CS202591B2 - Process for preparing derivatives of 9-fluorprednisolone - Google Patents

Abstract

The active compounds correspond to the general formula I <IMAGE> in which R1 denotes an alkanoyl group or cycloalkanoyl group having 1 to 8 carbon atoms or a benzoyl group and X represents a fluorine atome, a chlorine atom or an alkanoyloxy group having 3 to 8 carbon atoms. The novel 9-fluoroprednisolone derivatives can be obtained by opening corresponding 9,11 beta -epoxy compounds with hydrogen fluoride or halogenating or esterifying corresponding 9-fluoro derivatives in the 21-position or cleaving a corresponding 17 alpha -cycloalkanecarbonyloxy compound with a trimethylsilyl halide or triphenylmethyl halide. Medicaments which contain at least one of the abovementioned compounds as an active component can be used for the treatment of inflammations.

Description

The present invention relates to a process for the preparation of novel 9-fluorprednisolone derivatives. Further, pharmaceutical compositions containing these active ingredients are discussed.

9-Fluorprednisolone (9a-fluoro-11 / 3,17a, 21-trihydroxy-1,4-pregnadien-3,20-dione) has been known for a long time (J. Am. Chem. Soc. 77, 4181, 1955). This corticoid is unsuitable as an active ingredient for pharmaceutical preparations which are used for the local treatment of inflammatory diseases because it has very strong systemic effects.

It has been discovered that the hitherto unknown 9-fluorprednisolone derivatives are systemically only poorly effective, but have a surprisingly potent anti-inflammatory effect when topically applied, which often outperforms the most potent corticoids commercially available.

The new 9-fluoropredisolone derivatives have the general formula I

where

R 1 represents C 1 -C 8 alkanoyl or benzoyl;

X is fluorine, chlorine or C 3 -C 8 alkanoyloxy.

C 1 -C 8 alkanoyl R 1 and C 3 -C 8 alkanoyloxy X is to be understood as meaning a straight or branched chain derivative of a straight or branched chain carboxylic acid such as butyric acid, valeric acid, isovaleric acid, trimethylacetic acid, caproic acid, tert-butylacetic acid, cyclopentylcarboxylic acid, cyclohexyloxycarboxylic acid or caprylic acid or optionally formic acid, acetic acid or propionic acid.

Particularly preferred alkanoyl groups R 1 and alkanoyloxy group X are those derived from an alkanecarboxylic acid having up to 6 carbon atoms.

9-Fluoropredisolone derivatives of the formula I with X representing chlorine are, for example, the following compounds:

17 «^ -acxetoxy 214 hlcnr9r -fhiQr _{t-l (l-hydroxy-l,} 4-pregnadiene-3,20-dione,

21-A-chloro-9a-fluoro-4-chloro-9-fluoro-4- (4-a-propionyloxy-1-pregnadien-5-ol),

17.biphyrryloxy-21-chloro-9α-fluoro-11β-hydroxy-1,4-pregnadien-3,2Cl-dione,

21 - chloro-9a'-fluoro-11 / 3fhydrrxyf17αf-isobutyrylrxy-1,4-pregnadien-3,20-dione,

21-chloro-9α-fluoro-1H-hydroxy-17 (ε-valeryloxy-1,4-pregnadien-3,2C-dione; and

17 (α-Benzyloxy-21-chloro-9α-fluoro-13β-hydroxy-1,4-pregnadien-3,20-dione.

For example, the 9,21-diiluorphoedmsolrn derivatives of formula I are:

17.beta.-acetoxyf9a, 2'difCuorfC1S-hydroxy-1'-pregnadien-5'-C-dione,

9a, 2'-Difluoro-β-phenylamino-17α-propionyloxy-1 H -pregnadien-5 H -dione,

17α-butyryloxy-9α, 21-β-hydroxy-1 H -hydroxy-1 H -regnadien-5-C-dione, or

9a / 21-Fluoro-1'-glydoxy-17'-isophosphoryl-butyloxy-1'-pradadiene-4'-C-diphone.

