GB2160864A

GB2160864A - 10-Aryl-1,8-dihydroxyanthrones and their esters, the process for preparation thereof and pharmaceutical and cosmetic compositions containing them

Info

Publication number: GB2160864A
Application number: GB08514973A
Authority: GB
Inventors: Braham Shroot; Gerard Lang; Jean Maignan; Serge Restle
Original assignee: Centre International de Recherches Dermatologiques Galderma
Current assignee: Galderma Research and Development SNC
Priority date: 1984-06-13
Filing date: 1985-06-13
Publication date: 1986-01-02
Also published as: DE3521074A1; FR2565966B1; DK265185A; BE902642A; CA1253859A; IT1190365B; SE8502910L; IT8521130A0; DK265185D0; GB2160864B; FR2565966A1; NL8501699A; CH664557A5; SE8502910D0; GB8514973D0; JPS6140238A; SE459807B

Abstract

10-Aryl-1,8-dihydroxyanthrones of formula: <IMAGE> in which Ar is: <IMAGE> R1, R2, R3, R4 and R5 are each H, halogen, -CF3, -OH, lower alkyl, lower cycloalkyl, lower hydroxyalkyl, lower alkoxy, -C IDENTICAL N <IMAGE> r' and r'' are each H or lower alkyl, n is 0 or 1 to 3 inclusive, and R' and R'' are each H, lower alkyl or aryl at least one or R1 to R5 being other than H, <IMAGE> R6 having the same significance as for R1 to R5, or (iv> <IMAGE> and their esters are useful as anti-proliferative, anti-inflammatory, anti-acne, anti-dandruff and anti-seborrhoeic agents, and act against hair loss.

Description

SPECIFICATION 10-Aryl-1,8-dihydroxyanthrones and their esters, the process for preparation thereof and pharmaceutical and cosmetic compositions containing them.

The present invention-relates to derivatives of 1,8-dihydroxy-9-anthrone or anthraiine, in particular derivatives substituted in position 10 with an aromatic group, the mono-, di- And triesters of these new derivatives, a process for preparing these compounds which are useful in human or veterinary medicine and in cosmetics. These new derivatives find application especially as antiproliferative agents in the treatment of cancerous tumours, psoriasis and warts, and as anti-inflammatory agents in the treatment of rheumatism, dermatoses, eczema, seborrheic and pellicular dermatitis and sunburn. In cosmetics, these compounds are anti-acne, anti-dandruff and anti-seborrhoeic agents and act against hair loss.

The present invention provides 1 0-Aryl-1 ,8-dihydrnxyanthrnnes of formula (I);

in which: R1, R2, R3, R4, and R,, which may be identical or different, are each hydrogen, halogen, -CF3, hydroxyl, C,-C6 alkyl, C3-C6 cycloalkyl, C,-C3 hydroxyalkyl, C,-C4 alkoxy, nitrile,

in which r' and r", which may be identical or different, are each hydrogen or C,-C6 alkyl, n is 0 or an integer from 1 to 3, and R' and R" which may be the same or different are each substituted or unsubstituted C,-C6 alkyl, substituted or unsubstituted aryl, at least one of R, to F being other than hydrogen,

in which R6 has the same significance as R1 to R5,

or a mono-; di- or triester thereof.

When the R1 and R5 denote a halogen the latter is preferably fluorine or chlorine.

Preferably lower alkyls, ie. C1 to C6 alkyls include methyl, ethyl, propyl, isopropyl, outyl, isobutyl, t butyl, pentyl, isopentyl and hexyl.

Preferably lower alkoxys ie. C1 to C4 include methoxy, ethoxy, propoxy and isoproposy.

C3 to C6 cycloalkyl are referred to as lower cycloalkyl.

Preferably lower hydroxyalkyls ie. C1-C3 include hydroxymethyl, 2-hydroxyethyl and 2,3-dihydroxypropyl.

When in the compounds of formula (I) the radical Ar denotes an romatic residue of formula:

the preferred compounds are those in which: 1) R, (or R5) denotes a lower alkoxy or a group of formula

R' denoting a linear or branched alkyl of from 1 to 5 carbon atoms, R' denoting hydrogen, R3 denoting hydrogen or a lower alkoxy, and R2, R4 and F6 (or RI) each denoting hydrogen, 2) R2 (or R4) denotes -CF3, a lower alkoxy or a hydroxyl group, and RI, R3, R4 (or R2) and F6 each denote hydrogen, and 3) R3 denotes a lower alkoxy, and RI, R2, R4 and F6 each denote hydrogen.

According to a preferred embodiment, R6 denotes hydrogen.

Among the compounds of formula (I), special mention may be made of the following: 1,8-Dihydroxy-10-(2-[(2,2-dimethylpropanoyl)amino]phenyl) anthrone 1 ,8-Dihydroxy-1 0-(2,4-dimethoxyphenyl)anthrone 1 ,8-Dihydroxy-1 0-(4-methoxyphenyl)anthrone 1 ,8-Dihydroxy- I 3-(trifluoromethyl)phenyl anthrone 1 ,8-Dihydroxy-1 0-(3-methoxyphenyl )anth rone 1 ,8-Dihydroxy-1 0-(3-hydroxyphenyl)anth rone 1 ,8-Dihydroxy-1 0-(2-methoxyphenyl)anthrone 1,8-Dihydroxy-10-(2-thienyl)anthrone 1 ,8-Dihydroxy-1 0-(2-thiazolyl)anthrone.

