IE42112B1 - 2-bromo-6-fluoropregna-1,4-diene-3,20-diones - Google Patents

Abstract

1499822 2 - Bromo - 6# - fluoropregna- 1,4-diene-3,20-diones PIERREL SpA 6 Feb 1975 [27 Feb 1974 5 July 1974 25 July 1974 19 Nov 1974] 8928/74 29984/74 32945/74 and 49982/74 Heading C2U Novel steroids have the formula wherein either X is OH and Y is F, Cl or Br, or X and Y are each Cl, and (i) R 1 is OH, R 2 is OH and R 3 is H, α-CH 3 or #-CH 3 ; or (ii) R 1 is acyloxy, R 2 is OH and R 3 is H, α-acyloxy, α-CH 3 or #-CH 3 ; or (iii) R 1 is OH or acyloxy, R 2 is acyloxy and R 3 is H, α-ChH 3 or #-CH 3 ; or (iv) R 1 is OH or acyloxy and either R 2 is OH and R 3 is α-OH or R 2 , and R 3 together are wherein R 4 is H or hydrocarbyl and R 5 is hydrocarbyl; or (v) R 1 and R 2 together are wherein R 6 is H, hydrocarbyl or alkoxy and R 7 is hydrocarbyl, and R 3 is H, α-CH 3 or #-CH 3 . They may be prepared as illustrated in the following reaction scheme which is largely self-explanatory. (XI)#(XIV) is the reaction of a 17α-acetoxy-16-unsubstituted compound with KOAc in hot DMF. 17α- Esters are prepared from 17α,21-diols via 17,21- o - esters. 17,21 - Acetonides are prepared from the 17α,21-diols and 2,2-dimethoxypropane. The novel steroids have anti-inflammatory activity and they may be made up into pharmaceutical compositions with suitable carriers.

Description

The present invention relates to a new class of steroids having good anti-inflammatory activity, to processes of making them and to pharmaceutical compositions containing them.

Many steroids having anti-inflammatory activity upon b topical and/or systemic administration are known and some of them have quite satisfactory anti-inf1ammatory activity. Unfortunately they all tend to give undesired side effects such as disturbing the mineral balance in the subject to which they are administered, for example they may reduce the potassium and/or sodium balance, and they may adversely affect the adrenals function.

Accordingly their application has to be conducted with caution.

It has been our object to produce novel steroids that 15 have very good anti-inflammatory activity, preferably higher than that of most or all known steroids, and which have very low or no side effects, preferably when measured in absolute terms but in particular when measured as the therapeutic ratio, i.e. the ratio of the active dose that is required to achieve the desired anti-inflammatory activity to the minimum dose that incurs undesired side effects.

We have now found certain 2-bromo-6g-fluoropregna1,4-diene-3,20-diones which have high anti-inflammatory activity and which at the same time avoid completely or at least minimise the undesirable side effects of known steroid compounds. The <2112 novel compounds of the Invention have the' formula H2R1 > 42113 wherein either X is hydroxy and Y is fluorine, chlorine or bromine or X and Y are both chlorine; and (i) Rq is· hydroxy, Rg is hydroxy and is hydrogen, α-methyi or β-methyl; (ii) R^ is acyloxy, Rg is hydroxy and Rj is hydrogen, a-methyl, β-methyl or α-acyloxy; (iii) Rq is hydroxy or acyloxy, R2 is acyloxy and Rj is hydrogen,. α-methvl or β-methvlj (iv) R-f.-is 5 either R? is hydroxy and R, ise*· -hydroxy or hydroxy or acyloxy and/^Rg- and R^ are Taken together and are a group of the formula ' R4 Rwherein is hydrogen or hydrocarbyl and R^ is hydrocarbyl or (v) Rq and Rg are taken together and are a group of the formula . . /\ -0 R? wherein Rg is hydrogen, hydrocarbyl or- alkoxy and R? is hydrocarbyl, and R^ is hydrogen, α-methyl or β-methyl; or a pharmaceutically acceptable salt or ester thereof when at least one of Rp Rg and R^ is a polycarboxylic or inorganic acid radical. R^ and Rg are an alkyl orthoester when Rg is alkoxy. When two or more of R^, Rg and R^ are acyloxy, then the acyloxy groups may be the same or··different. Further, when R^ and R^, or Rg and Ry, are both hydrocarbyl (e.g. alkyl or aryl), they may be the same or different. - 4 43112 Typical values of aliphatic radicals suitable «a the esterifying radical in a dicarboxylic acyl group are alkyl, preferably containing up to 7 carbon atoms,and alkenyl. Particularly preferred are alkyl radicals containing up to 4 carbon atoms, especially methyl, ethyl and propyl. Typical cycloaliphatic radicals are cycloalkyl radicals containing 5 to 8 carbon atoms, for example cyclopentyl and cyelohexyl. are Typical arylaliphatic radicals / phenyl alkyl radicals, for example where alkyl is as described above, for instance benzyl.

Typical aryl radicals are those containing a phenyl ring, for example unsubstituted phenyl.

When Rp R2 and/or R3 is acyloxy, the acyl group may be the radical of an inorganic acid, for example sulphuric' acid or phosphoric acid, or an organic acid, for example a sulphonic acid or a·carboxylic acid, including aliphatic, alicyclic, aromatic, arylaliphatic and heterocyclic carboxylic acids, thiocarboxylic acids and amino carboxylic acids. Preferred carboxylic acids are formic acid, acetic acid, chloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, trimethylacetic acid, diethylacetic acid, caproic acid, crotonic acid, enanthic acid, caprylic acid, capric acid, palmitic acid, undecanoic acid, undecylenic acid, oxalic acid, succinic acid, glutaric acid, pimelic acid, tartaric acid, maleic acid, lactic acid, carbamic acid, glycine, alkoxy carboxylic acids, hexahydrobenzoic acid, cyclopentylpropionic acids, cyelohexylacetic acid, cyclohexylbutyric acids, benzoic acid, phthalic acid, phenylacetic acid, phenylpropionic acids, furane-2carboxylic acid, nicotinic acid and isonicotinic acid. 548112 Preferred sulphonic acids are methanesulphonic acid and toluenesulphonic acid.

Particularly preferred acyl radicals are those derived from acetic acid, trimethylacetic acid, propionic acid, β-phenyl-propionic acid, α-phenylpropionic acid, valeric acid and dicarboxylic acids, such as succinic acid.

It is often preferred that the acyl group in R^ should be as described above, particularly the preferred carboxylic acyl groups as described above, since 21-esters have particularly good biological activity. It is especially preferred that, when R-, is acyloxy, the acyl group should be the radical of a polycarboxylic acid ester or of an inorganic acid which is in the form of, or is convertible into a watersoluble salt.

A preferred cyclic ketal which may be formed at the 16,17 or 17,21 positions is the acetonide. Suitable cyclic orthoesters that may be formed at these positions include the 17,21 methylorthoacetate, the 17,2-1 ethylorthopropionate, the 17,21 methyl orthobenzoate and the 17,21 methylorthovalerate.

One preferred class of compounds of the invention are those wherein R3 is hydrogen, α-acyloxy or more preferably α-hydroxy. Another preferred class of compounds of the invention are those wherein R3 represents a or β methyl, more preferably a methyl.

It is often preferred that Y should be fluorine or chlorine, X is preferably hydroxy.

It is of course already known how to make pregna1,4-diene-3,20-dione compounds. It is also known how to produce a few 2-bromo steroids. Further, it is well known how to make 6a-fluoro steroids. There have been some references to the production of δβ-fluoro steroids in the literature but it seems to have been considered generally in the art that δ-β-fluoro steriods are inferior pharmaceutically to 6a-fluoro steriods. The combination of 2-bromo and δβ-fluoro substitution 1,4-diene-3,20-diones appears to be new and gives good anti-inflammatory activity with low or negligible side effects as discussed above.

The novel compounds of the invention have good antiinflammatory activity. This activity can be exhibited upon conventional methods of administration, for example topically and systemically. Some compounds give best results topically while other give best results systemically, for instance when taken orally as is preferred. Because of the very high activity possessed by preferred compounds of the invention lower dosages can be used than are useful with known antiinflammatory steroids; even at conventional dosages preferred compounds of the invention have much less, and generally no, side effects compared with known anti-infammatory steroids.

The compounds of the invention are useful for the treatment of a wide variety of inflammatory conditions, for example in the treatment of inflammatory conditions of the skin, eyes and ears of humans and of valuable domestic animals, as well as contact dermatitis and other allergic reactions and the compounds also possess valuable antirheumatoid arthritic properties.

Therapeutic compositions of the invention comprise a compound of the invention together with a pharmaceutically acceptable liquid or solid carrier. Any therapeutically acceptable and effective concentration of the compound in the composition may be used. Any suitable composition may be prepared, according to the chosen manner of administration. Suitable compositions include pills, tablets, capsules, solutions, syrups or elixirs for oral use, liquid forms of the types used to make injectable compositions of the natural and synthetic cortical steroid hormones, and topical compositions, for example in the form of ointments, creams and lotions.

The composition may also include coacting antibiotics, germicides or other active materials.

The local anti-inflammatory activity has been evaluated in rats by the cotton-pellet induced granuloma test, applying the compound directly to the pellet.

AU new compounds of the present invention show a remarkable anti-inflammatory activity without undesirable side effects on the thymus and on the body weight increase even at very high concentrations (40 micrograms/pellet).

The most active compound inhibit the cotton-pellet induced granuloma at doses as low as 0.002 - 0.1 micrograms/pellet whereas the known anti-inflammatory agent fluocinolone 16,17-acetonide evokes the same effect at a dose of 0.5-2 micrograms/pellet.

Other compounds of the present invention are active at doses ranging from 0.1 to 2 micrograms/pellet whereas betamethasone 17-valerate is active at a dose of 5-20 micrograms/pellet. Some other compounds of the present invention display activity at doses higher than 2 micrograms/pellet. Hydrocortisone acetate shows the same activity at about 100 - 200 micrograms/pellet.

The systemic anti-infammatory activity has been evaluated in rats by the cotton-pellet induced granuloma test, giving the compounds orally for 8 days. The most active compounds show activity at doses ranging from 0.01 to 0.1 mg/kg b.w. In the same experimental conditions betamethasone (alcohol or phosphate) shows activity at doses of about 0.05- 0.1 mg/kg b.w. while hydrocortisone acetate and Methylprednisol one are active at doses ranging from 10 to 50 mg/kg b.w. Most of the compounds of the present invention have, on this test, no inhibiting action on adrenal weight and a thymolitic or body weight reducing activity lower than that displayed by the most active known steroids.

The compounds of the invention can be made by various processes including the following:1. Compounds in which Rp Rg and Rg are as defined above, X is hydroxy and Y is Br can be made by dissolving the corresponding 9,11-unsaturated compound in an organic solvent such as methylene chloride, tert.butyl alcohol, dioxane, tetrahydrofuran, or tert, amyl alcohol and by reacting this at room temperature with an hypobromous acid releasing agent, such as N-bromoacetamide, N-bromosuccinimide or 1,3-dibromo-5-5dimethyl-hydantoin in the presence of an acid such as perchloric acid, or dilute sulfuric acid. Normally the bromination is 48112 conducted at room temperature, between 15 and 30°C. The reaction period may vary from about five minutes to one hour.

At the conclusion of the desired reaction the excess hypobromous acid is destroyed by the addition of sulfites or hydrosulfites, sodium sulfite being normally employed. The resulting compound can be isolated from the reaction mixture by adding an excess of water and extracting the product with organic solvents or by recovering the precipitated compound by filtration. 2. Compounds in which R-j, R2 and R3 are as defined above and X and Y are both chlorine can be made by reacting the corresponding 9,n-*unsaturated compound with a chlorinating agent. Suitable agents are N-chlorosuccinimide, N-bromosuccinimide, N-chlorophthalimide and N-chloroacetamide.

