LU86944A1 - COMPOSITION BASED ON HYDROXYPYRIDONE DERIVATIVES FOR REDUCING HAIR LOSS - Google Patents

Description

The:. R ~ zi 412 2. b535 '· V-. "*" Λ: # Ë ^ * r,! 4 v cX. * '- Grand Duchy of Luxembourg

Patent No. ..... L'J. ^ ......... * s du ... .1.7 .... 1987 ßgjöß Minister for the Economy and the Middle Classes

Title issued ........................................ Intellectual Property Service

© S / LUXEMBOURG

Manage the Patent Application ej. S?}? I. Request

The limited company known as: L'Oreal, 14 rue Royale, F-75008

Bet s -, ...... represented-by-Master- Âi'a'i'n '"RüKAV-ï'KÂ", - "" -' avOC'at .......... ..... ^ avoué .....- residan.t ... è - Lux © mt> ou-Fg ·, ...... l.0A -.--. b4 - d © --4-a »-XGipe-r ---- ag-issant ------------------------------... ......

in his capacity as agent ............................................. .................................................. .................................................. .. (2) deposit) this ......... seventeen. July 1900 eighty ..... seven .................. (3) to ...! 5.00 ...... hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent of invention concerning: ......... .................................................. .................................................. .................................................. .................................................. ....................................... (4) "..Comp.osi-tion . ... based ..... d © .... d4riväs ...- d: -, - bydro-xypyridone-ppur ................ ............................

decrease ..... hair loss ..... "................................. .................................................. .................................................. .....

2. the delegation of power, dated -Paris ....................................... .. on ..4..3. ,, 3.7 ..,. 4.934 .______ 3. the description in French κγ> __________________ of the invention in two copies; 4 .......... // ........... ... drawing boards, in two copies; 5. the receipt of taxes paid to the Luxembourg Registration Office, ... 7Z ..-. P7 .. · ..39.? ..?. _ ................................................. .................................................

declares (s) assuming responsibility for this declaration, that the inventor (s) is (are): ......................... ......-------------------------------------------- ---------------------------------------------------------- ---------------------------------------------------------- ---------------------------------------------..... ................................... (5)

Didier ...... SAINT ..... LIGHT .., ...... 5.5 ...... rjue ...... au .... Maire .., .... .E-.7.5.Q0.3 .... EARIS .................................... ..................

claims (s) for the suqdâe patent application the priority of one (s) request (s) of (6) ...................... / / . ................................ filed in (7) .......... .................................................. .................................................. ........

the ................................................. .................................................. .................................................. .................................................. ................................................ (8 ) on behalf of.............................................. .................................................. .................................................. .................................................. ..................... (9) elect (elect) for him / her and, if appointed, for his / her proxy, in Luxembourg_____________________ l.QA ... bd ..... de ..... la ... Eoir.e __________________________________________________________________________________________________________________________________________________________________________ (10) requests (s) the grant of a patent for the invention for the subject described and represented in the abovementioned appendices, - with postponement of this issue to eighteen t_______________ months. (11)

The mand afy # e h, 1 / UU Π. The above application for a patent for invention has been filed with the Ministry of the Economy and the Middle Classes, Intellectual Property Service in Luxembourg, on:

I 17.0 ^ 'jfèTiIX

/ fjOt% \ 4 \ Pr.lk Minister at _ 3 * hours I s -Φ the economy so sorry Average, ~ ....................... . U TWißj / \ Λ hUk UÄ-

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338/87 GD / DD / MG

LU 41Z

Public limited company called: L'OREAL

Composition based on hydroxypyridone derivatives to reduce hair loss.

Invention of Didier SAINT LEGER

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Composition based on hydroxypyridone derivatives to reduce hair loss.

The invention relates to compositions for reducing hair loss based on hydroxypyridone derivatives.

Those skilled in the art have known for a long time that natural hair loss in humans generally reflects the balance of the hair follicles between the alternative growth phases (anagen) and the fall phases (telogene). The average ratio of the number of follicles in the anagen phase to that in the telogene phase is of the order of 9 (90/10). The percentage of 15 follicles in the resting phase (catagen) appears to be very low.

Natural hair loss or loss can be estimated, on average, a few hundred hairs per day for a normal physiological state.

