IE47814B1 - Chloromethyl 17alpha-acetoxy-9alpha fluoro-11beta-hydroxy-16beta-methyl-3-oxoandrosta-1,4-diene-17beta-carboxylate - Google Patents

Abstract

The novel compound according to Claim 1 has a high local anti-inflammatory action, but only relatively weak systemic actions; it can therefore be used for the local treatment of inflammations with a minimum risk of undesired systemic side effects. It is prepared by esterification of the corresponding 17 beta -carboxylic acid or a functional derivative thereof, in particular with a chloromethyl chloride, bromide or iodide, or by acetylation of the corresponding chloromethyl 17 alpha -hydroxy-17 beta -carboxylate, or by replacement of iodine or bromine by chlorine, e.g. by means of a metal chloride, in a corresponding iodomethyl or bromomethyl ester.

Description

The present invention relates to an anti-inflammatory steroid of the androstane series.

In our Patsit Specification No. 37925 , we describe and claim anti-inflammatory steroids having the general formula wherein X reprcseiiLs a hydrogen, chlorine or fluorine atom; . X1 represents a β-hydroxy^roup, an oxo group or (when X ' .is’ a chlorine atom) a β-chlorine atom; K represents a hydrogen atom, a methylene group or an aJO or β-methyl group; - - R.-. represents a hydrogen atom or a alkyl group; . · κ£ represents a fluoro-, chloro-, bromo-, or iodo-methyl group or'a- fluoro ethyl group; and__represents 4781 a single or double bond.

We have now discovered a new compound falling within the broad scope of general formula I above and having particularly advantageous properties compared with close analogues thereof specifically described in our above-mentioned Patent Specification.

The new compound is chloromethyl 17u-acetoxy-ya-fiuorollf3-hydroxy-16p-methyl--3-oxoandrosta-l ,4-diene-17p-carboxylate It has been found that this compound has a high topical antiinflammatory activity in man, as measured by the McKenzie patch test, coupled with a relatively weak systemic activity, for example as measured by depression of the thymus weight in mice. Furthermore when the compound is applied locally to the skin of mice, it shows a good ratio of anti-inflammatory activity, as measured by the reduction of croton oil-induced oedema, to undesired systemic activity, as measured by the depression oi the hypothalamo-pituitary-adrenal axis.

These results indicate that the compound of the invention will be of value in the local treatment of Inflammations in man and animals with minimal liability to cause undesired# systemic side effects.

The new compound according to the present invention can be prepared, for example, according to the methods described in Patent Specifications Nos. ' 36000 and 37925.

Thus, according to a further feature of the present invention, we provide a process for the preparation of the above mentioned compound according to the invention which comprises esterifying the corresponding 17a-aeetoxy-androstadiene-17p-earboxylic acid (or functional equivalent thereof) or chioromethyl 17a-hydroxy-androstadiene-17p-carboxylate to produce the compound according to the invention.

Thus, for example, the compound of the invention may be prepared by reacting a salt of the parent 17aacetoxy 17p-carboxylic acid with a compound of formula ClCf^Y wherein Y is an appropriate displaceable substituent, e.g. a halogen atom other than fluorine, preferably bromine or iodine. The preferred halo compound is iodochloromethane.

The above-described reaction is advantageously effected using as the salt of the parent 17β-carboxylic acid an alkali metal, e.g. lithium, sodium,potassium or caesium salt or an ammonium salt such as the triethylammonium salt or a quaternary ammonium salt such as the tetrabutylammonium salt, conveniently in a polar solvent, particularly a dipolar aprotic solvent such as an amide solvent such as dimethylformamide, dimethyiacetamide or hexamethylphosphoramide or a siiphoxide solvent such as dimethylsulphoxide conveniently at a temperature in the range 15-100°C.

According to a further feature of the' present invention we provide a further process for the preparation of the compound according to the invention which comprises subjecting a corresponding iodomethyl or bromomethyl 17βcarboxylate to a halogen exchange reaction serving to replace the halogen substituent in the halomethyl group by chlorine. Thus, the chloromethyl 17p-carboxylate compound may be prepared from the corresponding iodomethyl or bromomethyl 17β-carboxyiate compound 'by reaction with for example an alkali metal, alkaline earth metal or an ammonium chloride, e.g. lithium chloride. The reaction is advantageously effected in a solvent medium comprising for example acetone, mfethyl ethyl ketone, dimethylformamide, dimethyiacetamide, hexamethylphosphoramide or ethanol.

