CH639669A5 - Oxoandrostadiene derivatives - Google Patents

Description

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

In GB-PS 1 438 940 the same owner anti-inflammatory steroids of the general formula t

CO

described in what

X represents a hydrogen, chlorine or fluorine atom;

R 'represents a β-hydroxy group, an oxo group or (if X is a chlorine atom) a β-chlorine atom;

s R2 represents a hydrogen atom, a methylene group or an a- or β-methyl group;

R3 represents a hydrogen atom or a Ci-4 alkyl group; R4 represents a fluorine, chlorine, bromine or iodomethyl group or a fluoroethyl group and

10 denotes a single bond or double bond.

In the context of the present invention, a new compound has been found which falls within the broad scope of the general formula I above and which has particularly outstanding properties in comparison with compounds close to ls, as are specifically described in the above GB-PS.

The new compound is chloromethyl-17 a-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl 1-20 l-3-oxoandrosta-l, 4-diene-17ß-carboxylate. It has been shown that this compound has a high topical anti-inflammatory activity in humans, measured according to the McKenzie patch test, in conjunction with a relatively weak systemic activity, such as, for example, 2s by reducing the thymus weight in mice is measured. Furthermore, if the compound is applied locally to the skin of mice, it shows a good ratio of the anti-inflammatory activity, measured by reducing the edema induced by croton oil, to the undesirable systemic, measured by reducing the hypothalamic-pituitary-adre -nalen axis. The results show that the compound according to the invention is valuable for the local treatment of inflammation in humans and animals, with a minimal tendency to produce undesirable systemic side effects.

The novel compound according to the invention can be produced, for example, by the processes described in GB Pat. Nos. 1,384,372 and 1,438,940.

40 According to the invention there is further provided a process for the preparation of the above-mentioned compound which consists in the corresponding 17a-acetoxy-androstane-17ß-carboxylic acid or a functional equivalent thereof or chloromethyl-17a-hydroxy-androstane-17ß-45 carboxylate to esterify to form the compound of the invention.

For example, the compound of the invention can be prepared by reacting a salt of the parent 17ct-acetoxy-17β-carboxylic acid with a compound of the formula CICH2Y, wherein Y is a suitable replaceable substituent, e.g. a halogen atom different from fluorine, preferably bromine or iodine. The preferred halogen compound is iodochloromethane.

The reaction described above is preferably carried out using an alkali salt of parent 17β-carboxylic acid, e.g. a lithium, sodium, potassium or cesium salt or an ammonium salt such as the triethylammonium salt or a quaternary ammonium salt such as the tetrabutylammonium salt, suitably in a polar solvent, especially a dipolar aprotic solvent such as an amide solvent, e.g. Dimethylformamide, dimethylacetamide or hexamethylphosphoramide, or a sulfoxide solvent, e.g. Dimethyl sulfoxide, useful at a temple temperature in the range of 15 to 100 ° C.

According to the invention there is provided a further process for the preparation of the compound mentioned, which consists in a corresponding iodomethyl or bromine

subjecting methyl-17β-carboxylate to a halogen exchange reaction which serves to replace the halogen substituent in the halomethyl group with chlorine. Thus the chloromethyl-17ß-carboxylate compound can be prepared from the corresponding iodomethyl or bromomethyl-17ß-carboxylate compound by reaction with, for example, an alkali metal, alkaline earth metal or an ammonium chloride, e.g. Lithium chloride. The reaction is advantageously carried out in a solvent medium which contains, for example, acetone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, hexamethylphosphoramide or ethanol.

The 17a-acetoxy-17ß-carboxylic acid can be prepared by the process described in GB-PS 1 384 372, as explained in the production process listed below. Alternatively, the parent 17a-hydroxy-17β-carboxylate, which corresponds to the compound according to the invention, can be subjected to an esterification of the 17a-hydroxyl group, the 17a-hydroxy-17β-carboxylate being prepared, for example, by esterification of the corresponding 17a-hydroxy-17ß- carboxylic acid using the procedures described above.