The derivatives 9-f of the general formula I in which X represents an alkanoyloxy group are preferably those in which the radicals R 1 and X together have 5 to 14 carbon atoms. Such fluorprednisolone derivatives are, for example:

17.alpha.-acetoxy-9 -affluoro-113-hydroxyoxy-21-prprionyloxy-1,4-pregnadien-3,20-dione;

17α-acetrxy-21-butyryloxy-9α'-fuoro-11β'-hydroxy-1,4-pregnadien-3,2C-dione,

17a-acetoxyd) affCuoL-118j-hydroxy-21f-isobutyryloxy-1,4-pregnadien-3,2C-dim, 4-acetoxy-Scluoro-11J-hydroxy4

-21-valeryloxy-1,4-pregnadien-3,20-dione,

21-butyryloxy-9 H -fluoro-11 H -hydroxy-17 (α-valeryloxy-1,4-pregnadien-3,2 C-dione),

17α-benzyloxy-21-butyryloxy-9α-fluoro-11-hydroxy-1,4-pregnadien-3,20f-dione,

9α: flclOΓ-11зз-hydroxy-17,21- Ш -brytytyloxy-1,4-pregnadien-3,20-dim and

9α-Fluoro-113-hydroxy-17α, 21-divaCefyloxy-1,4-pregnadiemЗ, 2C-dirn.

The novel 9-flurrprednisrCon derivatives can be prepared according to a method known per se which consists in opening the epoxide ring in a compound of the formula II by treatment with hydrogen fluoride.

CH ₂ X

where

R1 and X are as defined above.

The process of the invention can be carried out under the conditions described in US Patent Nos. 3,678,034, 3,718,671 and 3,828,083. The starting compounds for these processes can be prepared under the conditions described in US Patent No. 3,152,154 and in U.S. Pat. German DOS Nos 2,340,591 and 2,055,221.

The process according to the invention can also be carried out under conditions known per se, preferably by reacting the compound of the formula II in an inert solvent containing hydrogen fluoride. Suitable inert solvents are, for example, ethers (diethyl ether, isopropyl ether, tetrahydrofuran, pyridine and the like) or chlorinated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, tetrachloroethane and the like).

The starting compounds for the process according to the invention can be prepared in a simple manner and in high yield from prednisilone, which can itself be synthesized relatively easily from diosgenin. As a result, the compounds of the invention can be prepared from diosgenin at relatively low cost in an overall yield of about 15%. On the other hand, the synthesis of the known high-performance corticoids from diosgenin is considerably more expensive and the overall yields achieved are substantially lower (about 0.5-5%). with regard to expenditure on active substances which increase the cost of special corticoid-containing medicines.

As already mentioned, the compounds of the invention have a strong anti-inflammatory effect when topically applied, but are only weakly effective when administered systemically.

The anti-inflammatory effect is determined as follows:

Blood on the human skin is induced by spreading on the backs of volunteer male and female test subjects twenty times overlapped fragments of 2 centimeters wide tesafilm Stratum corneum. ·

Approximately 50 milligrams of the ointment preparation are applied to the 4 cm 2 labeled areas within the scuffed area.

To obtain a comparable baseline, relative numbers were used because the color of the untreated skin as well as the redness of the bloodied area is different for each person.

The color value of the untreated skin is given as 100 and the color value of the scuffed skin is 0.

The skin color value found on the skin during vasoconstriction (100) is a relative value.

Vasoconstriction of small, medium and high grade is evaluated with a value of 0 to 100.

The following table shows the average values obtained from the tests of the different subjects and from the different back areas.

Systemic. the effect of the compounds is determined by the adjuvant edema test as follows:

SPF rats weighing 130-150 kg were injected into the right hind paw by injection of 0.1 ml of a 0.5% suspension of Mycohacterium butyricum (available from Difco, USA) to achieve an outbreak of inflammation. Prior to injection, the paw volume of the rats was measured and, 24 hours after injection, the paw volume was again measured to determine the extent of edema. Finally, different rats were orally administered with different amounts of test substances. After a further 24 hours, the paw volume is measured again.

