LU86945A1 - PHARMACEUTICAL AND COSMETIC COMPOSITIONS BASED ON PYRIDONES AND ANTIBACTERIAL AGENTS - Google Patents

Description

1'OPEAL 413 2.5536 '7 £ Q TC ^ GRAND-DUCHY OF LUXEMBOURG * Patent N "..... ML .M .....' * ?. ... SJ S 'du ...... ... 17.07.1987 ............... 0¾¾¾¾ Mister the Minister of the Economy and the Middle Classes

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

, ’LUXEMBOURG

. Cÿ.SXsC * ^ Invention Patent Application.

L Request

The limited company known as L'OREAL S.A., 14 rue Royale, F-75008

Paris ......, · ..... represented ·?: ..... by -'Maîtr'e -'- Aialn ·· RüKAVlNAr-ax / o-cat ..... declared ... ............

residing · ..... at - Luxembeurgy - l-OA - fed ..... de ..... la-Foire- ·, · ..... ag-i-ssant ... ..in ............................................- sa. ... q.uali..té ..... dLe .... manda.tair.e .......................... .................................................. .................................................. .......................................... (2) remove (s) this ..... ninety-seven ...... july ..... 1.9QQ ..... eighty ..... seven ............ ............. (3) at 15 r .QQ ......... hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent for an invention concerning: .................................... .................................................. .................................................. ..: ............................................... ........-................-........................ ................................ (4) 11 Pharmaceutical and cosmetic compositions based ...... ......................

pyridones and antibacterial agents, "2. the delegation of authority, dated ................................ .......... the? - _____________________ 3. the description in French ........................... of] / inVention in two copies; 4. ....._ // .............. drawing boards, in two copies; 5. the receipt of the fees paid to the Office of the Registration in Luxembourg, on .......... 17.,. 07.,. 1.98.7 ........................ .................................................. .................................................. .................................................. ...................................

declares (s) assuming responsibility for this declaration, that the inventor (s) is (are): ..... F-75'00'3 "" "PARÏS (5) claims (s) for the above patent application the priority of one (or more) application (s) of (6) ___________________________ LL ________________________________________________________ filed in (7) -------------------- ---------------------------------------------------------- -------------------------------------------- _________________________________________________________________________________________________________________________________________________________________________________ (8) in the name of................................................. .................................................. .................................................. .................................................. —.............. (9) 10A bd (elle) and, if appointed, for its representative, in Luxembourg ---------------- ----------------- ________________________________________________________ _______________________________________________________________________________________________________________________________________________________________________________ (10) request) the grant of a patent for the invention for the subject described and represented in the abovementioned appendices, - with postponement of this grant to —--------------- --month. (11)

The representative ........ ”a Λ Aj T Π. P: verbal notice of filing / The aforementioned / patent application for invention has been filed with the Ministry of the Economy and the Middle Classes, Intellectual Property Service in Luxembourg, dated: / 07.17.1987 "'Æ ...... - Pr. E Minister ^ \ of Economy & Middle Classes,

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339/87 GD / DD

LU 413

Public limited company called: L'OREAL

Pharmaceutical and cosmetic compositions containing pyridones and antibacterial agents.

Invention of Didier SAINT-LEGER

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t * 4 *

Pharmaceutical and cosmetic compositions based on pyridones and antibacterial agents.

The present invention relates to new compositions based on pyridone derivatives and antibacterial agents from the family of macrolides and pyranosides, intended for use in the treatment of dermatoses such as acne and in the cosmetic treatment of skin.

The ethiopathology of acne, although poorly defined, originates in the formation of a characteristic lesion: the comedo. This results from obstruction of the pilosebaceous canal as a result of dyskeratinization of the infundibulum area of the canal.

This obstruction has the major effect of modifying the rheology of sebum and the physicochemical characteristics of the environment. This modification leads to the hyperproliferation of the resident cutaneous strains which trigger an inflammatory type reaction of the organism.

* 2 î * *

There are generally two types of lesions.

The first type corresponds to the so-called open comedo or black spot of banal clinical characteristic and whose evolution remains limited. These can easily be eliminated, either by extrusion, or by physical or chemical treatment by the use of so-called keratolytic topical agents well known in themselves.

