WO2003082233A1

WO2003082233A1 - Allyl-phenol compounds in androgenic disorders

Info

Publication number: WO2003082233A1
Application number: PCT/IB2003/001193
Authority: WO
Inventors: Carlo Ghisalberti
Original assignee: Carlo Ghisalberti
Priority date: 2002-04-03
Filing date: 2003-04-02
Publication date: 2003-10-09
Also published as: ITMI20020693A0; AU2003214499A1; ITMI20020693A1

Abstract

The present invention provides the use of allyl-phenol compounds of formula (I) for the manufacture of a pharmaceutical/cosmetic composition for the treatment of androgenic disorders on skin, such as for example male-pattern alopecia, acne, seborrhea and dandruff.

Description

"ALLYL-PHENOL COMPOUNDS IN ANDROGENIC DISORDERS"

FIELD OF THE INVENTION

The present invention relates to the use of an allyl-phenol compounds for the manufacture of a pharmacological, dermatological and cosmetic composition for the treatment of androgenic disorders by the 5α-reductase inhibition. BACKGROUND OF THE INVENTION

The androgen receptors allocating the 5 -testosterone reductase enzymes does convert testosterone into dihydrotestosterone and other androgen hormones having a potent modulation effect on keratin formation, sebum production and hair growth.

5α-Reductase occurs in two isoforms: type I represents the cutaneous type, being primarily located in the skin's sebocytes and in epidermal and follicular keratinocytes, dermal papilla cells, sweat glands and in fibroblasts; type II being mainly located in the seminal vesicles, prostate and in the inner root sheath of the hair follicle.

A subject identified with an excess of 5α-reductase activity may actually experience androgenic disorders such as alopecia, acne vulgaris, seborrhoea and dandruff.

The present therapeutic options for androgenic alopecia are limited to topical minoxidil and oral finasteride, the latter being the most effective non-surgical hair therapy although its anti-androgenic effects can cause a libido impairment by its hormone activity.

Androgen antagonists such as spironolactone, flutamide, 17- - propylmesterolone, and synthetic retinoids such as tazarotene, tretinoin, isotretinoin, adapalene are effective agents in acne, although their use is restricted to the severe forms due to the number of side-effects on either topical or systemic administration.

Conversely, mild acne, seborrhoea and dandruff are treated by cosmetic and OTC containing natural substances with antiseptic, astringent or weak anti- androgenic activity. For example, the partial inhibition of 5α-reductase is attained by the monoterpene eugenol (Ibata S, Fragr J 92:78-83, 1988) and by its glycosides, eugenyl β-D-glucoside (Hamada K, Hideyo U, et al., IFSCC Magazine 4(2):83-87, 2001), or by unsaturated fatty acids (Liang T, Liao S, Biochem J, 285:557-62, 1992). Nonetheless, none of the purported "natural solutions" for the treatment of the androgenic disorders may claim an efficacy resembling those of the afore mentioned synthetic androgen antagonists, retinoids and arotinoids.

Therefore, a treatment of the disorders consequent upon an excess of 5α- reductase activity which is furthermore characterized by a high therapeutic index was still sought.

Some of the natural occurring, simple allyl-phenols have been applied in skin care. For example a non-toxic antimicrobial agent for controlling Pseudomonas aeruginosa comprising hydroxychavicol for the use as disinfectant, preservative or drug for topical administration is disclosed in WOO 166097 (Dragoco), whilst cosmetics containing hydroxychavicol as effective anti-ageing and stabilizer against oxidative and microbial degradation is are in WO0106995 (Cognis). Eugenol and certain derivatives thereof have been applied in different cosmetic and dermatologic contexts, e.g. the combination with phenyl salicylate for the UN-induced erythema in U.S. Pat. Ν. 4,404,198 (Beecham). Chavicol is another terpenoid occurring in plants, e.g. in Origanum majorana and Ocinum basilicum, whose extract are used as botanical ingredient in the cosmetic practice. Applicant has first conceived the use of certain allyl-phenols derivatives for the treatment of androgenic disorders by the 5α-reductase inhibition. DESCRIPTION OF THE INVENTION

The Applicant has discovered that some allyl-phenol compounds present a high activity in dermal androgenic disorders, especially when formulated in pharmaceutical or cosmetic compositions.

Accordingly, one object of the present invention is to provide a pharmaceutical/cosmetic composition for the use on the skin that incorporates allyl- phenol compounds as the active ingredient for the treatment of androgenic disorders on skin, such as for example male-pattern alopecia, acne, seborrhea and dandruff. Therefore, the present invention provides the use of an allyl-phenol derivative of formula (I) :

wherein:

R¹ represents H, R⁶, P(O)(OH)-OR⁸ or S(O)_t-R⁸; with t = 0, 1, or 2; R² represents H, OH, OR⁶, R⁷, OR⁷ or halogen; R³, R⁴ and R⁵ represent, each independently, H, R⁷ or halogen ;

R⁶ represents a linear or branched, saturated or unsaturated (CrC₂₁)-acyl or a further non-glycosidic metabolically cleavable protecting group; R⁷ represents, independently in each occurrence, a lower alkyl, alkenyl, alkynyl, hydroxyalkyl, all being optionally substituted with one or more -COOH, -NH , - SH;