From the paw volume data obtained, the amount of test substance required is determined in the usual manner,. to achieve 50% healing of paw edema.

The results obtained in these tests are shown in the following table. ^to

Table

Number Substance Concentration (%) Vasoconstriction test Adjuvant edema test ED50 (mg / kg) 4 h Results after 8 h AND Sa, 9'-difluoro-11'-hydroxy- 0.1 58 68 -21-valeryloxy-1,4-pregna- 0.001 54 66 0.04 Diene-3,20-dione (difluorotolone valerate) 0.00001 32 36 II. 21-acetoxy-9α-lloro-11β- 0.1 55 66 -hydroxy-17α-valeryloxy-1,4- 0.001 52 63 3.8 -pregnadien-3,20-dione (DOS 2,055,221) 0.00001 31 42 III 17α-acetoxy-9α-fluoro-HS- 0.1 67 78 -hydroxy-21-hexanoyloxy- 0.001 60 74 7.7 -1,4-pregnadien-3,20-dione 0.00001 23 36 IV 17a-acetoxy-9'-fluoro-113- 0.1 57 74 -hydroxy-21-rimethylaceto- 0.001 57 68 7.0 xy-1,4-pregnadien-3,20-dione 0.00001 33 42 in 9a-fluoro-113-hydroxy-17u, 21- 0.1 65 83 -dipropionyloxy-1,4-pregna- 0.001 58 76 5.0 diene-3,20-dione 0.00001 39 47 VI 21-butyryloxy-9a-fluoro-11,3- 0.1 62 83 -hydroxy-17α-propionyloxy- 0.001 58 76 5.7 -1,4-pregnadien-3,20-dione 0.00001 43 47 VII ^And 9a-fluoro-113-hydroxy-17ia- 0.1 60 75 -propionyloxy-21-valeryloxy- 0.001 57 76 6.0 ´1,4'´pregnadien-3,20-dion 0.00001 40 43

Number Substance Concentration (%) Vasoconstriction test Adjuvant edema test ED50 (mg / kg) 4 h Results after 8 h VIII 17α-benzoyloxy-9α-fluoro- 0.1 62 78 -11 / S-hydroxy-21-proplonyl- 0.001 59 70 over 10 oxy-1,4-pregnadien-3,20-dione 0.00001 40 43 IX 17α-Benzoyloxy-21-buty- 0.1 68 82 Ryloxy-9a-fluoro-U / 3-hydroxy- 0.001 67 80 over 10 -1,4-pregnadien-3,20-dione 0.00001 51 58 X 17α-Benzyloxy-21-chloro-9α 0.1 60 72 -fluoro-11/3-hydroxy-1,4-preg- 0.001 56 64 over 10 nadien-3,20-dione 0.00001 43 45

Similar results are obtained when the systemic effect of the 9-fluorprednisolone derivatives of the invention is determined using a known thyomolysis assay or a known sodium and potassium retention test.

The novel compounds are useful in combination with carriers customary in galenical pharmacy for the topical treatment of contact dermatides, eczema of various kinds, neurodermatoses, erythrodermia, burns, Pruritis vulvae et ani, rosacea, Erythematodes cutaneus, psoriasis, flat lichen, and wart disease.

The manufacture of special medicaments is carried out in the customary manner by converting the active ingredient with suitable additives into the desired dosage form, such as solutions, lotions, ointments, creams or patches. In the medicaments thus prepared, the concentration of active ingredient is dependent on the dosage form. For lotions and ointments, the concentration of active ingredient is preferably 0.001 to%.

In addition, the novel compounds are optionally suitable in combination with conventional carriers and excipients also for the manufacture of inhalants which can be used in the treatment of allergic airway diseases such as bronchial asthma or rhinitis.

The following examples serve to illustrate the invention.

