FR2598420A1 - NOVEL RETINOIC ESTERS OF ANTIBIOTICS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL AND COSMETIC COMPOSITIONS CONTAINING SAME - Google Patents

Abstract

ALL TRANS RETINOIC ACID AND 13 CIS ESTERS OF ERYTHROMYCIN A, LINCOMYCIN AND CLINDAMYCIN. USE OF ESTERS IN THERAPEUTICS AND COSMETICS IN THE TREATMENT OF VARIOUS DERMATOSES, ESPECIALLY IN THE TREATMENT OF ACNE.

Description

The present invention relates to novel retinotec esters

  antibiotics more specifically retinoic esters of erythromycin A, lincomycin and clindamycin, their method of

  and pharmaceutical and cosmetic compositions containing them in the treatment of various dermatoses, especially in the treatment of acne.

  The subject of the present invention is essentially the use of new retinoid antibiotic esters in the treatment of infectious or non-infectious dermatoses, the origin of which may be bacterial,

  mycobacterial and / or related to the implantation of certain pathogenic yeasts.

  The invention relates more particularly to the use of new retinoic esters of antibiotics in the treatment of acne.

  Acne is a polymorphous skin disorder (several types of lesions existing in the same individual), occurring at puberty and regressing spontaneously, in the majority of cases, at 20-25 years of age.

  In affected individuals, acne affects areas rich in sebaceous glands such as the forehead, the face, the wings of the nose, the torso, and the back.

  shows some dependence of this dermatosis on sebum, a synthetic product of the gland.

  There is no acne without seborrhea. Although seborrhea is one of the translations of the sudden hormonal flux that occurs at puberty, acne does not seem to be related to any hormonal disorder.

  The etiopathogeny of acne, although poorly defined, takes its

  origin in the formation of a characteristic lesion, the comedo. This results from the obstruction of the pilosebaceous canal, as a result of a diskeratinization of the infundibilum zone of the canal.

  This obstruction has the major effect of modifying the viscosity of the sebum and the physicochemical characteristics of the medium (pH, tension

of oxygen vapor ...).

  This modification allows the hyperproliferation of resident cutaneous strains, mainly propionibacterium acnes, anaerobic or aero-tolerant strain.

  Acne has no infectious characteristic in the sense that this dermatosis does not correspond to the implantation of a

  particular pathogenic strain and that it is not transmissible.

  Finally, the bacterial hyperprofiltration has the effect of releasing into the medium certain proteases or hyaluronidases of bacterial origin which cause lysis of the follicular sac and thus the release of

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  inflammatory compounds within the dermis and trigger the inflammatory reaction of the body.

  If the nature of the inflammatory compounds is at present undetermined, their bacterial origin seems to make little doubt, explaining by this, the good therapeutic success in inflammatory acne, of

  antibiotic compounds both orally and topically.

  Among the antibiotics, erythromycin and clindamycin are very often recommended but require (especially for erythromycin) relatively high concentrations to obtain a satisfactory action.

  Furthermore, as recent studies have shown, some strains of propionibacterium acnes exhibit progressive resistance to erythromycin, lincomycin and clindamycin, so

  treatment with these antibiotics may not be effective.

  The topical application of clindamycin and more particularly of erythromycin also faces a problem of penetration through

  the stratum corneum thus limiting their effectiveness.

  The novel retinoid antibiotic esters, more particularly erythromycin A, clindamycin and lincomycin, according to the invention, provide a satisfactory solution to the problems encountered with the use of these antibiotics, insofar as the studies carried out have It has been shown that these new esters have a selective action on the main germ responsible for inflammation, namely propionibacterium acnes, while having a very low activity against cutaneous germs, such as Staphylococcus epidermidis, which allows to treat the affections of the skin without its balance being disturbed. It should also be noted that these novel retinoic antibiotic esters, especially the all trans and 13-cis retinoic esters of erythromycin A and lincomycin, have been found to be active against

  of propionibacterium acnes strains resistant to the parent antibiotic.