R⁸ represents H, R⁷ and (CH₂)_s-N(R^9a)(R ^b); with s = 0, 1, 2, 3 ; R^9a and R⁹ , each independently, represent H and lower alkyl, alkenyl or hydroxyalkyl; or R^9a and R^9b may form, together with N to which they are linked, a 5- or 6-membered aliphatic ring optionally substituted by methyl groups and/or optionally containing one ore more O or S;

R¹⁰ and R¹¹, each independently, represent H and lower alkyl, alkenyl or hydroxyalkyl; or R¹⁰ and R¹¹ form together an oxo (=O) or an alkylidene selected from =CH₂, =CH-R⁷, =CH-COOH and =CH-COOR⁷; Y is selected from Yl) H ;

Y2) a lower alkyl or hydroxyalkyl; Y3) 4-hydroxy-phenyl; Y4) phenyl substituted with R¹²; Y5) 4-pyridyl-N-oxide and l-(3-hydroxy)-pyridyl ; Y6) 2-naphthyl, optionally 6-substituted with OH, OCH₃ or R¹²;

R¹² represents -NHC(O)NH₂, -NHC(O)CH₃, -NH₂, -CH₂OH, -NHCN, -CH(CN)₂, -NHS(O)₂CH₃, Cl, and F; provided that when R² is OCH₃ or OH and R³, R⁵, R¹⁰, R¹¹ and Y are hydrogens, then R¹ is other than hydrogen; and with the proviso that the compound (I) is not dienestrol; or of a pharmaceutically acceptable salts and solvates, or optical or geometric isomers thereof, for the manufacture of a medicament for treating and/or preventing androgenic disorders.

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

The term "lower" associated with "alkyl, alkenyl, alkoxy, hydroxyalkyl, carboxyalkyl" is intended to mean aliphatic chains made of 1 to 6, preferably 1 to 4 carbon atom(s), unless otherwise indicated.

As used herein, "alkyl" refers to linear or branched chain saturated hydrocarbon chain; the tenn "alkyl", as used herein, also encompasses ethero-atom containing aliphatic chains, thus containing ethero moieties such as -C-O-C, -C-S-C-, -C-Si-O-, -C-Si-O-C- and the like. The term "alkenyl" refers to a linear or branched, unsaturated cis- or trans- unsaturated, acyclic hydrocarbon radical.

The term "alkynyl" refers to linear or branched radicals having two to about twenty carbon atoms, preferably two to about ten carbon atoms containing at least one carbon-carbon triple bond; and "hydroxyalkyl" similarly refer to alkyl groups containing a -C-OH group.

The term "acyl" as used herein means a straight or branched, saturated or unsaturated monocarboxylic or bicarboxylic residue of 2 to 22 carbon atoms, linked by the carbonyl group to the structure of formula (I).

Preferred acyl are unsaturated (Cι₄-C₂₂)- or saturated ω-carboxy-(C₂-Cιo) acyl.

Illustrative unsaturated (Cι₄-C₂₂)-acyls are gamma-linolenic acid, alpha- linolenic acid, gamma-linolenic acid, alpha-linoleic acid, conjugated linoleic acid, , oleic acid, palmitoleic acid, myristoleic acid, cis-4,7,10,13,16,19-docosahexaenoic acid, cis-6,9,12,15-octatetraenoic acid, and arachidonic acid. Illustrative saturated ω-carboxy-(C₂-Cιn)-acyls are succinic acid, adipic acid, sebacic acid, azelaic acid. The term "dienestrol" is the DCI of E,E di(4-hydroxyphenol)-2,4- hexadiene.

Preferred alkylidene groups are =CH₂, =CH-CH₃, =CH-CH=CH₂, =CH- COOH. According to a preferred aspect of the invention, when Y is Y4, then R12 is in the 4 position of the phenyl group.

The expression "pharmaceutically acceptable salts and solvates", designates salt and solvate derivatives of the compounds of formula (I) which are not toxic when administered to a mammal, especially to a human being. The expression "pharmaceutically acceptable" also comprises

"dermatologically" and "cosmetically" acceptable.

The expression "dermatologically acceptable" as used herein, means compatible with either or both of the skin and scalp.

More particularly, "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). Dermatologically/cosmetically acceptable salts of compounds of formula (I) include, for example, acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, p- toluenesulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates, and benzoates..

In some cases, salts may also be formed with bases; such salts include salts derived from inorganic or organic bases, for example alkali metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperdine, or dimethylamine salts.

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.

Preferred allyl-phenol compounds according to the present invention are: A) compounds of formulae (la), (lb) or (Ic) :

(la) (lb) (Ic) with R^la = H or R^6α; R^l = either H or R^6α, provided that at least one R^l is other than H; R^lc = R^6α;

R^6α = unsaturated (C₁ -C₂ )-acyl or saturated co-carboxy-(C₂-Cιo)-acyl. Preferred compounds include: 4-(2-propenyl)phenol ("chavicol") 4-(2-propenyl)phenol, oleoyl ester ("chavicol oleate") 4-(2-propenyl)phenol, linoleoyl ester ("chavicol linoleate")