I. Synthesis examples

Example 1

(a) A suspension of 8.7 g of 21-fluoro-17α-hydroxy-1,4,9 (11) -pregnatriene-3,20-dione in 100 ml of diethylene glycol dimethyl ether is stirred with 12 g of Ν, Ν-dimethylaminopyridine and 8.8 ml. acetic anhydride for 6.5 hours at 80 ° C. The reaction mixture was diluted with methylene chloride and washed

N hydrochloric acid. After steam distillation, extraction is performed with methylene chloride and dried with sodium sulfate. After evaporation, 7.9 g of 17α-acetoxy-21-fluoro-1,4,9 (1 H -pregnatriene-3,20-dione) is isolated.

b) 7.6 g of 17α-acetoxy-21-fluoro-1,4,9 (11J);

-pregnatriene-3,20-dione is dissolved in 76 ml of dioxane and 7.2 g of N-bromosuccinimide is added. After dropwise addition of 38 ml of 10% aqueous perchloric acid, it is further stirred at room temperature for 30 minutes and the reaction mixture is added to a solution of 3.5 g of sodium bisulphite in 350 ml of water. The precipitate was filtered off with suction and dried to give 10 g of 17α-acetoxy-9α-bromo-21-fluoro-11β-hydroxy-1,4-pregnadien-3,20-dione.

(c) 10 g of the above crude product is refluxed in 600 ml of ethanol with 14.0 g of potassium acetate for 2 hours at 110 ° C. The reaction solution was evaporated in vacuo and poured into ice water. The precipitate was filtered off and the crude product was purified on 700 g of silica gel with methylene chloride and acetone at varying concentrations (0-6% acetone). The yield is 3.4 g of 17α-acetoxy-9,11 / 3-epoxy-21-fluoro-1,4-pregnadien-3,20-dione.

d) 31 ml of a 70% (HF) _n solution in pyridine is cooled to -60 ° C and mixed with a solution of 3 g of 17α-acetoxy-9,11 / 3-epoxy-21-fluoro-1,4-pregnadien-3, Of 20-dione in 3 ml of pyridine. The reaction solution was stirred at -5 ° C for 10 hours and then stored in a refrigerator for 3 days. The mixture was poured onto ice water basified with ammonia and the precipitate was filtered off. The crude product is purified on 350 g of silica gel with methylene chloride and acetone at varying concentrations (0-15% acetone). Yield: 2.15 g of 17.alpha.-acetoxy-9.alpha., 21-difluoro-11.beta.-hydroxy-1,4-pregnadien-3,20-dione.

Mp 276 ° C (dec.);

[ια] ₀ ²⁵ = + 16 ° (chloroform);

UV: 239 239 = 15,800 (methanol).

Example 2

a) Analogously to Example 1a), from 7.9 g of 21-fluoro-17α-hydroxy-1,4,9 (11) -pregnatriene-3,20-dione and propionic anhydride, 5 g of 21-fluoro- 17α-propionyloxy-1,4,9 (11) -pregnatriene-3,20-dione, which is reacted with N-bromosuccinimide under the conditions described in Example 1b. The yield was 8.5 g of 9α-bromo-21-fluoro-11β-hydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione.

b) 8.5 g of the above crude product was reacted with potassium acetate under the conditions described in Example 1c. The crude product is purified on 700 g silica gel with methylene chloride and acetone of varying concentration (0-6% acetone). The yield is 5.3 g of 9,11 / 3-epoxy-21-fluoro-17α-propionyloxy-1,4-pregnadien-3,20-dione.

c) 5.0 g of 9,11'-epoxy-21-fluoro-17α-propionyloxy-1,4-pregnadien-3,20-dione was treated analogously to Example 1d) with a 70% (HF) _n solution. pyridine. The reaction product is purified on 700 g of silica gel with methylene chloride and acetone at varying concentrations (0-15% acetone). The yield was 3.98 g of 9α, 21-difluoro-11β-hydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione.

Mp 214 ° C;

[α] ²⁵ D = 4-15 ° (chloroform);

UV: 239 239 = 15,800 (methanol).

