CH664557A5 - ARYL-10 DIHYDROXY-1,8 ANTHRONES AND THEIR ESTERS, THEIR PREPARATION PROCESS AND PHARMACEUTICAL OR COSMETIC COMPOSITIONS CONTAINING THEM AND THEIR USE IN COSMETICS. - Google Patents

Description

DESCRIPTION

The subject of the present invention is new derivatives of 1,8-dihydroxy anthrone-9 or anthralin, in particular derivatives of substitution in position 10 with an aromatic radical, the mono-, di- and triesters of these new derivatives, the process for the preparation of these compounds, pharmaceutical or cosmetic compositions containing them and their use in cosmetics. These new derivatives find in particular an application as antiproliferative agents in the treatment of cancerous tumors, psoriasis and warts and as anti-inflammatory agents in the treatment of rheumatism, dermatoses, eczema, seborrheic and dandruff dermatitis, and sunburn. In cosmetics, these compounds are anti-acne, anti-dandruff, antiseborrhoeic agents and against hair loss.

The aryl-10 dihydroxy-1,8 anthrones according to the invention can be represented by the following general formula:

0 OK

3H

in which:

Ar represents an aromatic residue corresponding to one of the following formulas:

(i)

I "2

io in which:

Rj, R2, R3, R4 and Rs, identical or different, represent a hydrogen atom, a halogen atom, the radical - CF3, a hydroxyl function, a lower alkyl radical, a lower cycloalkyl radical, a lower hydroxyalkyl radical , a lower alkoxy radical, a nitrile function, a radical

/

/ /

—S02 N '(CH2) n —CON', - (CH2) n — N ',

r "r" r "

20 o

-N-CO R ', - (CH2) „- CO, R' or - (CH2) n- ^

R "N

r 'and r ", identical or different, representing a hydrogen atom or a lower alkyl radical, n is 0 or an integer from 1 to 3 inclusive, and R' and R" representing a hydrogen atom, a linear, branched or lower alkyl radical or an optionally substituted aryl radical,

at least one of the radicals R! at R5 being different from a hydrogen atom,

(ii)

(in)

40 Re representing one of the meanings given for the radicals RjàR5, and s.

(iv)

NOT

45 and the mono-, di- and triesters of the compounds of formula (I).

When the radicals R 1 to R 5 represent a halogen atom, the latter is preferably a fluorine or chlorine atom.

By lower alkyl radical is meant according to the invention a radical having from 1 to 6 carbon atoms, preferably a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl or hexyl radical.

The term “lower alkoxy radical” should be understood to mean a radical having from 1 to 4 carbon atoms, in particular a methoxy, ethoxy, propoxy or isopropoxy radical.

55 The term “lower cycloalkyl radical” should be understood to mean a cy-clopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.

The term “lower hydroxyalkyl radical” should be understood to mean a radical having from 1 to 3 carbon atoms and in particular a hydroxy-methyl, 2-hydroxy-ethyl or 2,3-dihydroxy-propyl radical.

When in the compounds of formula (I) the radical Ar represents an aromatic residue of formula:

(I)

Ar

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the preferred compounds are those in which:

1) R! (or R5) represents a lower alkoxy radical or a radical of formula:

-N-CO-R '

I

R "

R 'representing an alkyl radical, linear or branched, having from 1 to 5 carbon atoms and R "representing a hydrogen atom, R3 representing a hydrogen atom or a lower alkoxy radical, and R2, R4 and Rs (or R!) Representing a hydrogen atom,

2) R2 (or R4) represents a radical - CF3, a lower alkoxy radical or a hydroxyl function, and Rj, R3, R4 (or R2) and R5 represent a hydrogen atom, and

3) R3 represents a lower alkoxy and Rj, R2, R4 and R5 represent a hydrogen atom.

According to a preferred embodiment, the radical R6 represents a hydrogen atom.

Among the compounds of formula (I), the following may be mentioned in particular:

Dihydroxy-1,8 [(N-2 ", 2" dimethylpropanoyl) amino-2 'phenyl] -10 anthrone

Dihydroxy-1,8 (dimethoxy-2 ', 4' phenyl) -10 anthrone Dihydroxy-1,8 (methoxy-4 'phenyl) -10 anthrone Dihydroxy-1,8 (trifluoromethyl-3' phenyl) -10 anthrone Dihydroxy- 1,8 (3 'methoxy phenyl) -10 anthrone Dihydroxy-1,8 (3-hydroxy phenyl) -10 anthrone Dihydroxy-1,8 (2-methoxy phenyl) -10 anthrone Dihydroxy-1,8 (thienyl -2) -10 anthrone Dihydroxy-1,8 (thiazolyl-2) -10 anthrone The mono-, di- and triesters of the compounds of formula (I) can be represented by the following general formula:

0R8 ï (Vp? R9

Ar

(H) p '

in which:

Ar has the same meaning as given above for the compounds of formula (I),

p is 0 or 1,

when p = 0, Rs represents a hydrogen atom or

- CO Rio and Rg represents —CO R10 etp 'is 1,

when p = 1, R, represents:

i) either a hydrogen atom, Rs representing a hydrogen atom or the radical —CO R10, Rg representing the radical

- CO R10 and p 'is 0,

ii) either the radical —CO R10, Rs and Rg representing the radical

- CO R10 and p 'is 0,

R10 representing a linear or branched alkyl radical having from 1 to 10 carbon atoms, a cycloalkyl radical, a 2-pyridyl radical, a 2-thienyl radical or a phenyl radical optionally substituted by a lower alkyl, a lower alkoxy, a halogen atom, a nitro function, a radical - CF3 or a hydroxyl function.

