IL41579A - Fluorinated 2-chloro-16alpha-methyl-17alpha-hydroxypregna-1,4-dien-21-aldehydes and their derivatives,their production and pharmaceutical compositions containing them - Google Patents

Description

-4, "l-m .-'ο τη-ΰΐ T-^'na-al 6-n i D' Oan ninpn »τ:.··3ηι DIIS'» ,D,i>nnVim Fluorinated 2-Ghloro-l6a-methyl-17a-h.ydroxy-pregna-1, -dien-21-aldehydes and their derivatives, their production and pharmaceutical compositions containing them CIBA-GBICrY A.G.

C. 39740 The present invention relates to new -pregnane-21-aldehydes and their derivatives of the general formula I wherein R1 and R2 together represent an oxo group, or each represent a free hydroxy group, a lower alkoxy or a lower alkanoyloxy group, represents a free hydroxy group or a lower alkanoyloxy group, represents an oxo group, or a hydroxy group in the β-position together with a hydrogen atom, and one of the radicals and R^ represents a fluorine atom and the other hydrogen or a fluorine atom and to a process for the production thereof.

The symbols and in the above formula represent, besides an oxo group, particularly hydroxy groups which are esterified with lower aliphatic carboxylic acids, e.g. formic acid, principally with lower alkanecarboxylic acids such as acetic acid, propionic or butyric acid, and is, in particular, a free hydroxy group, or a hydroxy group esterified with a lower alkanecarboxylic acid such as acetic acid, propionic acid, n-valeric acid.

Lower alkoxy groups are particularly those derived fr lower aliphatic alkanols, ethyl alcohol, methyl alcohol, propyl alcohol, iso-propyl alcohol, butyl or amyl alcohols.

In German Patent Specification No. 1 961 867 was described the 2-chloro-6 , 9-difluoro-16 -methyl-pregna-1, 4-dien-21-aldehyde . This compound is of a quite different class of steroid compounds, having in 17-position no hydroxy1 group.

In German Patent Specification No. 1 928 609 as well as in the US Patent Specifications No. 3 519 659 and 3 519 660 antiinflammatory compounds of formula I but having no chlorine atom in position 2, are described.

These compounds have a high antiinflammatory activity.

Comparison tests, using the known foreign-body granuloma test on male rats,, show that the present new compounds have about the same activity as the described compounds not chlorinated in 2-position; but they have much less side-effects. Thus to produce the side-effects on the body-weigh and the adrenal glands due to a certain dosis of the known test compounds, a dosis which is 30 times, respectively 10 times greater is necessary.

The new compounds possess valuable pharmacological properties. They have, in particular, an an inflammatory action, which can be shown in an animal test, e.g. on the rat. The new compounds can be thus used as anti-inflammatory agents. They are however also valuable intermediates for the production of other pregnane compounds, especially such compounds having a pharmacological action.

To be specially emphasised are compounds of the above formula wherein and each represent a free hydroxy or lower alkoxy group, or a free hydroxy group and an etherified hydroxy group, or R1 together with represents an oxo group, whereby the lower alkoxy groups are derived from alkanols having 1-3 carbon atoms, and R_ represents a free hydroxy group or a hydroxy group esterified with a lower alkanecarboxylic acid, R^ represents a free hydroxy group in the β- position together with a hydrogen atom, or an oxo group, and and each represent a fluorine atom, particularly the compound 2-chloro-3,20,21-trioxo-6a, 9a-difluoro-ΙΙβ , 17a-dihydroxy-16a-methyl- -pregnadiene , which has, for example, in the foreign-body granuloma test on the male rat, administered in a dosage amount of 0.03 mg/kg, or applied locally in a dosage amount of 0.01 mg/kg, a pronounced anti-inflammatory action.

