WO2003075913A1

WO2003075913A1 - Topical compostions comprising furfuryl derivatives and their use for the treatment of dermatologic disorders

Info

Publication number: WO2003075913A1
Application number: PCT/IB2003/000852
Authority: WO
Inventors: Carlo Ghisalberti
Original assignee: Carlo Ghisalberti
Priority date: 2002-03-11
Filing date: 2003-03-10
Publication date: 2003-09-18
Also published as: ITMI20020508A1; ITMI20020508A0; AU2003209540A1

Abstract

The present invention relates to a dermatological composition comprising furfuryl derivatives and their use in the treatment of papulosquamous and eczematous dermatoses.

Description

TOPICAL COMPOSITIONS COMPRISING FURFURYL DERIVATIVES AND THEIR USE FOR THE TREATMENT OF DERMATOLOGIC DISORDERS

FIELD OF THE INNENTION

The present invention relates to a dermatological composition comprising a furfuryl derivative and its use in the treatment of papulosquamous and eczematous dermatoses.

BACKGROUND OF THE INNENTION

Atopic, inflammatory and allergic skin diseases have in common an unbalanced immunological system and or the inherited over-sensitivity to chemical moieties. The increasing occurrence of these skin disorders may be also triggered by environmental factors and the increased pressure of the oxidative stress.

Topical compositions for the use on the skin that incorporate certain furfuryl derivatives as the active ingredient in the treatment of papulosquamous and eczematous dermatoses have been disclosed in PCT/IB02/01653 in the name of the present Applicant.

These furfuryl derivatives, namely the esters and ethers of furfuryl alcohol, are efficient trap of singlet oxygen, thereby producing endo-peroxides which shall further evolve to eso-metabolites that may act by the interference with the prostanoid pathway. hi a multicenter clinical trial, a representative furfuryl ester (namely furfuryl palmitate) was applied in a 0.3% cream on patients under medical monitoring. The results indicate that furfuryl esters can be used with good efficacy and sufficient tolerability in a large number of cases. Specifically, they produced remissions in seborrhoeic dermatitis and irritant contact dermatitis; good results in atopic dermatitis on both adults and new-born children; while the effect in allergic contact dermatitis, in atopic dermatitis subjects from 3 to 16 years and in psoriatic skin have been moderate.

These data indicate that topical compositions comprising different furfuryl derivatives with higher therapeutic indexes, large tolerability and a broad-range action in the treatment of the pro-inflammatory skin conditions and eczematous dermatitis may be further conceived. The present invention aims to fulfil the needs of achieving further therapeutic advantages. DESCRIPTION OF THE INNENTION

We have now discovered that some furfuryl derivatives present an improved efficacy and high selectiveness in the treatment of the different form of papulosquamous and eczematous dermatoses when formulated in topical compositions.

Accordingly, one object of the present invention is to provide a topical composition for the use on the skin that incorporates certain furfuryl derivatives as the active ingredient in the treatment of papulosquamous and eczematous dermatoses.

Therefore, the present invention provides a topical composition comprising, as the active ingredient, a furfuryl derivative or dermatological acceptable salt or solvate thereof, specifically useful for treating and/or preventing papulosquamous and eczematous dermatoses, said furfuryl derivative having formula (I) :

wherein R° is hydrogen or halogen;

R¹ represents hydrogen or a lower alkyl, alkenyl, alkynyl, hydroxyalkyl or an alkoxymethyloxy;

X represent one of the following XI, X2 or X3 groups:

wherein R² represents hydrogen or a lower alkyl, alkenyl or alkynyl; R³ represents a saturated or unsarurated, linear or branched (Cι-C₂ )-alkyl, which can be substituted with carbonyl, -CN, -COHR¹¹, -COOR¹¹, -OSO₂Rⁿ, - SOsR¹¹ , -SOzNHR^{1 ]} , -NHR¹¹ , -N(R^π)₂, -OR¹¹ , -SR¹¹ ; -O-POsR¹¹ ; wherein R^{1 ]} represents hydrogen or a lower alkyl or hydroxyalkyl;

R⁴ represent hydrogen, alkyl or the residue of a conventionally hydrolyzable ester or amide;

wherein R⁵ represents hydrogen or a lower alkyl, alkenyl or alkynyl; R⁶ and R⁷, each independently, represent hydrogen or lower alkyl, alkenyl, cyloalkyl, which may be mono- or bi-substituted with (Cι-Cs)-alkoxy, carboxy, (Cι-Cs)-alkoxycarbonyl, amino, hydroxy; wherein R and R may join together to form a 4 to 6-membered aliphatic ring, wherein two or more hydrogen atoms may be optionally substituted by one oxygen atom or by an alkyhdene group or an aryl-alkylidene group said groups being optionally substituted;

wherein

R⁸ and R⁹ represent, each independently, hydrogen or a lower alkyl, alkenyl or alkynyl; n is 0 or 1 ; provided that when n = 0, W represents -C(O)-O- -C(S)-O- -C(O)NH- -C(S)NH-; when n = 1, W represents -O-C(O)-O- -O-C(O)-, -O-, -OP(O)(OR¹⁰)-, -

OC(S)-

-NHC(O)-, -NHC(S)-, -NHC(NH)NH- -NHC(O)NH- -NHS(O)-, -NHS-, -

NHC(S)NH-; Z is selected form the group consisting of:

