CS202593B2 - Process for preparing derivatives of 9-fluorprednisolone - Google Patents

Abstract

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of novel 9-fluoropropedisolone derivatives. Further, pharmaceutical compositions containing these active ingredients are discussed. 9-Fluoropropedisolone (9-fluoro-11 / 17a, 21-trihydroxy-1,4-pregnadien-3,20-dione) has been known for a long time (J. Am. Chem, Soc. 77, 4181, 1955 ) This corticosteroid is unsuitable as an active ingredient for pharmaceutical preparations, which serves for the local treatment of inflammatory diseases because it has very strong systemic effects. It has been discovered that hitherto unknown derivatives of 9-fluoropropednisolone are systemically poorly effective, but have a surprisingly strong anti-inflammatory effect in topical use, which often outperforms the most effective corticoids commercially available. The novel 9-fluoropropedisolone derivatives have the general formula I

Description

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

9-Fluorprednisolone (9'-fluoro-11β, 17α, 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

»Kde

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

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

C1-C8-alkanoyl R1 and C3-C8-alkanoyloxy X is to be understood as meaning a straight or branched chain derivative of straight or branched carboxylic acids, such as butyric acid, isobutyric acid, acid valeric acid, isovaleric acid, trimethylacetic acid, caproic acid, tert-butyl acetic acid, cyclopentylcarboxylic acid, cyclohexylcarboxylic acid or caprylic acid, or optionally formic acid, acetic acid or propionic acid.

Particularly preferred alkanoyl groups R1 and alkanyloxy groups X are those derived from an alkanecarboxylic acid having up to 6 carbon atoms.

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

17α-Acetoxy-21-chloro-9'-fluoro-1 H -hydroxy-1 H -pregnadien-5 H -dione

21-chloro-9α-fluoro-11β-hydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione,

17'-butyryloxy-21-chloro-9'-fluoro-11'-hydroxy-1,4-pregnadien-3,20-dione,

21-chloro-9a-fluoro-l _and 3-hydroxy-17a-isobutyryloxy-l, 4-pregnadiene-3,20-dione,

21-chloro-9α-fluoro-11β-hydroxy-17β-isobutyryloxy-1,4-pregnadien-3,20-dione; and

17α-benzoyloxy-21-chloro-9α-fluoro-11β-hydroxy-1,4-pregnadien-3,20-dione.

9,21-Difluoro-prednisolone derivatives of the formula I are, for example, the following compounds:

17α-acetoxy-9α, 21-difluoro-11 (3-hydroxy-1,4-pregnadien-3,20-dione),

9α, 21-difluoro-H / 3-hydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione,

17α-butryloxy-9α, 21-difluoro-11β-hydroxy-1,4-pregnadien-3,20-dione or

N, 21-difluoro-11β / 3-hydroxy-17α-isobutyryloxy-1,4-pregnadien-3,20-dione.

The 9-fluoro-prednisolone derivatives of formula I wherein X is alkanoyloxy are preferably those in which the radicals R 1 and X together have 5 to 14 carbon atoms. Such fluoropredlsolone derivatives are, for example:

17 ₍ α-acetoxy-9α-fluoro-11β-hydroxy-21-propionyloxy-1,4-pregnadien-3,20-dione 17α-acetoxy-21-butyryloxy-9α-fluoro-11β-hydroxy-1β) , 4-pregnadien-3,20-dione,

17α-acetoxy-9α-fluoro-11β-hydroxy-21-isobutyryloxy-1,4-pregnadien-3,20-dione, 11α-acetoxy-ga-fluoro-11β-hydroxy-21-valeryloxy-1, 4-pregnadien-3,20-dione

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

17α-benzyloxy-21-butyryloxy-9α-fluoro-11β-hydroxy-1,4-pregnadien-3,20-dione, 8α-fluoro-11β-1-hydroxy-11,4-diisobutyryloxy-1,4 -pregnadien-3,20-dione a

Sa-fluoro-11β-hydroxy-1'-divaleryloxy-1,4-pregnadien-3,20-dione.