The mono-, di-and triesters of the compounds of formula (I) can be represented by the following general formula:

in which: Ar has the same significance as given above for the compounds of formula (I), p is = or 1, when p = O, R6 denotes hydrogen or -CO R10, F6 denotes -CO R10, and p' is 1.

when p = 1, R7 denotes: either (i) hydrogen, R6 denoting hydrogen or -CO R10, R9 denoting -CO R10, and p' is 0, or (ii) -CO R10, R8 and F6 which may be the same or different denoting -CO R10, and p' is 0, RIo denoting a linear or branched alkyl having from 1 to 10 carbon atoms, cycloalkyl, 2-pyridyl, 2thienyl, or phenyl optionally substituted with lower alkyl or lower alkoxy, a halogen nitro -CF3 or hydroxyl, and the mixtures of said esters.

Among the linear or branched alkyl radicals having from 1 to 10 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, heptyl, nonyl and decyl radicals may be mentioned in particular.

When the radical F16 denotes a cycloalkyl radical, the latter is a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.

When the phenyl radical is subsituted with an alkyl radical, the latter is preferably a methyl, ethyl or tert-butyl radical.

When the phenyl radical is substituted with an alkoxy radical, the latter is preferably a methoxy or ethoxy radical.

When the phenyl radical is substituted with a halogen, the latter is preferably chlorine or fluorine.

As results from the general formula (II) above, the esters can take the form of mono-or diesters of 10acyl-1,8-dihydroxyanthrone or the isomer thereof, namely the mono-or diesters of 10-acyl-1,8-dihydroxy9-anthranol, or the form of triesters of 10-acyl-1,8-dihydroxy-9-anthranol Among the esters of formula (II), special mention may be made of the following: 1 0-(3-methoxyphenyl)-1 ,8,9-triacetoxyanthracene 1 0-(3-methoxyphenyl )-1 ,8,9-tri(propanoyloxy)-anthracene 10-(2-thienyl)-1 ,8,9-triacetoxyanthracene 1 0-(2-thienyl )-1 ,8,9-tri(propanoyl oxy)anthracene 1 0-(2-thienyl)-1 ,8-di(pivaloyloxy)anthrone.

The compounds of formula (I) are obtained in two stages from 1,8-dihydroxyanthraquinone according to the following reaction scheme:

The first stage consists in reacting an aromatic carbanion with 1,8-dihydroxyanthraquinone (1), which leads, after acidification, to the compound of formula (2).

The second stage consists in reducing the intermediate compound (2) in the presence of metallic tin or stannous chloride, which leads to the compound of formula (I).

The route to the aromatic carbanion can be undertaken starting either from an organolithium compound or from an organomagnesium compound.

The aromatic organolithium compounds can be obtained by two different methods: The first method consists in reacting butyllithium, or its complex with tetramethylethylenediamine, with an aromatic compound in which the substituent or substituents present activate the carbon on which it is desired to accomplish the metalation of the compound.

The methods such as those described by D.W. SLOCUM et al. J.O.C., p. 3653, 1976 or by V. SNIECKUS et al. J.O.C., 44, p. 4803, 1979, can be used in particular.

The second method for gaining access to the aromatic lithium compounds consists in treating a halogenated aromatic derivative, in particular a brominated derivative, with butyllithium according to the methods described by P. BEAK et al., Acc. Chem. Res., p. 306, 1982 and W.E. PARHAM et al., Acc. Chem.

Res. p. 300, 1982.

When it is desired to obtain the aromatic carbanion from a magnesium compound, as in the above method, a halogenated aromatic derivative is used, and this is converted, by the conventional methods to the magnesium compound in an anhydrous solvent such as tetrahydrofuran or ether.

The process which consists in reacting an aromatic lithium compound with l,8-dihydroxyanthraqui- none is especially preferred since, in contrast to the aromatic magnesium compound, this process leads to selective addition on the carbonyl at position 10 on the anthraquinone system, which is not the case with the aromatic magnesium compounds since, in some instances, addition is observed at position 9.

Moreover, it was observed that, by using a large excess of aromatic lithium compound of at least 4 molar equivalents relative to the 1,8-dihydroxanthraquinone, it was not necessary to resort, as in the known processes, to protection of the hydroxyl groups at position 1 or 8 for the purpose of obtaining aromatic derivatives at position 10 of the anthrone system.

The reaction of addition of the aromatic lithium compound to 1,8-dihydroxyanthraquinone is generally performed in an anhydrous solvent medium, such as ethyl ether or tetrahydrofuran, at a temperature of from -80OC to 0 C, by adding the aromatic lithium compound in ether or tetrahydrofuran to a solution of 1,8-dihydroxyanthraquinone in the same solvent.

After the addition, the reaction mixture is maintained with stirring at the same temperature for a period of from 30 min. to 2 hours. The end of the reaction is determined by the substantial absence of 1,8dihydroxyanthraquinone using thin layer chromatography.

The reaction mixture is then acidified at room temperature, and the organic phase is then washed with water and dried over anhydrous magnesium sulphate.

After evaporation of the solvent, the intermediate compound (2) or 10-aryl-1,8,10-trihydroxyanthrone is purified generally by recrystallisation or chromatography on silica gel.

When the reaction is performed starting from an aromatic magnesium compound, the reaction conditions are similar to those used when starting from an aromatic lithium compound but, after the addition is complete, the mixture is allowed to return to room temperature and stirring is continued for several hours, where appropriate under reflux of the solvent, until the 1,8-dihydroxyanthraquinone has substantially disappeared, using thin layer chromatography.

The second stage of the process consists in reducing the 10- aryl-1,8,10-trihydroxyanthrone (2) in order to obtain the compounds of formula (I), this reduction reaction being performed in acetic acid medium in the presence of stannous chloride, or metallic tin and concentrated hydrochloric acid.