The 17a-acetoxy-17p-carboxylie .acid may be prepared according to the process described in our Patent Specification No. 3G000 as illustrated in the Preparation given hereinafter.

Alternatively, the parent 17a-hydroxy-17p-carboxylate corresponding to the compound according to the invention may be subjected to esterification of the 17a-bydroxyl group, the 17a-hydroxy-17p-carboxylate being prepared for example by esterifying the corresponding 17a-hydroxy-17p-carboxylic acid by the methods described above.

The esterification of the 17a-hydroxy group in the preparation of the new androstadiene compound may. if desired, be effected by conventional techniques, e.g. by reacting the parent 17a-hydroxy compound with a mixed anhydride of acetic acid, which may, for example, be generated in situ by reacting acetic acid with an appropriate anhydride such as trifluoroacetic anhydride preferably in the presence of an acid catalyst, e.g. p-toluene-sulphonic acid or sulphosalicylic acid. Alternatively, the mixed anhydride may be generated in situ by reacting acetic anhydride with an appropriate further acid, e.g. trifluoroacetic acid.

The esterification reaction is advantageously effected in an organic solvent medium such as benzene, methylene chloride or an excess of the carboxylic acid employed in forming the mixed anhydride, the reaction being conveniently effected at a temperature of 20-100°C.

Alternatively, the 17a-hydroxy group may be esterified by reaction of the parent 17oc-hydroxy compound with acetic anhydride or acetyl chloride, if desired, in the presence of non-hydroxylic solvents, e.g. chloroform, methylene chloride or benzene, and preferably in the presence of a strong acid catalyst, e.g. per hloric acid, r-toiuc!:: sulphonic acid or a strongly acidic cation exchange resin, (Registered Trade Mark) e.g, Amberlite/' IR 120, the reaction being conveniently effected at a temperature of 25 to 100°C, For the preparation of the 17a-ester of the 17βcarboxylic acid which may be employed in the preparation of the compound of the invention, it is preferred to treat the parent 17a-hydroxy-17p-carboxylic acid with acetic anhydride, if desired in the presence of a base such as potassium carbonate. This reaction is conveniently effected at an elevated temperature. Any mixed anhydride formed tnay be solvolysed under acidic (e.g. aqueous acetic acid) or basic (e.g. aqueous pyridine or diethylamine/ acetone) conditions. Alternatively, the parent 17a-hydroxy17p-carboxylic acid may be treated with acetyl chloride, preferably in a solvent such as a halogenated hydrocarbon e.g. methylene chloride, and advantageously in the presence of a base such as triethylamine, preferably at a low temperature e.g. 0°C.

As is well known to those skilled in the art it may frequently be convenient to elaborate the desired substituents in the 17a- and 17p-positions at an intermediate stage of the preparation of the compound of the invention, one or more other substituents (or unsaturation) being intro duced at a later stage.

There are also provided pharmaceutical compositions (including veterinary compositions) for use in antiinflammatory therapy, comprising the said compound according to the invention together with one or more pharmaceutical carriers or excipients. Compositions adapted for topical administration are particularly preferred in view of the high topical activity of the compound of the invention. However since the compound has some systemic - 7 activity, following appropriate routes of administration, compositions adapted for internal use are also of value.

Thus the active androstadier.fc compound may advantageously be formulated into a preparation suitable for topical administration with the aid of a topical vehicle therefor.

By topical administration as used herein, we include administration by insufflation and inhalation. Examples of various types of preparation for topical administration, include ointments, lotions, creams, powders, drops, (e.g. eye or ear drops), sprays, (e.g. for the nose, throat, lung or skin), suppositories, retention enemas, chewable or suckable tablets or pellets (e.g. for the treatment of aphthous ulcers), capsules or cartridges, for use in an inhaler or insufflator, and aerosols, (e.g. for the nose, throat or lung). , Ointments and creams may,for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents. Such base may thus, for example, Include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as a polyethylene glycol having an average molecular weight in the range 200-600 or a mono-or di-ethylene glycol monoethyl ether or propylene carbonate. Thickening agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols having an average molecular weight in the range 4,000-6,000,wool fat and beeswax and/or glyceryl monostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will in general also include one or more of the following namely, emulsifying agents, dispersing agents, thickening agents, solvents, colouring agents, suspending agents and perfumes.

