferably contains 1 to 30 carbon atoms where R² is a skin lightening agent, R² is a group which has skin lightening properties when attached to the compound of the invention or when cleaved from the compound of the invention in situ (i.e. on the skin). An example of such a skin lightening agent is

R may be a group such as a fatty acid or a lipid which increases the hydrophobicity of the compound of the invention. Examples of such groups include stearic acid and lecithin.

R³ is any group preferably R³ is hydrogen, alkyl, aryl or a skin lightening agent, a fatty acid or a lipid; where R is alkyl, the alkyl group preferably contains 1 to 30 carbon atoms where R is a skin lightening agent, R is a group which has skin lightening properties when attached to the compound of the invention or when cleaved from the compound of the invention in situ (i.e. on the skin). An example of such a skin lightening agent is

R³ may be a group such as a fatty acid or a lipid which increases the hydrophobicity of the compound of the invention. Examples of such groups include stearic acid and lecithin.

or R2 and R3 together are

wherein X, Y and Z are as previously defined.

In compounds of formula I, alkyl moieties can be straight (unbranched) or branched chain. Straight or branched chain alkyl groups or moieties may contain from 1 to 10 carbon atoms, e.g. 1 to 8 carbon atoms, preferably 1 to 5 carbon atoms.

Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl. When R² or R³ is alkyl, the straight or branched chain alkyl groups or moieties may contain from 1 to 30 carbon atoms, preferably 1 to 10 carbon atoms, e.g. 1 to 5 carbon atoms.

Aryl groups are preferably optionally substituted monocyclic rings such as phenyl. Aryl groups may be fused to a further saturated, partially saturated or unsaturated ring to form for example naphythyl or tetrahydronaphythyl. Examples of substitutents that may be present on an aryl group include one or more of amino, alkyl, alkoxy, or aryloxy. Preferred subsitutents are alkoxy groups such as hydroxy, methoxy or ethyloxy, most preferably hydroxy. For the purposes of this invention, the term aryl encompasses both aromatic and non-aromatic groups. Preferred aryl groups for the purposes of this invention are therefore 5 and 6 membered monocyclic rings such as phenyl and cyclopentadiene. The aryl groups may be fully saturated, partially saturated or unsaturated to form for example cyclohexane, cyclohexene or cyclopentane.

A heteroaryl group or moiety may be an optionally substituted heterocyclic aromatic ring, preferably a 5- or 6- membered ring, which may contain from 1 to 4 heteroatoms selected from O, N or S. The heterocyclic ring may optionally be fused to a phenyl ring. Suitable substituents include one or more of amino, alkyl, alkoxy, or aryloxy. Preferred subsitutents are alkoxy groups such as hydroxy, methoxy or ethyloxy, most preferably hydroxy. The heteroaryl group or moiety may be fully or partially reduced. For the purposes of this invention the terms 'reduced' or 'reduction' relate to the addition of one or more electrons to an atom or the addition of hydrogen to a moiety. Examples of such reduced heteroaryl groups or moieties include any fully or partially saturated derivative or the aforementioned heteroaryl groups and include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl and piperidinyl groups.

An amino group is one or more of NH₂, NHR , NR⁶R⁷ or a salt thereof for example NH₃C1. R and R are independently selected from alkyl or aryl.

Alkoxyl groups are straight or branched chain alkyl groups as previously defined wherein the alkyl chain is interrupted with one or more oxygen atom. Examples of alkoxy groups include methyoxy and efhoxy groups.

Aryloxy groups are aryl groups as previously defined wherein the aryl group is substituted with one or more oxygen atoms. Examples of aryloxy groups include phenoxy and phenylphenoxy groups. In this text, the term "cosmetically acceptable salt thereof also includes dermatologically acceptable salts.

The compounds of the present invention as they are described in the first aspect relate to closed and open ring structures of Formula I . The open ring structure can be obtained by the opening of the closed ring structure by hydrolysis, acid or base conditions or by the action of an enzyme. In particular the open ring structure can be formed by the action of an esterase or an amidase enzyme on the closed ring structure. The obtained open ring structures can then be further derivatised to provide compounds of formula I. The present inventors have identified that compounds of both the closed and open ring structures have in vivo skin lightening activity, although compounds having the closed ring structure do not inhibit cell free tyrosinase (an in vitro test for skin lightening activity). Accordingly, the closed ring structures are more akin to a "skin pro-lightener". Without being bound by scientific explanation, it is believed that the closed ring structure is opened by an enzyme present in the skin such that the open ring structure is formed which is active in inhibiting tyrosinase. A skin lightening effect can thus be achieved by use of either the closed ring structure or by an open ring structure as set out in the claims.

Preferably, the compounds of the first aspect of the invention is a compound of formula la

Wherein R¹⁰, R¹¹, R¹², and R¹³ are hydrogen, alkyl, alkoxy or hydroxy and Z, X, W, Y, R¹, R² and R³ are as defined above; more preferably R¹¹ is hydroxy and R¹⁰, R¹², and R¹³ are hydrogen, alternatively R 12 is hydroxy and R¹⁰, R¹¹ and R¹³ are hydrogen, or R¹¹ and R¹² are hydroxy and R¹⁰ and R¹³ are hydrogen.