- Zl) a saturated or unsaturated, linear or branched (Cι-C₂₄)-alkyl which can be substituted with (Cι-C₈)-alkoxy, carboxy, (Cι-C₈)-alkoxycarbonyl, amino, hydroxy, said amino and hydroxy being optionally (Cι-C₂₂)-acylated or (Ci- C₂₂)-alkylated;

Z2) (6-methoxy-2-naphthyl)methyl; - Z3) phenyl, optionally substituted with one or more hydroxy, lower alkyl, alkoxy, hydroxyalkyl, -SH, -CH₂SH, -C₂H₅SH, -SCH₃, -SC₂H₅, - CH2SCH3, -C₂H₅SCH₃, -NO2, -OCH₂NH₂, -OC₂H₅NH₂, halogen, in which the free hydroxy group(s) may be protected by the residue of a conventionally hydrolyzable ester; R¹⁰ represents hydrogen, 2- or 3-furfuryl, or a lower alkyl, alkenyl or cycloalkyl group which group can be substituted with amino or hydroxy, said amino and hydroxy being optionally (Cι-C )-acylated or (Cι-C₂₂)-alkylated; and provided that when X =X3 in the α-position of the furan ring, n=l, W= O- C(O)- or O-, and Z is Zl or unsubstituted phenyl, then at least one of R¹ or R⁸ or R⁹ is other than hydrogen.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "lower" associated with "alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl" is intended to mean aliphatic chains made of 1 to 6, preferably 1 to 4 carbon atom(s), unless otherwise indicated. The term "alkyl" is intended to mean a straight or branched alkyl chains (of 1 to 22) carbon atoms, "alkenyl" refers to unsaturated cis- or trans-unsarurated, acyclic hydrocarbon radical, linear or branched, in so much as it contains at least one double bond, "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, containing at least a triple bonds, and "alkoxy" and "hydroxyalkyl" similarly refer to alkyl-containing -C-O-C- or C-OH groups, respectively.

"Alkoxycarbonyl" refers to the group -C(O)O-alkyl. The term "cycloalkyl" is intended to mean cyclic hydrocarbon groups of three to seven carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, and the like. The term "alkyl" as used herein also encompasses ethereo-substituted acyclic chains, thus containing at least unit such as -C-S-C-, -C-Si-O-, -C-Si-O-C- and the like.

The term "alkoxymethyloxy" is intended to mean the memylether groups which are substituted with one alkoxy group; typical alkoxymethyloxy groups include methoxymethyloxy, ethoxymethyloxy, isopropoxymethyloxy, and the like.

The term optionally substituted "alkyhdene" group means an aliphatic saturated or uinsaturated bivalent radical, such as CH₃-CH=, HOOC-CH₂-CH=, etc. Preferred substitutions for the alkyhdene group are CHO, OH, -COOH, amino, mono or di-alkylamino, and the like.

The term optionally substitued "aryl-alkylidene" group means an aliphatic saturated or uinsaturated bivalent radical carrying an optionally substituted aryl, such as p-CH₃-(C₆H₄)-CH=, naphthyl-CH=, etc. The term "aryl" means a phenyl or naphthyl radical which optionally carries one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-(t-butoxy)phenyl, 4- fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1 -naphthyl, 2-naphthyl, 6-methoxy- 2-naphthyl and the like. Unsubstituted or substituted phenyl, methoxyphenyl and methoxynaphthyl are preferred".

When R⁶ and R⁷ join together to form a 4 to 6-membered aliphatic ring, wherein two or more hydrogen atoms are substituted by an oxygen atom, said aliphatic ring comprises one or more oxo groups.

Illustrative examples of R and R forming a 4 to 6-membered aliphatic ring substituted by oxygen atoms and/or alkyhdene or aryl-alkylidene groups are given in Table II below.

The term "a residue of a conventional hydrolyzable ester" 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. In addition, they can be substituted by functional groups, for example, hydroxy, alkoxy containing up to 6 carbon atoms, acyloxy containing up to 22 carbon atoms, nitro, amino, halogeno and the like, attached to the hydrocarbon backbone chain. Typical conventional hydrolyzable esters thus include acetate, propionate, butyrate, valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate, phenylacetate, diphenylacetate, diethylacetate, trimethylacetate, t-butylacetate, trimethylhexanoate, methylneopentylacetate, cyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate, methoxyacetate, hemisuccmate, hemiadipate, acetoxyacetate, 2-chloro-4- nitrobenzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, beta- chloropropionate, trichloroacetate, beta-chlorobutyrate, and the like.

Particularly preferred hydrolyzable esters includes those derived from Cι₆-C₂₄ 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.

Some representative compounds useful according to the invention are shown in Tables I, II and HI; the symbol (*) denotes particularly preferred substituents. TABLE I -Furfuryl derivatives of formula (I) with X =X1 according to one of the following structures:

TABLE II -Furfuryl derivatives of foraiula (I) with X =X2 according to one of the following structures

^(#) Free hydroxyl groups may be in protected form.

TABLE m -Furfuryl derivatives of formula (I) with X =X3 according to one of the following structures

Preferred furfuryl derivatives for use according this invention are α- substituted furfuryl derivatives , i.e. those compound of formula (I) wherein X is in position 2 of the furan ring.