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

When the radical R10 represents a cycloalkyl radical, the latter is a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.

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

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

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

As follows from the general formula (II) above, the esters according to the invention can be in the form of mono- or di-5 esters of 10-acyl-1,8-dihydroxy-anthrone or their isomer, with namely the mono- or diesters of acyl-10 dihydroxy-1,8 anthranol-9, or also in the form of triesters of acyl-10 dihydroxy-1,8 anthranol-9.

Among the esters of formula (II), the following may be mentioned in particular:

io (3-methoxyphenyl) -10 triacetoxy-1,8,9 anthracene

(3-Methoxyphenyl) -10 tripropanoyloxy-1,8,9 anthracene (2-Thienyl) -10 triacetoxy-1,8,9 anthracene (2-Thienyl) -10 tripropanoyloxy-1,8,9 anthracene (Thienyl- 2) -10 dipivaloyloxy-1,8 anthrone The compounds of formula (I) according to the invention are obtained in two stages starting from dihydroxy-1,8 anthraquinone according to the following reaction scheme:

OH Q OH

The first step consists in reacting an aromatic carbanion on the 1,8-dihydroxy anthraquinone (2) which leads, after acidification, to the compound of formula (2).

The second step consists in reducing the intermediate compound (2) 40 in the presence of metallic tin or stannous chloride, which leads to the compound of formula (I) according to the invention.

Access to the aromatic carbanion can be envisaged either from an organolithian or from an organomagnesium.

Aromatic organoliths can be obtained by two 45 different methods:

The first method consists in reacting butyl lithium or its complex with tetramethylethylene diamine on an aromatic compound whose substituent (s) present activate the carbon on which it is desired to metallate the latter.

n / a The methods as 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.

The second method for accessing aromatic lithians consists in treating a halogenated aromatic derivative, in particular a brominated derivative, with butyl lithium 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, as in the preceding method, a halogenated aromatic derivative is used which is transformed according to conventional methods into magnesian in an anhydrous solvent such as tetrahydrofuran or ether.

The process consisting in reacting an aromatic lithien on 1,8-dihydroxy anthraquinone is particularly preferred because, unlike aromatic magnesian, this process leads to a selective addition on the carbonyl in position 10 of the anthraquinone nucleus, which n 'is not the case of aromatic magnesians since we observe in some cases an addition in position 9.

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It has also been found that by using a large excess of aromatic lithian of at least 4 molar equivalents relative to 1,8-dihydroxy anthraquinone, it was not necessary, as in the known methods, to have recourse protection of the hydroxyl functions in position 1 or 8 in order to obtain the aromatic derivatives, in position 10, of the anthrone nucleus.

The aromatic lithien addition reaction on 1,8-dihydroxy anthraquinone is generally carried out in an anhydrous solvent medium such as ethyl ether or tetrahydrofuran, at a temperature between - 80 ° and 0 ° C, by addition of lithien aromatic in ether or tetrahydrofuran to a solution in the same solvent of 1,8-dihydroxy anthraquinone.

After the addition, the reaction mixture is kept stirring at the same temperature for a time between 30 min and 2 hours. The end of the reaction is determined by the absence of 1,8-di-hydroxy anthraquinone by thin layer chromatography.

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

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

When the reaction is carried out from an aromatic magnesian, the reaction conditions are similar to those used from an aromatic lithian; however, after the end of the addition, the mixture is allowed to return to ambient temperature and the stirring is continued for several hours, optionally under reflux of the solvent, until disappearance by thin layer chromatography of 1,8-dihydroxy anthraquinone.

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

The reaction is generally carried out at room temperature for a time of between 1 and 5 hours, the end of the reaction being determined by the absence of the starting material by thin layer chromatography.

If the reaction is not complete, the reaction mixture can be brought to a water bath.

After returning to ambient temperature, the reaction mixture is poured into water, which causes the expected product to precipitate, which is then purified by recrystallization from an appropriate solvent.

The esters of formula (II) are obtained by reacting an appropriate acid anhydride on an aryl-10-dihydroxy-1,8 anthraquinone of formula (I) in the presence of a few drops of pyridine and optionally bringing the reaction mixture to a temperature between 50 and 130 ° C, or using an acid chloride, in the presence of pyridine, in stoichiometric amount in an aromatic solvent such as toluene.

The formation of the mono-, di- or triesters is a function of the molar proportions of the acid anhydride or of the acid chloride reacted and of the reaction time.

A subject of the invention is also pharmaceutical and cosmetic compositions, characterized in that they contain, as active ingredient, at least one compound of formula (I) or (II).

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

These compositions can also contain inert or pharmacodynamically active additives, for example binders, fillers, diluents, thickeners, preservatives, etc.

Orally administered compositions may also contain flavoring agents.

The compositions administered topically can be in the form of ointments, ointments, creams, gels, tinctures, solutions, lotions, sprays, suspensions, micronized powders or shampoos.