Hydroxylation of R¹¹ and R¹² can be carried out by conventional synthetic methods or by an enzymatic process. Alternatively, the hydroxyl groups may be added in situ by enzymes in the skin. It will be appreciated that when the aryl group is substituted with one or more hydroxyl group, oxidation may occur to form a quinone derivative of the compound of formula la as indicated below.

The present invention encompasses quinone derivatives of the compounds of the invention.

Specific examples of compounds of Formula I include

Compound number Structure

Compound 1 o-benzoic sulfimide (CAS number 81-07-2)

Compound 2 N-methyl-o-benzoic sulfimide

Compound 3

Compound 4

Compound 5

Compound 6 2-sulfobenzoic acid

Compound 7

Compound 8 2-sulfamide-benzoic acid

In a feature of the first aspect, the A group can be absent, providing a compound of formula II

wherein X, Y, Z, W, R² and R³ are as previously defined. The alkene moiety may be reduced or substituted with one or more of hydrogen, hydroxy, alkyl or aryl.

The compounds of Formula I have additional particular advantage for use as skin lighteners in that they exhibit an anti-irritant effect. Again, without being bound by scientific explanation, it is believed that the closed and the open ring structures and/or their metabolites, inhibit one or more enzymes involved in the inflammation pathway and thus exhibit reduced irritancy to the skin. Examples of cosmetically acceptable salts of the compounds of Formula I include those derived from organic acids such as methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid, mineral acids such as hydrochloric and sulphuric acid and the like, giving methanesulphonate, benzenesulphonate, p- toluenesulphonate, hydrochloride and sulphate, and the like, respectively or those derived from bases such as organic and inorganic bases. Examples of suitable inorganic bases for the formation of salts of compounds for this invention include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like to give salts such as metal salts. Salts can also be formed with suitable organic bases. Such bases suitable for the formation of cosmetically acceptable base addition salts with compounds of the present invention include organic bases, which are non-toxic and strong enough to form salts. Such organic bases are already well known in the art and may include amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimefhylamine, and trimethylamine, guanidine; N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like.

Salts of the compounds of Formula I may be prepared in a conventional manner using methods well known in the art. Acid addition salts of basic compounds may be prepared by dissolving the free base compounds according to the first or second aspects of the invention in aqueous or aqueous alcohol solution or other suitable solvents containing the required acid. Where a compound of formula (I) contains an acidic function a base salt of said compound may be prepared by reacting said compound with a suitable base or an appropriate enzyme. The acid or base salt may separate directly or can be obtained by concentrating the solution e.g. by evaporation. Whilst the closed and open ring compounds of the present invention exhibit skin lightening activity, the choice of compound to be used may depend on the level of skin lightening required and the period over which the skin lightening effect is desired.

The open ring compounds are more water soluble than the closed ring structures of the present invention. As such, their ability to penetrate the skin will differ from those compounds of the closed ring structure. In addition, the compounds having the closed ring structure require a level of metabolism in order to give the open ring structures which have tyrosinase inhibition activity. This is believed to be achieved by the presence of enzymes such as amidases in the skin. The requirement for metabolism by enzymes such as amidases gives a "reservoir effect" such that the active material is produced gradually so as to ensure a constant and even supply to the target cells which will give a more efficacious result.

The compounds for Formula I are, in general, white. This is preferred for cosmetics. Formulations with the compounds, in particular creams and lotions, are stable over long periods at elevated temperatures (40°C) in tests.

The compounds of the invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms (enantiomers). The present invention includes all such enantiomers and mixtures thereof, including racemic mixtures. The compounds of the invention may also exist in saturated or hydrated forms such as o-benzoic sulfimide sodium salt hydrate.

The compounds of the present invention act as skin lightening agents. For the purposes of this invention, a skin lightening agent may lighten age spots, reduce the brown-black colour of non-Caucasian skin and/or prevent the darkening of Caucasian and Asian skin. The term "skin lightener" or "skin lightening agent" includes an agent which when applied to the skin, inhibits melanogenesis, especially the enzymes (such as tyrosinase) which are associated with the formation of melanin by mammalian cells, such as melanocytes in the skin. The 'skin lightner' or 'skin lightening agent' may reduce the amount of pre-formed melanin present in the skin.

The compounds of the invention are provided for a number of different uses. Preferred uses are cosmetic, although they may also be therapeutic. Examples of such uses are to maintain a light or fair complexion, to reduce generalised over pigmentation, to lighten age spots, to lighten scars and to lighten hair. In the present text, a skin lightening agent also includes hair lightening, since hair colour is derived from the melanin produced in the skin (scalp) from which the hair grows.

