GB2207134A - Esters of thiamorpholinonecarboxylic acid - Google Patents

Description

ESMS OF THI"RPHOLINODMMWXYLIC ACID AND OF ITS DERIVATIVES, PROCESS FOR

THEIR PREPARATION AND THEIR USE IN THE CO=ICS AND DERMO-PHARMACEUTICAL FIELD

The present invention relates to new esters of thiamorpholinonecarboxylic acid and of its derivatives, the process for their preparation and their use in the cosmetics and dermo-pharmaceuticat field.

The present invention also relates to the sulphoxides of these new esters of thiamorpholinonecarboxyLic acid.

The Applicant Company has already described in French Patents No. 82106, 498 (2,525,220) and No.

82106,499 (2,525,106) the use of thiamorpholinone deri- vatives in the cosmetics and dermatological field, for their hydrating properties as well as for their emollient, softening and skin-suppling action.

The research carried out on these compounds has led to the synthesis of new esters of thiamorpholinonecarboxyLic acid and of its derivatives which, because of their structure, have been found to exhibit not only good cosmetic properties in respect of the suppleness and elasticity of the skin but also an effect on greasy skins.

The tests performed have. in fact, made it possible to demonstrate that these new esters had a beneficial action with regard to sebaceous excretion and in respect of bacterial proliferation.

These new esters are therefore very particularly suitable in the treatment of acne and in the treatment of seborrhoea.

1 - 1 1 The present invention relates, therefore., by way of new industrial products, to esters of thiamorpholinonecarboxylic acid and of its derivatives corresponding to the following general formula: (0)n 1 1 5 2:),co 2-CH C02 R 4 R 3 in which:

n is 0 or 1 R1 and R2, which are identical or different, denote a hydrogen atom or a lower aLkyL radical, R3 denotes a linear or branched alkyl radical containing from 1 to 18 carbon atoms, and R4 denotes a hydrogen atom or a Linear or branched aLkyl radical containing from 1 to 18 carbon atoms..

is and the salts and optical isomers of the said compounds of formula (1). When the radicals R1 and R2 denote a tower alkyl radical, this is a radical containing from 1 to 6 carbon atoms and, especially, a methyl, ethyl, propyl, isopro20 pyl, butyl, pentyl or hexyl radical. Among the linear or branched alkyl radicals containing from 1 to 18 carbon atoms there may be particularly mentioned not only the tower alkyl radicals listed i i above, but also heptyl, 2-ethylhexyl, octyl, nonyl, decyl, dodecyl, tetradecyl or hexadecyL radicals.

When the radical R4 denotes a hydrogen atom in the compounds of formula (I). the active compounds may then be in the form of saLts obtained either with the aid of an inorganic base such as, for example. an alkali or alkatine-earth metal hydroxide. or with the aid of an organic amine such as. for example. triethanolamine.

Among the compounds which correspond to the for- mula (I) above, the following may be mentioned in partic u 1 a r: - 21- ethoxycarbonytethyl 3-thiamorpholinone-5-carboxylate. - 21-carboxyethyl 3thiamorpholinone-5-carboxylate. - 21-ethoxycarbonytethyl 2-methyt-3thiamorpholinone-5- carboxylate, 21-ethoxycarbonylethyl 2,2-dimethyl-3-thiamorpholinone5- carboxylate. 21-ethoxycarbonytethyL 1-oxo-3-thiamorpholinone-ScarboxyLate, - 51-ethoxycarbonyLpentyL 3-thiamorpholinone-5-carboxylate.. 71- ethoxycarbonytheptyl 3-thiamorpholinone-5-carboxylate.. 91- ethoxycarbonylnonyl 2,2-dimethyt-3-thiamorpholinone- 5-carboxylate. and 71-ethoxycarbonylheptyt 2-methyl-3-thiamorpholinone5- carboxylate.

i The present invention also relates to the process for the preparation of the esters of thiamorphoLinonecarboxyLic acid and of its derivatives of formula This process may be represented with the aid of the following reaction scheme:

R R CO2p-4 2 X - C-r- R2:) e.1 CO 2 a 4 0 C02H 3 N C02 - CR (2) H H ( 1) ( I) X = Br or CL According to this process, an alkali metal salt of 3-thiamorpholinone-5-carboxylic acid or of one of its derivatives (1) is reacted with an cc-haloalkyl ester of formula (2) (R4 = Cl-C18 alkyO or an cc-haloalkyl acid (2), R4 = H, (converted into a salt, in the form of the sodium salt).

is The reaction is preferably carried out in an organic solvent such as N.N-dimethylformamide in the presence of an organic diamine such as N,N.NI,NI-tetramethyl-1,3-propanediamine.