4-(2-propenyl)phenol, α-linoleoyl ester ("chavicol α-linoleate") 4-(2-propenyl)phenol, γ-linolenoyl ester ("chavicol γ-linolenate") 4-(2-ρropenyl)phenol, α-linolenoyl ester ("chavicol α-linolenate") 4-(2-propenyl)phenol, succinoyl ester ("chavicol hemisuccinate") 4-(2-propenyl)phenol, azelaloyl ester ("chavicol hemiazelate") 3,4-dihydroxy-l-(2-propenyι)benzene, mono and dioleoyl esters 3,4-dihydroxy-l-(2-propenyl)benzene, mono and dilinoleoyl esters 3,4-dihydroxy-l-(2-propenyl)benzene, mono and di-α-linoleoyl esters 3,4-dihydroxy-l-(2-propenyl)benzene, mono and di-γ-linolenoyl esters 3 ,4-dihydroxy- 1 -(2-propenyl)benzene, mono and di-α-linolenoyl esters 3,4-dihydroxy-l-(2-propenyl)benzene, mono and di-succinoyl esters 3,4-dihydroxy-l-(2-propenyl)benzene, mono and di-azeloyl esters 2-methoxy-4-(2-propenyl)phenol, oleyl ester ("eugenyl oleate") 2-methoxy-4-(2-propenyl)phenol, linoleyl ester ("eugenyl linoleate") 2-methoxy-4-(2-propenyl)phenol, α-linoleyl ester ("eugenyl α-linoleate") 2-methoxy-4-(2-propenyl)phenol, γ-linolenoyl ester ("eugenyl γ-linolenate") 2-methoxy-4-(2-propenyl)phenol, α-linolenoyl ester ("eugenyl α-linolenate") 2-methoxy-4-(2-propenyl)phenol, succinoyl ester ("eugenyl hemisuccinate") 2-methoxy-4-(2-propenyl)phenol, azeloyl ester ("eugenyl hemiazelate") which are particularly suitable for the preparation of dermatologic composition to treat mild androgenic disorders.

B) compounds of formulae of formulae (Id), (Ie), (If) and (Ig) :

with Y^If, Y^Ig and Y^lh = H, lower alkyl, hydroxyalkyl, or a Y3, Y4, Y5 or Y6 group as defined above. Preferred compounds include:

4-(4-hydroxyphenyl)-2-methyl-2-butene ("4-(prenyl)phenol")

3-(4-hydroxyphenyl)-2-methyl-2-propene

3-(4-hydroxyphenyl)-2-methoxymethyl-2-propene

3-(4-hydroxyphenyl)-2-(4-hydroxybutyl)-2-propene 3 -(4-hydroxyphenyl)-2-(4-hydroxyphenyl)-2-propene

3 -(4-hydroxyphenyl)-2- [ 1 -(3 -hydroxy)-pyridyl)] -2-propene

3-(4-hydroxyphenyl)-2-(6-hydroxy-naphthyl)-2-propene

3-(4-hydroxyphenyl)-2-(6-methoxy-naphthyl)-2-propene

3-(4-hydroxyphenyl)-2-(4-pyridyl-N-oxide)-2-propene CE)-4-(4-hydroxyphenyl)-2,5-hexadiene (E,E^-4-(4-hydroxyphenyl)-2,4-hexadiene (E,E)-4-(4-hydroxyphenyl)-3-ethyl-2,5-hexadiene (E -4-(4-hydroxyphenyl)-4-hydroxybutyl-2,5-hexadiene (E,EJ-3-(4-hydroxyphenyl)-2-butyl-2,4-hexadiene which are particularly suitable for the preparation of dermatologic composition to treat severe androgenic disorders.

The allyl-phenol compounds are either known compounds or can be prepared from readily available starting materials using general methods and procedures.

3-Methoxy-4-(2-propenyl)phenol ("eugenol"), l-methoxy-4-(2- propenyl)benzene ("estragole") and 5-(2-propenyl)-l,3-benzodioxol ("safrole") are readily available aroma chemicals obtained from clove, estragon and sassafras oils, respectively, which represent key building blocks for the preparation of some allyl- phenol compounds suitable for our purposes. Εugenol as well as estragole can be converted into 3,4-dihydroxy-4-(2-propenyl)benzene ("hydrochavicol") and 4-(2- propenyl)phenol ("chavicol"), respectively by the methyl ether cleavage in harsh conditions such as refluxing in ΕtMgBr, MeMgl, HBr or BBr and the like. By similar reactions safrole may be either converted directly into hydrochavicol or in 2- step dealkylation via l-ethoxy-4-(2-propenyl)benzene ("homoeugenol") (Cabiddu S. et al., Gazz. Chim. It., 98:800-809, 1968). The acyl esters of lower allyl-phenols, namely eugenol, chavicol and hydroxychavicol as well as those of higher allyl-phenols may be prepared by the reaction of the acid halide or anhydride of a carboxylic acid, previously prepared by contacting the carboxylic part with an inorganic acid halide, such as SOCl₂, PC1 , 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, said acyl-esters may also be prepared by the condensation reaction of an allyl-phenols and carboxylic acid in the presence of a dehydrating condensing agent, e.g. N,N'-dicyclohexylcarbodiimide, l-cyclohexyl-3-(4- diethylaminocyclohexyl) carbodiimide, l-ethyl-3-(3- diethylaminopropyl)carbodiimide or the like, generally carried out at room temperature or under cooling in halogenated solvent. The molar ratio of allyl-phenol to carboxylic acid to dehydrating condensing agent is approximately 1:1:1.

The higher allyl-phenols may be prepared by the metal-halogen exchange (MHE) coupling of an organometal (aryl or benzyl) with an organohalogen (allyl or vinyl), for example as outlined in Schemes I, II and IH, wherein R^a and R^b are H or methyl; and Y is Y 1-6 as defined in formula (I). Scheme I

In the reactions illustrated by Schemes I and II , the organometal may be generated from the corresponding organohalogen (aryl or benzyl) via MHE reaction with a suitable elemental metal (step i and iv).