A compound of the first aspect can also exhibit one or more useful activities selected from antioxidant, antimicrobial, antibrowning, aroma/flavour and acidulant activities. Skilled persons will appreciate that the antibrowning and skin lightening activities of a compound of the first aspect are linked. Without being bound in any way by scientific theory, they appear to work by inhibiting enzymes associated with coloured material formation which is undesirable in the skin preparation during storage, during distribution and during use of the skin preparation. For example, the compound inhibits polyphenol oxidase (tyrosinase and laccase) enzymes which catalyse formation of brown-black pigments (melanoids) formed by oxidative polymerisation of plant phenols such as chlorogenic acid in plant tissue. Similarly, the compound or its metabolite inhibits tyrosinase enzyme in the skin to prevent melanin formation from precursor materials present in skin cells, such as tyrosine.

The invention also relates to the use of a compound of the first aspect in combination with an antioxidant. For the purposes of this invention, an anti-oxidant is any compound or substance, which inhibits or slows the rate of oxidative reactions. Examples of antioxidants include ascorbic acid, a tocopherol (including alpha-tocopherol), a carotenoid (including beta-carotene), ferulic acid, selenium, butylated hydroxytoluene, butyrated hydroxyanisole, an ascorbyl ester (including ascorbyl palmitate) caffeic acid, a flavanoid, a flavanol and ubiquinone.

More preferably, the antioxidant may exhibit both antioxidant and skin lightening properties. Examples of agents with both antioxidant and skin lightening properties include ferulic acid and ascorbic acid.

The first aspect of the invention may further provide the use of a compound of the invention in combination with an additional skin lightener. The additional skin lightener includes one or more of kojic acid, hydroquinone, arbutin or a plant extract containing arbutin such as Bearberry extract, glycyrrhizic acid or liquorice extracts, protocatechuic acid, vinylguaiacol, ethylguaiacol and lactic acid.

In accordance with the first aspect of the invention, each of the components can be provided in varying concentrations and ratios. The relative ratios of the components (skin lightening compound of the invention: antioxidant: other skin lightening agent) may vary from 100 to 1 fold, preferably in the range of 10 to 1 fold. The components may be provided in approximately a 1: 1:1 ratio.

Where the compound of the invention is used with an antioxidant and/or a further skin lightening agent, the compound and the antioxidant and/or skin lightening agent are provided for simultaneous, sequential or separate use.

In addition, the compound of the invention may be provided in combination with other active ingredients with complementary activities to the compound of the first aspect and/or the other ingredients, such as antioxidants, anti-irritants, antimicrobials, anti-dandruff and anti-acne ingredients. The composition may also include actives responsible for exfoliation (e.g. alpha- and beta-hydroxy acids), UN absorbtion, inhibition of collagenase/elastase (i.e. anti ageing) and stabilisation of labile antioxidants.

The present invention also relates to, as a second aspect, a skin composition comprising a compound of Formula I or a cosmetically acceptable salt thereof.

All preferred features of the first aspect of the invention, particularly with regard to different compounds of Formula I also apply to the second aspect.

The composition according to the second aspect may further comprise an antioxidant and/or one or more additional skin lightening agents. The composition may also comprise a cosmetically acceptable carrier, diluent or excipient.

In addition, the composition may contain other active ingredients with complementary activities to the compound of the first aspect and/or the other ingredients, such as antioxidants, anti-irritants, anti-microbials, anti-dandruff and anti-acne ingredients. The composition may also include actives responsible for exfoliation (e.g. alpha- and beta-hydroxy acids), UV absorption, inhibition of collagenase/elastase (i.e. anti ageing) and stabilisation of labile antioxidants.

Suitable carriers and/or diluents are well known in the art and include grade starch, mannitol, lactose, magnesium stearate, talcum, cellulose, glucose, sucrose (or other sugar), magnesium carbonate, gelatin, oil, alcohol, detergents, emulsifiers or water (preferably sterile). The composition may be a mixed preparation of a composition or may be a combined preparation for simultaneous, separate or sequential use (including administration).

In terms of delivery systems, those generally known in the art can be used. They include solvents such as ethanol, propylene glycol, butylene glycol, hexylene glycol, dimethyl formamide and dimethyl isosorbate. Alternatively, or in addition, the active compound of the invention may be encapsulated. Examples of suitable cosmetic encapsulation systems include: Microsponges (Primcare, from Cognis), Liposomes (Rovisomes, from RONL), Νanosomes (Νanospheres, from Exsymol) and Microencapsulates (Tagravit, from Tagra and Primaspheres from Cognis).

A range of custom and customer specific liposomes are available from Brooks Industries Inc. under the trade name Brookosomes. Also Rovi GmbH, "Rovisomes".

Active ingredients are encapsulated at between 0.1 and 10.0% typically 5%.

Liposome is primarily composed of phospholipids choline esters of phosphoric acid and a mixture of fatty acid diglycerides. Active ingredients can be incorporated in the interior of the liposome (water soluble actives) or into the bilayer structure of the phospholipid (oil soluble).