It is known, moreover, that certain factors such as hormonal imbalance, physiological stress, malnutrition, can accentuate the phenomenon.

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In certain dermatoses of the scalp with an inflammatory characteristic such as for example psoriasis or seborrheic dermatitis / hair loss can be strongly accentuated or cause cycles of the follicles highly disturbed.

Hydroxypyridone derivatives are known per se. Among the most representative compounds, mention may be made of ciclopirox or 6-cyclohexyl 1- hydroxy 4-methyl 2- (1H) -pyridone known as antifungal agent and octopirox or 1-hydroxy 4- methyl 6- ( 2,4,4-trimethylpentyl) -2- (1H) -pyridone known for its dandruff properties.

Surprisingly, the Applicant has discovered that the use of these derivatives makes it possible to reduce hair loss.

According to a particularly preferred embodiment, it has found that the combination with steroidal anti-inflammatory drugs or not such as in particular hydrocortisone, indomethacin, glycyrrhetinic acid, bisabolol, betamethasone, acetonide fluorinolone, dexxymetasone, further enhanced this effect.

The subject of the invention is therefore a new composition for reducing the drop based on hydroxypyridone derivatives.

Another object of the invention is constituted by their application to the treatment of hair and of the scalp.

Other objects of the invention will appear on reading the description and the examples which follow.

The composition according to the invention is essentially characterized by the fact that it contains, in a medium suitable for an application

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3 t topically, at least one compound corresponding to formula (I):

OH

J, 0 = Ç —Ri 5 (I) * 3 10 in which:

R1 denotes a hydrogen atom, an alkyl group, linear or branched, having from 1 to 17 carbon atoms, cycloalkyl having 5 to 8 carbon atoms, cycloalkyl-alkylene, the alkylene group having from 1 to 15 carbon atoms , aryl, aralkyl, the alkyl group having from 1 to 4 carbon atoms, aryl-alkenyl, the alkenyl group having from 2 to 4 carbon atoms, the cycloalkyl and aryl groups may be substituted by an alkyl group having 1 to 4 atoms Carbon or alkoxy having from 1 to 4 carbon atoms, · R2 denotes hydrogen, alkyl having from 1 to 4 carbon atoms, alkenyl having from 2 to 4 carbon atoms, a halogen atom or a benzyl radical; R3 denotes hydrogen, alkyl having from 1 to 4 carbon atoms or phenyl; and R4 denotes hydrogen, alkyl having from 1 to 4 carbon atoms, alkenyl having from 2 to 4 carbon atoms, methoxymethyl or a halogen atom or a benzyl radical, as well as their cosmetically or pharmaceutically acceptable salts.

Among these compounds, those which are particularly preferred consist of 1-hydroxy 4-methyl 6- (2,4,4-trimethylpentyl) 2- (1H) -pyridone and 6-cyclohexyl 1-hydroxy 4-methyl 2- ( 1H) -pyridone.

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Among the salts which can be used, there may be mentioned the salts of lower alkanolamines such as ethanolamine, diethanolamine, amine or ethylamine salts, quaternary ammonium salts as well as the salts with inorganic cations such as salts alkaline, ammonium, alkaline earth.

The compositions in accordance with the invention contain, according to a particularly preferred embodiment, in combination with the pyridones defined above, steroidal or non-steroidal anti-inflammatory agents such as more particularly Tiocortisone, 1 indomethacin, glycyrrhetinic acid, 1 '-bisabolol, betamethasone, fluorinolone acetonide, deoxymetasone, etc.

In another preferred embodiment of the invention, the composition additionally contains antibacterial agents chosen more particularly from antibiotics of the macrolide family and more particularly erythromycin and its derivatives, pyranosides such as lincomycin and its derivatives and clindamycin and its derivatives.

Among the erythromycin derivatives, mention may more particularly be made of erythromycin itself and its derivatives, such as estolate, ethylcarbonate, ethylsuccinate, glucoheptonate, lactobionate, propionyl laurylsulfate, propionate, stearate, linoleate, mono-enic esters such as erythromycin A mono-oleate. Among the clindamycin derivatives, there may be mentioned in addition to clindamycin itself, hydrochloride, palmitate, phosphate.

5 .-. 1 ”l

Among the lincomycin derivatives, mention may be made of the hydrochloride and lincomycin itself.