Suitable elemental metal include magnesium [M¹ = MgBr] or litium [M¹ =

Li], the former being carried out under the common conditions to produce the

Grignard reactants, the latter being produced by the reaction of Li° and an organohalogen in ethereal solvents, optionally in the presence of a Lewis base, e.g. triethylamine (cfr. U.S. Pat. N. 5,626,798).

Preferably both X¹ and X² are bromine [X¹ and X² = Br] in order to facilitate both the formation of the aryl or benzyl-metal reactant (steps i and iii) as well as the further MHE coupling with an allyl or vinyl halides (step ii and iv). The OH-phenolic moiety shall have a protecting groups (P), for examples benzyl ethers [P = -CH₂-C₆H₅], acetals [P = CH(CH₃)OCH₃], carbamates [P = -C(O)- NEt₂], alkyl ethers [P = -CH₂-O-CH₃ "MOM"], silanes [P = 2- (trimethylsilyl)ethoxymethyl, "SEM"], and the like. The deprotection reaction (step iii and vi) may be carried out in the usual way for each protecting group, i.e. pyridinium p-toluene-sulfonate when P = benzyl, concentrated H⁺ when P = acetals, reduction with LiAlH₄ when P = carbamates, reduction with Na/NH₃ when P = MOM, and tetrabuthylammonium fluoride when P = SEM.

Conversely, Scheme in depict a synthetic approach by the use of a p- dihalogen aryl, wherein the hydroxy group of the phenolic moiety is generated after the aryl-metal formation (step vii) and condensation with an allyl-halide (step vii).

Scheme III

In this case a 1,4-dihalogen-aryl is needed with a highly reactive halogen [X¹ = I] and a less reactive halogen [X³ = Cl or F], wherein the former is finally substituted by 2-(trimethylsilyl)ethanol and potassium bis(trimethylsilyl)amide in tetrahydrofuran to afford the p-(trimethylsilyl)ethoxy group (SEM) (step ix), which may afford allyl-phenols by the reaction with tetrabuthylammonium fluoride (TBAF) (step x). Note that the TMSE group is stable to either acids or bases and specifically cleaved by fluoride compounds (e.g. TBAF), thus the TMSE-protected allyl-phenols can be also conceived as suitable intermediates for the synthesis of further allyl- phenols.

Scheme IV illustrates the isomerization reaction of an diallyl-phenol to a vinyl-allyl penol (step xi), which is generally carried out under strong acid conditions (e.g. H₂SO₄), a step which may either precede (step xii) or follow the deprotection reaction.

Schemes V and VI show the formation of an allyl-phenol monophosphate ester and carbamate which may be performed with POCl₃ and NH₂COCl under common condition (step xiii and xiv, respectively), unless Y is a particular substituent in need of any further steps of protection-deprotection or functionalizations .

Schemes VII illustrate the MHE coupling of an organometal with an organohalide, either by producing the organometal from the aryl halide (step xv) or in the allyl halide (step xvi) and the halogenation to produce a diallyl-halide (step xvii).

The allylic halogenation (step xvii) may be carried out by common methods, e.g. by reacting the diallyl with elemental halogen in the presence of UV-radiation to afford an allyl-halide suitable for the MHE coupling (e.g. step ii) It will be appreciated that while some illustrative methods are provided by the Examples 1-8, several modifications as well as alternative synthetic approaches to those set forth in the Schemes I- VI can also be conceived.

The compound of formula (I) can be administered for treating conditions consequent upon an excess of 5 -reductase activity in a composition suitable for topical and systemic (oral, enteral, parenteral, etc.) administration to a patient identified with excess 5α-reductase activity.

The compounds of formula (I) may be administered either by systemic or topical route. Topical compositions are the preferred compositions according to the invention for being particularly useful in the treatment and/or prevention of androgenic disorders on skin.

The present invention therefore provides a topical composition comprising the allyl-phenol derivative of formula (I) or a salt thereof in combination with a dermatologically acceptable carrier.

Another object of the invention is the use of the compositions of the invention for treating and/or preventing androgenic disorders of the skin.

The use of the allyl-phenol compounds of formula (I) or of salts and solvates thereof for the manufacture of a topical medicament for treating and/or preventing androgenic disorders on skin, is another object of the invention.

The use of the allyl-phenol compounds of formula (I) or of salts and solvates thereof for the cosmetic treatment of the skin is a further object of the present invention.

A further object of the present invention is to provide a method for the treatment and/or prevention of androgenic disorders on skin, more particularly those which are mentioned in the present application, which comprises administering to a mammal in need thereof an effective amount of an allyl-phenol derivative of formula

(I) or a salt or solvate thereof.

According to a further aspect, the invention provides a cosmetic method for treating conditions consequent upon an excess of 5α-reductase activity comprising the administration of a compound of formula (la) to (Ic) above to a patient identified with excess 5α-reductase activity.

According to a preferred aspect, the invention provides a cosmetic method as defined above, wherein R^6α is an unsaturated (C₁₄-C₂ )-acyl residue selected from the group consisting of myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, α- linolenic acid, conjugated linoleic acid, γ-linolenic acid, α-linolenic acid, arachidonic acid, EPA, DHA and mixture thereof.