  The novel retinoid antibiotic esters according to the invention have been shown to be active without the disadvantages of retinoic acid.

  Thus, the new esters are better tolerated by the skin and have been found to be much less toxic orally than the combination

antibiotic / retinoic acid.

  The retinoic esters of antibiotics according to the invention, as compared with the other known esters of antibiotics, have the advantage of possessing a keratolytic activity in the case of the esters of the acid.

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  retinoic trans garlic and anti-seborrhelic activity in the case of 13-cis retinolic acid, which gives these

of "prodrug".

  The new retinoic esters of antibiotics according to the invention are more lipophilic, which makes it possible to improve the penetration to

through the epidermis.

  The state of the art relating to the combination of retinoic acid and erythromycin consists of the product sold by the

  CILAG Laboratories under the name "Antibio-Aberel".

  The state of the art relating to erythromycin A esters is represented by US Pat. No. 2,862,921 which relates to the preparation of saturated and monounsaturated fatty esters of erythromycin A such as erythromycin A monostearate and erythromycin monooleate A. The state of the art relating to clindamycin and lincomycin esters is represented in particular by German Patent 2,017,003 which describes the preparation of lincomycin and clindamycin esters whose

  acyl chain is between 1 and 18 carbon atoms.

  The subject of the present invention is retinoic esters of antibiotics and more particularly esters of retinoic acid all trans 20 and 13cis of erythromycin A, lincomycin and clindamycin, and

salts of said esters.

  The retinoic esters of antibiotics according to the invention may optionally be in the form of mixtures but, preferably, these are on the one hand the retinoic esters in the 2 'position of erythromycin A and on the other hand the esters retinoids in position 3 of

lincomycin and clindamycin.

  The retinoic esters at the 2 'position of erythromycin A can be represented by the following formula: ## STR13 ##

H OH OH CH3

H C '1 [-CH 3 RO,

H. CCH3

CH2 3H

CH3; CH3

  In which R represents the retinoyl all trans radical or the retinoyl radical Cis, the retinoyl radical having the formula:

(E) (E) (E "() (IZ)

  The 3-position retinolic esters of lincomycin and clindamycin may be represented by the following formulas: 4: C 3 H 3 H 3 H

CONH - CH

HO HO H

HCOH S3 n --HSCH3

III IV

  in which R has the same meaning as that given above.

  The subject of the present invention is also the process for the preparation of the all trans and 13-cis retinolous esters of erythromycin A, of

lincomycin and clindamycin.

  Different esterification processes may be used, but preferably this esterification is carried out in an anhydrous organic solvent medium, preferably in tetrahydrofuran alone or in a mixture with another organic solvent such as pyridine, by reacting an excess of mixed carbon dioxide with retinolec acid all trans or 1330 cis (prepared in situ, for example from ethyl chloroformate and

  of all trans or 13-cis acid) with erythromycin A, lincomycin or clindamycin in base form in the presence of an organic or inorganic base such as pyridine and / or sodium hydrogencarbonate.

  This mixed anhydride method makes it possible to obtain the retinolate esters at the 2 'position of erythromycin A and at the 3-position of the

  lincomycin and clindamycin, without isomerization of the retinoyl radical.

  Other esterification processes, in particular lincomycin and clindamycin by the method using the imidazolides of retinolic acids in an anhydrous solvent such as NN dimethylformamide, in the presence of a base such as sodium or potassium tertiobutylate,

  lead to a mixture of retinoic esters of these antibiotics.

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  Thus, by the latter method, the 7-ester of lincomycin is obtained mainly with the esters at 2, 3 and 4.

  Likewise, a mixture of monoesters at 2, 3 and 4 of clindamycin is obtained.

  Moreover, the latter method sometimes provokes a

  isomerization of the retinoyl radical.