The esterification of the 17a-hydroxy group in the preparation of the new androstane compound can optionally be carried out using conventional techniques, e.g. by reaction of the parent 17a-hydroxy compound with a mixed anhydride of acetic acid, which can be generated, for example, by reaction of acetic acid with a suitable anhydride such as trifluoroacetic anhydride, preferably in the presence of an acidic catalyst, e.g. of p-toluenesulfonic acid or sulfosalicylic acid. Alternatively, the mixed anhydride can be prepared in situ by reacting acetic anhydride with a suitable other acid, e.g. Trifluoroacetic acid.

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

Alternatively, the 17a-hydroxy group can be esterified by reacting the parent 17a-hydroxy compound with acetic anhydride or acetyl chloride, optionally 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. of perchloric acid, p-toluenesulfonic acid or a strongly acidic cation exchange resin, e.g. Amberlite IR 120; The reaction is expediently carried out at a temperature of 25 to 100.degree.

To prepare the 17a ester of 17β-carboxylic acid, which can be used in the preparation of the compound according to the invention, the parent 17a-hydroxy-17ß-carboxylic acid is preferably treated with acetic anhydride, optionally in the presence of a base such as potassium carbonate. This reaction is conveniently carried out at an elevated temperature. A mixed anhydride formed can be solvolysed under acidic (e.g. aqueous acetic acid) or basic (e.g. aqueous pyridine or diethylamine / acetone) conditions. Alternatively, the parent 17a-hydroxy-17β-carboxylic acid can 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 known to the person skilled in the art, it can often be expedient to add the desired substituents in FIGS

639 669

Incorporate 17β positions in an intermediate stage in the preparation of the compound according to the invention, one or more other substituents (or an unsaturation) being introduced in a later stage.

Pharmaceutical compositions (including veterinary compositions) for use in anti-inflammatory or anti-inflammatory therapy are also provided which contain the compound according to the invention together with one or more pharmaceutical carriers or excipients. Compositions which are suitable for topical administration are particularly preferred because of the high topical activity of the compound according to the invention. However, since the compound has some systemic activity when appropriately administered, compositions made for internal use are also valuable.

The active androstane compound can thus be advantageously formulated into preparations which are suitable for topical administration, using a topical vehicle for this. The term "topical administration" as used herein also includes administration by blowing and inhalation. Examples of different types of preparations for topical administration are ointments, lotions, creams, powders, drops (e.g. eye or ear drops), sprays (e.g. for the nose, throat, lungs 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 lungs).

Ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of suitable thickening and / or gelling agents and / or solvents. Such a base can thus be, for example, 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 with an average molecular weight in the range from 200 to 600 or a mono- or diethylene glycol monoethyl ether , or include propylene carbonate. Thickeners that can be used depending on the nature of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols with an average molecular weight in the range of 4000 to 6000, wool fat and beeswax and / or glycerol monostearate and / or non-ionic emulsifiers.

Lotions can be formulated with an aqueous or oily base and generally also include one or more of the following, namely, emulsifiers, dispersants, thickeners, solvents, colorants, suspending agents and fragrances.

Powders for application to the skin can be formulated using any suitable powder or powder base, e.g. Talc, lactose or starch. Drops can be formulated with an aqueous vehicle that also contains one or more dispersants, suspending or solubilizing agents, etc.

Spray compositions can be formulated, for example, as aqueous solutions or suspensions or as aerosols with the aid of a suitable propellant, e.g. Dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or another suitable gas.

Capsules and cartridges for use in an inhaler or a blowing device made of gelatin, for example, can be formulated so that they form a powder mixture of

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639 669

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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 according to the invention depends on the exact nature of the formulations to be produced, but is generally in the range from 0.001 to 5.0% by weight. In general, however, the content for most types of agents is advantageously in the range from 0.005 to 0.5%, and preferably from 0.01 to 0.25%. In the case of powders for inhalation or for blowing in, however, the content is in the range from 0.1 to 2%.

The above formulations for topical application to the skin can be used for the treatment of inflammatory dermatoses of humans and animals, for example eczema, which normally respond to corticosteroid therapy, as well as of less sensitive diseases, such as human psoriasis.