According to another prefened aspect, the invention provides a cosmetic method as defined above, wherein R^6α is a ω-carboxy-(C₂-Cιo)-acyl residue selected from the group consisting of succinic acid, adipic acid, sebacic acid, azelaic acid and mixture thereof.

The aforementioned allyl-phenol compounds show high dermal compatibility and acceptable irritation behavior when applied to human skin.

The topical compositions of the present invention are effective in the fields of medicaments and cosmetics. The topical compositions of the invention comprise an allyl-phenol derivative 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 are manufactured by known methods for example by mixing the allyl-phenol compounds with conventional dermatologically 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 androgenic disorders on skin. A composition comprising these non-steroid anti-androgenic agents capable to produce the 5α-reductase inhibition in epidermal and follicular keratinocytes, dermal papilla cells, sweat glands and in the inner root sheath of the hair follicle.

Therefore the composition of the invention are particularly indicated for the treatment of androgenic disorders on skin. Exemplary, non-limiting androgenic disorders on skin include male-pattern alopecia (alias androgenic alopecia), acne, seborrhea, hirsutism, and dandruff. The term "acne" as used herein encompasses acne-related skin disorders which may have either a non-inflamed (comedons) or an inflammatory pattern, thus including acne vulgaris, comedonal acne, infantile acne, acne conglobata, acne fulminans, acne medicamentosa, acne excorie, gravidic acne, acne rosacea and acne scarring.

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 cosmetic compositions and hair-treatment compositions. As topical skin compositions for medical use and topical skin cosmetic compositions, many types of ointments and lotion maybe used.

The ointments may contain either an oil base or an emulsion base, including oil-in-water type and water-in-oil type emulsions.

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.

According to the invention, it is possible, inter alia, to combine allyl-phenol compounds with other active agents intended in particular for the prevention and/or treatment of androgenic disorders on skin.

A further object of the present invention is to provide a method for the treatment and/or prevention of androgenic disorders on skin which comprises administering to a mammal in need thereof an effective amount of an allyl-phenol derivative of formula (I) or a salt or solvate thereof in combination or in conjunction with the current treatments of androgenic disorders on skin, as those which are mentioned in the present application

Illustrative examples of said current treatments include, inter alia, topical antibiotics such as azelaic acid, erythromycin, clindamycin, tetracycline, sulfonamide; cimetidine; corticosteroids; antifungal agents such as ketoconazole; topical retinoids such as tretinoin, adapalene, tazarotene, isotretinoin; oral broad- spectrum antibiotics such as oral tetracycline, erythromycin, minocycline and doxycycline; hormonal therapies such as spironolactone, flutamide, estrogen- containing oral contraceptives, further 5α-reductase inhibitors such as l-diethyl-4- methyl-3-oxo-4-aza-5α-androstane-17beta-carboxamide, (5 α,2OR)-4-diaza-21- hydroxy-20-methyl-pregnan-3-one or (4R)-5,10-seco-19-norpregna-4,5-diene- 3,10,20-trione cyproterone acetate (21-acetoxy-6-chloro-l,2.alpha.-methylene-4,6- pregnadiene-3,20-dione) or 17. alpha. -propyl mesterolone (17 β-hydroxy-1 α-methyl- 17 α-n-propyl-5α-androstane-3-one) as well as those which are described in U.S. Pat. Nos. 3,234,093, 4,344,941, 4,456,620, 4,558,041, 4,565,600 and 4,673,673. Further illustrative examples of said current treatments include OTC products such as benzoyl peroxide, salicylic acid and salt and esters, sulfur, sulfurated lime, resorcinol, alcohol and acetone, herbal, organic and "natural" medications; physical therapies such as comedo extraction, ultraviolet light therapy, light chemical peels and the like. Another object of the invention relates to a composition comprising an effective amount of an allyl-phenol derivative of formula (I) along with a trichogenic agents.

Illustrative examples of trichogenic agents are minoxidil, 2,4-diamino- pyrimidine 3 -oxide, finasteride, dunasteride, pyroglutamic acid and esters thereof, plant extracts and derivatives with estrogen-like activities (e.g. glycolic extracts of willow herbs, nettle herbs, dwarf palms, african plum), and plant actives with vasokinetic action (e.g. visnadine, kellin, esculoside, esculetin, xymenynic acid, raubasine and vincamine).

The following examples are intended to illustrate the scope of the present invention but not to limit it.

Example 1 - General synthesis of pure esters of lower allyl-phenols A stirred solution of 0.5 mol chavicol (or eugenol) (or 0.25 mol hydroxychavicol) and 0.55 mol triethylamine in 500 ml CH₂C1₂ was slowly added to 0.505 mol of the appropriate acyl reactant at 20° C for 30 minutes under nitrogen.

The reaction was stirred for 3 hours at room temperature, then poured into water (500 ml) and extracted with CH₂C1₂ (2x300 ml), the organic phases were washed with 10% HCl (200 ml), H₂O (500 ml), saturated NaHCO₃ (300 ml), brine (300 ml), then dried (MgSO₄) and vacuum distilled to afford the desired esters, which are crystallized in ethanol.

Analytical-grade acyl reactants as oleyol chloride, linoleoyl chloride, α- linoleoyl chloride; γ-linolenoyl, α-linolenoyl chloride, propionyl chloride, azelaic acid monochloride and succinic anhydride afford the compounds of formulae (Ila-i), (ma-i) and (IVa-i).