The preparation of 3-thiamorpholinone-5-carboxy20 lic acids (1) has been described in French Patents No. 82106,498 and No. 82106,499.

1 3 1 i i i 3 i 1 The cc-haloalkyl esters and the cc-haloalkyl acids of formula (2) are either commercially available pro ducts, or are obtained by following the usual methods of halogenation of alkylearboxylic acids.

The compounds according to the invention of for mula (I), in which n = 1, that is to say sulphoxides, are obtained according to known methods by reacting, at OOC, one equivalent of hydrogen peroxide with an ester of thiamorpholinonecarboxylic acid or with one of its derivatives of formula (I) in which n = 0, in the pre sence of an organic acid such as acetic or formic acid.

The present invention also relates to a cosmetic composition containing, in a cosmetically acceptable medium, at least one compound of formula (I) or one of its salts andlor one of its optical isomers, this com position beijig especially in the form of Lotions, facial creams, body milks, milks or creams for removing makeup, sunscreen milks or creams, foundations, tinted creams, make-up bases. antiwrinkle or eye liner creams. masks, liquid soaps and in the form of shampoos.

In these cosmetic compositionso the concentra tion of active compound is generally between 0.1 and 15% by weight and. preferabLy. between 1 and 10% by weight.

When the compositions according to the invention are dermo-pharmaceutical compositions intended more par ticularly for the treatment of acne, they are preferably in the form of ointments, dyes, creamse salves, powders.

saturated pads, solutions, lotions, gets, sprays or even suspensions.

According to this embodiment, the compositions generally contain from 0.1 to 20% by weight of active compound and, preferably, from 1 to 15% by weight reLative to the total weight of the coffiposition.

These compositions for topical application may be either in anhydrous form or in aqueous form, depending on the clinical indication.

According to an embodiment of the invention, the cosmetic and pharmaceutical compositions may also contain, in addition to the active compound, a pharmacodynamically or cosmetically active agent such as, for example, a hydrating agent like thiamorpholinone and its derivatives, urea, glycerol, pyrrolidonecarboxylic acid, tactic acid or one of the salts of these acids, an antiseborrhoeic or antiacne agent, such as carboxymethylcysteine, S-benzyLcysteamine, their salts and their derivatives. thioxalone. benzoyL peroxide or saticylic acid, an antibiotic Like erythromycine and its esters, neomycin, tetracyclines and 4,5-polymethylene-3-isothiazotones, an agent promoting new hair growth such as minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and its derivatives, diazoxide (7-chloro-3-methyt-1,2,4-benzothiadiazine 1,1dioxide) and phenytoin (5,5-diphenyt2,4-imidazolidinedione). a steroid or nonsteroid antiinfLammatory agent, or a carotenoid, especially 0-carotene.

The compositions according to the invention may also contain preserving agents. stabilizers, moisture regulators, pH regulators, emulsifiers. LIV- A and LIV-S screens, and antioxidants such as cc-tocopherot, butyLhydroxyanisole or butylhydroxytoLuene.

A number of examples of preparation of the active compounds of formula (I) according to the invention and, furthermore, of the cosmetic and deroo-pharmaceutical compositions containing them will now be given by way of illustration and without any Limitation being implied. EXAMPLE I Preparation of 21-ethoxycarbonylethyl 3-thiamorpholinone-5-carboxyLate (Ia: mixtures of diastereoiso- mers; Ib: separation of the two isomers) Ia: A mixture of 96.7 g (0.6 mole) of 3-thiamor pholinone-5-carboxyLic acid, 1 litre of anhydrous N,N dimethylformamide and 41.6 9 (0.3 mole) of potassium carbonate is heated for 10 to 15 min to 800C.