The reaction is preferably conducted in an organic solvent such as a lower aliphatic carboxylic acid, for example glacial acetic acid, diethylacetic acid, propionic acid or butyric acid, or in ether solvents, for example tetrahydrofuran or dioxane, or in halogen solvents for example methylene chloride or -θ chloroform, or in a mixture of these solvents. The reaction is carried out at temperature of 0 to 50°C, preferably ambient temperature in the presence of an alkali metal halide, e.g. a chloride or bromide and preferably potassium or lithium chloride. 3. Compounds in which Rp R2 and R3 are as defined above, I c X is OH, and Y is F or Cl can be made by reacting the corresponding 9,11-epoxide (for instance prepared by dehydrobromination with an alkaline carbonate solution of the 9-bromo-ll-hydroxy compound prepared as described above) with hydrogen halide, namely HF or HG1. This may be generated in situ but preferably is introduced as an aqueous solution. The steroid is first dissolved in an organic solvent such as tetrahydrofuran or methylene chloride and the like. The halogenation reaction is operative at room temperature but is preferably conducted at lower temperatures, such as 0 to -80°C., with continuous stirring. After the reaction is completed, the mixture is poured into water and neutralized with diluted base, such as dilute sodium or potassium hydroxide, or a bicarbonate such as sodium bicarbonate or potassium bicarbonate. The reaation mixture is then extracted in the usual manner, such as with methylene chloride, and the resulting compound is recovered in a purified form by recrystallization or chromatography. 4. Compounds in which Rp X and Y are all as defined for Formula A, and R2 and R3 are both OH may be made by oxidising the corresponding 16,17 unsaturated compound. Any oxidising agents known for oxidising a double bond in a steroid to produce a dihydroxy compound can be used, for example potassium permanganate. The reaction is preferably conducted in an acidic aqueous organic solution such as glacial acetic acid or formic acid in aqueous acetone at a temperature of -20 to +50°C. The reaction may be terminated by adding a reducing agent, such as sodium sulphite.

. Any compound of the invention in which any or all of Rp R2 and R3 are hydroxy can be made by hydrolysing the corresponding acyloxy compound. Hydrolysis can be conducted under acidic conditions, for example in the presence of an acid such as hydrochloric acid, or under alkaline conditions, for example in the presence of an alkali such as sodium hydroxide or sodium carbonate, in an aqueous, organic or aqueous organic solvent, for example a lower alcohol, at a temperature of 0 to 100°C., preferably under reflux. 6. Any compound of the invention in which one or more of Rp Rg and Rj is acyloxy can be made by esterifying the corresponding hydroxy compound. Esterification can be conducted by reaction with the appropriate acid halide or acid anhydride in pyridine or other suitable organic solvent, preferably a basic solvent. The reaction is best conducted in organic solvent at temperatures of 0 to 100°C preferably under reflux. This process is best carried out on the 16 or 21 positions, the hydroxy group in the 11 and 17 positions usually remaining unchanged during the reaction. The 17 position requires acid anhydrides with mineral acids as catalyst.

The 17 monoesters are prepared by a mineral or organic acid hydrolysis of cyclic 17,21-alkyl orthoesters.

The cyclic 17,21-alkyl orthoesters are prepared from the corresponding 17,21-dihydroxy compound by exchange reaction with trimethyl orthoesters in the presence of an acid catalyst. The orthoesterification steps are carried out at temperature ranging from 60° to 130°C and preferably around 100-110°C for a period of 4-24 hours. The orthoesters thus obtained are then h/drolized with a mineral or organic acid to give the 17-monoesters.

The cyclic 16,17-alkyl orthoesters are also prepared from the corresponding diols with trimethylorthoesters in the presence of an acid catalyst. The orthoesterification step is carried out at temperature ranging from 20° to 30°C for a period of 1-2 hours. 43112 7. Compounds of the invention in which the 16 and 17 or the 17 and 21 positions are part of a cyclic acetal or a cyclic ketal can be made by treating a suspension or solution of the corresponding diol in the desired aldehyde or ketone (or an organic solvent, if the aldehyde or ketone is a solid) with an acid catalyst (e.g., perchloric acid, p-toluene sulfonic acid or hydrochloric acid), neutralizing the acid and recovering the cyclic acetal or ketal derivative which is formed.

The reaction is preferably carried out at a temperature of ]θ from 16° to 60°C. It is usually completed within from one to eighteen hours.

The 17,21-cyclic acetals and ketals are prepared by an acid catalyzed interchange reaction between the corresponding diols and lower alkyl acetals of aliphatic, cycloaliphatic or arylaliphatic aldehydes or ketones.

The reaction is best conducted in an organic solvent at a temperature from 20 to 100°C preferably under reflux.

The 16,17 unsaturated compound described above as the starting material for the production of the 16,17 dihydroxy com2Q pound may be made by dehydration of the corresponding 17-hydroxy compound in which R3 is H so that all the processes described above can be considered to start from the 9,11-unsaturafed compound wherein R3 is hydrogen or methyl. These compounds, having Formula VIII, are claimed in our British Patent Specification No. 1,499,823, where processes for their preparation are described.

Convenient ways of carrying out the processes 1 to 7 following listed above are 3hown in the/reaction scheme: - 14 42112 The reaction of the compound VIII with hypobromous acid produces the corresponding 9a-bromo compound IX. When this 9abromo compound is reacted with potassium carbonate in acetone the 9β,Π B-oxido compound X is obtained. Reaction of the latter compound with hydrofluoric acid affords 2-bromo-6f3,9a-difluoi?o11 B,17a,21-trihydroxypregna-l,4-diene-3,20-dione 17,21diacetate (XI, Rq = Rg = OCOCHg) which upon hydrolysis is converted into the corresponding free alcohol XIa, (XI, R-|=Rg=OH).

In similar manner reaction of compound X with hydrochloric acid yields the ll-hydroxy-9a-chloro analogue. This reaction with the hydrochloric acid is particularly convenient when Rg represents methyl.

The fluorine atom at the δβ-position of the compound XI (Rq=R2=0C0CH3) is considered to be in a stable configuration on the basis of the following observation. In attempts to isomerize 2-bromo-6β,θαfl uoro- Π ,17a, 21-tri hydroxy-pregna-1,4-diene-3,20-dione 17,21-diacetate (XI, Rq=R2=0C0CH3) with dry hydrochloric acid in chloroform at 0°C for 2 hours, the optical rotatory dispersion curve of the crude produce was not altered. Reorystallization gave the pure product identical in all aspects to the starting sample XI (Rq=R2=0C0CH3).

Reaction of compound X with hydrochloric acid affords 2-bromo-6 0-flu.oro-9a-chloro.-ll β, 17a,21 - trihydroxy-pregna-1,4diene-3,20 dione 17,21-diacetate (XIII).

The triene VIII is reacted with N-chlorosuccinimide to obtain the 2-bromo-6B-fluoro-9a,11 β-dichioro-17a,21-dihydroxy pregna-1,4diene-3,20-dione-17,21-diacetate (XII, R^=R2=OCOCH3) which upon hydrolysis is converted into the corresponding free alcohol Xlla (XII, RpRg-OH). 42113 When the compound XI (where R-, =R2=OCOCHg and R3=H) is reached with potassium acetate in hot dimethylformamide the 2-bromo-66,9adifl uoro-Π β,21-di hydroxypregna-1 ,4,16-triene-21-acetate (XIV, R-|=0C0CH3) is obtained. The compound XI 'bis (R-j=0C0CH3) is then fa oxidised with potassium permanganate to produce the corresponding 2-bromo-6g,9ct-difluoro-Πβ, 16«, 17a, 21 -tetrahydroxypregna-1,4diene-3,20-dione 21-acetate (XVII, R-j=0C0CH3) which upon hydrolysis is converted into the corresponding free alcohol XVIIa (XVII, RpOH).

Esterification of the hydroxy function at the 21-position is conveniently effected with a lower fatty acid anhydride, such as acetic anhydride, or preferably with a lower aliphatic acid chloride such as acetyl chloride in the presence of pyridine, which simultaneously serves as solvent. The 17a-esters are prepared by treatment of the corresponding 17a,21 diols with a lower alkyl orthoester in the presence of an acid catalyst followed by acid hydrolysis of the resulting 17a,21-orthoester (a mixture of two epimeric orthoesters), The esterification of the hydroxy function at the 21-position can also be achieved by trans-esterification of the corresponding 17a-esters.

Treatment of the corresponding 17 Treatment of the compounds XVII with acetone and perchloric acid produces the 16,17-acetonides XVIII.

The esterification of the hydroxyl function at the 16-position of the compounds XVII is effected with a lower fatty acid anhydride in the presence of pyridine which simultaneously serves as solvent.

The following Preparation and Examples illustrate how the compounds of the invention may he prepared. The compounds of the Examples are particularly preferred compounds of the invention and,for convenience, a Roman numeral corres5 ponding to the formula in the above reaction scheme is given after each compound name.

Compounds particularly preferred for topical administration are XI, Xld, Xie, Xlf, Xii, Xlm, XIp, Xlq, XIx, Xllf and Xllh. Compounds which are particularly 'suitable for systemic administration, and also for topical administration, are XIa, XIo, Xie, XIn, XIv, XIx and XIX. The most preferred compounds of this invention are XI and XIa.

Example 1 7.:,1 g. of 1,3-dibromo-5,5-dimethylhydantoin were added in the dark at room temperature with stirring over 30 minutes to a suspension of 10 g. of 2-bromo-6p-fluoro~ 17a,21-dihydroxypregna-1,4,9(11)-triene-3,20-dione 17,21diacetate (VIII) in 200 ml. of tetrahydrofuran and 1 g. of 70% perchloric acid in 10 ml. of water. - 17' During the addition the suspension began to thin and after a total reaction time of 45 minutes all the starting material was dissolved. After an additional 2 hours, 10% sodium sulfite aqueous solution was added under stirring until potassium iodide starch paper no longer turned blue. The solution was then slowly poured into 1000 ml. of cold water. The product (IX) was filtered and utilized moist in the next reaction.

Analytically pure 2,9a-dibromo-68-fluoro~n8,17a,21trihydroxypregna-1,4-diene-3,20-dione 17,21-diacetate (IX) was obtained by additional crystallization from acetone-hexane. It was dried in vacuo at room temperature M.P. 208-10°C (decomposition) Γα] -18,2° (C 1.0 in chloroform) Amax (methanol) 248 mp (e 10250) IR(KBr) 3520, 1755, 1740 1710, 1675, 1640, 1605, 1230cm’1.

Analysis: Calculated for CggHggBrgWy (percent) C48.41; H 4.71 Br 25,76; F 3,06 Found (percent) C 48,74; H 4,65; Br 25.60; F 3.31 Preparation 1 ml. of a 14% potassium carbonate aqueous solution were added over a period of 20 minutes at 20°C under stirring to the solution of the moist product (lX)2,9a-dibromo-66-fluoro-ll8,17a;2l-tribydroxy pregna-l,4-diene-3,20 dione 17,21-diacetate (obtained in example from 10 g. of the product VIII) in 200 ml. of acetone. The solution was stirred for 4 hours. Ice water was added under stirring, upon which crystallization occurs rapidly. The product 2-bromo-6β-fl uoro17a,21 -dihydroxy-98,11 8-oxido pregna-l-,4-diene -3,20-dione 17,21-diacetate (X) was filtered, washed with water, dried and characterized by M.P. 241-2°C. (decomp.), raised by crystallization from benzene-cyclohexane to 248-9°C. 48112 Η» -88,40 (Ο 0.5 in chloroform) IR(KBr) 1755, 1740 (broad), I67O, 1040, 1600, 1230 (broad) cm1. Analysis: Calcd. for Cgs^gBrFOy (percent) 0 55,67» H 5,23; Br 14,81; 1·' 3,52.

Found (percent) C 55,80; H 5,15; Br 14,72; F 3,45.

Example 2. 100 ml. of a 70% hydrofluoric acid aqueous solution were cooled to -10°C in a polyethylene flask equipped with electromagnetic stirrer, g. of 2-bromo-6p-fluoro-17a,21-dihydroxy-9p,llg-oxido-pregna«l,410 -diene-3,20-dione-17,21-diacetate (X) were added under stirring during 15 min. After 0.5 hr. the reaction mixture was precipitated in water and ammonia, The solid was collected by filtration, washed with water and dried to a constant weight, giving about 9.5 g. of 2-bromo-6β,9e-difluoro-11β,17c,21-trihydroxy pregna-1,4-diene-3,20-dione 15 17,21-diacetate (XI) (rx=«2=OCOCH3).

Crystallization from benzene gave 7 g. of pure product, homogeneous by TLC on silica gel (6:3:2 CHCl^-acetone-cyclohexane).