The reaction is generally performed at room temperature for a period of from 1/2 to 5 hours, the end of the reaction being determined by the substantial absence of the starting material, using thin layer chromatography.

If the reaction is not complete, the reaction mixture can be heated on a water bath.

After the reaction mixture has returned to room temperature, it is poured into water, which causes the precipitation of the expected product, which is then purified by recrystallisation in a suitable solvent.

The esters of formula (II) are obtained by reacting a suitable acid anhydride with a 10-aryl-1,8-dihydroxyanthraquinone of formula (I) in the presence of a few drops of pyridine and, where appropriate, by bringing the reaction mixture to a temperature of from 50 to 1300C, or by using an acid chloride in the presence of pyridine, in a stoichiometric amount in an aromatic solvent such as toluene.

The formation of the mono-, di-or triesters depends on the molar proportions of the acid anhydride or acid chloride used in the reaction, and the reaction time.

The invention also provides pharmaceutical and cosmetic compositions, which contain as active ingredient at least one compound of formula I or ester thereof.

In these compositions, the concentration of active ingredient generally varies from 0.005 to 70% by weight, according to the administration route.

These compositions can contain, in addition, inert or pharmacodynamically active additives, for example binding agents, fillers, diluents, thickeners and/or preservatives.

The compositions administered orally can also contain flavour modifiers.

The compositions administered topically can take the form of pomades, ointments, creams, gels, tinctures, solutions, lotions, sprays, suspensions, micronised powders or shampoos.

According to this form of embodiment, from 1 to 5 g of the composition, containing from 0.01 to 5 g of the active compound per 100 g of the composition, are applied to the areas of the skin to be treated, in one or two applications.

The compositions administered enterally or parenterally can take the form of tablets, granules, gelatine, capsules, capsules, syrups, suspensions for oral administration, powders for oral administration in sachets, or the form of injectable solutions or suspensions.

For the enteral or parenteral route, from 0.05 to 5 g of the active compound are generally administered per day in adults, in one or two doses.

Trials carried out have enabled it to be shown that the compounds according to the invention possess favourable activity when they are incorporated in various pharmaceutical or cosmetic vehicles.

Several examples of preparation of the compounds according to the invention will now be given by way of illustration, and without any implied limitations.

Example 1 Preparation of 1,8-dihydroxy-10-{2-[2.2-dimethylpropanoyl)amino]phenyl} anthrone a) To 18 g of N-pivaloylaniline in 100 cm3 of anhydrous tetrahydrofuran (THF), 100 cm3 of n-butyllithium (2.5 M) are added at 0 C under an inert atmosphere.

After the addition, the reaction mixture is left for 24 hours at room temperature. A solution of 5 g of 1,8-dihydroxyanthraquinone in 100 cm3 of anhydrous tetrahydrofuran (THF) is then added dropwise at 0 C.The mixture is stirred for 4 hours at room temperature and the solution is then acidified with 75 cm3 of acetic acid. The mixture is poured into 500 cm3 of water and the product is extracted using dichloromethane. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The expected product is purified by chromatography on silica gel. 1 g of yellow crystals of 10 {2-[2,2-dimethylpropanoyl)amino]phenyl}-1,8,10-trihydroxy anthrone, of melting point 257-259"C, is thus obtained.

The NMR spectrum is in accordance with the structure of the expected product.

Elementary analysis: C26 H22 O6 N Calculated: C 71.92 H 5.55 0 19.16 N 3.35 Found: 71.71 5.56 18.92 3.43 b) To a suspension of 250 mg of 1 0-(2-[(2,2-dimethylpropanoyl)amino]pheny ,8,10-trihydroxy anthrone, obtained under (a) above, in 25 cm3 of glacial acetic acid, 400 mg of stannous chloride and a few drops of concentrated hydrochloric acid are added under an inert atmosphere.

The reaction mixture is stirred for 2 hours at room temperature and then poured into 100 cm3 of water.

The expected product precipitates, and is filtered and then dried. It is then taken up with 50 cm3 of dichloromethane, which is stirred in the presence of 2 g of silica. The solution is filtered and then concentrated under reduced pressure. The expected product is precipitated by adding hexane, drained and then dried. 100 mg of yellow crystals of melting point 176-177 C are thus obtained.

The NMR spectrum is in accordance with the structure of the expected product, and likewise the mass spectrum m/e 401.

Example 2 Preparation of 1,8-dihydroxy- 10-K2,4-dimethoxyphenyl)anthrone a) To a solution of 22.1 g of 1,3-dimethoxybenzene dissolved in 50 cm3 of anhydrous ethyl ether, 100 cm3 of n-butyllithium (1.6 M) are added at room temperature and under argon.After 24 hours, this solution is rapidly added to a suspension of 5 g of 1,8-dihydroxyanthraquinone in 150 cm2 of anhydrous THF at a temperature of -78 C. After the reaction is complete, the reaction medium is acidified with 50 cm3 of glacial acetic acid. After the organic phase is washed with water (200 cm3) and dried over magnesium sulphate, it is concentrated under reduced pressure and then purified by chromatography on silica gel.

200 mg of a yellow powder of 10-(2,4-dimethoxyphenyl)- 1,8,10-trihydroxyanthrone, of melting point 207"C, are thus obtained.

The H NMR spectrum at 250 MHZ is in accordance with the structure of the expected product.

Elementary analysis: C22 H16 OG Calculated: C 69.85 H 4.79 Found: 70.54 4.85 b) To a solution of 100 mg of 10-(2,4-dimethoxyphenyl)-1,8,10- trihydroxyanthrone, as obtained under (a) above, in 25 cm3 of glacial acetic acid, 200 mg of stannous chloride and a few drops of concentrated hydrochloric acid are added under an inert atmosphere. The reaction mixture is stirred for 5 hours at room temperature and then poured into 100 cm3 of water, which has the effect of precipitating the expected product, which is then filtered and then dried. 50 mg of a cream powder, the melting point of which is 152"C, are thus obtained.