The novel 9-fluoro-predisolone derivatives can be prepared according to a process known per se which comprises halogenating or esterifying the 9-fluoro derivative of the general formula II at the 21-position.

where

R1 is 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 23 40 591 and 20 55 221.

The process according to the invention is carried out under conditions known per se.

For example, hydroxysteroids can be esterified with carboxylic acid chlorides or anhydrides in the presence of acids such as hydrochloric acid and p-toluenesulfonic acid or trifluoroacetic acid, or in the presence of bases such as calcium carbonate, pyridine, collidine or p-dimethylaminopyridine.

A preferred method for chlorinating the compounds of formula II is to esterify the 21-hydroxy group with sulfonic acid, preferably methanesulfonic acid or p-toluenesulfonic acid, and finally the sulfonic acid group is 202093

S changes to chlorine. Esterification of the 21-hydroxy group occurs, for example, when sulfonic acid chloride is treated with compounds of formula II in the presence of an organic base such as pyridine or in the presence of an aqueous alkali solution. The exchange of the sulfonic acid group to the chlorine atom is preferably carried out by reacting the 21-sulfonic acid ester with an alkali metal chloride such as lithium chloride in the presence of a polar solvent such as dimethylformamide.

The starting compounds for the process according to the invention can be prepared in a simple manner and in high yield from prednisolone, which itself can be synthesized relatively simply from diosgenin. As a result, the compounds of the invention can be prepared from diasgenin at relatively low cost in an overall yield of about 15%. On the other hand, the synthesis of known high-activity corticoids from diosgenin is considerably more expensive and the overall yields achieved are substantially lower (about 0.5 to 5%). This is of no significance in view of the increasing difficulty in obtaining appropriate starting materials for corticoid synthesis in sufficient quantities and in view of the expense of the active substances which increase the cost of special corticoid-containing drugs.

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 marked 4 cm ² patches inside 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 given as

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 various observers and from different areas of the back.

The systemic effect of the compounds is determined by the adjuvant edema test as follows:

SPF rats weighing 130-150 g were injected into the right hind paw by injection of 0.1 ml of a 0.5% suspension of Mycobacterium butyricum (available from Difco, USA) to measure the inflammation of the rats. Injection · Paw volume is again measured to determine the extent of edema Finally, different rats are orally administered to the rats and paw volume is again measured after a further 24 hours.

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

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

Table

Number Substance

Vasoconstriction Test Concentration Results after (%) 4h 8h

Adjuvant edema test ED 50 (mg / kg)

AND 6α, 9α-difluoro-11β-hydroxy-21- -valeryloxy-1,4-pregnadien- 3,20-dione (dif luorortolonvalerate) 0.1 0.001 0.00001 58 54 32 68 66 36 0.04 II 21-acetoxy-9α-fluoro-11β-hydroxy- 0.1 55 66 17'-valeryloxy-1,4-pregnadien- 0.001 52 63 3.8 -3,20-dione (DOS 20 55 221) 0.00001 31 42 III 17α-acetoxy-9'-fluoro-11β / 3-hydroxy- 0.1 67 78 -21-hexanoyloxy-1,4-pregnadien- 0.001 60 74 7.7 -3.20-dione 0.00001 23 36 IV 17α-acetoxy-9'-fluoro-11H-hydroxy- 0.1 57 74 -21-trimethylacetoxy-1,4-pregnadien- 0.001 57 68 7.0 -3.20-dione 0.00001 33 42 in 9'-Fluoro-11/3-hydroxy-17'-21- 0.1 65 83 -diprop; onyloxy-1,4-pregnadien 0.001 58 76 5.0 -3.20-dione 0.00001 39 47 VI 21-butyryloxy-9a-fluoro-11/3-hydroxy- 0.1 62 83 -17'-propionyloxy-1,4-pregnadien- 0.001 58 76 5.7 -3.20-dione 0.00001 43 47 VII 9α-fluoro-11β-hydroxy-17α-propionyloxy-0.1 60 75 -21-valeryloxy-1,4-pregnadien- 0.001 57 76 6.0 -3.20-dione 0.00001 40 43 VIII 17α-benzyloxy-9α-fluoro-11 H -hydroxy- 0.1 62 78 -21-propionyloxy-1,4-pregnadien- 0.001 59 70 over 10 -3.20-dione 0.00001 40 43 IX 17α-Benzyloxy-21-butyryloxy-9 "- 0.1 68 82 -fluoro-1173-hydroxy-1,4-pregnadien- 0.001 67 80 over 10 -3.20-dione 0.00001 51 58 X 17α-Benzoyloxy-21-chloro-9α 0.1 60 72 -fluoro-11 (3-hydroxy-1,4-pregnadien- 0.001 56 64 over 10 -3.20-dione 0.00001 43 45