  The subject of the present invention is also pharmaceutical compositions which can be administered topically, orally, parenterally or rectally as well as compositions of a cosmetic nature for the treatment of various dermatoses, in particular acne, this composition being in anhydrous form and containing at least minus a retinoic acid ester all trans or 13-cis of erythromycin A, lincomycin or clindamycin according to the invention, at a concentration of between 0.01 and 10% but of

  preferably between 0.05 and 1% by weight relative to the total weight of the composition.

  For the preparation of the compositions according to the invention containing, as active ingredient, at least one all-trans or 13-cis retinoic ester of erythromycin A, lincomycin or clindamycin, it is possible to make

  use of vehicles and adjuvants described in the literature for pharmacy, cosmetics and related fields.

  For the preparation of the solutions, it is possible to use, for example, one or more physiologically acceptable organic solvent (s).

  The acceptable organic solvents are taken in particular from the group consisting of acetone, isopropyl alcohol, triglycerides of fatty acids, glycol ethers, C1-C4 alkyl esters.

  of short-chain acids and the ethers of polytetrahydrofuran.

  The compositions according to the invention may also contain thickeners such as cellulose and / or cellulose derivatives in a proportion of 0.5 to 20% by weight relative to the total weight of the composition.

  The compositions according to the invention may furthermore contain, in combination with at least one retinoic antibiotic ester according to the invention, at least one other known anti-acnelic agent.

  It is possible, if necessary, to add a conventional adjuvant taken from the group formed by the antioxidants, the preserving agents, the

perfumes and dyes.

  Among the antioxidants that may be used, mention may be made, for example, of t-butylhydroxyquinone, butylhydroxyanisole, butylhydroxytoluene and tocopherol and its derivatives.

15 20

30 40 -6-

  The pharmacological and galenic transformations of the compounds according to the invention are carried out in a known manner.

  The dosage forms can be poured for topical treatment, creams, milks, gels, lotions more or less thickened, lotions carried by tampons, ointments, sticks or aerosol formulations in the form of spray or of mosses.

  The oral compositions may be in the form of tablets, capsules, dragees, syrups, suspensions, emulsions, powders, granules or solutions.

  The compositions may also be in the form of suppositories.

  The treatment of acne using the topical compositions according to the invention consists in applying two or three times a day a sufficient amount to the areas of the skin to be treated and this for a period of time of 6 to 30 weeks and preferably from 12 to 24 weeks.

  The compositions according to the invention can also be used as a preventive measure, that is to say on areas of skin that may be affected by acne.

  COMPARATIVE STUDY ON THE ACTIVITY OF RETINOIC ESTERS OF ANTIBIOTICS

  The activity of the retinoic esters of erythromycin A,

  lincomycin and clindamycin was studied by the dilution method to determine the Minimum Inhibitory Concentration (MIC), method described and employed by GA DENYS et al, Antimicrobial Agents and Chemotherapy (1983) 23, 335-337 and JJ LEYDEN and al. J. Am. Acad. Dermatol. (1983) 8 (1) 41-5, using as strain of propionibacterium acnes, strain P37 provided by CUNLIFFE and HOLLAND.

  This strain P 37 has been the subject of studies described in the following publications: - J. GREENMAN, K.T. HOLLAND and W. J. CUNLIFFE, Journal of General Microbiology (1983) 129, 1301-1307, - E. INGHAM, K.T. HOLLAND, G. GOWLAND and W. J. CUNLIFFE, ibid (1980) 118, 59-65 and

  - K.T. HOLLAND, J. GREENMAN and W. J. CUNLIFFE, Journal of Applied Bacteriology (1979) 47, 383-394.