The new compounds can be obtained in a manner known per se. The process by which they can be produced, for example, is such that a) in a compound of the formula It wherein R^, R^ and R^ have the above given meanings, and R-, represents an oxo group, or a free or esterified hydroxy group in the β-position, the radical CH?0H is /Rl converted into the CL -group, and obtained ΙΙ-β-acylates R2 r- hydrolysed to the Ιΐβ-hydroxy compounds; or b) in a compound of the formula wherein R^, R^, R^ and have the above given meanings, the 9β , 11/3-epoxy group is split with hydrogen fluoride or with compounds releasing hydrogen fluoride; or c) in a compound of the formula wherein meanings, chlorine is added, if necessary with temporary protection of the 11-hydroxy and/or 20-oxo group, to the 1,2-double bond, and hydrochloric acid eliminated from the obtained 1,2-dichloro compound; and, optionally, obtained compounds of formula (I) wherein and R2 together represent an oxo group, or at least one of the radicals R^ and R^ represents a free hydroxy group, are treated with esterifying or etherifying agents; or obtained compounds of formula (I) wherein at least one of the radicals R^ and R2 represents an esterified or etherified hydroxy' group treated with hydrolysing agents; or in obtained compounds wherein R^ represents a free hydroxy group this group oxidised to the oxo group.

In the case of the introduction of the grouping in Rl compounds of formula (II) by conversion of the group Cl^OH according to the above method a) , the last-mentioned is converted in a manner known per se into the aldehyde group or its above mentioned derivatives . According to a preferred method of procedure, the 21-hydroxyl group is converted into a sulphonic acid ester, e.g. into the p-tosyl ester, this converted with a tertiary aromatic base, e.g. with pyridine, into the quaternary salt, this then converted, in weakly alkaline solution, with a p-nitroso-dialkylaniline, e.g. p-nitroso-dimethylaniline , into the 21-nitrone, and this hydrolysed with diluted aqueous mineral acid to the desired 21-aldehyde.

A further general method of procedure is the direct dehydrogenation of the 21-hydroxypregnane compounds used as starting materials, in a manner known per se, with reducible metal salts. The oxidising agent employed is, - for example, copper- (II) -acetate , in a suitable solvent such as methanol or ethanol, optionally in the presence of an acid, e.g. acetic acid. A special embodiment of this dehydrogenation consists in the treatment of the 21-hydroxypregnane compounds in the presence of the above mentioned reducible metal salts, e.g. copper- (Il)-a-cetate, in catalytic amounts with molecular oxygen. The dehydrogenation of the 21-hydroxy group in the stated starting materials may also be performed with selenium dioxide, advantageously in a suitable solvent, such as methanol or glacial acetic acid.

The reaction can be accelerated or completed by heating.

Finally, dehydrogenation can be effected also with manganese dioxide .

The final materials obtained from the stated starting materials by dehydrogenation in the 21-position with the aid of the above described processes are obtained in various forms depending on the isolation conditions. Thus, the formed aldehydes precipitate from anhydrous alcohols mostly in the form of their hemiacetals . There are formed from hydroxyl-free solvents with the presence of water the 21 , 21-dih.ydroxy compounds corresponding to the aldehydes, which in most cases lose water just on standing over phosphorus pentoxide, and convert with a yellow colouration into the free aldehydes.

By the action of acylating agents, such as carboxylic acid halides or -anhydrides, e.g. acetic acid anhydride, preferably in the presence of a strong inorganic acid, e.g. sulphuric acid, or of an organic sulphonic acid such as p-toluenesulphonic acid, or of a tertiary base such as pyridine, the 21,21-diacyl esters are obtained from the free aldehydes as well as from their hemiacetals and from the corresponding 21 , 21-dihydroxy compounds.

If alcohols in the presence of an acid catalyst are allowed to act on the free aldehydes, on their hemiacetals or on the corresponding 21 , 21-dihydroxy compounds of formula (I), then the corresponding diacetals are obtained. The corresponding reaction with polyvalent alcohols produces the initially mentioned cyclic acetals. To effect the acetal formation, the free aldehydes, their hemiacetals or the corresponding 21, 21-dihydroxy compounds can also be reacted with ortho-formic acid esters of the alcohols concerned.