Powders for application to the skin may be formed with the aid of any suitable powder base e.g, talc, lactose or starch. Drops may be formulated with an aqueous vehicle also comprising one or more dispersing agents, suspending agents or solubilising agents etc.

Spray compositions may for example be formulated as aqueous solutions or suspensions or as aerosols with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.

Capsules and cartridges for use in an inhaler or insufflator, of e.g. gelatin, rnaj' be formulated containing a powder mix of the compound of the invention and a suitable powder base such as lactose or starch.

The proportion of the active andrcstadiene compound in the topical compositions according to the invention depends on the precise type of formulations to be prepared but will generally be within the range of from 0.001 to 5.0% weight. Generally however for most types of preparations advantageously the proportion used will be within the range of from 0.005 to 0.5% and preferably 0.01 to 0.25%. However with powders Cor inhalation or insufflation the proportion used will be within the range of from 0.1 - 2%.

The forgoing formulations for topical application to the skin may be used for the treatment of inflammatory dermatoses of humans and animals, for example eczema, which are normally responsive to corticosteroid therapy, and also of less responsive conditions such as psoriasis in humans.

The formulations for administration by inhalation or insufflation are intended for administration on a prop47814 hylactic basis to humans suftaring from allergic and/or inflammatory conniLions oi the nose, throat or lungs such as asthma and rhinitis, including hay fever. Aerosol formulations are preferably arranged so that each metered dose or 'puff' of aerosoi contains 25-200 ng, preferably about 50pg of (he compound of the invention. Administration may be several times daily, for example 2,3 or 4 times, giving for example 1,2 or 3 doses each time. The overall daily dose with an aerosol will be within the range 100u.g-2000pg, preferably, 200-800ng. The overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double those with aerosol formulations.

Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may often be used with advantage.

For internal administration the new compound according to the invention may, for example, be formulated for oral, parenteral or rectal administration. For oral adminstration, syrups, elixirs, powders and granules may be used which may be formulated in conventional manner.

Dosage unit forms are however preferred as described below.

For parenteral administration the compounds may be presented in sterile aqueous or oily vehicles, suitable oily vehicles including arachis oil and olive oil.

Preferred forms of preparation for internal administration arc dosage unit forms i.e. presentations in unitary form in which each unit contains a desired dose of the active steroid. Such dosage unit forms contain from bag to 20mg preferably from 2.5 to lu mg of the active steroid. For oral administration suitable Josnge unit forms include* 478 14 - 10 tablets, coated tablets and capsules. For parenteral administration dosage unit forms include sealed ampoules or vials each containing a desired dose of the steroid. Suppositories, which may be prepared for example with con5 ventional commercial suppository bases, provide a dosage unit form for rectal administration.

The compound according to the invention may in general be given by internal administration in cases where systemic adreno-cortical therapy is indicated.

In general terms preparations for internal administration may contain from 0.05 to 107» of the active ingredient dependent upon the type of preparation involved. The daily dose may vary from 2.5 to 60mg, e.g. 5-30mg, dependent on the condition being treated, the route of administration and the duration of treatment desired.

The compositions according to the invention nay also include one or more preservatives or bacteriostatic agents e.g. methyl hydroxy benzoate, propyl hydroxy' benzoate, thiomersal, chlorocresol or benzalkonium chloride. The compositions according to the invention may also contain other active ingredients such as antimicrobial agents, particularly antibiotics, such as neomycin, nystatin, gentamycin, tetracyclines anti clioquinol.

The following examples illustrate the present inven25 tion. All temperatures are in °C., and organic extracts were dried over magnesium sulphate.

Preparation 1 17a-Acetoxy-9g-fluoro-lip-hydroxy-16p-methyl-3-oxoandrosta-1^-diene-l/p-carboxylic acid a suspension of 9a-fluoro-lip, 17a-dihydroxy-16pmethyl-3-oxoandrosta-l,4,-diene-17p-carboxylic acid (5.0g) and potassium carbonate (2.llg.) in acetone (20ml.) was stirred and treated with acetic anhydride (19.4ml.), then heated under reflux for 2 hours. After being cooled, the mixture was treated with water (63ml), acidified with concentrated hydrochloric acid (3ml.) whilst stirring at ca 0° for 1 hour. The solid was collected, washed with water and dried in vacuo at 50° overnight and then suspended in acetone (114ml.) and treated with diethylamine (4.8ml).