The second type corresponds, at the origin, to the evolution of so-called closed comedones or microcysts, the final stage of which is the rupture of the pilosebaceous follicle which formed it and which releases in the dermis many inflammatory products causing the reaction of the host organism.

The lesions that characterize inflammatory acne are therefore intermediate stages of microcysts and are grouped under generic names of papules, pustules, nodules or cysts, nodulocystic acne representing the most severe form of acne.

At the present time, the products generating inflammation or the mechanisms by which they generate inflammation, remain poorly defined although numerous clinical experiments suggest that the bacterial flora of which Propionibacterium Acnes is the major representative, is greatly involved.

It is known that the topical or systemic use of antibiotic compounds such as erythromycin, clindamycin, lincomycin or their derivatives, in acne therapy, has the immediate consequence of a very obvious anti-inflammatory effect.

It is believed, moreover, that certain skin yeasts, in particular the yeast Pityrosporum ovale or I "3" •

Pityrosporum orbiculare, are present in inflammatory acne lesions and oval Pityrosporum has been shown to be one of the primary causes of some of the inflammatory skin conditions such as dandruff (Pytiriasis capitis) and seborrheic dermatitis.

When the comedo breaks, the yeast Pityrosporum ovale or its transient forms are released and also generate inflammation.

The Applicant has discovered, which is the subject of the invention, that by combining pyridone derivatives and antibacterial agents chosen from macrolide antibiotics and pyranosides, it was surprisingly possible to improve the treatment of 'acne.

The Applicant has discovered that the combination of antifungals, of the pyridone derivative type, and of the abovementioned antibacterials, combats inflammation due to acne much more quickly and more effectively than an antifungal alone or than an antibacterial alone.

The subject of the invention is therefore a pharmaceutical composition intended for the treatment of acne combining a pyridone derivative with certain antibacterial agents.

Another object of the invention consists of the use, for the preparation of an acne treatment composition, of the composition defined above.

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

4 d * * *

The composition intended for topical application for the treatment of acne is essentially characterized in that it contains in a physiologically acceptable medium at least one pyridone derivative corresponding to the formula; 7 <>

Jl (I) * 3 in which:

Rl denotes a hydrogen atom, an alkyl group, linear or branched, having from 1 to 17 carbon atoms, cycloalkyl having from 5 to 8 carbon atoms, cycloalkyl-alkylene, the alkylene group having from 1 to 4 carbon atoms , aryl, aralkyl, the alkyl group having from 1 to 4 carbon atoms, arylalkenyl, the alkenyl group having from 2 to 4 carbon atoms, the aryl and cycloalkyl groups may be substituted by an alkyl group having from 1 to 4 carbon 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, and at least one anti »5 i *

Bacterial ir selected from macrolide antibiotics and pyranosides as well as their salts or esters.

The particularly preferred compounds of formula (I) are those for which R 1 denotes a cyclohexyl group, and R 3 a lower alkyl group or else those for which R 1 denotes an alkyl group, linear or branched and R 3 a lower alkyl group. Among these compounds, those which are more particularly preferred are 6-cyclohexyl 1-hydroxy 4-methyl 2- (1H) -pyridone, called Ciclopirox, when it is in the form of an ethanolamine salt, and 1-hydroxy 4-methyl 6 - (2,4,4-trimethylpentyl) 2- (1H) -pyridone called Octopirox, when it is in the form of ethanolamine salt.

The particularly preferred antibacterial agents are chosen from: - erythromycin derivatives such as erythromycin, its salts and esters and more particularly erythromycin estolate, erythromycin ethylcarbonate, erythromycin ethyl succinate , erythromycin glucoheptonate, erythromycin lactobionate, erythromycin propionyl lauryl sulfate, erythromycin linoleate, erythromycin propionate, erythromycin stearate, mono-enic esters such as mono-oleate erythromycin A; - the clindamycin derivatives are the hydrochlorides, palmitates and phosphates7 and the lincomycin derivatives are the hydrochlorides.

