SE435626B - ANTI-INFLAMMATORY STEROID - Google Patents

Description

7901100-3 spot test, coupled with a relatively weak systemic activity, for example as measured by lowering the thymus weight in mice.

Furthermore, when the compound is applied topically to the skin of mice, it shows a high degree of anti-inflammatory activity, which is determined on the basis of reduction of croton-induced fate, to undesired systemic activity, is determined on the basis of the lowering of the joint - hypothalamic / pituitary / adrenal axis. These results indicate that the compound of the invention will be valuable in the local treatment of inflammations with minimal tendency to cause undesirable systemic side effects. human and animal The compound of the invention has been compared with the compound of Example 1 of British Pat. The McKenzie patch test, which gives an indication of topical anti-inflammatory activity, found that the compound of the invention had a therapeutic ratio of 36.0 while the compound of Example 1 of British Patent Specification 1,438,940 had a therapeutic ratio of only 7.2.

The novel compound of the invention can be prepared, for example, according to the methods described in British Patents 1,384,372 and 1,438,940.

A process for the preparation of the above compound is described below, which comprises esterifying the corresponding 1α-acetoxy-androstane-126-carboxylic acid (or functional equivalents thereof) or chloromethyl-1-oxy-hydroxy-androstene-126-carboxylate for the preparation of the compound of the invention.

Thus, for example, the compound of the invention may be prepared by reacting a salt of the original 17α-acetoxy-176-carboxylic acid with a compound of the formula ClCH 2 Y, wherein Y is a suitable exchangeable substituent, for example a halogen atom other than fluorine, preferably bromine or iodine. The preferred halogen compound is iodochloromethane. The reaction described above is preferably carried out using Salt salt of the original 17-carboxylic acid, an alkali metal salt, for example lithium, sodium, potassium I or cesium salt or an ammonium salt, such as the triethylammonium salt or a quaternary salt. ammonium salt, such as the tetrabutylammonium salt, preferably in a polar solvent, especially a dipolar aprotic solvent, such as an amide solvent, such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide or a sulfoxide solvent, such as dimethylsulfoxide, suitably at a temperature in the range of 15 ° C. .

According to a further process, the compound of the invention can be prepared by subjecting a corresponding iodomethyl or bromomethyl-17β-carboxylate to a halogen exchange reaction which is to replace the halogen substituent in the halomethyl group with chlorine. Thus, the chloromethyl-17β-carboxylate compound can be prepared from the corresponding iodomethyl- or bromomethyl-17E-carboxylate compound by reaction with, for example, an alkali metal, alkaline earth metal or an ammonium chloride, for example lithium chloride. The reaction is advantageously carried out in a solvent comprising, for example, acetone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, hexamethylphosphoramide or ethanol. The 17α-acetoxy-17B-carboxylic acid can be prepared according to the procedure described in English patent 1,384,372, as also illustrated in the description below.

Alternatively, the original 17α-hydroxy-176-carboxylate corresponding to the compound of the invention may be subjected to esterification of the 17α-hydroxyl group, the 17d-hydroxy-17β-carboxylate being prepared, for example, by esterification of the corresponding 17α-hydroxy-17β-carboxylic acid according to the methods described above.

The esterification of the 17α-hydroxy group in the preparation of the new androstane compound can, if desired, be carried out by conventional techniques, for example by reacting the original 17α-hydroxy compound with a mixed anhydride of acetic acid, which can be prepared, for example, in situ by Acetic acid is reacted with a suitable anhydride, such as trifluoroacetic anhydride, preferably in the presence of an acid catalyst, for example p-toluenesulfonic acid or sulfosalicylic acid. Alternatively, the mixed anhydride can be prepared in situ by reacting acetic anhydride with a suitable additional acid, for example trifluoroacetic acid.

The esterification reaction is conveniently carried out in an organic solvent such as benzene, methylene chloride or an excess of the carboxylic acid used in the formation of the mixed anhydride, the reaction is suitably carried out at a temperature of 20-100 ° C.