M.P. 290-2°C (decomposition) Hd 36° (Ο 1.0 in chloroform) Xmax (methanol) 246 mp (S 12500) IR(KBr) 3520, 1758, 1733, 1705, 1680, 1650, 1610, 1235 cm1.

NMR (dimethyl-dg sulfoxide-TMS) Hz at 60 mHz 471 (S,1,C-1 H) 393,389 (d,l,C-4H) 350,300 (doublet of triplets,1,C-6H) 341,335 (d,l,C-110H) 270-240 289 (S,2,CH20Ac) / (I'm, ,1,C-11H) 127 (S,3,0Ac) 122 (S,3,0Ac) 25 99,96 (d,3, 19 CH3 split by 6pF) 56 (S,3, 18 CH3).

M.S. (70 e.v., ion souroe temperature 210% direct sample introduction) ions at m/e 558/560 (Mt, C25H29BrF207), 54Ο/542, 538/540, 518/520, - 19 42112 498/500, 483/485, 478/480, 458/460, 397/399, 377/379, 359/361, 357/359, 339/341, 317/319, 315/317, 299/301, 278, 217/219, 212/214, 199/201, 165, 147, 139, 121, 109, 101, 91, 79, 73 (base peak), 69, 60, 55. Analysis: Calculated for C. ?5H29BrF2°7 (percent) C 53,67; H 5,22; F 6,79 ; Br 14,28.

Found (percent) C 53,27; H 5.22; F 6,80; Br 14,32.

Example 3 A suspension of 10 g. of 2-bromo-6B, 9a-difluoro-ll B,17a,21-trihydroxypregna-l,4-diene-3,20-dione-17,21-diacetate (XI) (Rq=R2=QC0CH3) in 200 ml. of 1% potassium hydroxide methanolic solution was stirred under nitrogen at 0°C for 3 hours.

Addition of cold water, elimination of methanol in vacuo, acidification with acetic acid and filtration gave 7 g. of 2-bromo-66,9a-difluro~llB,17c(,21trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rq=R2=0H).

M.P. 223-227°C (decomposition), raised by crystallization from diehloroethane to 228-230°C. fa]D - 5.6° (C 1.0 in dioxane) λ max (methanol) 246 mp (e 11700) IR(KBr) 3430 (broad), 1715, 1670, 1645,. 1600cm1.

NMR (dimethyl-dg sulfoxide-TMS) Hz at 60 mHz 470(5,1,C-1H) 392,388 (d,l , C-4H) 348,298 (doublet of triplets, 1 ,C-6H) 327,322(d,l,C-11 -0H)316 (S,l,C-170H) 280,276,270,266,261,257,250,246 (octuplet which becomes a quartet bu deuterium exchange, 2,C0CH20H) 99, 96(d,3, 19 CH3 split by 60F) 48 (S,3, 18 CHg) M.S. (70 e.v., ion source temperature 210°C, direct sample introduction) ions at m/e 474/476 (M+, C21H25BrF205) 456/458,444/446, 427/429, 414/416, 394/396, 379/381, 359/361, 317/319, 315/317, 219(221, 217/219 (base peak), 212/214, 199/201, 139, 109, 95, 67, 55.

Analysis: Calculated for Cg;^25®Γ^2θ5 (percent) C 53,06; H 5,30; Br 16.31; F 7. 99 Found (percent) C 53» 15; H 5,30; Br 16,73; F8,05 Example 4 ' To a solution of TOg. of 2-bromo-6β-fluoro-17a,21 dihydroxy-pregna-1,4,9(11)-triene-3,20 dione 17,21-diacetate (VIII) and 40 g. lithium chloride in 200 ml. of glacial acetic acid werd added at 20°C under stirring 5 g. of N-chlorosuccinimide. The mixture was kept at 20°C and stirred while dropwise adding 10 ml. of a 12% hydrochloric acid tetrahydrofurane solution over a period of about 10 minutes. After 3.5 hours the reaction mixture was poured into cold water, the solid collected by filtration, washed with water and dried, giving 6g. of pure product 2-bromo-6β-f1uoro-9ct,118-dich1oro-17a,21-dihydroxypregna-1, 4-diene-3,20-dione-l7,21-diacetate (XII) (R-j=R2=0C0CH3). M.P. 244-6°C (decomposition, [ix] D -2.5° (C 1.0 in chloroform IR(KBr) 1753, 1740, 1672, 1645, 1602, 1230 cm1.

NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 465 (S,l,C-1H) 394,390 (0,1 ,C-4H) 350,300 (doublet of triplets, 1,C-6H) 320^305 (m.l.C-HH) 289 (S,2,CH20Ac) 127 (S,3,0Ac) 122 (S,3,0Ac) 110, 106 (d,3, 19 CH3 split by 6BF) 61 (S,3, 18 CHg) Analysis: Calculated for C2gH28BrCl2F0g (percent) C 50,27; H 4,72; F 3.18; Cl 11.87; Br 13,38.

Found (percent) C 50.55; H 4.81; F 3.25; Cl 12.05, Br 13,67.

Amax (methanol) 245-6 mu (ε 12280) 48112 Example 5 ( Using the general procedure of Example 3 the 2-bromo-6gfluoro-9a,ll β -dichloro-17a,21-dihydroxy-pregna-l,4-diene3,20-dione-17,21-diacetate (XII) (R-|=R2=0C0CH3) was converted to 2-bromo-6B-fluoro-9a,ll β -dichloro-17a,21-dihydroxy pregna1,4-diene-3,20-dione (Xlla) XII, R1=R2=0H) M.P. 185-7°C (decomp.) Xmax (methanol) 245 (ε!2000) LJq + 34° (C 0.7 in chloroform) IR(KSr) 3450 (broad), 1715, 1675, 1645, 1605 cm1.

Analysis: Calculated for C2^Hg^BrCl2F04 (percent) C 49.43; H 4.74; F 3.72; Cl 13„90; Br 15,66.

Found (percent) C 49,78; F 3,70; Cl 14,07; Br 15,75; H 4.76. Preparation 2 A mixture of 7 g. of 2-bromo-6 β,9α -difluoro-Π β,17α,2115 trihydroxy-pregna-l,4-diene-3,20-dione 17,21-diacetate (XI) (R-]=R2=0CQCH3), 70 ml. of dimethylformamide and 3,5 g. of anhydrous potassium acetate was refluxed at 120°C under nitrogen for 0.5 hours. The reaction mixture was then cooled and poured into cold water. The precipitate was filtered off, washed with water, dried.

Crystallization of the residue from acetone-hexane gave 5 g. of 2-bromo-6B,9a-difluoro-11β,21-dihydroxy pregna-1,4,16triene-3,20-dione 21-acetate (XIV) (R-pOCOCHg) characterized by M.P. 257-8°C (decomposition).

Klg + 24° (C 1.0 in chloroform) IR(KBr) 3520, 1730, 1680, 1640, 1600, 1588, 1220 cm-1.

Xmax (methanol) 242-3 mp (e 21500) Analysis: Calculated for c23H25BrF2°5 (percent) C 55,32; H 5,04; Br 16,00; F 7,61. Found (percent) C 55,21; H 4,89; Br 16,25; F 7,49. 43112 Example 6 A solution of potassium permanganate (3.5 g.) in acetone (75 ml.) and water (25 ml.) was added, in one portion, at -5°C to a solution of 5 g. of 2-bromo-6β,9a-dif 1 uoro-Π β,21 -dihydroxy5 pregna-1, 4,16-triene-3,20-dione-21-acetate, (XIV) (R^OCOCHg) in acetone (150 ml.) and formic acid (1.7 ml.).

The mixture of reaction was stirred for 5 minutes at -5°C and then 50 ml. of 10% Na2S03 aqueous solution were added. The mixture was filtered through Celite (trade mark) and the pale yellow filtrate concentrated in vacuo and poured into cold water, The solid filtered after crystallization from acetone-hexane yielded 4.5 g. of 2-bromo-6β,9a-dif1uoro-11 β,16a,17a,21 tetrahydroxy pregna-1,4-diene-3,20-dione-21-acetate (XVII) (R^=0C0CH3) characterized by M.P. 225-7°C (decomposition). [a]0 -16° (C 1.0 in dioxane) λ max (methanol) 245-6 mp (ε 12000) IR(KBr) 3440 (broad), 1745, 1732, 1672, 1645, 1605, 1230 cm1.

NMR (dimethyl-dg sulfoxide-TMS) Hz at 60 mHz 472 (S,l ,C-1H) 392,388 (d,l ,C-4H) 348,298 (doublet of triplets, 1,C-6H) 337 , 332 (d,l ,C-11 OH) 328, 323 (d,1,C-l6 OH) 312, 296, 292, 276 (doublet of doublets, 2,CH20Ac) 290 (S,l ,C-17 OH) 290-280 (m, 1, C-16H) 265-240 (m.l, C-11H) 126 (S,3,0Ac) 98, 95, (d,3,19 CH3 split by 6£F) 52 (S,3,18 CHg) Analysis: Calculated for C^HjjyBrFgOy (percent) c 51.79; H 5.10; F 7.12; Br 14.98.

Found (percent) C 52.05; H 5.02; F 7.25; Br 16.18. 43113 Example 7 Using the general procedure of Example 3 the 2-bromo-6 g,9a-difluoro-ll β, 16a,17a,21-tetrahydroxy-pregna-1,4diene-3,20-dione-21-acetate (XVII) (R-j=0C0CH3) was converted to 2-bromo-6 8,9&-di fluoro-11 8,16a,17a,21-tetrahydroxy pregna1,4-diene-3,20-dione (XVIIa) (XVII R·, =0H). M.P.208-10°C (decomposition).

IR(KBr) 3460 (broad), 1715, 1670, 1645, 1605 cm1.

Analysis: Calculated for θ21Η25θΓ^2θ6 (Percent) C 51.33; H 5.13; Br 16.26; F 7.37 Found (percent) C 51.51; H 5.10; Br 16.15; F 7.81 £α] θ -30° (C 1.0 in dioxane) λ max (methanol) 246-7 mp (ε 11400) Example 8 A solution of 5 g. of 2-bromo-6β,9a-difluoro-Π 8,17a,21 trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rj=R2=0H) in 10 ml. of dimethylformaimide and 37 ml. of 2,2-dimethoxypropane with 0.025 g. of p-toluenesulfonic acid was heated for 6 hours, at 115°C. ?0 The reaction mixture was cooled, poured in 10% sodium bicarbonate aqueous solution and chloroform. The chloroform solution was then washed with water, dried and evaporated to a residue which by crystallization from acetone gave 4 g. of 2-bromo-68,9a-difluoro-11 8,17a,21trihydroxy pregna-l,4-diene-3,20-dione 17,21-acetonide (Xlb) characterized by M.P. 230-l°C (decomposition) Ho -1° (C 1.0 in chloroform) Amax (methanol} 245-6 (e 12100) IR(KBr) 3400 (broad), 1720, 1670, 1645, 1600cm'1.

Analysis: Calculated for C24H 29^2¾ (Percent) C 55.93; H 5.67; Br 15.50; F 7.37.

Found (percent) C 56.07; H 5.72-, Br 15.37, F 7.50 Example 9 2.5 ml. of 70% perchloric acid were added under stirring at 15°C to a suspension of 10 g. of 2-bromo-6β,9a-dif 1 uoroΠ β,16a,17a,21-tetrahydroxy-pregna-1,4-diene-3,20-dione 21-acetate (XVII) (Rq=OCOCHg) in 400 ml. of acetone. The solution was stirred at 15°C for 50 minutes and 5 g. of sodium bicarbonate were added.

The mixture was stirred for 10 minutes and then filtered. The acetone solution was evaporated to dryness in vacuo at 60°C. The solid residue was crystallized from ethyl acetate-light petroleum giving 6 g. of pure 2-bromo-6 β,θα-difluoro11 B,16a,17a,2l-tetrahydroxy-pregna-l,4-diene-3,20-dione 21-acetate-16,17-acetonide (XIX) (R^OCOCHg, R4=R5=CH3) IR(KBr) 3560, 3480, 3430, 1755, 1730, 1670, 1645, 1600, 1225 cm'1.