The fiirfuryl derivatives are either known compounds or can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, etc.) are given in the Examples 1-10, other conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Exemplary synthetic methods are included in March, Advanced Organic Chemistry, 4th Ed.

Furfuryl aldehyde (furfural), furfuryl alcohol and furfurylamine are readily available chemicals which are preferred starting materials for the manufacturing of the forfuryl derivatives suitable for our purposes. Other commercially available starting materials include 5-hydromethyl-furfuryl alcohol, 5-hydromethyl-2-methyl- furfuryl ("2-(5-hydromethyl-furan-2-yl)ethanol"), (β)3-furfuryl alcohol, (β)3-furfural ("3-(5-hydromethyl furan-2-yl)acetalheyde") and the like.

The furfuryl derivatives of fonuula (I) wherein X = XI can be prepared by several known methods. Typically, 2-(l -hydroxy- alkyl)furans can be prepared from furfuryl aldehyde by nucleophilic reaction of an organo-metallic reagent, such as in Grignard reaction, Reformatsky reaction, the reaction with organo-lithium compounds, etc.

Alternatively, the reaction can be carried out with alkyl halides in the presence of zinc and organic quaternary ammonium salt, as described in J. Org. Chem.,50, 910-912, 1985 or in the Examples 3 to 5.

Other 2-(l-hydroxy-alkyl)furans substituted in the alkyl chain may be obtained by the reaction of organo-metallic reagents obtained from an protected alkyl-substituted reactants, for example as disclosed in Example 6 or in U.S. Pat. No. 4,076,732. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known, for example described by T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991.

The furfuryl derivatives of formula (I) wherein X= X2 can be prepared by ketalization reaction of a furfuryl ketone or aldehyde with a suitable mono- or polyol in the presence of a catalyst.

In order to reduce by-products, the furfurylketals and acetals are preferably obtained by the reaction of a furfuryl ketone or aldehyde, e.g. furfuryl aldehyde, with the selected alcohol or polyol in the presence of trace amount hydrogen iodide as catalyst, for example as disclosed in U.S. Pat. No. 4,464,530,.

Noteworthy, the conventional ketalization methods involving the use of catalysts such as mineral acids (e.g. H₂SO₄, HC1, HBr, H₃PO₄, HC10₄), organic acids (e.g. acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, acidic ion exchange resins) or Lewis acids (anhydrous A1C1₃, SnCl₄, BF₃, ZnCl₂, FeCl₃) lead to the polymerization of the furfuryl moiety in most cases, whenever the acid catalyst is used in large quantities to serve also as dehydrating agent.

Furfuryl condensed in cyclic malonic esters are obtainable by the condensation reaction of the cyclic malonic esters containing the furfuryl radical, which as been previously obtained by the reaction of furfuryl aldehydes (or ketones) in the presence of acetic anhydride, with an aromatic or aliphatic aldehyde or ketone, for example as described by Abramovitch R. in Can. J. Chem. 1959, 37, 361 and in U.S. Pat. No. 6,132,703.

The furfuryl derivatives of formula (I) wherein X= X3 can be prepared by coupling reaction of the two moieties using any conventional coupling reagent including, for example, carbodiimides such as dicyclohexylcarbodiimide and other promoting agents, such as N,N'-carbonyldiimidazole, optionally with N- hydroxysuccinimide, 1-hydroxybenzotriazole, etc.

It will be understood that the above discussions include thioesters, urea, thioureas, phosphates and further ethero-linked, furfuryl derivatives as defined by the formula (I) with X= X3. Alternatively, the ester and amide can be prepared also by the reaction of the suitable the acid halides or anhydrides can be employed, in the presence of a suitable base to scavenge the acid generated during the reaction, including, for example, triethylamine, diisopropylethylarnine, N-methylmorpholine and the like.

Further information about the preparation of the compounds suitable for the present invention is to be found in the examples, which, while certainly not intended to limit the present invention, are exemplary of the processes by which the compounds are prepared.

The aforementioned ftirfuryl derivatives show high dermal compatibility and low irritation behavior when applied to human skin. The present invention also provides an topical composition comprising the furfuryl derivative of formula (I) or a salt thereof in combination with a dermatologically acceptable carrier.

The topical composition of the invention is particularly indicated in the treatment and/or prevention of papulosquamous and eczematous dermatoses.

So, another object of the invention is the use of the composition of the invention for treating and/or preventing papulosquamous and eczematous dermatoses.

The use of the furfuryl derivatives of formula (I) or of dermatological acceptable salts and solvates thereof for the manufacture of a topical medicament for treating and/or preventing papulosquamous and eczematous demiatoses is another obj ect of the invention.

A further object of the present invention is to provide a method for the treatment and/or prevention of papulosquamous and eczematous dermatoses, more particularly those which are mentioned in the present application, which comprises administering to a mammal in need thereof an effective amount of a furfuryl derivative of formula (I) or a salt or solvate thereof.

The compounds of the formula (I) can be employed both a free form or as its dermatologically acceptable salts.