Alternatively, the 107-hydroxy group may be esterified by reacting the original 17α-hydroxy compound with acetic anhydride or acetyl chloride, if desired in the presence of non-hydroxylic solvents, for example chloroform, methylene chloride or benzene and preferably in the presence of a strong acid catalyst, e.g. p-toluenesulfonic acid or a strongly acidic cation exchange resin, for example Amberlite IR-120, the reaction is conveniently carried out at a temperature of 25-100 ° C.

For the preparation of the 17α-ester of the 173-carboxylic acid which can be used in the preparation of the compound of the invention, it is advantageously prepared by treating the original 17α-hydroxy-178-carboxylic acid with acetic anhydride, if desired in the presence of a base such as potassium carbonate. This reaction is conveniently carried out at an elevated temperature. Any mixed anhydride may be solvolyzed under acidic (eg aqueous acetic acid) or basic (eg aqueous pyridine or diethylamine / acetone) conditions. Alternatively, the original 17α-hydroxy-17β-carboxylic acid may be treated with acetyl chloride, preferably in a solvent such as a halogenated hydrocarbon, for example methylene chloride and preferably in the presence of a base, such as triethylamine, suitably at a low temperature, for example 0 ° C. As is well known to those skilled in the art, it may occasionally be convenient to design the desired substituents in the 17 and 17 positions at an intermediate stage in the preparation of the compound of the invention, one or more other substituents (or unsaturation) being introduced at a later steps.

The compound of the invention may be used for the preparation of pharmaceutical compositions (comprising veterinary compositions) for use in anti-inflammatory therapy, comprising said compound of the invention together with one or more pharmaceutical carriers or excipients. Compositions adapted for topical administration are particularly suitable in view of the high topical activity of the compound of the invention. Since the compound has some systemic effect, the following routes of administration of the compositions adapted for internal use are also of value.

Thus, the active androstane compound can be advantageously formed into a product suitable for topical administration by means of a topical vesicle therefor. By topical administration as used herein is meant administration by huaffh fi ng u fl xinhakr ring. Examples of different types of products for topical administration include ointments, lotions, creams, powders, drops (for example, eye or ear drops), sprays (for example for the nose, throat, lungs or skin), suppositories, enemas, chewable or suction tablets or pellets (for example for the treatment of aphthous ulcers), capsules or cartridges for use in an inhaler or inhaler and aerosols (for example for the nose, throat or lungs).

Ointments and creams may, for example, be prepared with an aqueous or oily base with the addition of suitable thickening and / or gelling agents and / or solvents. Such a base may comprise, for example, water and / or an oil such as liquid paraffin or a vegetable oil such as peanut 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 diethylene glycol monoethyl ether or propylene carbonate. Thickeners which can be used in accordance with the base used include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol having an average molecular weight in the range 4000f6000, wool grease and beeswax and / or glyceryl monostearate and / or non-ionic emulsifiers.

Lotions can be prepared with an aqueous or oily base and generally also comprise one or more of the following: emulsifiers, dispersants, thickeners, solvents, dyes, suspending agents and perfumes.

Powders for application to the skin can be prepared using any suitable powder base such as talc, lactose or starch.

Drops can be prepared with an aqueous substance and also comprise one or more dispersants, suspending agents or solubilizing agents, etc.

Spray compositions may, for example, be prepared as aqueous solutions or suspensions or as aerosols using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases.

Capsules and cartridges for use in an inhaler or respirator of, for example, gelatin may be prepared containing a powder mixture of the compound of the invention and a suitable powder base, such as lactose or starch.

The proportion of the active androstane compound in the topical compositions depends on the type of product to be prepared but is generally in the range of 0.001 to 5.0% by weight. In general, for most types of products it is advantageous that the proportion used is in the range 0.005 to 0.5% and preferably 0.01 to 0.25%.

However, in the case of powder for inhalation or respirator, the proportion used should be in the range 0.1-2%. The above products for topical application to the skin can be used for the treatment of inflammatory dermatoses in humans and animals, for example eczema, which is normally affected by corticosteroid therapy and also by less susceptible conditions such as psoriasis in humans. The products for administration by inhalation or insufflation are intended for administration on a prophylactic basis to people suffering from allergies and / or inflammatory conditions in the nose, throat or lungs, such as asthma and rhinitis, incl. hay fever. The aerosol products are preferably designed so that each dose or "puff" of aerosol contains 25-200 ng, preferably 50 ng of the compound of the invention. Administration can be several times daily, for example 2, 3 or 4 times, giving for example 1, 2 or 3 doses each time. The average daily dose with an aerosol is in the range of 100 ng - 2000 ng, preferably 200-800 ng. The average daily dose and the measured dose given with capsules and ampoules in an inhaler or insufflator are generally double that of aerosol products.