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

The compositions administered by the enteral or parenteral route can be in the form of tablets, granules, capsules, capsules, syrups, oral suspensions, ingestible powders in sachets, or alternatively in the form of solutions or injectable suspensions.

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

The tests carried out made it possible to show that the compounds according to the invention exhibited good activity when they were incorporated into different pharmaceutical or cosmetic vehicles.

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

Example 1

Preparation of dihydroxy-1,8 [(N-2 ", 2" dimethyl propanoyl) amino-2 'phenylj-10 anthrone

A) To 18 g of N-pivaloyl aniline in 100 cm 3 of anhydrous tetrahydrofuran (THF), 100 cm 3 of n-butyl lithium (2.5 M) are added at an inert atmosphere.

After addition, the reaction mixture is left for 24 hours at room temperature. A solution of 5 g of 1,8-dihydroxy-1,8 anthraquinone in 100 cm 3 of anhydrous tetrahydrofuran (THF) is then added dropwise 30 at 0 ° C. The mixture is stirred for 4 hours at room temperature, then the solution is acidified with 75 cm 3 of acetic acid. It is poured into 500 cm3 of water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, then concentrated under reduced pressure. The expected product is purified by chromatography on silica gel. This gives 1 g of yellow crystals of [(N-2 ", 2" dimethyl propanoyl) 2-amino-phenyl] -10 trihydroxy-1,8,10 anthrone with melting point 257-259 ° C.

The NMR spectrum conforms to the structure of the expected product.

Elementary analysis for C2.5H23O5N:

Calculated: C 71.92 H 5.55 0 19.16 N3.35% 45 Found: C 71.71 H 5.56 0 18.92 N3.43%

b) To a suspension of 250 mg of [(N-2 ", 2" dimethyl propanoyl) 2-amino-phenyl] -10 trihydroxy-1,8,10 anthrone, obtained above under a), in 25 cm3 d 'glacial acetic acid, 400 mg of stannous chloride and a few drops of concentrated hydrochloric acid are added under an inert atmosphere.

Stirred for 2 hours at room temperature, then the reaction mixture is poured into 100 cm3 of water. The expected product precipitates and is filtered, then dried. Then taken up using 55 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 addition of hexane, drained, then dried. 100 mg of yellow crystals with melting point 176-177 ° C. are thus obtained.

The NMR spectrum as well as the mass spectrum (m / e = 401) conform to the structure of the expected product.

Example 2

Preparation of dihydroxy-1,8 (dimethoxy-2 ', 4' phenyl) -10 anthrone

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a) To a solution of 22.1 g of 1,3-dimethoxy-benzene dissolved in 50 cm 3 of anhydrous ethyl ether, 100 cm 3 of n-butyl lithium (1.6 M) are added at room temperature and under argon. After

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24 h, this solution is rapidly added to a suspension of 5 g of 1,8-dihydroxy anthraquinone in 150 cm 3 of anhydrous THF at a temperature of -78 ° C. After the end of the reaction, the reaction medium is acidified with 1 using 50 cm3 of glacial acetic acid.

After washing with water (200 cm 3) and drying over magnesium sulphate, the organic phase is concentrated under reduced pressure, then purified by chromatography on silica gel. 200 mg of a yellow powder of (dimethoxy-2 ', 4' phenyl) -10 trihydroxy-1,8,10 anthrone with a melting point of 207 ° C. are thus obtained.

The 250 H NMR spectrum conforms to the structure of the expected product.

Elementary analysis for C22H1806:

Calculated: C 69.85 H 4.79%

Found: C 70.54 H 4.85%

b) To a solution of 100 mg of (dimethoxy-2 ', 4' phenyl) -10 trihydroxy-1,8,10 anthrone, 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, 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 are thus obtained, the melting point of which is 152 ° C.

Mass spectrum: m / e = 362.

Example 3

Preparation of dihydroxy-1,8 (4-methoxy-phenyl) -10 anthrone a) To a solution of 28 g of para-bromoanisole in 50 cm3 of anhydrous tetrahydrofuran, 100 is added, at -78 ° C. and under argon, 100 cm3 of n-butyl lithium (1.6M). The solution is left to return to ambient temperature for 1 h. It is transferred to a dropping funnel and it is added to a suspension of 7.2 g of dihydroxy-1,8 anthraquinone in 300 cm3 of anhydrous THF at a temperature of -78 ° C and under argon. After the end of the addition, the reaction mixture is allowed to return to ambient temperature for 24 h. The reaction mixture is then acidified with 50 cm3 of glacial acetic acid and poured into 500 cm3 of water.

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

3.4 g of expected product are thus obtained, after chromatography on silica gel. After recrystallization from a toluene-hexane mixture, yellow crystals of (methoxy-4 'phenyl) -10 trihydroxy-1,8,10 anthrone with melting point 172-173 ° C. are obtained.

The NMR spectrum conforms to the structure of the expected product.

Elementary analysis for C21H1605:

Calculated: C 72.40 H 4.63 0 22.97%

Found: C 72.47 H 4.61 0 22.87%

b) To a suspension of 200 mg of (4-methoxy-phenyl) -10 trihydroxy-1,8,10 anthrone, as obtained under a) above, in 10 cm 3 of glacial acetic acid, 200 is added. mg of stannous chloride and a few drops of concentrated hydrochloric acid. 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 greenish yellow powder are thus obtained which decomposes at 215 ° C.