A preferred embodiment is to use erythromycin, clindamycin or lincomycin retinoates as antibacterial agents. Such compounds are in particular described in * δ »* * * French patent application No. 86.06528. These are more particularly the retinoic esters at position 21 of erythromycin A, the retinoic esters at position 3 of lincomycin and clindamycin. The retinoic esters in position 2 ′ of erythromycin A can be represented by the following formula; 0 "îsA. /“) H \ A ° H k / ° B ^ c "3" 3C- "'" CH3 R ° V (Vc, ck -; \ !! ιγ ·' '· ο - <^ 7 CHj j (II) JP och3 CH3 x ° -iè ^ 0R 'in which R represents an all-trans retinoyl radical or the retinoyl radical 13-cis and R' denotes H. The retinoyl radical having the formula: ι 7 I * »k .

The retinoic esters in position 3 of lincomycin and of clindamycin can be represented by the following formulas: P "3 ^ 3 i / Vf T3! / N \ f | u3h7 hS hoch y H | 1 M" [COffli —CH H 1 f C0NE -01

4 H HO, -V a S E ° / ^ V

A \ A Λ

SB M M_V

E> - 'SCH3 HT— SM3 a oh .a «(iv) (v) in which R has the same meaning as that given above.

These compounds can be prepared by various esterification processes and in particular an esterification carried out in an anhydrous organic solvent medium, preferably in tetrahydrofuran alone or in mixture with another organic solvent such as pyridine, by reacting an excess of carbon dioxide mixed all-trans or 13-cis retinoic acids (prepared in situ, for example, from ethyl chloroformate and all-trans or 13-cis acid) with erythromycin A, lincomycin and clindamycin under base form in the presence of an organic or inorganic base such as pyridine and / or sodium hydrogencarbonate.

Another esterification process consists in particular for lincomycin and clindamycin to "8> *> using the imidazolides of retinoic acids in an anhydrous solvent such as Ν, Ν-dimethylformamide in the presence of a base such as sodium tertiobutylate or potassium resulting in a mixture of retinoic esters of these antibiotics.

Other erythromycin A derivatives described in particular in FR-A-2,582,000 are represented by the formula (II), in which: R or R ′ represents a linear acyl radical in Ci8 bi- or tri-enic configuration stereochemical 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-octadecadiênoyl or linoleoyl Z-9, Z-12, Z-15-octadêcatriênoyl or ° C-linolenoyl, and Z-6 , Z-9, Z-12-octadêcatriênoyle or J ^ -linolénoyle ·

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

These compositions can also contain other compounds as known substances which can have an effect on the treatment of acne and in particular 3-carboxymethylcysteine, thiamorpholinone, 3-benzylcysteamine and their derivatives and tioxolone.

In one embodiment, the compositions according to the invention contain ceratolytic agents such as for example salicylic acid in proportions of 0.01 to 10% by weight, benzoyl peroxide in proportions of 0.01 to 10% by weight, resorcinin in proportions of 0.01 to 5% by weight, retinoic acid and its derivatives, as well as humectants such as, for example, glycerin and urea.

\ 9> *

‘X

In another embodiment, the compositions also contain steroidal or non-steroidal anti-inflammatory agents such as more particularly hydrocortisone, indomethacin, glycyrrhetinic acid, C> C-bisabolol, betamet thasone, fluorinolone acetonide , deoxy-methasone.

The pyridone derivatives are preferably used in proportions of 0.01 to 5% by weight relative to the total weight of the composition and the antibacterial agents in proportions of 0.01 to 5% by weight relative to the total weight of the composition.

Hydrocortisone or indomethacin when they are present are also present in proportions of between 0.01 and 5% by weight relative to the total weight of the composition.

The compositions according to the invention can be in various forms such as gel, tampon, cream, lotion, spray, foam, powder, ointment, stick, bread or soap liquid.

The compositions can also contain adjuvants usually used in pharmaceutical compositions applied to the skin and in particular water or mixtures of water and solvents such as lower alcohols such as ethanol or isopropanol, ethylene glycol , mono-methyl, monoethyl or monobutyl ethers of ethylene glycol, propylene glycol, monomethyl ethers of propylene glycol and dipropylene glycol, antioxidants, thickeners.