Other derivatives which can be used in accordance with the invention are the retinoates of these antibiotics and more particularly esters of all-trans and 13-cis retinoic acid of erythomycin A, of lincomycin and of clindamycin and their pharmaceutically acceptable salts such as more particularly described in French patent application No. 86.06528 of the applicant. The retinoic esters in the 2 ′ position of erythromycin are more particularly represented by the formula: 0 H3CV /vet\,.-- CH3

15 T

HV> 0H ^ / 0H ^ CH3 H3C "" "‘ CH3 R0V / NX-CH3 I. C „3 I P och3

ch. I

in which R represents the all-30 trans retinoyl radical or the 13-cis retinoyl radical, and R ′ denotes H. The retinoyl radical having the formula s \ (III)

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6 \ Γ ^ (E) (E) <E> (E)

The retinoic esters in position 3 of lincoraycine and clindamycin can be represented by the formulas: 15 f3 “3“ / \ f f "3 L / H \ f fs Çj3H7 h) sock \ Î3H7 U" f1

h> —r conh - "J Γ c ° ® —CH

10 Γ J η / ί-ν 'S

dTj / l jCj / \ H r SCH3 H> SCH3

i QH H ÔH

25 (IV) (V) in which R has the same meaning as that indicated above.

These different retinoic esters can be prepared according to different esterification processes and preferably in an anhydrous organic solvent medium, in particular in tetrahydrofuran alone or in a mixture

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7 ”with another organic solvent such as pyridine, by reacting an excess of mixed carbon dioxide of all-trans or 13-cis retinoic acids (prepared in situ, for example from ethyl chloroformate and acid all-trans or 13-cis) with erythromycin A, lincomycin or clindamycin as a base in the presence of an organic or inorganic base such as pyridine and / or sodium hydrogencarbonate.

Another method of esterification, in particular of lincomycin and of clindamycin, consists in using imidazolides of the retinoic acids in an anhydrous solvent such as Ν, Ν-dimethylformamide, in the presence of a base such as sodium or potassium tert-butoxide. According to this latter process, the ester in position 15 7 of lincomycin is obtained for the most part with esters in position 2, 3 and 4. A mixture of monoesters in positions 2, 3 and 4 of clindamycin is similarly obtained. .

Other erythromycin A derivatives are represented by the formula (II) described in particular in FR-A-2 582 000, in which: R or R ′ represents a linear acyl radical Ci8 bi or tri-enic of stereochemical configuration all -cis (Z) and R 'or R remaining represents a hydrogen atom.

According to a preferred embodiment, R or R ′ represents the following radicals: Z-9, Z-12-octadêcadiênoyl or linoleoyoy Z-9, Z-12, Z-15-octadécatriénoyl or 30 linolenoyl, and Z-6, Z -9, Z-12-octadêcatriénoyl ou ^ -linolénoyl.

Mention may in particular be made of O-linoleyl-2 'erythromycin A, 10-linoleyl-4 "erythromycin A and O-O ^ Linoleyl-4" erythromycin A.

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According to the invention, the pyridones are used in the compositions in accordance with the invention in proportions of between 0.01 and 5% by weight relative to the total weight of the composition. The anti-inflammatory agents are preferably used in proportions of between 0.01 and 5% by weight for hydrocortisone or indomethacin and 1'-bisabolol, in proportions of the order of 0.001 to 0.02 % by weight for the derivatives of betamethasone, fluorinolone 10 or dexsoxymethasone.

Antibacterial agents, in particular clindamycin, erythromycin, lincomycin or their derivatives, are preferably used in proportions of between 0.01 and 5% by weight and in particular between 0.01 and 3% by weight.

The compositions in accordance with the invention can be in various forms usually used in pharmacy or in cosmetics for the treatment of the scalp.

They can be more particularly in the form of lotions, shampoos, foams, creams, gels, sticks, spray, balms, powders, soap in the form of bread or in liquid form. When the composition is liquid it may comprise a medium containing water or a mixture of water and physiologically acceptable organic solvents. Among these solvents, mention may be made of lower alcohols such as ethanol, isopropyl alcohol, acetone, ethylene glycol, monomethyl, monoethyl or monobutyl ethers of ethylene glycol, propylene glycol, monoethyl ethers of propylene glycol and dipropylene glycol, C1-C4 alkyl esters of short chain acid and polytetrahydrofuran ethers.

