WO2003075901A2

WO2003075901A2 - Use of s-substituted l-crysteine for the manufacture of a medicament for the treatment of dermatological disorders

Info

Publication number: WO2003075901A2
Application number: PCT/IB2003/000857
Authority: WO
Inventors: Carlo Ghisalberti
Original assignee: Individual
Current assignee: Individual
Priority date: 2002-03-11
Filing date: 2003-03-10
Publication date: 2003-09-18
Anticipated expiration: 2004-09-11
Also published as: AU2003209542A1; WO2003075901A3; ITMI20020510A1; ITMI20020510A0; AU2003209542A8

Abstract

The invention relates to the use of S-substituted L-cysteine and derivatives for the manufacture of a topical medicament or a cosmetic agent useful to improve conditions and to alleviate the symptoms of dermatologic disorders related to the impairment of lipid metabolism, suitable for the treatment of edematous-fibrosclerotic panniculopathy, ichthyosis, hyperkeratosis, Darier disease, lichen simplex chronicus, keloid, scar, acne, rosacea and couparose.

Description

"DERMATOLOGIC USE OF S-SUBSTITUTED L-CYSTEINES"

FIELD OF THE INVENTION

The present invention relates to the use of S-substituted L-cysteine and derivatives thereof to prepare a topical medicament for the preventive and the therapeutical treatment of a skin disorders related to the impairment of lipid metabolism such as edematous-fibrosclerotic panniculopathy, ichthyosis, hyperkeratosis, Darier disease, lichen simplex chronicus, keloids, scars, acne, rosacea and couparose.

Also disclosed is a cosmetic and/or dermatological method of treating and/or preventing skin conditions related to the impairment of lipid metabolism by S- substituted L-cysteine and derivatives thereof.

BACKGROUND OF THE INVENTION

There are several skin disorders which are due to an impairment of lipid metabolism at the different types of skin cells. The metabolic impairment of lipid metabolism in adipocytes primarily correlates with their hyperthrophy, thereby causing an excess triglyceride storage which is often accompanied by capillary permeability and inadequate lymphatic drainage, then leading to a progressive impairment known as "edematous- fibrosclerotic panniculopathy". The impairment in steroidal lipid metabolism plays an important role in the pathogenesis of several skin disorders.

In fact, the steroid lipid metabolism is primarily regulated by the 5α- reductase enzymes which convert testosterone into dihydrotestosterone and related androgens with potent action on the modulation of keratin formation, sebum production and hair growth.

5α-Reductases occurs in two forms: type 1 being mainly located in skin's sebocytes but also in epidermal and follicular keratinocytes, dermal papilla cells and sweat glands as well as in fibroblasts; type II being located mainly in the seminal vesicles, prostate and in the inner root sheath of the hair follicle. According to the clinical and laboratory findings of Schmidt JB, Gebhart W,

Raff M, Spona J (Acta Derm Venereol 1984; 64(1):15-21), the sebaceous gland dysfunction play also an important role in the pathogenesis of rosacea.

The role of sebaceous gland was documented by both histological and skin sebum parameters, wherein the diminution of sebaceous gland size and the decrease of skin sebum with alteration of single sebum fractions in rosacea, also corresponding with the pattern to acne.

Moreover, the lipid metabolism impairment in keratinocytes and fibroblasts may lead to several skin disturbance including dry skin, ichthyosis, hyperkeratosis, Darier disease, lichen simplex chronicus, keloid and scar formation.

Model active ingredients on modulation of the impaired lipid metabolism in skin are retinoids. In fact some retinoids such as isotretinoin and retinoic acid (tretinoin) are effective agent in most of the afore mentioned skin disorders.

However, the systemic or local administration of isotretinoin bring about a number of side-effects including cheilitis (90%), dry or chapped skin (90%), dry nose and eyes (80%), hair shedding (10%), arthralgias and myalgias (15%), elevated liver transaminases (15%), elevated serum triglycerides (25%), as well as high teratogenic risks.

Therefore, substances capable of ameliorate the skin disorder related to the impairment of lipid metabolism, which are furthermore easily applied by the topical route, and also displaying good tolerability and low toxicity, are still desired. DESCRIPTION OF THE INVENTION

We have now found out that the S-substituted L-cysteine and derivatives thereof can be used to treat certain skin disorder related to the impairment of lipid metabolism, being therefore indicated as pharmaceutical, dermatologic and cosmetic ingredients for the preventive and the therapeutical treatment of such skin disorders. Therefore, one object of the present invention is to provide a composition that incorporates S-substituted L-cysteine and derivatives thereof as the active ingredient useful for the treatment of a skin disorder related to the impairment of lipid metabolism.