Mass syectrum m/e: 362.

Example 3 Preparation of 1,8-dihydroxy-10-(4-methoxyphenyl)anthrone a) To a solution of 28 g of para-bromoanisole in 50 cm3 of anhydrous tetrahydrofuran, 100 cm3 of nbutyllithium (1.6 M) are added at -780C and under argon. The solution is left to return to room temperature for 1 hour. It is transferred to a dropping funnel and added to a suspension of 7.2 g of 1,8-dihydroxyanthraquinone in 300 cm3 of anhydrous THF at a temperature of -78 C and under argon. After the addition is complete, the reaction mixture is left to return to room temperature for 24 hours.

The reaction mixture is then acidified with 50 cm3 of glacial acetic acid and poured into 500 cm3 of water.

After extraction using dichloromethane, the organic phase is dried over magnesium sulphate and then concentrated under reduced pressure.

After chromatography on silica gel, 3.4 g of expected product are thus obtained. After recrystallisation in a toluene/hexane mixture, yellow crystals of 10-(4-methoxyphenyl)-1,8,10-trihydroxyanthrone, of melting point 172-173"C, are obtained.

The NMR spectrum is in accordance with the structure of the expected product.

Elementary analysis: C2, H,6 O5 Calculated: C 72.40 H 4.63 0 22.97 Found: 72.47 4.61 22.87 b) To a suspension of 200 mg of 10-(4-methoxyphenyl)-1,8,10- trihydroxyanthrone, as obtained under (a) above, in 10 cm3 of glacial acetic acid, 200 mg of stannous chloride and a few drops of concentrated hydrochloric acid are added. Stirring is continued under an inert atmosphere for 2 hours. The expected product is obtained by precipitation of the reaction medium in 100 cm3 of water. 150 mg of a greenishyellow powder which decomposes from 215"C are thus obtained.

The NMR spectrum and mass spectrum (m/e = 332) are in accordance with the structure of the expected product Elementary analysis: C2, H,6 O, Calculated: C 75.89 H 4.85 0 19.25 Found: 75.78 4.80 19.26 Example 4 Preparation of 1,8-dihydroxy-10-[3-{trifluoromethyl)-phenyllanthrone a) To a solution of 25 g of 3-trifluoromethyl-1-bromobenzene in 100 ml of anhydrous THF, 100 cm3 of n-butyllithium (1.6 M) are added at -78 C under argon.

After the addition is complete, the reaction medium is left to return to room temperature.

The solution obtained is then added dropwise and under an inert atmosphere to a suspension of 7.2 g over 1,8-dihydroxyanthraquinone in 200 cm3 of anhdyrous THF at -78 C.

The reaction mixture is maintained at this temperature for 1 h and then brought back to room temperature. The reaction solution is then acidified by adding 50 cm2 of glacial acetic acid. The reaction medium is washed with 200 cm2 of water, dried, concentrated and then purified on a column of silica gel. 1.2 g of expected product are isolated, and this is recrystallised in a toluene/hexane mixture. Yellow crystals of 10-[3-(trifluoromethyl)phenyl]-1,8,10-trihydroxyanthrone, of melting point 222-223"C, are obtained.

Elementary analysis: C21 H12 F2 04 Calculated: C 65.30 H 3.39 Found: 64.95 3.35 b) To a solution of 150 mg of 10-[3-(trifluoromethyl)phenyl]- 1,8,10-trihydroxyanthrone, as obtained under (a) above, in 25 cm2 of glacial acetic acid placed under nitrogen, 200 mg of stannous chloride and a few drops of concentrated hydrochloric acid are added. The reaction mixture is stirred for 3 hours at room temperature and the expected product is then precipitated by adding 100 cm3 of water. The product is filtered and then dried.50 mg of a yellow powder, the melting point of which is 210-211 C, is obtained.

Mass spectrum: m/e = 370 Example 5 Preparation of 1, 8-dihydroxy- lO-(3-methoxyphenyl)anthrone a)Organomagnesium method To 2.7 of magnesium in 40 cm3 of anhydrous THF, 20.8 g of m- bromoanisole are added under nitrogen and with the THF refluxing. Refluxing is maintained for 1 h after the addition is complete. The reaction mixture is then added dropwise to a suspension of 5 g of 1,8-dihydroxyanthraquinone in 60 cm2 of anhydrous THF under nitrogen at 0 C. The reaction mixture is left overnight at room temperature and then heated for 8 hours at 50"C.

The reaction mixture is acidified by adding 9 cm3 of glacial acetic acid, and 150 cm3 of water are then added. The product is extracted with ethyl ether (100 cm") and the organic phase is dried and then concentrated under vacuum. The reaction mixture is then purified by chromatography on silica gel, and 1.2 g of 1 O-(3-methoxyphenyl )-1,8,1 O-trihyd roxyanth rone is obtained.

Both the NMR spectrum and the mass spectrum (m/e = 348) are in accordance with the structure of the expected product.

a')Organolithium method To a solution of 28 g of m-bromoanisole in 50 cm3 of anhydrous THF, 100 cm3 of n-butyllithium (1.6 M) are added at -78 C and under argon. The reaction solution is then left to return to room temperature for 1 hour. The solution is then transferred to a dropping funnel and added to a suspension of 7.2 g of 1,8dihydroxyanthraquinone in 300 cm3 of anhydrous THF at -78 C and under argon. After the addition is complete, the reaction mixture is left to return to room temperature for 24 hours. It is then acidified with 50 cm3 of glacial acetic acid, and then washed with 500 cm3 of water. The organic phase is separated, then dried over magnesium sulphate and concentrated under reduced pressure.The expected product crystallises on adding toluene. 4.2 g of 10-(3-methoxyphenyl)-1,8,10-trihydroxyanthrone, of melting point 202"C, are thus isolated.