"Dermatologically acceptable salts" refers to salts of the compounds of formula (I) which retain the biological activity of the parent compounds and are not biologically or otherwise undesirable (e.g. the salts are stable and not toxic for topical use). Salts of the two types may be formed from the compounds of this invention: (1) Salts of inorganic and organic bases from compounds of formula (I) which have a carboxylic acid functional group and; (2) Acid addition salts may be formed at the amine functional group of many of the compounds of this invention. Dermatologically acceptable salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, ferroμs, zinc, copper, manganous, aluminum, ferric, manganic salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Dermatologically acceptable salts derived from organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Such salts are exemplified by, for example isopropopylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, dicyclohexamine, lysine, arginine, histidine, caffeine, procaine, hydrabramine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine and dicyclohexylamine.

Dermatologically acceptable acid addition salts are formed with inorganic acids such as halo acids, sulfuric acid, nitric acid, phosphoric acid and the like and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like. Another dermatologically acceptable salt is a resin-bound salt. 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 a cationic counterion and an anionic counterion.

Compounds object of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S- enantiomers, diastereomers, d-isomers, 1 -isomers, the racemic mixtures thereof and other mixtures thereof, all of them being encompassed within the scope of the invention. Dermatologically acceptable salts of such tautomeric, geometric or stereoisomeric forms are also included within the invention. The furfuryl derivataives of formula (I) as well as topical compositions of the invention are effective in the fields of medicaments and cosmetics.

The topical compositions of the invention comprise a furfuryl derivative of formula (I), for example, in amounts of 0.01% to 10% by weight, preferably in amounts of 0.1% to 1% by weight, advantageously 0.2% to 0.5% by weight of the total weight of the composition.

The topical compositions according to the present invention are manufactured by known methods for example by mixing the furfuryl derivative with conventional deraiatologically acceptable carriers, thus including bases for topical medicaments, cosmetics or hair-care products.

As set forth above, the topical compositions according to the present invention are particularly useful for treating a variety of skin dermatitis and diseases.

The composition of the invention are particularly indicated for the treatment of papulosquamous and eczematous dermatoses.

Exemplary, non-limiting dermatoses include dermatitis conditions and skin impairments such as: atopic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, seborrheic dermatitis, nummular dermatitis, chronic dermatitis of hands and feet, generalized exfoliative dermatitis, stasis dermatitis, neonatal dermatitis, pediatric dermatitis, generalized exfoliative dermatitis; stasis dermatitis; localized scratch dermatitis, toxic/irritating contact eczema, allergic contact eczema, type I or type IN, photoallergic contact eczema, contact urticaria, dyshidrosiform eczema, age-caused wrinkles, sun damage and itching.

Other papulosquamous and eczematous dermatoses which may be treated by the composition of the invention are:

- Psoriasis: psoriasis vulgaris, flaking eczema, psoriasis pustulosa, psoriasis artl ropatica, psoriatic erythroderma; - Lichen planus, pityriasis, parapsoriasis, dyshidrosis, lichen simplex chronicus, eczema cracquele, cutaneous T cell lymphoma patch and plaque stages;

- Photodermatosis: radiodermatitis acuta and chronica (UN and ionizing radiation therapy), chronic actinic dermatitis, photourticaria (urticaria Solaris), polymorphic photodermatosis and other polymorphic photodermatosis; - Prurigo: p. simplex acuta (strophulus, urticaria papulosa), subacuta, chronica;

- Acne: acne vulgaris, juvenile and adult (acne with comedones, papulous, pustulous, nodose, i.e. nodular, nodulocystic acne), acne conglobata (special form: hidradenitis suppurativa), acne fumiinans, acne tetrad, acne neonatorum, senile acne, mechanical acne forms (excoriated acne), acne cosmetica, folliculitis with superinfected acne (Staphylococci), occupation-related acne forms (for example chlorine acne);

- Decubitus and Ulcus cruris; - Deficient ipoactive or i munocompromised skin: localized dermatitisrinophyma, ichthyosis, xerosis, lichen planus, pityriasis, parapsoriasis, dyshidrosis, lichen simplex chronicus, eczema cracquele, cutaneous T cell lymphoma patch and plaque stages; - Perioral dermatitis.

Using routine methods, the topical compositions of the present invention may be formulated into a variety of preparations, depending on the intended use. These preparations include, but are not limited to, topical skin compositions for medical use, topical skin dermatologic compositions and hair-treatment compositions. As topical skin compositions for medical use and topical skin dermatologic compositions, many types of ointment, lotion, paste, fluid and/or creamy emulsion, powder, lotion, gel, oil, solution, soap, foam and shampoo may be produced.-

The ointments may contain either an oil base or an emulsion base, including oil-in-water type and water-in-oil type emulsions. The oil base is not particularly critical, for example vegetable oils, animal oils, synthetic oils, fatty acids, and natural or synthetic glycerides are suitable.

When the topical compositions of the present invention are used as dermatologic compositions, the dermatologic 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.

According to the invention, it is possible, inter alia, to combine furfuryl derivatives with other active agents intended in particular for the prevention and/or treatment of papulosquamous and eczematous dermatoses. Thus, another object of the invention relates to a composition comprising an effective amount of a furfuryl derivative of formula (I) along with one or more anti- oxidant substances active on neutral ROS such as ^₂.

Among said antioxidants there may be mentioned carotenoid, flavonoids and plant polyphenols, nucleosides and azulenes.