In another aspect, the present invention provides a novel use of S-substituted L-cysteine and derivatives thereof for the preparation of a medicament suitable for the treatment of a skin disorder related to the impairment of lipid metabolism. Therefore the present invention concerns the use of S-substituted L-cysteine and derivatives, and dermatologically acceptable salt or solvate thereof, of formula (I):

wherein: n is from 0 to 2;

R is selected from the group consisting of a (Cι-C₆)-alkyl, ( -C^-alkenyl, (Ci-

C )-alkynyl, (C₁-C₈)-alkoxy, and (C₄-C₁₂)-arylalkyl groups, all groups being optionally substituted with one or more halogen, -OR¹, and -NR²R³; R¹ is hydrogen, (Cι.-C )-alkyl, or the residue of a conventional hydrolyzable ester;

R² and R³ are, each independently, hydrogen, (Cι-C₄)-alkyl, (d-C^-alkylimino, or the residue of a conventional hydrolyzable amide;

X is hydroxy, an alkyamine, a the residue of a conventional hydrolyzable ester, or an amino acid residue;

Z is hydrogen, the residue of a conventional hydrolyzable amide or an amino acid residue; for the manufacture of a medicament useful in the treatment of a skin disorder related to the impairment of lipid metabolism. As used herein, the term "alkyl" means straight or branched alkyl chains,

"alkyl" refers to unsaturated cis- or trans-unsaturated, acyclic hydrocarbon radical, linear or branched which contains at least one double bond, "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical, linear or branched containing one or more triple bonds, and "alkoxy" and "alkylamine" similarly refers to O-alkyl, NH-alkyl and N-dialkyl groups.

Preferred alkyl, alkenyl, alkynyl, and alkoxy are linear (Cj_.-C₆)-chain, with optionally substituted as defined above. The term "arylalkyl" means an alkyl radical in which one hydrogen atom is replaced by an aryl, such as benzyl, phenylethyl, beta-methylen-naphthyl, and the like.

"Halogen" refers to fluorine, chlorine, bromine or iodine radicals. The term "the residue of conventional hydrolyzable ester and amides" as used herein denotes those hydrolyzable ester groups conventionally employed in the art, preferably those derived from hydrocarbon carboxylic acids or their salts. The term "hydrocarbon carboxylic acid" defines both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation, can be of straight chain, branched chain, or cyclic structure and, preferably, contain from 2 to 24 carbon atoms. In addition, they can be substituted by functional groups, for example, hydroxy, alkoxy containing up to six carbon atoms, acyloxy containing up to twelve carbon atoms, nitro, amino, halogen and the like. Particularly preferred hydrolyzable esters and amides includes those from

C₁₆-C ₄ natural fatty acid, such as palmitic acid, stearic acid, conjugated linoleic acid, palmitoleic acid, oleic acid, myristoleic acid, alpha-linolenic acid, linoleic acid, gamma-linolenic acid, cis-4,7,10,13,16,19-docosahexaenoic acid, arachidonic acid, and mixture thereof. The term "amino acid residue" as used herein means any of the naturally occurring alpha-, beta-, and gamma-amino carboxylic acids, including their D and L optical isomers and racemic mixtures thereof, and the N-lower alkyl- and N-phenyl lower alkyl-derivatives of these amino acids. The amino acid residue is either bonded through a nitrogen of the amino acid or the carboxyl carbon of the amino acid. The natural amino acids which can be used according to the present invention include alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, ^■ lysine, cysteine, methionine, ornithine, phenylalanine, proline, serine, threonine, thyroxin, tryptophan, tyrosine, valine, and γ-aminobutyric acid. Preferred amino acid residues include proline, lysine, leucine, phenylalanine, tyrosine, isoleucine, alanine, gamma-amino butyric acid, valine, glycine and phenlyglycine. The "homo-dipeptides" S-substituted-L-cysteinyl(oxides) can be prepared, e.g. by reacting the intermediate of formula (IN-NLTa-e) with compounds (H-UIa-i) or Ν^omega-protected compounds (π-HIf-g)

The "amino acid residue" may present C- or N-protecting groups such those disclosed, for example, in "Protective Groups in Organic Synthesis", T. V. Greene, J. Wiley & Sons NY (1981) 219-287.

The term "amino acid residues" further includes commonly known synthetic non-natural amino acids, logically designed peptidomimetic and amino acid residue in isosteric forms, as described in U.S. Pat. No. 6,162,791. The S-substituted L-cysteine and derivatives thereof of formula (1) contain at least one asymmetric carbon atom, hi case of presence of another asymmetric atom, such as a chiral carbon linked at the S-substituent, the chiral sulphur on the sulfoxides, or the chiral of any amino acid residue (except glycine), said compounds may exist as mixtures of diastereoisomers or as a single diastereoisomer; said mixtures as well as any single diastereosiomer can be conveniently used according to the present invention.

The compounds of formula (I) can be employed both in free form and as salts. "Dermatologically acceptable salts" refers to addition salts of the compounds of formula (I) which retain the biological activity of the parent compounds and are not biologically or otherwise undesirable.

Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic and isethionic acids.

The salts may be formed by conventional means, as by reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.