Formulation requires the addition of the liposomes with low-shear stirring and temperatures of below 40°C.

In one example, the compounds of the invention could be provided in a cosmetic encapsulation system such as micro-encapsulation by the Primosphere method as developed by Cognis. In this example, the micro-encapuslation liposomes primarily consist of a chitin - carboxymethyl cellulose shell in which soluble active ingredients are entrapped at levels of 1-5%. Formulation requires the addition of the microencapsulate with low shear stirring at temperature of 50°C or below. This allows use in a wide range of oil free and emulsified products, including both oil in water, and water in oil based products. This can be applied by hand, aerosol, pump or solid stick or sponge applicator, in the form of a cream, lotion mousse or spray. The skin composition of the second aspect is provided for use on the skin. This composition can be used on any part of the body including face, arms, hands, legs and torso. For the purposes of this invention, the term "skin" includes skin such as the scalp which produces hair. Skin does not include lips, teeth or any internal linings of the body.

The skin composition of the second aspect can be provided as a lotion, cream, spray, gel, bar or powder for application to the skin. It may be an oil-in-water or a water-in-oil formulation. Alternatively, the skin preparation can be provided as a powder, liquid, solid, gel or capsule which is added to water which is applied to the skin or in which the skin is then soaked, for example the addition of bath salts containing the compound or composition of the invention to a bath. The compound or composition of the invention may further be applied to or impregnated into an article such as a cloth, sponge or towel and be applied to the skin from the article. Alternatively, the compound or composition of the invention can be supplied in a form suitable for applying to or impregnating onto clothing, towels, sponges, washcloths, etc. The compounds of the invention can be provided as a powder, spray, foam, gel, cream, bar or liquid or a capsule or block containing same, and can be or can be incorporated into for example a washing powder or liquid or a fabric conditioner for application onto clothes.

Preferably, the second aspect of the invention relates to a skin lightening composition comprising a compound of formula I or a cosmetically acceptable salt thereof. All preferred features of the second aspect also apply to the skin lightening composition.

The second aspect additionally relates to a skin composition as described herein which is in a form suitable for cosmetic, dermatological or personal care use. The composition can be formulated with an ingredient or in a manner, which enhances or facilitates the penetration into or across the outer layers of the skin, so as to enhance their action on living cells. The penetration-enhancing ingredient may have this effect by altering the diffusional barrier of the stratum corneum. One or more of such ingredients can be used depending on the solubilities of the compounds of formula I. Examples of such penetration-enhancing ingredients include dimethyl sulphoxide, dimethyl formamide, dimethylacetamide, propylene glycol, lauryl alcohol, oleyl alcohol, isopropylmyristrate, isopropyl linoleate, lecithin, oleic acid or menthol.

All preferred features of the first and second aspects of the invention also apply to the third aspect.

A third aspect of the invention provides a process for making a skin composition according to the second aspect of the invention. The process comprises combining a compound of Formula I with a diluent, carrier or excipient. The process may also comprise combining one or more other components into the composition such as other cosmetically acceptable materials. The process may include any necessary high speed mixing, heating or other processing.

A fourth aspect of the present invention provides the use of a compound of Formula I in the manufacture of a composition for use as a skin lightening agent.

All preferred features of the first to third aspects also apply to the fourth.

The compositions of the invention are preferably provided as a formulation, which is applied externally to the skin surface or to the hair. The composition can be in the form of a cream or lotion (including oil in water and water in oil creams and lotions), spray, powder, gel, shampoo, conditioner, mousse, serum, oil, stick or patch. The formulation can be provided specifically as a skin lightening product, or the skin lightening preparation can be added to a formulation for a different use (i.e. sunscreen lotion, day cream, moisturiser, perfume, body spray, bath or shower product). The compositions of the invention can be provided as a cosmetic product, which includes a personal care product. For the purposes of this invention "cosmetic products" are products intended for increasing the appeal, visually and olfactively, of the human body. Likewise "personal care products" are products intended for cleaning, smoothing or otherwise improving the health and well-being of the outside of the human body. Examples of such products are: perfumes and like products known as "eau de toilette" and "eau de parfum", hand and body lotions, skin tonics, shaving products, bath and shower products, deodorant and antiperspirant products, hair care products such as shampoos and hair conditioners, mouth and dental care products. Such products are well known in the art. Thus, examples of skin care products are described in "Harry's Cosmeticology", R. G. Harry, 6^th edition, Leonard Hill Books (1973), Chapters 5-13, 18 and 35; examples of deodorants and antiperspirants are described in C. Fox, cosmetics and Toiletries 100 (Dec. 1985), pp 27-41; examples of hair care products are described "Harry's Cosmeticololgy", vide supra, chapters 25-27; examples of dental care products are described in M. Pader, Oral Hygiene: Products and Practice, Marcel Dekker, New York (1988). Cosmetic and personal care products are usually perfumed, on the one hand to give pleasant odour to the products themselves and on the other hand to have the body parts to which they are applied emit a pleasant odour after their use.