Exemplary carotenoids includes all-trans-beta-carotene, alpha- gamma- and delta-carotene, docapreno- and dodecaprono-beta-carotene, lycopen, zaxanthin, astaxanthin, violaxanthin, lutein, bixin, canthaxnthin, cryptoxanthin. Exemplary flavonoids include taxifoline, catechin, epicatechin, eriodictyol, naringenin, rutin, troxerutin, chrysin, quercetin, fisetin, kaempferol and galangin. Exemplary plant polyophenols include gallic acid and esters thereof, caffeic acid, protocatechuic acid and ellagic acid. Exemplary nucleosides and derivatives include adenosine, guanosine, cytidine, thymidine and uridine, the corresponding deoxyribose derivatives. Exemplary azulenes include azulene, camazulene, procamazulenes.

In the topical composition of the invention, the proportion by weight of product having a peroxidase activity capable of reducing organic peroxides may vary from 0.005%) to 5%, and in particular from 0.01%> to 3% by weight of the total composition.

A further object of the invention is a topical composition comprising an effective amount of furfuryl derivative of formula (I) in combination with one ore more other pharmaceutical active agents which are suitable for topical application. Mention may be made, among these active agents, of, by way of example: agents which modulate cutaneous pigmentation and/or proliferation and/or differentiation, such as retinoic acid and its isomers, retinol and its esters, vitamin D and its derivatives, oestrogens, such as oestradiol, kojic acid or other withening agents;- agents which modulate bacterial adhesion to the skin and/or mucous membranes, such as honey, in particular acacia honey, and certain sugar derivatives; agents for combating parasites, in particular metronidazole, crotamiton or pyrethroids; antifungals, in particular compounds belonging to the imidazole class, such as econazole, ketoconazole or miconazole or their salts, polyene compounds, such as amphotericin B, compounds of the allylamine family, such as terbinafme, or alternatively octopirox; antiviral agents, such as acyclovir; steroidal anti- inflammatory agents, such as hydrocortisone, betamethasone valerate, clobetasol propionate or non-steroidal anti-inflammatory agents, such as ibuprofen and its salts, diclofenac and its salts, acetylsalicylic acid, or acetaminophen; anaesthetic agents, such as lidocaine hydrochloride and its derivatives; antipruriginous agents, such as thenaldine, trimeprazine or cyproheptadine; keratolytic agents, such as alpha- and beta-hydroxycarboxylic acids or beta-ketocarboxylic acids, their salts, amides or esters and more particularly hydroxyacids, such as glycolic acid, lactic acid, salicylic acid, citric acid and generally fruit acids, and 5-(n-octanoyl)salicylic acid; anti radical agents, such as alpha-tocopherol or its esters, superoxide dismutases, certain metal chelating agents or ascorbic acid and its esters; anti-seboπhoeics, such as progesterone; antidandruff agents, such as octopirox or zinc pyrithione; antiacne agents, such as retinoic acid or benzoyl peroxide; substances such as substance P, CGRP or bradykinin antagonists or NO-synthase inhibitors, compounds described as being active in the treatment of sensitive skin and as exhibiting anti-irritant effects, in particular with respect to irritant compounds possibly present in the compositions. The formulations of the present invention may further include as optional ingredients one or more agents already known for their use in the therapy of papulosquamous and eczematous diseases, for added clinical efficacy. Such combinations will in some cases provide added benefit. As mentioned above, these agents include glucocorticosteroids, chemotherapeutic agents, retinoids, antibiotics, tars and antibacterial agents. Appropriate amounts in each case will vary with the particular agent, and will be either readily known to those skilled in the art or readily determinable by routine experimentation.

Another object of the invention, is a topical composition comprising combination a furfuryl derivative of formula (I) in combination with one or more UN filters to afford an enhanced resistance to the UN- and solar radiation.

The UN filters which can be used in combination with the active compound according to the invention also include those in Section I of Annex to 93/35/ECC article 5a.1 to the paragraph "UN. absorbers", although this list is not intended to be limiting. The UN filters can advantageously be used according to the invention, for example: 3-benzylidenecamphor derivatives, 4-aminobenzoic acid derivatives; esters of cynnamic acid, esters of salicylic acid, derivatives of benzophenone, esters of benzalmalonic acid, 2,4,6-trianilino-(p-carbo-2'-ethyl-r-hexyloxy)-l,3,5-triazine, 2- phenylbenzimidazole-5-sulphonic acid and salts, sulfonic acid derivatives of benzophenones, sulfonic acid derivatives of 3-benzylidenecamphor, derivatives of dibenzoylmethane (UNA fiters).

Cosmetic and/or dermatological compositions intended for light protection can also comprise inorganic pigments and physical UN-absorbers which are usually used in cosmetics, e.g. oxides of titanium, zinc, iron, zirconium, silicon, manganese, aluminum, cerium and mixtures thereof. The present invention is more specifically described and explained by means of the following Examples.