Analysis: Calculated for CggH^BrFgOy (percent) C 54.46; H 5.45; Br 13.93; F 6.62 Found (percent) C 54.65; H 5.57; Br 13.85; F 6.47 [α] θ + 8° (C.10 in chloroform) Xmax (methanol) 246 mp (ε 11550) 481 IS Example 10 ml. of acetic anhydride were dropwise added to a mixture of 50 ml. of pyridine and 10 g. of 2-bromo-6£5,9a-difluoro11 B,16a,17a,21-tetrahydroxy-pregna-l,4-diene-3,20-dione-21acetate (XVII) (R^=0C0QH3). The mixture was kept at room temperature for 1.5 hours and then poured under vigorous stirring into 500 ml. of cold water. After about 0.5 hour the solid was collected by filtration, washed thoroughly with cold water, dried to a constant weight, giving about 9.5 g. of 2-bromo6 β, 9a-di f 1 uoro-Π β, 16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20dione-16,21-diacetate (XV111)(R^=R3=0C0CH3), crystallized by methanol-water.

IR(KBr) 3570, 3500 (broad), 1760, 1735 (broad), 1670, 1645, 1605, 1240 (broad) cm1.

Analysis: Calculated for CggHggBrFgOg (percent) C 52.18; H 5.08; Br 13.89; F 6.60. Found (percent) C 52.07; H 5.10; Br 14.07; F 6.70.

M.P. 238-40°C (decomposition) [α]θ - 49.4° (C 1.0 in chloroform) Amax (methanol) 246 mp (e 11900) Example 11 g. of 2-bromo-6B,9a-difluoro-Π β, 17a,21-trihydroxy pregna1,4-diene-3,20-dione (XIa) were dissolved in 50 ml. of pyridine containing 25 ml. of acetic anhydride and kept at room temperature for 12 hours. Addition of ice water afforded a product which was extracted with chloroform. The chloroform solution was washed with water, 2N HCl 5% sodium bicarbonate solution and water.

After drying (Na2S04) and removal of the solvent in vacuo the residue was crystallized from acetone-hexane to give 2-bromo-6 β, 9a-dif1 uoro-Π β, 17a,21 - tri hydroxy-pregna-1,4-di ene -21-acetate (XIc) (XI, Rq=0C0CH3, R2=OH) characterized by M.P. 194-6°C (decomposition). [ajq + 12° (C l.d in chloroform) λ max (methanol) 246 mp (e 11800) IR(CHC13) 3620, 3500 (broad), 1745, 1730, 1672, 1645, 1605, 1230 (broad) cm1.

Analysis: Calculated for C23H2yBrF2O6 (percent) C 53.39; H 5.26; Br 15.44; F 7.34 Found (percent) C 53.51; H 5.21; Br 15.70; F 7.28.

Example 12 Using the general procedure of Example 11, the 2-bromo-6 6,9a-difluoro-Π β,17a,21-tri hydroxy pregna-1,4-di ene3,20-dione (XIa) was converted to 2-bromo-6β,9α- difluoroll|3,l7a,21-tri hydroxy-pregna-1,4-di ene-3,20-dione-21-propionate (Xld) (Xl, Rq—0C0CH2CH3, R2=0H) by reaction with propionic anhydride.

M.P. 180-3°C (decomposition) Qa]q + 22° (C 1.0 in chloroform) λ max (methanol) 246 mp (e 10900) XR(CHCi3) 3610, 3500 (broad), 1740, 1728, 1672, 1645, 1605, 1220 cm1. Analysis: Calcd. for (percent) C 54,25; H 5,50; Br 15,θ4ί F 7,15.

Found (percent) C 54,°9j H 5,60; Br 14,92; F 7,05.

Example 13 Using the general procedure of Example11-,the 2-bromo-6p,9a-difluoro-11β,17a,21-trihydroxy pregna-l,4-diene-3,20-dione (XIa) was converted to 2-bromo^,9a-difluoro-llp,1.7a,21-trihydroxy-pregna-l,4-diene~3,20-dione-21-valerate (XXe) (XI7Ri=OCO(CH2)3CH3 j R2=0B) by reaction with valeric anhydride.

M.P. 155-7°C (decomposition) tip +27° (C 1.0 in chloroform) Amax (methanol) 246 mg (£ 11600) IR(KBr) 3500 (broad), Ι74θ, 1720, 1670, I64O, 1600, 1230 (broad) cm~ Analysis: Calcd.· for C26H33BrF20g (percent) C 55,82; H 5,94; Br 14,28; F 6,79.

Found (percent) C 55,70; H 5,91; Br 14,35; F 6,87.

Example 14 Using the general procedure of Example 11,the 2-bromo-6p,9“-difluoro-11β,17a,2l-trihydroxy-pregna~l,4-diene-3,20-dione (XIa) was converted to 2-bromo-6β,9α-difluoro-llβ,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione-21-pivalate (Xlf) (XI, R1=OCOC(CH3)3/R2=OH) by reaction with pivalic anhydride.

M.P. 224-6°C (decomposition) 4211 ίΑ +22° (Ο 1.0 in chloroform) λ mux (methanol) 245-6 mp (¢ 10900) IR(KUr) 3470 (broad), 1740, 1730, 1665, 1640, l600, 1220 cm-1 Analysis: Calcd. for 026®33ΒΓΐ2θ6 (percent) C 55,82; H 5,945 Br 14,28; F 6,79.

Found (percent) C 55,75; H 5,88; Ur 14,07; F 6,65.

Example 15 g. of 2-bromo-6p,9a-difluoro-llp,17n,21-trihydroxy pregna-l,4-diene-3,20-dione (Xia) were dissolved^i^ 30 ml, of pyridine con10 taining 1 ml. of tert-butyl acetyl chloride / kept at room temperature for 16 hrs.

Addition of ice water afforded a product which was extracted with chlo roform. The chloroform solution was washed with 5% sodium bicarbonate solution and water. After drying (^SO^) and removal of the solvent in vacuozthe residue was crystallized from acetone-hexane to give 2-bro mo-6p,9e-difluoro-ixp,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione 21-ter|butylacetate (Xlg) (XI^RpOCOCHgCtCH^ 7 R2=OH).

M.P. 198-200°C (decomposition) Wp +25° (° 1,0 *** chloroform) Amax (methanol) 245-6 mp ( £ 10900) K(KBr) 3490 (broad), 1735 (broad), I67O, I64O, 1600, 1230 cm-1.

Analysis: Calcd. for C27H.j,.BrF20g (percent) C 56,55; H 6,15; Br 13,93; F 6,62.

Found (percent) C 56,71; H 6,02; Br 13,85; F 6,75.

* Example T6 Using ttiu general procedure of Exumpie 15 2-bromo-6p,9a-difiuoro-llp,l7u,2i-trihydroxy-pregnu~l,4-diune-3,20-dlone (XIa) was converted to 2-brotno-6p,9a-dif luoro-1 Ιβ, 17a, 2 i-trihydroxy pregna5 -l,4-diene-3,2O-dione-2l-onnntato (Xlh) (XI, 11^000(0¾)jCHg; U2-OH) by reaction with enanthyl chloride.

M.P. 173-5°O (decomposition) Lajp +28° (C 1.0 in chloroform) A max (methanol) 245-6 mg (£ 11500) IR(KBr) 3500 (broad), 1735 (broad), 1670, 1640, 1600, 1230 (broad) cur1. Analysis: Calcd. for O28H37BrF20g (percent) C 57,24; H 6,35; Br 13,60; F 6,47.

Found (percent) C 57,31; H 6,30; Br 13,72; F 6,29.

Example 17 Using the general procedure of Example Π the 2-bromo-6p,91 °ύ ” M.P. 2Q9-10°C (decomposition) CaJp + 93° (C 1,0 in chloroform) Xmax (methanol) 233-4 (6 22000) IR(KBr) 3600, 3420 (broad), 1725, 1710, 1670, I64O, 1600 cm1.

Analysis: Calcd. for 028^2913¾% (Percettt) 0 58,04; H 5,04; Br 13,79; F 6,56.

Found (percent) C 58,21; H 4,93; Br 13,68; F 6,39.

Example 18 A mixture of 5 g. of 2-bromo-68,9a-difluoro-ll β,17α-21trihydroxy-pregna-l,4-diene-3,20-dione (XI, R-|=R2=OH), 5 ml. of methyl orthovalerate and 0.020 g. of p-toluene sulphonic acid in 15 ml. of dimethylformamide was maintained for 4 hours under nitrogen at 115°C. Then the mixture was neutralized by pyridine and concentrated under vacuum to dryness. Purification by column chromatography on FLORISIL (trade mark) (ratio 1:30) with benzene-chloroform (8:2) as eluant, gave 3.5 g. of 2-bromo-6 β,9ct- difluoro-11 β-hydroxy-l7a,21 -(1'-butyl 1'-methoxymethylene dioxy)-pregna-l,4-diene-3,20-dione, which without further purification was suspended in 25 ml. of methanol and 3 ml. in HCl and heated on a water bath at 40-50°C.

After complete solubilization of the product, the mixture was concentrated under vacuum.

The insoluble product was filtered off, washed with water and then dried. The 2-bromo-68,9a-difluoro-ll β,17a,21-trihydroxy pregna-1,4-diene-3,20-dione-17-valerate (XI 1) (XI, Rq-OH, Rg^COtCH^)3CH3) thus obtained was crystallized from acetonehexane and characterized by M.P. 201-3°C (decomposition). £a]D -74° (C 1.0 in chloroform) λ max (methanol) 246 IR(KBr) 3500 (broad), Analysis: Calculated for Found (percent) mu (ε 12600) 1730, 1715, 1670, 1645, C26B33BrF2°6 (Percent) C 55.82; H 5.94; Br 14 C 55.91; H 6.07; Br 14 1600 cm'1. 28; F 6.79 27; F 6.72 43112 Example 19 Using the general procedure of Example 11 the 2-bromo68,9a-difl uoro-Π β,17α.21-trihydroxy pregna-1,4-diene-3,20-dione17-valerate (XI 1) was converted to 2-bromo-60,9a-difluoro5 ll8,17a-21-trihydroxy-pregna-l,4-diene-3,20-dione 17-valerate 21-acetate (XI m) (XI, R, = 0C0CH3, R2=0(CH2)3CH3 by reaction with acetic anhydride. The product was crystallized from acetone-hexane. The crystals showed at 125°C a transition from the low melting form II to the form I melting at 173-5°C (decomposition). [oJq -25° (C 1.0 in chloroform) λ max (methanol) 245-6 mp (ε 11400) IR(KBr) 3500 (broad), 1735 (broad), 1672, 1645, 1605, 1230 (broad) tm'1.

Analysis: Calculated for C28H35BrF207 (percent) C 55.91; H 5.86; Br 13.28; F 6.32 Found (percent) C 56.03; H 5.91; Br 13.07; F 6.28 Example 20 Using the general procedure of Example 18 the 2-bromo-68,9a20 difluoro-118,17a,21-trihydroxy-pregna-l,4-diene-3,20 dione (XIa) was converted to 2-bromo-6B,9a-difluoro-ll8,17a,21-trihydroxypregna-1,4-diene-3,20-dione-l7-acetate (XI η) (XI, RpOH, R2=0C0CH3) by reaction with ethylorthoacetate followed by acid hydrolysis of the resulting 17,21-orthoacetate. The product was crystallized from acetone-hexane. M.P. 230-2°C (decomposition) 2112 [ct] θ - 75,8° (C 1.0 in chloroform) λ max (methanol) 245 mp (ε 11700) IR/KBr 3500, 3420, 1730, 1720, 1675, 1640, 1610, 1220 cm-1.

Analysis: Calculated for ^HgyB^Og (percent) a C 53.40; H 5.26; Br 15.44; F 7.34.

Found (percent) C 53.52; H 5.32; Br 15.52; F 7.27.

Example 21 Using the general procedure of Example 11 the 2-bromo60,9ct-dif1 uoro-Π β,,17a,21 - tri hydroxy-pregna-1,4-diene10 3,20-dione-17-acetate (XI n) was converted to 2-bromo-60,θαdi fluoro- 1 10,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione 17-acetate, 21-valerate (XI ο) (XI, Rq=0C0(CH2)3CH3, R2=0C0CH3) by reaction with valeric anhydride. The product was crystallized from acetone-hexane. la M.P. 159-60°C (decomposition) [α]p -37° (C 1.0 in chloroform) Xmax (methanol) 246-7 mp (ε 11750) IR(KBr) 3660, 3520, 3380, 1730 (broad), 1675, 1640,1600, 1240 cm'1.

