Pharmaceutical compositions of 6.alpha.,9.alpha.-difluoro-androst-4-ene-17.beta.-carboxylates and derivatives thereof

The specification describes anti-inflammatory steroids having the following formula ##STR1## wherein X represents a hydrogen or fluorine atom, R' represents a methyl, ethyl, n-propyl or iso-propyl group, R" represents a methyl, chloromethyl, fluoromethyl, bromomethyl or 2-fluoroethyl group and represents a single or double bond. The specification describes processes for preparing such compounds as well as pharmaceutical compositions containing the compounds.

The present invention relates to novel anti-inflammatory steroids of the 
androstane series. 
U.S. Pat. No. 3,636,010 broadly discloses a class of androstane steroids 
having the general formula 
##STR2## 
(wherein R.sub.1 represents either a .beta.-hydroxy group together with a 
hydrogen atom, or an oxo group, R.sub.2 represents a hydrogen atom or a 
free or esterified hydroxy group and represents a single or double bond) 
together with carboxylic acid metal salts and esters thereof. These 
steroids are described in the Patent as having a pronounced 
anti-inflammatory action as well as a strong thymolytic action after 
systemic administration. The said Patent suggests that .DELTA..sup.1,4 
-16.alpha.-methyl-6.alpha.,9.alpha.-difluoro-11.beta.,17.alpha.-dihydroxy- 
3-oxo-androstadiene-17.beta.-carboxylic acid methyl ester is the preferred 
compound according to the invention on account of its good 
anti-inflammatory activity. It should be noted that this compound is a 
17.alpha.-hydroxy compound and that the remaining compounds specifically 
described in the Patent (including the Examples) likewise possess a free 
hydroxy group in the 17.alpha.-position. Indeed, the Patent does not 
specifically describe any androstane compounds of the above general 
formula having an esterified hydroxy group in the 17.alpha.-position. 
We have now discovered that a narrow class of new androstane compounds, 
some of which fall within the scope of the above general formula, having 
certain ester groups (as hereinafter defined) in the 17.alpha.-position, 
possess greatly superior anti-inflammatory activities, particularly on 
topical application, to those of the 17.alpha.-hydroxy compounds disclosed 
in the above Patent. We have further discovered that the new class of 
androstane compounds referred to above possess, in general, a good ratio 
of topical anti-inflammatory activity to undesired glucocorticoid activity 
as measured for example in the thymus involution test on the mouse. 
The new class of androstane compounds can be represented by the general 
formula 
##STR3## 
wherein X represents a hydrogen or fluorine atom, R' represents a methyl, 
ethyl, n-propyl or iso-propyl group, R" represents a methyl, chloromethyl, 
fluoromethyl, bromomethyl or 2-fluoroethyl group and represents a single 
or double bond. In the above general formula I, R' preferably represents 
an ethyl group. R" preferably represents a methyl, chloromethyl or 
fluoromethyl group. 
Preferred compounds according to the present invention on account of their 
high topical anti-inflammatory activity are methyl 
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha. 
methyl-3-oxo-17.alpha.-propionyloxyandrosta-1,4-diene-17.beta.-carboxylate 
and 
fluoromethyl-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3 
-oxo-17.alpha.-propionyloxy-androst-4-ene-17.beta.-carboxylate. 
The new compounds described above may be prepared in a number of ways, for 
example from appropriate 6.alpha.-fluoro compounds or by the introduction 
of a fluorine substituent into corresponding 6-unsubstituted compounds. 
Thus, for example, the new compounds may be prepared by esterifying a 
corresponding 17.alpha.-acyloxy 17.beta.-carboxylic acid (or functional 
equivalent thereof) or 17.alpha.-hydroxy 17.beta.-carboxylate to produce 
the desired compound. 
Thus, the parent 17.alpha.-acyloxy-17.beta.-carboxylic acid of compounds of 
formula I may be esterified, to provide 17.beta.-carboxylate esters 
according to the invention. For example, in order to prepare a methyl 
ester the 17.beta.-carboxylic acid may be reacted with diazomethane, the 
reaction being preferably effected in a solvent medium, e.g. ether, 
tetrahydrofuran or methanol, and at a low temperature, preferably at 
-5.degree. to +30.degree. C. Alternatively, the 17.beta.-carboxylic acid 
may be reacted with O-methyl N,N'-dicyclohexyl-isourea, preferably in an 
aprotic solvent such as ethyl acetate, and advantageously at a temperature 
of 25.degree.-100.degree. C. Alternatively, a salt of the parent 
17.beta.-carboxylic acid for example, an alkali metal e.g. lithium, sodium 
or potassium, salt or a quaternary ammonium, e.g. triethylammonium or 
tetrabutylammonium, salt may be reacted with a methylating agent, for 
example, a methyl halide e.g. the iodide, or a sulphonyloxy compound 
including dimethylsulphate, preferably in a polar solvent medium such as a 
ketone, e.g. acetone or methylethyl ketone or an amide solvent e.g. 
dimethylformamide or hexamethylphosphoramide conveniently at a temperature 
in the range 15.degree.-100.degree. C. 