The NMR spectrum is in accordance with the structure of the expected product.

Elementary analysis: C2, H,6 O, Calculated: C 72.40 H 4.63 0 22.97 Found: 72.73 4.61 22.62 b) To a solution of 3 g of 10-(3-methoxyhenyl)-1, 8,10- trihydroxyanthrone, as obtained by one of the methods under (a) or (a') above, in approximately 100 cm3 of glacial acetic acid, placed under an inert atmosphere, 3 g of stannous chloride are added, followed by 3 cm3 of concentrated hydrochloric acid.

The reaction mixture is then stirred for two hours at room temperature, and the expected product is then precipitated by adding 500 cm3 of water. After being dried, 2.7 g of a yellow powder, the melting point of which is 187"C, are obtained.

The NMR spectrum is in accordance with the structure of the expected product.

Elementary analysis: C2, H,6 O4 Calculated: C 75.89 H 4.85 0 19.25 Found: 75.71 4.92 19.24 Example 6 Preparation of 1, 8-dih ydroxy- lO-(3-h ydroxyphen yl) anthrone 500 mg of 1,8-dihydroxy-10-(3-methoxyphenyl)anthrone, as obtained in Example 5, are added to a solution of 35 cm3 of acetic acid and 17 cm3 of hydrobromic acid under an inert atmosphere. The mixture is heated to 100- 110"C, and the progress of the reaction is followed by thin layer chromatography. After complete disappearance of the starting material, the solution is poured into approximately 200 cm3 of water and the precipitate is filtered. After being dried, the product is dissolved in 150 cm3 of dichloromethane and then agitated in the presence of 3 g of silica. The solution is filtered and then concentrated under reduced pressure. The expected product crystallises when hexane is added. 310 mg of yellow crystals of melting point 204"C are thus obtained.

The NMR spectrum is in accordance with the structure of the expected product.

Elementary analysis: C26 H,4 O4 Calculated: C 75.46 H 4.43 0 20.11 Found: 75.57 4.37 19.96 Example 7 Preparation of 1,8-dihydroxy- 10-f2-methoxyphenylJ an throne a) To 2.55 g of magnesium in 15 cm3 of anhydrous THF, 16.2 g of o-bromoanisole are added under nitrogen and with the THF refluxing. Refluxing is maintained for 1/2 hour after the addition is complete.

The solution obtained is then added dropwise to a suspension of 5 g of 1,8-di- hydroxyanthraquinone in 50 cm3 of anhydrous THF under nitrogen and at 0 C. The reaction mixture is left overnight at room temperature and then acidified with 9 cm2 of glacial acetic acid to which 150 cm3 of water are added.

The organic phase is decanted, washed twice with water (100 cm3) and then dried over magnesium sulphate. The solution is then concentrated under vacuum and then taken up with toluene. The solution is filtered and, by adding hexane, 5 g of a yellow precipitate are obtained and this is recrystallised in a toluene/hexane mixture. The pale yellow crystals of 10-(2-methoxyphenyl)-1,8,10-trihydroxyanthrone obtained have a melting point of 220- 2216C.

Elementary analysis: C2, H.6 O6 Calculated: C 72.40 H 4.63 0 22.97 Found: 72.59 4.65 23.21 b) To a solution of 2.8 g of 10-(2-methoxyphenyl)- 1,8,10-trihydroxyanthrone, as obtained under (a) above, in 90 cm2 of glacial acetic acid placed in an inert atmosphere, 4.9 g of stannous chloride are added, followed by 14.5 cm3 of concentrated hydrochloric acid. The reaction mixture is then agitated at room temperature for 3 h. The expected product is precipitated by pouring the reaction medium into 200 cm3 of water. 1 g is thus obtained of pure product after chromatography on silica gel. The yellow crystals obtained have a melting point of 191"C.

Both the NMR spectrum and the mass spectrum (m/e 332) are in accordance with the structure of the expected product.

Elementary analysis: C2, H,6 O4 Calculated: C 75.89 H 4.85 0 19.25 Found: 75.96 4.92 19.30 Example 8 Preparation of 1,8-dihydroxy- 10-62-thienyl)anthrone a) To a solution of 12.7 cm3 of thiophene in 100 cm3 of anhydrous ethyl ether, 100 cm3 of n-butyllithium (1.6 M) are added at 0 C under argon. After the addition, the solution is maintained at 0 C for 1 h and is then left to return to room temperature.

The solution is then added dropwise to a suspension of 9.2 g of 1,8-dihydroxyanthraquinone in 1000 cm3 of anhydrous THF at -78 C under argon. The reaction mixture is left to return to room temperature, and is then acidified with 50 cm3 of glacial acetic acid.

The solution is concentrated under reduced pressure, and then taken up in ethyl ether. The brown pre cipitaterformed is then filtered and then taken up in 100 cm3 of hot methanol. Yellow crystals of 10-(2thienyl)-1,8,10-trihydroxyanthrone, of melting point 191-192"C, are thus obtained.

Elementary analysis: C16 H.2 O1 S Calculated: C 66.65 H 3.73 S 9.89 Found: 66.20 3.66 9.10 b) To a solution of 5 g of 10-(2-thienyl)-1,8,10, trihydroxyanthrone, as obtained under (a) above, in 100 cm3 of acetic acid, 14.6 g of stannous chloride and 20 cm3 of concentrated hydrochloric acid are added under an inert atmosphere. The mixture is stirred at room temperature for 2 h and the solution is then poured into 200 cm3 of water. The product obtained is filtered and then dried. 4.55 g of 1,8-dihydroxy-10- (2-thienyl)anthrone, which after recrystallisation in toluene has a melting point of 181-182"C, are thus isolated.