It is to be understood that the present invention is not limited to those Examples, as changes and modifications may be made without departing from the scope or spirit of the present invention. Example 1 - Synthesis of β-furfuryl palmitate (3-(palmitoyloxy-methyl)furan)

To a stirred suspension of 49 g (0.5 mol) furan-3-methanol and 55 g (0.54 mol) triethylamine in 500 ml CH₂C1₂, 137.5 g (0.5 mol) of palmitoyl chloride in 100 ml CH₂C1₂ were added at 20° C in 30 min., then the reaction was heated to reflux for 20 min. The reaction mixture was quenched with water and, after stirring for 10 min, the aqueous phase was extracted with CH₂C1₂. The organic phases were combined, washed with diluted HC1, water, saturated ΝaHCθ₃, brine, dried (MgSO₄) and concentrated to provide whitish solid. The product was crystallized in ethanol to afford an off-white powder identified as the compound of formula (II).

Example 2 - Synthesis of β-furfuryl octadecyl ether (3-(palmitoxy-methyl)furan

To a stirred suspension of 49 g (0.5 mol) 3-furfuryl alcohol (furan-3- methanol) in 500 ml CH₂C1₂ were added 22 g of NaH 60% in oil (0.55 mol), the reaction mixture was stirred for 20 min. under cooling conditions (ice bath). Then 151.5 g of 1-bromohexadecyldecane in 200 ml CH₂C1₂ were added at 20° C in 30 min. and the reaction was heated at 30-35° for 4 hours. The reaction mixture was quenched with water and, after stirring for 10 min, the aqueous phase was extracted with CH₂CI₂. The organic phases were combined, washed with diluted HC1, water, saturated NaHCO₃, brine, dried (MgSO₄) and concentrated to provide whitish solid. The product was re-crystallized in ethanol to afford an off-white powder identified as the compound of formula (in).

Example 3 - Synthesis of 2-octadecyl-α-furfuryl alcohol (2-(l-hydroxy- heptadecypfuran) To a stfrred suspension of 39 g (0.40 mol) furfural, 146.6 g (0.48 mol) hexadecyl bromide, 52.3 g (0.8 g.atom) Zn° in powder and 26 g (0.08 mol) tetrabutylammonium bromide in 600 ml of mixture water :toluene 5:1, was added 440 g of an aqueous solution of ammonium chloride 21%> w/w over 1 h at 35° C, then kept under stirring for 2 h. The organic phase was separated, washed with diluted HC1, water, saturated

NaHCO₃, brine, dried (MgSO₄) and concentrated to provide an off-white solid. The product was re-crystallized in ethanol to afford an off-white powder identified as the compound of formula (TV).

Example 4 - Synthesis of 5-methyl-2-octadecyl-α-furfuryl alcohol (2-d -hydroxy- heptadecyl)-5-methyl-furan^')

The same procedure of Example 3 was applied with 44 g of 5-methyl furfural (0.48 mol) instead of furfural, to afford an off-white powder identified as the compound of formula (N).

(V)

Example 5 - Synthesis of 2-allyl-α-furfuryl palmitate

The same procedure of Example 3 was applied with 58.1 g of allyl bromide (0.48 mol) instead of 146.6 g of hexadecyl bromide, and upon rectification under reduced pressure to obtain 46.0 g of the fraction of a pale oily product, identified as 2-(l-hydroxy-3-butenyl)furan.

To a st red solution of 46 g of this intermediate in 55 g (0.54 mol) triethylamine and 500 ml CH₂C1₂, was added 137.5 g (0.5 mol) of palmitoyl chloride in 100 ml CH₂C1₂ at 20° C in 30 min, then the reaction was refluxed for 20 minutes. The reaction mixture was quenched with water and, after stirring for 10 min, the aqueous phase was extracted with CH Ci₂. The organic phases were combined, washed with 10%> HCl, water, saturated ΝaHCθ₃, brine, dried (MgSO ), filtered and concentrated to provide an off-white solid. The product was crystallized in ethanol to afford a whitish powder identified as the compound of formula (VI).

Example 6 - Synthesis of 2-α-(6-carboxyhexyl^')furfuryl alcohol sodium salt

To a stured suspension of 6.1 g (0.25 g.atom) of Mg° in 100 ml of ether was added 17.6 g (110 mmol) of bromine dropwise during 20 min at 15-20 °C. After 15 min. the mixture was treated dropwise with a solution of 29 g (100 mmol) of 2-(6- bromohexyl)-4,4,6-trimethyl-5,6-dihydro-l,3-oxazine (prepared as per J. Org.

Chem., 1973, 38, 36) in 5 ml of ether and stiπed at ambient temperature for 3 h, then refluxed for 30 min. The mixture was cooled to 0 °C and treated during 20 min. with a solution of 11.5 g (120 mmol) of furfural. The stirred mixture was brought to reflux temperature during 40 min., cooled and treated with 2.5 ml of saturated ammonium chloride, diluted with ether and water and filtered.

The organic phase was separated, washed with brine, dried over potassium carbonate and concentrated. The concentrate was added with 37.5 ml NaOH 3N and 12.5 ml ethanol, then refluxed for 16 hr. The solution was diluted with brine and extracted with ether, the aqueous phase was acidified to pH 2 and extracted with ethyl acetate, and the extract was dried (MgSO₄) and concentrated.

The concentrate was re-suspended in water and added with a solution of

NaOH IN until pH 9, and the resulting solution was concentrated under vacuum, to afford a white powder identified as the compound of formula (Nil).