I Analysis: Calculated for C2gH35BrF207 (percent) 2θ C 55.91; H 5.86; Br 13.28; F 6.32.

Found (percent) C 56.07; H 5.73; Br 13.21; F 6.55. 48113 Example 22 Using the general procedure of Example 18 the 2-bromo68,9a~difluoro-Π8,17a- 71 -tri hydroxy-pregna-1,4-diene-3,20-dione (XIa, Rq=R2=0H) was converted to 2-bromo-68,9a-difluoro5 11β,Ι7a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propionate (XI ρ) (XI, R-,=0H, R2=0C0CH2CH3) by reaction with ethylorthopropionate followed by acid hydrolysis of the resulting 17,21-orthopropi on ate.

The product was crystallized by acetone-hexane.

M.P. 215-7°C (decomposition) Amax (methanol) 245-6 mp (ε 12300) fql D -75° (C 1.0 in chloroform) .

IR (KBr) 3500, 3420, 1730, 1712, 1675, 1640, 1605, 1200 cm' Analysis: Calculated for C24H2gBrF20g (percent) C 54.24; H 5.50; Br 15.04; F 7.15-. Found (percent) C 54.20; H 5.52; Br 14.79; F 6.97.

Example 23 Using the general procedure of Example 18, the 2-bromo6 8,9a-difl uoro-11 8,17a,21-trihydroxy-pregna-1,4-diene-3,20dione (XIa), R1=R2=0H) was converted to 2-bromo-68,9a-difluoro-llB, .17a,21- trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate (XI q) (XI, R-|=OH, R2=0C0CgHg) by reaction with ethylorthobenzoate followed by aci The product was crystallized by acetone-hexane. M.P. 241-3° (decomposition) [ct] - 103° (C 1.0 in chloroform) D Xmax (methanol) 234-5 mp (ε 23500) b IR(KBr) 3520, 3430, 1730, 1700, 1680, 1645, 1610 cm-1. Analysis : : Calculated for C23 H2gBrF206 (percent) C 58.04; H 5.04; Br 13.79; F 6.56 Found (percent) C 58.12; H 4.95; Br 13.62; F 6.50 Example 24 q0 Using the general procedure of Example 18 the 2-bromo-6β-fluoro-9a,11 β dichloro-17a,21-dihydroxypregna-1,4-diene-3,20-dione (XII a) was converted to 2-bromo-68-fluoro-9a,llB-dich1oro-17a,21-dihydroxy pregna -1,4-diene-3,20-dione 17-acetate (Xllb) (Xll, R^OH, R2 = 0C0CH3) by reaction with ethyl orthoacetate followed by acid hydrolysis of the resulting 17,21-orthoacetate.

The product was crystallized by acetone-hexane.

M.P. 193-4° (decomposition) [dD -32° (C 1.0 in chloroform) Xmax (methanol 245 mp (ε 11700) IR(KBr) 3500, 1730 (broad), 1705, 1680, 1650, 1605, 1240 (broad) cm1.

Analysis: Calculated for CgjH^gBrCl<>F0g (percent) C 50.02; H 4.74; Brl4.47i Cl 12.8^; F 3.44.

Found (percent) C 50.11; H 4.82; Brl4.35; Cl 13.03; F 3.32.

Example 25 Using the general procedure of Example 11 the 2-bromo-6 β-fluoro-9a,11β-di chioro-17a,21 -dihydroxy-pregna1,4-diene-3,20-dione (Xlla) was :converted to 2-bromo-6β-fl uoro-9a, 11β-dichl oro-17a, 21-dihydroxy pregna1,4-diene-3,20-dione 21-acetate (XII c) (XII, RpOCOCHg', R2=0H) by reaction with acetic anhydride.

The product was crystallized from benzene-light petroleum M.P. 202-4°C (decomposition) 0*3 D + 49° (C 1.0 in chloroform) Xmax (methanol) 245 mp (e 11800) IR(KBr) 3470, 1750, 1730, 1668, 1640, 1600, 1230 cm'1· Analysis: Calculated for C23H26FC12Br05 (percent) C 50.02; H 4.74; Br 14.47; Cl 12.84; F 3.44.

Found (percent) C 50.21; H 4.63; Br 14.41; Cl 12.79; F 3.38. • ΛΙΙΖ Example 26 Using the general, procedure of exampie 9 the 2-bromo-6p,9a-difluoro-iip,i6a,i7u,2i-tctrahydroxy-pregna-l,4-diene-3,20-dione (XVIIa) (XVii, K -OH) was converted into 2-broino-6p,9a-difiuoro-lip,l6a,17«, 2i-tetrahydroxy-pregna-l,4-diene-3,20-dione-l6,17-acetonide (XIXai) (XIX, Rj=OH, crystallized from acetone-hexane, M.P. 221-3°G (decomposition) Wd° + 9 (C I.O in chloroform) A max (inethanol) 246 mg ( ί 11950) IR(KHr) 3500, 3280, 1730, 1670, 1645, 1605 cm-1.

Analysis: Calcd. for C2^H2qBrF20g (percent) C 54,25; H 5,50; Br 15,04; F 7,15.

Found (percent) C 54,37; H 5,42; Br 14,95; F 7,10.

Example 27 50 ml. of hydrochloric aoid were added at 0°G over a period of 30 min, to a suspension of 5 g. of 2-bromo-6p-fluoro-17a,21-dihydroxy-9P,llp-oxido-pregrta-l,4-diene-3,20-dione-17,21-diacetate (X) in 30 ml. of acetone.

The mixture was held at 0°C under stirring for 6 hrs. and then the pre20 oipitated 2-bromo-6p-fluoro-9a-chloro-Hp, i7a,21-trihydroxy-pregrta-l,4-diene-3,20-dione 17,21-diacetate ( JCIIl) was recovered by filtration, from washed repeatedly with water, dried and crystallized / acetone-hexane. M.P. 258-£o°C (decomposition) -220 (c i.o in chloroform) A max (methanol) 246 mg (EillOO) IR(KBr) 3440 (broad), 3350, 1753, 1740, 1705, 1675, 1645, 1600, 1230 cm-1. Analysis: Calcd. for c25H29BrC1J?®7 (percent) C 52,14? H 5,08} Br 13,88; Cl 6,16; F 3,30.

Found (percent) C 52,34; H 5,02; Br 13,72? Cl 6,22; F 3,25. 43112 EXAMPLE 28 8.5 g. of l,3-dibromo-5,5-dimethyl-hydantoin were added in the dark at 15°C under stirring over a period of 0.5 hr. to a suspension of 11 g. of l6a-methyl-2-hromo-6p-fIuoro-17 9fll)-triene-3,20-dione-17,2l-d.i.acetatc(VIIIajCRj'^CH^) in 250 ml. of tetrahydrofuran and 1.1 g. of 70% perchloric acid in 11 ml. of water. During the addition the suspension began to thin and after a total reaction time of 45 min. ail the starting material was dissolved.

After an additional 2 hrs., 10% sodium sulfite aqueous solution was m potassium iodide turned 10 added under stirring until / -starch paper no 1 ongeryolue . The solution was slowly poured into 1000 ml. cold water, and then the 16a-methyl-2,9a-dihromo-6p-fluoro-llp,17 M.P. 205-7°C (decomposition) IR(KBr) 3470. I76O, 1730, 1670, I64O, 1610, 1230 cm-1.

Analysis: Calcd. for C26H31Br2F07 (percent) C 49,23; H 4,93; Br 25,19; F 2,99.

Found (percent) C 49,31; H 5,05; Br 25,35; F 3,10.

EXAMPLE 29 Using the general procedure of example 28 the l6(l-methyl-2-bromo-6P~fluoro-17a,21~dihydroxy-prcgna-l ,4,9(11) -triene-3,20-dionc-l7,21-diacetate (Vllb) =ΡΠΗ^J was converted into I6p-methyl-2,9a-dibromo-6p-fluoro-lip,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione-17,21-diacetate[IX b) (R =pCH ) characterized hy M.P. 2O7-9°C (decomposition) IR(KBr) 3500 (broad), 1740, 1725, 1675, 1645, 1600, 1235 cm”1.

Analysis: Calcd. for 02(,11^11^07 (percent.) C 49,23; H 4,93; Hr 25,19; F 2,99.

Found (percent) C 49,37; H 5,10; Hr 24,95; F 2,91.

However, the product. (10 b) was filtered and utilized moist in the next, reaction.

Preparation 3 ml. of a 14% potassium carbonate aqueous solution were added over a period of 20 min. at 20°0 under stirring to the solution of the moist product ( IX a) (RyaiCH^) l6a-methyl-2,9 M.P. 232-4°C (decomposition) - 96« (C 1.0 in chloroform) IR(KBr) 1755, 1735, 1675, 1645, 1610, 1235 cbH.

Analysis: Calcd. for CjCjH^QBrFOy (percent) 0 56,43; H 5,46; Hr 14,44 F 3,43.

Found (percent) C 56,61; H 5,32; Hr 14,27; F 3,52. 43113 Preparation 4 Using the general procedure of Preparation/the l6p-methyl-2,9a-dibromo-6p-fluoro-llp,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione-17,21-diacetate (IX b) (R^CH^) was converted into 16p-methyI-2-bromo-6p-fluoro5 -17a,21-dihydroxy-9P,lip-oxido-pregna-l,4-diene-3,20-dione-l7,21-diacetate (X b) (R^=pCH^) characterized by M.P. 234-5°C (decomposition) E“Jp° - 5& (c l.o in chi oroform) IR(KBr) 1755, 1730, 1675, 1645, 1010, 1240 cm-1.

Analysis: Calcd. for C^HgQBrFO? (percent) C 56,43; H 5,4-6; Br 14,44; F 3,43.

Found (percent) C 56,29; H 5,32; Br 14,57; H 3,37.

EXAMPLE 30 ml. of a 7θ% hydrofluoric acid aqueous solution were cooled to -10°C 15 in a polyethylene flask equipped with electromagnetic stirrer. 3.7 g. of 16a-methyl-2-bromo-6 p-f luoro-17a,21-dihydroxy-9p ,11 p-oxi.do-pregna-1,4 -diene_3,20-dione-17,21-diacetate (X‘ a) (R =aCH ) were added under stirring during 15 min. After 1.5 hr. the reaction mixture was precipitated in water and ammonia. The solid was collected by filtration,washed with water and dried to a constant weight, giving about 3.5 g. of I6a-methyl-2-bromo-6 β,9a-difluoro-1lp,17a,21-trihydroxy-pregna-1,4-diene-3,2 0-dione-17,21-diacetate (XI r) (X=0H, Y=F, R =«CH ).

Crystallization from benzene.-n-hexane gave 3 g. of pure product characte rized by M.P, 288-9°C (decomposition) Wd° ” (C Α·θ chloroform) λ max (methanol) 246 mp ( £ 12100) IR(KBr) 3500, 1760, 1730, 1710, 1680, I64O, 1610, U30 cm-1.

Analysis: Calcd. for C25tl31DrF2°7 (percent) C 54,46; H 5,45; Br 13,93; K 6,63.

Found (percent) C 54,58; H 5,37; Br 13,80; F 6,75.

Example 31 Using the general procedure of example 30, the 16g-methyl-2-bromo-6g-fluoro -17a,21-dihydroxy· 9β, 11β-oxide-pregna-l,4-diene-3,20-dione-l7,21-diacetate (X b) (Rg=eCHg) was converted into 165-methy1-2-bromo-6g,9a-difluoroΠ B,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione-17,21-diacetate (XI s) (X=0H, Y=F, R1=R2=0C0CH3, R3=ECH3), characterized by θθ - 13° (C 1.0 in chloroform) λ max (methanol) 246 mp (e 12000) IR(KBr) 3480, 1755, 1740, 1725, 1678, 1645, 1600, 1235cm'1.

Analysis: Calculated for C2gHgqBrF207 (percent) C 54.46; H 5.45; Br 13.93; F 6.63 Found (percent) C 54.65; H 5.38; Br 14.10; F 6.75. Example 32 50 ml.of hydrochloric acid were added at 0°C over a period of 40 minutes to a solution of 5 g of 16a-methyl-2-bromo-68-fluoro-17a,21-hydroxy-98,n βoxido-pregna-1,4-diene-3,20-dione-l7,21-diacetate (XI a) (Rg aCHj) in 30 ml. of acetone. The mixture was held at 0°C with stirring for about 2.5 hours and then the precipitate of 16a-methyl-2-bromo-6B-fluoro-9a-chloro-ll β,17α,21trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI b) X=OH, Y=C1, Rg=aCHg, Rq=R2=0C0CHg) was recovered by filtration, washed repeatedly with water and dried (4.9 g.). The solid was crystallized from acetone-hexane and characterized by M.P. 245-6°C (decomposition).