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9

These compositions may contain thickening agents such as cellulose or cellulose derivatives as well as heterobiopolysaccharides such as xanthan gum, polyacrylic acids crosslinked with a polyfunctional agent such as the products sold under the name CARBOPOL.

These compositions may also contain other adjuvants usually used in cosmetics or in pharmacy, in particular in the scalp and more particularly surfactants, perfumes, preservatives, pH regulators, dyes, polymers cationic, anionic, nonionic or amphoteric.

An object of the invention is also constituted by the use of pyridone derivatives as defined above for the preparation of pharmaceutical compositions intended for the treatment of hair loss.

Finally, the subject of the invention is a method of cosmetic treatment of the hair consisting in applying to the hair at least one of the compositions as defined above, the composition having for this purpose an effect essentially on the appearance of the hair.

The following examples are intended to illustrate the invention without, however, being limiting in nature.

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k - 10 PREPARATION EXAMPLE 1

Preparation of O-retinoyl (13-cis) -2 'erythromycin A

5 In a flask, under an inert atmosphere, 5 g (16.6 mmol) of retinoic acid (13-cis) are dissolved in 35 ml of anhydrous tetrahydrofuran; the reaction mixture is cooled to 0 ° C, then 3 ml (38 mmol) of anhydrous pyridine and 1.6 ml (16.6 mmol) of ethyl chloroformate are poured in. The solution is stirred for 5 minutes and 2.5 g (30 mmol) of sodium hydrogencarbonate are added, then 4.9 g (6.7 mmol) of erythromycin A previously dissolved in 150 ml of tetrahydrofuran. The reaction mixture is then left under stirring for 10 hours while allowing to rise to room temperature (chromatography on a thin layer of silica gel: methylene chloride / methanol 10%). The solution is poured into 60 ml of water, then extracted with ethyl acetate. The organic phase 20 is dried over magnesium sulfate, filtered and then concentrated under partial vacuum. The crude product thus obtained is chromatographed on a column of silica gel (HPLC) using the eluent: ethyl acetate (7) / hexane (3) to result in the isolation of 4.4 g (65% of 25 yield) of pure 0-retinoyl (13-cis) -2'-erythromycin A. P = 82 ° C (hexane / ethyl acetate). 22 joCj = -17 ° (C = 6 mg / ml dichloromethane)

D

Microanalysis: C57H93NO14; M = 1016.4

C H N

Calculated%: 67.36 9.22 1.38

Found%: 67.48 9.32 1.38

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11 ". »Ft '

Infrared: band at 1735 cml (ester) 13c NMR (CDC13 / internal TMS dream)

Negative effects at 11 (—2.2 ppm) and 3 * (—2.1 ppm) indicate the position of the ester at 2 '. The 5 carbons C "2o (20.94 ppm), C14 (117.28 ppm) and C" i2 (131.9 ppm) of the retinoic chain are in agreement with the 13-cis stereochemistry of the retinoic chain.

PREPARATION EXAMPLE 2 10

Preparation of 0-retinoyl (all-trans) -2'-erythromycin A

In a flask, under an inert atmosphere, 5 g (16.6 mmol) of retinoic acid (all-trans) are dissolved in 35 ml of anhydrous tetrahydrofuran, the reaction mixture is cooled to 0 ° C. and then poured 3 ml ( 38 mmol) of anhydrous pyridine and 1.6 ml (16.6 mmol) of ethyl chloroformate; the solution is stirred for 5 minutes and 2.5 g (30 mmol) of sodium hydrogen carbonate are added, followed by 4.9 g (6.7 mmol) of erythromycin A previously dissolved in 150 ml of tetrahydrofuran. The reaction mixture is then left under stirring for 10 hours, allowing to rise to ambient temperature (chromatography on a thin layer of silica gel: methylene chloride / methanol 10%). The solution is poured into 60 ml of water and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then concentrated under partial vacuum. The crude product thus obtained is chromatographed on a silica gel column (HPLC) using the eluent: ethyl acetate (7) / hexane (3) to result in the isolation of 4.1 g (60% yield) of pure O-retinoyl (all-trans) -2'-erythromycin A.