The NMR spectrum and the mass spectrum (m / e = 332) conform to the structure of the expected product.

Elementary analysis for C2, H1604:

Calculated: C 75.89 H 4.85 0 19.25%

Found: C 75.78 H 4.80 0 19.26%

Example 4

Preparation of 1,8-dihydroxy (3'-trifluoromethyl-phenyl) -10 anthrone a) To a solution of 25 g of 3-trifluoromethyl-bromobenzene in 100 ml of anhydrous THF, 100 cm3 of n-butyl lithium are added, ( 1.6M) at - 78 ° C under argon.

After the end of the addition, the reaction medium is allowed to return to ambient temperature.

The solution obtained is then added, drop by drop under an inert atmosphere, to a suspension of 7.2 g of 1,8-dihydroxy anthraquinone in 200 cm3 of anhydrous THF at - 78 ° C.

The reaction mixture is kept at this temperature for 1 h and then brought back to room temperature. The reaction solution is then acidified by adding 50 cm3 of glacial acetic acid. The reaction medium is washed with 200 cm3 of water, dried, concentrated, then purified on a column of silica gel. 1.2 g of the expected product are isolated and recrystallized from a toluene-hexane mixture. Yellow crystals of (trifluoromethyl-3. Phenyl) -10 trihydroxy-1,8,10 anthrone with a melting point of 222-223 ° C. are obtained.

The 250 H NMR spectrum conforms to the structure of the expected product.

Elementary analysis for C21H13F304:

Calculated: C 65.30 H 3.39%

Found: C 64.95 H 3.35%

b) To a solution of 150 mg of (3-trifluoromethyl-phenyl) -10-trihydroxy-1,8,10 anthrone, as obtained under a) above, in 25 cm3 of glacial acetic acid placed under nitrogen, add 200 mg of stannous chloride and a few drops of concentrated hydrochloric acid. The reaction mixture is stirred for 3 hours at room temperature, then the expected product is precipitated by adding 100 cm3 of water. The product is filtered, then dried. 50 mg of a yellow powder are obtained, the melting point of which is 210-211 ° C.

Mass spectrum: m / e = 370.

Example 5

Preparation of dihydroxy-1,8 (3-methoxy-phenyl) -10 anthrone a) Organomagnesium method

To 2.7 g of magnesium in 40 cm 3 of anhydrous THF, 20.8 g of m-bromoanisole are added under nitrogen under reflux of THF. The reflux is maintained for 1 hour after the end of the addition. The reaction mixture is then added dropwise to a suspension of 5 g of dihydroxy-1,8 anthraquinone in 60 cm3 of anhydrous THF under nitrogen and at 0 ° C. The reaction mixture is left overnight at room temperature, then heated for 8 hours at 50 ° C.

The reaction mixture is acidified by adding 9 cm3 of glacial acetic acid, then 150 cm3 of water are added. The product is extracted with ethyl ether (100 cm3) and the organic phase is dried, then concentrated in vacuo. The reaction mixture is then purified by chromatography on silica gel and 1.2 g of (3-methoxy-phenyl) -10-trihydroxy-1,8,10 anthrone are obtained.

The NMR spectrum as well as the mass spectrum (m / e = 348) conform to the structure of the expected product.

a ') Organolithian method

To a solution of 28 g of m-bromoanisole in 50 cm3 of anhydrous THF, 100 cm3 of n-butyl lithium (1.6 M) are added at -78 ° C. and under argon. The reaction solution is then allowed to return to ambient temperature for 1 hour. The solution obtained is then transferred to a dropping funnel and added to a suspension of 7.2 g of dihydroxy-1,8 anthraquinone in 300 cm3 of anhydrous THF at - 78 ° C and under argon. After the addition is complete, the reaction mixture is allowed to return to room temperature for 24 hours. Then acidified with 50 cm3 of glacial acetic acid, then washed with 500 cm3 of water. The organic phase is separated, then dried over magnesium sulfate and concentrated under

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reduced pressure. The expected product crystallizes on addition of toluene. 4.2 g of (methoxy-3 'phenyl) -10 trihydroxy-1,8,10 anthrone, melting point 202 ° C., are thus isolated.

The NMR spectrum conforms to the structure of the expected product.

Elementary analysis for C2iH1 <; Os:

Calculated: C 72.40 H 4.63 0 22.97%

Found: C 72.73 H 4.61 0 22.62%

b) To a solution of 3 g of (3-methoxy-phenyl) -10-trihydroxy-1,8,10 anthrone as obtained according to one of the above methods under a) or a ') in approximately 100 cm3 glacial acetic acid, placed under an inert atmosphere, 3 g of stannous chloride are added, then 3 cm3 of concentrated hydrochloric acid. The reaction mixture is then stirred for 2 hours at room temperature, then the expected product is precipitated by adding 500 cm3 of water. After drying, 2.7 g of a yellow powder are obtained, the melting point of which is 187 ° C.

The NMR spectrum conforms to the structure of the expected product.