9.6 cm 3 (0.06 moLe) of N.N,NI.NI-tetramethyL 1,3-propanediamine are added to the solution obtained, the heating is discontinued, and 78.3 cm 3 (0.6 mole) of ethyl 2-bromopropionate are then run in dropwise over approximately 30 min. The reaction is instantaneous with simultaneous precipitation-of potassium bromide. The stirring is continued for about 1 h and the reaction mixture is cooled to about 200C and is then poured into 1.5 litres of water. The solution is saturated by adding sodium chloride and is then extracted with toluene (5 x 500 cm3). The toluene phase is dried over sodium sulphate and is evaporated to dryness under reduced pressure. The yellow oil obtained is purified by chromatography on silica gel 60 in the etuent mixture of dichloromethaneltetrahydrofuran (9515). After evaporation and drying in vacuo at 70-800C, 72 9 of 21ethoxycarbonylethyl 3-thiamorpholinone-5-carboxyLate are obtained in the form of a pale yellow waxy solid corresponding to the mixture of diastereoisomers.

The 1H and 13C NMR spectra are consistent with the expected structure.

Elemental analysis: C10H15N05S is C% H% N% 0% S% Calculated 45.96 5.79 5.36 30.62 12.27 Found 45.62 5.76 5.30 30.47 12.08 Ib: Separation of the diastereoisomers (in pairs) into two isomers marked A and S.

22 9 of the mixture of diastereoisomers (obtained according to Example Ia) are taken up with 50 em 3 of ethyl ether; one isomer crystallizes. It is carefully dispersed, filtered off. washed twice with 30-cm 3 portions of ethyl ether, and is dried under vacuum. A first 25 fraction of 10.0 9 of isomer A is thus obtained.

The filtrate is evaporated to dryness. taken up with 20 em 3 of ethyl ether, and is left overnight at 1 1 1 1 1 1 i 1 1 ambient temperature. It is filtered to separate a small quantity of isomer A which has crystallized out. A second fraction of 0.95 9 of isomer A is thus obtained. The two fractions are tombined, are washed with ethyl ether (2 x 10 cm3) and are' dried under vacuum. 10.9 9 of pure isomer A are obtained in the form of white needles mith a melting point of 1070C. Its purity is confirmed by HPLC (5 lim Novapack C18 Z module) and 13 C NMR in deuterochloroform.

Elemental analysis: C10015NOSS C% H% N% 0% S% Calculated 45.96 5.79 5.36 30.62 12.27 Found 45.99 5.86 5.29 30.40 12.27 The filtrate from crystallization of the second fraction of isomer A is evaporated to dryness and dried under vacuum-at 600C. 10.6 9 of isomer a are obtained in the form of a pale yellow oil which slowlv at a temnerature beLow or enuaL crystallizes ver to 200C, taking on the appearance of crvstaltized honey. On heating to a temperature above or equal to 250C, an oil is obtain- ed again (melting point in the region of 25'00. The isomer a thus isolated zontains a quantity of isomer A which is lower than or equal to 5% (HPLC and 13 C NMR).

Elemental analysis: Clofil5NOSS C% H% N% 0% S% Calculated 45.96 5.79 5.36 30.62 12.27 Found 45.98 5.81 5.30 30.51 12.20 - EXAMPLE II Preparation of 21-carboxyethyL 3-thiamorpholinone-5- carboxylate A mixture of 16.1 9 (0.1 mole) of 3-thiamorpho linone-5-carboxyLic acid, 160 em 3 of anhydrous N,Ndimethytformamide and 6.9 9 (0.05 mole) of potassium carbonate is heated up to 1100C under a gentle stream of nitrogen and with stirring. 1.6 em 3 (0.01 mole) of N,N,NI,Nl-tetramethyl-1,3-propanediamine are then added, followed by 16.8 9 (0.11 mole) of 2-bromopropionic acid, added dropwise over 1 h 30. When the addition is complete, stirring and heating are continued for another 30 min. The reaction mixture is then cooled to ambient temperature and is poured into 400 em 3 of water. The solution is saturated by adding sodium chloride and is then extracted four times with 150-cm 3 portions of dichloromethane. The dichtoromethane phase is washed with a saturated sodium chloride solution, is decolourized with animal charcoal, is dried over sodium sul- phate and is evaporated to dryness under reduced pressure. The yellow oil obtained (23 9) crystallizes over a week at ambient temperature. The crystals are dispersed in 30 em 3 of ethyl acetate. are filtered off and are washed three times with 15cm 3 portions of ethyl acetate. The white solid thus isolated is recrystallized from acetonitrite containing a little acetic acid. After drying under vacuum at 800C, 7.9 g of white crystals of 2-carboxyethyl 3-thiamorpholinone-5-carboxylate are obtained. with a melting point of 1760C.

The 1 H 250 MHz NMR spectrum is.consistent with the expected structure.