For the preparation of those compounds of formula I wherein R" represents a 
chloromethyl, fluoromethyl, bromomethyl or 2-fluoroethyl group, the 
esterification of the 17.beta.-carboxyl group can be carried out in an 
analogous manner to that described above for the preparation of the methyl 
ester. Thus, for example, such esters may be prepared by reacting a salt 
of the parent 17.beta.-carboxylic acid with a compound R" Y where Y is an 
appropriate displaceable substituent e.g. a halogen atom, preferably 
iodine. This method is particularly applicable to the preparation of those 
compounds of formula I wherein R" represents a chloromethyl group, the 
said halo compound in this case being iodochloromethane. The salt of the 
parent 17.beta.-carboxylic acid employed in this process may be one 
specifically mentioned above in relation to the preparation of the methyl 
17.beta.-carboxylate compounds of the invention. 
Alternatively, the parent 17.alpha.-hydroxy-17.beta.-carboxylates 
corresponding to compounds of formula I may be subjected to esterification 
of the 17.alpha.-hydroxyl group; such 
17.alpha.-hydroxy-17.beta.-carboxylates may be prepared by esterifying the 
corresponding 17.alpha.-hydroxy-17.beta.-carboxylic acids by the methods 
described above. 
The esterification of the 17.alpha.-hydroxy group in the preparation of the 
new androstance compounds may, if desired, be effected by conventional 
techniques, e.g. by reacting the parent 17.alpha.-hydroxy compound with a 
mixed anhydride of the required carboxylic acid, which may, for example, 
be generated in situ by reacting the carboxylic 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 reaction of 
a symmetrical anhydride of the required acid with an appropriate further 
acid, e.g. trifluoroacetic acid. 
The reaction is advantageously effected in an organic solvent medium such 
as benzene, methylene chloride or an excess of the carboxylic acid 
employed, the reaction being conveniently effected at a temperature of 
20.degree.-100.degree. C. 
Alternatively, the 17.alpha.-hydroxy group may be esterified by reaction of 
the parent 17.alpha.-hydroxy compound with the appropriate acid anhydride 
or acid 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. perchloric acid, p-toluene 
sulphonic acid or a strongly acidic cation exchange resin, e.g. Amberlite 
IR 120, the reaction being conveniently effected at a temperature of 
25.degree. to 100.degree. C. 
For the preparation of the 17.alpha.-esters of the 17.beta.-carboxylic 
acids which may be employed in the preparation of the compounds according 
to the invention, it is often preferred to treat the parent 
17.alpha.-hydroxy 17.beta.-carboxylic acid with the appropriate carboxylic 
acid anhydride, if desired in the presence of a base such as potassium 
carbonate. Any mixed anhydride formed may be solvolysed under acidic (e.g. 
aqueous acetic acid) or basic (e.g. aqueous pyridine or 
diethylamine/acetone) conditions. Alternatively, the parent 
17.alpha.-hydroxy 17.beta.-carboxylic acid may be treated with the 
appropriate carboxylic acid chloride, preferably in a solvent such as an 
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.degree. C. 
Those compounds of formula I wherein R" represents a chloromethyl, 
fluoromethyl, bromomethyl or 2-fluoroethyl group may also be prepared by 
reacting a compound of formula 
##STR4## 
(wherein X, R' and are as defined above, n is 1 or 2 and Y represents a 
displaceable substituent) with a compound serving to replace the group Y 
by a fluorine, chlorine or bromine atom when n is 1 or by a fluorine atom 
when n is 2. Y may thus, for example, be a chlorine, bromine or iodine 
atom. 
In accordance with the last-mentioned process fluoromethyl or 2-fluoroethyl 
17.beta.-carboxylate compounds of formula I may be prepared from the 
corresponding chloro-, bromo- or iodo-methyl or -ethyl compounds by 
reaction with an appropriate fluoride, e.g. silver monofluoride or silver 
difluoride, conveniently in a solvent, for example acetonitrile. 