The NMR spectrum and mass spectrum (m/e 308) correspond to the structure of the expected product.

Elementary analysis: C16 H12 O3 S Calculated: C 70.11 H 3.92 0 15.57 S 10.40 Found: 69.75 3.80 15.54 9.98 Example 9 Preparation of 1. 8-dihydroxy- 10-{2-thiazolyl)anthrone a) To a solution of 100 cm3 of n-butyllithium (1.5 M) in 100 cm3 of anhydrous ethyl ether, 24.6 g of 2bromothiazole are added dropwise at -40 C under an inert atmosphere. After the addition, the reaction mixture is brought to -78 C and 9.6 g of 1,8-dihydroxyanthraquinone dissolved in 1000 cm3 of THF are added. The reaction medium is then left for 48 h at room temperature. It is acidified with 50 cm3 of acetic acid and the solution is then poured into 1000 cm3 of water.

The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure.

The expected product is purified by chromatography on silica gel. 3.5 g of 10-(2-thiazolyl)-1,8,10-trihy- droxyanthrone, which take the form of a yellow solid which is recrystallised in a toluene/hexane mixture, are thus isolated. The crystals have a melting point of 223-225"C.

Both the NMR spectrum and the mass spectrum (m/e 325) are in accordance with the structure of the expected product.

Elementary analysis: C17 H,1 N 04 S Calculated: C 62.76 H 3.41 0 19.67 N 4.30 S 9.86 Found: 62.85 3.41 19.63 4.39 9.66 b) To a suspension of 2 g of 10-(2-thiazolyl)-1,8,10- trihydroxyanthrone, as obtained under (a) above, in 75 cm2 of acetic acid, 2 g of metallic tin and 25 cm2 of hydrochloric acid are added. The mixture is heated on a water bath for 1 h, the starting material going completely into solution. The mixture is poured into 200 cm3 of water and the product obtained is then filtered. 1 g of 1, 8-dihydroxy-10-(2-thiazolyl)anthrone, which is recrystallised in methanol, is thus obtained. The melting point of the recrystallised product is 142"C.

Elementary analysis: Cl7 H,1 N O3 S Calculated: C 66.00 H 3.58 N4.52 0 15.51 S 10.35 Found: 66.15 3.60 4.60 15.92 10.15 Example 10 Preparation of 10-r3-methoxyphenyl)- 1,8,9-triacetoxyanth- racene In a three-necked flask equipped with a magnetic stirrer and a nitrogen inlet, 200 mg of 10-(3-methoxy phenyl)-1,8-dihydroxyanthrone, obtained according to Example 5, are stirred in 5 cm2 of acetic anhydride and a few drops of pyridine. The mixture is stirred at 80"C for 3 h and then cooled. The expected triester crystallises, and is drained and then washed with hexane. 150 mg of pale yellow crystals of melting point 278"C are obtained.

Elementary analysis: C27 H22 7 Calculated: C 70.73 H 4.84 0 24.43 Found: 70.47 5.01 24.24 Example 11 Preparation of 10-{3-methoxyphenyl)- 1,8.9-trizpropanoyloxy) anthracene In a three-necked flask equipped with a magnetic stirrer, 250 mg of 10-(3-methoxyphenyl)-1,8-dihydroxyanthrone obtained according to Example 5, are stirred in 5 cm3 of propionic anhydride and a few drops of pyridine. The mixture is stirred at 80"C for 6 h under an inert atmosphere.

The solution is poured into 100 cm3 of water, extracted with ether and then washed with aqueous sodium bicarbonate solution. The product is then dried over magnesium sulphate and then concentrated under reduced pressure. 200 mg of the expected triester are isolated by adding hexane.

The yellow crystals obtained have a melting point of 177- 178do. The NMR spectrum and mass spectrum (m/e 500) correspond to the structure of the expected product.

Example 12 Preparation of 1 0-(2-thienyl)- 1,8,9-triacetoxy- anthracene In a three-necked flask equipped with a magnetic stirrer, 250 mg of 10-(2-thienyl)-1,8-dihyrnxyanthrnne, obtained according to Example 8, are stirred in 5 cm3 of acetic anhydride and a few drops of pyridine.

The mixture is stirred for 3 hours at 800C under an inert atmosphere, and then cooled. The expected triester crystallises and is then drained and washed with hexane. 300 mg of pale yellow crystals of melting point 2606C are thus obtained.

Elementary analysis: C24 Hl8 6 S Calculated: C 66.35 H 4.17 0 22.10 S 7.38 Found: 66.35 4.19 22.20 7.26 Example 13 Preparation of 10-(2-thien yl)- 1,8,9-tri(propano yloxy) anthracene In a three-necked flask equipped with a magnetic stirrer, 250 mg of 10-(2-thienyl)-1,8-dihydroxyanthrone, obtained according to Example 8, are stirred in 5 cm2 of propionic anhydride and a few drops of pyridine. The mixture is stirred at 80"C for 6 h under nitrogen. On being cooled, the expected product precipitates. 120 mg of yellow crystals are isolated. The filtrate is poured into 100 cm3 of water, extracted with ether and washed with aqueous sodium bicarbonate solution, and the ether phase is then dried and concentrated under reduced pressure.On adding hexane to the residue, a further 130 mg of the expected triester are obtained. The pale yellow crystals have a melting point of 192"C. The NMR spectrum and the mass spectrum (m/e : 476) correspond to the structure of the expected product.