Optionally, the mentioned diacylates and acetals can be converted by acid or alkaline saponification into the free aldehydes or into the corresponding 21, 21-dihydroxy compounds .

According to method b) , the 9£,ll -epoxy group is split with hydrogen fluoride in a manner known per se .

Anhydrous hydrogen fluoride is used, optionally in an inert solvent such as chloroform, tetrahydrofuran or, in particular, dimethylformamide , or also aqueous hydrofluoric acid. It is also possible to use compounds which release hydrogen fluoride, such as, e.g. the salts of this acid with a tertiary organic base, such as, e.g. pyridine or derivatives of hydrofluoric acid. A particularly favourable process is described and claimed in the US-Patent Specification No. 3,211,758, according to which the hydrofluoric acid is employed in the form of an adduct with a carbamic acid or thiocarbamic acid, or especially with urea.

The addition of chlorine to the 1,2-double bond according to method c) is performed in a manner known pe se. For example, in an inert solvent such as dioxane, chlorination can be performed in the presence of a carboxylic acid, such as, e.g. propionic acid, at low temperature in the dark. The elimination of hydrochloric acid from the 1,2-dichloro compounds is effected by treatment with a base, preferably a tertiary organic nitrogen base such as, e.g. triethylamine, pyridine or collidine.

The free 21-aldehydes obtained by the described methods or the 21 , 21-dihydroxy compounds formed from these by hydration, can be converted, as described above under a) , into the hemiacetals, acetals or acylates . Obtained hemi-acetals, acetals or acylates can be converted with hydrolysing agents into the corresponding 21-aldehydes.

The compounds of the above formulae II to V to be used as starting materials are known or can be produced in a manner known per se. In particular, the aldehyde group in compounds which correspond to those of formulae III to IV, but which contain no aldehyde group in the 21-position, can be formed by method a) , and the obtained aldehyde group converted into the acetals, hemiacetals or acylates.

The invention relates also to those embodiments of the process where a starting compound which occurs as an intermediate at any particular stage of the said process is employed and the further required stages performed; or where a starting material is formed under the reaction conditions .

The present invention relates also to the production of pharmaceutical preparations for administration in human or veterinary medicine which contain the above described new pharmacologically effective substances of the present application as active substances, together ; with a pharmaceutical carrier substance. The carriers used are organic or inorganic substances which are suitable for enteral administration, e.g. oral, parenteral or topical adminstration. For the formation of these carriers suitable substances are those which do not react with the new compounds, such as, e.g. water, gelatine, lactose, starch, magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, vaseline, cholesterol, and other known carriers for pharmaceutical active substances.

The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees or capsules; or in liquid or semiliquid form as solutions, suspensions, emulsions, ointments or creams. If required, these pharmaceutical preparations are sterilised; they can moreover contain auxiliaries, such as preservatives, stabilising, wetting or emulsifying agents, salts for modification of the osmotic pressure, or buffer substances. They may also contain other therapeutically valuable substances . The new compounds can also serve as starting materials for the production of other valuable compounds.

The compounds of the present application can also be used as feed additives .

The invention is further described in the following examples. The temperatures are expressed in degrees Centigrade .