In yet another embodiment of the present invention, the compound of formula (I) can be present in a zwitterionic form, which can exist without a separate counterion or it can exist with both cationic and anionic counterion. The S-substituted L-cysteine and derivatives thereof of formula (I) are either known compounds or can be prepared from known compounds by conventional procedures.

Several processes for the preparation of S-substituted-L-cysteines are described in the literature. Examples are the reaction with alkyl halides in alkaline medium as described by D H Hwang et al. (J Org Chem, 50, 1264, 1985), M. Frankel et al. (J Chem Soc, 1390, 1960), and MD Amstrong et al. (J Org Chem, 16, 749, 1951). Further processes use different methylating agents, such as dimethylsulfate in the presence of Ba(OH)₂ (V. du Vigneaud et al., J. Biol. Chem., 105, 481, 1934) or trimethylphosphate in water at pH 8 (K. Yamauchi, Tet Lett, 1199 1977). For instance, S-substituted-L-cysteines for our purposes are formed either by the reaction of S-alkylation with dialkylcarbonates as described in U.S. Pat. No. 6,147,257, or by reacting a alkyl halide solution of Sn(Cys)₂ salt, previously formed by the reaction of L-cysteine in HC1 with Sn° (Stoll & Seebeck, Helvetia, 31, 189, 1948). (+/-)S-substituted-L-cysteine sulfoxides and sulfones may be prepared according to the oxidation of S-substituted-L-cysteines with hydrogen peroxide (Stoll & Seebeck, Helv Chim Acta, 34, 481-487, 1951), whilst pure (+) and (-) diastereoisomers sulfoxides may be obtained by repeated separative crystallization in acetone:water binary solutions. S-alkylamidino-L-cysteine and sulfoxides thereof may be prepared by the reaction of Cu(Cys) salt, previously formed by the reaction of copper carbonate with L-cysteine, with ethyl acetimidate in aqueous alkaline solution, as described in U.S. Pat. No.5863931.

N-acetylated S-substituted-L-cysteine and oxides thereof may be prepared by the reaction of the acid halide or anliydride of a carboxylic acid, previously prepared by contacting the carboxylic part with an inorganic acid halide, such as SOCl₂, PC1₃, PBr₃ or PC1₅, or alternatively, with oxalyl chloride, typically in the presence of an amine as acid-scavenger, e.g triethylamine, diisopropylethylamine, N- methylmorpholine and the like.

Alternatively, N-acylation of S-substituted L-cysteine and derivatives thereof with amines or carboxylic acid can be conducted using any conventional coupling reagent including carbodiimides such as dicyclohexylcarbodiimide, N,N'- carbonyldiimidazole, N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. to facilitate the coupling of carboxylic acids and amines.

S-substituted-L-cysteinamides as well as S-substituted-L-cysteinyl dipeptides and their S-oxides thereof be prepared by the condensation of reactive derivatives of N-protected S-alkylcysteines, for example N-protected by t-butyloxycarbonyl, t- amyloxycarbonyl or benzyloxycarbonyl.

These reactive derivatives include, for example, mixed acid anhydrides such as mixed anhydrides with an alkyl carbonate, acid chlorides, etc. It is not always necessary to isolate and purify these reactive derivatives. For example, an N-rptected S-substituted-L-cysteine is reacted with a chloroformate or SOCl₂ and the resulting alkyl carbonate mixed anliydride or acid chloride may be used without isolation and purification.

Although the dipeptides comprising S-alkyl-L-cysteine and S-oxides suitable for our purposes may be prepared in many ways by those skilled in the art, a preferred method is described in Preparative Examples 5 and 6.

This preferred embodiment, which represents a further inventive object, the synthesis of these dipeptides is carried out according the following steps: a) protecting one or more amino functions of S-substituted L-cysteine and derivatives thereof by treatment with a chloroformate of formula R'-O-

COC1, wherein R' represents lower alkyl, alkenyl, benzyl or trichloroethyl groups, in an aqueous alkaline medium; b) reacting the product of step a) in an inert solvent with SOCl₂ in the presence of N,N-dimethylformamide (DMF); c) reacting the N-carboxyanhydrides of the S-derivative of L-cysteine obtained in step b) with a amino acid in aqueous or hydroacetonic alkaline medium. d) deprotecting the N-carboxycarbonyl derivatives of the S-derivative of L- cysteine obtained in step c) in aqueous or hydroacetonic acid medium, wherein the steps above are preferably carried out as follows: a) at pH 10-14 at 10- 30°C for 2-6 h; b) in halo- or aromatic solvents at 0-30°C for 2-6 h; and c) at 0-10°C for 1-3 h.

According to a particularly preferred embodiment, the present invention relates to the process above wherein said S-substituted L-cysteine and derivatives thereof of formula (I) contain at least a primary or a secondary amino group, advantageously said amino is an alkylamino or an alkylamidino. The dipeptides of S-alkyl-L-cysteine and sulfoxides thereof may be prepared by know means, as well as S-alkyl-L-cysteinamides (e.g. U.S. Pat. No. 4,440,788).