Xmax (methanol) 246 mp (e 12000) [a]20 - 34° (C 1.0 in chloroform) D IR(KBr) 3460, 1757, 1730, 1710, 1678, 1645, 1608, 1230 cm'1.

Analysis: Calculated for C26H31BrCIFOy (percent) C 52.94; H 5.30; Br 13.54; Cl 6.01; F 3.22.

Found (percent) C 53.12; H 5.37; Br 13.71; Cl 6.12; F 3.14.

EXAMPLE 33 Using the general procedure of example 32 . the 16B-methyl-2-bromopregna-6p-fluoro-17 M.P, 250-l°C (decomposition) Λ max (methanol) 246 mp ( £ 12150) [a]20 + 2o (c 1>0 in chloroform) IR(KBr) 3480, 1740 (broad), 1723, 1675, 1645, 1600, 1235 cm-1.

Analysis: Calcd. for C^Hgj^BrClFO^ (percent) C 52,94; H 5,30; Br 13,54; Cl 6,01; F 3,22.

Found (percent) C 52,73; H 5,32; Br 13,60; Cl 6,15; F 3,31.

EXAMPLE '34 To a solution of 10 g. of l6a-methyl-2+bromo-6p-l'luoro-17a,21-dihydroxy-pregna-l,4,9(ll)-triene-3,20-dione-17,21-diaeetatc (/a) (R =aCH ) and «5 i$ g. lithium chloride in 200 ml. of glacial acetic acid were added at 20°C under stirring 5 g. of N-chlorosuccinimidc. The mixture was kept at 2Q°C and stirred while dropwise adding 10 ml. of a 12% hydrochloric acid tetrahydrofurane solution over a period of about 10 min. After 3*5 hrs, the reaction mixture was poured into cold water, the solid was collected by filtration, washed with water and dried, giving 7,5 g. of pure product l6a-methyl-2-bromo-6p-fluoro-9a,11p-dichioro-17^,21-dihydroxy-pregna-1,4-diene-3,20~dione-17,21-diacetate (Xild) (X-Y=C1., R R^rlOOCH., R --siCH ) characterized by M.P. 253-5°C (decomposition) a 2° _ lo° (C 1.0 in chloroform) max (methanol) 245 mp ( 12350) XR(KBr) 1745, 1730 , 1670, 1645, 1605, 1235 cm1.

^Analysis: Calcd. for C26H3oBrC12FO6 (percent) C 51,335 H 4,975 Br 13,14; Cl 11,66; F 3,12.

Found (percent) C 51,45; H 5,07; Hr 13,04; Cl 11,81; F 3,19* NMR (dlmetjiyl-dg sulfoxide-TMS) Hz at 60 mHz 464 (S, 1, C-l H) 393, 398 (d, 1, C-4 H) 346,296 (doublet of triplets, 1, C-6 H) 318-304 (m, 1, C-ll H) 309, 293, 288, 272 (doublet of doublets, 2, C^OAc.) 125 (S, 1, «Ac) 123 (S, 1, oAc) 108,104 (d, 3, 19 CH split by 6BF) (S, 3, 18 CH ) 58,51 (d, 3, ΙόαΟφ. 43112 EXAMPLE, 35 Using the general procedure of example 34’ the l6p-methyl-2-bromo-6p-fluoro-17a,21-dihydroxy-pregna-l 4,9(11)-triene-3,20-dione 17,21-diacetate ( (R^^CH^) was converted into 16p-methyl-2-bromo-6pfluoro-9a,lfp-dichloro-l7®,21-dihydroxy-pregna-l,4-dicne-3,20-dione-17,21-diacetate (Xlle) (R =R=OCOCH , R =PCH , X=Y=C1) characterized hy M.P. 224~6°C (decomposition) faJ^O + 21° (C 1.0 in chloroform) IR(KBr) 17·50’ 'i73Q/67-5> 1645’ l6°5’ 1230 Cnrl’Analysis: Calcd. for C^H^BiC^FO^ (percent) C 51,33; H 4,97; Br 13,14; Cl 11,66; F 3,12.

Found (percent) C 51,55; H 4,82; Br 12,98; Cl 11,65; F 3,12. NMR (dimethyl-dg sulfoxide-TMS) Hz at 60 mHz 465 (S, 1, C-l H) 394, 390 (d, 1, C-4 H) 348,298 (doublet of triplets, 1, C-6 H) 320-305 (m, 1, C-ll H) 295,279,270,254 (doublet of doublets, 2, CH^Ac) 126 (S, 6, 2xCAc) 109, 105 (d, 3, 19OH3 split by 60F) 78,72 (d, 3, 16PCH ) (S, 3, 18 CH ). 43112 EXAMPLE 36 A suspension of 5.2 g. of 16a-methyl-2-bromo-6p,9a-dif luoro-Hp,17«,2l-trihydroxy-pregna-l,4-diene-3,2O-dione-17,21-diacetate (XII) in 120 ml. of 1% potassium hydroxide methanolic solution was stirred under nitrogen at 0°C for 3 hrs. Addition of cold water, elimination of methanol, in vacuo, acidification with acetic acid and filtration gave 4 g. of l6a-incthyl-2-bromo-6p,9a-difl.uoro-lip,17«,21-trihydroxy-pregna-l,4-dicne-3,20-dione (XIV) (Χ'ΌΗ, Y=F, R1=R_=OH, R ~aCH ) n20 J |aj “24° (c 1.0 in chloroform) Amax (methanol) 245-6 mg ( 6 12250) IR(KBr) 3460 (broad), 1710, 1665, 1640, 1603 cm1.

NMR (dimethyl-d^. sulfoxide-TMS) Hz at 60 mHz 466 (3,1,0-1 H) 388,384 (d, l,C-4 H) 345,295 (doublet of triplets, 1, C-6 H) 318-314 (d, 1,0-11 OH) 296 (S,1,C-17 OH) 280-225 (mU,tiplFt«tieh becomes a quartet by deuterium exchange,2,C0CH20H) 96,94 (d,3,19 CH3 split by 6pF) 54 (S,3,l8 CH.^ 54,44 (d,3,C-l6aCH3) Analysis: Calcd. for C22^27BrF20j (percent) C 53,99; H 5,56; Br 16,33; F 7,76. Found (percent) C 54,10; H 5,70; Br 16,41; F 7,85. 43113 EXAMPLE 37 Using the general procedure of example 36 the l6p-methyl-2-bromo6p,9a-difluoro-lip,17 3 3 M.P. 216-7°C (decomposition) [a]20 + IK (C 1.0 in chloroform) A max (methanol) 246 mg ( £ 10900) 10 IR(KBr) 3440 (broad), 1715, 1665, I64O, 1600.cm-1, NMR (dimethyl-dg sulfoxide-TMS) Hz at 60 mHz 472 (S, 1, C-l H) 388,384 (d, 1, C-4 H) , 346,296 (doublet of triplets, 1, C-6 H) 339-334 (m, 1, C-ll OH) 315 (S, 1, C-17 OH) 280-240 (multiplet which becomes a quartet by deuterium exchange, 2, COGH^OH'1L5 96,94 (d, 3, 19 CH3 split by 6pF) 65,58 (d, 3, C-16PCH ) (S, 3, 18 CH ).

Analysis: Calcd. for C^HgyBrF^^ (percent) C 53,99; H 5,56; Br 16,33; F 7,76.

Found (percent) C 53,75; H 5,45; Br 16,41; F 7,87.

EXAMPLE38 Using the general procedure of example 36 the l6a-methyl-2-bromo-6p-fluoro-9a,llp-dichloro-l7a,21-dihydroxy-pregna-l,4-dlene-3,20-dione-17»21-diacetate (XII tl) > * - was con verted into l6a-methyl-2-bromo~6P-fluoro-pa, llp-dicliloro-17a, 21-dihydroxy-pregna-l,4-diene-3,20-dione (XII f)(R1=R2=0H, R3=aCH^, X=Y=C1). The product was crystallized from acetone-hexane.

M.P. 216-8°C + 1,0 i*1 cM-orc,:form) IR(KBr) 3640, 3500, 3400, 1705, 1665, 1642, 1605 cm”1.

Analysis: Calcd. for C22H26BrC12F04 (Percent) c 50,40; H 4,99; Br 15,24; Cl 13,5?; F 3,62.

Found (percent) C 50,63; H 5,12; Br 15,34} Cl 13,68; F 3,61.

EXAMPLE ·39 ‘ Using the general procedure of example 36 the 16p-methyl.-2-bromo-6R-fluoro-9«,1lp-dichloro-l7a,21-dihydroxy-pregna-l,4-diene-3,20-dione-17,21-diacetate (ΧΪΙ e) 1 was converted into 16p-methyl-2-bromo-6p~fluoro-93=PCH3, X=Y=C1) 0*3pO + 51° (C 1.0 in chloroform) Λ max (methanol) 245-6 mp (£ 11500) ffi(KBr) 3600, 3480, 3360, 1710, 1665, 1645, 1610 cm”1.

Analysis: Calcd. for Cg^gBrC^FO^ (percent) C 50,40; H 4,99; Br 15,24; Cl 13,52; F 3,62.

Found (percent) C 50,35; H 4,81; Br 15,20; Cl 13,31; F 3,68.

EXAMPLE -40 g. of l6a-methyl-2-bromo-6p,9e-difluoro-llp,17n,21-trihydroxy-pregna-1,4-diene—3,20-dione (XI v) X=0H, X=4P) were dissolved in 70 ml. of pyridine containing 35 ml· of acetic anhydride and kept at room temperature for 12 hrs. Addition of ice water afforded a product which was extracted with chloroform. The chloroform solution was washed with water, 2N HCl, 5% sodium bicarbonate solution and water.

After drying (NagSO^) and removal of the solvent iu vacuo the residue was crystallized from acetone-hexane to give 6.7 g. of l6«-methyl-2-bromo-6p,9J21-trihydroxy-pregna-l,4-diene-21-acetate (XI X) (R =OCOCH , R„=OH, X=OH, Y=F, R.=nCH,) i 3 & 3 3 M»P. 229~31°C - 6* (C 1.0 in chloroform) A max '(methanol) 246 mp (£ 11300) IR(KBr) 3520 (broad), 1740, 1720, 1665, 1640, 1605, 1230 cm-1.

Analysis: Calcd. for C^HggBrF^g (percent) C 54,25; H 5,50; Br 15,04; F 7,15.

Found (percent) C 54,41; H 5,60; Br 14,95; F 7,12. 48112 EXAMPLE ,41 Using the general procedure of example 40 the 16p-methyl-2-bromo-66, 9a-dxfluoro-1 ϊβ,i7a,21-trihydroxy-prcgna-1,4-dien e-3,2 O-d ion e (XI w) was converted into l60-methyl-2-brorao5 -6p,9a-difluoro-llB,17a,21-trihydroxy-pregna-l,4-diene-3i20-dione 21- -acetate (XI y) (^=0000^, R3=OH, X=OH, Y=F, R3=0CH3) M.P. 2l6-8eC [e]JO + 2So (C i.o in chloroform) A max (methanol) 245-6 mp ( £ 11500) 10 IR(KBr) 3500 (broad), 1745, 1720, 1675, 1645, 1610, 1230 cm-1.

Analysis: Calcd. for C2^H2gBrF20g (percent) C 54,25; H 5,50; Br 15,04; F 7,15.

Found (percent) C 54,45; H 5,38; Br 15,11; F 7,08.

EXAMPLE,. 42 Using the general procedure of example 40 the 16a-methyl-2-bromo-6P, 9a-difluorO-llg,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione (XI V) was converted into l6a-methyl-2-bromo-6p,9a-d'ifluoro-lip,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione-21-propionate (XI z) (R^=OCOCH2CH3, R2=^3H, R3=eCH3, X=OH, Y=F) by reac2° tion with propionic anhydride. [^0^° (C 1.0 in chloroform) A max (methanol) 246 mp (£ 1θ8θθ) IR(KBr) 3520 (broad), 1740, 1728, 1672, 1645, 1605, 1225 cm1. Analysis: Calcd. for OajHjjBrFgO^ (percent) C 55,05; H 5,735 Bn 14,65; F 6,97.