Elemental Analysis: C8H11NOSS C% H% N% 0% S% Calculated 41.21 4.72 6.01 34.33 13.73 Found 41.15 4.70 6.03 34.22 13.58 EXAMPLE III

Preparation of 71-ethoxycarbonylheptyl 3-thiamorpholinone-5-carboxylate (mixture of diastereoisomers) A mixture of 96.7 9 (0.6 mole) of 3thiamorpholinone-5-carboxylic acid, 800 cm3 of anhydrous N, Ndimethylformamide and 41.6 9 (0.3 mole) of potassium carbonate is heated for 10 to 15 min to 800C. 9.6 cm 3 (0.06 mole) of N,N, NI,Ng-tetramethyl-1,3-propanediamine is added to the solution obtained, the heating is discontinued and 150.8 9 (0.6 mote) of ethyl 2bromooctanoate are run in dropwise over approximately 30 min. When the addition is complete, the stirring is continued until ambient temperature is regained and the mixture is poured into 2 litres of iced water. The aqueous solution is extracted four times with 300-cm3 portions of dichloromethane. The dichloromethane phase is washed with water, is dried over sodium sulphate and is evaporated to dryness under reduced pressure. The oil obtained is purified by chromatography on silica gel 60 in the eluent mixture of dichloromethaneltetrahydrofuran (9515). After evaporation and drying, 124 g of 7' ethoxycarbonylheptyl 3-thiamorpholinone-5-carboxyLate are obtained in the form of a very pale yellow liquid.

The 1H 250 MHz NMR spectrum is consistent with the expected structure.

Elemental analysis: C15H25NO5S C% H% Calculated 54.36 7.60 Found 53.87 7.63 EXAMPLE IV

N% 0% S% 4.23 24.14 9.68 4.14 24.57 9.47 Preparation of 21-ethoxycarbonylethyl 2-methyt3-thiamorphotinone-5- carboxylate (mixture of diastereoisomers) is A mixture of 3.5 g (0.02 mole) of 2-methyl-3thiamorpholi.pone-5-carboxylic acid, 70 cin3 of anhydrous N,Ndimethylformamide and 1.41 g (0.01 mole) of potassium carbonate is heated for 45 minutes to 800C. 0.3 cin 3 of N,N..NI.NI-tetramethyt-1,3propanediamine is then added to the solution obtained. which is stirred for 10 minutes, and 2.9 cm 3 (0.022 mole) of ethyl 2-bromopro- pionate are run in dropwise over approximately 30 minutes. Stirring is continued for 1 hour while the temperature is allowed to return to the ambient. The reaction mixture is then cooled to below 200C and is poured into 200 cm 3 of iced water. The aqueous solution is extracted with dichloromethane (3 x 150 cm3).

i 1 1 1 1 i i i 1 i i 1 1 1 i i i j i 13 - The dichtoromethane phase is washed with 100 cm 3 of water and is then dried over sodium sulphate and evaporated to dryness. The yellow oil obtained is puri fied by chromatography on silica get 60 in the eLuent mixture of 9515 dichloromethaneltetrbhydrofuran. After evaporation and drying, 4.9 9 of 21-ethoxycarbonylethyl 2-methyL-3-thiamorpholinone-5- carboxyLate are obtained in the form of a colourless oil.

The 1 H 80 MHz NMR spectrum is consistent with the expected structure. Elemental analysis: C11H17NOSS c H N 0 S Calculated 47.98 6.22 5.09 29.06 11.65 Found 47.41 6.27 3.04 29.49 11.50 15 EXAMPLE V Preparation of 71-ethoxycarbonylheptyl 2-methyl3-thiamorphotinone-5- carboxylate (mixture of diastereoisomers) A mixture of 3.5 9 (0.02 mote) of 2-methyL-3thiamorpholinone-5-carboxylic acid, 50 cm 3 of anhydrous N.Ndimethytformamide and 1.45 9 (0.0105 mole) of potassium carbonate is heated for 45 minutes to 800C. 0.3 cin 3 of N.N.NI.NI-tetramethyl-103propanediainine is added to the solution obtainedo which is stirred for 15 minutes.

and 5 cm 3 (0.022 mote) of ethyt'2-bromooctanoate are run, in dropwise over approximately 30 minutes. When the addition is complete. stirring is continued for 2 hours while the temperature is allowed to return to the ambient, and the mixture is then poured into 150 CM3 of iced water. The aqueous solution is extracted three times with 150cm 3 portions of dichloromethane. The dichlorome-thane phase is washed with water, is dried over sodium sulphate and is evaporated to dryness under reduced pressure. The crude oil obtained is purified by chromatography on silica get 60 in di- chloromethane. After evaporation and drying, 5.1 9 of 71ethoxycarbonylheptyl 2-methyl-3-thiamorpholinone-5- carboxylate are obtained in the form of a colourless oil.