The new 2-fluoroethyl 17.beta.-carboxylate compounds of formula I can also 
be prepared from a corresponding sulphonyloxyethyl, e.g. mesyloxyethyl, 
compound of formula II by reaction with an appropriate alkali metal, 
alkaline earth metal or quaternary ammonium fluoride conveniently in a 
solvent medium, e.g. acetone, dimethyl formamide, hexamethylphosphoramide 
or ethanol. The sulphonyloxy ethyl compound may be prepared from a 
corresponding 2-hydroxyethyl compound produced, for example, by reaction 
of a 17.beta.-carboxylic acid salt with an appropriate halohydrin. 
The compounds of general formula II as well as the parent 
17.beta.-carboxylic acids referred to above may be prepared for example in 
accordance with the general procedures described in Belgian Pat. Nos. 
778285 and 802481. 
The .DELTA..sup.4 compounds according to the invention can conveniently be 
prepared by partial reduction of the corresponding .DELTA..sup.1,4 
compound, for example, by hydrogenation using a palladium catalyst, 
conveniently in a solvent e.g. ethyl acetate or by homogeneous 
hydrogenation using for example tris(triphenylphosphine)rhodium chloride, 
conveniently in a solvent such as benzene, or by exchange hydrogenation 
using for example cyclohexene in the presence of a palladium catalyst in a 
solvent e.g. ethanol, preferably under reflux. This reduction may be 
carried out on a haloalkyl ester where this is sufficiently stable in such 
a reaction or may be effected at an earlier stage. 
The new compounds can also be prepared, as indicated above, from the 
corresponding 6-unsubstituted compounds, e.g. by preparation of a 
corresponding 3-enol ester or ether followed by reaction with an 
electrophilic fluorinating agent such as perchloryl fluoride and 
subsequent hydrolysis to yield the corresponding 6.beta.-fluoro compound. 
Where no 1,2-double bond is present, treatment with a strong acid such as 
hydrogen chloride or more preferably hydrogen bromide effects 
epimerisation to form the desired 6.alpha.-fluoro compound. The 
epimerisation is preferably effected in a non-aqueous solvent medium, 
dioxan being particularly preferred; other solvents which may be used 
include tetrahydrofuran, ester solvents such as ethyl acetate, ketone 
solvents and amide solvents such as dimethylacetamide or 
dimethylformamide. The epimerisation is also advantageously effected in 
the presence of a carboxylic acid such as acetic acid, especially when 
hydrogen bromide is employed. In the case of .DELTA..sup.1,4 -compounds, 
it is necessary to hydrogenate the 1,2-double bond, e.g. by catalytic 
hydrogenation, effect the epimerisation and re-introduce the 1,2-double 
bond by dehydrogenation, normally under neutral or mildly acidic 
conditions e.g. using dichlorodicyanoquinone or chloranil. Suitable 
solvents for this reaction include hydrocarbon solvents, e.g. benzene, 
esters e.g. ethyl acetate, and ether solvents, e.g. dioxan. 
As is well known to those skilled in the art it may frequently be 
convenient to elaborate the desired substituents in the 17.alpha.- and 
17.beta.-positions at an intermediate stage of the preparation of the 
desired final compound, one or more other substituents (or unsaturation) 
being introduced at a later stage. Instances where the desired 
substituents may be introduced before final elaboration of the remainder 
of the desired androstane molecule include for example preparing 
.DELTA..sup.9(11) or Ring A saturated compounds having the desired 
17.alpha.-acyloxy and 17.beta.-carboxylate ester groups, completion of the 
elaboration of Rings A, B and C then being effected in conventional 
manner. 
There are also provided pharmaceutical compositions for use in 
anti-inflammatory therapy, comprising at least one androstane compound of 
formula I (as defined above), together with one or more pharmaceutical 
carriers or excipients. Such compositions may be in forms adapted for 
topical or internal administration. 
The active androstane compounds may be formulated into preparations 
suitable for topical administration with the aid of a topical vehicle 
therefor. Example 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 or throat), suppositories, 
retention enemas, chewable or suckable tablets or pellets (e.g. for the 
treatment of aphthous ulcers) and aerosols. 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 glycols. Such a 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 glycolic solvent 
such as propylene glycol or 1,3-butane-diol. Thickening agents which may 
be used according to the nature of the base include soft paraffin, 
aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, 
hydrogenated lanolin and beeswax and/or glyceryl monostearate and/or 
non-ionic emulsifying agents. 