Elementary analysis for C21H1604:

Calculated: C 75.89 H 4.85 0 19.25%

Found: C 75.71 H 4.92 0 19.24%

Example 6

Preparation of 1,8-dihydroxy (3-hydroxyphenyl) -10 anthrone

500 mg of dihydroxy-1,8 (3-methoxy-phenyl) -10 anthrone, as obtained in Example 5, are added to a solution of 35 cm3 of acetic acid and 17 cm3 of hydrobromic acid under inert atmosphere. The mixture is heated to 100-110 ° C. and the course of the reaction is monitored by thin layer chromatography. After complete disappearance of the. starting material, the solution is poured into about 200 cm3 of water and the precipitate is filtered. After drying, the product is dissolved in 150 cm3 of dichloromethane, then stirred in the presence of 3 g of silica. The solution is filtered and then concentrated under reduced pressure. The expected product crystallizes on addition of hexane. 310 mg of yellow crystals with a melting point of 204 ° C. are thus obtained.

The NMR spectrum conforms to the structure of the expected product.

Elementary analysis for C20H14O4:

Calculated: C 75.46 H 4.43 0 20.11%

Found: C 75.57 H 4.37 0 19.96%

Example 7

Preparation of dihydroxy-1,8 (2-methoxy-phenyl) -10 anthrone a) To 2.55 g of magnesium in 15 cm3 of anhydrous THF, 16.2 g of o-bromoanisole is added under nitrogen at reflux of the THF. The reflux is maintained for 1/2 hour after the end of the addition. The solution obtained is then added dropwise to a suspension of 5 g of dihydroxy-1,8 anthraquinone in 50 cm3 of anhydrous THF under nitrogen and at 0 ° C. The reaction mixture is left overnight at room temperature, then acidified with 9 cm3 of glacial acetic acid to which 150 cm3 of water are added.

The organic phase is decanted, washed twice with water (100 cm3), then dried over magnesium sulfate. The solution is then concentrated in vacuo, then taken up with toluene. The solution is filtered and, by addition of hexane, 5 g of a yellow precipitate are obtained which is recrystallized from a toluene-hexane mixture. The light yellow crystals obtained from (methoxy-2 'phenyl) -10 trihydroxy-1,8,10 anthrone have a melting point of 220-221 ° C.

Elementary analysis for C21H1S05:

Calculated: C 72.40 H 4.63 O 22.97%

Found: C 72.59 H 4.65 0 23.21%

b) To a solution of 2.8 g of (2-methoxy-phenyl) -10-trihydroxy-1,8,10 anthrone, as obtained under a) above, in 90 cm3 of glacial acetic acid placed under inert atmosphere, 4.9 g of stannous chloride are added, then 14.5 cm3 of concentrated hydrochloric acid. The reaction mixture is then stirred at room temperature for 3 h. The expected product is precipitated by pouring the reaction medium into 200 cm3 of water. 1 g of pure product is thus obtained after chromatography on silica gel. The yellow crystals obtained have a melting point of 191 ° C.

The NMR spectrum as well as the mass spectrum (m / e = 332) conform to the structure of the expected product.

Elementary analysis for C21H1604:

Calculated: C 75.89 H 4.85 0 19.25%

Found: C 75.96 H 4.92 0 19.30%

Example 8

Preparation of dihydroxy-1,8 (2-thienyl) -10 anthrone a) To a solution of 12.7 cm3 of thiophene in 100 cm3 of anhydrous ethyl ether, 100 cm3 of n-butyl lithium (1, 6M) at 0 ° C under argon. After addition, the solution is kept at 0 ° C for 1 h, then allowed to return to room temperature.

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

The solution is concentrated under reduced pressure, then taken up in ethyl ether. The dark brown precipitate is then filtered, then taken up in 100 cm3 of hot methanol. This gives yellow crystals of (2-thienyl) -10-trihydroxy-1,8,10 anthrone with a melting point of 191-192 ° C.

Elementary analysis for C18H1204S:

Calculated: C 66.65 H 3.73 S 9.89%

Found: C 66.20 H 3.66 S 9.10%

b) To a solution of 5 g of (2-thienyl) -10 trihydroxy-1,8,10 anthrone, as obtained under a) above, in 100 cm3 of acetic acid, is added, under an inert atmosphere , 14.6 g of stannous chloride and 20 cm3 of concentrated hydrochloric acid. The mixture is stirred at ambient temperature for 2 h, then the solution is poured into 200 cm 3 of water. The product obtained is filtered and then dried. 4.55 g of dihydroxy-1,8 (2-thienyl) -10 anthrone are thus isolated, which after recrystallization from toluene has a melting point of 181-182 ° C.

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

Elementary analysis for Q 8H1203S:

Calculated: C 70.11 H 3.92 015.57 S 10.40%

Found: C 69.75 H 3.80 0 15.54 S 9.98%

Example 9

Preparation of 1,8-dihydroxy (2-thiazolyl) -10 anthrone a) To a solution of 100 cm3 of n-butyl lithium (1.5M) in 100 cm3 of anhydrous ethyl ether, the mixture is added dropwise at -40 ° C under an inert atmosphere, 24.6 g of 2-bromo thiazole. After addition, the reaction mixture is brought to -78 ° C and 9.6 g of dihydroxy-1,8 anthraquinone in solution in 1000 cm3 of THF are added. The reaction medium is then left for 48 h at room temperature. Acidified with 50 cm3 of acetic acid, then the solution is poured onto 1000 cm3 of water.