  Selection and isolation of susceptible and resistant populations The P 37 strain is sensitive to erythromycin as shown by the Minimum Inhibitory Concentration (MIC = 0.78 μg / ml) In contrast, after 8 consecutive subcultures in the same medium, (RCM 19/20, DMSO 19/20 by volume) in order to obtain a progressive stabilization of this strain in this medium, a progressive resistance to * Reinforced Clostridium Medium (OXOID) -7 erythromycin manifests itself in the following form: After display of a standardized inoculum (OD = 1.8 to 450 nm) on agar medium (RCM + furazolidone), in a Petri dish, a disc of 9 mm in diameter is deposited in the center of it. On the disk, 50 μg of erythromycin (in solution in DMSO) are deposited. - After 6 days at 36 C in anaerobic environment (GAS-PAK system, B.B.L) a zone of inhibition of the shoot of the strain is clearly visible (total diameter = 42mm), the vast majority of colonies being located

  at the periphery of the inhibition zone.

  On the other hand, inside of it some colonies appear clearly.

  The two types of colonies are then removed by tearing off the agar medium (sterilized platinum loop): 1) within the zone of inhibition, the strains designated P 37 EG are taken because of their apparent resistance to erythromycin. 2) at 1 cm beyond the periphery of the zone of inhibition, the strains designated P 37 E are taken. After isolation and culture, strains P 37 Es and P 37 E 20 show indeed very different sensitivities to erythromycin

  illustrated by the following values of the respective MICs.

MIC (ig / ml)

P 37 0.78

P 37 EG 0.78

P 37 EQ

  This phenomenon is confirmed by the study of IC 50 (50% inhibitory concentration), which represents the concentration of erythromycin o, at a constant culture time, 50% of survivors among the population are found. IC 50 (pg / ml)

P 37 50

P 37 E 5

P 37 E @ 100

  Minimal Inhibitory Concentration (MIC) expressed in g / ml

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  Retinotech esters of erythromycin A, lincomycin and clindamycin tested against strains P 37 "and P 37 are reported in the following table:

RETINOIC ESTERS P 37 E P 37 E

  ANTIBIOTICS (sensitive) (resistant) 0-retinoyl (all trans) 2'-erythromycin A 14 13 O-retinoyl (13-cis) -2'-erythromycin A 34 Oretinoyl (13-cis) -3lincomycin 17.5 25 0 retinoyl (all-trans) -3clindamycin 18 50 O-retinoyl (13-cis) -315 clindamycin 1.5 35

WITNESSES:

  0-oleoyl-2'-erythromycin A (Z-9) 50 100 0-oleoyl-3-lincomycin 19 42 Oleolyl-3-clindamycin 54> 138 Erythromycin A 1> 50 Lincomycin 13 66 Clindamycin 1 10

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  The table below shows the minimum inhibitory concentrations of the retinoic esters of antibiotics with respect to two strains of Staphylococcus Epidermidis: RETINOIC ESTERS Staph. Epi.3 Staph. Epi.6

ANTIBIOTICS

  O-retinoyl (all trans) -2-erythromycin A 75 80 O-retinoyl (13-cis) erythromycin A 110 110 O-retinoyl (13-cis) -3clindamycin 113 113 Oretinoly (13-cis) -3lincomycin 100 100

WITNESSES:

  Erythromycin A 13 Clindamycin 7 8 lincomycin 14 The strain "Staph., Epi." 3 is isolated from an acnellular patient while the strain "Staph., Epi., 6" is isolated from a nonacneic patient. The isolation of these strains is carried out according to the method of WILLIAMSON-KLIGMAN (P. Williams and A. KLIGMAN, J.I.D., Vol 45, No. 6, 1965). Decimal dilutions of the sample are made and 0.1 ml of these dilutions is

  seeded on a selective medium allowing the isolation of staphylococci.

  As can be seen in the first table, the retinoic esters of erythromycin A and lincomycin are more active on the resistant propionibacterium acnes strains than the parent antibiotics. In addition, the 2'-oleic acid ester of erythromycin A (US Pat. No. 2,882,921) as well as the olefinic ester of clindamycin (DOS 2,017,003), taken as comparator esters, were found significantly less active on the sensitive strains (P 37 E) and resistant (P 37 E 'than the esters of the invention thus reinforcing the interest in particular retinoic esters of erythromycin A and clyndamycin. , shows the interest of all these retinoic esters of antibiotics vis-à-vis the "cutaneous ecology" since they are much less active on strains of Staphylococcus epidermidis that the

antibiotic parents.