The 1H 80 MHz NMR spectrum is consistent with the expected structure. Elemental analysis: C16H27NOSS c H N 0 S Calculated 55.63 7.88 4.06 23.16 9.26 Found 55.65 7.89 4.15 22.95 9.23 EXAMPLE VI Preparation of 21-ethoxycarbonylethyl 3-thiamorpholinone-5-carboxylate (mixture of the two isomers DL and LL) 4.86 9 (30 mmol) of N,NI-carbonyIdiimidazole are added to a suspension of 4.03 9 (25 fflmol) of D.L 3-thiamorpholinone-5-carboxylic acid in 20 cm 3 of dry 1,2-dichtoroethane. kept under nitrogen by means of gentle bubbling, and the mixture is stirred for 1 hour 30 at ambient temperature. 5.9 g (50 mmol) of ethyl L-Lactate are added to the solution thus obtained and Z 1 i - is stirring is continued for 5 hours at ambient temperature.

The mixture is transferred into a separating funnel, is 3 diluted to 100 cm and washed with.0.1 N hydrochloric acid and then with water, is dried over sodium sulphate and is concentrated under-reduced pressure. The yellow oil isolated (3.9 9) is purified by chromatography on silica gel 60 in the eluent mixture of 9515 dichloromethane/tetrahydrofuran. Aft er evaporation and drying, 3. 3 g of a mixture of TL and LL isomers of 21-ethoxyr carbonylethyl 3-thiamorpholinone-5-carboxylate are obtained in the form of a very pale yellow colourless oil.

The 1H 80 MHz NMR spectrum is consistent with the expected structure. Elemental analysis: C10H5NOSS c H N 0 S Calculated -45.96 5.79 5.36 30.62 12.27 Found 45.79 5.65 5.43 30.53 12.21 EXAMPLE VII Separation of the two isomers of 21-ethoxycar- bonylethyl 3-thiamorpholinone-5-carboxylate (DL and LL) obtained in Example VI The mixture of isomers obtained in Example VI is separated by chromatography under pressure on silica gel 60 (230-400 mesh) with elution with a 9713 dichloro- methaneltetrahydrofuran mixture. The first isomer eluted is marked isomer I. It is in the form of a colourless oil. The second isomer is marked isomer II. This 16 - is also an oil which becomes waxy with time. Elemental analysis: C10H15N05S c H N 0 S Calculated 45.96 5.79 5.36 30.62 12.27 Found (isomer 1) 46.07 5.81 5.27 30.80 12.20 Found (isomer 11) 45.91 5.78 5.29 30.82 11.98 1H 250 MHz NMR in CDC13 + TMS: spectra consistent EXAMPLES OF COMPOSITIONS Example 1 - Antiacne gel Ethanol......................................

Propylene glycol.............................

Water........................................

inyl polymer sold by Goodrich under the name of!'Carbopot 940............. ........

Diisopropanolamine 71-Ethoxycarbonylheptyl 3-thiamorpholinone 5-carboxylate 10.00 -Example 2 - Cream for greasy skins with a tendency to acne Cetyl alcohol. ............ Glycerol monostearate..... Polyethylene glycol monostearate.. ........ Liquid paraffin Carboxyv 44.44 9 22.16 g 22.05 g 0.9 9 0.45 9 Sunflower oil.....

71-Ethoxycarbonytheptyl 3-thiamorpholinone- i 5.00 9 3.00 9 3.00 9 6.00 9 13.00 g i i 17 - 5-carboxylate..... Preserving agent.. Water............................... ......... Example 3 - Antiacne get Propylene glycol................. 3,5-Di-tert-butyt-4-hydroxytoLuene HydroxypropyL cellulose.......... PoLyethyLene glycol EthanoL.......................... 10 Compound of ExampLe I, isomer A..