After 30 minutes, volatile material was removed under reduced pressure and the residue was treated with water (107ml ); ethyl acetate (600ml.) was added and the mixture was acidified to pH 1 with 2N-hydrochloric acid. The aqueous phase was separated and further extracted with ethyl acetate, the combined ethyl acetate phases were washed well with water, dried and concentrated to low volume. The solid product was collected, washed with ethyl acetate and dried in vacuo at 60° for 2 days to give the title compound as colourless crystals (4.916g.), λ (ethanol) 239.5nm η,, rn«x (E^m 337).

A portion of the title acid (l.Olg.) in methanol (5ml.) was converted with 2M methanolic sodium hydroxide (1.3ml.) to the sodium salt (976mg) which was precipitated with ether.

Preparation 2.

Tetra-n-butylammonium and caesium salts of 17ct-acetoxy-9«fluoro-llg-hydroxy-16g-niethyl-3-oxoandrosta-l,4-diene-17gcarboxylic acids. a) Tetra-n-butylammonium salt.

A suspension of the title androstadiene-178-carboxylic acid (2.102g.) in chloroform (10ml) was mixed with a solution of tetra-n-butylammonium hydrogen sulphate (1.7G2g.) and sodium hydroxide (394mg.) in water (10 ml) and stirred for 30 minutes. The organic layer, containing the tetran-butylammonium androstadifcue-178-carboxylate, was separated and used directly. b) Caesium salt A solution of the androstadiene-l7g-carboxylic acid - 12 (944 mg.) in methanol (20 ml) was stirred and treated with aqueous 20% caesium carbonate (3.7 ml), giving a slightly turbid solution of pH7, This was evaporated to dryness and the residue was re-evaporated twice from methanol, then dried overnight in vacuo to give the caesium salt as a foam (1-5929>' \nax 241nm iESm196>· Preparation 3 Chloromethyl 9ct-fluoro-118,17a-dihydroxy-168-methyl-3-oxoandrosta-1,4-dtene-17B-carboxylate.

A mixture of sodium 9a-£luoro-116 ,il7a-dihydroxy-16£5methy1-3-oxoandrosta-l,4-diene-17f5-carboxylate (400mg.) and chloroiodomethane (0.36ml.)in hexamethylphosphoramide (1.3ml.) was stirred at room temperature for 3 1/3 hours. The solution was diluted with ethyl acetate and washed successively with water (3x), 5% sodium bicarbonate (lx), water (to pH 5-6), then dried and evaporated to a yellow solid (443mg.). This was triturated with ethyl acetate-ether, then with ether (twice)( the resulting liquors were evaporated to a foam (230mg.) whicn was subjected to preparative layer chromatography on silica in chloroform-acetone (40:1, four runs) to give a colourless foam (162mg). Two crystallizations from acetone-ether gave the title chloromethyl ester (37mg.), mp. 174-^8^ (decomp., Kofler), λ___ (ethanol) max 237.5nm (ε 15,400). ' he mother liquors were recovered, evaporated and the residue was crystallized twice from aqueous methanol to give a second crop (69mg,), mp. 174-178°C (decomp. Kofler).

Preparation 4.

Iodomethyl 17a-Acetoxy-9a-fluoro-118-hydroxy-168-methyl-330 oxoandrosta-1,4-diene-17g-carboxylate.

A solution of chloromethyl 17a-acetoxy-9a-fluoro-llghydroxy-16g-methy1-3-oxoandrosta-l,4-diene-17g-carboxylate (1.056g) and sodium iodide (3.774g) in acetone (30ml) was stirred and heated at reflux for 1.5 hours. The mixture was evaporated, then dissolved in ethyl acetate and washed with water, aqueous 10% sodium thiosulphate,water, aqueous - 13 5% sodium bicarbonate, water and brine, dried and evaporated to a yellow foam (1.277g).