Example 3

a) 20.0 g of 17α-butyryloxy-21-fluoro-1,4,9 (11) -pregnatriene-3,20-dione, prepared analogously to Example 1a) from 21-fluoro-17α, -hydroxy-1, 4,9 (11) -Pregnatriene-3,20-dione and butyric anhydride were treated analogously to Example 1b with N-bromosuccinimide. Yield: 24.9 g of 9a-bromo-17a-butyryloxy-21-fluoro-ll _and S-hydroxy-4-pregnadiene-3,20-dione.

b) Under the conditions described in Example 1c), the above crude product is treated with potassium acetate. 16.1 g of 17α-butyryloxy-9,11 / 3-epoxy-21-fluoro-1,4-pregnadien-3,20-dione are isolated.

c) 15.1 g 17a-butyryloxy-9, ll / L-epoxy-21-fluoro-4-pregnadiene-3,20-dione is treated analogously to example ld) ^70:% solution (HF) _n in pyridine. The crude product is purified on 1.5 g silica gel with methylene chloride and acetone at varying concentrations (0-15% acetone). 13.4 g of 17? -Butyryloxy-9?, 21-difluoro-11? -Hydroxy-1,4-pregnadien-3,20-dione are obtained.

Mp 126 ° C;

[α] _D ²⁵ = 4-11 ° (chloroform);

UV: 239 239 = 15,300 (methanol).

Example 4

a) Analogously to Example 1a), 7.1 g of 21-fluoro was prepared from 9.0 g of 21-fluoro-17α-hydroxy-1,4,9 (11) -pregnatriene-3,20-dione and valeric anhydride. -17α-valeryloxy-1,4,9 (11) -pregnatriene-3,20-dione. This compound was treated with N-bromosuccinimide analogously to Example 1b). The yield is

8.7 g of 9? -Bromo-21-fluoro-11? -Hydroxy-17? -Valeryloxy-1,4-pregnadien-3,20-dione.

b) 8.0 g of the above crude product was treated with potassium acetate in a manner similar to Example 1c). Purification of the reaction product on 700 g of silica gel with methylene chloride and acetone at varying concentrations (0 to 5% acetone) yielded 4.2 g of 9,11'-epoxy-21-fluoro-17α-valeryloxy-1,4-pregnadien-3. , 20-dione.

c) Reaction of 3.8 g of 9,11'-epoxy-21-fluoro-17α-valeryloxy-1,4-pregnadien-3,20-dione with a 70% (HF) _n solution in pyridine, analogous to Example 1d 3.1 g of 9?, 21-difluoro-11? -hydroxy-17? -valeryloxy-1,4-pregnadien-3,20-dione are obtained, which is purified on 450 g of silica gel with methylene chloride and acetone of variable concentration (0). % to 15% acetone).

Mp 139 ° C;

[Α] ²⁵ D = 4-10 ° (chloroform);

UV: £ 239 = 15,800 (methanol).

Example 1 a d 5

a) Under the conditions described in Example 1a), 7.3 g of 21-fluoro-17α-hydroxy-1,4,9 (11) -pregnatriene-3,20-dione and caproic anhydride were prepared from 7.3 g. 21-fluoro-17α-hexanoyloxy-1,4,9 (11) -pregnatriene-3,20-dione, which was reacted with N-bromosuccinimide analogously to Example 1b). The yield was 8.2 g of 9α-bromo-21-fluoro-17α-hexanoyloxy-11'-hydroxy-1,4-pregnadien-3,20-dione.

b) 8.0 g of the above crude product was treated analogously to Example 1c) with potassium acetate and the crude product was purified with methylene chloride and acetone at varying concentrations (0-5% acetone). 5.8 g of 9,11 / 3-epoxy-21-fluoro-17α-hexanoyloxy-1,4-pregnadien-3,20-dione is isolated.

c) 3.2 g of 9,110-epoxy-21-fluoro-17α-hexanoyloxy-1,4-pregnadien-3,20-dione was treated with a 70% (HF) _n solution in pyridine as described in Example 1d. The reaction product is purified on 350 g of silica gel with methylene chloride and acetone at varying concentrations (0-15% acetone). The yield was 2.6 g of 9α, 21-difluoro-17α-hexanoyloxy-11'-hydroxy-1,4-pregnadien-3,20-dione.