Formulations for inhalation or blowing administration are intended for prophylactic administration to people suffering from allergic and / or inflammatory diseases of the nose, throat or lungs, such as asthma and rhinitis, including high fever. Aerosol formulations are advantageously produced in such a way that each metered dose or each measured blowing volume of the aerosol contains 25 to 200 p.g, preferably approximately 50 µg, of the compound according to the invention. The administration can take place several times a day, for example two, three or four times, with 1,2 or 3 doses being given, for example. The total daily dose with an aerosol is in the range from 100 to 2000 p.g, preferably from 200 to 800 [xg. The total daily dose and the metered dose released by capsules and cartridges in an inhaler or injector is generally twice that of aerosol formulations.

Topical preparations can be administered daily on the diseased area by one or more orders; Final wound dressings over skin areas can often be advantageous.

For internal administration, the new compound according to the invention can be formulated, for example, for oral, parenteral or rectal administration. For oral administration, syrups, elixirs, powders and granules can be used, which can be formulated in the usual way. However, as described below, unit dosage forms are preferred.

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

Preferred forms for internal administration agents are unit dosage forms, i.e. Unit-form preparations, each unit containing a desired dose of the active steroid. Such dosage unit forms contain 1 to 20 mg, preferably 2.5 to 10 mg, of the active steroid. Dosage unit forms suitable for oral administration are, for example, tablets, coated tablets and capsules. For parenteral administration, unit dosage forms include sealed ampoules or vials, each containing the desired dose of the steroid. Suppositories, which can be produced with conventional suppository bases, for example, represent a unit dose form for rectal administration.

The compound according to the invention can generally be applied by internal administration in those cases in which systemic adrenocortical therapy is indicated.

Generally speaking, preparations can be used internally

Administration contain 0.05 to 10% of the active ingredient depending on the type of agent. The daily dose can be from 2.5 to 60 mg, e.g. 5 to 30 mg, vary depending on the disease to be treated, the route of administration and the desired duration of treatment.

The compositions according to the invention may also contain one or more preservatives or bacteriostatic agents, e.g. Methyl hydroxybenzoate, propyl hydroxybenzoate, thiomersal, chlorocresol or benzalkonium chloride. The compositions according to the invention can also contain other active ingredients, such as anti-microbial agents, in particular antibiotics, such as neomycin, nystatin, gentamycin, tetracyclines and cliochinol.

The following examples serve to illustrate the invention. All temperatures are given in ° C and the organic extracts were dried over magnesium sulfate.

Production of the starting products

17a-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoane-drosta-1,4-diene-17ß-carboxylic acid

A suspension of 5.0 g of 9a-fluoro-11β, 17a-dihydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylic acid and 2.11 g of potassium carbonate in 20 ml of acetone was stirred and 19 , 4 ml of acetic anhydride are added and the mixture is then heated under reflux for 2 hours. After cooling, the mixture was treated with 63 ml of water and acidified with 3 ml of concentrated hydrochloric acid, with stirring at 0 ° for about 1 hour. The solid was collected, washed with water and dried in vacuo at 50 ° overnight and then suspended in 114 ml of acetone and treated with 4.8 ml of diethylamine. After 30 minutes volatile material was 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 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 a small volume. The solid product was collected, washed with ethyl acetate and dried in vacuo at 60 ° for 2 days to give 4.916 g of the title compound as colorless crystals, (ethanol) 239.5 nm (El "cm337).

A portion of 1.01 g of the title acid in 5 ml of methanol was converted into 976 mg of the sodium salt, which was precipitated with ether, with 1.3 ml of 2M methanolic sodium hydroxide.

Tetra-n-butylammonium and cesium salts of 17a-ace-toxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylic acids a) Tetra-n-butylammonium salt

A suspension of 2.102 g of the title androstane-17β-carbonic acid in 10 ml of chloroform was 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 the tetra-n-butylammoniumandrostane-17β-carboxylate was separated and used directly.

b) Cesium salt

A solution of 944 mg of androstane-17β-carboxylic acid in 20 ml of methanol was stirred and treated with 3.7 ml of 20% aqueous cesium carbonate to give a slightly cloudy solution of pH 7. This was evaporated to dryness, and the residue was again evaporated twice from methanol and then over s

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639669

Dried overnight in vacuo to give the cesium salt in the form of a foam of 1.592 g, Ju ™ 241 nm (E 196).