Similar results are obtained when the systemic effect of the 9-fluorprednisolone derivatives according to the invention is determined by a known thymolysis test 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 and warty lichen and similar diseases.

The manufacture of special medicaments is carried out in the usual 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, a concentration of active compound of 0.001 to 1% is preferably used.

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. examples of synthesis

Example 1 and 500 mg of pyridintosylate twice evaporated with benzene under vacuum to dryness in 500 ml of benzene and 40 ml of N, N-dimethylformamide are added to 5 g of 9α-fluorprednisolone. At a bath temperature of 130 [deg.] C., 50 ml of solvent was distilled off and 6 ml of triethyl orthoacetic acid ester were added. The remaining benzene was distilled off over 2.5 hours and, after addition of 2.4 ml of pyridine, concentrated in vacuo. 17α, 21- (1-ethoxyethylidenedioxy) -9afluoro-1 H / S-hydroxy-1,4-pregnadien-3,20-dione is isolated as a yellow oily mixture of epimers.

b) A solution of the obtained oil in 150 ml of methanol was refluxed with a mixture of 54 ml of 0.1 N acetic acid and 6 ml of 0.1 N aqueous sodium acetate solution for 1 hour at 90 ° C. Evaporate to dryness, pour into water and extract with ethyl acetate. The organic extracts were washed with water, dried and evaporated in vacuo. 9 g of 17α-acetoxy-9α-fluoro-11 (S, 21-dihydroxy-1,4-pregnadien-3,20-dione) are obtained in the form of a foam.

cj 3.0 g of 17α-acetoxy-9-α-fluoro-11,3,21-dihydroxy-1,4-pregnadien-3,20-dione in 17 ml of pyridine and 8 ml of propionic anhydride are stirred at room temperature for 1.5 hours. rooms. After precipitation with ice water, filtration is carried out, the residue is taken up in methylene chloride and, after washing and drying with sodium sulphate, evaporated. 4.9 g of material are isolated, which is chromatographed on 450 g of silica gel with methylene chloride and acetone of variable concentration (0-15% acetone). The yield was 2.96 g of 1? -Acetoxy-ga-fluoro-11? -Hydroxy-21-propionyloxy-1,4-pregnadien-3,20-dione.

Mp 219 ° C;

[α] _D ²⁵ = + 81 ° C (pyridine);

UV: £ 239-15100 (methanol).

Example 2

4.5 g of 17α-acetoxy-9α-fluoro-11β, 21-dihydroxy-1,4-pregnadien-3,20-dione are stirred in 50 mL of pyridine and 25 mL of butyric anhydride overnight at room temperature. The reaction product is precipitated with ice water, filtered off and dissolved in methylene chloride. The solution was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed at varying concentrations of methylene chloride and acetone (0-15% acetone). The yield is 3.6 g of 17α-acetoxy-21-butyryloxy-9α-fluoro-1H-hydroxy-1,4-pregnadien-3,20-dione.

Melting point 218 ° C.

Example 3

1.0 g of 17α-acetoxy-9α-fluoro-11,21,2-dihydroxy-1,4-pregnadiene-3,20-dione was reacted in analogy to Example 2 with 6 ml of valeric anhydride instead of butyric anhydride , in 10 ml of pyridine. Yield: 680 .mu.g of 17.alpha.-acetoxy-9.alpha.-fluoro / 3-hydroxy-21-valeryloxy-1,4-pregnadien-3,20-dione. Melting point 213 ° C.