22 * * 12 MJ = -65 ° (C = 2 mg / ml dichloromethane)

D

Microanalysis - C57H93NO14.4H20; M = 1088.5 5 C H N

Calculated%: 62.89 9.35 1.29

Found%: 62.91 8.90 1.29 13c NMR (CDCI3, internal ref. TMS) 10 Negative effects in 1 '(—2 ppm) and 3 * (-1.9 ppm) indicate the position of the 'ester in 2'. The carbons C ”20 (14.1 ppm), C14 (119.36 ppm) and C" i2 (135.19 ppm) are in agreement with the all-trans stereochemistry of the retinoic chain.

15 PREPARATION EXAMPLE 3

Preparation of 0-retinoyl (all-trans) -3-clindamycin In a flask, under an inert atmosphere, 5 g (16.6 mmol) of retinoic acid (all-trans) are dissolved in 30 ml of anhydrous tetrahydrofuran; the reaction mixture is cooled to 0 ° C and then 6 ml (76 mmol) of anhydrous pyridine and 1.6 ml (16.6 mmol) of ethyl chloroformate are poured; the solution is stirred for 5 minutes and 1.25 g (15 mmol) of sodium hydrogen carbonate are added, then 2.35 g (5.5 mmol) of clindamycin previously dissolved in 100 ml of a tetrahydrofuran mixture (8) / pyridine (2). The reaction mixture is then left under stirring for 10 hours while allowing to rise to room temperature (chromatography on a thin layer of silica gel s methylene chloride / methanol 5%). The solution is poured into 80 ml of water and then extracted with ethyl acetate. The organic phase is dried over ”sulfate. \% V '13 magnesium, filtered and then concentrated under partial vacuum. The crude product thus obtained is chromatographed on a column of silica gel (HPLC) using the eluent: ethyl acetate (5) / hexane (5) to result in the isolation of 2.15 g (55% of yield) of pure O-retinoyl (all-trans) -3-clindamycin.

F = 62 ° C

= + 50 ° (C = 100 mg / ml dichloromethane)

10 D

Microanalysis: C38H59N2SO6CI, 2.5H20; M = 752.5 C H N

Calculated%: 60.44 8.08 3.23

Found%: 60.66 8.57 3.72 15c NMR (CDClβ, internal ref. TMS): negative effects in position 4 (-2.8 ppm) and in position 2 (-1.9 ppm). The chemical shifts of C "] _ 4 (117.84 ppm) and C" 20 (14.11 ppm) confirm the all-trans stereochemistry of the retinoyl chain.

PREPARATION EXAMPLE 4

Preparation of 0-retinoyl (13-cis) -3-clindamycin 25

In a flask, under an inert atmosphere, 5 g (16.6 mmol) of retinoic acid (13-cis) are dissolved in 30 ml of anhydrous tetrahydrofuran; the reaction mixture is cooled to 0 ° C. and then 6 ml (76 30 mmol) of anhydrous pyridine and 1.6 ml (16.6 mmol) of ethyl chloroformate are poured; the solution is stirred for 5 minutes and 1.25 g (15 mmol) of sodium hydrogen carbonate are added followed by 2.35 g (5.5 mmol) of clindamycin previously dissolved in 100 ml of a tetrahydrofuran mixture (8 ) / pyridine (2). The mixture

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14 *. % k * reaction is then left under stirring for 10 hours, allowing to rise to room temperature (chromatography on a thin layer of silica gel; 5% methylene chloride / methanol). The solution is poured into 80 ml of water and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then concentrated under partial vacuum. The crude product thus obtained is chromatographed on a column of silica gel (HPLC) using the eluent: 10 ethyl acetate (5) / hexane (5) to result in the isolation of 2 g (51% yield) of pure O-retinoyl (13-cis) -3-clindamycin.

P = 95 “C (hexane / ethyl acetate) 15 & = + 111 ° (C = 15 mg / ml dichloromethane)

D

Microanalysis: C38H59CIN2SO6; M = 707.4 C H

Calculated% s 64.52 8.41 20 Found%: 64.47 8.45 NMR of (CDCI3, internal ref. TMS)

The position of the ester is indicated by the positive β effect in 3 (+1.77 ppm) and the negative effects in 2 (-1.4 ppm) and 4 (-2.5 ppm). The 13-cis configuration is confirmed by C'20 (20.93 ppm) and C'14 (115.94 ppm).