Topical products can be administered by one or more applications per day in the affected area; on skin areas, occlusive dressings can often be used to advantage.

For internal administration, the novel compound of the invention may be prepared, for example, for oral, parenteral or rectal administration. For oral administration, syrups, elixirs, powders and granules can be used which can be prepared in a conventional manner. However, dosage unit forms are preferred as described below.

For parenteral administration, the compounds may be present in sterile, aqueous or oleaginous carriers, suitably oily carriers, including peanut oil and olive oil.

Suitable forms of products for internal administration are dosage unit forms, for example in unitary form in which each unit contains a desired dose of the active steroid. Such dosage unit forms contain from 1 mg to 20 mg, preferably from 2.5-10 mg of the active steroid. Suitable dosage unit forms for oral administration include tablets, coated tablets and capsules. For parenteral administration I, the dosage unit forms comprise closed ampoules or vials, each containing a desired dose of the steroid. Suppositories, which can be prepared from, for example, conventional commercial suppository bases, provide a dosage unit form for rectal administration.

The compound of the invention may generally be administered by internal administration in cases where systemic adrenocortical therapy is desired.

In general, products for internal administration may contain from 0.05 to 10% of the active substance, depending on the type of product used. The daily dose may vary from 2.5 to 60 mg, for example 5-30 mg, depending on the condition of the person to be treated, the mode of administration and the duration of treatment desired.

Chemicals may also comprise one or more preservatives or bacteriostatic agents, for example methyl hydroxybenzoate, propylhydroxybenzoate, thiomersal, chlorocresol or benzalkonium chloride. The compositions of the invention may also contain other active ingredients such as antimicrobials, especially antibiotics such as neomycin, nystatin, gentamycin, tetracyclines and clioquinol.

The following examples illustrate the preparation of the compound of the invention. The temperatures are given in degrees Celsius and organic extracts were dried over magnesium sulphate.

Preparation 1. 17α-Acetoxy-9α-fluoro-11β-hydroxy-168-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid A suspension of 5.0 g of Qaffluoro-11β, 17β-dihydroxy-16β-methyl -3-Oxoandrosta-1,4-diene-173-carboxylic acid and 2.1 g of potassium carbonate in 20 ml of acetone were stirred and treated with 19.4 ml of acetic anhydride and then refluxed for 2 hours.

After cooling, the mixture was treated with 63 ml of water, acidified with 3 ml of concentrated hydrochloric acid with stirring at about 00 for one hour. The solid was collected, washed with water and dried in vacuo at 500 overnight and then suspended in 14 ml of acetone and treated with 4.8 ml of diethylamine.

After 30 minutes, volatiles were removed under reduced pressure and the residue was treated with 107 ml of water, 600 ml of ethyl acetate was added and the mixture was acidified to pH 1 with 2N hydrochloric acid. The aqueous phase was removed and further extracted with ethyl acetate, the combined ethyl acetate phases were washed well with water, dried and concentrated to a small volume. The solid product was collected, washed with ethyl acetate and dried in vacuo at 600 for 2 days to give the title compound as colorless crystals (4.916 g), gmax (ethanol) 239.5 nm (Elim 337).

An aliquot (1.0 g) of the title acid in 5 ml of methanol was converted with 2M methanol-containing sodium hydroxide (1.3 ml) to 976 mg of sodium salt, which was precipitated with ether.

Pregaration 2.