Example 4

3.0 g of 17α-acetoxy-9α-fluoro-11 (3,21-dihydroxy-1,4-pregnadien-3,20-dione in 30 ml of pyridine are stirred with 15 ml of caproic anhydride for 1.5 hours at room temperature. The crude product is purified by chromatography with varying concentrations of methylene chloride and acetone (0-12% acetone) and 2.36 g of 17α-acetoxy-9α-fluoro-21-hexanoyloxy-11 / 3- is isolated. hydroxy-1,4-pregnadien-3,20-dione.

Mp 222 ° C;

[α] _D ²⁵ = + 82 ° (pyridine);

UV: 239 239 = 15,500 (methanol).

Example 5

3.0 g of 17α-acetoxy-9α-fluoro-11 / 3,21-dihydroxy-1,4-pregnadien-3,20-dione were stirred with 15 ml of trimethylacetic anhydride in 30 ml of pyridine for 48 hours at room temperature. The crude product is isolated as described in Example 2 and chromatographed on 700 grams of silica gel with varying concentrations of methylene chloride and acetone (0-12% acetone).

Yield: 2.06 g 17-acetoxy-9AF-fluoro-l _l 3-hydroxy-21-trimethylacetoxy-L 4_pregnadiene-3,20-dione.

Melting point 227 ° C;

[Α] D ²⁵ = + 79 ° (pyridine);

UV: 239 239 = 15,500 (methanol).

Example 6

5.0 g of 9α-fluoro-11 (S, 21-dihydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione made from 9α-fluorprednisolone analogously to Example 1a and 1b by reaction with triethyl orthopropionate instead of s) The triethyl orthoacetate was stirred in 50 ml of pyridine with 25 ml of propionic anhydride for 2 hours at room temperature The treatment was carried out as described in Example 2. 4.8 g of crude product was purified on 450 g of silica gel with varying concentrations of methylene chloride and acetone ( Yield: 4.62 g of 9α-fluoro-11β-hydroxy-17,11-dipropionyloxy-1,4-pregnadien-3,20-dione.

Mp 191 ° C;

[α] _D ²⁵ = + 51 °, (chloroform);

UV: 239 239 = 15,700 (methanol).

Example 7

5.0 g of 9α-fluoro-11 / 5,21-dihydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione were reacted in analogy to Example 2 with butyric acid hydride. The crude product is chromatographed on 450 g of silica gel with varying concentrations of methylene chloride and acetone (0-12% acetone). 4.93 grams of 21-butyryloxy-9α-fluoro-11β-hydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dlone is isolated.

Mp 179 ° C;

[ _.alpha. ] _D @ ²⁵ = + 51 DEG (chloroform);

UV: 239 239 = 15,700 (methanol).

Example 8 g of 9a-fluoro-II _I II, 21-dihydroxy-17.alpha.-propionyloxy-l, 4-pregnadiene-3,20-dione is reacted analogously to Example 2 with valeric anhydride instead of butyric anhydride. The work-up is also carried out as described in Example 2. The crude product is purified on 750 g of silica gel with varying concentrations of methylene chloride and acetone (0-15% acetone). Yield: 5.03 g of S-fluoro-11α-hydroxy-iya-propionyloxy-21-valeryloxy-1,4-pregnadien-3,20-dione.

Mp 190 ° C;

[α] _D ²⁵ - + 54 ° (chloroform);

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

Example 9

5.0 g of 9α-fluoro-11β / 3,21-dihydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione were reacted analogously to Example 2 with caproic anhydride instead of butyric anhydride . The crude product (5.8 g) is purified on 700 g of silica gel with methylene chloride and acetone of varying concentration (0-12 percent acetone). 4.32 g of 9of-fluoro-21-hexanoyloxy-1H-hydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione are isolated.

Mp 208 ° C;

[α] _D ²⁵ - + 52 ° (chloroform);

UV: 239 239 = 15,900 (methanol).

Example 10

5.0 g of 9α-fluoro-11 (3,21-dihydroxy-17H-propionyloxy-1,4-pregnadien-3,20-dione) was reacted and treated as in Example 2 with trimethyl acetic acid anhydride instead of butyric acid anhydride. The crude product (5.9 g) is chromatographed on 450 g of silica gel with varying concentrations of methylene chloride and acetone (0-12% acetone) to yield 2.23 g of 9α-fluoro-11β-hydroxy-17α-propionyloxy-21-trimethylacetoxy- 1,4-pregnadien-3,20-dione.

