GB2191483A

GB2191483A - New retinoic acid esters of antibiotics

Info

Publication number: GB2191483A
Application number: GB08710673A
Authority: GB
Inventors: Michel Philippe; Henri Sebag; Didier Dupuis; Andre Rougier
Original assignee: LOreal SA
Current assignee: LOreal SA
Priority date: 1986-05-06
Filing date: 1987-05-06
Publication date: 1987-12-16
Anticipated expiration: 2007-05-06
Also published as: DK169345B1; NL193946C; BE1004152A4; DE3714937A1; JP2504990B2; NL8701054A; JPS62289593A; FR2598420A1; NO168041B; DK229387A; ES2006478A6; NO871870D0; DE3714937C2; GB2191483B; SE470379B; IT1204556B; NO871870L; NL193946B; GB8710673D0; SE8701845D0

Description

SPECIFICATION New retinoic acid esters of antibiotics, process for the preparation thereof and pharmaceutical and cosmetic compositions containing them The present invention relates to new retinoic acid esters of antibiotics and more precisely to retinoic acid esters of erythromycin A, lincomycin and clindamycin, to the process for the preparation thereof and to pharmaceutical and cosmetic compositions containing them used in the treatment of various dermatitides, especially in the treatment of acne.

Moreover, current studies also show that the retinoic acid esters of the invention have antitumour activity.

The subject of the present invention is primarily the use of new retinoic acid esters of antibiotics in the treatment of infectious or non-infectious dermatitides which may be of bacterial or mycobacterial origin and/or which may be related to infection by some yeasts which are pathogenic in nature.

More particularly, the invention relates to the use of new retinoic acid esters of antibiotics in the treatment of acne.

Acne is a polymorphic (several types of lesions occurring in the same individual) skin disorder which appears during puberty and resolves spontaneously at the age of 20-25 years in most cases.

In the affected individuals, acne occurs in areas with a high density of sebaceous glands such as the forehead, the face, the sides of the nose, the chest and the back, and this shows a certain dependence of this dermatidis on sebum, the product synthesized by the gland.

There is no acne without seborrhoea.

Although seborrhoea is one of the manifestations of the sudden hormone flux occurring at puberty, acne does not appear to be related to any hormonal disorder.

Although the aetiopathogenesis of acne is not well defined, it starts with the formation of a characteristic lesion, the comedo. The latter results from an obstruction of the pilosebaceous canal following a dekeratinization of the infundibilum region of the canal.

The main effect of this obstruction is a change in the viscosity of the sebum and in the physical/chemical properties of the medium (pH, oxygen vapour pressure and the like).

This change permits hyperproliferation of strains which are resident in the skin, mainly Propionibacterium acnes, the anaerobic or air-tolerant strain.

Acne is in no way infectious by nature, in the sense that this dermatitis does not correspond to an infection by a particular pathogenic strain and that it is not transmissible.

Finally, hyperproliferation of bacteria results in a reiease into the medium of some proteases or hyaluronidases of bacterial origin which give rise to the lysis of the follicular sac and therefore the release of inflammatory compounds into the cutis and trigger the inflammatory type of reaction of the organism.

Although the nature of the inflammatory compounds has not so far been established, there appears to be little doubt about their bacterial origin, which therefore explains the successful therapeutic effect, in the treatment of inflammatory acne, of antibiotic compounds administered orally or locally.

Among antibiotics, erythromycin and clindamycin are very often recommended, but relatively high concentrations are required (especially in the case of erythromycin) in order to obtain a satisfactory effect.

Moreover, as recent studies have shown, some strains of Propionibacterium acnes develop a gradual resistance to erythromycin, lincomycin and clindamycin, so that treatment with these antibiotics may not prove to be very effective.

Local application of clindamycin and more particularly of erythromycin also involves the problem of penetration through the stratum corneum, thereby limiting the effectiveness thereof.

The new retinoic acid esters of antibiotics, more particularly of erythromycin A, clindamycin and lincomycin, according to the invention offer a satisfactory solution to the problems encountered in the use of these antibiotics, insofar as the investigations carried out have made it possible to demonstrate that these new esters have a selective action on the main organism responsible for the inflammation, i.e. Propionibacterium acnes, while having a very iow activity against skin organisms such as Staphylococcus epidermidis, thus making it possible to treat diseases of the skin without disturbing its equilibrium in the process.

It should also be noted that these new retinoic acid esters of antibiotics, especially all-transand 13-cis-retinoic acid esters of erythromycin A and lincomycin have proved to be effective against strains of Propionibacterium acnes resistant to the parent antibiotic.

The new retinoic acid esters of antibiotics according to the invention have proved to be effective, without having 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 antibiotic/retinoic acid combination.

In comparison with other known esters of antibiotics, the retinoic acid esters of antibiotics according to the invention have the advantage of having a keratolytic activity in the case of the all-transretinoic acid esters and a potential antiseborrhoeic activity in the case of the 13-cisretinoic acid, which gives these esters the image of a "prodrug".