Example 6

a) 6.2 g of 21-fluoro were prepared analogously to Example 1a) from 8.1 g of 21-fluoro-17α-hydroxy-1,4,9 (11) -pregnatriene-3,20-dione and isobutyric anhydride. -17α-isobutyryloxy-1,4,9 (11) -pregnatriene-3,20-dione, which was reacted with N-bromosuccinimide, similar to Example 1b. The yield was 6.9 grams of 9α-bromo-21-fluoro-11β-hydroxy-17α-isobutyryloxy-1,4-pregnadien-3,20-dione.

b) 6.0 g of the above crude product was treated with potassium acetate analogously to Example 1c) and the reaction product was purified on 600 g silica gel with methylene chloride and acetone of variable concentration (0-5% acetone). 4.1 g are obtained

9β-epoxy-21Tluoro-17a-isobutyryloxy-1,4-pregnadien-3,20-dione.

c) 3.5 g of 943 N-epoxy-21-fluoro-17 H -isobutyryloxy-1,4-trans-gnadien-3,20-clione was reacted with a 70% (HF) n solution in pyridine analogously to Example ld. The crude product is purified on 400 g silica gel with methylene chloride and acetone of varying concentration (0-15% acetone). Yield: 2.9 g 9a, 21 <ШΊusrill3 _{17αisobutyгylsxy-hydroxy-l)} 4-pгegnadien · 320-disπu.

Example 7

(a) 8.0 g of 21-ω-117-hydroxy-1,4,9 (11) -pregnatrieib3,20-dione are added to a mixture of 80 ml of isovaleric acid and 32 ml of trifluoroacetic anhydride and then stirred for 2.5 hours. at 80 ° C. The mixture was added. into warm water to quench the excess anhydride and then extracted with methylene chloride. After neutralization with a 1% solution of pyridine in water and drying with sodium sulfate, it is evaporated in vacuo. Dissolve the substance in a small amount of pyridine, pour it into ice water and neutralize the pyridine with dilute hydrochloric acid. After the usual work-up, 5.8 g of 21-fluoro-17α ^: β-missalogyloxy-1,4,9 (11) -pregnatrium-β 3,20-dione is isolated.

b) 5.3 g of 21-fluoro-17? 4 -ovaleryloxy-1,4,9 (1)) - pregaatriene-3,20-dione was treated with N-bromosuccinimide analogously to Example 1b. 6.2 g of 9.alpha.-bromo-21-fluoro-1H-hydroxy-17.alpha.-issvalrryloxyil, 4-preega.

c) 6.0 g of the above crude product was treated with potassium acetate analogously to Example 1c. The reaction product is purified on 600 g of silica gel with methylene chloride and acetone at varying concentrations (0-5% acetone). The yield is

3.7 g of 9,11S-epoxy-21-fluoro-17α-isovaleryloxy-1,44-preggadieg-3,20-diog.

d) 3 g of [gamma] -1- [eta] &lt; 3 &gt; -tetyl-1,7-bis-valetyl-oxy-14-pregnadien-3,20-dlone was treated with a 70% (HF) n solution in pyridine under the conditions described in Example 1d. The crude product was purified on 300 g of silica gel with methyl acetate and acetone at varying concentrations (0-15% acetone). The yield was 2.1 g of 9w, 21-difluoro-11H-piperazinyl-1,4-propylene-1,4,20-disne.