The amino-protecting group in the condensation reactions preferably such that can be readily eliminated with an acid (e.g., hydrogen chloride, hydrogen bromide). Since the compounds are sulfur-containing amino acids, those amino- protecting groups which are eliminated by means of catalytic hydro genation are not preferred.

Functional groups, such as amino, hydroxyl, or carboxyl groups optionally present in the various compounds may need to be protected before any reaction is initiated, wherein removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality apparent to those skilled in the art. For specific details see "Protective Groups in Organic Synthesis", Wiley Interscience, TW Greene, PGM Wuts.

Illustrative, preferred compounds of fonnula (I) include the compounds of formulae (U-Xa-g) described in the Preparative Examples 1, 2, 3, 5 and 6. As set forth above, the compositions according to the present invention are particularly useful for treating a skin disorder related to the lipid metabolism impairment.

A further object of the present invention is to provide a cosmetic and/or dermatological method for the treatment and/or prevention of skin disorders, more particularly those which are mentioned in the present application, which comprises the local application to a mammal in need thereof of an effective amount of S- substituted L-cysteine and derivatives thereof of formula (I).

A more specific embodiment of this invention relates to the above method wherein the disorder is edematous-fibrosclerotic panniculopathy, also known as "cellulite". Another more specific embodiment of this invention relates to the above method wherein the disorder include dry skin, .ichthyosis, hyperkeratosis, Darier disease, lichen simplex chronicus, keloid and scar.

Another more specific embodiment of this invention relates to the above method wherein the disorder include acne, rosacea and couparose. The topical compositions of the invention comprise a S-substituted L-cysteine and derivatives thereof of formula (I), for example, in amounts of 0.05% to 50% by weight, preferably in amounts of 0.5% to 5% by weight of the composition.

The topical compositions according to the present invention may be manufactured by known methods by mixing the S-substituted L-cysteine and derivatives thereof with conventional dermatologically acceptable carriers, i.e. bases for topical medicaments and cosmetics.

When the topical compositions of the present invention are used as cosmetic compositions, the cosmetic acceptable ingredients may be optionally incorporated in arbitrary combinations as desired and determined in accordance with conventional skill in the art: oils, fats, waxes, surfactants, chelating agents, pH modifiers, preservatives, viscosity modifiers, colorants, preservatives, perfumes, dyestuffs, lower alkanols, etc.

The composition can contain humectants such as proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and derivatives, water- soluble vitamins, plant extracts, hydroxyacids, polyols (e.g. glycerol), vitamins (e.g. D-panthenol), allantoin.

Other additives, e.g., preservatives, fragrance, sunscreen, or other cosmetic ingredients, such those in the INCI list by the European Cosmetic Toiletry and Perfumery Association (COLJTA) issued in 96/335/EC and further modifications, can be present.

Noteworthy, the topical compositions comprising the S-substituted L-cysteine and derivatives thereof of formula (I) are in a substantially pure fonn, and therefore substantially odorless, thus are suitable for the topical treatment of the skin disorders related to the lipid metabolism impairment.

The expression "substantially odorless" as used herein means that the composition and/or the application of said composition onto the skin is free of any perceivable off-odor, i.e. substantially free odorous organosulfur contaminants.

The expression "odorous organosulfur contaminants" as used herein encompasses the volatile organosulfur compounds typically occurring in Alliums spp.

Volatile organosulfur compound include thiosulfmates such as allyl 2- propenthiosulfinate (allicin), allyl methanthiosulfinate, methyl 2-propenthiosulfinate, allyl 1-propen-thiosulfinate, methyl methanthiosulfinate, 1-propenyl methantiosulfinate; sulfides such as diallyl n-sulfides, allyl methyl «-sulfide, dimethyl n-sulfides,^' allyl 1-propenyl 72-sulfides, allyl ethyl n-sulfides, allyl 1- propenyl n-sulfides (with "n" an integer from 1 to 6); dithiins such as 1,3-vinyldithiin (2-vinyl-4H-l,3-dithiin), 1,2-vinyldithiin (3-vinyl-4H-l,2-dithiin); and mixed thiosulfinate-sulfides such as E,Z-4,5,9-trithiadodeca-l,6,ll-triene 9-oxide (ajoene).

The topical composition can be applied and removed immediately, or it can be applied and left on the skin surface, e.g., the face, for an extended period of time, e.g., overnight or throughout the day. The following examples are intended to illustrate the scope of the present invention but not to limit it.