The solubility of the steroid in the ointment or cream may be enhanced by 
incorporation of an aromatic alcohol such as benzyl alcohol, phenylethyl 
alcohol or phenoxyethyl alcohol. 
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, suspending agents, thickening agents, colouring agents, 
perfumes and solvents. 
Powders may be formed with the aid of any suitable powder base e.g. talc, 
lactose or starch. Drops may be formulated with an aqueous base also 
comprising one or more dispersing agents, suspending agents or 
solubilising agents etc. 
Spray compositions may for example be formulated as aerosols with the use 
of a suitable propellant, e.g. dichlorodifluoromethane or 
trichlorofluoromethane. 
The proportion of active androstane 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 0.0001 to 5.0% 
by weight. Generally however for most types of preparations advantageously 
the proportion used will be within the range of from 0.001 to 0.5% and 
preferably 0.01 to 0.25%. 
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 compounds according to the invention 
may, for example, be formulated for oral, parenteral or rectal 
administration. For oral administration 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, 
olive oil etc. 
Preferred forms of preparations for internal administration are 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 
0.05 to 2.0 mg, preferably from 0.25 to 1.0 mg of the active steroid. For 
oral administration suitable dosage unit forms include 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 
conventional commercial suppository bases, provide a dosage unit form for 
rectal administration. Sterile tablets or pellet implants may also be 
used, e.g. where slow systemic absorption is desired. 
The compounds 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 
0.01 to 5.0% of active ingredient depending upon the type of preparation 
involved. The daily dose may vary from 0.5 to 10.0 mg. dependent on the 
condition being treated and the duration of treatment desired. 
The compositions according the invention may also include one or more 
preservatives or bacteriostatic agents e.g. methyl hydroxy benzoate, 
propyl hydroxy benzoate, chlorocresol or benzalkonium chlorides. The 
compositions according to the invention may also contain, other active 
ingredients such as antimicrobial agents, particularly antibiotics such as 
neomycin.

The following Examples illustrate the present invention. In the Examples 
(and also the Preparations), the ultra viclet spectra are in ethanol. 
Melting points were determined on a Kofler block, and are uncorrected. 
Preparative thin layer chromatography (P.L.C.) was carried out on silica; 
following P.L.C., products were isolated by elution with ethyl acetate. 
EXAMPLE 1 
Methyl 6.alpha.,9.alpha.- difluoro - 
11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyloxyandrosta 
-1,4-diene-17.beta.-carboxylate. 
A suspension of methyl 6.alpha.,9.alpha.- difluoro- 11.beta., 
17.alpha.-dihydroxy-16.alpha.-methyl-3-oxoandrosta-1,4-diene-17.beta.-carb 
oxylate (394 mg.) in propionic acid (3.9 ml.) was treated, at room 
temperature, with trifluoroacetic anhydride (0.78 ml.) and toluene 
p-sulphonic acid (0.08 ml. of a dry chloroform solution concentration 
0.12g. per ml.). The resulting solution was stirred at 
75.degree.-80.degree. C for 30 mins., then added slowly to a stirred 
solution of 3% aqueous sodium bicarbonate (ca.250 ml). The product was 
extracted into ethyl acetate. The extract was washed with saturated 
aqueous sodium bicarbonate solution, and water, dried over magnesium 
sulphate, and evaporated in vacuo to give an off-white solid (466 mg.) 
which was purified by preparative thin layer chromatography (on silica, 
developing the plates three times in chloroform). A portion (156mg.) of 
the total purified material (356 mg.) was recrystallised twice from 
methanol to give the title compound (119 mg.) as white hexagonal plates, 
m.p. 267.degree.-269.degree. C(with decomposition) [.alpha.].sub.D + 
9.degree. (c 1.0 dioxan), .lambda..sub.max 236 nm (.epsilon. 16,800). 
EXAMPLE 2 
Chloromethyl 
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha 
.-propionyloxyandrost-4-ene-17.beta.-carboxylate 
(a) A solution of 
6.alpha.,9.alpha.-difluoro-11.beta.,17,21-trihydroxy-16.beta.-methylpregn- 
4-ene-3,20-dione (0.848g.) in tetrahydrofuran (10ml) was treated with a 
solution of periodic acid (0.682g., H.sub.5 IO.sub.6) in water (3ml.). 