Chloromethyl-9a-fluoro-11β, 17a-dihydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate

A mixture of 400 mg sodium 9a-fluoro-lß, 17a-dihydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate and 0.36 ml of chloroiodomethane in 1.3 ml of hexamethylphosphorus amide was stirred for V / i hours at room temperature. The solution was diluted with ethyl acetate and washed successively 3 × with water, 1 × with 5% sodium bicarbonate, water (to a pH of 5 to 6), then dried and evaporated to 443 mg of a yellow solid. This was triturated with ethyl acetate / ether and then with ether (2x); the remaining liquids were evaporated to 230 mg of a foam which was subjected to preparative thin layer chromatography on silica in chloroform-acetone (40: 1, four runs) to give 162 mg of a colorless foam. Two crystallizations from acetone ether gave 37 mg of the title chloromethyl ester from F 174 to 178 ° C (dec., Kofier), À.max (ethanol) 237.5 nm (e 15 400). The mother liquors were collected, evaporated, and the residue was crystallized twice from aqueous methanol to give a second yield of 69 mg from F 174 to 178 ° C (dec.

Kofi he).

Iodomethyl-17a-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate

A solution of 1.056 g of chloromethyl-17cc-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate and 3.774 g of sodium iodide in 30 ml of acetone was stirred and 1. Heated under reflux for 5 hours. The mixture was evaporated, then dissolved in ethyl acetate and washed with water, 10% aqueous sodium thiosulfate, water, 5% aqueous sodium bicarbonate,

Washed water and brine and dried to give 1.277 g of a yellow foam. The product was isolated after preparative thin layer chromatography (chloroform acetone, 20: 1, three runs) as a 951 mg foam and this was crystallized twice from acetone to give the title iodomethyl ester as 677 mg pale yellow crystals of F 174 up to 176 ° C, [a] jy + 18.6 ° (c 1.10, dioxane).

Bromomethyl-17a-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate

A suspension of 250 mg sodium 17a-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-

carboxylate in 7.5 ml hexamethylphosphoramide was stirred with 4.0 ml dibromomethane. The solid had dissolved after about 15 minutes and the reaction was almost complete after about 5 hours as shown by thin layer chromatography (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 of 291 mg io. Preparative layer chromatography (silica, chloroform-acetone 4: 1, three runs) gave 70 mg of the less polar, lower product as crystals; two recrystallizations from acetone gave 42 mg of the title bromomethyl-17a-acetoxy-androstane-17ß-is carboxylate in the form of colorless crystals, F199 to 200 ° (dec., Kofier), [a] 5 ° + 25 ° (c 0 , 51, dioxane), which was found to be about 90% pure by thin layer chromatography on silica (chloroform, eight runs) and 1H NMR.

The following examples illustrate the preparation of the compound according to the invention.

example 1

2s (a) 976 mg of sodium 17cc-acetoxy-9a-fluoro-1ß-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate were in 5 ml of hexamethylphosphoramide with 0.8 ml of chloroiodomethane during Treated for 19 hours and then with a further 0.8 ml of reagent for a further 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 472 mg of colorless 35 crystals of the desired chloromethyl ester. A 170 mg portion, recrystallized from acetone, gave an analytical sample of 144 mg, [a] n> + 32.7 ° (dioxane c 0.308), A. max (ethanol) 239 nm (el5 100).

40 (b) The sodium, cesium and tetra-n-butylammoni salts of 17a-acetoxy-9a-fluoro-l 1β-hydroxy-16ß-methyl-3-oxoandrosta-l, 4-diene-17ß-carboxylic acid were treated with chloroiodomethane in the same manner as described in (a) above, the solvent and the reaction time being listed in the following table. In the experiments carried out with the sodium salt, lithium chloride was added after the reaction. The amount of the desired chloromethyl ester present in the reaction mixture was indicated by HPLC or TLC so (thin layer chromatography).

table

Used as a raw material

17 | i-carboxylate salt

solvent

CICHzI

Mole equivalents

Time (hrs)

LiCJ- (Mol-Aqu.) Added after d. React.

Raw product

yield

(% By weight) *

Product analysis%

according to the invention.