The therapeutic treatment of acne, according to the invention, is preferably carried out according to a process consisting in applying two or three times a day a sufficient amount of the composition "10> *" according to the invention to the areas of the skin to be treated and this for a period of 6 to 30 weeks and preferably 12 to 24 weeks.

The compositions according to the invention can be used as a preventive measure, in particular on the areas of skin liable to be affected by acne.

The compositions according to the invention can also be used for the cosmetic treatment of the skin, in particular, they make it possible to · treat blackheads and facilitate their extrusion, and therefore purify the skin.

The Applicant has found that the compositions in accordance with the invention not only make it possible to obtain a very rapid improvement in the acne-causing inflammatory state, but also to lead to the reduction of so-called first type lesions with non-inflammatory characteristic.

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

λ 11 y ‘* PREPARATION EXAMPLE 1

Preparation of Q-retinoyl (13-cis) -21 erythromycin A

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. The solution is stirred for 5 minutes and 2.5 g (30 mmol) of sodium hydrogen carbonate 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, 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 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% yield ) of pure 0-retinoyl (13-cis) -2'-erythromycin A. F = 82 ° C (hexane / ethyl acetate) - -17 ° (C = 6 mg / ml dichloromethane)

D

Microanalysis ï C57H93NO14 y M = 1016.4 C H N

Calculated%: 67.36 9.22 1.38

Found%: 67.48 9.32 1.38 * 12 "

• V

*

Infrared: band at 1735 cm3 (13C NMR (ester) (CDCI3, internal TMS ref.)

Negative effects Y in the (- 2.2 ppm) and 3 '(- 2.1 ppm) indicate the position of the ester in 2'. The carbons C "2o (20.94 ppm), C'14 (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

Preparation of O-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. 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 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 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 4.1 g (60% yield) of pure 0-retinoyl (all-trans) -2'-erythromycin A.

fr 13

X

\ W22 = -65 ° (C = 2 mg / ml dichloromethane)

D

Microanalysis: C57H93NO14.4H2O; Μ = 1088.5 C H N

Calculated%: 62.89 9.35 1.29

Found%: 62.91 8.90 1.29 13c NMR (CDCI3, internal TMS dream)

Negative effects Y in 1 '(- 2 ppm) and 3' (- 1.9 ppm) indicate the position of the ester in 2 '. The carbons C "20 (14.1 ppm), C'14 (119.36 ppm) and C” i2 (135.19 ppm) are in agreement with the all-trans stereochemistry of the retinoic chain.

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, allowing to rise to room temperature (chromatography on a thin layer of silica gel: 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 y 14 ”‘ \ t 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 2.15 g (55% yield ) of pure O-retinoyl (all-trans) -3-clindamycin.

F = 62 ° C 22 £ 7 = + 50 ° (C = 100 mg / ml dichloromethane)

D

Microanalysis: C38H59N2SO5CI, 2.5H20? M = 752.5 C H N

Calculated%: 60.44 8.08 3.23

Found%: 60.66 8.57 3.72 13c NMR (CDCI3, internal TMS dream): negative Y effects in position 4 (-2.8 ppm) and in position 2 (-1.9 ppm). The chemical shifts of C'14 (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

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 poured 6 ml (76 mmol) of anhydrous pyridine and 1.6 ml (16.6 mmol) of ethyl chloroformate? 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 mixture is 15

‘1 A

the reaction 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 5%). 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 silica gel column (HPLC) using the eluent: ethyl acetate (5) / hexane (5) to result in the isolation of 2 g (51% yield) of Pure 0-retinoyl (13-cis) -3-clindamycin.

F = 95eC (hexane / ethyl acetate) 20 / p \ y = + 111 ° (C = 15 mg / ml dichloromethane)

D

Microanalysis: C3SH59CIN2SO6; M = 707.4 C H

Calculated%: 64.52 8.41

Found%: 64.47 8.45 13c NMR (CDCI3, internal TMS dream)

The position of the ester is indicated by the positive ß 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).