  Several examples of the preparation of retinoic esters of antibiotics according to the invention will now be given by way of illustration.

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  as well as several examples of pharmaceutical or cosmetic compositions in the treatment of dermatoses, especially acne.

EXAMPLE 1

  Preparation of 0-retinoyl (13 cis) -2 'erythromycin A In a flask under an inert atmosphere, 5 g (16.6 mmol) of retinolic acid (13-cis) are dissolved in 35 ml of anhydrous tetrahydrofuran; the reaction mixture is cooled to 0 C and then poured 3ml (38 mmol) of anhydrous pyridine and 1.6ml (16.6 mmol) of ethyl chloroformate. The solution is stirred for 5 minutes and 2.5 g (30 mmol) of sodium hydrogencarbonate and then 4.9 g (6.7 mmol) of erythromycin A dissolved in 150 ml of tetrahydrofuran are then added. The reaction mixture is then left stirring for 10 hours and allowed to rise to room temperature (thin layer chromatography on 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 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 obtain isolation of 4.4 g (65% yield). ) of 0-retinoyl (13

cis) -2'-erythromycin A pure.

  F - 82 C (hexane / ethyl acetate) [122 -. (C = 6 mg / ml dichloromethane) Microanalysis: C57H93NO5; M1016.4 5793 15 '

C H N

  Cal. Z: 67.36 9.22 1.38 Found. Z: 67.48 9.32 1.38 Infra-red: 1735 cm -1 band (ester) R.M.N. 13C (CDCl 3, internal ref T.M.S.) Negative effects at 1 '(- 2.2 ppm) and 3' (- 2.1ppm) indicate the position I of the ester at 2 '. The C20 (20.94ppm), C14 (117.28ppm) and C12 (131.9ppm) carbons of the retinol cat are in agreement with the

  13 cis stereochemistry of the retinolus cat.

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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. at 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 and then 4.9 g (6.7 mmol) of erythromycin A dissolved in 150 ml of tetrahydrofuran are then added. The reaction mixture is then left stirring for 10 hours, allowing to rise to room temperature (thin layer chromatography on 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 sulphate, filtered and then concentrated under partial vacuum. The crude product thus obtained is chromatographed on a column of silica gel (H.P.L.C.) using the eluent: acetate

  of ethyl (7) / hexane (3) to result in the isolation of 4.1 g (60% yield) of pure O-retinoyl (all trans) -2'-erythromycin A.

  Mp = 76 ° C (ethyl acetate / hexane) 22 = -65 (C = 2 mg / ml dichloromethane) D Microanalysis: C57H93NO15 • 4H2O; M = 1080.5 C H N Calc. %: 63.36 9.42 1, 29 found. %: 62.91 8.90 1.29 R.N.M. 13C (CDCl3, internal T.M.S. ref.) negative Y-effects in 1 '(-2ppm) and 3' (-1.9ppm) indicate the position of the ester at 2 '. C- (14.1ppm), C14 (119.36ppm) and C12-12 (120.19ppm) carbons are consistent with the all-trans stereochemistry of the retinoic chain.

EXAMPLE 3

  Preparation of O-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 6 ml (76 mmol) of anhydrous pyridine and 1.6 ml (16.6 mmol) of ethyl chloroformate are then added; the solution is stirred for 5 minutes and 1.25 g (15 mmol) of sodium hydrogencarbonate and then 2.35 g (5.5 mmol) of clindamycin dissolved beforehand in 100 ml of a mixture are added.

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  tetrahydrofuran (8) / pyridine (2). The reaction mixture is then left stirring for 10 hours, allowing to rise to room temperature (thin layer chromatography silica gel: methylene chloride / methanol 5%). The solution is poured over 80 ml of water and then ex5 treated with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated under partial vacuum. The crude product thus obtained is chromatographed on a column of silica gel (H.P.L.C) using the eluent: ethyl acetate (5) / hexane (5) to obtain

  isolation of 2.15 g (55% yield) of pure 0-retinoyl (all trans) -3 clindamycin.