Compositions of the present invention may also be used in food and beverage compositions.

A fifth aspect of the invention relates to a method for lightening the colour of skin. This method comprises applying to skin, a compound of Formula I or a composition of the second aspect.

The compound or composition can be applied to the skin or hair daily or more frequently, every other day, biweekly or weekly. Alternatively, the skin can be soaked in a compound or composition of the invention. The compound or composition can be applied to the skin or hair as a lightening preparation or can be incorporated into a product with another use such as a moisturiser, sun screen, body spray, perfume, bath or shower product, shampoo or conditioner.

For the purposes of the fifth aspect, the compound of the first aspect or the composition of the second aspect is in a form suitable for cosmetic, dermatological or personal care use. The compounds or compositions of the invention can be formulated with ingredients or in a manner, which enhances or facilitates the penetration into or across the outer layers of the skin, so as to enhance their action on living skin cells.

All preferred features of the first to fourth aspects also relate to the fifth aspect.

A sixth aspect of the invention relates to novel compounds of Formula I. Examples of such novel compounds include:

an open ring compound of Formula I as defined above in relation to the first aspect of the invention, wherein:

Z is C=0, x is S0₂, R3 is H, Y is NH and group R2 is

or an open ring compound of Formula I wherein, Z is C=0, R2 is H, x is S0₂, and

Y is NH and R3 is

or an open ring compound of Formula I wherein, Z is C=Q, x is S0₂ and R2 and R3 are together the group

wherein X, Y and Z are as defined for the first aspect of the invention,

or an open ring compound of Formula I wherein Z is C= =0, X is S0₂

and R^J is

All preferred aspects of the first to fifth aspects also apply to the sixth aspect.

A seventh aspect of the invention relates to a process for making a compound of the present invention. Open ring compounds of the present invention can be prepared from the corresponding ring closed form by hydrolysis of the Z-Y bond or the Y-X bond as illustrated.

A hydrolysis step can be carried out using conditions and reagents known in the art.

The open ring compounds can be further derivatised by esterification or amidation reactions using conventional conditions and reagents as illustrated below.

All preferred aspects of the first to sixth aspect also apply to the seventh aspect.

An eighth aspect of the invention relates to a composition comprising a compound according to a sixth aspect of the invention for use as a skin lightening agent.

All preferred aspects of the first to seventh aspect also apply to the eighth aspect. A ninth aspect of the invention relates to the compound of formula III

or a cosmetically acceptable salt or hydrate thereof as a skin lightening agent and its use in a method for lightening skin.

A tenth aspect of the invention relates to the compound of formula IN

or a cosmetically acceptable salt, such as sodium cyclamate, or hydrate thereof, as a skin lightening agent and its use in a method for lightening skin.

The invention will now be illustrated by the following non-limiting examples.

EXAMPLE 1 - Compounds of the invention

Media and Reagents

Growth Medium: RPMI 1640 Medium, supplemented with: L-Glutamine, 2mM; Foetal Calf Serum, 10%.

Assay Medium: Minimum Essential Medium (MEM) w/o phenol red supplemented with: L-Glutamine, 4mM; foetal Calf Serum, 10%; Penicillin/Streptomycin, 1%.

Hanks Balanced Salt Solution (without Ca²⁺ & Mg²⁺). Trypsin/EDTA Solution. Neutral Red Solution. (3.3g/L in DPBS)

Neutral Red Desorb: Glacial Acetic Acid, 1%; Ethanol, 50% deionised water, 49%.

Phosphate Buffered Saline (with Ca²⁺ & Mg²⁺).

Preparation of Test Article

To enhance solubility of compounds of the invention insoluble in assay medium, a lOOx concentrate of compound in Dimethylsulphoxide (DMSO) was prepared. An aliquot of lOOx compound was diluted in assay medium, to yield a stock solution.

The pH of the highest assay concentration of each test articles was measured. No compound was found to significantly influence the buffer capacity of the assay medium. All solutions containing compound were used within 3 hours of preparation.

Subculturing the cells into 96 well plates

When the cell cultures were 50 to 80% confluent, the growth medium was removed from the flasks and the cultures rinsed with 10ml of HBSS. Two ml of the Trypsin EDTA solution was added and the flasks were incubated at 37°C ± 1°C for 2 to 5 minutes. When the cells started to dislodge, the flask was rapped sharply against the palm of the hand and approximately 5ml of assay medium added to neutralise the trypsin.

The concentration of cells was determined by counting an aliquot of the stock cell suspension in a haemocytometer. A seeding suspension of 5 x 10⁴ cells/ml was prepared in assay medium. 100 microlitres of the seeding cell suspension was added to the appropriate wells on each 96 well plate. 100 microlitres of growth medium was added to the outer wells to maintain humidity. The cells were incubated at 37° ± 1°C in humidified atmosphere containing 5 ± 1% C0₂ in air for 24 hours. Skin lightening assay

Different doses were used in the assay.