Example 14 Preparation of 1. 8-dllpivaloyloxy)- 10-(2-thienyl)ant- hrone To a stirred solution of 2 g of 10-(2-thienyl)-1,8-dihydroxyanthrone in 150 cm3 of anhydrous toluene, at normal temperature and shielded from the light and from atmospheric humidity, five equivalents of pyridine are added, immediately followed by five molar equivalents of pivaloyl chloride. The reaction mixture is then brought to reflux for 8 hours, after which time all the starting material is converted.

The reaction mixture is then concentrated under reduced pressure, taken up in water and extracted with methylene chloride.

The methylene chloride phase is washed with water, decanted, dried over magnesium sulphate and concentrated.

The solid obtained is recrystallised in a hexane/ethyl acetate mixture. 1.5 g of yellow crystals melting at 1706 is obtained.

The NMR spectrum and mass spectrum (m/e : 476) correspond to the structure of the expected product.

Pharmaceutical and cosmetic compositions Example 1 Gelatin capsules containing 0.5 g of powder In gelatine capsules consisting of gelatine, titanium dioxide and a preservative, 0.5 g of the following powder is packaged: -1 ,8-dihydroxy-1 0-(2-methoxyphenyl)anthrone 0.3 g -Potato starch 0.1 g -Lactose q.s. 0.5 g Example 2 1-g tablets are prepared from the mixture of the following ingredients: -1 ,8-dihydroxy-1 0-(2-thienyl)anthrone 0.4 g -Polyvinylopyrrolidone 0.013 g -Crosslinked polyvinylpyrrolidone 0.05 g -Talc 0.08 g -"Aerosil 200" silica sold by DEGUSSA 0.001 g -Lactose q.s. 100 g In this example, the 1,8-dihydroxy-10-(2-thienyl)anthrone can be replaced by an equivalent amount of 1 ,8-dihydroxy- 1 0-(3-methoxyphenyl)anthrone.

Example 3 Composition in the form of a syrup At the time of use, 30 g of a powder having the following composition is mixed with stirring in 60 ml of mineral water: -1 ,8-dihydroxy-1 0-(3-hydroxyphenyl)anthrone 0.6 g -Sodium benzoate 0.15 g -Sodium chloride 0.23 g -Anhydrous sodium citrate 1.1 g -Ammonium glycyrrhizinate 0.06 g -Flavouring q.s.

-Colouring q.s.

-Sucrose q.s. 30 g Once it has been produced, the syrup should be stored cold, since its stability does not exceed 7 days Example 4 Hydrophobic anhydrous gel -1 ,8-dihydroxy-1 0-(3-hydroxyphenyl)anthrone 1g -"AEROSIL 200" silica sold by DEGUSSA 79 -Isopropyl myristate q.s. 100 g Example 5 Occlusive hydrophobic ointment -1 ,8-dihydroxy-10-(2-methoxyphenyl)anthrone 1.6 g -Ceresin 15 g -Liquid paraffin 35 g -Vaseline q.s. 100 g In this example, 1,8-dihydroxy-10-(2-methoxyphenyl) anthrone can be replaced by an equivalent amount of 1,8- dihydroxy-1 0-(3-methoxyphenyl)anthrone.

Example 6 Hydrophobic ointment in paste form -1 ,8-dihydroxy-1 0-(2-thienyl)anthrone 1.5 g -Isopropyl myristate 36.4 g -Silicone oil (dimethylpolysiloxane sold by RHONE POULENC under the name RHODORSIL 47 V 300) 36.4 g -Beeswax 13.6 g -Silicone oil sold by GOLDSCHMIDT under the name "ABIL 300,000 cst" q.s. 100 g Example 7 One-dose shampoo in two portions to be mixed extemporaneously 1) Treatment portion in suspension -1,8-dihydroxy-10-(3-methoxyphenyl)anthrone 0.5 g -Liquid paraffin q.s. 100 g 2) Washing portion -Dodecane diol polyglycerolated with 3.5 moles 20 g -Compound of the following formula 1.75 g

R = C14 H26, x + y = 3 and n~70 -Water q.s. 100 g After being vigorously agitated, the treatment portion is mixed in an applicator bottle with the washing portion in a ratio of 10:90. Once the mixture has been produced, it should be used immediately.

Example 8 Anti-acne composition in the form of a cream -Magnesium lanolate 3.4 g -Lanolin alcohol 2.8 g -Perhydrosqualene 20 9 -Isopropyl myristate 59 -Virgin sesame oil 109 -Liquid paraffin 8.8 g -Saiicylic acid 1g -1 0-(2-Thienyl)-1 ,8,9-tri(propanoyloxy)anthracene 1g -Methyl para-hydroxybenzoate 0.3 g -Water q.s. 100 g Example 9 Hair-care composition for hair loss and dandruff -1 0-(3-methoxyphenyl)-1 ,8,9-triacetoxy anthracene 0.5 g -Salicylic acid 0.1 g --Benzyl salicylate 100 g Example 10 Hair-care composition for hair loss and dandruff -1,8-di(pivaioyloxy)-10-(2-thienyl) anthrone 0.8 g -Stannous chloride 0.3 g -Isopropyl myristate q.s. 100 g Example 11 Anti-seborrhoeic lotions To a solution consisting of 10 cm3 of ethanol at 956 and 303 of polyethylene glycol (PEG) 400 containing 20 mg of butylated hydroxytoluene, 0.2 g of 1,8-di(pivaloyloxy)-10-(2-thienyl)anthrone is added.

After solubilisation with agitation, the lotion is applied to the whole head of hair.

This treatment should preferably be carried out twice daily.