Example 1 An amount of 0.214 g of 2-chloro-3 , 20-dioxo-9a- fluoro-11β , 17a , 21- rihydroxy-16a-methyl-Z^"' pregnadiene is suspended in 10 ml of methanol and, after the addition of 2.5 ml of a 0.05-molar solution of Cu(II) -acetate-monohydrate in methanol, oxygen introduced, with vigorous stirring, during 4 hours at 22-25°. There is then added to the reaction mixture 2.5 ml of a separately prepared solution of 0.50 g of ethylenediaminetetra-acetic acid in 50 ml of water as well as 3.5 ml of IN sodium hydroxide solution; the whole is subsequently concentrated in a water-jet vacuum to ca. 2.5 ml, an addition made of 7.5 ml of water, and the whole finally concentrated in an oil- pump vacuum to a residual volume of ca . 2.5 ml. The aldehyde precipitating in the process becomes on cooling in an ice-water mixture completely crystalline. Filtration under suction, washing with water and drying over calcium chloride are performed to isolate 0.215 g of colourless crystals of 2-chloro-3 , 20, 21-trioxo-9a-fluoro-ΙΙ , 17a-dihydroxy-l6a-methyl-V"' pregnadiene in the form of 21-methylhemiacetal ; double M.P. 140-142° and 208-250° (after partial recrystallisation) .

By dissolving of the above described 21-methylhemiacetal water-saturated ethyl acetate, concentration in vacuo to a syrupy consistency, taking up of the residue in acetone and repeated concentration with addition of water, there is obtained the hydrate of 2-chloro-3, 20, 21-trioxo-9 -fluoro-ΙΙβ Δ1 ' 4-pregnadiene m.p. 130-140°C.

The unhydrated form of the aldehyde is a yellow substance which has a tendency towards polymerisation.

Example 2 An amount of 10 ml of methanol is poured over 0.427 g of 2-chloro-3 , 20-dioxo- 6a-fluoro-ΙΙβ , 17a, 21-trihydroxy- there is then added 2.5 of an 0.05-molar solution of Cu (II) -acetate-monohydrate in methanol, and the whole stirred at normal temperature as oxygen is . introduced . After 6 hours, the reaction is stopped by addition of 2.5 ml of a separately prepared solution of 0.50 g of ethylenediaminetetraacetic acid in 50 ml of water and 3.5 ml of IN sodium hydroxide solution, and the reaction mixture concentrated in a water-jet vacuum to ca . 2.5 ml. On addition of 7.5 ml of water and concentration in an oil- pump vacuum, the formed aldehyde precipitates almost quantitatively in a practically colourless, semisolid form. The precipitate becomes when triturated at 2-5° completely crystalline after a few minutes. The aqueous mother liquor is removed by filtration under suction, the filter cake washed with ice-cold water, and dried over calcium chloride to obtain 0.415 g of practically colourless crystals of 2-chloro-3 , 20, 21-trioxo-6a-fluoro-ΙΙβ-17a-dihydroxy-16a-methyl- -pregnadiene in the form of 21-methylhemiacetal, M.P. 136-138°.

Recrystallisation of the above described 21-methylhemiacetal from acetone/water, with the use of water-saturated ethyl acetate, yields the hydrate of 2-chloro-3 , 20, 21- pregnadiene, m.p. 140-148°C.

Example 3 An amount of 40 ml of a separately prepared 0.05-molar solution of Cu (II) -acetate-monohydrate in methanol is added all at once, with stirring, to a solution of 2.22 g of 2-chloro-3 , 20-dioxo- 6a, 9a-difluoro-lljS , 17a, 21-trihydroxy-16a-methyl-Δ ' -pregnadiene in 160 ml of methanol. While a moderate flow of oxygen is fed in, the whole is stirred for 2 hours at 22-25°; there are then added to the reaction mixture 40 ml of a solution of 0.50 g of ethylenediaminetetraacetic acid in 50 ml of water and 3.5 ml of IN sodium hydroxide solution, and the whole concentrated in a water- et vacuum, with the supply of 40 ml of water, to a residual volume of ca „ 40 ml. The residue is extracted by shaking with ethyl acetate and the extracts washed with 0.2N sodium hydrogen carbonate solution and water; the organic phase if collected and concentrated in a rotary evaporator to ca. 20 ml to obtain the steroidal fraction. The ethyl acetate is removed by the distilling off 5 times of 20 ml of acetone each time; the whole is finally concentrated to a residual volume of 3 ca. 10 m , 10 ml of water added and inoculation performed. With the additio of water and further removal of acetone by distillation, there is ultimately obtained a final volume of 25 cm of ca . 207o aqueous acetone. After 16 hours' standing, filtration under suction is carried out; the crystals are washed with a little acetone/water (1:4), (1:9) and (1:19), and dried over calcium chloride. There is obtained 1.80 g of colourless crystals of 2- chloro-3 , 20, 21- trioxo-6a, 9 -difluoro-11/3 , 17a-dihydroxy-l6a-me hyl- pregnadiene in the form of its hydrate, M.P. 142-146°, and, by concentration by evaporation of the aqueous mother liquor, additionally 0.178 g of almost equally pure substance, M.P. 140-146°.