The organic phase is dried over magnesium sulphate, then concentrated under reduced pressure. The expected product is purified by chromatography on silica gel. Is thus isolated 3.5 g of (2-thiazolyl) -10 trihydroxy-1,8,10 anthrone in the form of a yellow solid which is recrystallized from a toluene-hexane mixture. The crystals have a melting point of 223-225 ° C.

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The NMR spectrum as well as the mass spectrum (m / e = 325) conform to the structure of the expected product.

Elementary analysis for C17HuN04S:

Calculated: C 62.76 H 3.41 O 19.67 N 4.30 S 9.86%

Found: C 62.85 H 3.41 0 19.63 N4.39 S 9.66%

b) To a suspension of 2 g of (thiazolyl-2) -10 trihydroxy-1,8,10 anthrone as obtained under a) above in 75 cm3 of acetic acid, 2 g of metallic tin are added and 25 cm3 of hydrochloric acid. The mixture is heated in a water bath for 1 hour, the starting material passing entirely into solution. Poured onto 200 cm3 of water and then filtered the product obtained. 1 g of dihydroxy-1,8 (thiazolyl-2) -10 anthrone is thus obtained which is recrystallized from methanol. The melting point of the recrystallized product is 142 ° C.

Elementary analysis for C17H11N03S:

Calculated: C 66.00 H 3.58 N 4.52 0 15.51 S 10.35%

Found: C 66.15 H 3.60 N 4.60 O 15.92 S 10.15%

Example 10

Preparation of (methoxy-3'phenyl) -10 triacetoxy-1,8,9 anthracene 200 mg of (methoxy-3 'phenyl) are stirred in a three-necked flask fitted with a magnetic stirrer and a nitrogen inlet. 10 dihydroxy-1,8 anthrone obtained according to Example 5 in 5 cm3 of acetic anhydride and a few drops of pyridine. The mixture is stirred at 80 ° C for 3 h, then cooled. The expected triester crystallizes and is drained, then washed with hexane. 150 mg of light yellow crystals with a melting point of 278 ° C. are obtained.

Elementary analysis for C27H2207:

Calculated: C 70.73 H 4.84 0 24.43%

Found: C 70.47 H 5.01 0 24.24%

Example 11

Preparation of (methoxy-3 'phenyl) -10 tripropanoyloxy-1,8,9 anthracene

In a three-necked flask fitted with a magnetic stirrer, 250 mg of (3-methoxy-phenyl) -10 dihydroxy-1,8 anthrone obtained according to Example 5 are stirred in 5 cm 3 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, then washed with an aqueous solution of sodium bicarbonate. It is then dried over magnesium sulfate, then concentrated under reduced pressure. 200 mg of the expected triester are isolated by addition of hexane.

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

Example 12

Preparation of (2-thienyl) -10 triacetoxy-1,8,9 anthracene

In a three-necked flask provided with magnetic stirring, 250 mg of (2-thienyl) -10-dihydroxy-1,8 anthrone obtained according to Example 8 are stirred in 5 cm 3 of acetic anhydride and a few drops of pyridine. The mixture is stirred for 3 hours at 80 ° C. under an inert atmosphere, then cooled. The expected triester crystallizes and is then drained and washed with hexane. 300 mg of light yellow crystals with a melting point of 260 ° C. are thus obtained.

Elementary analysis for C24H1806S:

Calculated: C 66.35 H 4.17 0 22.10 S 7.38%

Found: C 66.35 H 4.19 0 22.20 S 7.26%

Example 13

Preparation of (2-thienyl) -10 tripropanoyloxy-1,8,9 anthracene

In a three-necked flask fitted with a magnetic stirrer, 250 mg of (2-thienyl) -10 dihydroxy-1,8 anthrone obtained according to Example 8 are stirred in 5 cm 3 of propionic anhydride and a few drops of pyridine. The mixture is stirred at 80 ° C for 6 h under nitrogen. By cooling, the expected product precipitates. 120 mg of yellow crystals are isolated. The filtrate is poured into 100 cm3 of water, extracted with ether, washed with an aqueous solution of sodium bicarbonate, then the ethereal phase is dried and concentrated under reduced pressure. By adding hexane to the residue, an additional 130 mg of the expected triester is obtained. The light yellow crystals have a melting point of 192 ° C. The NMR spectrum and the mass spectrum io (m / e = 476) correspond to the structure of the expected product.

Example 14

Preparation of dipivaloyloxy-1,8 (thienyl-2 ') - 10 anthrone

In a solution stirred at room temperature, protected from light and air humidity, 2 g of (2'-thienyl-10 '-1,8-dihydroxy-anthrone in 150 cm3 of toluene anhydrous, five equivalents of pyridine are added and immediately after five molar equivalents of pivaloyl chloride. The reaction mixture is then brought to reflux for eight hours, after which time all of the starting material is transformed.

The reaction medium 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 sulfate and concentrated.

25,,

The solid obtained is recrystallized from a hexane-ethyl acetate mixture. 1.5 g of yellow crystals are obtained, melting at 170 ° C.