Example 2 - Synthesis of mixed fatty acid esters of lower allyl-phenols

Instead of pure-grade acyl reactants used in the Example 1, the following fatty acid mixtures obtained from the saponification of natural trygliceride oils may be used to prepare the acyl ester of allyl-phenols. (1) The "n-9" mixture rich in oleic acid (OA, 18:1, n-9) from fatty acids of high-oleic sunflower containing up to 90% OA.

(2) The "low n-6" mixture rich in gamma-linolenic acid (GLA, 18:3, n-6) and linoleic acid (LA, 18:2, n-6) from primrose fatty acids containing about 80%

GLA+LA. (3) The "low n-3" mixture rich in alpha-linoleic acid (ALA, 18:3, n-3) from linseed fatty acids containing about 65% ALA.

(4) The "high n-6" mixture rich in arachidonic acid (AA, 22:4, n-6) from fatty acids by the fungi Mortierella alpina containing around 40% AA (Arasco™, Martek,

USA). (5) The "high n-3" mixture rich in eicosapentaenoic acid (EPA, 20:5, n-3) and docosahexaenoic acid (DHA, 22:6, n-3) from fish fatty acid concentrate 70%

EPA+DHA.

(6) The "conjugated" mixture rich in conjugated linoleic acid (CLA; 18:2), a group of isomeric cis and trans 9,11-octadecadienoic acids, obtained by the dehydration of mesylate ricinoleic methyl ester, containing about 80% CLA.

The l-to-6 mixtures listed herein may be transformed in the conesponding acyl chlorides by the reaction with thionyl chloride or oxalyl chloride in toluene, then reacted with chavicol, eugenol and hydroxychavicol to afford the corresponding fatty esters which are particularly suitable for the preparation of cosmetic compositions. If desired, the listed fatty acid mixtures can be further enriched by applying one or more separative fractionation method, i.e. by storing the fatty acid mixture at cold temperatures, e.g. form -20° to 5°C, and split out the supernatant liquid.

Example 3 - General procedure for the synthesis of protected prenyl and diallyl- phenols 10 ml of tetrahydrofuran, 1.34 g (55 mmol) of metallic magnesium and a piece of iodine were mixed and stirred at room temperature. After disappearance of the color of iodine, a solution of 50 mmol of protected 4-bromo-phenol (e.g. 4- benzyloxy-bromobenzene) in 20 ml of THF was added dropwise to the reaction over about 1 hour while the temperature was kept at 40 to 50°C. The reaction liquid was then stirred under reflux for 1 hour to obtain a Grignard reagent. The reaction liquid was added 0.05 g (0.25 mmol) to manganese chloride tetrahydrate (It) (MnCl₂.4H₂O) and 55 mmol of an organobromine (*) over 10 minutes while maintaining the temperature at 20 to 30°C. The reaction mixture was allowed to warm to room temperature and stirred for a further 2.5 hours until the reaction was complete. The precipitated magnesium salt was filtered off. The reaction mixture was poured into an aqueous solution of ammonium chloride, the organic phase was dried over magnesium sulphate, filtered, vacuum and extracted with 2x200 ml of toluene, purified by crystallization with a suitable solvents.

According to the organobromine (*) selected, i.e. l-methyl-3 -butenylbromide ("prenyl bromide"), l-methyl-3 -ethyl-butenylbromide, l-methyl-3 -ethoxymethyl- butenylbromide, 3-(l,4-hexadienyl)bromide, 4-methyl-3-(l,4-hexadienyl)bromide, 4- i-propyl-3-(l,4-hexadienyl)bromide, the reaction shall afford compounds of formulae (Va,b,c) and (VId,e,f), for examples wherein P = Bn.

-CH(CH₃)₂ 0

Example 4 - General procedure to isomerize diallyl-phenols into vinyl-allyl-phenols The toluene solution of compounds of formula (VI) (50 mmol) was added to

300 ml of 5% sulfuric acid at 0 to 10°C, followed by stirring for 1 to 4 hours. After phase-separation, the oil layer was washed with 200 ml of water, followed by separation of the organic phase which was dried over magnesium sulphate, filtered and crystallization (e.g. in CHCl₃:ethanol mixtures) to afford compounds of formula (VHd,e,f).

(VII) Example 5 - General procedure for the synthesis of allyl-phenol phosphate esters

The protected compounds of formulae (V-VII) obtained according to the Examples 3 and 4 may be deprotected by common methods, e.g. those illustrated by Hoaraus C, Pettus T.R.R. in Synlett, 2003, 1, 127-137, Ralph J., Zhang Y, Ede M.R in J. Chem. Soc, Perkin Trans. 1, 1998, 2609-2613, and references therein.

The solution of the deprotected compound (50 mmol) in dry pyridine (300 ml) was cooled down at -10°C and slowly added with stirring to a solution of 30 ml phosphorus oxychloride in 300 ml dry pyridine. After one hour at -10°C the temperature was allowed to rise to +20°C and kept under stirring for 2 hours. The reaction mixture was poured on ice, separated and evaporated in vacuo, the residue dissolved in 300 ml ethanol, then poured into 600 ml HCl 2N. The precipitate was collected and dissolved in 300 ml acetone. The monophosphate was separated buy addition of 600 ml of water, then recrystallized from ethyl acetate^hexane mixtures to afford the pure O-phenolic monophosphate esters (-O-P(O)(OH)₂) of the conesponding allyl-phenol compounds. Example 6 - General procedure for the synthesis of aliyl-phenol-carbamates

A solution of deprotected (40 mmol) in 20 ml NaOH 5M and 1.4 g dodecylbenzyl triethyl ammonium chloride was added with 8.97 g carbamoyl chloride in 150 ml chloroform at room temperature. The mixture is stirred for 4 hours, then the organic phase was separated and washed with 1M HCl and water. The solution was evaporated in vacuo and the residue recrystallized from methanol: chloroform mixtures to afford to afford the pure O-phenolic carbamates (- O-CONH₂) of the corresponding allyl-phenol compounds. Biological Example 1 - In vivo test for anti-androgenic activity

The inhibitory effect on 5α-reductase activity may be tested by micro- radioassay.