5.00 g 0.3 g 64.7 g 40.00 g 0.02 g 1.00 9 14.9 9 34.08 9 10.00 g

Claims (25)

1. A thiamorpholinonecarboxylic acid compound having the following formula:

R 2)::: CO

2 -111CO2R4 in which:

n is 0 or 1 RI and R 2' which are identical or different, denote a hydrogen atom or a lower alkyl radical, R3 denotes a linear or branched alkyl radical containing from 1 to 18 carbon atoms, and R 4 denotes a hydrogen atom or a linear or branched alkyl radical containing from 1 to 18 carbon atoms. or a salt or optical isomer of a said compound. 2. A compound according to claim lr in which R denotes a hydrogen atom which is in the form of a salt of an inorganic base or an drganic amine.

3. 21-Ethoxycarbonylethyl 3-thiamorpholinone-S carboxylate.

1

4 A i 4. 21-Carboxyethyl 3-thiamorpholinone-5carboxylate

5. 21-Ethoxycarbonylethyl 2-methyl-3thiamorpholinone-5-carboxylate.

6. 21-Ethoxycarbonylethyl 2,2-dimethyl-3thiamorpholinone-5-carboxylate.

7. 21-Ethoxycarbonylethyl 1-oxo-3thiamorpholinone-5-carboxylate.

8. 5'-Ethoxycarbonylpentyl 3-thiamorpholinone10 5-carboxylate.

9. 71-Ethoxycarbonylheptyl 3-thiamorpholinone5-carboxylate.

10. 91-Ethoxycarbonylnonyl 2,2-dimethyl-3thiamorpholinone-5-carboxylate.

is

11. 71-Ethoxycanbonylheptyl 2-methyl-3- thiamorpholinone-5-carboxylate.

12. Process for the preparation of a compound as claimed in any one of claims 1 to 11. which comprises reacting an alkali metal salt of 3thiamorpholinone-520 carboxylic acid compound of formula:

0 1 R A 5 R 2) 1 CO2E a in which:

R 1 and R 2 are as defined in claim ly with a salt of anW -haloalkyl ester or anc.,<-haloalkyl acid of formula:

X - CH CO 2 R 4 R 3 in which:

R 3 and R 4 are as defined in claim 1, and X denotes a bromine or chlorine atom, and if desired,converting the compound obtained into the corresponding sulphoxide using hydrogen peroxide.

13. Process according.to claim 12 which is carried out in N,Ndimethylformamide in the presence of N,bl,NI,Nl-tetramethyl-1,3propanediamine.

14. Process according to claim 12 or 13, in which one equivalent of hydrogen peroxide is reacted in the presence of an organic acid.

15. Process according to claim 12 substantially as described in any one of Examples I to VII.

16. A composition suitable for cosmetics use which contains, in a cosmetic carrier, at least one compound as claimed in any one of claims 1 to 11 or obtained by a process as claimed in any one of claims 12 to 15.

I I

i 7 17. A composition according to claim 16 which contains from 0.1 to 15% by weight of compound of formula (I).

18. A composition according to claim 17 which contains from 1 to 10% by weight of compound of formula I.

19. A dermo-pharmaceutical composition which contains, in a dermopharmaceutical carrier, at least one compound of formula (I) as claimed in any one of claims 1 to 11 or obtained by a process'as claimed in any one of claims 12 to 15.

20. A composition according to claim 19, which contains from 0.1 to 20% by weight of compound of formula (I).

21. A composition according to claim 20 which contains from 1 to 15% by weight of compound of formula

22. A composition according to any one of claims 16 to 21 which additionally contains at least one hydrating agent, an antiseborrhoeic or antiacne agent, an antiobiotic, an agent promoting new hair growth, an antlinflammatory agent or a carotenoid.

23. A composition according to any one of claims 16 to 22 which additionally contains at least one preserving agenty stabilizerp moisture regulatory pH regulator, emulsifier, UV-A and/or W-B screen or an 1 1 antioxidant.

24. A composition according-to claim 16 or 19 1 substantially as described in any one of Examples 1 to 2 0

25. The use of a compound as defined in an. y one of claims 1 to 11 in the treatment of diseases of-the skin 1 i or scalp.

1 i i i i 1 i i i 1 1 i i 1 1 i i i i i 1 i Published 1988 at The Patent Office. State House. 6671 High Holborn. London WC1R 4TP. Purther copies may be obtained from The Patent 0Mce, Wes Branch, St Mary CraY. Orpington. Kent BR5 3RD. Printed by Multiplex techniques ltd, St Mary Cray, Kent. Con. 1,187.