F = 62C

  [? 22, +50 (C = 100 mg / ml dichloromethane) D Microanalysis C38H59N2S 6Cl, 2.5H2O; M = 752.5 CHN Calc.%: 60.44 8.08 3.23 Found%: 60, 66 8.57 3, 72 13C NMR (CDC13, TMS internal ref.): Negative effects in position 4 (-2.8ppm) and position 2 (-1.9ppm) Chemical displacements of C14 (117.84ppm) and C-20 (14.11ppm) confirm the

  all-trans stereochemistry of the retinoyl cat.

EXAMPLE 4

  Preparation of O-retinoyl (13 cis) -3-clindamycin In a flask under an inert atmosphere, 5 g (16.6 mW) of retinoic acid (13cis) are dissolved in 30 ml of anhydrous tetrahydrofuran; the reaction mixture is cooled to 0 ° C. and 6 ml (76 mmol) of anhydrous pyridine and 1.6 ml (16.6 mmol) of ethyl chloroformate are then added; the solution is stirred for 5 minutes and 1.25 g (15 mmol) of sodium hydrogencarbonate and then 2.35 g (5.5 mmol) of clindamycin dissolved beforehand in 100 ml of a mixture of tetrahydrofuran (8) / pyridine (2 ). The reaction mixture is then left stirring for 10 hours, allowing to rise to room temperature (thin layer chromatography 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 concentrated under partial vacuum. The gross product as well

  obtained is chromatographed on a column of silica gel (HPLC) using the eluent: ethyl acetate (5) / hexane (5) to yield the isolation of 2 g (51% yield) of O-retinoyl ( 13cis) -3clindamycin pure.

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  M.p. = 95 ° C (hexane / ethyl acetate) [] = +1110 (C = 15 mg / ml dichloromethane) D Microanalysis: C38H59ClN2SO6; M = 707.4

C H

  Calc. %: 64.52 8.41 Found. %: 64.47 8.45 R.M.N. 13C (CDC13, internal ref TMS) The position of the ester is indicated by the positive effect 8 in 3 (+ 1, 77ppm) and the negative effects y in 2 (-1,4ppm) and 4 (-2 , 5ppm). The 13cis configuration is confirmed by C20 (20.93ppm) and C14 (115.94ppm).

EXAMPLE 5

  Preparation of 0-Retinoyl (13cis) -3-lincomycin In a flask, under an inert atmosphere, 5 g (16.6 mmol) of retinoic acid (13cis) are dissolved in 30 ml of anhydrous tetrahydrofuran; the reaction mixture is cooled to 0 ° C. and 6 ml (76 mmol) of anhydrous pyridine and 1.6 ml (16.6 mmol) of ethyl chloroformate are then added; the solution is stirred for 5 minutes and 1.25 g (15 mmol) of sodium hydrogencarbonate and then 2.2 g (5.4 mmol) of lincomycin dissolved beforehand in 100 ml of a tetrahydrofuran (7) / pyridine (3) mixture are added (3) . The reaction mixture is then left stirring for 10 hours, allowing to rise to room temperature (thin layer chromatography silica gel: methylene chloride / methapol 10%). The solution is poured onto 100 ml of water and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated under partial vacuum. The crude product thus obtained is chromatographed on a column of silica gel (H.P.L.C.) using the eluent: acetate

  of ethyl (8) / hexane (2) to result in the isolation of 1.85 g (50% yield) of pure O-retinoyl (13cis) -3-1incomycin.

  F = 95 (hexane / ethyl acetate) [αd = +103 (C-7 mg / ml dichloromethane) D Microanalysis: C38H60N2SO7, 2.5H2O; M = 734.5CH Calc. Z: 62.18 9.03 Found. %: 62.33, 8.64 R.M.N. 13C (CDCl3, internal reference T.M.S.) 3b

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-14

  The position of the ester is indicated by the positive 8 effect in 3 (+ 1.6ppm) and the negative Y effects in position 2 (-2.4ppm) and 4 (-1.9ppm).