The new retinoic acid esters of antibiotics according to the invention are more lipophilic, which enables penetration through the epidermis to be improved.

The prior art relating to a combination of retinoic acid and erythrkomycin consists of the product sold by CILAG Laboratories under the name "Antibio-Aberel".

The prior art relating to the esters of erythromycin A is represented by US Patent 2,862,921 which relates to the preparation of saturated and monounsaturated fatty acid esters of erythromycin A such as erythromycin A monostearate and erythromycin A monooleate.

The prior art relating to the esters of clindamycin and lincomycin is represented especially by the German Patent 2,017,003 which describes the preparation of esters of lincomycin and clindamycin, the acyl chain of which contains between 1 and 18 carbon atoms.

The present invention relates to retinoic acid esters of antibiotics and more particularly to alltrans- and 13-cis-retinoic acid esters of erythromycin A, lincomycin and clindamycin and to the salts of the said esters.

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

The esters with retinoic acid substituted in position 2' of erythromycin A may be represented by the following formula:

in which R represents an all-trans-retinoyl radical or a 1 3-cis-retinoyl radical, the retinoyl radical having the following formula:

The esters with retinoic acid substituted in position 3 of lincomycin and clindamycin may be represented by the following formuiae:

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

The present invention also relates to a process for the preparation of all-trans- and 13-cisretinoic acid esters of erythromycin A, lincomycin and clindamycin.

Different esterification processes may be employed, but this esterification is preferably carried out in an anhydrous organic solvent medium, preferably in tetrahydrofuran, alone or mixed with another organic solvent such as pyridine, by reacting an excess of all-trans- or 13-cis-retinoic acid/carbonic acid mixed anhydride (prepared in situ, for example using ethyl chloroformate and the all-trans- or 13-cis-acid) with erythromycin A, lincomycin or clindamycin in the basic form in the presence of an organic or inorganic base such as pyridine and/or sodium hydrogencarbonate.

This method using the mixed anhydride enables esters with retinoic acid substituted in position 2' of erythromycin A and position 3 of lincomycin and clindamycin to be obtained, without the isomerization of the retinoyl radical.

Other processes for the esterification, especially of lincomycin and clindamycin, by the method which employs imidazolides of retinoic acids in an anhydrous solvent such as N,N-dimethylformamide, in the presence of a base such as sodium or potassium tert-butylate, lead to a mixture of retinoic acid esters of these antibiotics.

Thus, the ester in which the substitution is in position 7 of lincomycin is mainly obtained, with smaller amounts of esters in which the substitution is in position 2, 3 and 4, by the latter method.

Similarly, a mixture of monoesters in which the substitution is in positions 2, 3 and 4 of clindamycin is obtained.

Moreover, the latter method sometimes causes an isomerization of the retinoyl radical.

The present invention also relates to pharmaceutical compositions which can be administered locally, orally, parenterally or rectally as well as to compositions of a cosmetic nature for the treatment of various dermatitides, especially acne, this composition being in an anhydrous form and containing at least one all-trans- or 13-cis-retinoic acid ester of erythromycin A, lincomycin or clindamycin according to the invention, at a concentration of between 0.01 and 10%, but preferably between 0.05 and 1% by weight relative to the total weight of the composition.

In order to prepare the compositions according to the invention which contain, as active ingredient, at least one all-trans- or 13-cis-retinoic acid ester of erythromycin A, lincomycin or clindamycin, use may be made of carriers and adjuvants described in the literature relating to the pharmaceutical, cosmetic and related fields.

In order to prepare solutions, one (or more) organic solvent(s) acceptable from a physiological point of view may, for example, be used.

The acceptable organic solvents are chosen especially from the group consisting of acetone, isopropyl alcohol, fatty acid triglycerides, glycol ethers, C,-C4 alkyl esters of short-chain acids and polytetrahydrofuran ethers.

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

The compositions according to the invention may additionally contain at least one other known anti-acne agent in combination with at least one retinoic acid ester of antibiotic according to the invention.

A common adjuvant chosen from the group consisting of antioxidants, preservatives, perfumes and colorants may be added if required.

Among antioxidants which can be used, there will be mentioned, for example, tert-butylhydroxyquinone, butylhydroxyanisole, butylhydroxytoluene and a-tocopherol and its derivatives.

The conversions of the compounds according to the invention into pharmacological and galenical forms are carried out in a known manner.

The galenical forms may be for local application, creams, milks, gels, lotions thickened to different extents, lotions carried on pads, ointments or sticks, or aerosol formulations in the form of sprays or foams.

The compositions for oral administration may be in the form of tablets, capsules, dragees, syrups, suspensions, emulsions, powders, granuies or solutions. The dosage by oral administration is approximately 0.1 to 5 mg/kg/day and preferably 1 to 2.5 mg/kg/day.

The compositions may also be in the form of suppositories.

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

The compositions according to the invention may also be used preventatively, i.e. on skin areas which are likely to be affected by acne.