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t to · 15 PREPARATION EXAMPLE 5

Preparation of Q-retinoyl (13-cis) -3-lincomycin 5 In a flask / under an inert atmosphere / 5 g (16.6 mmol) of retinoic acid (13-cis) are dissolved in 30 ml of anhydrous tetrahydrofuran; the reaction mixture is cooled to 0 ° C and then 6 ml (76 mmol) of anhydrous pyridine and 1.6 ml (16.6 mmol) of ethyl chloroformate are poured; the solution is stirred for 5 minutes and 1.25 g (15 mmol) of sodium hydrogen carbonate are added, followed by 2.2 g (5.4 mmol) of lincomycin previously dissolved in 100 ml of a tetrahydrofuran mixture (7) / pyridine (3). The reaction mixture is then left under stirring for 10 hours, allowing to rise to room temperature (chromatography on a thin layer of silica gel: methylene chloride / methanol 10%). The solution is poured into 100 ml of water and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then concentrated under partial vacuum. The crude product thus obtained is chromatographed on a column of silica gel (HPLC) using the eluent: ethyl acetate (8) / hexane (2) to result in the isolation of 1.85 g (50% of yield) of pure 0-retinoyl (13-cis) -3-lincomycin.

F = 95 ° (hexane / ethyl acetate) r i20 [c / J = + 103 ° (C = 7 mg / ml dichloromethane)

30 D

Microanalysis: C3qH60n2so7'2'5H2 ° 'M - 734.5 C H

Calculated%: 62.18 9.03

Found%: 62.33 8.64

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Ht '16 13c NMR (CDC13, internal ref. TMS)

The position of the ester is indicated by the positive ß effect at 3 (+1.6 ppm) and the negative effects at position 2 (-2.4 ppm) and 4 (-1.9 ppm). The 13-cis configuration is confirmed by C'20 (20.98 ppm) and C'14 (115.83 ppm).

PREPARATION EXAMPLE 6 10 Preparation of the mixture of monoesters of 0-retinoyl (all-trans) -7-lincomycin, 0-retinoyl (all-trans) -3 lincomycin and 0-retinoyl (all-trans) -2 lincomycin

In a flask, under an inert atmosphere, 30 g (74 mmol) of lincomycin are dissolved in 300 ml of anhydrous Ν, Ν-dimethylformamide and then 830 mg (7.4 mmol) of potassium tert-butylate are added and the mixture is continued. agitation at room temperature for 90 minutes. A solution of 13 g (37 mmol) of retinoyl (all-trans) -l imidazole is then poured into 150 ml of Ν, Ν-dimethylformamide and the resulting medium is stirred at room temperature for 12 hours (thin layer chromatography of silica gel: methylene chloride / methanol 7.5%). The solution is poured into 500 25 ml of water and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then concentrated under partial vacuum. The crude product thus obtained is chromatographed on a column of silica gel (HPLC) using the eluent: ethyl acetate (7) / hexane (3) to result in the isolation of 39 g (77%) of a mixture of retinoic monoesters (all-trans) of lincomycin in positions 2, 3 and 7.

17 t 1 - * fc '13c NMR (CDCI3, internal TMS ref) - Negative effects in 8 (-2.5 ppra) and in 6 (-3.8 ppm) indicate the place of esterification of a monoester in position 7, 5 - Negative Y effect in position 1 (-4 ppm) indicates the monoester in position 2 and the negative Y 'effects in 2 (-2 ppm) and 4 (-2.6 ppm) indicate the position of the monoester in position 3. The positions of are at 85.06 ppm for the monoester in 2, at 88.45 ppm for the monoester in 7 and at 89.67 ppm for the monoester in position 3.

The configuration of the all-trans retinoic chain is indicated for C'14 at 117.78 ppm and for C "20 at 14.08 ppm; there is a trace of isomerization 15 by the presence of a peak at 115 , 2 ppm (C'14) indicating the 13-cis isomer.