By . dissolving and crystallising the above described hydrate from methanol, with addition of methylene chloride as a dehydrating agent, and concentration in vacuo, there is obtained the colourless and amorphous 21-methylhemiacetal 2-chloro-3 , 20 , 21-trioxo-6 , 9a-difluoro-11 β , 17a-dihydroxy-16a- _ Δ1 ' 4-pregnadiene.

If the hydrate of 2-chloro-3,20,21-trioxo-6a,9a.-difluoro 11β, 17a-dihydroxy-16 -methyl-Z_^"' ^"-pregnadiene , p oduced by the procedure described above, is treated at room temperature for 120 hours with IN hydrochloric acid in anhydrous methanol, then there is obtained, after extraction of the water-diluted reaction mixture by means of methylene chloride, concentration by evaporation of the dried extract, and purification by preparative thin-layer chromatography on silica gel, with the use of chloroform/methanol (97:3) as eluant : the 21, 21-dimethylacetal of 2-chloro-3 , 20, 21- pregnadiene, m.p. 254-257°C.

Example 4 In a polyethylene vessel, 0.441 g of hydrate of 2-chloro-3 , 20, 21-trioxo- 6a-fluo 0-9/3 , ll -oxido-16a-methyl- is caused to react for 40 hours at 0-3°, while stirring is maintained, with 9.0 ml of a urea/hydrogen fluoride adduct containing ca. 0.4 mole of hydrogen fluoride. The reaction mixture is then poured on 100 g of ice and 15 ml of cone, ammonia, and the pll-valu adjusted to 7 with glacial acetic acid. After standing overnight, the precipitated substance is collected on a suction-filter, washed with water and dissolved in 16 ml of acetone; the crude product is then purified by preparative thin-layer chromatography on four 1 metre long plates coated with silica gel PF 254 to give a coating thickness of 1.5 mm. The UV-adsorbing main, zone is removed and eluted with moist acetic ester; the eluate is thereupon greatly concentrated, the acetic ester remaining behind removed by repeated addition of acetone and distillation, and the residue finally crystallised from acetone/water (ca. 1:4). There is obtained 0.196 g of hydrate of 2-chloro 3 , 20, 21- trioxo-6a, 9a-difluoro-ΙΙβ , 17a-dihydroxy-16a- in the form of fine interlaced needles, M.P. 142-146° .

The starting material used in this example is obtained as follows: An amount of 25 ml of a 0.02-molar solution of Cu-(II)- 4f acetate-monohydrate in methanol is added to a suspension of 1.063 g of 2-chloro-3 , 20-dioxo- 6a-fluoro-9 , Ιΐβ-oxido- -pregnadiene in 25 ml of methanol, and oxygen introduced in the course of 2 hours at room temperature while continuous stirring is maintained. There is then added to the reaction mixture ml of a separately prepared solution of 0.125 g of ethylenediaminetetraacetic acid in 12.5 ml of water and 0.875 ml of IN sodium hydroxide solution, and the whole concentrated in a water-jet vacuum to ca. 10 ml.