COMPARATIVE STUDY ON THE ACTIVITY OF RETINOIC ACID ESTERS OF ANTIBIOTICS The activity of the retinoic acid esters of erythromycin A, lincomycin and clindamycin was studied by the dilution method in order to determine the Minimal Inhibitory Concentration (MIC), method described and used by G.A. DENYS et al, Antimicrobial Agents and Chemotherapy (1983) 23, 335-337 and J.J. LEYDEN et al, J. Am. Acad. Dermatol. (1983) 8, (1) 41-5, using Propionibacterium acnes strain P37 supplied by CUNLIFFE and HOLLAND as the strain.

This strain P37 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 sensitive and resistant populations Strain P37 is sensitive to erythromycin as shown by the minimal inhibitory concentration (MIC=0.78 g/ml).

In contrast, after 8 successive sub-cultures in the same medium (RCM* 19/20 and DMSO 19/20 by volume) in order to achieve a gradual adaptation of the strain to this medium, a gradual resistance to erythromycin manifests itself in the following form: *Reinforced Clostridium Medium (OXOID) After spreading a standardized inoculum (OD= 1.8 at 450 nm) on the agar (RCM+furazolidone) in a Petri dish, a 9 mm-diameter disc is placed at the centre of the dish. 50 ,ug of erythromycin (dissolved in DMSO) are deposited on the disc.

After 6 days at 36"C in an anaerobic medium (B.B.L) GAS-PAK system), a zone over which the growth of the strain is inhibited is cleariy visible (total diameter=42 mm), the vast majority of the colonies being located at the periphery of the inhibition zone.

In contrast, some colonies appear clearly within this zone.

The two types of colonies are then withdrawn by scraping the agar medium (sterilized platinum ioop): 1) strains designated as P37 EO because of their apparent resistance to erythromycin are withdrawn from within the inhibition zone and 2) strains designated as P37 E are withdrawn from an area 1 cm beyond the periphery of the inhibition zone.

After isolation and culture, strains P37 E" and P37 EO indeed show very different sensitivities to erythromycin as illustrated by the following respective MIC values: MIC (,zg/ml) P 37 0.78 P 37 E 0.78 P 37 E' 50 This phenomenon is confirmed by studying the IC50 (50% inhibitory concentration) which represents the erythromycin concentration at which 50% of the organisms in the population are found to survive, at a constant culture period.

IC50 (,ag/ml) P 37 50 P 37 E 5 P 37 E-- 100 The Minimal Inhibitory Concentration (MIC) expressed as Hg/ml of the retinoic acid esters of erythromycin A, lincomycin and clindamycin tested against strains P 37s and P 376 is reported in the following table: RETINOIC ACID ESTERS P 37 Es P 37 Ee OF ANTIBIOTICS (sensitive) (resistant) 2'-0-(all-trans-retinoyl)erythromycin A 14 13 2'-0-(1 3-cis-retinoyl)- erythromycin A 20 34 3-0-(13-cis-retinoyl)- lincomycin 17.5 25 3-0-(all-trans-retinoyl)clindamycin 18 50 3-0-(1 3-cis-retinoyl)clin- damycin 1.5 35 CONTROLS: 2'-0-oleoylerythromycin A (Z-9) 50 100 3-0-oleoyllincomycin 19 42 3-0-oleoylclindamycin 54 > 138 Erythromycin A 1 > 50 Lincomycin 13 66 Clindamycin 1 10 The table below shows the minimal inhibitory concentrations of the retinoic acid esters of antibiotics for two strains of Staphylococcus epidermidis: RETINOIC ACID ESTERS Staph. epi. 3 Staph. epi. 6 OF ANTIBIOTICS 2'-0-(all-transretinoyl)erythromycin A 75 80 2'-0-( 1 3-cis-retinoyl)- erythromycin A 110 110 3-0-(13-cis-retinoyl)- clindamycin 113 113 3-0-(13-cis-retinoyl)- lincomycin 100 100 CONTROLS: erythromycin A 13 30 ciindamycin 7 8 lincomycin 14 20 The strain "Staph. epi. 3" is isolated from a patient carrying acne whereas the strain "Staph.

epi. 6" is isolated from a patient not carrying acne. The isolation of these strains is carried out according to the WILLIAMSON-KLIGMAN method ("A new method for the quantitative investigation of cutaneous bacteria" P. WILLIAMSON and A. KLIGMAN, J.l.D., Vol. 45, No. 6, 1965).

Decimal dilutions of the samples are carried out and a selective medium which enables Staphylococcus to be isolated is inoculated with 0.1 ml of these dilutions.

As can be seen from the first table, the retinoic acid esters of erythromycin A and lincomycin are more active against the resistant strains of Propionibacterium acnes than the parent antibiotics. Additionally, the 2'-oleic acid ester of erythromycin A (US Patent 2,862,921) and the 3-oleic acid ester of clindamycin (German Offenlegungsschrift 2,017,003), taken as the esters for comparison, prove to be significantly less active against the sensitive (P 37 E +) and the resistant (P 37 E -) strains than the esters of the invention, thus emphasizing the value especially of the retinoic acid esters of erythromycin A and clindamycin. The second table, for its part, shows the value of all these retinoic acid esters of antibiotics with regard to the "ecology of the skin", given that they are much less active against Staphylococcus epidermidis strains than the parent antibiotics.