PREPARATION EXAMPLE 7 Preparation of the mixture of the monoesters of 0-retinoyl (all-trans) -2 clindamycin, 0-retinoyl (all-trans) -3 clindamycin and 0-retinoyl (all-trans) -4 clindamycin

In a flask, under an inert atmosphere, 20 g (47 mmol) of clindamycin are dissolved in 250 ml of anhydrous Ν, Ν-dimethylformamide and then 527 mg (4.7 mmol) of potassium tert-butoxide are added to the reaction medium which is then stirred at room temperature for 90 minutes. A solution of 8.250 30 g (23.5 mmol) of retinoyl (all-trans) -1 imidazole is then poured into 150 ml of anhydrous Ν, Ν-dimethylformamide and the resulting medium is stirred at room temperature for 12 hours (chromatography on thin layer of silica gel: 5% methylene chloride / methanol). The fc * solution. · N '18 is then poured into 500 ml of water and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then concentrated under partial vacuum. The crude product thus obtained is chromatographed on a column of silica gel (HPLC) using the eluent: ethyl acetate (5) / hexane (5) to result in the isolation of 28 g (85%) of a mixture of retinoic monoesters (all-trans) of clindamycin in positions 2, 3 and 4.

10 NMR of (CDC13, internal ref. TMS) - Negative effect in position 1 (-3 ppm) indicates the position of the ester in 2, - Negative effects in position 4 (-2.8 ppm) and 2 (- 1.9 ppm) indicates the monoester in position 3 and weak negative effect in position 3 indicates the monoester in position 4.

The positions of Ci are at 84.63 ppm for the monoester in 2, at 88.79 ppm for the monoester in 3 and at 87.98 ppm for the monoester in 4.

20 The all-trans configuration of the retinoic chain is predominant (C "i4 at 117.5 ppm and C''20 at 14.08 ppm) but traces of isomerization are clear, in particular in C'20 and in C” i4 · »'EXAMPLE 1 19% \ β ANTI-FALL SHAMPOO (for frequent use) 5 - Sodium lauryl ether sulfate 7 g - Hydroxyethyl cellulose 2 g - Clindamycin 0.4 g - Octopirox 0.5 g - © (-bisatoolol 0.75 g 10 - Butylhydroxy toluene (BHT) 0.3 g - Perfume 0.05 g - Triethanolamine qs pH = 6.5 - H2O qs 100 g 15 EXAMPLE 2

ΑΝΤΙ-FALL TREATMENT SHAMPOO

20 - Nonionic surfactant ototenu by condensation of 3.5 moles of glycidol on uno-diol in C; qC] _4 according to FR 2 091 516 12.5 g - Linoleic ester of erythromycin 1 g - Octopirox 0.5 g 25 - Hydrocortisone 0.5 g - BHT 0.2 g - H2O qs 100 g ♦ 'EXAMPLE 3 20 ANTI-FALL LOTION (product not rinsed) 5 - Clindamycin 0.5 g - Ciclopirox 0, 5 g - Hydrocortisone 0, 2 g - Perfume 0.05g - Water / ethanol (70/30 V / V) qs 100 g 10 EXAMPLE 4

ΑΝΤΙ-FALLING FOAMING GEL

15 - Lauryl ether triethanolamine sulfate 8 g - Carbopol 2 g - Sodium chloride 2 g - Glycerol 3 g - Glycyrrhetinic acid 1.5 g 20 - Octopirox 0.8 g - Trans retinoic garlic ester of erythromycin 0.05g - BHT 0.3 g - H2O qs 100 g 25 EXAMPLE 5 ♦ · 21

ANTI-FALL HAIR SPRAY

5 - Ethanol 30 g - Xanthan gum sold under the name Keltrol by the company KELCO 2 g - Octopirox 0.5 g 10 - Linolenic ester of erythromycin 1 g - BHT O, 2 g - Perfume 0.05g - H2O qs 100 g 15 This composition is conditioned in a conventional aerosol device and the presence of 6 g of a propellant consisting of a mixture of FREON 12 and 114 (40/60).