An addition is then made of 15 ml of water, and concentration in vacuo again performed, whereupon the formed aldehyde precipitates as resin. By dissolving and crystallisation of the crude product from acetone /water , there is obtained 0.825 g of hydrate of 2-chloro-3 , 20, 21-trioxo-6a-fluoro- 9β , ll -oxido-lGa-methyl-iya-hydroxy-Z!^5 ^-pregnadiene in the form of practically colourless crystals, M.P. 152-159°. 49 Example 5 To a solution (prepared with the exclusion of moisture) of 1.065 g of hydrate of 3 , 20, 21-trioxo- 6a, 9a-difluoro- -pregnadiene in 2.5 ml of pyridine and 7.5 ml of tetrahydrofuran there is added, after cooling to -30° to -33°, within 10 minutes and while stirring is maintained, a separately prepared solution of 1.25 ml of trifluoroacetic anhydride in 3.75 ml of anhydrous methylene chloride. After a further 20 minutes reaction time at -30° to -33°, the whole is poured, with rinsing with a little methylene chloride, on a mixture of 30 g of finely crushed ice and 5 ml of cone, l^d ochloric acid, and extracted with methylene chloride. The extracts washed with water are combined, dried over sodium sulphate, filtered, and the filtrate concentrated in. vacuo at 27-30° bath temperature. The yellow lacquer remaining behind is the crude 11/3-0-trifluoroacetyl derivative. This is taken up in 6.25 ml of dioxane and 6.25 ml of methylene chloride and the solution cooled to 0-3°; an addition is then made of 12.5 ml of a ca. 1-molar solution of chlorine in propionic acid, prepared at 0°, and the mixture is allowed to stand for 7 days at 0°. After this period of time, the excess chlorine is reduced by the mixture being ■poured into a mixture of 10 ml of 2-molar sodium hydrogen sulphite solution and 40 g of crushed ice, and the chlorination product taken up in acetic acid ester. The extracts are washed with water, dried, and concentrated by evaporation.

There is thus obtained a yellowish residue which becomes solid on trituration with ether. The resulting crude 1 , 2-dichloride is dissolved in 20 ml of methanol and 3 ml of aqueous 5-molar sodium acetate solution, and the solution refluxed for 2 hours. The cooled reaction mixture is concentrated in vacuo at 40° bath temperature and the resulting suspension extracted with ethyl acetate; the extracts are washed with water, IN sodium hydrogen carbonate solution and water, dried, and then concentrated in vacuo. The residue is dissolved in 25 ml of chloroform/ methanol (95:5), and chromatographed on a column of 50 g of silica gel (deactivated with 3% of water) with use of the same mixture. The evaporation residues of the fractions which in the thin- layer chromatogram with the use of chloroform/methanol (90:10) as eluant show essentiall}' a main spot having an Rf-value of ca. 0.50 are recrystallised together from aceton/wate . There is obtained 0.160 g of hydrate of 2-chloro-3 , 20, 21- trioxo-6a, 9a-difluoro-ΙΙβ , 17a-dihydroxy-16 -methyl-Z_''"'^-pregnadiene, M.P. 142-144°.

There are obtained analogously to these examples, for example, 2-chloro-3 , 11 , 20 , 21-tetraoxo-6ct , 9oc-difluoro-17 - hydroxy- ' ^-pregnadiene , he hydrate of which melts at 121-123 °C and 2-chloro-3 , 20 , 21-trioxo-6 , 9a-difluoro-llg-hydroxy-17a- propionoxy-A1,4-pregnadiene, the hydrate of which melts at 130-133 °C .