Tetra-n-butylammonium and cesium salts of 17α-acetoxy-9α-fluoro-11-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acids a) Tetra-n-butylammonium salt A suspension of 2,102 g of the title androstane-17β-carboxylic acid in 10 ml of chloroform were mixed with a solution of 1.702 g of tetra-n-butylammonium hydrogen sulfate and 394 mg of sodium hydroxide in 10 ml of water and stirred for 30 minutes. The organic layer, containing tetra-n-butylammonium androstane-17β-carboxylate, was separated and used directly. b) Cesium salt A solution of 944 mg of the androstane-17% carboxylic acid in 20 ml of methanol was stirred and treated with 3.7 ml of aqueous 20% cesium carbonate to give a slightly cloudy solution with 7901100-3 pH 7 This was evaporated to dryness and the residue was re-evaporated twice from methanol, then dried overnight in vacuo to give the cesium salt as a foam (1.592 g), λmax 241 nm (Eïšm 196).

Preparation 3.

Chloromethyl-9u-fluoro-118,17u-dihydroxy-16B-methyl-3-oxoandrosta-1,4-diene-17B-carboxylate - A mixture of 400 mg of sodium f9a-fluoro-11β, 17d-dihydroxy-16C-methyl -3-Oxoandrosta-1,4-diene-17β-carboxylate and 0.36 ml of chloroiodomethane in 1.3 ml of hexamethylphosphoramide were stirred at room temperature for 3 l / 3 hours. The solution was diluted with ethyl acetate and washed successively with water (3 times), 5% sodium bicarbonate (1 time), water (to pH 5-6), then dried and evaporated to a yellow solid (443 mg). This was triturated with ethyl acetate / ether, then with ether (twice), the resulting liquids evaporated to a foam (230 mg), which was subjected to preparative layer chromatography on silica in chloroform / acetone (40: 1, four runs) to give a colorless foam (162 mg). Two crystallizations from acetone / ether gave the title chloromethyl ester (37 mg), m.p. 174 DEG-114 DEG (sonar solution, Koflerpamax (ethanol) 237.5 nm (E-IS.400). The mother liquors were recovered, evaporated and the residue was crystallized twice from aqueous methanol to form a second crop (69 mg), m.p. 174-1780 (decomposition, Kofler).

Preparation 4.

Iodomethyl-17u-acetoxy-9c-fluoro-116-hydroxy-16E-methyl-3-oxo-androsta-1,4-diene-176-carboxylate A solution of 1,056 g of chloromethyl-17a-acetoxy-9a-fluoro-11E- Hydroxy-16F-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate and 3.774 g of sodium iodide in 30 ml of acetone were stirred and refluxed for 1.5 hours. The mixture was evaporated, then dissolved in ethyl acetate and washed with water, aqueous 10% sodium thiosulfate, water, aqueous 5% sodium bicarbonate, water and brine, dried and evaporated to a yellow foam (1.277 g). The product was isolated after preparative layer chromatography (chloroform / acetone, 20: 1, three runs) as a foam (951 mg) and this was crystallized twice from acetone to give the title iodomethyl ester as pale yellow crystals. (677 mg), m.p. 174 DEG-176 DEG, [.alpha.

Preparation 5.

Bromomethyl-17g-phacetoxy-9a-fluoro-11E-hydroxy-166-methyl-3-oxo-androsta-1,4-diene-17β-carboxylate A suspension of 250 mg of sodium 17-acetoxy-9d-fluoro-11-hydroxy 16-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate in 7.5 ml of hexamethylphosphoramide was stirred with 4.0 ml of dibromomethane.

The solid had dissolved after about 15 minutes and the reaction was almost complete after 5 hours as shown by TLC (silica, chloroform / acetone, 4: 1). After 5.5 hours, the mixture was diluted with 5% 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 (70 mg); two recrystallizations from acetone gave the title bromomethyl-17d-acetoxyandrostane-17β-carboxylate as colorless crystals (42 mg); melting point 199-2000 (decomposition, Kofler), [α] D 25 + 25 ° (c 0.51, dioxane), which by TLC on silica (chloroform, eight runs) and by 1 H-NMR -igt clean.

The following Examples 1-5 illustrate the products of the compound of the present invention.

Example 1. (a) 976 mg of sodium 17d-acetoxy-9-difluoro-11β-hydroxy-16β-methyl--3-oxoandrosta-1,4-diene-17β-carboxylate were treated in 5 ml of hexamethylphosphoramide with 0.8 ml of chloroiodomethane for 19 hours and then with an additional 0.8 ml of reagent for an additional 4.5 hours. The mixture was diluted with ethyl acetate and ether and washed with water, 5% sodium bicarbonate solution, sodium thiosulfate and water, dried and evaporated to give 664 mg of the non-acidic fraction. Recrystallization from acetone gave colorless crystals of the desired chloromethyl ester (472 mg).