After stirring for 2 hours, water (10ml.) was added and the solution 
concentrated in vacuo. Water (40ml.) was added and the product (an oil) 
was extracted into ethyl acetate. The combined extracts were washed with 
water, dried and evaporated to give 
6.alpha.,9.alpha.-difluoro-11.beta.,17.beta.-dihydroxy-16.beta.-methyl-3-o 
xoandrost-4-ene-17.beta.-carboxylic acid as a foam [0.866g. (ethyl acetate 
solvate, ca 1 mole)], 
(b) A stirred suspension of 
6.alpha.,9.alpha.-difluoro-11.beta.,17.alpha.-dihydroxy-16.beta.-methyl-3- 
oxoandrost-4-ene-17.beta.-carboxylic acid [0.828g., (ca. 1 mole, ethyl 
acetate solvate)] in dry, redistilled dichloromethane (22ml.) was cooled 
to 0.degree. C. and treated with redistilled triethylamine (0.96ml), then 
with propionyl chloride (0.63ml.), added dropwise. After stirring at ca. 
0.degree. C for 80 minutes, dichloromethane (15ml.) was added, and the 
solution washed with 3% aqueous sodium bicarbonate, N hydrochloric acid 
and water, dried (MgSO.sub.4) and evaporated to give the intermediate 
mixed anhydride as a foam (1.02g). The foam was dissolved in acetone 
(33ml) and treated with diethylamine (0.75ml). After being stirred for 85 
mins. solvent was evaporated, and the residue was dissolved in water 
(50ml.). The mixture was washed with ethyl acetate. The aqueous phase was 
acidified with 2N-hydrochloric acid, and the product extracted into ethyl 
acetate. 
The combined extracts were washed with water, dried and evaporated to give 
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha 
.-propionyloxyandrost-4-ene-17.beta.-carboxylic acid as a solvated (ethyl 
acetate) foam (0.803g.), .lambda..sub.max 234nm (.epsilon. 14,990). 
(c) A suspension of 
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha 
.-propionyloxyandrost-4-ene-17.beta.-carboxylic acid (0.754g.) in methanol 
(4ml.) was treated with 2M sodium hydroxide in methanol (0.9ml) to give a 
solution of pH 10. Ether (100ml) was added and the mixture was then 
refrigerated for 2 hours. The precipitate was collected by filtration, 
washed well with ether, then dried in vacuo to give the sodium salt 
(0.379g.) of the above 17.beta.-carboxylic acid. The filtrates were 
evaporated, triturated with ether (50ml.) and the solid collected by 
filtration, washed withether, and dried in vacuo, giving more of the 
sodium salt (0.336.g). 
The sodium salt (0.714g.) was slowly added to a stirred solution of 
chloroiodomethane (0.53ml., freshly redistilled b.p. 108.degree. C) in 
hexamethylphosphoramide (1.8ml.). More hexamethylphosphoramide (1.8ml.) 
was added, after about half of the sodium salt had been added, due to a 
sudden gelatinous precipitation. Stirring and steroid addition were 
continued. After 3 hours, the mixture was diluted with ethyl acetate 
(100ml) and washed with water 5% aqueous sodium bicarbonate and water, 
dried and evaporated to a foam (0.713g.). P.L.C. (chloroform-acetone 40:1) 
gave two products; the major, more polar component was a foam (472mg.), a 
portion was crystallised twice from acetone to afford the title 
chloromethyl ester as solvated (acetone) colourless crystals (98mg.). m.p. 
183.degree.-184.degree. C, [.alpha.].sub.D + 48.4.degree. (c 0.135, 
dioxan), .lambda..sub.max 233nm (.epsilon. 16,570). 
EXAMPLE 3 
Fluoromethyl 
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha 
.-propionyloxyandrost-4-ene-17.beta.-carboxylate 
A solution of chloromethyl 
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha 
.-propionyloxy-androst-4-ene-17.beta.-carboxylate (0.368g.) in dry 
acetonitrile (5.5ml.) was stirred with silver fluoride (0.648g.) in the 
dark. After 7 days, the mixtured was filtered through kieselguhr, which 
was then washed with ethyl acetate (200ml.). The combined filtrates were 
washed with water, dried and evaporated to a foam (354mg.). P.L.C. 
(chloroform) and crystallisation twice from acetone/ether gave the 
solvated (ether) title compound (177mg.), m.p. 183.degree.-184.degree. C, 
[.alpha.].sub.D + 57.6.degree. (c 0.11, dioxan), .lambda..sub.max 233.5nm 
(.epsilon. 15.670). 