Found (percent) C 55,25; H 5,62; Br 14,55? F 7,07· EXAMPLE 43 Using the general procedure of example 40 the l6[3-methyl-2-bromo-6p, 9«-difluoro-l1β,17α,21-trihydroxy-pregna-l,4-diene-3,20-dione (XI w) was converted into l6P-methyl-2-bromo-6β,9a-difluoro-11β,17a,21-trihyd roxy-pregna-1,4-diene-3,20-dione-215 -propionate (Xl 88)(^=0000^0^, R2=0H, R3=pCH3, X=OH, Y=F) by reaction with propionic anhydride. ία1υ° 1 θ 1·° “ tbloroform) Λ max (methanol) 246 mp (£ 11000) IR(KBr) 3500 (broad), 1745, 1730, 1670, 1645, 1605, 1220 cnT1.

Analysis: Calcd. for C25H31BrF206 (percent) C 55,05; H 5,735 Br 14,65; F 6,97.

Found (percent) C 55,10; H 5,72; Br 14,85; F 7,08.

EXAMPLE^ 44 Using the general procedure of example 40 the 16a-methyl.-2-bromo-6i315 -fluoro-9a,llB-dichioro-l7a,21-dihydroxy-pregna-l,4-diene-3,20-dione (ΧΠ f) was converted into l6a-methyl-2-bromo-6p-fluoro-9a,llB-dichloro-l7a,21-dihydroxy-pregna-l,4-diene-3,20-dione-,21-acetate (XII fl) (Rj=0C0CH3, R2=OH, R3=aGH3, X=Y=Cl). The product was crystallized from methanol. The crystals showed at 158°C a transat ition from the low melting form IX to the form I melting/237°-8°C (decomp.) {aJ^O + (0 *·® i*1 chloroform) A max.(methanol) 246 mp ( £ 11550) IR(KBr) 3550, 3460, 3340, 1755, 1730, 1673, 1635, 1605, 1230 cm1. Analysis: Calcd. for C2^H2gBrCl2F0^ (percent) C 50,90; H 4,98; Br 14,11; 01 12,52; F 3,35.

Found (percent) C 51,12; H 5,05; Br 13,98; Cl 12,40; F 3,28.

EXAMPLE 45 Using the general procedure of example 40 the 16P-methyl-2_bromo-6p-fluoro-9a,llp-dichloro-l7a,21-dihydroxy-pregna-l,4-diene-3,20-dione (Χ1Ί 9) was converted into 16p-me5 thyl-2-brorao-6 β-fluoro-9a,1lp-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-2l-acetate (R^=OCOCH3, ^“OH, R^CH^, X=Y=C1).

Hd° + 61° (° l‘° I*1 chloroform) A Max (methanol) 245-6 mg (£ 11000) IR(KBR) 3500 (broad), 1750, 1730, 1675, 1645, 1605, 1230 cm-1.

Analysis: Calcd. for Cg^gBrfJljFC^ (percent) C 50,90; H 4,98; Br 14,11; Cl 12,52; F 3,35.

Found (percent) C 51,12; H 4,88; Br 13,955 Cl 12,41; F 3,28.

EXAMPLE 46 A mixture of 5 g. of l6a-methyl-2-bromo-6p,9a-difluoro-lip,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione (XI v), 5 ml. of methyl orthovalerate and 0.02 g of p-toluenesulphateyand in / 5 ml. of dimethylformamide was maintained for 4 hrs. under ni5 trogen at 115°C. Then the mixture was neutralized by pyridine and concentrated under vacuum to dryness. Purification by column chromatography on FLORISIL (Registered Trade Mark) (ratio 1:150) with benzene-chloroform (1:1) as eluant, gave 4 g. of l6a-methyl-2-bromo-6R, 9a-difluoro-iiB /?7α,2ΐ- (11-butyl-1‘-methoxymethylenedi oxy)pregnawhich, without further purification, was suspended in 25 ml. of methanol and 3 ml. IN hydrochloric acid aqueous solution, and heated on a water bath at 40-50°C.

After complete solubilization of the product, the mixture was concentrated under vacuum. The insoluble product was filtered off,washed with water and then dried.

The l6e-methyl-2-bromo-6|3,9“-difluoro-ilp,i7a,21-trihydroxy-pregna-l,4-diene-3,20-dione-17-valerate (XI ab)(2=H, R =OH, R 0C0(CH2)3 CH3, Y=F) thus obtained was characterized by Εα1ρθ ~ (C 1.0 111 cbloroform) 2o λ max (methanol) 246 mp (ί, I2300) IR(KBr) 3500 (broad), 1730, 1715, 1672, 1640, 1605 cm-1.

Analysis: Calcd. for C2yH3^BrF20g (percent) C 56,55; B 6,15; Br 13,93; F 6,63.

Found (percent) C 56,67; H 6,05; Br 14,12; F 6,75.

EXAMPLE. 47 Using the general procedure of example 46 the 16a-methyl-2-bromo-6g,9a-difLuoro-lip, 17a,21-t.rihydroxy-prcgna-l,4-diene-3,20-dione (XI v) was converted into 16a-methyl-2-bromo8 -6β,9a-difluoro-llp,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione-17-acetate (XI ac)(^=0^ R2=OCOCH , X=OH, Y-F) M.P. 212-4°C (decomposition) jaj^O ~ (C 1,0 i*1 cdlorof°rm) A max (methanol) 245-6 mp ( £ 12100) IR(KBr) 3450 (broad), 1725, 1710, 1680, 1640, 1610, 1250 cm-1.

Analysis: Calcd. for C24H29BrF206 (percent) C 54,25; H 5,50; Br 15,04; F 7,15.

Found (percent) C 54,48; H 5,57; Br 15,18; F 7,20.

EXAMPLE 48 Using the general procedure of example 46 the 16B-methyl-2-bromo-6p,9a-difluoro-llp,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione (XI w) was converted into 16p-methyl-2-bromo-6β,9a~difluoro-1ip,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione-17-valerate (XI ad/R^H, B2=OCO(CH2)3CH3, R3=PCH3, X=OH, Y»F). 2° Ηυθ ~ 60° (C 4.0 ^n chloroform) A max (methanol) 246 mp ( {. 12000) IR(KBr) 3480 (broad), 1730, 1710, 1675, 1640, 1610 cm1.

Analysis: Calcd. for (percent) C 56,55; H 6,15; Br 13,93; F 6,63.

Found (percent) C 56,80; H 6,08; Br 13,83; F 6,75. 43113 EXAMPLE 4Q Using the general procedure of example 46 the l6p-methyl-2-bromo-6β,9a-difluoro-110,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione(XI w) was converted into l6p-rnethyl-2-bromo-6p, 9a-difluoro-lΙβ,17a,21-trihydroxy-pregna-l,4-diene-3,2O-dione-17-acetate (XI ae) (f^OH, r2=ococh3, r3=Pgh3> X=OH, Y=F)· M.P. 227-8°C (decomposition) A max (methanol) 246 ma ( £ 11100) IR(KBr) 3500 (broad), 1670, 1642, 1005, 1230 cm-1.

Analysis: Calcd. for C24H29BrF206 (percent) C 54,25; H 5,50; Br 15,04; F 7,15.

Found (percent) C 53,97; H 5,61; Br 15,24; F 7,27.

EXAMPLE, 50 Using the general procedure of example 46 the t6a-methyl-2-bromo15 -6p-fluoro-9a,llp-dichloro-17a,21-dihydroxy-pregna-l,4-diene-3,20-dione (ΧΠ f) was converted into l6a-methyl-2-bromo-6|3-fluoro-9a}llp-dichloro-17a,21-dihydroxy-pregfta-l,4-diene-3,20-dione-17-acetate (xn j )(^=0^ r2=ococh3, r3=“ch3, x=y=ci).

M.P. 245-7°C (decomposition) HpO “ 43° (0 1.0 in chloroform) A max (methanol) 245 mg ( Z 11750) lR(KBr) 3500, 1720, 1710, 1675, 1640, 1607 cm-1.

Analysis: Calcd. for C^J^gBrC^FO^ (percent) C 50,90; H 4,98; Br 14,11; Cl 12,52; F 3,35.

Found (percent) C 51,12; H 5,07; Br 13,97; Cl 12,30; F 3,27.

EXAMPLE_ 51 Using the general procedure of example 46 the l6p-methyl-2~bromo-6$-f luoro -9®, llp-dichioro-17 * * * J *J V JaJ2B - 12° (C 1.0 in chloroform) /\ max (methanol) 246 mp ( E 11600) IR(KBr) 3500 (broad), 1720, 1710, 1670, 1645, 1605 cm-1.

Iq Analysis: Calcd, for C^f^gBrC^FOj (percent) C 50,90; H 4,98; Br 14,11; Cl 12,52; F 3,35.

Found (percent) C 51,15} H 5,19; Br 14,05; Cl 12,47} F 3,28.

EXAMPLE 52 A solution of 6 g. of l6a-methyl-2-bromo-6p,9®-difluoro~llp,17a,21-tri15 hydroxy-pregna-l,4-diene-3,20-dione (Xl v) in 12 ml. of dimethylformamide and 40 ml. of 2,2-dimcthoxypropane with 0,030 g, of p-toluenesulfonic acid was heated for 5 hrs. at 115°C. The reaction mixtu re was cooled, poured in 10% sodium bicarbonate aqueous solution and chlo roform. The chloroform solution was then washed with water, dried and e20 vaporated to a residue which by crystallization from acetone-hexane gave 5 g. of 16a-methyl-2-bromo-6p,9a-difluoro-llp,17a,21-trihydroxy-pregna-l,4-diene~3,20-dione-17,2l-acetonide (Xl Ό characterized by 18° <C in chloroform) Λ max (methanol) 246 mp (E 11950) IR(KBr) 3480 (broad), 1725, 1678, 1645, 1605 cm-1.

Analysis: Calcd. for C2sH31BrF2O5 (percent) C 56,72} H 5,90} Br 15,09} F 7,18.

Found (percent) C 56,90} H 6,08; Br 15,25} F 7,27. <3113 EXAMPLE 53 Using the general procedure of example 52 the 16p-methyl-2-bromo-60,9a-difluoro-11β,I7α,21-trihydroxy-pregna-l,4-diene-3,20-dione (Xl w) was converted into 160-methyl5 -2-bromo-60,9 A max (methanol) 246 mg ( £ 12000) IR(KBr) 3475 (broad), 1720, 1675, 1640, 1605 cm-1.

Analysis: Calcd. for 025^^1^205 (percent) C 56,72; H 5,90; Br 15,09? F 7,18.

Found (percent) C 56,91? H 5,73? Br 14,89; F 7,12. 43113 EXAMPLE 54 Using the general procedure of Example 40 the 16a-methyl-2-hromo-6B,9a-difluoro-llp,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione (XI v) was converted into l6a-methyl-2.-hromo-6p, 9a-dif luoro-11 β, 17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate (XI ah) (R^OfCH^CH , R2=0H, X=OH, Y=F) by reaction with valeric anhydride. £aj20 + 10° (C 1.0 in chloroform) A max (methanol) 246 mp ( £. 11700) IR(KBr) 3500 (broad), 1740, 1725, 1670, I640, 1605, 1230 cm-1. Analysis: Calcd. for c27H35BrF2°6 (percent) c 56,55» H 6,15; Br 13,93; F 6,62.

Found (percent) C 56,48; H 6,21; Br 14,05; F 6,55» EXAMPLE 55 Using the general procedure of Example 40 the 16p-methyl-2-hrotno-6p,9a-difluoro-lip,17a,21-trihydroxy-pregna-l,4-dienc-3,20-dione (XI w) was converted into Ιόβ-methyl-2-browo-6p,9a-difluoro-1Ιβ,17a,21-trihydroxy-pregna-l,4-dien e-3,20-dione-21-valerate (XI ai) ^=000(0^) CH , R2=0H, R^C^, X=OH, Y«?) by reaction with valeric anhydride.

[®J20 + 390 (c 1,0 in chloroform) A max-(methanol) 246 mp ( £ 11800) IR(KBr) 3520 (broad), 1745, 1730, 1670, 1645, 1605, 1230 cm1. Analysis: Calcd. for c27H35BrF2°6 (percent) C 56,55; H 6,15; Bn 13,93; F 6,62.