The product was isolated after preparative layer chromatography (chloroform-acetone, 20:1, three ,'uns) as a foam (951 mg) and this was crystallised twice from acetone to give the title iodomethyl ester as pale yellow crystals (677 mg)', m.p. 174-176°C, [a]^2 + 18.6° (c 1.10, dioxan) . Preparation 5 Bromomethyl 17a-Acetoxy-9a-fluoro-llg-hydroxy-16B-methyl-3oxoandrosta-1,4-diene-17g-carboxylate.

A suspension of sodium 17a-acetoxy-9a-fluoro-llghydroxy-16|3-methyl-3-oxoandrosta-l,4-diene-17B-carboxylate (250mg.) in hexamethylphosphoramide (7.5ml) was stirred with dibromomethane (4.0ml.), Solid had dissolved after ca 15 minutes and reaction was almost complete after 5 hours as f.bnt.yp hy t.l.c. (silica, chloroform-acetone 4:1) After .5 hours the mixture was diluted with 5¾ sodium bicarbonate and extracted with ethyl acetate; the combined extracts were washed with water, dried and evaporated in vacuo to a foam (291 mg.). Preparative layer chromatography (silica, chloroform-acetone 4:1 three runs) gave the less polar minor product as crystals (70mg.); two recrystallizations from acetone gave the title bromomethyl 17a-acetoxyandrostadiene 178-carboxylate as colourless crystals (42mg.), mp. 199-200° (decomp., Kofler), + 25° (c 0.51, dioxan), shown by t.l.c. on silica (chloroform, eight runs), and by H nmr. to be ca 905 pure.

The following Examples 1-6 illustrate the preparation of the compound according to the present invention.

Example 1 (a) Sodium 17a~acetoxy-9a~fluoro-llg-hydroxy-16gmethyl-3-oxoandrosta-l,4-diene 178-carbcxyla.te (976mg;) was treated in hexamethyl phosphoramide (5ml.) with chloroiodomethane (0.8ml.) for 19 hours then with more reagent (0.8ml.) for a further 4.5 hours. The mixture was diluted with ethyl acetate and ether and washed with water, 5% sodium bicarbonate solution, sodium thiosulphate and water, dried and evaporated to give the non-acidic fraction (664mg.). Recrystallization from acetone gave colourless crystals of the desired chioromethyl ester (472mg). A portion (170mg). recrystallized from acetone gave the analytical sample (144 mg), [o)D + 32.7° (dioxane 0.308), λ max (ethanol) 239nm (ε15,100). (b) The sodium, caesium, and tetra-n-butylammonium salts of 17a-acetoxy-9a-fluoro-118-hydroxy-168-methyl-310 oxo-androsta-l,4-diene-178-carboxylic acid were treated, following a similar procedure to that described in (a) above, with chloroiodomethane, the solvent and the period of reaction being specified in the following Table. In the experiments employing the sodium salt, lithium chloride was added after the reaction. The amount of the desired chloromethyl ester present in the reaction mixture was estimated by HPLC or TLC as indicated.

TABLE 17 β Carboxylate Salt used as starting material Solvent C1CH2X mol.eq. time (hrs) LiCl (mol eq) added after reac- tion Crude Product + yield (w/w) % Product analysis Product acc. to • invention Sodium (Me,N)?PO 2.0 1.5 3 105 80 II Me2SO 2.1 23.5 3 91.5 68 If Me,N.COCH2 2.1 23.5 3 94 61 II Me2N.CHO 2.1 23.5 3 88 60 ▼ Caesium (Me?N)-, PO 2.0 5 - 96 (th) ~90 M Me2NCHO 2.0 33.5 - 115 zv75 ' ▼ T-Bu^N CHC13 2.7 69 106 j w/w unless stated otherwise •j-estimated by h.p.l.c. or, where indicated (▼) , by t.l.c. (approximate), with respect to observable impurities with detection by ultraviolet absorption and fluorescence quenching (254nm) respectively.

Example 2 A mixture of iodomethyl 17a-acetoxy-9a-fluoro-ΙΙβhydroxy-168-methy1-3-oxoandrosta-l,4-diene-176-carboxylate (50mg.) and lithium chloride (38mg.) in hexamethylphosphoramide (0.5ml.) was stirred at room temperature for 1 hour. The resulting pale-yellow solution was shown to contain the desired chloromethyl ester by comparison with an authentic specimen on thin-layer chromatography on silica in chloro15 form-acetone (10:1, two runs): no'startin.g iodomethyl ester remained.