Ventral prostate biopsies homogenized with 9 volumes of 0.1M PBS shall be filtered with gauze mesh and spun down at 3000 rpm for 10 minutes to obtain the crude nuclear fraction. The supernatant shall be discarded and the pellet resuspended in PBS. This process shall be performed twice and the second suspension used as the enzyme solution for the assay. One mCi of [4-¹⁴C] testosterone and the test sample shall be dried in the assay tube, then 10 μl of 50 mM NADPH and 60 μl of PBS added. After addition of 30 μl of 5 -testosterone reductase solution, the assay mixture shall be incubated for 1 hour at 37°C, then 0.4 ml of chloroform: methanol (1:2 v/v) added to terminate the reaction, then centrifuged at 3000 rpm for 10 minutes. The samples applied to a TLC plate shall be concentrated into a sharp band running 3 cm from the bottom in two ascents of acetone, than the chromatogram developed in dichloramethane:diethyl ether (7:1 v/v), followed by chloroform :diethyl ether (9:1 v/v). The radioactive content of each extract with reference to testosterone, 5α-dihydro-testosterone, 5α-androstane-3α,17β-diol, and 5α-androstane-3β,17β-diol may be measured by loading the plates into an isotope image analysis system. The conversion rate of testosterone expressed as 50% inhibitory concentration (IC₅₀) indicate the anti-androgenic activity of the allyl-phenol compounds. Biological Example 2 - Protocol for clinical pilot study on hair re-growth A preliminary clinical pilot study of a hair growth agent containing from

0.1%) to 2% of compound of formula (I) may serve as investigative tool the evaluate the effects on hair growth. The inclusion criteria is for subjects with androgenic alopecia otherwise healthy patients, while those with another condition in addition to alopecia are excluded. The test sample may be a lotion, as in the next Composition Example 1, an adequate amount of the test sample shall be applied by rubbing onto the scalp in the area with hair loss and the surrounding area twice daily, in the morning and evening. The treatment shall continue for at least 3 months, unless discontinued for adverse reactions or others. The visual examination shall be performed before the study and after 3 months of treatment. Each subject's improvement will be categorized into one of the following 5 categories according to its condition before treatment: a) markedly improved, b) moderately improved, c) slightly improved, d) no change, and e) aggravated. The expected efficacy rate shall fall within the range from (b) to (c) for at least 80% of the subjects, thus suggesting that allyl-phenol compounds can be effective ingredient for the hair growth treatment.

Composition Example 1 - Anti-alopecia lotion

100 g of lotion contain:

Esculoside 0.3 g

Ximenynic acid 0.5 g

Compound of formula (I) 0.1 - 0.2 g

Glycolic extract of Pigeum Africanum 1.0 g

Butylhydroxytoluene 0.1 g

Ethyl alcohol 70° q.b. to 100 g

Composition Example 2 - Gel to control armpit sweating and vellus

100 g of lotion contain:

Aluminum oxychloride 1.2 g

Alantoin 0.1 g alfa-Bisalobol 0.1 g

Compound of formula (I) 2.0 g

Colorless fluid extract of Witch-hazel 5.0 g

Acrylic gel of Carbopol™ q.b. to 100 g

Composition Example 3 - Anti-acne lotion

100 g of lotion contain:

Erythromicin base 2.0 g

L- Ascorbic acid 0.5 g

Compound of formula (I) 1.5 g

Allantoin 3.0 g

Roses distilled water 10% 5.0 g

Ethyl alcohol 70° q.b. to 100 g

Composition Example 4 - Anti-acne gel 100 g of lotion contain: Compound of formula (I) 5.0

Benzoyl peroxide 5.0

L- Ascorbic acid 0.2 alfa-Bisalobol 0.1

Glycolic extract of aloe 3.0

Glycolic extract of althea 3.0

Acrylic gel of Carbopol™ q.b. to 100 g

Composition Example 5 - Anti-seborrhea O/W cream

100 g of cream contain:

Compound of formula (I) 0.3 g

Fluid paraffin 2.0 g

Cethyl alcohol-(10)-POE 4.0 g

Cetestearyl alcohol 4.0 g

Triethanolamine 1.75 g

Glycolic extract of Althea 5.0 g

Oat glycolic extract 10 g

Menthil lactate O.lg

Hops glycolic extract 1.0 g

Glycolic acid 2.0 g

Butan-l,3-diol 3.0 g

Xanthan gum 0.3 g

Deionized water q.b. to 100 g

Composition Example 6 - Anti-dandruff & baldness shampoo

100 g of shampoo contain:

Sodium laurylsulfate 5.0 g

Triethanolamine laurylsulfate 5.0 g

Betaine lauryldimethylaminoacetate 6.0 g

Ethylene glycol distearate 2.0 g

Polyethylene glycol 5.0 g

Compound of formula (I) 5.0 g

Ethanol 2.0 g Perfume 0.3 g

Deionized water q.b. to 100 g

Claims

1. Use of an allyl-phenol derivative of formula (I) :

wherein: R¹ represents H, R⁶, P(O)(OH)-OR⁸ or S(O)_t-R⁸; with t = 0, 1 , or 2;