Product**

sodium

(Me2N) 3PO

2.0

1.5

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80

sodium

MeîSO

2.1

23.5

3rd

91.5

68

sodium

MeiN.COCHs

2.1

23.5

3rd

94

61

sodium

Me2N.CHO

2.1

23.5

3rd

88

60

Cesium

(Me2N) 3PO

2.0

5

-

96 (th)

-90

Cesium

Me2NCHO

2.0

33.5

-

115

-75

Bu ^ N

CHCh

2.7

69

-

106

-30 '

* W / W unless otherwise stated "Rated by HPLC or, if indicated as ("), by thin layer chromatography (approximate) for the detectable contaminants by visualization by ultraviolet absorption or fluorescence quenching (254 nm).

639 669

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Example 2

A mixture of 50 mg iodomethyl-17a-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate and 38 mg of lithium chloride in 0.5 ml of hexamethylphosphoramide was added Stirred for 1 hour at room temperature.

By comparison with an authentic sample in thin layer chromatography on silica in chloroform-acetone (10: 1, two runs), it was found that the resulting pale yellow solution contained the desired chloromethyl ester: no starting iodomethyl ester remained.

Example 3

1 mg chloromethyl-9a-fluor-lß, 17a-dihydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate was mixed with a 0.1 ml portion of a mixture made from 1 ml of 15 glacial acetic acid, 0.2 ml of trifluoroacetic anhydride and 0.025 ml of a solution of anhydrous toluene-p-sulfonic acid in chloroform (concentration about 80 mg / ml) were treated. The steroid reaction mixture was then heated to 78 to 80 ° C. for 23 minutes. The resulting solution was cooled and treated with 0.5 ml of 2N sodium carbonate solution and then extracted with 3 × 0.3 ml of ethyl acetate. The combined extracts were evaporated under a stream of nitrogen and the residue was dissolved in chloroform for evaluation by thin layer chromatography on silica. No starting steroid remained and the major product was found to be identical to an authentic sample of the desired chloromethyl-17cc-acetoxyandrostane-17β-carboxylate, using thin layer chromatography on silica in two solvent systems 30 [chloroform-acetone (4: 1 ) and ethyl acetate-petroleum ether (bp. 40 to 60 ° C) (1: 1)].

Example 4

A suspension of 250 mg of sodium 17a-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate in 7.5 ml of hexamethylphosphoramide was mixed with 3.64 ml of chlorobromomethane touched. The solid had dissolved after 15 minutes and evaluation by thin layer chromatography [silica, chloroform-acetone (4: 1)] after 1.5 hours showed that an almost complete reaction had proceeded to form a single major product, equipolar with one 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 255 mg of a colorless crystalline solid, which is characterized by the proton magnetic resonance spectrum in deuterochloroform the desired chloromethyl ester, solvated with hexamethylphosphoramide (about 'A mol) proved.

Example 5

A suspension of 250 g of sodium 17a-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate in 7.5 ml of hexamethylphosphoramide and 3.59 ml Methylene chloride was stirred at room temperature. A clear solution resulted after 5 minutes: after 16 hours, thin layer chromatography on silica in chloroform-acetone (4: 1) showed an approximately 50% conversion into a mixture of two products in approximately equal amounts, one of which was identical to that desired chloromethyl ester.

Example 6

5 mg bromomethyl-17a-acetoxy-9a-fluoro-11β-hydroxy-16ß-

methyl 3-oxoandrosta-1,4-diene-17β-carboxylate and 4 mg lithium chloride in 0.05 ml hexamethylphosphoramide were stirred together at room temperature for 64 hours. Thin layer chromatography on silica in chloroform (five runs) showed that no starting bromomethyl ester remained and that it had been completely converted to the desired chloromethyl ester, as indicated by comparison with an authentic sample.

The following examples (A) to (D) illustrate topical formulations according to the invention. In each example, the active ingredient is chloromethyl-17a-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate.

Example (A)

ointment

Active ingredient 0.1% w / w.

liquid paraffin B.P. 10% w / w.

soft white paraffin to form 100 parts by weight

The active ingredient is ball-milled with a small amount of the liquid paraffin until the particle size is reduced to 95% by number less than 5 ji.m. The paste is diluted and rinsed from the mill with the remaining liquid paraffin and mixed, and the suspension is added to the melted white soft paraffin at 50 ° C. It is stirred until it cools down to form a homogeneous ointment.