Several examples for the preparation of retinoic acid esters of antibiotics according to the invention and several examples of pharmaceutical or cosmetic compositions for use in the treatment of dermatitides, especially of acne, will now be given by way of example.

EXAMPLE Preparation of 2'-0-(13-cis-retinoyl)erythromycin A 5 g (16.6 mmoles) of 13-cis-retinoic acid are dissolved in 35 ml of anhydrous tetrahydrofuran, in a round-bottomed flask, under an inert atmosphere; the reaction mixture is cooled to 00C and 3 ml (38 mmoles) of anhydrous pyridine and 1.6 ml (16.6 mmoles) of ethylchloroformate are then poured in. The solution is stirred for 5 minutes and 2.5 g (30 mmoles) of sodium hydrogencarbonate and then 4.9 g (6.7 mmoles) of erythromycin A which has previously been dissolved in 150 ml of tetrahydrofuran are added. The reaction mixture is then maintained stirred for 10 hours, allowing the temperature to rise to the ambient temperature (silica gel thin layer chromatography: methylene chloride : methanol 10%).The solution is then 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 thereby obtained is chromatographed on a silica gel column (HPLC) using an ethyl acetate : hexane (7 : 3) mixture as the eluant, which results in the isolation of 4.4 g (65% yield) of pure 2'-0-(13-cisretinoyl)erythromycin A.

m.p.=82 C (hexane : ethyl acetate) [a]202=-170 (C=6 mg/ml dichloromethane) Microanalysis: C5,Hg3NO,4; M=1016.4 C H N Calculated % : 67.36 9.22 1.38 Found % 67.48 9.32 1.38 Infrared spectroscopy: band at 1735 cm-1 (ester) '3C NMR (CDCl3, internal reference TMS) The negative y effects in positions 1' (-2.2 ppm) and 3' (-2.1 ppm) show the 2-position of the ester. The carbon atoms C"20 (20.94 ppm), C"14 (117.28 ppm) and C",2 (131.9 ppm) of the retinoic acid chain are in agreement with the 13-cis-stereochemistry of the retinoic acid chain.

EXAMPLE 2 Preparation of 2'-0-(all-trans-retinoyl)erythromycin A 5 g (16.6 mmoles) of all-trans-retinoic acid are dissolved in 35 ml of anhydrous tetrahydrofuran in a round-bottomed flask, under an inert atmosphere. The reaction mixture is cooled to 0 C and 3 ml (38 mmoles) of anhydrous pyridine and 1.6 ml (16.6 mmoles) of ethyl chloroformate are then poured in; the solution is stirred for 5 minutes and 2.5 g (30 mmoles) of sodium hydrogencarbonate and then 4.9 g (6.7 mmoles) of erythromycin A which has previously been dissolved in 150 ml of tetrahydrofuran are added. The reaction mixture is then maintained stirred for 10 hours allowing the temperature to rise to the ambient temperature (silica gel thin layer chromatography: 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 thereby obtained is chromatographed on a silica gel column (HPLC) using an ethyl acetate : hexane (7:3) mixture as the eluant, which results in the isolation of 4.1 g (60% yield) of pure 2'-0-(all-trans-retinoyl)eryth- romycin A.

m.p.=76 C (ethyl acetate : hexane) [aj202=-650C (C=2 mg/ml dichloromethane) Microanalysis: C57Hg3NO,4. 4H20; M=1088.5 C H N Calculated 9/0 : 62.89 9.35 1.29 Found % 62.91 8.90 1.29 '3C NMR (CDCl2, internal reference TMS) The negative y effects in positions 1'(-2 ppm) and 3'(- 1.9 ppm) show the 2'-position of the ester. The carbon atoms C"20 (14.1 ppm), C"14 (119.36 ppm) and C"12 (135.19 ppm) are in agreement with the all-trans-stereochemistry of the retinoic acid chain.