EXAMPLES Preparative Example 1 - Synthesis of S-substituted-L-cysteines

The S-alkyl-, S-alkenyl, S-alkynyl and S-aralkyl-L-cysteine were prepared according to Stoll and Seebeck (Helvetia, 31, 189, 1948) by reacting a solution of Sn(Cys)₂ salt, previously formed by the reaction of L-cysteine in HC1 with powdered Sn° at 25°C for 8-10 h with 3 equivalent of methyl bromide, propyl bromide, allyl bromide, propargyl bromide, benzyl bromide and 2-bromoetylamine to afford, respectively, the compounds of formulae (Ha-f). H₂ _R^N. _C00H

R = -CH₃ (lla)

^ ? 3 (lib)

"CH^CH—CH (lie)

-Crl,-CsCH (lid)

-Cl^-Ph (He)

-CH2-CH2-NH2 (llf)

NB: Ph = phenyl group.

Preparative Example 2 - S nthesis of S-substituted-L-cysteine sulfoxides

The (+/-) S-substituted-L-cysteine oxides were prepared as diasteroisomeric pair according to Stoll and Seebeck (Helv. Chim. Acta, 34, 481-487, 1951), thereby reacting the substances of formulae (LTa-i) as obtained before with hydrogen peroxide in neutral aqueous solution, the reaction mixture was filtrated and concentrated in vacuum. The solid was crystallized in acetone:water binary solutions to afford the compounds of formulae (Hla-f).

R = -CH₃ (Ilia)

-CH_j-CH^CHg (lllb) -CH2-CH=CH₂ (lllc) -CH.-C=CH (Hid) -CH_j-Ph (Hie)

-CH^CHg-NHz (lllf)

Pure (+) and (-) diastereoisomers of S-substituted-L-cysteine oxides are obtainable by re-crystallization of (+/-)-pairs in acetone:water (Experientia, VI/9, 330, 1950).

Preparative Example 2 - Synthesis of S-alkylamidino-L-cisteine(sulfoxide) hi separate vessels, 13.7 mmoles each of S-substituted-L-cysteine and oxide thereof of formulae (Uf) and (IHf) in 50 ml of water were added with 5 g of cupric carbonate. The mixtures were stirred at 60°C for 1 h and filtered. The pH of the filtrated solutions were adjusted to pH 9.5 with 0.5N NaOH. Ethyl acetimidate HC1 (1.78 g; 14.5 mmol) was added and the pH kept at 9-9.5 for 1 h. The solutions were then adjusted to pH of 7.5 and kept at RT for 12 h. The solutions were added with HCl IN until pH 4 and applied to a Dowex 50 x 4 (H⁺ form), washed with water, then with 10 % pyridine to afford, respectively, the compounds of formulae (Tig) and (ffl ).

•ι = 0 (Ilg) " = 1 (lllg)

Preparative Example 3 - Synthesis of N-acyl S-substituted-L-cysteine(sulfoxides^') 50 mmoles of the S-allyl-L-cysteine and oxides of formulae (Ila-e) and (Hla- e) and 55 moles of triethylamine in 0,5 1 of CH₂C1₂ and slowly added with 0.52 moles of acyl reactant, at 20° C for 30 minutes under N₂, then stirred for 2 h.

The reaction mixture is quenched with H₂O (50 ml), and after stirring for 10 min, the aqueous phase was extracted with CH C1₂ (2x30 ml). The organic phases were combined, washed with 10% HCl (20 ml), H₂O (50 ml), saturated NaHCO₃ (30 ml), saturated NaCl (30 ml), dried (MgSO₄) and concentrated to provide waxy whitish solids.

The solvent was evaporated to afford a waxy solids, which were re- crystallized in ethanol, to afford compounds of formulae (IVa-e) and (Va-e) with Z_J-vj as indicated.

-CI-^-CsCH (IV-Vd)

-CH,-Ph (IV-Ve)

Λ^ COOH

v Λ

Acyl reactants: γ-linolenoyl chloride (*) SOCl₂-treated fatty acid mix containing ~ 20% γ-linolenic acid from borage oil; α-linoleoyl chloride (**) SOCl₂-treated fatty acid mixture containing ~ 60% α-linoleic acid from linseed oil; CLA chloride (***) SOCl -treated fatty acids mixture containing ~ 55% conjugated linoleic acid (CLA) as mixture of cis and trans 9,11-, 10,12-, 8,10-octadecadienoic acids, by alkali isomerization according to Example 1 in Applicant patent WOO 1/17497; reagent grade oleyl chloride; reagent grade succinic anhydride; and reagent grade acetic anhydride.