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

30

Pharmaceutical and cosmetic compositions Example 1

0.5 g powder capsules

0.5 g of the following powder are packaged in capsules consisting of gelatin, titanium dioxide and a preservative:

Dihydroxy-1,8 (2-methoxy-phenyl) -10 anthrone 0.3 g

Potato starch 0.1 g

Lactose q.s.p. 0.5 g

40 Example 2

1 g tablets are prepared from the mixture of the following ingredients:

Dihydroxy-1,8 (2-thienyl) -10 anthrone 0.4 g

45 Polyvinyl pyrrolidone 0.013 g

Crosslinked polyvinyl pyrrolidone 0.05 g

Talc 0.08 g

"Aerosil 200" silica sold by the company DEGUSSA 0.001 g

Lactose q.s.p. 100g

In this example, 1,8-dihydroxy (2-thienyl) -10 anthrone can be replaced by an equivalent amount of 1,8-dihydroxy (3-methoxy-phenyl) -10 anthrone.

Example 3

55 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:

Dihydroxy-1,8 (hydroxy-3 'phenyl) -10 anthrone 0.6 g

Sodium benzoate 0.15 g

0.23 g sodium chloride

Anhydrous sodium citrate 1.1 g

Ammonium glycyrrhizinate 0.06 g Flavor q.s.

Colorant q.s.

Sucrose q.s.p. 30g

Once obtained, the syrup must be kept cool, its stability not exceeding 7 days.

9

664,557

Example 4

Hydrophobic anhydrous gel

Dihydroxy-1,8 (hydroxy-3'phenyl) -10 anthrone 1g

"Aerosil 200" silica sold by the company DEGUSSA 7 g

Isopropyl myristate q.s.p. 100g

Example 6

Hydrophobic ointment in paste form

Dihydroxy-1,8 (2-thienyl) -10 anthrone

Isopropyl myristate

Silicone oil (dimethyl polysiloxane sold by the company RHÔNE-POULENC under the name Rhodorsil 47 V 300)

Beeswax

Silicone oil, sold by the company

GOLDSCHMIDT under the name of "Abil 300000 est" q.s.p.

R = C14 H29, x + y = 3etn =: 70

Water q.s.p. 100 d

The treating part, after having been vigorously agitated, is mixed in an applicator bottle with the washing part in a 10/90 ratio. Once the mixture is obtained, it must be used immediately.

Example 5

Hydrophobic occlusive ointment

Dihydroxy-1,8 (2-methoxy-phétiyl) -10 anthrone 1,6 g io Ceresin 15 g Vaseline oil 35 g

Vaseline q.s.p. 100g

In this example, 1,8-dihydroxy (2-methoxy-phenyl) -10 anthrone can be replaced with an equivalent amount of 1,8-dihy-droxy (3-methoxy-phenyl) -10 anthrone.

1.5 g 36.4 g

36.4 g 13.6 g

100g

Example 7 30

Two-part single-dose shampoo to be mixed immediately

1) Processing part in the form of a suspension

Dihydroxy-1,8 (3-methoxy-phenyl) -10 anthrone 0.5 g

Vaseline oil q.s.p. 100g 35

2) Washing part

Dodecanediol polyglycerolated 3.5 moles 20 g

Compound of the following formula: 1.75 g

Example 8

Anti-acne composition in the form of a cream Magnesium lanolate Lanolin alcohol Perhydrosqualene Isopropyl myristate Virgin sesame oil Vaseline oil Salicylic acid

(2-Thienyl) -10 tripropanoyloxy-1,8,9 anthracene Methyl parahydroxybenzoate Water q.s.p.

Example 9

Hair loss and dandruff composition

(3-methoxyphenyl) -10 triacetoxy-1,8,9 anthracene Salicylic acid Benzyl salicylate

Example 10

Hair loss and dandruff composition Dipivaloyloxy-1,8 (thienyl-2 ') - 10 anthrone

Stannous chloride Isopropyl myristate q.s.p.

3.4 g 2.8 g 20 g

5g

10 g 8.8 g

1 g 1 g 0.3 g 100 g

0.5 g 0.1g 100 g

0.8 g 0.3 g 100 g

HO - (CH - CH20) - (CH2 - CH2 - O) - (CH2 R

"ÇH) —H R

Example 11

Antiseborrheic lotion

To a solution consisting of 10 cm3 of 95 ° ethanol and 30 cm3 of polyethylene glycol (PEG) 400 containing 20 mg of butylhydroxy-toluene, 0.2 g of 1,8-dipivaloyloxy (2-thienyl) is added -10 anthrone.

After solubilization with stirring, the lotion is applied to the whole of the hair.