Example 7 - Synthesis of 2-aminoethyl-α-furfuryl-phosphate To a stiπed solution of POCl₃ (18.4 g. 120 mmol) in toluene (30 ml) a solution of furfuryl alcohol (98 g, 1 mol) and triethylamine (121 g, 1.2 mol) in toluene (250 ml) was added for a period of 1 h at 15°C. After further stirring for 1 h, triethylammonium chloride was removed by filtration. The solvent was removed under reduced pressure. The residue was diluted with tetrahydrofurane (300 ml). To this diluted solution a solution of ethanolamine (71 g, 1.1 mol) and triethylamine (202 g, 2 mol) in THF (300 ml) was added for a period of 1 h at 20°C. After stirring for 2 h, triethylammonium chloride was removed by filtration. The residue was washed with aqueous NaCI solution (15%>, 200 ml). The organic layer was separated and dried (MgSO₄) followed by filtration. The filtrate was concentrated under reduced pressure.

The resulting 2-(α-furfuryl-methyloxy)-[l .3.2]oxazaphospholidine-2-oxide was solubilized in a mixture of tetrahydrofurane (100 ml) and water (300 ml) and heated at 50°C for 12 h. The pH of the solution was maintained during hydrolysis.

After hydrolysis, the solvent was removed under reduced pressure, the residue was re-crystallized with aqueous acetonitrile to afford a white powder identified as the compound of formula (NITI).

(VIII)

Example 8 - Synthesis of oleyl-α-furfuryl-phosphate

The same procedure of Example 3 was applied but with oleyl alcohol (537 g,

2 mol) instead of ethanolamine. The reaction mixture was quenched with water and, after stirring for 10 min, the aqueous phase was extracted with CH₂CI₂. The organic phases were combined, washed with 10% HCl, water, saturated ΝaHCO₃, brine, dried (MgSO₄), filtered and concentrated to provide an off-white solid.

The product was re-crystallized with aqueous acetonitrile to afford a whitish powder identified as the compound of formula (NET).

(^|χ)

Example 10 - Synthesis of α-furfuryl-palmitoylamide

To a stiπed suspension of 48.5 g (0.5 mol) furfurylamine and 25 g (0.24 mol) triethylamine in 500 ml CH₂C1₂, 137.5 g (0.5 mol) of palmitoyl chloride in 100 ml CH2CI2 were added at 20° C in 30 min., then the reaction was heated for 20 min.

The reaction mixture was quenched with water and, after stirring for 10 min, the aqueous phase was extracted with CH₂CI₂. The organic phases were combined, washed with diluted HCl, water, saturated NaHCO₃, brine, dried (MgSO₄) and concentrated to provide whitish solid. The product was crystallized in ethanol to afford an off-white powder identified as the compound of formula (X).

Example 11

A patient suffering from seboπhoeic deπnatitis can be topically treated with 0.3%o furfuryl derivative in a dermatological composition until recover from erythema, xerosis, scaling and itching. Example 12

A patient suffering from psoriasis can be topically treated with 0.3%> furfuryl derivative in a dermatological composition until recover from erythema, xerosis, scaling and itching. Example 13

A patient suffering from iπitant contact dermatitis can be topically treated with 0.3%) furfuryl derivative in a dermatological composition until recover from erythema, xerosis, scaling and itching. Example 14 A patient suffering from allergic contact dermatitis can be topically treated with 0.3%) furfuryl derivative in a dermatological composition until recover from erythema, xerosis, scaling and itching. Example 15

A patient suffering from photoallergic contact eczema can be topically treated with 0.3%) furfuryl derivative in a dermatological composition until recover from erythema, xerosis, scaling and itching. Example 16

A patient suffering from perioral dermatitis can be topically treated with 0.3% furfuryl derivative in a dermatological composition until recover from erythema, xerosis, scaling and itching. Example 17

A patient suffering from atopic dermatitis can be topically treated with 0.3% furfuryl derivative in a dermatological composition until recover from erythema, xerosis, scaling and itching. Example 18

A patient suffering from solar erythema can be topically treated with 0.3%> furfuryl derivative in a sun-care composition to increase the minimal erythema dose.

The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims

CLA S

1. Use of a furfuryl derivative of fonnula (I) :

wherein R° is hydrogen or halogen;

X represent one of the following XI, X2 or X3 groups:

R^

X1

-C -

OR^ wherein R >2 represents hydrogen or a lower alkyl, alkenyl or alkynyl;

R³ represents a saturated or unsaturated, linear or branched (Cι-C₂₂)-alkyl, which can be substituted with carbonyl, -CN, -COHR¹¹, -COOR¹¹, -OSO₂R^π, - SO₃R^π, -SO2NHR¹¹, -NHR¹¹, -N(R^π)₂, -OR¹¹, -SR¹¹; -O-PO3R¹¹; wherein R¹¹ represents hydrogen or a lower alkyl or hydroxyalkyl; R⁴ represent hydrogen, alkyl or the residue of a conventionally hydrolyzable ester or amide;