Mp 214 ° C;

[ _.alpha. ] _{D @} ²⁵ = + 53 DEG (chloroform);

UV: 239 239 = 15,700 (methanol).

They did

(a) 25 g of 9α-fluorprednisolone are stirred at room temperature overnight in 250 ml of pyridine and 125 ml of butyric anhydride. After precipitation with ice water, filtration is carried out and the residue is dissolved in methylene chloride. The solution was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 2.5 g of silica gel with methylene chloride and acetone at varying concentrations (0-15% acetone). Yield: 23.1 g of 21-butyryloxy-9α-fluoro-11β, 17α-dihydroxy-1,4-pregnadien-3,20-dione.

b) To a suspension of copper (I) iodide (24 g) in dry tetrahydrofuran (480 ml) at 0 ° C was added dropwise a 5% methyllithium solution in ether (100 ml) under argon. The yellow mixture was cooled to -30 ° C and then a solution of 22.3 g of 21-butyryloxy-9afluoro-11 / 3,17α-dlhydroxy-1,4-pregnadien-3,20-dione was added dropwise to 400 mL of dry tetrahydrofuran at This temperature is stirred for 3 to 4 hours. Excess reagent is quenched with aqueous ammonium chloride solution. After extraction with methylene chloride, the organic phase is washed, dried over sodium sulphate and evaporated in vacuo. Yield: 20.3 g of 17.alpha.-butyryloxy-9.alpha.-fluoro-11,13,21-dihydroxy-1,4-pregnadien-3,20-dione.

c) 2.0 g of 17α-butyryloxy-9, α-fluoro-11 / 3,21-dihydroxy-1,4-pregnadien-3,20-dione were treated with propionic anhydride in a similar manner as in Example 1c, processes and cleans. 1.4 g of 17'-butyryloxy-9'-fluoro-11β-hydroxy-21-propionyloxy-1,4-pregnadien-3,20-dione is isolated. Melting point 146 degrees Celsius.

Example 12

1.5 g of 1α-butyryloxy-ga-fluoro-11,14,4-dihydroxy-1,4-pregnadien-3,20 dione were reacted in analogy to Example 2 with valeric anhydride instead of butyric anhydride to 17α-butyryloxy- 9α-Fluoro-11β-hydroxy-21-valeryloxy-1,4-pregnadien-3,20-dione. Melting point 220 ° C.

Example 13

1.4 g of 17α-butyryloxy-9'-fluoro-11,11,11-dihydroxy-1,4-pregnadien-3,20-dione are stirred in 15 ml of pyridine and 10 ml of enantic anhydride at room temperature overnight. The mixture was then poured into ice water and extracted with methylene chloride. The extract was washed with water, dried over sodium sulfate and evaporated in vacuo. The excess enantic acid is removed from the residue by distillation with water vapor. The crude product is chromatographed on 250 g of silica gel with methylene chloride and acetone of average concentration (0-12% acetone). 790 mg of 17'-butyryloxy-9a202593 is isolated

-fluoro-21-heptanoyloxy-11β-hydroxy-1,4-pregnadien-3,20-dione.

Example 14

4.5 g of 17α-butyryloxy-9α-fluoro-11,2,2,1-dihydroxy-1,4-pregnadien-3,20-dione were reacted analogously to Example 2 but with isobutyric anhydride instead of butyric anhydride. The crude product was purified on 700 g silica gel with methylene chloride and acetone of varying concentration (0-12% acetone). The yield was 2.1 g of 17α-butyryloxy-9or-fluoro-11β-hydroxy-21-isobutyryloxy-1,4-pregnadien-3,20-dione.