  The 13cis configuration is confirmed by C20 (20.98ppm) and C14 (115.83ppm).

EXAMPLE 6

  Preparation of the mixture of monoesters of O-retinoyl (all-trans) -lincomycin, O-retinoyl (all-trans) -3-lincomycin and O-retinoyl (all-trans) -2-lincomycin In a flask under an inert atmosphere, 30 g (74 mmol ) of lincomycin in 300 ml of anhydrous N, N-dimethylformamide and then 830 mg (7.4 mmol) of potassium tert-butoxide are added and stirring is continued at room temperature for 90 minutes. A solution of 13 g (37 mmol) of retinoyl (all trans) -l imidazole in 150 ml of N, N-dimethylformamide is then poured in and the resulting medium is stirred at ambient temperature for 12 hours (silica gel thin layer chromatography). 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 sulphate, filtered and then concentrated under partial vacuum. The crude product thus obtained is chromatographed over 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 2-positions,

3 and 7.

  NMR 13C (CDCl3, internal ref T.M.S.).

  - Y effects negative in 8 (-2.5 ppm) and in 6 (-3.8 ppm) indicate the esterification site of a monoester in position 7, - 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 C1 are at 85.06 ppm for the monoester in 2, at 88.45 ppm for the monoester at 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 to 117.78 ppm and for C 14 to 14.08 ppm; a trace of isomerization is noted by the presence of a peak at 115.2 ppm (C 14) indicating the cis isomer.

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EXAMPLE 7

  Preparation of the mixture of monoesters of O-retinoyl (all trans) -2 clindamycin, O-retinoyl (all trans) -3 clindamycin and O-retinoyl (all trans) -4 clindamycin In a flask under an inert atmosphere, 20 g (47 mmol) of clindamycin in 250 ml of anhydrous N, N-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 g (23.5 mmol) of retinoyl (all trans) -1 imidazole in 150 ml of anhydrous N, N-dimethylformamide is then poured in and the resulting medium is stirred at room temperature for 12 hours (thin layer chromatography). silica gel: methylene chloride / methanol 5%). The solution is then poured into 500 ml of water and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and 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 retinoic monoesters (all trans) of clindamycin at the 2, 3 and 4 positions. 13C (CDC13, internal ref TMS) - Y effect negative in position 1 (-3 ppm) indicates the position of the ester in 2. - Y effects negative in position 4 (-2.8 ppm) and 2 (- 1.9 ppm) indicate the

  monoester in position 3 and low negative effect in position 3 indicates the monoester in position 4.

  The C1 positions are at 84.63 ppm for the monoester at 2, at 88.79 ppm for the monoester at 3 and at 87.98 ppm for the monoester at 4.

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

  PHARMACEUTICAL AND COSMETIC COMPOSITIONS A-GELS FOR THE TOPIC TREATMENT OF ACNE

  1. Hydroxypropyl cellulose .............................. lg Butylhydroxytoluene .............. ................. O 0.05g Oretinoyl (13cis) -3-lincomycin .................... 0.5g Isopropanol qsp ..

  ............................. 100g..DTD: -16-.2598420

  -16 2. Hydroxypropyl cellulose .................. 1.5g Butylhydroxytoluene ..

  ........................... O.05g O-retinoyl (all trans) -3-clindamycin ..... DTD: .. ........ 0.3g Isopropanol qsp ................................. 100g B- LOTIONS FOR TOPICAL TREATMENT OF ACNE 1. Butylhydroxytoluene ............................... 0.05g 0-retinoyl (all trans) -2 'erythromycin A ... g ................................... g Triglycerides of fatty acids in C 8 -C 12 qsp ........................... 100g In this example, the active compound can be replaced by the same amount of O-retinoyl (13-cis) -2 'erythromycin A. 2. Butylhydroxytoluene ............................... 0.05g O-retinoyl (13cis) -3-clindamycin ................... 0.7g Dimethyl ether of polytetrahydrofuran (viscosity 22Cpo) of formula: CH 3 O (CH 2) 2 - CH2 CH2 - -CH3 .... qsp ... 100g nnn = 5.DTD: C - STICK FOR THE TOPIC TREATMENT OF ACNE

  White Vaseline .................................... 52g Vaseline oil.