> Λ 16

* V

PREPARATION EXAMPLE 5 Preparation of 0-retinoyl (13-cis) -3-lincomycin

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 101). 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% yield) of pure 0-retinoyl (13-cis) -3-lincomycin.

F = 95 ° (hexane / ethyl acetate) = + 103 ° (C = 7 mg / ml dichloromethane)

D

Microanalysis; C3‘gH50N2SO7,2,5EÏ20; M = 734.5 C H

Calculated%; 62.18 9.03

Found%: 62.33 8.64 4 17> • “13c NMR (CDCI3, internal ref. TMS)

The position of the ester is indicated by the positive Q effect at 3 (+1.6 ppm) and the negative} f 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

Preparation of the mixture of monoesters of O-retinoyl (all-trans) -7-lincomycin, 0-retinoyl (all-trans) -3 linco-mycin and O-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 N, N-dimethylformamide and then 830 mg (7.4 mmol) of potassium tert-butoxide are added and the mixture is continued for 1 ' stirring 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 (chromatography on a thin layer of gel silica: methylene chloride / methanol 7.5%). The solution is 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 silica gel column (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.

* 18 "*

* V

13C NMR (CDC13, internal TMS ref.) - Negative effects in 8 (-2.5 ppm) and in 6 (-3.8 ppm) indicate the place of esterification of a monoester in position 7, - Effect negative in position 1 (-4 ppm) indicates the monoester in position 2 and the negative effects in 2 (-2 ppm) and 4 (-2.6 ppm) indicate the position of the monoester in position 3. The positions of Ci are at 85.06 ppm for the monoester in 2, 88.45 ppm for the monoester in 7 and 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 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 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 mraoles) of clindamycin are dissolved in 250 ml of anhydrous Ν, Ν-dimethylformamide and then 527 mg (4.7 mmol) of potassium tertiotoutylate are added to the reaction medium which is then stirred at room temperature for 90 minutes. A solution of 8.250 g (23.5 mmol) of retinoyl (all-trans) -l imidazole is then poured into 150 ml of anhydrous Ν, Ν-imethylformamide and the resulting medium is stirred at room temperature for 12 hours (chromatography on a thin layer of silica gel (methylene chloride / methanol 5%). The solution

* V

* Λ 19 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.

13c NMR (CDCI3 / internal TMS ref.) - 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) indicate 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.

The all-trans configuration of the retinoic chain is predominant (C'14 at 117.5 ppm and C'20 at 14.08 ppm) but traces of isomerization are clear, especially in C'20 ei · in C'14 .

20

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EXAMPLE 1

ANTI-ACNEIC LOTION

The following composition is prepared: - Erythromycin 2 g - Octopirox 1 g - Antioxidant butyl hydroxy toluene (BHT) / butyl hydroxy anisole (BHA) 0.4 g - Water-isopropanol solution (60/40 by volume) qs 100 g EXAMPLE 2

ANTI-ACNEIC LOTION

The following composition is prepared: - Clindamycin 0.6 g - Octopirox 0.02 g - Benzoyl peroxide 2.5 g - Antioxidant (BHT, BHA) 0.1 g - Water-ethanol solution (60/40 by volume) qs 100 g 4É

1 V

21

EXAMPLE 3 ANTI-ACNE GEL

The following composition is prepared: - Erythromycin 2 g - Salicylic acid 0.5 g - Octopirox 2 g - Polyacrylic acid crosslinked with a polyfunctional agent, sold by the company BF GOODRICH under the trade name of "CARBOPOL 941" 0.5 g - Antioxidant (BHT, BHA) 0.5 g - Ethanol 20 g - Water qs 100 g

EXAMPLE 4 GEL

The following composition is prepared: - Erythromycin linoleate 3 g - Cyclopirox 1 g - Hydroxypropylcellulose sold by the company HERCULES under the trade name of "KLUCEL H" 1 g - Antioxidant (BHT, BHA) 0.1 g - Ethanol 20 g - Water qs 100 g

Claims (20)