Claims

1. 10-aryl-1,8-dihydroxyanthrones of formula (I):

in which: Ar is of formula:

in which: Rl. R2, R3, R4 and R5, which may be identical or different, are each hydrogen, halogen, -CF2, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, Cl-C3 hydroxyalkyl, Cl-C4 alkoxy, nitrile,

in which r' and r" which may be identical or different, are each hydrogen or Cl-C6 alkyl, n is O or an integer from 1 to 3, and R' and R' which may be the same or different are each hydrogen, substituted or unsubstituted Cl-Cs alkyl, substituted or unsubstituted aryl, at least one of R1 to R5 being other than hydrogen,

in which R6 has the same significance as R1 to R5, or (iv)

or a mon-, di-or triester thereof.

2. A compound according to claim 1, in which Ar is of formula:

in which: one of R1 and R6 is hydrogen and the other is Cl-C4 or alkoxy or -NH-CO-R' in which R' is a C1 to C6 alkyl, R2 is hydrogen or C1 to C4 alkoxy, and R2 and R4 are each hydrogen.

3. A compound according to claim 1, in which Ar is of formula:

in which: one of R2 and R4 is hydrogen and the other is -CF2, Cl-C4 alkoxy or C1 to C2 hydroxyl, and Rl, R3, and R6 are each hydrogen.

4. A compound according to claim 1, in which Ar is of formula:

in which: R2 is C1 to C4 alkoxy and Rl, R2, R4 and R6 are each hydrogen.

5. 1,8-Dihydroxy-10-2-[(2,2-dimethylpropanoyl)amino]-phenyl anthrone, 1 ,8-dihydroxy-1 0-(2,4-dime- thoxyphenyl)- anthrone, 1,8-dihydroxy-10-(2,4-methoxyphenyl)anothrone, 1,8-dihydroxy-10-[3-(trifluoromethyl)phenyl]anthrone, 1,8-dihydroxy-10-(3-methoxyphenyl)anthrone, 1,8-dihydroxy-10-(3-hydroxyphenyl )anth rone, 1,8-dihydroxy-10-(2-methoxyphenyl)anthrone, 1,8-dihydroxy-10-(2-thienyl)anthrone or 1,8-dihydroxy-10-(2-thiaxolyl)anthrone.

6. A compound according to claim 1, which is a mono-, di-or triester of a dihydroxyanthrone of formula (I) which is of formula (II):

in which: Ar is as defined in claim 1, p is 0 or 1, when p = O, R6 is hydrogen or -COR10 R9 d is -CO R, and p' is 1, when p = 1, R7 is: i) hydrogen, in which case R8 is hydrogen or -CO R10, R6 is -CO Rlo, and p' is 0, or ii) -CO Rlo, in which case R6 and R6 which may be the same or different are each -CO R10, and p' is O, in which R10 is cycloalkyl Cl-ClO alkyl, halogen nitro -CF3 hydroxyl Z-pyridyl, Z-thienyl, or phenyl optionally substituted with Cl-C6 alkyl or C1-C2 alkoxy, or a mixture of the said esters.

7. 10-(3-Methoxyphenyl)-1,8,9-triacetoxyanthracene, 10-(3-methoxyphenyl)-1,8,9-tri(propanoyloxy)-anthracene, 10-(2-thienyl)-1,8,9-triacetoxy-anthracene, 10-(2thienyl)- 1,8,9-tri(propanoyloxy)-anthracene, or 1 0-(2-thienyl)- 1,8-di(pivaloyloxy)-anthracene.

8. A compound according to any one of claims 1 to 7, substantially as described in any one of Examples 1 to 14.

9. A process for preparing a compound as claimed in any one of claims 1 to 8, which comprises: 1) reacting with 1,8-dihydroxyanthraquinone at least 4 molar equivalents of an aromatic lithium compound (Ar Li), in an anhydrous solvent medium and, after acidification, isolating the 10-aryl-1,8, 10-trihy droxyanthrone formed, 2) reducing the 1 O-aryl-1 ,8,1 O4rihydroxyanthrone, and isolating the 1 0-aryl-I 8-dihydroxyanthrone of formula (I), and optionally 3) esterifying the producer using a suitable acid anhydride or acid chloride.

10. A process according to claim 9 in which the 10- aryl-1,8,10-trihydroxyanthrone is reduced in acetic acid medium in the presence of stannous chloride or metallic tin and concentrated hydrochloric acid and the 10-aryl-1,8- dihydroxyanthrone is isolated by precipitation in water.

11. A process according to claim 9 or 10, in which stage 1) is carried out in ethyl ether ortetrahydro- furan, at a temperature of from -80 to 0 C, or a period of from 30 min to 2 hours.

12. A process according to any one of claims 9 to 11, in which stage 2) is carried out at room temperature for a period of from 0.5 to 5 hours.

13. A process according to any one of claims 9 to 12 substantially as described in any one of Examples 1 to 14.

14. A pharmaceutical or cosmetic composition, which comprises at least one compound as claimed in any one of claims 1 to 9, or produced by a process as claimed in any one of claims 9 to 12.

15. A composition according to claim 14, which contains said compound at a concentration at from 0.005 to 70% by weight relative to the total weight of the composition.

16. A pharmaceutically acceptable composition according to claim 14 or 15, for use in the treatment of cancerous tumours, psoriasis, warts, rheumatism, dermatoses, eczema, seborrhoeic or pellicular dermatitis, or sunburn..

17. A cosmetic composition according to claim 14 or 15, for use in the treatment of acne, dandruff, seborrhoea or hair loss.

18. A composition according to any one of claims 14 to 17 substantially as described in any one of composition Examples 1 to 11.