Claims (16)

1. Composition intended to be used for the treatment of hair, in particular for reducing hair loss, characterized in that it contains, in a medium suitable for topical application, at least one compound corresponding to the formula: OH i 10 0 = Ç ^ -Ri (I) * 3 in which: R1 denotes a hydrogen atom, an alkyl group, linear or branched, having 1 to 17 carbon atoms, cycloalkyl having 5 to 8 carbon atoms, cycloalkyl-alkylene , in which the alkylene group has 1 to 4 carbon atoms, aryl, aralkyl, in which the alkyl group has 1 to 4 carbon atoms, arylalkenyl, in which the alkenyl group has 2 to 4 carbon atoms, the aryl groups may be substituted by an alkyl group having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms; R2 denotes hydrogen, alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, a halogen atom or a benzyl radical; R3 denotes hydrogen, alkyl having 1 to 4 carbon atoms or phenyl; and R4 denotes hydrogen, alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, methyloxymethyl or a halogen atom or a K 23 benzyl radical / as well as the cosmetically or pharmaceutically acceptable salts of these compounds. 2. Composition according to claim 1, characterized in that it contains 1-hydroxy 5 4-methyl 6- (2,4,4-trimethylpentyl) 2- (1H) -pyridone and 6-cyclohexyl 1-hydroxy 4-methyl 2- (1H) -pyridone. 3. Composition according to claim 1 or 2, characterized in that it also contains steroidal anti-inflammatory agents or not. 4. Composition according to claim 3, characterized in that the anti-inflammatory agents are chosen from hydrocortisone, indomethacin, glycyrrhetinic acid, © C-bisabolol, betamethasone, acetonide of fluorinolone, dessoxymetasone. 5. Composition according to any one of claims 1 to 4, characterized in that it also contains antibacterial agents chosen from macrolides and pyranosides. 6. Composition according to claim 5, characterized in that the macrolides are chosen from erythromycin or its derivatives and that the pyranosides are chosen from lincomycin and clindamycin and their derivatives. 7. Composition according to any one of claims 5 and 6, characterized in that the erythromycin derivatives are chosen from estolate, ethylcarbonate, ethylsuccinate, glucoheptonate, lactobionate, priopionyl laurylsulfate, 30 propionate, stearate, linoleate, mono-enic, bi- or tri-enic esters of erythromycin, that the clindamycin derivatives are chosen from hydrochloride, palmitate, phosphate, and that the lincomycin derivative is a hydrochloride. · '* 14 ”24 ♦ - 8. Composition according to any one of claims 5 to 7, characterized in that the derivatives of erythromycin, of lincomycin and of clindamycin are chosen from esters of retinoic acid, trans garlic and 13-cis of erythromycin A , lincomycin and clindamycin as well as their pharmaceutically or cosmetically acceptable salts. 9. Composition according to any one of claims 1 to 8, characterized in that the 10 pyridone derivatives are present in proportions of between 0.01 and 5% by weight relative to the total weight of the composition. 10. Composition according to any one of claims 5 to 9, characterized in that the antibacterial agents are present in proportions of between 0.01 and 5% by weight and in particular between 0.01 and 3% by weight . 11. Composition according to any one of claims 3, 4 or 9, characterized in that the anti-inflammatory agents are present in proportions of between 0.01 and 5% by weight for hydrocortisone, indomethacin and 1'-bisabolol, in proportions of the order of 0.001 and 0.02% by weight for the derivatives of betamethasone, fluorinolone or dexsoxymethasone. 12. Composition according to any one of claims 1 to 11, characterized in that it is in the form of lotions, shampoos, mousses, creams, gels, sticks, spray, 30 balms. 13. Composition according to any one of claims 1 to 12, characterized in that the medium suitable for topical application consists of water or a mixture · of water and »25. '♦ · physiologically acceptable solvents. 14. Composition according to any one of claims 1 to 13, characterized in that the compositions also contain thickening agents, surface-active agents, preserving agents, pH regulators, dyes, cationic polymers, anionic, nonionic, amphoteric, perfumes and any other adjuvant used in topical application. 15. Cosmetic hair treatment method, characterized in that at least one composition as defined in any one of claims 1 to 14 is applied to this hair. 16. Use of the composition as defined in any one of claims 1 to 14, for the preparation of a composition intended for the pharmaceutical treatment of hair loss. Drawings: ...... pages pages of which ......... PaSe of 93rcJe ....... pages of description ....... ÿ ....... pages of claim ....... ^ ...... descriptive abbreviation Luxembourg, le \\\ ^ \\ "\. Le mandi. -ire: Ivîe Alain Rukov'ng