Preparative Example 4 - Synthesis of S-substituted-L-cysteine(sulfoxide N-carboxy- anhydrides (intermediate for dipeptides) hi a stirred solutions of 0.50 moles of the compounds of formulae Ee-g and πie-g in 800 ml of water were added with NaOH ION until the pH 11.5, then 0,52 moles of 97% benzylchloroformate (or 1.05 moles in case of π-HIf,g) are added at 25°C with pH maintained at 11-11.5 by NaOH ION. After 2 h, HCl cone, was added until pH 7-8, then 500 ml of ethyl acetate and further HCl until pH 1-1.5. The organic layers were separated, washed with 150 ml of brine and vacuum evaporated. The residues were solubilized in 10 g of N,N-DMF and 250 ml CH₂C1₂ at 0°C, then added dropwise with 16.54 g of SOCl₂. The mixtures were kept for 1 h at 0°C, then at 10°C for 2 h, and vacuum evaporated to afford the intermediate of formulae (Nla- g) and (Nπa-g).

n = 1 (VII)

R = -CH₃ (Vl-Vlla)

-CH 'CH^CHg (Vl-Vllb)

-CR,-CsCH (Vl-VIId)

-CH_j-Ph (Vl-Vlle)

-CH^CH^ΝH-CO-O-Bz (Vl-Vllf)

-CH₂-CH₂-N-C(=NH)-CH₃ (Vl-Vllg)

CO-O-Bz NB: Bz = benzyl group.

Preparative Example 5 - Synthesis of the S-substituted-L-cysteinyl(sulfoxide^')-L- proline

In a stirred solution of 12.66 g of L-proline (0.11 mmol), 43.2 g of KHCO , 7.42 g of 85% KOH and 390 ml of water were mixed at RT, then added with 295 ml of acetone, cooled to 0°C containing the 0.1 mmol of the compounds of formulae (Vla-g) or (NrJa-g) in 50 ml of acetone. The reaction mixtures were kept for one hour under stirring at 0°C, then washed with ethyl acetate (2x200 ml). The aqueous layers were collected and treated with HCl cone until pH 8-9, concentrated to half volume and then 200 ml of n-butanol and HCl cone were added until pH 8-9. The aqueous layers were extracted with n-butanol (2x150 ml) and ΝaOH 10Ν added until pH about 5.0, the mixture is vacuum evaporated and the oily residues added with 2x100 ml of n-butanol and filtered, affording Ν-phenylmethoxy)carbonyl-protected S-substituted L-cysteine dipetides. These were solubilized in CH₂C1₂ (10 ml) were treated with 25% HBr in acetic acid (18.6 ml) and stirred at RT for 1 h. Water (10 ml) was added and the mixtures washed with CH₂C1₂ (3x15 ml). The aqueous phase were added with NaOH ION until pH 14, then extracted with CH₂C1₂ (4x30 ml). The combined organic extracts were washed with brine (30 ml), dried (MgSO₄) and vacuum evaporated to provide the dipeptide compounds of formula (Vϋa-g) and

n = 1 (IX)

CH, (Vlll-IXa)

'CH^CH^-CHg (Vlll-IXb)

CRj-CHMCH (VIII-IXc)

Cr^-CsCH (Vlll-IXd)

CH_j-Ph (Vlll-IXe)

CH^CH^NI-^ (Vlll-lXf)

CH₂-CH₂-NH-C(=NH)-CH₃ (Vlll-IXg)

- S-methyl-L-cysteinyl-L-proline (VlHa)

- S-methyl-L-cysteinylsulfoxide-L-proline (IXa)

- S-propyl-L-cysteinyl-L-proline (Vlllb)

- S-propyl-L-cysteinylsulfoxide-L-proline (LXb) - S-allyl-L-cysteinyl-L-proline (Vmc)

- S-allyl-L-cysteinylsulfoxide-L-proline (IXc)

- S-propargyl-L-cysteinyl-L-proline (Viπd)

- S-propargyl-L-cysteinylsulfoxide-L-proline (IXd)

- S-benzyl-L-cysteinyl-L-proline (VUIe) - S-benzyl-L-cysteinylsulfoxide-L-proline (LXe)

- S-2-aminoethyl-L-cysteinyl-L-proline (Vmf)

- S-2-aminoethyl-L-cysteinylsulfoxide-L-proline (IXf)

- S-2-(l-iminoethylamino)ethyl-L-cysteinyl-L-proline (VDIg)

- S-2-( 1 -iminoethylamino)ethyl-L-cysteinylsulfoxide-L-proline (LXg) Further S-substituted-L-cysteinyl(oxides)-L-dipeptides may be obtained using, instead of L-proline, several amino acids, e.g. phenylalanine, tyrosine, alanine, γ-amino butyric acid, L-valine, glycine, cysteine and L-phenlyglycine. The "homo- dipeptides" S-substituted-L-cysteinyl(oxides) are conceivable, e.g. by reacting the intermediate of formula (IN-VIIa-e) with compounds (TL-HJa-f) or Ν^omega-protected compounds (U-IIIf-g). Preparative Example 6 - Synthesis of S-substituted-L-cvsteinamides

By the reaction of compounds of formulae (Vla-g) with ethylamine and work- up, as described in the Example 4 of U.S. Pat. No. 4,440,788 compound of formulae (Xa-e) were obtained.