EXAMPLE 4 
Methyl 
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha 
.-propionyloxyandrost-4-ene-17.beta.-carboxylate 
(a) A solution of 
6.beta.,9.alpha.-difluoro-11.beta.,17,21-trihydroxy-16.beta.-methylpregna- 
1,4-diene-3,20-dione (3.970g.) in tetrahydrofuran (40ml.) was treated with 
a solution of periodic acid (3.307g., H.sub.5 IO.sub.6) in water (10ml.). 
After being stirred for 11/2 hours, the solution was diluted with 5% 
aqueous sodium bicarbonate solution (100ml.) then concentrated in vacuo to 
ca. 100ml. The solution was washed with ethyl acetate, then acidified with 
2N hydrochloric acid, and stirred for 45 minutes. The product was 
collected by filtration, washed well with water and dried in vacuo to give 
6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.-dihydroxy-16.beta.-methyl-3-o 
xoandrosta-1,4-diene-17.beta.-carboxylic acid (3.509g.). 
(b) A stirred solution of 
6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.-dihydroxy-16.beta.-methyl-3-o 
xoandrosta-1,4-diene-17.beta.-carboxylic acid (3.443g.) in dry, redistilled 
dichloromethane (90ml.) and redistilled triethylamine (3.03ml.) was cooled 
to 0.degree. C and treated with propionyl chloride (1.93ml.). After 
stirring at ca. 0.degree. C. for 40 minutes, dichloromethane (60ml.) was 
added, and the solution washed with 3% aqueous sodium bicarbonate, 
N-hydrochloric acid and water, dried and evaporated to give the 
intermediate mixed anhydride as a foam (4.913g.). The foam was dissolved 
in acetone (75ml.) and treated with diethylamine (3.1ml.) After being 
stirred for 50 minutes, the suspension was concentrated in vacuo and 
dissolved in water (100ml.). The solution was acidified to pH3 with 2N 
hydrochloric acid and the product was extracted into ethyl acetate. The 
combined extracts were washed with water, dried and evaporated to a foam 
(4.637g.). Crystallisation from ethyl acetate gave 
6.beta.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha. 
-propionyloxyandrosta-1,4-diene-17.beta.-carboxylic acid (2.553g). A 
portion (92mg.) was further crystallised from ethyl acetate to give an 
analytical sample as solvated (ethyl acetate) colourless crystals (89mg). 
m.p. 171.degree.-174.degree. C, [.alpha.].sub.D - 25.4.degree. (c 1.08, 
dimethylsulphoxide), .lambda..sub.max 240nm (.epsilon. 16,360). 
Further quantities of the 17.alpha.-propionyloxy-17.beta.-carboxylic acid 
were obtained from the evaporated mother liquors, from above, by repeated 
extractions with 5% aqueous sodium bicarbonate and washing with ethyl 
acetate, acificiation and extraction with ethyl acetate. This was 
performed twice to give the 
6.beta.-fluoro-17.alpha.-propionyloxy-17.beta.-carboxylic acid (0.800g., 
and 0.262g.). 
(c) A solution of 
6.beta.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha. 
-propionyloxy-androsta-1,4-diene-17.beta.-carboxylic acid (2.966g.) in 
methanol (8ml.) and benzene (200ml.) was treated with 
tris(triphenylphosphine)rhodium chloride (1.694g.), and stirred with 
hydrogen gas at room temperature and atmospheric pressure for 93 hours 
(uptake 262ml). The solution was concentrated in vacuo to ca. 100ml., 
diluted with benzene (50ml., as a wash) and extracted with 2N sodium 
carbonate solution. The combined extracts were washed with benzene 
(200ml.) then acidified to pH2 with 6N hydrochloric acid, and the products 
were extracted into ethyl acetate. Combined extracts were washed with 
water, dried and evaporated to a foam (2.923g.), containing 
6.beta.,9.alpha.-difluoro-11.beta.-hydroxy, 
16.beta.-methyl-3-oxo-17.alpha.-propionyloxy-androst-4-ene-17.beta.-carbox 
ylic acid. 
(d) The above prepared material (2.906g.) was dissolved in methanol, cooled 
to 0.degree. C and treated with an excess of ethereal diazomethane. A few 
drops of acetic acid were added, and the solution was evaporated to a foam 
(2.985g.). This was redissolved in ethyl acetate (100ml.) and washed with 
5% aqueous sodium bicarbonate and water, dried and evaporated (2.757g.). 