R² represents H, OH, OR⁶, R⁷, OR⁷ or halogen; R³, R⁴ and R⁵ represent, each independently, H, R⁷ or halogen ; R represents a linear or branched, saturated or unsaturated (C₁-C ι)-acyl or a further non-glycosidic metabolically cleavable protecting group; R⁷ represents, independently in each occurrence, a lower alkyl, alkenyl, alkynyl, hydroxyalkyl, all being optionally substituted with one or more -COOH, -NH₂, - SH;

R⁸ represents H, R⁷ and (CH₂)_s-N(R^9a)(R^9b); with s = 0, 1, 2, 3 ; R^9a and R⁹ , each independently, represent H and lower alkyl, alkenyl or hydroxyalkyl; or R^9a and R ^b may form, together with N to which they are linked, a 5- or 6-membered aliphatic ring optionally substituted by methyl groups and/or optionally containing one ore more O or S;

R¹⁰ and R ^λ, each independently, represent H and lower alkyl, alkenyl or hydroxyalkyl; or R¹⁰ and R¹¹ form together an oxo (=O) or an alkylidene selected from =CH₂, =CH-R⁷, =CH-COOH and =CH-COOR⁷;

Y is selected from Y1) H ;

Y2) a lower alkyl or hydroxyalkyl; Y3) 4-hydroxy-phenyl; Y4) phenyl substituted with R¹²;

Y5) 4-pyridyl-N-oxide and l-(3-hydroxy)-pyridyl ; Y6) 2-naphthyl, optionally 6-substituted with OH, OCH₃ or R¹²; R¹² represents - HC(O)NH₂, -NHC(O)CH₃, -NH₂, -CH₂OH, -NHCN, -CH(CN)₂,

-NHS(O)₂CH₃, Cl, and F; provided that when R² is OCH₃ or OH and R³, R⁵, R¹⁰, R¹¹ and Y are hydrogens, then R¹ is other than hydrogen; and with the proviso that the compound (I) is not dienestrol; or of a pharmaceutically acceptable salts and solvates, or optical or geometric isomers thereof, for the manufacture of a medicament for treating and/or preventing androgenic disorders.

2. Use according to claim 1, for treating a condition consequent upon an excess of 5α-reductase activity.

3. Use according to claim 2, for topically treating a condition consequent upon an excess of 5α-reductase activity in a patient identified with excess 5α-reductase activity.

4. Use according to claims 2 or 3 wherein the 5α-reductase is Type I 5 - reductase.

5. Use according to claim 2 or 3 wherein the 5α-reductase is both Type I and Type II 5α-reductase.

6. Use according to claim 4 wherein said condition is male pattern baldness.

7. Use according to claim 4 wherein said condition is acne vulgaris.

8. Use according to claim 4 wherein said condition is seborrhea.

9. Use according to claim 4 wherein said condition is androgenic alopecia.

10. Use according to claim 1 wherein the compound of formula (I) is selected in the group consisting of a compound of formula (la), (lb) and (Ic):

wherein R^la = H or R^6α; R^l = either H or R⁶ , provided that at least one R^lb is other than H; R^lc = R^6α; R^6α = unsaturated (Cι -C₂₂)-acyl or saturated ω-carboxy-(C₂-Cιo)-acyl.

11. Use according to claim 1 wherein the compound of formula (I) is selected in the group consisting of a compound of formula (Id), (Ie), (If) and (Ig) :

with Y^ff, Y^Ig and Y^lh = H, lower alkyl, hydroxyalkyl, or a Y3, Y4, Y5 or Y6 group as defined in claim 1.

12. Topical composition comprising as the active principle a compound of formula (I) or (la) to (Ig) as defined in claim 1, 10 or 11, wherein said active principle is present in an amount ranging from 0.05 to 50% by weight of the total composition.

13. Topical composition according to claim 12, wherein said active principle is present in an amount ranging from 0.5 to 2% by weight of the total composition.

14. Cosmetic method for treating conditions consequent upon an excess of 5α- reductase activity comprising the administration of a compound of formula (I) or (la) to (Ig) as defined in claim 1, 10 or 11, to a patient identified with excess 5α-reductase activity.

15. Cosmetic method according to claim 14 wherein in said compound of formula (la), (lb) or (Ic) as defined in claim 10.

16. Method according to claim 15, wherein R^6α is an unsaturated (Cι₄-C₂₂)-acyl residue selected from the group consisting of myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, α-linolenic acid, conjugated linoleic acid, γ-linolenic acid, α-linolenic acid, arachidonic acid, EPA, DHA and mixture thereof.

17. Method according to claim 15, wherein R^6α is a ω-carboxy-(C₂-C₁₀)-acyl residue selected from the group consisting of succinic acid, adipic acid, sebacic acid, azelaic acid and mixture thereof.

18. Method of claim 16 or 17 wherein the 5α-reductase is Type 1 5α-reductase.

19. Method of claim 16 or 17 wherein the 5α-reductase is both Type I and Type II 5α-reductase.

20. Method of claim 16 or 17 wherein the condition is male pattern baldness, acne vulgaris, seborrhoea, scalp dandruff and/or hirsutism.