WO2003075913A1 - Compositions topiques comprenant des derives de furfuryl et leur utilisation pour traiter des troubles dermatologiques - Google Patents

Compositions topiques comprenant des derives de furfuryl et leur utilisation pour traiter des troubles dermatologiques Download PDF

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WO2003075913A1
WO2003075913A1 PCT/IB2003/000852 IB0300852W WO03075913A1 WO 2003075913 A1 WO2003075913 A1 WO 2003075913A1 IB 0300852 W IB0300852 W IB 0300852W WO 03075913 A1 WO03075913 A1 WO 03075913A1
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dermatitis
furfuryl
eczema
contact
hydroxy
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PCT/IB2003/000852
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English (en)
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Carlo Ghisalberti
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Carlo Ghisalberti
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Publication of WO2003075913A1 publication Critical patent/WO2003075913A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics

Definitions

  • the present invention relates to a dermatological composition comprising a furfuryl derivative and its use in the treatment of papulosquamous and eczematous dermatoses.
  • 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.
  • furfuryl derivatives namely the esters and ethers of furfuryl alcohol
  • a representative furfuryl ester namely furfuryl palmitate
  • 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
  • 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.
  • 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.
  • the present invention provides a topical composition
  • 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) :
  • R° is hydrogen or halogen
  • R 1 represents hydrogen or a lower alkyl, alkenyl, alkynyl, hydroxyalkyl or an alkoxymethyloxy
  • X represent one of the following XI, X2 or X3 groups:
  • R 2 represents hydrogen or a lower alkyl, alkenyl or alkynyl
  • R 3 represents a saturated or unsarurated, linear or branched (C ⁇ -C 2 )-alkyl, which can be substituted with carbonyl, -CN, -COHR 11 , -COOR 11 , -OSO 2 R n , - SOsR 11 , -SOzNHR 1 ] , -NHR 11 , -N(R ⁇ ) 2 , -OR 11 , -SR 11 ; -O-POsR 11 ; wherein R 1 ] represents hydrogen or a lower alkyl or hydroxyalkyl;
  • R 4 represent hydrogen, alkyl or the residue of a conventionally hydrolyzable ester or amide
  • R 5 represents hydrogen or a lower alkyl, alkenyl or alkynyl
  • R 6 and R 7 each independently, represent hydrogen or lower alkyl, alkenyl, cyloalkyl, which may be mono- or bi-substituted with (C ⁇ -Cs)-alkoxy, carboxy, (C ⁇ -Cs)-alkoxycarbonyl, amino, hydroxy
  • 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;
  • NHC(S)NH-; Z is selected form the group consisting of:
  • - Zl a saturated or unsaturated, linear or branched (C ⁇ -C 24 )-alkyl which can be substituted with (C ⁇ -C 8 )-alkoxy, carboxy, (C ⁇ -C 8 )-alkoxycarbonyl, amino, hydroxy, said amino and hydroxy being optionally (C ⁇ -C 22 )-acylated or (Ci- C 22 )-alkylated;
  • Z2 (6-methoxy-2-naphthyl)methyl; - Z3) phenyl, optionally substituted with one or more hydroxy, lower alkyl, alkoxy, hydroxyalkyl, -SH, -CH 2 SH, -C 2 H 5 SH, -SCH 3 , -SC 2 H 5 , - CH2SCH3, -C 2 H 5 SCH 3 , -NO2, -OCH 2 NH 2 , -OC 2 H 5 NH 2 , halogen, in which the free hydroxy group(s) may be protected by the residue of a conventionally hydrolyzable ester;
  • halogen means fluorine, chlorine, bromine or iodine.
  • 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.
  • 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
  • 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.
  • cycloalkyl is intended to mean cyclic hydrocarbon groups of three to seven carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • 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.
  • 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.
  • Preferred substitutions for the alkyhdene group are CHO, OH, -COOH, amino, mono or di-alkylamino, and the like.
  • 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".
  • 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.
  • 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 C ⁇ 6 -C 24 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.
  • C ⁇ 6 -C 24 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
  • Preferred furfuryl derivatives for use according this invention are ⁇ - 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"), ( ⁇ )3-furfuryl alcohol, ( ⁇ )3-furfural ("3-(5-hydromethyl furan-2-yl)acetalheyde") and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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,.
  • the conventional ketalization methods involving the use of catalysts such as mineral acids (e.g. H 2 SO 4 , HC1, HBr, H 3 PO 4 , HC10 4 ), organic acids (e.g. acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, acidic ion exchange resins) or Lewis acids (anhydrous A1C1 3 , SnCl 4 , BF 3 , ZnCl 2 , FeCl 3 ) 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.
  • catalysts such as mineral acids (e.g. H 2 SO 4 , HC1, HBr, H 3 PO 4 , HC10 4 ), organic acids (e.g. acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic
  • 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.
  • carbodiimides such as dicyclohexylcarbodiimide
  • other promoting agents such as N,N'-carbonyldiimidazole, optionally with N- hydroxysuccinimide, 1-hydroxybenzotriazole, etc.
  • 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.
  • 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.
  • Another object of the invention is the use of the composition of the invention for treating and/or preventing papulosquamous and eczematous dermatoses.
  • 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, ferro ⁇ s, zinc, copper, manganous, aluminum, ferric, manganic salts and the like.
  • 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.
  • the compound of formula 1 is a resin-bound salt.
  • (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.
  • 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.
  • topical compositions according to the present invention are particularly useful for treating a variety of skin dermatitis and diseases.
  • 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.
  • dermatitis conditions and skin impairments such as: atopic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, se
  • 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;
  • 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 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);
  • 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.
  • 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.
  • 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.
  • furfuryl derivatives with other active agents intended in particular for the prevention and/or treatment of papulosquamous and eczematous dermatoses.
  • 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 .
  • 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.
  • 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.
  • active agents include, 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
  • 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.
  • 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.
  • 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.
  • Example 3 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.
  • 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 (MgSO 4 ) and concentrated.
  • the concentrate was re-suspended in water and added with a solution of
  • the reaction mixture was quenched with water and, after stirring for 10 min, the aqueous phase was extracted with CH 2 CI 2 .
  • the organic phases were combined, washed with diluted HCl, water, saturated NaHCO 3 , brine, dried (MgSO 4 ) 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).
  • a patient suffering from sebo ⁇ hoeic de ⁇ natitis can be topically treated with 0.3%o furfuryl derivative in a dermatological composition until recover from erythema, xerosis, scaling and itching.
  • 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.
  • a patient suffering from i ⁇ itant 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.
  • 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.
  • 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.
  • 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.