1. Composition intended for topical application for the treatment of acne, characterized in that it contains in a physiologically acceptable medium at least one pyridone derivative corresponding to the formula: (j> HI (I) * 3 in which: R] _ denotes a hydrogen atom, an alkyl group, linear or branched, having from 1 to 17 carbon atoms, cycloalkyl having from 5 to 8 carbon atoms, cycloalkyl-alkylene, the alkylene group having from 1 to 4 carbon atoms, aryl, aralkyl, the alkyl group having from 1 to 4 carbon atoms, arylalkenyl, the alkenyl group having from 2 to 4 carbon atoms, the aryl and cycloalkyl groups may be substituted by an alkyl group having from 1 with 4 carbon atoms 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 or phenyl atoms; 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; * 23 as well as their cosmetically or pharmaceutically acceptable salts and at least one antibacterial agent chosen from antibiotics of the family of macrolides and pyranosides as well as their salts or esters. 2. Composition according to claim 1, characterized in that in formula (I) denotes a cyclohexyl or linear or branched alkyl group and R3 denotes a lower alkyl group. 3. Composition according to claim 1 or 2, characterized in that the compounds of formula (i) are chosen from 6-cyclohexyl 1-hydroxy 4-methyl 2- (1H) -pyridone and 1-hydroxy 4-methyl 6- (2,4,4-trimethylpentyl) 2- (1H) -pyridone. 4. Composition according to any one of claims 1 to 3, characterized in that the antibacterial agents are chosen from derivatives of erythromycin, clindamycin or lincomycin. 5. Composition according to claim 4, characterized in that the erythromycin derivatives are erythromycin and its derivatives chosen from estolate, ethylcarbonate, ethylsuccinate, glucoheptonate, lactobionate, propionyl lauryl sulfate, propionate, stearate, linoleate, mono-enic, bi or triene esters of erythromycin. 6. Composition according to claim 4, characterized in that the clindamycin derivatives are chosen from hydrochlorides, palmitates and phosphates, and that lincomycin derivatives are chosen from lincomycin hydrochlorides. 7. Composition according to any one of claims 1 to 6, characterized in that the derivatives of erythromycin, of clindamycin and of 24 4 * κ "* 4 lincomycin are chosen from retinoates of erythromycin, of clindamycin and of lincomycin. 8. Composition according to any one of claims 1 to 7, characterized in that it also contains a keratolytic agent. 9. Composition according to claim 8, characterized in that the keratolytic agent is chosen from benzoyl peroxide, salicylic acid, resorcinol. 10. Composition according to any one of claims 1 to 9, characterized in that it also contains S-carboxymethylcysteine, thiamorpholinone, S-benzylcysteamine and their derivatives or tioxolone. 11. Composition according to any one of claims 1 to 10, characterized in that it also contains steroidal anti-inflammatory agents or not. 12. Composition according to claim 11, characterized in that the anti-inflammatory agents are chosen from hydrocortisone, indomethacin, glycyrrhetinic acid, 1'-bisabolol, betamethasone, fluorinolone acetonide, dexoxymethasone . 13. Composition according to any one of claims 1 to 12, characterized in that the pyridone derivatives are present in proportions of between 0.01 and 5% by weight relative to the total weight of the composition and that the agents antibacterials are present in proportions of between 0.01 and 5% by weight relative to the total weight of the composition. 14. Composition according to any one of claims 1 to 13, characterized in that it 25, * 'to be in the form of gels, tampons, creams, lotions, spray, ointments, sticks . 15. Composition according to any one of claims 1 to 14, characterized in that it contains water or a mixture of water and lower alcohols or glycols or glycol ethers. 16. Composition according to any one of claims 1 to 15, characterized in that it also contains thickening agents, antioxidant agents, coloring agents, perfumes and any other adjuvant used in topical applications. 17. Composition according to any one of claims 1 to 16, for its use in the therapeutic treatment of acne. 18. Composition according to any one of claims 1 to 16, for its use in the cosmetic treatment of the skin. 19. Use of the composition as defined in any one of claims 1 to 16, for the preparation of a medicament intended to treat acne. 20. Cosmetic treatment process, in particular for purifying the skin, characterized in that a composition is applied as defined in any one of claims 1 to 16. 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