EXAMPLE 3 Preparation of 3-0- (all- trans-re tino yI)clindamycin 5 g (16.6 mmoles) of ali-trans-retinoic acid are dissolved in 30 ml of anhydrous tetrahydrofuran in a round-bottomed flask, under an inert atmosphere; the reaction mixture is cooled to 0 C and 6 ml (76 mmoles) of anhydrous pyridine and 1.6 ml (16.6 mmoles) of ethyl chloroformate are poured in; the solution is stirred for 5 minutes and 1.25 g (15 mmoles) of sodium hydrogen carbonate and then 2.35 g (5.5 mmoles) of clindamycin, which has previously been dissolved in 100 ml of a tetrahydrofuran : pyridine (8 : 2) mixture, are added. The reaction mixture is then maintained stirred for 10 hours, allowing the temperature to rise to the ambient temperature (silica gel thin layer chromatography; 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 sulphate, filtered and then concentrated under partial vacuum. The crude product thereby obtained is chromatographed on a silica gel column (HPLC) using an ethyl acetate RETINOIC ACID ESTERS P 37 Es P 37 Ee OF ANTIBIOTICS (sensitive) (resistant) 2'-0-(all-trans-retinoyl)erythromycin A 14 13 2'-0-(1 3-cis-retinoyl)- erythromycin A 20 34 3-0-(13-cis-retinoyl)- lincomycin 17.5 25 3-0-(all-trans-retinoyl)clindamycin 18 50 3-0-(13-cis-retinoyl)clin- damycin 1.5 35 CONTROLS: 2'-0-oleoylerythromycin A (Z-9) 50 100 3-0-oleoyllincomycin 19 42 3-0-oleoylclindamycin 54 > 138 Erythromycin A 1 > 50 Lincomycin 13 66 Clindamycin 1 10 The table below shows the minimal inhibitory concentrations of the retinoic acid esters of antibiotics for two strains of Staphylococcus epidermidis: RETINOIC ACID ESTERS Staph. epi. 3 Staph. epi. 6 OF ANTIBIOTICS 2'-0-(ali-trans- retinoyl)erythromycin A 75 80 2'-0-(1 3-cis-retinoyl)- erythromycin A 110 110 3-0-(1 3-cis-retinoyl)- clindamycin 113 113 3-0-(13-cis-retinoyl)- lincomycin 100 100 CONTROLS: erythromycin A 13 30 clindamycin 7 8 lincomycin 14 20 The strain "Staph. epi. 3" is isolated from a patient carrying acne whereas the strain "Staph.

EXAMPLE Preparation of 2'-0-(13-cis-retinoyl)erythromycin A 5 g (16.6 mmoles) of 13-cis-retinoic acid are dissolved in 35 ml of anhydrous tetrahydrofuran, in a round-bottomed flask, under an inert atmosphere; the reaction mixture is cooled to 0 C and 3 ml (38 mmoles) of anhydrous pyridine and 1.6 ml (16.6 mmoles) of ethylchloroformate are then poured in. The solution is stirred for 5 minutes and 2.5 g (30 mmoles) of sodium hydrogencarbonate and then 4.9 g (6.7 mmoles) of erythromycin A which has previously been dissolved in 150 ml of tetrahydrofuran are added.The reaction mixture is then maintained stirred for 10 hours, allowing the temperature to rise to the ambient temperature (silica gel thin layer chromatography: methylene chloride : methanol 10to). The solution is then 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 thereby obtained is chromatographed on a silica gel column (HPLC) using an ethyl acetate : hexane (7 : 3) mixture as the eluant, which results in the isolation of 4.4 g (65% yield) of pure 2'-0-(13-cisretinoyl)erythromycin A.

m.p.=82 C (hexane : ethyl acetate) [aj022=-170 (C=6 mg/ml dichloromethane) Microanalysis: C57Hg3NO,4; M=1016.4 C H N Calculated %: 67.36 9.22 1.38 Found % 67.48 9.32 1.38 Infrared spectroscopy: band at 1735 cm-' (ester) '3C NMR (CDCl3, internal reference TMS) The negative y effects in positions 1' (-2.2 ppm) and 3' (-2.1 ppm) show the 2'-position of the ester. The carbon atoms C"20 (20.94 ppm), C"14 (117.28 ppm) and C",2 (131.9 ppm) of the retinoic acid chain are in agreement with the 13-cis-stereochemistry of the retinoic acid chain.

EXAMPLE 2 Preparation of 2 '-O-(all-trnns-retinoyll erythromycin A 5 g (16.6 mmoles) of all-trans-retinoic acid are dissolved in 35 ml of anhydrous tetrahydrofuran in a round-bottomed flask, under an inert atmosphere. The reaction mixture is cooled to 0 C and 3 ml (38 mmoles) of anhydrous pyridine and 1.6 ml (16.6 mmoles) of ethyl chloroformate are then poured in; the solution is stirred for 5 minutes and 2.5 g (30 mmoles) of sodium hydrogencarbonate and then 4.9 g (6.7 mmoles) of erythromycin A which has previously been dissolved in 150 ml of tetrahydrofuran are added. The reaction mixture is then maintained stirred for 10 hours allowing the temperature to rise to the ambient temperature (silica gel thin layer chromatography: 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 thereby obtained is chromatographed on a silica gel column (HPLC) using an ethyl acetate : hexane (7:3) mixture as the eluant, which results in the isolation of 4. 1 g (60% yield) of pure 2'-0-(all-trans-retinoylìeryth- romycin A.

m.p.=76 C (ethyl acetate : hexane) [a]202=-650C (C=2 mg/ml dichloromethane) Microanalysis: Cs7Hg3N0l4 4H20; M=1088.5 C H N Calculated O/o : 62.89 9.35 1.29 Found % 62.91 8.90 1.29 '3C NMR (CDCl3, internal reference TMS) The negative y effects in positions 1'(-2 ppm) and 3'(- 1.9 ppm) show the 2-position of the ester. The carbon atoms C"20 (14.1 ppm), C",4 (119.36 ppm) and C",2 (135.19 ppm) are in agreement with the all-trans-stereochemistry of the retinoic acid chain.