A portion (170 mg) recrystallized from acetone gave the analytical sample (144 mg), [α] D + 32.70 (dioxane, c 0.308), λmax (ethanol) 239 nm (g -11.100). f (b) The sodium, cesium and tetra-n-butylammonium salts of 17α-acetoxy: 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-androsta-1,4-diene-17β-carboxylic acid were treated according to a similar procedure as described under (a) above with chloroiodomethane, the solvent and the reaction time are specified in the following table. In the experiments using the sodium salt, lithium chloride was added after the reaction. The amount of the desired chloromethyl ester present in the reaction mixture was determined by HPLC or TLC.

Table 17P Carboxylate Solution ClCH I Time LiCl Impure Product salt used seed mol. Eq. (h) (mol product analysis as starting material eq) yield **% rial to- (weight / Product set weight)% acc. invention The Sodium (Me2N) 3PO 2.0 1.5 3 105 80 “Me2SO 2.1 23.5 3 91.5 68" Me2N.COCH3 2.1 23.5 3 94 61 "Me2N.CH0 2,1 23,5 3 88 60 cesium (Me2m3Po 2,0 5 - 96 (th) aao:" Meznc fl o 2, o 33, 5 - 115 .v75 vi BuQN cnclz 2,7 69 - los ~ so * w / w unless otherwise stated ** determined by HPLC or where indicated (VW by TLC (approximate), taking into account observable impurities determined by ultraviolet absorption: aä® fluorescence quenching (254 nm). 7901100- 3 13 Exemgel 2.

A mixture of 50 mg of iodomethyl-17d-acetoxy-9d-fluoro-11B-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate and 38 mg of lithium chloride in 0.5 ml of hexamethylphosphoramide was stirred at room temperature. temperature below one hour. The resulting pale yellow solution was found to contain the desired chloromethyl ester when compared with an authentic sample on thin layer chromatography on silica in chloroform / acetone (10: 1, two runs); no starting iodine methyl ester remained.

Exemgel 3.

In mg of chloromethyl-9α-fluoro-11β, 17α-dihydroxy-169-methyl-3-oxo-androsta-1,4-diene-175-carboxylate was treated with a portion (0.1 ml) of a mixture prepared from 1 ml of glacial acetic acid, 0.2 ml of trifluoroacetic anhydride and 0.025 ml of a solution of anhydrous p-toluenesulfonic acid in chloroform (concentration approximately 80 mg / ml); the steroid reaction mixture was then heated at 78-800 for 23 minutes. The resulting solution was cooled and treated with 0.5 ml of 2N sodium carbonate solution, then extracted with 3 x 0.3 ml of ethyl acetate; 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 main product was found to be identical with an authentic sample of the desired chloromethyl-17α-acetoxy-androstane-17-carboxylate by TLC on silica in two solvent systems [chloroform / acetone (4: 1) and ethyl acetate / petrol (boiling point 4o-so °) (min.

Exemgel 4.

A suspension of 250 mg of sodium 17α-acetoxy-90-fluoro-11G-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17E-carboxylate in 7.5 ml of hexamethylphosphoramide was stirred with 3.64 ml of chlorobromomethane. .

The solid had dissolved after 15 minutes and TLC examination (silica, chloroform / acetone 4: 1) after 1.5 hours showed that almost complete reaction had taken place, yielding a single main product equivalent to an authentic sample of the desired chloromethyl ester. After 3.25 hours, the reaction mixture was diluted with 20 ml of ethyl acetate and 100 ml of 5% sodium bicarbonate solution; the aqueous phase was further extracted with 2 x 20 ml of ethyl acetate and the combined extracts were washed with 3 x 20 ml of water, dried and evaporated in vacuo to a colorless crystalline solid (255 mg), which was shown by its proton magnetic resonance spectrum in deuteriochloroform the desired chloromethyl ester should be dissolved with about 1/3 mol of hexamethylphosphoramide.