  ................................ 15g Fine Paraffin ............... ..... DTD: .............. 32g O-retinoyl (all trans) -2 'erythromycin A ................ DTD: ..................... lg..DTD: D - SUPPOSITORY (COMPOSITION FOR 1 UNIT)

  0-retinoyl (all trans) -2'-erythromycin A ............ 0.05g Triglycerides of C 8 -C 12 fatty acids ..... 0.25g Semi-synthetic glycerides qs .. ..

............. 2g -17..DTD:

Claims (14)

  1. All trans and 13-cis retinoic acid esters of erythromycin A, lincomycin and clindamycin, and mixtures and salts of said esters. 2. Compounds according to claim 1, characterized by the fact   that the retinoic esters of erythromycin A are in position 2 '.   3. Compounds according to claim 1, characterized in that the retinoic esters of lincomycin and clindamycin are in position 3.   4. Compounds according to claims 1 to 3 characterized by   they are taken from the group consisting of: 0-retinoyl (all trans) -2 'erythromycin A O-retinoyl (13-cis) -2' erythromycin A 0-retinoyl (13cis) -3-lincomycin 0-retinoyl (all trans) -3-clindamycin and   O-retinoyl (13-cis) -3 clindamycin.   5. Process for the preparation of the all trans and cis cis retinoic esters of erythromycin A, lincomycin and clindamycin according to any one of Claims 1 to 4, characterized in that it consists in reacting in an organic solvent medium anhydrous, an excess of anhydride   mixed all-trans or 13-cis retinoic acid with erythromycin A, lincomycin or clindamycin base, in the presence of a organic or mineral.   6. Process according to claim 5, characterized in that the anhydrous organic solvent is tetrahydrofuran alone or as a mixture with pyridine.   7. Process according to Claim 5, characterized in that the organic or inorganic base is pyridine and / or hydrogen carbonate sodium.   8. Process for the preparation of all trans retinoic esters and 13   cis lincomycin and clindamycin according to any one of claims I to 3, characterized in that it consists in reacting in a   anhydrous solvent in the presence of a base all-trans or cis-retinoic acid imidazolide with lincomycin or clindamycin in the form of based.   9. Process according to Claim 8, characterized in that the anhydrous solvent is N, N-dimethylformamide and that the base is the   sodium or potassium tertiobutylate.   10. Pharmaceutical or cosmetic composition for the treatment of various dermatoses, in particular acne, characterized by the fact -18   it contains in an anhydrous carrier, as active compound, at least one all-trans or 13-cis retinoic acid ester of erythromycin A, lincomycin or clindamycin according to any one of claims 1 to 4 or obtained according to any one of claims 5 to 9.   11. Composition according to claim 10, characterized in that it contains from 0.01 to 10% by weight and preferably from 0.05 to 1%. of active compound.   12. Composition according to any one of claims 10 and 11, characterized in that the vehicle is acetone, alcohol   isopropyl alcohol, triglycerides of fatty acids, glycol ethers, C1-C4 alkyl esters of short chain acids, ethers of   polytetrahydrofuran and mixtures thereof.   13. Composition according to any one of claims 10 to 12, characterized in that it further contains a thickening agent such as cellulose and / or cellulose derivatives in a proportion   from 0.5 to 20% by weight relative to the total weight of the composition.   14. Composition according to any one of Claims 10 to 13, characterized in that it also contains an antioxidant, a preserving agent, a perfume, a dye or another antiacnitic agent.