Example 8

a) As described in Example 1a), 8.7 grams of 21-fluoro-7α-hydroxy-1,4,9 (11'-pregeatrien-3,20-diol) was treated with trimethylacetaghydride to 6.3 g. -luop-17α-β-dimethylation of Soxy-1,4,9 (11) -pregnatriene-320-Sulfuric acid, which was treated with N -butosuccinimide analogously to Example 1b. 4-pregnadieei-3,2θ-dione.

b) 6.0 g of the above crude product was treated with potassium acetate analogously to Example 1c) and the crude product was purified on 600 g of silica gel with methyl chloride and acetone at varying concentrations (0-5% acetone). The yield was 3.1 g of 9,11-S-epoxy-21-fluoro-17α-thimethyl-acetoxy-1,4-pregnadieg-3,20-diog.

c) 3.0 g of 9,11'-ethoxy-21-fluoro-17α-trimethylaethoxy-1,4-pregnadien-3,20-dione were reacted analogously to Example 1d) with a 70% solution (HF) n in pyridine.

1.9 g of 9921-1iCluop-rlЗ-hydppo-117-trimethyl acetoxy-1,4-pregnadien-3,20-dione, obtained after purification on 300 g of silica gel with methylene chloride and acetone at a relative concentration (0 to 15% acetone) ).

Example 9

a) Analogously to Example 1a), from 15.4 g of 21-g-17-hydroxy-4,9 (i) -glutpieg-320-diog and 2-enylpropionic acid chloride, 7.0 g of 21- fluoro-17α- (2-egylptspisgyloxy) -1,4,9 (11) -ppegnatrieg-3,20- (which is reacted with N-bromosuccigimide analogously to Example 1b). To give 6.9 g of 9a-bromo-21 - Luoto _L1-one 3-hydroxy-17 "- (2-- enχlprspiogylsxχ) -1,4-preggadieg-3,20-dione.

b) 6.5 g of the above crude product was reacted with potassium acetate under the conditions of Example 1c). The crude product was purified on 650 g silica gel with methyl chloride and acetone at varying concentrations (0-5% acetone). The yield is

3.8 g of 9,11-β-epoxy-fluoro-17α- (2-enylpropionyloxy) -1,4- [1,2-d] -3,2-dione.

c) 3.5 g of 9,113-epoxy-21-fluoro-17a- (2-enyl-propionyloxy) -1,4-pregnadien-3,20-dione are treated analogously to Example 1b) with a 70% solution (HF) n in pyridine and the crude product are purified on 400 g of silica gel with methyl chloride and acetone at varying concentrations (0-15% acetone). The yield was 2.1 g of -9211-Ciuos-113 ' -hydroxy-117-112-propionoxy) -1,4-pentadiegieg-3,20-diog.

Example 10

a) From 9.1 g of 21-fluoro-177-hydroxy-1,4,9 (11) -pentenatrieg-3,20-diog, 91 ml of cyclopentanoic acid and 44 ml of trifluoroacetic anhydride are analogous to in Example 7, 5.8 g of 177-cyclopeithiocarbonyloxy-21-fluoro-1,4,9 (11) -pregaatriene-3,20-disg was prepared, which was treated with N-bromosuccinimide analogously to Example 1b). After the usual work-up, 6.1 g of 9α-bromo-17α-cyclopegtanecarbonyloxy-4-iodo-113-hydtoxy-1,4-pregnadien-3,20-dione were isolated.

b) 6.0 g of the above crude product was treated with potassium acetate analogously to Example 1c) and the crude product was purified on 600 g silica gel with methylene chloride and acetone at a variable con202591 by centration (0-5% acetone). 4.5 g of 17α-cyclopentanecarbonyloxy-9,11 / 3-epoxy-21-fluoro-1,4-pragnadien-3,20-dione are obtained.

c) 4.0 g of 17α-cyclopentanecarbonyloxy-9,11,3-epoxy-21-fluoro-1,4-pregnadien-3,20-dione were reacted with a 70% (HF) _n solution in pyridine analogously to Example 1d) . The crude product is purified on 400 g silica gel with methylene chloride and acetone at varying concentrations (0-15% acetone). The yield was 2.8 g of 17α-cyclopentanecarbonyloxy-9α, 21-difluoro-11'-hydroxy-1,4-pregnadien-3,20-dione.