NH₂

R /v ^CO NH-C irCH₃

R'" = -CH₃ (Xa)

-CH,-C=CH (Xd)

-CH2-CH_?NH₂ (Xf)

-CH₂-CH₂-NH-C(=NH)-CH₃ (X^β)

Example 1 - Treatment of edematous fibrosclerotic panniculopathy

Ingredients (g per 100 g) Composition # 1 Control # 1

Hydrogenated coconut oil 3.9 3.9

Ceramides 0.1 0.1

Sodium L-lactate 2.0 2.0

Oleth-2 5.0 5.0

Quaternium-18-ectorite 0.5 0.5

Compound lie (as hydrochloride) 2.5 -

Polygala tenuifolia ethanolic extract - 1.5

Ginkgo biloba, extract (Phytelene™) - 1.5

Caffeine 1.0 1.0

Escine 0.5 0.5

MgSO₄.7H₂O 0.3 0.3 Parfum, additives, preservatives qb qb Demineralized water qb to 100 g qb

Standard Protocol The selection of female subjects is based on the cellulite intensity in the thigh area and by a bi- lateral symmetry. Subjects with grades 1 and 2 cellulite shall be chosen, as a 5-point grading scale was used to rate the cellulite severity of each subject.

The scale ranges from 0 to 4, being 0 = No cellulite; 1 = Small bumps or depressions;

2 = Striations and bumps; 3 = Pronounced lumpiness of the skin and striations; 4 = All of the above plus hard sub-surface nodules. The subjects were instructed to apply in the only in right thigh, twice a day, at morning and at night, during 2 months the cream as described below. The condition and score after the treatment can be evaluated according to Smith WP (Cosmetics & Toiletries, 61-70, June 1995) by the comparative evaluation of the right thigh versus left thigh. Example 2 — Treatment of couparose and rosacea

Ingredients (g per 100 g) Comp. # 2a Comp. # 2b Control # 2

White petrolatum 10.0 10.0 10.0

Light liquid paraffin 9.0 9.0 9.0

Stearyl alcohol 4.0 4.0 4.0 Cetyl alcohol 4.0 4.0 4.0

Polyoxyethylene cetyl ether 3.0 3.0 3.0

Compound Ua(as hydrochloride) 1.0 „ -

Compound LTg (as dihydrochloride) - 1.0

Hesperidin 1.0 Glycerin 10.0 10.0 10.0

Parfum, additives, preservatives qb qb qb

Demineralized water qb to 100 g qb to 100 g qb to 100 g

Standard Protocol Subjects with rosacea shall be classified based on the progression of the disorder. The first group with couparose and stage I-II rosacea shall be asked to apply the Compostion # 2A, which is a cosmetic formulation, to one side of the face and the Control # 2 to the other side. The second group with rosacea with stage m or higher (i.e. nontransient erythema, telangiectasia, phytomatous and granulomatous rosacea) shall be asked to apply either Compostion # 2b, which is a pharmaceutical-type formulation, and Control # 2 on the bi-lateral side of the face. Physician shall assess the patients at the beginning of the study to establish a baseline. For the first two weeks of the trial, in order to minimize adverse reactions all subjects shall apply once daily Compostion # 2a and 2b on one side, and Control

#2 on the other side. The physician shall possibly increase application to twice daily, then assessing every two weeks the first group for erythema and flushing blushing response on each side, while the second group on clinical attribution on each side, with a classification rate based on a scale of 1 (slight difference) to 6 (dramatic difference) between treated and control side.

Example 3 - Treatment of acne

Ingredients (g per 100 g) Composition # 3 Laurylmethicone copolyol 2.0

Liquid paraffme 1.0

Compound JVa-Zjj (as hydrochloride) 2.0

Lanolin 1.5

Soybean oil 10.0 Cyclomethycone 6.0

Azelaic acid 1.5

Oily extract of rosemary 2.0

Parfum, additives, preservatives qb

Demineralized water qb to 100 g Sodium biphosphate qb to pH 3,8

Case study A male patient with plugged pores (blackheads and whiteheads), pimples and some deeper cysts over 30-40% of his face. The patient had previously undergone treatments using prescription and over-the-counter remedies with only temporary reduction in the degree of acne. Over the course of the treatment may underwent using Composition #3, the patient experience over high remission of the symptoms and, in long term follow-up, free of recurrence of the disease except for some residual acneic lumps. and lichen simplex chronicus

Ingredients (g per 100 g) Composition # 4a Composition # 4b

Glycerol monostearate 10.0 10.0

Cetyl alcohol 4.0 4.0

Polyethylene glycol 400 stearate 10.0 10.0

Polyethylene glycol sorbitan monostearate 8.5 8.5

Propylene glycol 6.0 6.0

Compound πic (as hydrochloride) 3.0 -

Compound Ve-Zj - 5.0

Parfum, additives, preservatives qb qb

Demineralized water qb to 100 g qb to 100 g

Examples 5 and 6 - Treatments of hyperkeratosis, keloid and scar

Ingredients (g per 100 g) Composition # 5a Composition # 5b

White petrolatum 10.0 10.0

Light liquid paraffin 9.0 9.0

Stearyl alcohol 4.0 4.0

Polyoxyethylene cetyl ether 3.0 3.0

Glycerine 10.0 10.0

Methyl salicylate 0.2 0.2

Compound VHJa 0.5 -

Compound JJia - 0.5

Demineralized water qb to 100 g qb to 100 g

Ingredients (g per 100 g) Composition # 6a Composition # 6b

Idroxyethyl cellulose 0.4 0.4

Compound TVa-Zjj 2.5 -

Compound lie - 2.5

Ethanol 25.0 25.0

Propylenglycol 38.0 38.0

Demineralized water qb to 100 g qb to 100 g

Claims

1. Use of a S-derivative of L-cysteine of formula (I) :

wherein: n is from 0 to 2;