EXAMPLE 3 Preparation of 3-O-(all-trans-retino yl)clindam ycin 5 g (16.6 mmoles) of all-trans-retinoic acid are dissolved in 30 ml of anhydrous tetrahydrofuran in a round-bottomed flask, under an inert atmosphere; the reaction mixture is cooled to 0 C and 6 ml (76 mmoles) of anhydrous pyridine and 1.6 ml (16.6 mmoles) of ethyl chloroformate are poured in; the solution is stirred for 5 minutes and 1.25 g (15 mmoles) of sodium hydrogen carbonate and then 2.35 g (5.5 mmoles) of clindamycin, which has previously been dissolved in 100 ml of a tetrahydrofuran : pyridine (8 : 2) mixture, are added. The reaction mixture is then maintained stirred for 10 hours, allowing the temperature to rise to the ambient temperature (silica gel thin layer chromatography; 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 sulphate, filtered and then concentrated under partial vacuum. The crude product thereby obtained is chromatographed on a silica gel column (HPLC) using an ethyl acetate hexane (5 : 5) mixture as the eluant, which results in the isolation of 2.15 g (55% yield) of pure 3-0-(all-trans-retinoyl)clindamycin.

m.p.=62"C [a]2D2=+50 (C=100 mg/ml dichloromethane) Microanalysis: C38H59N2SO6CI. 2.5H20: M=752.5 C H N Calculated O/o : 60.44 8.08 3.23 Found % : 60.66 8.57 3.72 13C NMR (CDCl3, internal reference TMS): negative y effects in position 4 (-2.8 ppm) and in position 2 (-1.9 ppm). The chemical shifts of carbon atoms C"14 (117.84 ppm) and C"20 (14.11 ppm) confirm the all-trans-stereochemistry of the retinoyl chain.

EXAMPLE 4 Preparation of 3-0-( 1 3cis-retino yl)clindamycin 5 g (16.6 mmoles) of 13-cis-retinoic acid are dissolved in 30 ml of anhydrous tetrahydrofuran in a round-bottomed flask, under an inert atmosphere; the reaction mixture is cooled to 0 C and 6 ml (76 mmoles) of anhydrous pyridine and 1.6 ml (16.6 mmoles) of ethyl chloroformate are then poured in; the solution is stirred for 5 minutes and 1.25 g (15 mmoles) of sodium hydrogencarbonate and then 2.35 g (5.5 mmoles) of clindamycin, which has previously been dissolved in 100 ml of a tetrahydrofuran : pyridine (8 : 2) mixture, are added. The reaction mixture is then maintained stirred for 10 hours, allowing the temperature to rise to the ambient temperature (silica gel thin layer chromatography; 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 sulphate, filtered and then concentrated under partial vacuum. The crude product thereby obtained is chromatographed on a silica gel column (HPLC) using an ethyl acetate hexane (5 : 5) mixture as the eluant, which results in the isolation of 2 g (51% yield) of pure 30-(1 3-cis-retinoyl)clindamycin.

m.p.=95 C (hexane : ethyl acetate) [a]200= + 1110 (C= 15 mg/ml dichloromethane) Microanalysis: C38H59CIN2SO6; M=707.4 C H Calculated 9b : 64.52 8.41 Found % 64.47 8.45 '3C NMR (CDC13, internal reference TMS) The position of the ester is shown by the positive fi effect in position 3 (+ 1.77 ppm) and the negative y effects in positions 2 (- 1.4 ppm) and 4 (-2.5 ppm). The 13-cis configuration is confirmed by the carbon atoms C"20 (20.93 ppm) and C",4 (115.94 ppm).

EXAMPLE 5 Preparation of 3-0-(13-cis-retinoylJlincomycin 5 g (16.6 mmoles) of 13-cis-retinoic acid are dissolved in 30 ml of anhydrous tetrahydrofuran in a round-bottomed flask, under an inert atmosphere; the reaction mixture is cooled to 0 C and 6 ml (76 mmoles) of anhydrous pyridine and 1.6 ml (16.6 mmoles) of ethyl chloroformate are poured in; the solution is stirred for 5 minutes and 1.25 g (15 mmoles) of sodium hydrogen carbonate and then 2.2 g (5.4 mmoles) of lincomycin, which has previously been dissolved in 100 ml of a tetrahydrofuran : pyridine (7 : 3) mixture, are added. The reaction mixture is then maintained stirred for 10 hours, allowing the temperature to rise to the ambient temperature (siiica gel thin layer chromatography: 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 sulphate, filtered and then concentrated under partial vacuum. The crude product thereby obtained is chromatographed on a silica gel column (HPLC) using an ethyl acetate hexane (8 2) mixture as the eluant, which results in the isolation of 1.85 g (50% yield) of pure 3-0-(1 3-cis-retinoyl)lincomycin.

m.p.=95 (hexane : ethyl acetate) [a]020=+1030 (C=7 mg/ml dichloromethane) Microanalysis: C38H60N2S07. 2.5H20; M = 734.5 C H Calculated 9/0 : 62.18 9.03 Found O/o % 62.33 8.64 '3C NMR (CDCI3, internal reference TMS) The position of the ester is indicated by the positive ss effect in position 3 (+ 1.6 ppm) and the negative y effects in positions 2 (-2.4 ppm) and 4 (-1.9 ppm). The 13-cis configuration is confirmed by the carbon atoms C"20 (20.98 ppm) and C",4 (115.83 ppm).