Example 11

a) From 9.2 g of 21-fluoro-17α-hydroxy-1,4,9 (11) -pregnatriene-3,20-dione, 92 ml of cyclohexanecarbonyl acid and 40 ml of trifluoroacetic anhydride were prepared under the conditions of Example 7 5.8 g of 17α-cyclohexanecarbonyloxy-21-fluoro-1,4,9 (11) -pregnatriene-3,20-dione, which was reacted with N-bromosuccinimide analogously to Example 1b). Yield: 6.1 g of 9α-bromo-17α-cyclohexanecarbonyloxy-21-fluoro-11'-hydroxy-1,4-pregnadien-3,20-dione.

(b) 6.0 g of the above crude product was treated with potassium acetate analogously to Example 1c) and the crude product was purified on 600 g of silica gel with methylene chloride and acetone at varying concentrations (0-5% acetone). The yield is

3.4 g of 17α-cyclohexanecarbonyloxy-9,11'-epoxy-21-fluoro-1,4-pregnadien-3,20-dione.

c) From 3.1 g of 17α-cyclohexanecarbonyloxy-9,11-β-epoxy-21-fluoro-1,4-pregnadien-3,20dione with a reaction analogous to Example 1d), with a 70% (HF) _n solution in Pyridine produced 2.4 g of 17α-cyclohexanecarbonyloxy-9α, 21-difluoro-11'-hydroxy-1,4-pregnadien-3,20-dione, which was obtained after purification to 300 g of silica gel with methylene chloride and acetone at varying concentrations (0-15% acetone).

II. Pharmaceutical preparations

Example A

Ointment composition

0.03% of 9a-fluoro-l l _t 6-hydroxy-17a, 21-Dipropionyloxy-l, 4-pregnadiene-3,20-dione

2.50% Allercurhexachlorophenate [micronized, particle size about 8 µm (Allercur = registered trademark for 1-p-chlorobenzyl-2-pyrrolidylmethylbenzimide201]]

6.00% of the orthophosphoric acid t-ester and tetraglycol ether of the alcoholate contained in the wax (Hostaphat KW 340 ^(R) ).

0,10% sorbic acid

10.00% neutral oil (Migloyol 812 ^(R) )

3.50% stearyl alcohol

1.50% sheep wool wax, anhydrous (DAB 6)

76.36% desalinated water.

Example В

Manufacture of inhalation agent

1,000 g of micronized 9α-fluoro-11β-hydroxy-17α, 21-dipropionyloxy-1,4-pregnadien-3,20-dione (average grain size less than 7 µm) was placed with 39,000 g ground milled lactose.

Doses with 20 mg of inhalation agent are used for inhalation.

Claims (3)

OBJECT OF THE INVENTION A process for the preparation of a 9-fluoropredisolone derivative of the general formula I AND; where R 1 represents C 1 -C 8 alkanoyl or benzoyl; X represents a fluorine atom, a chlorine atom or a C 3 -C 8 alkanoyloxy group, characterized in that the epoxide ring in the compound of formula II is opened in a manner known per se by treatment with hydrogen fluoride 0 'where R1 and X are as defined above, 2. The process according to item 1 for the preparation of the 9-fluoropredissars dertvates of the general formula 1 X is as defined in this point. 3. The process according to item 1, for the preparation of 9-luorpredgisolsg derivatives of the general formula I wherein where R1 is as defined in 1 and X is -luoro R1 is as defined in 1 a X represents a chlorine atom or an anovloxy group having from 3 to 8 carbon atoms, characterized in that the epoxide ring in the compound of the general formula (11) is opened in a manner known per se by treatment with hydrogen fluoride. in a manner known per se by treatment with hydrogen fluoride, an -oxide ring is opened in the compound of formula (II) wherein where R1 is as defined in 1 a R1 is as defined in point 1 and X is as defined in point.