Example 3 Chloromethyl 9a-fluoro-ΙΙβ, 17a-dihydroxy-16f3-methyl3-oxoandrosta-l,4-diene-17g-carboxylate (lmg.) was treated with a portion (0.1ml.) of a mixture prepared from glacial acetic acid (1ml.), trifluoroacetic anhydride (0.2ml.) and a solution (0.025ml) of anhydrous toluene-p-sulphonic acid in chloroform (concentration ca 80mg/ml); the steroid - 16 reaction mixture was then heated at 78-80°C for 23 minutes. The resulting solution was cooled and treated with 2N-sodium carbonate solution (0.5ml.), then extracted with ethyl acetate (3 x 0.3ml.)} the combined extracts were evaporated under a stream of nitrogen and the residue was dissolved in chloroform for examination by thin-layer chromatography on silica. No starting steroid remained and the major product was shown to be identical to an authentic specimen of the desired chioromethyl 17a-acetoxyandrostane-178-carboxylate by t.l.c. on silica in two solvent systems [chloroformacetone (4:1) and ethyl acetate-petrol (bp 40-60°C) (1:1)]. Example 4 A suspension of sodium 17a-acetoxy-9a~fluoro-118hydroxy-16g-methyl-3-oxoandrosta-l,4-diene-178"carboxylate (250mg.) in hexamethylphosphoramide (7.5ml) was stirred with chlorobromomethane (3.64ml.). Solid had dissolved after 15 minutes, and t.l.c. examination (silica, chloroform-acetone 4:1) after 1.5 hours showed almost complete reaction had occurred to give a sole major product, eguipolar with an authentic sample of the desired chioromethyl ester. After 3.25 hours the reaction mixture was diluted with ethyl acetate (20ml) and 5% sodium bicarbonate solution (100ml): the aqueous phase was extracted further with ethyl acetate (2 x 20ml); and the combined extracts were washed with water (3 x 20ml), dried and evaporated in vacuo to a colourless crystalline solid (255mg.) which was shown by its proton magnetic resonance spectrum in deuteriochloroform to be the desired chioromethyl ester solvated with hexamethylphosphoramide (ca. 1/3 mol).

Example 5.

A suspension of sodium 17ct-acetoxy-9a-£luoro-llghydroxy-16g-methyl-3-oxoandrosta-l,4-diene-17g-carboxylate (250mg.) in hexamethylphosphoramide (7.5 ml) and dichloromethane (3.59ml.) was stirred at room temperature. After minutes a clear solution resulted: after 16 hours t.l.c. on silica in chloroform-acetone (4:1) showed ca 50% con47814 - 17 version to a mixture of two products in approximately equal amounts, one of which was identical to the desired chloromethyl ester.

Example 6 Bromotne thyl l?a-acetoxy-9a-fluoro-11 β -hydroxy-16β methyl-3-oxoandrosta-l,4-diene-17p-carboxylate (5 mg ) and lithium chloride (4 mg ) in hexamethylphosphoramide (0.05 ml) were stirred together for 64 hours at room temperature. Thin-layer chromatography on silica in chloroform (five runs) showed that no starting bromomethyl ester remained and that it had all been converted to the desiredchloromethyl ester as indicated by comparison with an authentic specimen. 7814 - 18 The following Examples (A) - (D) illustrate topical formulations in accordance with the invention. In each Example the active ingredient is chloromethyl 17a-acetoxy9a-fluoro-118-hydroxy-16f3-methyl-3-oxoandrosta-l,4-diene176-carboxylate.

Example (A) Ointment Active Ingredient Liquid Paraffin B.P. White soft paraffin to produce 0.1% w/w 10% w/w 100 parts by weight Ball-mill the active ingredient with a little of the liquid paraffin until the particle size is reduced to 95% by number below 5μ. Dilute the paste and rinse out the mill with the remaining liquid paraffin, mix and add the suspension to the melted white soft paraffin at 50°C. Stir until cold to give a homogenous ointment.