EXAMPLE 6 Preparation of the mixture of monoesters of 7-0-(all-trans-retinoyl)lincomycin, 3-0-(all-trans-reti- noyl)lincomycin and 2-O-(aII-trans-retinoyl)llncomycin 30 g (74 mmoles) of lincomycin are dissolved in 300 ml of anhydrous N,N-dimethylformamide in a round-bottomed flask, under an inert atmosphere, and 830 mg (7.4 mmoles) of potassium tert-butylate are then added and the mixture is stirred for 90 minutes at ambient temperature. A solution of 13 g (37 mmoles) of 1-(all-trans-retinoyl)imidazole in 150 ml of N,N-dimethylformamide is then poured in and the resulting medium is stirred for 12 hours at ambient temperature (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 thereby obtained is chromatographed on a silica gel column (HPLC) using an ethyl acetate hexane (7 : 3) mixture as the eluant, which results in the isolation of 39 g (77%) of a mixture of monoesters of lincomycin substituted with all-trans-retinoic acid in positions 2, 3 and 7.

'3C NMR (CDCI3, internal reference TMS) The negative y effects in positions 8 (-2.5 ppm) and 6 (-3.8 ppm) show the site of esterification of a 7-substituted monoester and the negative y effect in position 1 (-4 ppm) shows the 2-substituted monoester and the negative y effects in positions 2 (-2 ppm) and 4 (2.6 ppm) show the 3-substituted position of the monoester. The positions of C, are at 85.06 ppm for the 2-substituted monoester, at 88.45 ppm for the 7-substituted monoester and at 89.67 ppm for the 3-substituted monoester.

The configuration of the all-trans-retinoic acid chain is shown at 117.78 ppm for carbon atom C",4 and at 14.08 ppm for carbon atom C"20; a trace of isomerization is noted by the presence of a peak at 115.2 ppm (C"14) indicating the presence of the 13-cis-isomer.

EXAMPLE 7 Preparation of the mixture of the monoesters of 2-O-(all-trans-retinoyl)clindam ycin, 3-O-(all-trans- retinoyl)clindamycin and 4-0-(all-trans-retinoyl)clindamycin 20 g (47 mmoles) of clindamycin are dissolved in 250 ml of anhydrous N,N-dimethylformamide in a round-bottomed flask, under an inert atmosphere, and 527 mg (4.7 mmoles) of potassium tert-butylate are then added to the reaction mixture which is then stirred for 90 minutes at ambient temperature. A solution of 8.250 g (23.5 mmoles) of 1-(all-trans-retinoyl)imidazole in 150 ml of anhydrous N,N-dimethylformamide is then poured in and the resulting medium is stirred for 12 hours at ambient temperature (silica gel thin layer chromatography: 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 sulphate, filtered and then concentrated under partial vacuum. The crude product thereby obtained is chromatographed on a silica gel column (HPLC) using an ethyl acetate : hexane (5 : 5) mixture as the eluant, which results in the isolation of 28 g (85%) of a mixture of monoesters of clindamycin substituted with all-trans-retinoic acid in positions 2, 3 and 4.

'3C NMR (CDCl3, internal reference TMS) The negative y effect in position 1 (-3 ppm) shows the 2-substituted position of the ester and the negative y effects in positions 4 (-2.8 ppm) and 2 (- 1.9 ppm) show the 3-substituted position of the monoester and the low negative y effect in position 3 shows the 4-substituted position of the monoester.

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

The ail-trans configuration of the retinoic acid chain is predominant (C"14 at 117.5 ppm and C"20 at 14.08 ppm), but traces of isomerization are obvious, especially at C"20 and C"14.

PHARMACEUTICAL AND COSMETIC COMPOSITIONS A. GELS FOR THE LOCAL TREATMENT OF ACNE 1. Hydroxypropylcellulose 1 g Butylhydroxytoluene 0.05 g 3-0-(1 3-cis-retinoyl)lincomycin 0.5 g Isopropanol qs 100 g 2. Hydroxypropylcellulose 1.5 g Butylhydroxytoluene 0.05 g 3-0-(all-trans-retinoyl)clindamycin 0.3 g Isopropanol qs 100 g B. LOTIONS FOR THE LOCAL TREATMENT OF ACNE 1. Butylhydroxytoluene 0.05 g 2'-0-(all-trans-retinoyl)erythromycin A 1 g C8-C,2 fatty acid triglycerides qs 100 g The active compound in this example may be replaced with the same quantity of 2'-0-(13-cisretinoyl)erythromycin A.