R is selected from the group consisting of a (Cι-C₆)-alkyl, (Ci-C₆)-alkenyl, (Ci-

C₄)-alkynyl, (Cι-C₈)-alkoxy, and (C -C₁₂)-arylalkyl groups, all groups being optionally substituted with one or more halogen, -OR¹, and -NR R³;

R¹ is hydrogen, (C_!-C₄)-alkyl, or the residue of a conventional hydrolyzable ester;

R² and R³ are, each independently, hydrogen, (CrC^-alkyl, (CrC^-alkylimino, or the residue of a conventional hydrolyzable amide;

X is hydroxy, an alkyamide, a the residue of a conventional hydrolyzable ester, or an amino acid residue; Z is hydrogen, the residue of a conventional hydrolyzable amide, or an amino acid residue; or of a dermatologically acceptable salt or solvate thereof, for the manufacture of a medicament useful in the treatment of a skin disorder related to the impairment of lipid metabolism.

2. Use according to claim 1, wherein said skin disorder is edematous-fibrosclerotic panniculopathy.

3. Use according to claim 1, wherein said skin disorder is selected in the group consisting of dry ichthyosis, hyperkeratosis, Darier disease, lichen simplex chronicus, keloid, and scar.

4. Use according to claims 1, wherein said skin disorder is acne.

5. Use according to claims 1, wherein said skin disorder is rosacea and couparose.

6. Use according to claim 1, wherein said conventional hydrolyzable ester or amide is derived from a (C₁₆-C₂₄)-natural occurring fatty acid.

7. Use according to claim 6 wherein said fatty acid is selected from the group consisting of gamma-liiiolenic acid, cis-4,7,10,13,16,19-docosahexaenoic acid, cis-6,9,12,15-octatetraenoic acid, arachidonic acid, alpha-linolenic acid, linoleic acid, conjugated linoleic acid, palmitoleic acid, oleic acid, myristoleic acid, and mixture thereof.

8. Use according to any of claims from 2 to 4, wherein R is selected from the group consisting of methyl, ethyl, propyl, allyl, 2-propenyl, propargyl, and benzyl.

9. Use according to claim 5, wherein R is 2-(l-iminoethylamino)ethyl.

10. A cosmetic method of treating and/or preventing a skin disorder related to the impaired lipid metabolism comprising applying to the skin of a mammal in need thereof a S-substituted L-cysteine and derivatives thereof, or a dermatologically acceptable salt or solvate thereof of formula (I) according to claim 1.

11. Method according to claim 10, wherein the skin disorder is edematous- fibrosclerotic panniculopathy.

12. Method according to claim 10, wherein the skin disorder is selected form the group consisting of ichthyosis, hyperkeratosis, Darier disease, lichen simplex chronicus keloid and scar.

13. Method according to claim 10, wherein the skin disorder is acne.

14. Method according to claim 10, wherein the skin disorder is rosacea and couparose.

15. Process for the production of S -derivative of L-cysteine of formula (I) wherein X is an amino acid residue, said process comprising the following steps: a) protecting one or more amino functions of a S -derivative of L-cysteine by treatment with a chloroformates of formula R'-O-COCl, wherein R' is a lower alk(en)yl, or benzyl or a trichloroethyl group, in an aqueous alkaline medium; b) reacting the product of obtained in step a) in an inert solvent with thionyl chloride in the presence of N,N-dimethylformamide; c) reacting the N-carboxyanhydrides of the S-derivative of L-cysteine obtained in step b) with a amino acid in aqueous or hydroacetonic alkaline medium. d) deprotecting the N-carboxycarbonyl derivatives of the S-derivative of L- cysteine obtained in step c) with an acid catalyst, wherein, preferably, step a) is carried out at a pH 10-14 at 10-30° C for 2-6 h; step b) is carried out in a halogenated or aromatic solvent at 0-30°C for 2-6 h; and step c) is carried out at 0-10°C for 1-3 h.

16. Process according to claim 15, wherein the R substituent in said S-substituted L- cysteine and derivatives thereof of formula (I) contain at least a primary or a secondary amino group.

17. Process according to claim 16, wherein said amino group is an alkylamino.

18. Process according to claim 16, wherein said amino group is an alkylamidino.