Example 5.

A suspension of 250 mg of sodium polyacetoxy-9d-fluoro-11β-hydroxy-16F-methyl-3-oxoandrosta-1,4-diene-175-carboxylate in 7.5 ml of hexamethylphosphoramide and 3.59 ml of dichloromethane was stirred at room temperature. After 5 minutes a clear solution was obtained; after 16 hours of TLC on silica in chloroform / acetone (4: 1), about 50% conversion to a mixture of two products was obtained in approximately equal amounts, one of which was identical to the desired chloromethyl ester.

Example 6. 5 mg of bromomethyl-17c-acetoxy-9u-fluoro-11β-hydroxy-16B-methyl-3-oxoandrosta-1,4-diene-175-carboxylate and 4 mg of lithium chloride in 0.05 ml of hexamethylphosphoramide were stirred together under 64 hours at room temperature. Thin layer chromatography on silica in chloroform (five runs) showed that no starting bromomethyl ester remained and that everything had been converted to the desired chloromethyl ester which was obtained by comparative experiments with an authentic sample.

The following examples (A) - (D) illustrate topical products in accordance with the invention. In each example, the active substance is chloromethyl-17α-acetoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-androsta-1,4-diene-175-carboxylate. 7901100-3 Example (A) Ointment Active substance 0.1 s (w / w) Liquid paraffin B.P. 10% White soft paraffin to form 100 parts by weight Grind the active substance in a ball mill with a small amount of the liquid paraffin until the particle size has been reduced to 95% for 5 h. Dilute the paste and rinse the mill with the remainder of the liquid paraffin. mix and add the suspension to the melted white soft paraffin at 50 ° C. Stir until everything is cold to form a homogeneous ointment.

Example (B) Cream% (w / w) Active substance 0.1 Cetostearyl alcohol l0.0 Cetomacrogol 1,000 2.5 White, soft paraffin l0.0 Liquid paraffin 10.0 Chlorocresol 0.1 Acidic sodium phosphate 0.5 Purified water to 100 Process for the preparation The chlorocresol and the acidic sodium phosphate were dissolved in water at about 70-750. The wax was melted together at about 65-700 and added with stirring to the aqueous phase when it had cooled to 65-700. The steroid was pulverized (particle size as defined in BPC 1973, p. 911 for ultrafine powder) and dispersed in a portion of the liquid paraffin.

The steroid suspension and the remainder of the liquid paraffin were added to the base with stirring at 60-650. The product was cooled with stirring to ambient temperature. 7901100-3 16 Example (C) Z Aerosol preparation at a controlled dose per dose% (w / w) Active component 0.05 mg 0.059 Fluorotrichloromethane 25.5 mg 30.0 Dichlorodifluoromethane to 85.0 mg 100.0 The active substance is pulverized ( particle size as defined in BPC 1973, p. 911 for ultrafine powder) and dispersed in fluorotrichloromethane. This suspension is filled into an aluminum aerosol canister, the main space Sp0läS with dichlorodifluoromethane in gaseous form to exclude air and a dosing type aerosol valve is attached to the canister. Liquid dichlorodifluoromethane is pumped through the metering valve under pressure to the specified weight.

Example (D) Inhaler capsules (100 Hg / dose) per capsule §_lightweight) Active component 0.1 mg '0.4 Lactose to 25.0 mg 100.0 The active component is pulverized (particle size as defined in BPC 1973, p. 911 for ultrafine powder) and mixed with lactose in the proportions given above. The steroid lactose mixture is filled into hard gelatin capsules for administration with an inhaler.

Claims (1)

1. 79-01 1 00 - 3 h PATENTK RAV Chloromethyl-UK-acetoxy-Qcc-fluoro-11β-hydroxy-solvent-methyl-β-oxoandrosta-1,4-diene-β-carboxylate. 1901100-3 SUMMARY Chloromethyl-.alpha.-oxy-acetoxy-5-fluoro-1,1'HYOOX5- "166'mGtY1'3" C040 "androsta-1,4-diene-17β-carboxylate, which has useful anti-inflammatory properties, process for the preparation thereof and pharmaceutical compositions containing such compounds.