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  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition dermatologique comprenant des dérivés de furfuryl et leur utilisation pour traiter des dermatoses papulosquameuses et eczémateuses.
PCT/IB2003/000852 2002-03-11 2003-03-10 Compositions topiques comprenant des derives de furfuryl et leur utilisation pour traiter des troubles dermatologiques WO2003075913A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003209540A AU2003209540A1 (en) 2002-03-11 2003-03-10 Topical compostions comprising furfuryl derivatives and their use for the treatment of dermatologic disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2002A000508 2002-03-11
IT2002MI000508A ITMI20020508A1 (it) 2002-03-11 2002-03-11 Composizioni ad uso topico contenenti derivati furanici

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WO2003075913A1 true WO2003075913A1 (fr) 2003-09-18

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AU (1) AU2003209540A1 (fr)
IT (1) ITMI20020508A1 (fr)
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2918412A (en) * 1955-11-09 1959-12-22 Givaudan Corp Perfume oils containing 3-methyl-1-nonyn-3-ol
US3987189A (en) * 1973-06-22 1976-10-19 Henkel & Cie G.M.B.H. Anti-inflammatory composition and method containing cyclic 2-furfural-acetals
EP0296580A2 (fr) * 1987-06-26 1988-12-28 G.D. Searle & Co. Composés analogues du leucotriène B4 de phénylène, furyl et thiényle
WO1995018607A1 (fr) * 1994-01-04 1995-07-13 Norsk Hydro A.S Compositions pharmaceutiques
JPH09216821A (ja) * 1996-02-09 1997-08-19 Taisho Pharmaceut Co Ltd 血流改善剤
US5780042A (en) * 1993-02-25 1998-07-14 Beiersdorf Ag Synergistic light protection combinations and cosmetic and dermatological formulations comprising such combinations
WO2000000483A2 (fr) * 1998-06-29 2000-01-06 Parker Hugues Institute Composes capables de se lier avec la tubiline
WO2002092026A2 (fr) * 2001-05-17 2002-11-21 Carlo Ghisalberti Compositions dermatologiques et cosmetiques

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2918412A (en) * 1955-11-09 1959-12-22 Givaudan Corp Perfume oils containing 3-methyl-1-nonyn-3-ol
US3987189A (en) * 1973-06-22 1976-10-19 Henkel & Cie G.M.B.H. Anti-inflammatory composition and method containing cyclic 2-furfural-acetals
EP0296580A2 (fr) * 1987-06-26 1988-12-28 G.D. Searle & Co. Composés analogues du leucotriène B4 de phénylène, furyl et thiényle
US5780042A (en) * 1993-02-25 1998-07-14 Beiersdorf Ag Synergistic light protection combinations and cosmetic and dermatological formulations comprising such combinations
WO1995018607A1 (fr) * 1994-01-04 1995-07-13 Norsk Hydro A.S Compositions pharmaceutiques
JPH09216821A (ja) * 1996-02-09 1997-08-19 Taisho Pharmaceut Co Ltd 血流改善剤
WO2000000483A2 (fr) * 1998-06-29 2000-01-06 Parker Hugues Institute Composes capables de se lier avec la tubiline
WO2002092026A2 (fr) * 2001-05-17 2002-11-21 Carlo Ghisalberti Compositions dermatologiques et cosmetiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KUBO, MICHITOKU ET AL: "Blood circulation improvers containing (hydroxymethyl)furans", XP002244103, retrieved from STN Database accession no. 127:257630 *

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ITMI20020508A0 (it) 2002-03-11
ITMI20020508A1 (it) 2003-09-11
AU2003209540A1 (en) 2003-09-22

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