The test article was tested by treating six wells per dilution of B16-F1 cells seeded approximately 24 hours earlier. Prior to treatment the medium was removed, and 200 microlitres of the prewarmed (37 ± 1°C) compound dilutions and solvent control were added to the appropriate wells. These compound concentrations were dosed into a single outer well (200 microlitres) of the corresponding plate to serve as a turbidity controls. The remaining wells around the edge of the plate, designated as blanks, received 200 microlitres of assay medium prior to incubation. Following dosing, the plates were incubated at 37 ± 1°C for 96 hours ± 2 hours.

After exposure, 150 microlitres of each treatment solution (containing any secreted melanin) was removed and transferred to the corresponding wells of a new 96 well plate (melanin production plate). Turbidity controls were also transferred. The absorbance of the melanin present in the melanin production plates was measured at 405nm (OD₄₀₅) with an Anthos 2010 microplate reader.

The cells remaining in the assay plate were used to determine the cytotoxicity of the test article (cytotoxicity plate). The remaining media was removed and 100 microlitres of growth medium containing 50micrograms/ml of neutral red was added to each well. The plates were returned to the incubator for 3 hours ± 5 minutes, after which time the NR medium was decanted and the cells washed with 150 microlitres of PBS. The PBS was removed by gently tapping the plate. 150 microlitres of NR desorb solution was added to each well. After a minimum of 20 minutes incubation at room temperature, the plates were agitated and the absorbance of the neutral red was measured at 540 nm (OD₅₄₀) with an Anthos 2010 microplate reader.

Melanin Production The mean of the six OD ₀₅ values for each concentration of compound, negative control was calculated. The blank value, or turbidity control values (if present), were subtracted to obtain a corrected OD₄₀₅ value. The corrected OD ₀₅ value of the compounds were divided by the corrected OD₄₀₅ value for the negative control to obtain a melanin production ratio.

Cytotoxicity

The mean of the six OD_{5 0} values for each concentration of compound, and negative control was calculated. The blank control value was subtracted to obtain a corrected OD₅₄₀ value. The corrected OD₅₄₀ values of the compound were divided by the corrected OD₅₄₀ value for the negative control to obtain a cytotoxicity ratio.

Skin lightening effect

A skin lightening effect was calculated using the following formula to give an arbitrary Skin Lightening Unit (SLU):

Cytotoxicity Ratio xlO = Skin Lightening Units

Melanin Production Ratio

Criteria for determination of a valid test

The B16-F1 Skin Lightening Assay was accepted if the positive control compound produced a SLU of > 10 at any test concentration.

Results - The above analysis was carried out using compound I. All concentrations of compound I or control are indicated in micrograms per ml.

Table 1

Melanin production ratio

This data indicates that compound I is effective in reducing melanin production in cultured melanocyte cells.

Table 2 Cytotoxicity ratio

This table indicates that compound I is non-cytotoxic up to high levels of use (10 micrograms or below).

Table 3

Skin lightening units

EXAMPLE 2 - In vivo data of composition of the invention

A moisturising cream according to the present invention was used, in comparison with a commercial product, to determine skin lightening efficacy. Moisturising cream oil in water with Compound 1

Ingredient %

Aqua 67.850%

Octyl stearate 10.000%

Paraffinum Liquidum 6.000%

Methyl Glucose Sesquistearate 4.000%

Glycerin 4.000%

Propylene Glycol 3.000%

Isopropyl Myristate 2.300%

Stearyl alcohol 2.300%

Compound 1 0.250%

Methyl Paraben 0.150%

Triethanolamine 0.100%

Butyl Paraben 0.050%

100.0%

Appearance: smooth, white cream pH 5.56

The commercial product contained Aqua (water), Glyceryl stearate, Glycerin, PEG- 100 stearate, Paraffinum liquidum (mineral oil), Dimethicone, Octylmethoxycinnamate, Propylene glycol, Laolin, Kojic acid (1-2%), Stearyl stearate, Isopropyl alcohol, Butylmethodcybenxomethane, Cetearth-20, Phenoxyethanol, Lanolin alcohol, Methylparabens, Panthenol, Tocopherol acetate, Propyl parabens, Parfum (fragrance), Glyceryloleate, Arctostaphylos uvA-ursi (bearberry extract), Butylene glycol, Glycyrrhiza glabra (licorice extract), Moras Bombycic (Mulberry extract), BHA, Butylparabens, Ethylparabens, Citric acid, Isobutyl paraben, Ascorbyl palmitate, Tocopherol, Ascorbic acid polpeptide, BHT. The study comprised 5 subjects. The testing methodology involve daily application of 2 test products and a marketed comparator product, applied for comparison to both arms. Visual assessments and measurements of skin colour, using the Minolta Chroma Meter, over a 10 week period. Visual assessments and instrumental measurements were performed at baseline and at weeks 4, 6, 8 and 10. Measurements were taken prior to application of the test and marketed comparator products.