Preferably, this treatment should be carried out twice a day.

r

Claims (14)

664,557 1) reacting at least 4 molar equivalents of an aromatic lithian Ar Li on the 1,8-hydraxy anthraquinone, in an anhydrous solvent medium, and after acidification to isolate the aryl-10,10,10,10-trihydroxy , and 1 "2 20 in which: R2 or R4 represents a radical - CF3, a lower alkoxy radical or a hydroxyl function and R1; R3, R4 or R2 and R5 represent a hydrogen atom. 1. Aryl-10 dihydroxy-1,8 anthrones, characterized in that they correspond to the following general formula: (I) in which: Ar represents an aromatic residue corresponding to one of the following formulas: (i) in which: R ,, R2, R3, R4 and Rs, which are identical or different, represent a hydrogen atom, a halogen atom, the radical - CF3, a hydroxyl function, a lower alkyl radical, a lower cycloal-kyl radical, a lower hydroxyalkyl radical, a lower alkoxy radical, a nitrile function, a radical / / / -S02N ^ .- (CHA-CON ^, - (CH2) „- N ^, -N-CO R ', - (CH2) „- C02R'or - (CH,), h ^ R" O. NOT' (iii) R6 representing one of the meanings given for the radicals Rj to R5, and vs (iv) NOT and the mono-, di- and triesters of the compounds of formula (I). 2) to reduce the aryl-10 trihydroxy, l, 8,10 anthrone in acetic acid medium in the presence of stannous chloride or metallic tin and concentrated hydrochloric acid and to isolate aryl-10 dihydroxy-1,8 anthrone of formula (I) by precipitation in water. 2. Compounds according to claim 1, characterized in that the radical Ar represents the aromatic residue of the formula: in which: R! (or Rs) represents a lower alkoxy radical or a radical of formula: -N-CO-R ' I R " R 'representing an alkyl radical, linear or branched, having from 1 to 5 carbon atoms and R "representing a hydrogen atom, R3 representing a hydrogen atom or a lower alkoxy radical, and R2, R4 and R5 or Rj representing a hydrogen atom. 2 3 664,557 R10 representing an alkyl radical, linear or branched, having from 1 to 10 carbon atoms, a cycloalkyl radical, a pyridyl-2 radical, a 2-thienyl radical or a phenyl radical optionally substituted by a lower alkyl, a lower alkoxy, a halogen atom, a nitro function, a radical - CF3 or a hydroxyl function. 3. Compounds according to claim 1, characterized in that the radical Ar represents the aromatic residue of formula: 4. Compounds according to claim 1, characterized in that the radical Ar represents the aromatic residue of formula: r 'and r ", identical or different, representing a hydrogen atom or a lower alkyl radical, n is 0 or an integer from 1 to 3 inclusive, and R' and R" representing a hydrogen atom, a radical lower, linear or branched alkyl or an optionally substituted aryl radical, at least one of the radicals Rj to R5 being different from a hydrogen atom, (ii) in which: R3 represents a lower alkoxy radical and R1; R2, R4, R5 represent a hydrogen atom. 5. Compounds according to one of claims 1 to 4, characterized in that they are taken from the group consisting of: Dihydroxy-1,8 [(N-2 ", 2" dimethylpropanoyl) amino-2 'phenyl] -10 anthrone Dihydroxy-1,8 (dimethoxy-2 ', 4' phenyl) -10 anthrone Dihydroxy-1,8 (methoxy-4 'phenyl) -10 anthrone Dihydroxy-1,8 (trifluoromethyl-3' phenyl) -10 anthrone Dihydroxy- 1,8 (3 'methoxy phenyl) -10 anthrone Dihydroxy-1,8 (3-hydroxy phenyl) -10 anthrone Dihydroxy-1,8 (2-methoxy phenyl) -10 anthrone Dihydroxy-1,8 (thienyl -2) -10 anthrone Dihydroxy-1,8 (thiazolyl-2) -10 anthrone 6. Compounds according to claim 1, characterized in that the mono-, di- and triesters of the compounds of formula (I) correspond to the following general formula: 0 R, Wp? R9 (II) Ar (H) p ' in which: Ar has the same meaning as given in claim 1, 60 p is 0 or 1, when p = 0, Rs represents a hydrogen atom or - CO R10 and R9 represents —CO R10 and p 'is 1, when p = 1, R, represents: (i) either a hydrogen atom, Rs representing a hydrogen-65 atom or the radical —CO R10, R9 representing the radical —CO R, o and p 'is 0, (ii) either the radical —CO RI0, Rs and R9 representing the radical - CO Rjo and p 'is 0, 7. Compounds according to claim 6, characterized in that they are taken from the group consisting of: (3-methoxyphenyl) -10 triacetoxy-1,8,9 anthracene (3-methoxyphenyl) -10 tripropanoyloxy-1,8,9 anthracene (2-Thienyl) -10 triacetoxy-1,8,9 anthracene (2-Thienyl) -10 tripropanoyloxy-1,8,9 anthracene (2-Thienyl) -10 dipivaloyloxy-1,8 anthrone 8. Method for preparing the compounds of formula (I) according to one of claims 1 to 4, characterized in that it comprises the stages consisting: 9. Method according to claim 7, characterized in that the first step is carried out in ethyl ether or tetrahydrofuran, at a temperature between -80 ° and 0 ° C and for a time between 30 min and 2 hrs. 10. Method according to claim 7, characterized in that the second step is carried out at room temperature for a time between 0.5 and 5 h. 11. Pharmaceutical composition, characterized in that it contains, as active ingredient, at least one compound according to one of claims 1 to 7. 12. Cosmetic composition, characterized in that it contains, as active ingredient, at least one compound according to one of claims 1 to 7. 13. Composition according to claim 11 or 12, characterized in that it contains the active compound at a concentration of between 0.005 and 70% by weight relative to the total weight of the composition. 14. Use in cosmetics of a compound according to one of claims 1 to 7 or of a composition according to claim 12 in the treatment of acne, dandruff and hair loss.