Found (percent) C 56,61; H 6,05; Br 13,89; F 6,70.

EXAMPLE 56 Using the general procedure of Example 40 the l6a-methyl-2-bromo-6p, 9®-dif luoro-11β’, 17®, 21-trihydroxy-pregna-1,4-diene-3,20-dione (XIv) was converted into 16a-methyl5 -2-bromo-6p,9®-difluoro-ΙΙβ,17®,21-trihydroxy-pregna-l,4-diene-3,20-dione-21-pivalate (XIaj) (R =OCOC(CH ) , R„=OH, R =nCH , X=OH, 3 3^ 33 Y=F) by reaction with pivalic anhydride.

[„J20 + 5„ (c It0 in chloroform) A max (methanol) 245-6 mp ( fc 10850) IR(KBr) 3480 (broad), 1740, 1730, 1670, 1645, 1605, 1225-cm-1.

Analysis: Calcd. for C^Hjj-BrF^g (percent) C 56,55; H 6,15; Br 13,93; F 6,62.

Found (percent) C 56,60; H 6,12; Br 13,95; F 6,55.

EXAMPLE 57 · Using the general procedure of Example 40 the l6p-methyl-2-bromo-6 β, 9 3 3 3 * 3 Y=F) by reaction with pivalic anhydride.

J7J2° + 36° (C 1.0 in chloroform) A max(methanol) 245-6 mp (fc, 11000) IR(KBr) 3490 (broad), 1740, 1730, I67O, I64O, 1600, 1230 cm-1. Analysis: Calcd, for C27H35BrF2°6 (Percent) c 56,55; H 6,15; Br 13,93; F 6,62. .

Found (percent) C 56,7θ| H 6,23; Br 14,08; F 6,75. 48113 EXAMPLE 5B Using the general procedure of Example 40 the 16a-methyl-2-bromo-6β,9a-difluoro-llB,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione (XI v) was converted into 16a-methyl-2-bromo-6B,9a-difluoro-llp,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione-21-benzoate (XI al) (R,=OCOCrH , R„=OH, R„-=aCH„, X=OH, Y=F) ο 5 2 3 3 by reaction with benzoic anhydride [a]*> + 75° (G 1,0 111 chloroform) A max (methanol) 234 mg ( 22500) IR(KBr) 3600, 3430 (broad), 1730, 1710, 1670, 1645, 1605 cm-1. Analysis: Calcd. for G29H3iBrF2°6 (percent) C 58,69; H 5,26; Br 13,46; F 6,40.

Found (percent) C 58,85; H 5,35; Br 13,37; F 6,30.

EXAMPLE 59 Using the general procedure of Example 40 the 16p-fflethyl-2-bromo—6 $, 92=OH, X=OH, Y=F) by reaction with benzoic anhydride, + 106° (C 1.0 in chloroform) A max (methanol) 234 mp ( έ, 22700) IR(KBr) 3580, 3420 (broad), 1725, 1710, 1670, I64O, 1600 cm1.

Analysis: Calcd. for c29H3iBrF2°6 (Percent) G 58,69; H 5,26; Br 13,46; F 6,40.

Found (percent) C 58,78; H 5,15; Br 13,27; F 6,25.

EXAMPLE 60 Using the general procedure of Example 46 the 16a-methyl-2-bromo-6β,9a-difluoro-ΙΙβ,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione ’(XI v) was converted into l6a-methyl-2-bromo5 -6 β,9a-difluoro-ΙΙβ,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione-17-propionate (XI an) (R =OH, R =OCOCH CH , R =aCH , X=OH, Y=F) 2 2333 - 92° (c 1.0 in chloroform) A max (methanol) 246 mp * ( £, 12100) IR(KBr) 3500, 3430, 1730, 1710, 1675, 1645, 1605 cm“l.

Analysis: Calcd. for c25H3iBrF2°6 (percent) C 55,05; H 5,73; Br 14,65; F 6,97.

Found (percent) C 55,15; H 5,68; Br 14,47; F 7,02.

EXAMPLE 61 Using the general procedure of Example 46 the 16a-methyl-2-bromo-6B,9a-difluoro-llB,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione (XI v) was converted into 16a-methyl-2-bromo-6β,9a-difluoro-11β,17a,21-trihydroxy-pregna-l,4-diene-3,20-dione-17-benzoate (Xi ao) (R^H, R^COC^, R^CH^, X=OH, Y=F) ~ I2®0 1·0 c^-oro^ornlf z\max (methanol) 234 mp (L 23ΟΟΟ) IR(KBr) 3490, 3420, 1730, 1710, 1678, 1645, 1605 cm-1.

Analysis: Calcd. for C2 H^BrF,^ (percent) C 58,69; H 5,26; Br 13,46; F 6,40.

Found (percent) C 58,75; H 5,18; Br 13,35; F 6,30.

The following Examples illustrate compositions of the invention.

EXAMPLE 62 Topical cream formulations containing various amounts of 2-bromo6R,9a-difluoro-llR,17a,21-trihydroxy-pregaa-l,4-diene-3,20-dione-17,21diacetate (XI).

Ingredients Percent range(w/w) Compound XI 0.005-0.5 Cetostearyl alcool 5-20 Polysorbate 60 1-5 Polysorbate 80 1-5 Isopropyl myristate 5-15 Glyceryl monostearate 1-5 Sorbitol solution 1-10 Preservatives 0,2-0,5 Distilled water q.s.ad 100 The ingredients are mixed in a conventional manner for preparing a pharmaceutical topical cream.

If desired,an antibacterial component such as neomycin may be added to the.formulation in Amount ranging from 0.1% to 3%· EXAMPLE 63 Topical ointment formulations containing various amounts of 2-bromo -68,9a-dif luoro-HR, 17a, 21-trihydroxy-pregHa-l, 4-diene-3,20dione —17,21-diacetate (XI).

Ingredients Percent range (w/w) Compound XI 0.OO5-O.5 white petrolatum q.s. ad. 100 The ingredients are blended in a conventional manner providing a colorless topical ointment. lo If desired,an antibacterial component such as neomycin may be added an to the formulation in/amount ranging from 0.1% to 3%. .62 EXAMPLE 64 Topical gel formulations containing various amounts of 2-bromo- 68,9a-dif luoro-1 IR, l?fl, 21-trihydroxj^regha-l, 4-diene~3,20-dione-17,21diacetate (XI). Ingredients Percent range (w/w) Compound XI O.OO5-O5 Carbopol 934 0.5-2.5 Di isopropanolamine 0.2-1 Propylene glycol 5-50 Polysorbate 80 0.5-5 Potassium sorbate 0.05-0.25 Distilled water q.s. ad 100 The ingredients are mixed in a conventional manner for preparing a pharmaceutical topical gel. Carbopol is a Registered Trade Mark. 4> 43113 EXAMPIE 65 Topical lotion formulations containing various amounts of 2-bromo6R,9a-difluoro-llR,17a,21-trihydroxj^regUa-l,4-diene-3,20-dione-17,21-diacetate (XI).

Ingredients Percent range (w/w) Compound XI Propylene glycol Cetostearyl alcohol Isopropyl myristate Eumulgin C-700 Potassium sorbate 0.005-0.5 -35 0.5-2 0.5-2 0.25-1 Ο.Ο5-Ο.25 Distilled water q.s. ad 100 The ingredients are mixed in a conventional manner providing a topical lotion. (Eumulgin is a Registered Trade Mark).

If desired,an antibacterial component such as neomycin may be an added to the formulation in/amount ranging from 0.1% to 3%.

EXAMPLE 66 Ophthalmic (otic) ointment containing various amounts of 2-bromo6fi,9a-difluoro-1IR,17a,21-trihydroxj^regte-l,4-diene-3,20-dione-17,21-diacetate (XT).

Ingredients Percent range (w/w) Compound XI 0.005-0.5 Mineral oil 1-10 White petrolatum q.s. ad 100 Ingredients are blended in a conventional manner providing an opthal 10 mic or otic preparation.

If an antibacterial ingredient is desired,neomycin may be added as the micronized sulfate salt.

Example 67 Tablets containing various amounts of 2-bromo-6p,9adifluoro-Π β,17α,21-tri hydroxy-pregna-1,4-di ene-3,20-di one (XIa) Ingredients Amount in mg per 200 mg tablet Compound XIa 1 - 50 Starch 99 - 75 Lactose 90-65 Talc 8 Magnesium stearate 2 The active compound, starch and lactose are blended and compressed into slugs which are then granulated.

Talc and magnesium stearate are added to the granulated mixture which is compressed into tablets each weighing 0.200 g. Each tablet contains 1t50 mg of active compound.

Example 68 Oral suspension containing various amounts of 2-bromo-6 β, 9a-difluoro-Π β, 17a,21-trihydroxy-pregna1,4-diene-3,20 dione-21-acetate (XIc) Ingredients 100 ml of suspensior (w/v ) Compound XIc Tragacanth gum Glycerol Tween 80 (trade mark) Sucrose Methylparaben Propylparaben Flavourant and colourant Distilled water 0.010-0.5 0-3 0.1 0.15 0.05 9.5 q.s. ad 100 The ingredients are mixed in a conventional manner «ο provide a flavoured suspension ExampTe 69 Suspension for injections containing various amounts of 2-bromo-6 0,9a-difluoro-11 0,17a,21-trihydroxy-pregna -1,4diene-3,20-dione-21-acetate (XIc) Ingredi ents 100 ml of suspension Compound XIc 0.5 - 10 Sodium CMC 0.75 Sodium chloride 0.65 Polysorbate 80 0.04 10 Benzyl alcohol 0.9 Distilled water q.s. ad 100 The ingredients are mixed in a conventional manner to provide a sterile suspension of the active compound in very fine particles.

Compositions of the invention may also be made by replacing the active ingredient in each of Examples 62 to 69 by any of the other compounds named above.

Claims (12)

1. CLAIMS A compound of the formula 42113 wherein either X is hydroxy and Y is fluorine chlorine or bromine or X and Y are both chlorine; and (i) R 3 is hydroxy, Rg is hydroxy and R^ is hydrogen, α-methyl or β-methyl; (ii) R^ is acyloxy, R 2 is hydroxy and R^ is hydrogen, a-methyl, β-methyl or a-acyloxy; (iii) R^ is hydroxy or acyloxy, R2 is acyloxy and R, is hydrogen, α-methyl or β-methyl; (iv) R. is 3 either Rg is ^.hydroxy and R, is <=<-hydroxy or L hydroxy or acyloiqr and/Rg and are taken together and are a group of the formula wherein R^ is hydrogen or hydrocarbyl and R^ is hydrocarbyl; or (v) R^ and Rg 'are-taken together and are a group of the formula ,C, • -0 wherein Rg is hydrogen, hydrocarbyl or alkoxy and R? is hydrocarbyl, and R x is hydrogen, α-methyl or β-methyl; or a pharmaceutically acceptable salt or ester thereof when at least .one of R^, Rg and R^ is a polycarboxylic or inorganic acid radical
2. 2. A compound as claimed in claim 1 wherein X i s hydroxy.
3. 3. A compound as claimed in claim 2 wherein Y is fluorine.
4. 4. A compound as claimed in claim 1 or claim 2 wherein Y is chlorine. b.
5. A compound as claimed in any preceding claim wherein R 3 is hydrogen, α-hydroxy or ι a-acyloxy.
6. 6. A compound as claimed in any of claims 1 to 4 wherei n R 3 is α-methyl or β-methyl.
7. 7. A compound as claimed in any preceding claim. wherei n at least one of R 1 , R 2 and R 3 is acyloxy.
8. 8. A compound as claimed in any of claims 1 to 4 wherein R 1 ! , R 2 and R 3 are all hydroxy.
9. 9. A compound as claimed in any of claims 1 to 4 wherei n R 1 and R 2 together form an alkyl orthoester.
10. 10. A compound as claimed in any of claims 1 to 4 wherein R 1 is acyloxy and the acyl group is the radical of a polycarboxylic acid ester or of an inorganic acid which is in the form or, or is convertible into, a water-soluble salt.
11. 11. A compound as claimed in claim 1 which is named herein.
12. 12. A therapeutic composition comprising a compound as claimed in any preceding claims as an active ingredient, together with a pharmaceutically acceptable carrier.