P.L.C. (chloroformacetone, 20:1) gave three components; the least polar 
foam (1.420g.) was methyl 
6.beta.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha. 
-propionyloxyandrost-4-ene-17.beta.-carboxylate. 
(e) A solution of methyl 
6.beta.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha. 
-propionyloxyandrost-4-ene-17.beta.-carboxylate (1.420g.) in dioxan (18ml.) 
was treated with 50% w/v hydrogen bromide in acetic acid (0.22ml.). After 
48 hours, the mixture was added to water (300ml.) and the product 
extracted with ethyl acetate. The combined extracts were washed with 5% 
aqueous sodium bicarbonate and water, dried and evaporated to a foam 
(1.410g.). P.L.C. (chloroformacetone, 14:1) gave two components; the more 
polar was the title 6.alpha.-fluoro ester (0.365g.), the less polar was 
unchanged 6 .beta.-fluoro ester (0.974g.). 
The latter material was redissolved in dioxan (12ml.) and treated with 50% 
w/v hydrogen bromide in acetic acid (0.15ml.). After 66 hours a similar 
isolation of product, followed by P.L.C. (chloroform-acetone, 16:1) gave 
two components; the more polar was the title 6.alpha.-fluoro ester 
(0.557g.). 
The two batches (0.365g. and 0.557g) were combined and crystallised twice 
from methanol to give the analytical sample (0.423g.), m.p. 
195.degree.-197.degree. C, [.alpha.].sub.D + 44.degree. (c 0.17, dioxan), 
.lambda..sub.max 233.5nm (.epsilon. 15,730). 
EXAMPLE 5 
Methyl 
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha 
.-propionyloxyandrosta-1,4-diene-17.beta.-carboxylate 
A solution of methyl 
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha 
.-propionyloxyandrost-4-ene-17.beta.-carboxylate (0.657g.) and 
2,3-dichloro-5,6-dicyanobenzoquinone (0.546g.) in benzene (50ml) was 
heated under reflux for 7 days. The solvent was evaporated, and the 
mixture was purified by P.L.C. (chloroform/acetone, 20:1). The major 
steroid product was a foam (0.413g.). Crystallisation (3.times.) from 
methanol gave the title compound (0.273g.) m.p. 236.degree.-238.degree. C. 
[.alpha.].sub.D + 31.6.degree. (c 0.1 dioxan), .lambda..sub.max 237.5nm 
(.epsilon. 16,200). 
PREATION 1 
21-Acetoxy-3-benzoyloxy-9.alpha.-fluoro-11.beta.,17.alpha.-dihydroxy-16.bet 
a.-methyl pregna-1,3,5-trien-20-one 
Redistilled benzoyl chloride (340ml.) was added to a solution of 
betamethasone acetate (134g.) in pyridine (550ml.), cooled in an ice-bath, 
and the mixture was then heated at 50.degree., in a thermostatically 
controlled bath, for 2 hr. The cooled suspension was poured into an excess 
of saturated aqueous sodium hydrogen carbonate and the product was 
extracted into ethyl acetate. The extract was washed with 2N-hydrochloric 
acid, aqueous sodium hydrogen carbonate, and water, and dried 
(MgSO.sub.4). The extract was concentrated in vacuo and the crystals of 
the enol benzoate which separated (57.9g.) m.p. 124.degree.-126.degree., 
[.alpha.].sub.D - 138.degree. (c, 1.0 in CHCl.sub.3) were collected and 
washed with ether. 
Recrystallisation of a sample of the enol benzoate from benzene - ether 
gave an analytical sample of the title compound m.p. 124.degree., 
[.alpha.].sub.D - 144.degree. (CHCl.sub.3), .lambda..sub.max 230nm, 
(.epsilon. 20,200) and 309nm (.epsilon. 6,880). 
PREATION 2 
6.beta.-Fluorobetamethasone 21-acetate 
(21-Acetoxy-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.-dihydroxy-16.beta 
.-methylpregna-1,4-diene-3,20-dione) 
Perchloryl fluoride (ca 25 g., = ca. 14 ml. at -70.degree.) was passed 
slowly in a nitrogen stream, into a solution of 
21-acetoxy-3-benzoyloxy-9.alpha.-fluoro-11.beta.,17.alpha.-dihydroxy-16.be 
ta.-methylpregna-1,3,5(10)-trien-20-one (117g.) in pyridine (400ml., 
previously distilled from selenium dioxide) kept at 5.degree.. The 
reaction flask was fitted with a cold finger condenser at -70.degree. and 
the excess of perchloryl fluoride was kept refluxing from the stirred 
suspension for 1 hr. The excess of reagent was removed with a vigorous 
stream of nitrogen and the mixture was poured into ice-water and carefully 
neutralised with hydrochloric acid. The precipitate was collected by 
filtration and dried at room temperature in air. 