Five subjects were recruited into the study in the accordance with the following criteria:

Inclusion criteria

1. Male or Female

2. Aged 18-65

3. In good general health, free from any systemic or dermatological disorder that could interfere with the test results or increase risk of adverse reaction

4. Willing to wear clothing that will not rub the treatment areas during assessments

5. Willing to refrain from use of any products on the upper arms, for the duration of the study

6. Fitzpatrick Skin types V or VI

7. Written informed consent

Exclusion criteria

1. Pregnant, lactating or likely to become pregnant

2. Any significant concurrent illness or history of skin disease or allergy likely to interfere with the study, e.g. cleansers, lipstick 3. Use of any topical or systemic medication likely to interfere with the study

4. Participation in any other test on the same kin sites during the previous 4 weeks

5. Obvious skin pathology, Birthmarks, Tattoos or scars on the upper outer arms.

The Fitzpatrick skin type is defined as follows:-

The Study Products

The study products were 3 formulations of 2 test products and 1 marketed comparator as follows:

Five 3 x 3cm areas of skin on each of the subjects' left and right Upper Outer arms were market out with indelible ink, baseline visual assessments and Chroma Meter measurements were performed. 15μl of each of the products were then evenly applied to four of the areas on each arm. Each study product was applied to the skin sites via micro-pipette and rubbed evenly over the test area using a gloved finger, pre-coated in the appropriate study product, for 20 seconds. One 3 x 3cm area one each arm remained untreated to confirm no change from baseline of the Chroma Meter measurement due to possible UV exposure, visual assessment was not performed on these sites.

Test sites were assessed visually under standard lighting conditions by a single training assessor who was unaware of which product has been applied to which site and assessed as follows:

0 = None (No skin lightening)

1 = Minimal (Barely perceptible skin lightening)

2 = Moderate (Definite well defined skin lightening)

3 = Maximum (Strong skin lightening)

Chroma Meter Measurements

The product sites were assessed instrumentally using a Chroma Meter prior to product application at baseline, weeks 4 and 6. The Chroma Meter was used in accordance with the manufacturers operating instructions and the testing facility's Standard Operating Procedure (SOP).

Products were applied according to the following randomisation pattern where E, F and H refers to product number as listed above.

1 2 3 4 L. Arm L. Arm L. Arm L. Arm

Shoulder A B C A C B

Elbow C B B A A C

Each eligible subject was sequentially allocated the next pattern in the series and the coded pattern recorded in a manner blinded to the assessor.

Evaluation

The following were conducted at baseline, weeks 4 and 6 prior to treatment with the study products. Subjects have acclimatised in a controlled atmosphere (20+ 2°C; 45+5% Relative Humidity (RH) for at least 15 minutes prior to measurements. Compliance and health check questionnaires will be completed at each visit (Appendix 4).

Visual Assessments

Skin sites were assessed visually by a trained skin assessor, at baseline, weeks 4, 6, 8 and 10. The changes in skin pigmentation, at the test sites, were entered directly into a validated computer system (QPatch).

EXAMPLE 3 - Comparison of Compound 1, the sodium salt of Compound 1 and the commercial product

The results in terms of amount of lightening by mean visual amendments is shown in Figures 1 and 2. Figure 1 compares the amount of skin lightening at 4, 6 and 8 weeks using compound 1 (A) with the commercial product (C). Figure 2 compares the amount of skin lightening after 10 weeks using the sodium salt of compound 1 (B) with the commercial product (C). In both cases, the amount of skin lightening observed with the compounds of the invention were greater that that observed with the commercial product even though the commercial product contains a greater concentration of active skin lightening material, than the concentration of the compound 1 or the sodium salt of compound 1.

EXAMPLE 4 - Compositions of the invention

Tables 4 to 6:

Personal Care Products including the compounds of the invention

Table 4 : A photostable sunscreen lotion

Table 5

All purpose dry skin cream

Add Phase A to Phase B. Mix at 80°C. Cool to 60°C and add Phase C. Cool to 50°C and package.

Table 6

Moisturiser with sun protection

Add phase B to phase A; disperse well and hold at 45°C. Then add phase C slowly. Hold at 45°C, mix well then add phase D. Cool and mix to 30°C and pack.

EXAMPLE 5 - Skin Lightener Cream Formulation

A formulation was produced containing 0.1% of the sodium salt of Compound 1 by formulating the following ingredients:

Water, Butylene glycol, Arbutin, PEG 8, Alcohol, Jojoba oil, Squalane, Dimethicone, Glycerin, Petrolatum, Pentaerythrityl tetraoctanoate, PEG-60 hydrogenated castor oil, Behenyl alcohol, Potassium carbomer, Butyl alcohol, Methylparaben, Octyl methoxycinnamate, Benzophenone-3, Compound of formula I, Xanthan gum, Tocopheryl acetate, Stearyl glycyrrhetinate, Panthenenyl ethyl ether, Ethylparaben, Cholesteryl hydroxystearate, Trisodium edta, Sodium hyaluronate, Sodium citrate, Sodium metabisulfite, Tocopherol, Iron oxides.