2. Butylhydroxytoluene 0.05 g 3-0-(1 3-cis-retinoyl)clindamycin 0.7 g Polytetrahydrofuran dimethyl ether (viscosity 22 cpo) of formula: CH30 CH2)2CH2CH2OinCH3 qs 100 g in which n=5 C. STICK FOR THE LOCAL TREATMENT OF ACNE White petroleum jelly 52 g Liquid paraffin 15 g Refined wax 32 g 2'-0-(ail-trans-retinoyl)erythromycin A 1 g D. SUPPOSITORY (COMPOSITION FOR I UNIT) 2'-0-(all-trans-retinoyl)erythromycin A 0.05 g C8-C12 fatty acid triglycerides 0.25 g Semi-synthetic glycerides qs 2 g E. 500 mg CAPSULES The walls of the capsules are comprised of glycerin, sorbitol and gelatin.

1. Capsule with 50 mg of active compound 2'-0-(13-cis-retinoyl)erythromycin A 50 mg Liquid paraffin 200 mg Thickened liquid paraffin 250 mg 2. Capsule with 10 mg of active compound 2'-0-(13-cis-retinoyl)erythromycin A 10 mg Butylhydroxyaminose 0.05 mg Butylhydroxytoluene 0.05 mg Glycerol tribehenate 100 mg C8-C12 fatty acid triglycerides q.s. 500 mg F. CAPSULES The walls of the capsules are comprised of gelatine and titanium dioxide.

2'-0-(all-trans-retinoyl)erythromycin A 20 mg Colloidal silica 2 mg Magnesium stearate 2 mg Corn starch 76 mg Lactose q.s. 250 mg

Claims

1. A compound which is an ail-trans- or 1 3-cis-retinoic acid ester of erythromycin A, lincomycin or clindamycin, or a salt thereof, or a mixture of such compounds.

2. A compound according to claim 1 wherein the retinoic acid ester is formed in position 2' of erythromycin A.

3. A compound according to claim 1 wherein the retinoic acid ester is formed in position 3 of lincomycin or clindamycin.

4. A compound according to claim 2 or 3 which is: 2'-0-(all-trans-retinoyl)erythromycin A, 2'-0-(1 3-cis-retinoyl)erythromycin A, 3-0-(13-cis-retinoyl)lincomycin, 3-O-(all-trans-retinoyl)clindamycin, or 3-0-(1 3-cis-retinoyl)clindamycin.

5. A process for the preparation of a compound as defined in any one of claims 1 to 4 which comprises reacting, in an anhydrous organic solvent medium, an excess of mixed anhydride of all-trans- or 1 3-cis-retinoic acid with erythromycin A, lincomycin or clindamycin in the basic form, in the presence of an organic or inorganic base.

6. A process according to claim 5 wherein the anhydrous organic solvent is tetrahydrofuran or a mixture of tetrahydrofuran and pyridine.

7. A process according to claim 5 or 6 wherein the organic or inorganic base is pyridine or sodium hydrogen carbonate or a mixture thereof.

8. A process for the preparation of a compound which is an all-trans- or 13-cis-retinoic acid ester of lincomycin or clindamycin as defined in any one of claims 1 to 3 which comprises reacting, in an anhydrous solvent, an imidazolide of all-trans- or 1 3-cis-retinoic acid with lincomycin or clindamycin in the basic form, in the presence of a base.

9. A process according to claim 8 wherein the anhydrous solvent is N,N-dimethylformamide and the base is sodium or potassium tert-butylate.

10. A process according to claim 5 or 8 substantially as hereinbefore described with reference to any one of Examples 1 to 7.

11. A pharmaceutical or cosmetic composition suitable for the treatment of various dermatitides which comprises at least one compound as defined in any one of claims 1 to 4 or obtained by a process as defined in any one of claims 5 to 10, as an active compound, in an anhydrous carrier.

12. A composition according to claim 11 which comprises 0.01 to 10% by weight of the active compound relative to the total weight of the composition.

13. A composition according to claim 12 which comprises 0.05 to 1% by weight of the active compound.

14. A composition according to claim 11, 12 or 13 wherein the carrier is acetone, isopropyl alcohol, a fatty acid triglyceride, a glycol ether, a C1-C4 alkyl ester of a short-chain acid, polytetrahydrofuran ether or a mixture thereof.

15. A composition according to any one of claims 11 to 14 which additionally comprises a thickener.

16. A composition according to claim 15 wherein the thickener is a cellulose or cellulose derivative and is present in a proportion of from 0.5 to 20% by weight relative to the total weight of the composition.

17. A composition according to any one of claims 11 to 16 which additionally comprises an antioxidant, a preservative, a perfume, a colorant or another anti-acne agent.

18. A composition according to claim 11 substantially as hereinbefore defined in any one of Examples A to F.