Example (B)

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Active ingredient cetostearyl alcohol 40 cetomacrogol 1000 white soft paraffin liquid paraffin chlorocresol acid sodium phosphate 45 purified water

0.1 10.0 2.5 10.0 10.0

0.1

0.5

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Preparation process

The chlorocresol and the acidic sodium phosphate are thus dissolved in the water at about 70 to 75 ° C. The waxes are fused together at about 65 to 70 ° C and added to the aqueous phase with stirring when it has cooled to 65 to 70 ° C. The steroid is micro-comminuted (particle size as defined in BPC 1973, page 911, for Ultra-Fine 55 Powder) and dispersed in a portion of the liquid paraffin. The steroid suspension and the rest of the liquid paraffin are added to the base with stirring at 60-65 ° C. The preparation is cooled to room temperature with stirring.

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Example (C)

Aerosol formulation with metered dosage per dose

% W / w.

65 Active ingredient fluorotrichloromethane dichlorodifluoromethane

0.05 mg 25.5 mg to 85.0 mg

0.059 30.0 to 100.0

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The active ingredient is micro-crushed (particle size as defined in BPC 1973, page 911, for ultra-fine powder) and dispersed in the fluorotrichloromethane. This suspension is placed in an aluminum aerosol container, the headspace is made with gaseous dichlorodifluoromethane

The active ingredient is micro-crushed (particle size as defined in BPC 1973, page 911, for ultra-fine powder) and flushed with lactose in the air exclusion in the above form, and the calibrated aerosol valve is placed in the container. Liquid dichlorodifluoromethane is pumped through the measuring valve under pressure on the weight.

./Weight

specified proportions mixed. The steroid-lac-tose mixture is filled into hard gelatin capsules, which are administered with an inhalation device.

Example (D) Inhalation capsule (100 iig / dose)

per capsule% by weight

Active ingredient 0.1mg 0.4

Lactose to 25.0 mg to 100.0

ß

Claims (10)

639 669 PATENT CLAIMS 1. Chloromethyl-17a-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate. 2. Process for the preparation of chloromethyl-17a-ace-toxy-9a-fluoro-11β-hydroxy-16ß-methy 1-3-oxoandrosta-1,4-diene-17ß-carboxylate, characterized in that 17a-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoane-drosta-l, 4-diene-17ß-carboxylic acid or a functional derivative thereof or chloromethyl-9a-fluoro-lß, 17a-dihy -droxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate esterified accordingly. 3. The method according to claim 2, characterized in that a salt of 17a-acetoxy-9a-fluoro-l lß-hydroxy- 16ß-methyl-3-oxoandrosta-1,4-diene-l 7ß-carboxylic acid with a compound of the formula CICH2Y, wherein Y is a halogen atom different from fluorine. 4. The method according to claim 2, characterized in that chloromethyl-9a-fluorine-lß, 17a-dihydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate with acetyl chloride or acetic anhydride or one mixed anhydride of acetic acid. 5. Process for the preparation of chloromethyl-17a-ace-toxic-9cc-fluoro-11β-hydroxy-16ß-methyl-3-oxoaridrosta-1,4-diene-17ß-carboxylate, characterized in that iodomethyl or bromomethyl -17a-acetoxy-9a-fluoro-1 ß-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate undergoes a halogen exchange reaction which serves to replace the halogen substituent in the halomethyl group with chlorine. 6. The method according to claim 5, characterized in that Y is an iodine or bromine atom. 7. The method according to claim 5, characterized in that iodomethyl- or bromomethyl-17a-acetoxy-9a-fluoro-11 ß-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate with an alkali metal -, alkaline earth metal or an ammonium or quaternary ammonium chloride. 8. Pharmaceutical compositions containing as the active ingredient chloromethyl-17cc-acetoxy-9a-fluoro-11β-hydroxy-16ß-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylate together with one or more pharmaceutical carriers or excipients. 9. Pharmaceutical compositions according to claim 8 for use in the topical treatment of inflammation, which contain the active ingredient together with a vehicle suitable for topical administration. 10. Pharmaceutical compositions according to claim 8, comprising the active ingredient together with a vehicle suitable for internal administration.