Part (90%) of the crude solid was suspended in ethyl acetate (500ml.) and 
water (200ml.) containing sodium metabisulphite (30g.) and then acetic 
acid (15ml.) was added. The mixture was shaken until all the steroid 
dissolved and the organic layer was then separated, washed with aqueous 
sodium hydrogen carbonate and water, and dried (MgSO.sub.4). Removal of 
the solvent in vacuo left a residue, which was partly-dissolved by warm 
chloroform. After separation of the insoluble material (5.3g.), the 
chloroform was evaporated to dryness and the resultant foam was 
crystallised from ethyl acetate to give 6.beta.-fluorobetamethasone 
21-acetate as a solvate (41.3 g.), m.p. 111.degree.-112.degree., 
.lambda.max. 239nm.(E.sub.1cm.sup.1%, 292,) [.alpha.].sub.D + 41.degree. 
(CHCl.sub.3). After drying at 150.degree. in vacuo it had m.p. 130.degree. 
and analysed approximately for a solvate with one molecule of ethyl 
acetate. 
PREATION 3 
6.beta.,9.alpha.-Difluoro-11.beta.,17,21-trihydroxy-16.beta.-methylpregna-1 
,4-diene-3,20 -dione 
A solution of 6.beta.-fluoro-betamethasone 21-acetate (6.184g.) in methanol 
(130ml.) and dioxan (130ml.) was treated with a solution of potassium 
carbonate (1.651g.) in water (10ml.). The mixture was stirred for 80 mins, 
acidified to pH 5 with acetic acid, then concentrated in vacuo to ca. 
100ml. Water (700ml.) was added, and the mixture stirred in ice for 1 
hour. The solid was collected by filtration washed well with water and 
dried in vacuo to give the title compound (3.998g.) 
The following Examples illustrate pharmaceutical compositions according to 
the invention. 
______________________________________ 
Example A: Water-miscible cream 
Active ingredient 0.1% w/w 
Beeswax (White) 15.0% w/w 
Cetostearyl alcohol B.P.C. 
7.0% w/w 
Cetomacrogol 1000 B.P.C. 
3.0% w/w 
Liquid paraffin B.P. 5.0% w/w 
Chlorocresol 0.1% w/w 
Distilled water to produce 
100 parts by weight 
______________________________________ 
Ball-mill the steroid with a little liquid paraffin until the particle size 
is reduced to 95% by number below 5.mu.. Heat the available water to 
100.degree. C, add the chlorocresol, stir to dissolve and cool to 
65.degree. C. Melt together the beeswax, cetostearyl alcohol and 
cetomacrogol and maintain at 65.degree. C. Add the steroid suspension 
using the remaining liquid paraffin for rinsing. Add the steroid oil phase 
at 60.degree. C to the chlorocresol aqueous phase at 65.degree. C and stir 
rapidly while the emulsion cools over the gelling point 
(40.degree.-45.degree. C). Continue to stir at slow speed until the cream 
sets. 
______________________________________ 
Example B: Oral tablet 
Active ingredient 0.5 mg. 
Lactose 175.5 mg. 
Maize starch (dried) 20.0 mg. 
Gelatin 2.0 mg. 
Magnesium stearate 2.0 mg. 
Tween 80 Trace 
Total weight 200.0 mg. 
______________________________________ 
A suspension of 300mg. of the active ingredient in 2ml. of water containing 
0.1% of Tween 80 is milled for 16 hours in a 10ml. nylon pot about three 
quarters filled with steatite balls, until 90% by number of the particles 
have a diameter of less than 5 microns with none greater than 50 microns. 
The maize starch and lactose are blended and passed through a 60 mesh B.S. 
sieve and granulated with a 10% solution of gelatin containing the 
suspension of the active ingredient and washings from the nylon pot, by 
passing through a 16 mesh B.S. sieve. The granules are dried at 40.degree. 
C overnight, passed through a 20 mesh B.S. sieve and blended with 
magnesium stearate and tabletted using a tabletting machine having a 5/16 
inch flat-bevelled punch.