X2

^■C — OR⁶

OR⁷ wherein R • 5^J represents hydrogen or a lower alkyl, alkenyl or alkynyl; f 7 R and R , each independently, represent hydrogen or lower alkyl, alkenyl, cyloalkyl, which may be mono- or bi-substituted with (Cι-C₈)-alkoxy, carboxy, (Cι-Cs)-alkoxycarbonyl, amino, hydroxy; wherein R⁶ and R⁷ may join together to form a 4 to 6-membered aliphatic ring, wherein two or more hydrogen atoms may be optionally substituted by one oxygen atom or by an alkyhdene group or an aryl-alkylidene group said groups being optionally substituted;

wherein

R⁸ and R⁹ represent, each independently, hydrogen or a lower alkyl, alkenyl or alkynyl; n is 0 or 1 ; provided that when n = 0, W represents -C(O)-O-, -C(S)-O-, -C(O)NH- -C(S)NH-; when n = 1, W represents -O-C(O)-O- -O-C(O)-, -O-, -OP(O)(OR¹⁰)-, -

OC(S)-

-NHC(O)-, -NHC(S)-, -NHC(NH)NH- -NHC(O)NH- -NHS(O)-, -NHS-, - NHC(S)NH-;

Z is selected form the group consisting of: - Zl) a saturated or unsaturated, linear or branched (Cι-C₂₄)-alkyl which can be substituted with (Cι-C₈)-alkoxy, carboxy, (Cι-C₈)-alkoxycarbonyl, amino, hydroxy, said amino and hydroxy being optionally (Cι-C₂2)-acylated or ( - C₂2)-alkylated;

Z2) (6-methoxy-2-naphthyl)methyl; - Z3) phenyl, optionally substituted with one or more hydroxy, lower alkyl, alkoxy, hydroxyalkyl, -SH, -CH₂SH, -C₂H₅SH, -SCH₃, -SC₂H₅, - CH2SCH₃, -C₂H₅SCH₃, -NO₂, -OCH₂NH₂, -OC₂H₅NH₂, halogen, in which the free hydroxy group(s) may be protected by the residue of a conventionally hydrolyzable ester; R¹⁰ represents hydrogen, 2- or 3-furfuryl, or a lower alkyl, alkenyl or cycloalkyl group which group can be substituted with amino or hydroxy, said amino and hydroxy being optionally (Cι-C₂₂)-acylated or (Cι-C₂₂)-alkylated; and provided that when X =X3 in the α-position of the furan ring, n=l, W= O- C(O)- or O-, and Z is Zl or unsubstituted phenyl, then at least one of R¹ or R⁸ or R⁹ is other than hydrogen; or a dermatologically acceptable salt or solvate thereof; for the manufacture of a topical medicament for treating and/or preventing papulosquamous and eczematous dermatoses.

2. Use according to claim 1, wherein X is in position 2 of the furan ring.

3. Use according to claims 1 or 2, for treating papulosquamous and eczematous diseases selected from the group consisting of topic dermatitis, contact dennatitis, allergic contact dermatitis, irritant contact dermatitis, seboπheic dermatitis, nummular dermatitis, chronic dennatitis of hands and feet, generalized exfoliative dermatitis, stasis dermatitis, neonatal dermatitis, pediatric dermatitis, generalized exfoliative dermatitis; stasis dermatitis; localized scratch dermatitis, toxic/irritating contact eczema, allergic contact eczema, photoallergic contact eczema, contact urticaria, dyshidrosiform eczema, age-caused wrinkles, sun damage, itching.

4. Use according to claim 3, for treating papulosquamous and eczematous diseases selected from the group consisting of psoriasis, lichen planus, pityriasis, parapsoriasis, dyshidrosis, lichen simplex chronicus, eczema cracquele, cutaneous T cell lymphoma patch and plaque stages, and photodermatosis.

5. Method for the treatment and/or prevention of papulosquamous and eczematous diseases which comprises topically administering to a mammal in need thereof an effective amount of a furfuryl derivative of formula (I) according to claims 1 to 2.

6. Method according to claim 5, for the treatment and/or prevention of atopic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, seboπheic dennatitis, nummular dermatitis, chronic dermatitis of hands and feet, generalized exfoliative dermatitis, stasis dermatitis, neonatal dermatitis, pediatric dermatitis, generalized exfoliative dermatitis, stasis dennatitis, localized scratch dermatitis, toxic/irritating contact eczema, allergic contact eczema, photoallergic contact eczema, contact urticaria, dyshidrosiform eczema, age-caused wrinkles, sun damage, itching, psoriasis, lichen planus, pityriasis, parapsoriasis, dyshidrosis, lichen simplex chronicus, eczema cracquele, cutaneous T cell lymphoma patch and plaque stages, and photodermatosis.

7. Topical composition comprising a furfuryl derivative of formula (I) according to claim 1 or a dennatologically acceptable salt or solvate thereof, optionally in admixture with one or more suitable carriers and excipients.

8. Topical composition according to claim 7, wherein the amount of the furfuryl derivative is 0.01%> to 10% by weight based on total weight of the composition.

9. Topical composition according to claim 8, wherein the amount of the furfuryl derivative is 0.1% to 1%> by weight based on the total weight of the composition.

10. Topical composition according to claim 9, wherein the amount of the furfuryl derivative is 0.2%> to 0.5% by weight based on total weight of the composition.

11. Topical composition according to claims 7 to 10, for the treatment an d/or prevention of papulosquamous and eczematous dermatoses, optionally also comprising one ore more further pharmaceutical agents which are suitable for topical application.

12. Topical composition according to claims 7 to 11, in combination with one or more UN filters.