Claims (3)

1. 41579 WHAT WE CLAIM IS: 1. New fluorina ed 2-Chlor- 16a-methyl-17a-hydroxy-pregna-1 ,4-dien-21-aldehydes and their " deriva ives of the general form wherein and together represent an oxo group, or each represent a free hydroxy group, a lower alkoxy or a lower alkanoyloxy group, represents a free hydroxy group or a lower alkanoyloxy group represents an oxo group, or a hydroxy group in the ^-position together with a -hydrogen atom, and one of the radicals R^ and R^ represents a fluorine atom and the other hydrogen or a fluorine atom.
2. 2. Pregnane- 21-aldehydes according to Claim 1, wherein R^ and R together represent an oxo group, or each represents a free hydroxy group, or a lower alkoxy group, and R^, R^, R^ and R^ have the given meanings.
3. 3. Pregnane-21-aldehydes according to one of the Claims 1-2, wherein R^ and R2 together represent an oxo group, or each represents a free hydroxy group or a lower alkoxy group, R^ represents a free hydroxy group, or a hydroxy group esterified with a lower alkanecarboxylic acid, and R^, and have the given meanings . 41579- 4. 2-Chloro-3 , 20, 1-txIoxo-9a-fluoro-ΙΙβ, 17a-dihydroxy 16a-methyJL -Δ1·4-pregnadiene 5. The 21-hemiacetal of 2-chloro-3 , 20, 21-trioxo-9a-fluoro-ΙΙβ , 17a-dihydroxy-16a-methyl-Z_Y''' ^-pregnadiene . 6. 2-Chloro-3,20,21-trioxo-6a-fluoro-ll/3, 17a-dihydroxy .1 a-me h l-Z^' -pregnadiene . 7. The 21-methylhemiacetal of 2-chloro-3 , 20, 21-trioxo-6a-fluoro-ll3 , 17a-dihydroxy-16a-methyl- -pregnadiene . 8· 2-Chloro-3,20,21-trioxo-6a,9a-difluoro-ll/3,17a-dihydroxy-l6a-methyl- -pregnadiene. The 21-methylhemiacetal of 2-chloro-3 , 20, 21-trioxo- Λΐ 4 6a,9a-difluoro-ll£,17a-dihydroxy-l6a-methyl-ZA ' -pregnadien . 10. Process for the production of a new pregnane-21-aldehyde and its derivatives of the formula wherein and together represent an oxo group, or each represents a free hydroxy group, a lower alkoxy or a lower alkanoyloxy group, represents a free hydroxy or a lower alkanoyloxy ■ 41579- group, R^ represents an oxo group, or a hydroxy group i the /3-position together with a hydrogen atom, and one of the radicals R^ and R^ represents a fluorine atom and the other hydrogen or a fluorine atom, the said process being such that a) in a comp R wherein R^, and R^ have the above given meanings, and R-. represents an oxo group, or a free or esterified hydroxy group in the β- position, /Rl the radical CH OH is converted into the group CH 'R, and obtained Ιΐβ-acylates hydrolysed to the Ιΐβ-hydroxy compounds; or b) in a compound of the formula wherein R^, R2, R^ anc* ^ have the above given meanings, the 9/3, 11/3-epoxy group is split with hydrogen fluoride or with compounds releasing hydrogen fluoride; or c) in a compound of the formula wherein R-^, R2, R3, ^, R5 and R6 have the above given meanings, chlorine is added, if necessary with temporary protection of the 11-hydroxy and/or 20-oxo group, to the 1,2-double bond, and hydrochloric acid eliminated from the obtained 1,, 2-dichloro compound; and, optionally, obtained compounds of formula (I) wherein R^ and R2 together represent an oxo group, or at least one of the radicals R^ and R2 represent a free hydroxy group, are treated with esterifying or etherifying agents; or obtained compounds of formula (I) wherein at least one of the radicals R-^ and R2 represents an esterified or etherified hydroxy group are treated with hydrolysing agents; or in obtained compounds wherein R^ represents a free hydroxy group this is oxidised to^ the oxo group. 11. Pharmaceutical preparations containing one of the compounds claimed in Claims 1 to 10, together with a carrier substance.