Example (B) w/w Cream Active ingredient 0.1 Cetostearyl alcohol 10.0 Cetomacrogol 1,000 2.5 White soft paraffin 10.0 Liquid paraffin 10.0 Chlorocresol 0.1 Sodium acid phosphate 0.5 Purified water to 11 Method of Preparation The chlorocresol and sodium acid phosphate are dissolved in the water at about 70-75°C. The waxes are melted together at about 65-70°C and added with stirring to the aqueous phase When this has cooled to 65-70°C. The steroid is micronised (particle size as defined in BPC 1973 pg.911 for Ultra-Fine powder) and dispersed in a - 19 portion of the liquid paraffin. The steroid suspension and the remainder of the liquid paraffin are added to the base with stirring at 60 to 65°C. The preparation is cooled With stirring to ambient temperature.

Example (C) Metered dose aerosol formulation per dose % w/w Active ingredient 0.05 mg 0.059 Fluorotrichloromethane 25.5 mg 30.0 Dichlorodifluoromethane to 85.0 mg to 100.0 The active ingredient is micron5 zed (-art.i -.1e size as defined in BPC 1973 pg.911 for Ultra-line powder) and dispersed in the fluorotrichloromethane. This suspension is filled into aluminium aerosol containers, the headspace purged with gaseous dichlorodifluoromethane to exclude air, and a metered aerosol valve crimped into position on the container. Liquid dichlorodifluoromethane is pumped through the metering valve, under pressure, to weight.

Example (D) Inhalation capsule (100 Pg/dose) per capsule % w/w Active ingredient 0.1 mg 0,4 Lactose to 25.0 mg to 100.0 The active ingredient is micronized (particle size as defined in BPC 1973 pg.911 fox Ultra-Fine powder) and blended with lactose in the proportions given in the above formula. The steroid lactose blend is filled into hard gelatin capsules to be administered with an inhalation device.

Claims (9)

1. Chloromethyl 17a-acetoxy-9a-fluoro-.l Ιβ-hydroxy-l6βmethyl-3-oxoandrosta-l,4-diene-17B-carboxylate.

2. A process for the preparation of chloromethyl 17aacetoxy-9a-fluoro-HP-hydroxy-16g-methyl-3-oxoandrosta5 l,4-diene-178-carboxylate which comprises either (A) esterifying 17a-acetoxy-9a-fluoro-llg-hydroxy-16g-methyl3-oxoandrosta-l,4-diene-178-carboxylic acid (or a functional equivalent thereof) or chloromethyl 9c-fluoro11β,17a-dihydroxy-16g-methyl-3-oxoandrosta-l,4-diene10 176-carboxylate to produce the desired compound) or (B) subjecting iodomethyl or bromomethyl I7a-acetoxy-9a-fluoro116-hydroxy-168-methyl-3-oxoandrosta-l,4-diene-176carboxylate to a halogen exchange reaction serving to replace the halogen substituent in the halomethyl group 15 by chlorine.

3. A process a? claimed in claim 2 wherein a salt of the said 17a-acetoxy-ya-fiuoro-llp-hydroxy-lbp-niethyl-3oxoandrosta-l,4-dienc-17p-carboxylic acid is reacted with a compound of formula ClCli^Y where Y is a halogen 20 atom other thuii i. 'unr ne.

4. A process as claimed in claim 3 in which Y is an iodine or bromine atom.

5. A process ar claimed in claim 2 wherein the said chloromethyl 9u-fluoro-Lb· ,17it'dihydroxy-16p-mcthyl-325 oxoandrosta-1,4-diene-17p-carboxylate is reacted with acetyl chloride or acetic anhydride or a mixed anhydride of acetic acid.

6. Λ process as claimed in claim 2 wherein iodomethyl or bromomelhyl 17a-accLoxy-9u-fluoro-llg-hydroxy-J6β30 methyl-3-oxoandrosta-J,4-diene-L7p-carboxylate is reacted with an alkali metal, alkaline earth metal or an ammonium or quaternary · '·<ίιimu cliloridi .

7. Pharmaceutical compositions comprising, as active ingredient, chloromethyl 17a-acetoxy-9a-fluoro-llf> -hydroxy35 166-methyl-3-oxoandrosta-l,4-diene-170-carboxylate together with one or more pharmaceutical carriers or excipients.

8. Pharmaceutical compositions as claimed in claim 7 for use in the topical treatment of inflammations comprising - 21 the said active ingredient together with a topical vehicle therefor.

9. Pharmaceutical compositions as claimed in claim 7 5 comprising the said active ingredient together with a vehicle adapted for internal administration.