The ingredients are in order of concentration and are standard cosmetic agents ingredients.

EXAMPLE 6: Skin Wύtener

Ingredients % weight

Surfac GMS SE40 10.00 Mineral Oil 2.00

Waglinol 6014 2.00

Cetearyl Alcohol 2.00

DC 200/350 1.00

Nipasol M 0.10

Eusolex 6007 0.50

Water To 100%

Propylene Glycol 5.00

Empicol LZV 0.60

Nervanaid BA2 0.10

Sodium salt of compound 1 2.00

Ascorbic Acid 0.10

Sodium Metabisulphite 0.15

Irgasan DP300 0.10

Fragrance qs

Colour qs

qs indicates that the components are added "to taste" i.e. to a preferred amount.

Claims

1. The use of a compound of formula I

A is an optionally substituted aryl or heteroaryl group;

Z is C=0, C=S, C=CH₂ or CH₂,

Y is NR¹, O or S,

and X is S, SO or S0₂,

and where R¹ is hydrogen, alkyl, alkylaryl or aryl,

or a ring opened derivative of formula I as illustrated below:

I (open ring structure)

wherein X, Z, A and Y are as defined above, W is O, NR¹, or S, R² is any group and R³ is any group. 9 "

The use as claimed in claim 1, wherein R and R are independently hydrogen, alkyl, aryl, a skin lightening agent, a fatty acid or a lipid.

The use of as claimed in claims 1 or 2 wherein the compound is

wherein R , R¹¹, R¹², and R are hydrogen, alkyl, alkoxy or hydroxy and Z, X, W, Y, R¹, R² and R³ are as defined in claim 1.

4. The use as claimed in any one of claims 1 to 3, wherein the compound is one or more of;

Compound number Structure

Compound 1 o-benzoic sulfimide (CAS number 81-07-2)

Compound 2 N-methyl-o-benzoic sulfimide

Compound 3

Compound 4

Compound 5

Compound 6 2-sulfobenzoic acid

Compound 7

Compound 8 2-sulfamide-benzoic acid

or a cosmetically acceptable salt thereof.

5 A skin composition comprising a compound of formula I or a cosmetically acceptable salt thereof

6. A skin composition, as claimed in claim 5, wherein the composition further comprises an antioxidant.

7. A skin composition as claimed in claim 5 or claim 6 wherein the composition further comprises one or more skin lightening agents.

8. A skin composition as claimed in any one of claims 5 to 7 which is a skin lightening composition.

9. A skin composition as claimed in any one of claims 5 to 8, which is in a form suitable for cosmetic, dermatological or personal care use.

10. A process for making a skin composition as claimed in any one of claims 5 to 8, the process comprising combining a compound of Formula I with a diluent, carrier or excipient.

11. The use of a compound of Formula I

I (closed ring structure) or a cosmetically acceptable salt thereof in the manufacture of a composition for use as a skin lightening agent, wherein in formula I:

A is an optionally substituted aryl or heteroaryl group;

Z is C=0, C=S, C=CH₂ or CH₂,

Y is NR¹, O or S,

and X is S, SO or S0₂,

and where R¹ is hydrogen, alkyl, alkylaryl or aryl,

or a ring opened derivative of formula I as illustrated below:

I (open ring structure) wherein X, Z, A and Y are as defined above,

W is O, NR\ or S,

R² is any group and R³ is any group.

12. A method of lightening skin, the method comprising administering a compound of Formula I

I (closed ring structure) or a cosmetically acceptable salt thereof, wherein in formula I:

A is an optionally substituted aryl or heteroaryl group;

Z is C=0, C=S, C=CH₂ or CH₂,

Y is NR¹, O or S,

and X is S, SO or S0₂,

and where R¹ is hydrogen, alkyl, alkylaryl or aryl,

or a ring opened derivative of formula I as illustrated below:

I (open ring structure)

wherein X, Z, A and Y are as defined above,

W is O, NR¹, or S,

R² is any group and R³ is any group.

13. A method as claimed in claim 12, wherein the compound is in the form of a cream or lotion.

14. A compound of formula I

or a cosmetically acceptable salt thereof ,wherein A is an optionally substituted aryl or heteroaryl group;

Z is C=0, W is O, x is S0₂, R3 is H, Y is NH, and R2 is

or Z is C=0, W is O, R2 is H, x is S0₂, and Y is NH and R3 is

or Z is C=0, W is NR .1¹, r R.1¹ is H, x is S0₂ and R^z and W are together the group

wherein X and Z are as defined in claim 1.

or Z is C=0, X is S0₂

and R is

15. A process for making a compound as claimed in claim 14 comprising reacting the intermediate

with one or more of the groups R²-p or R³-q wherein R² and R³ are as defined in claim 1 and p and q are leaving groups.

16. A compound as claimed in claim 14 for use as a skin lightening agent.