Example 15

(a) 3 g of 9α-fluorprednisolone are stirred in 30 ml of pyridine and 15 ml of valeric anhydride at room temperature overnight. It is then stirred into ice water and extracted with methylene chloride. The extract was washed with water, dried over sodium sulfate and evaporated in vacuo; the excess valeric acid is removed from the residue by distillation with water vapor. The crude product is chromatographed on 300 g of silica gel with methylene chloride and acetone of varying concentration (0-15% acetone). The yield was 2.87 g of 9'-fluoro-11β, 17α-dihydroxy-21-valeryloxy-1,4-pregnadien-3,20-dione.

b) 2 g of 9α-fluoro-11β, 17α-dihydroxy-21-valeryloxy-1,4-pregnadien-3,20-dione was rearranged in analogy to Example 11b with lithium dimethyl acetate to 1.86 g of 9α-fluoro-11,13,21 -dihydroxy-17'-valeryloxy-1,4-pregnadien-3,20-dione.

c) 1.8 g of 9α-fluoro-11 ', 21-dihydroxy-17'-valeryloxy-1,4-pregnadien-3,20-dione was reacted analogously to Example 2, but with propionic anhydride instead of anhydride butyric acid, to 920 milligrams of 9α-fluoro-11β-hydroxy-21-propionyloxy-17α-valeryloxy-1,4-pregnadien-3,20-dione. Mp 206 ° C.

Example 16

3.4 g of 9α-fluoro-11,11,2-dihydroxy-17α-valeryloxy-1,4-pregnadien-3,20-dione are treated in a manner similar to Example 2 with butyric anhydride and further processing is carried out in the same manner. . Isolated 1.96 g of 21-butyryloxy-9a-fluoro-l _j 3-hydroxy-17a-valeryloxy-l, 4-pregnadiene-3,20-dione. Mp 234 ° C.

Example 17 i

A solution of 2.0 g of 9'-fluoro-11 (3,21-dihydroxy-17'-valeryloxy-pregnadien-3,20-dione in 20 ml of pyridine is stirred with 10 ml of caproic anhydride for 1.5 hours at room temperature. The reaction product is precipitated with ice water, filtered and dissolved in methylene chloride, the solution is washed with water, dried and evaporated in vacuo and the residue of 1.96 g of crude product is chromatographed on 200 g of silica gel with methylene chloride and acetone at varying concentrations (0-12%). The yield was 1.58 g of 9α-fluoro-21-hexanoyloxy-11H-hydroxy-17α-valeryloxy-1,4-pregnadien-3,20-dione.

Example 18

a) 12 g of 9α-fluoro-prednisolone were reacted as in Example 11a, but with isobutyric anhydride instead of butyric anhydride, to 10.4 g of 9α-fluoro-H, 17,7-dihydroxy-21-isobutyryloxy-1,4 -pregnadien-3,20-dione.

b) 10 g of 9a-fluoro-11) 3,17a-dihydroxy-21-isobutyryloxy-1,4-pregnadien-3,20-dione was analogously to Example 11b switched to 6.9 g of 9a-fluoro-11j3 using lithium dimethyl acetate. 21-dihydroxy-17α-isobutyryloxy-1,4-pregnadien-3,20-dione.

c) 2.1 g of 9α-fluoro-11 / 3,21-dihydroxy-17α-isobutyryloxy-1,4-pregnadien-3,20-dione were reacted in analogy to Example 1c with propionic anhydride to 1.3 g 9α-fluoro-11 + hydroxy-17α-isobutyryloxy-21-propionyloxy-1,4-pregnadien-3,20-dione.

Example 1 9

1.2 g of 9α-fluoro-11 (3,21-dihydroxy-17α-isobutyryloxy-1,4-pregnadien-3,20-dicne) was reacted with butyric anhydride, worked up and chromatographed as in Example 2. with 670 mg of 21-butyryloxy-9α-fluoro-11 (S-hydroxy-17α-isobutyryloxy-1,4-pregnadien-3,20-dione).

Example 20

a) 5.0 g of 9α-fluoro-11 / 3,17α-dihydroxy-21-trimethylacetoxy-1,4-pregnadien-3,20-dione was analogously to Example 11b switched to 3.4 g of 9α-fluoro with lithium dimethyl acetate. - 11 / S, 21-dihydroxy-17α-trimethylacetoxy-1,4-pregnadien-3,20-dione.

(b) 2.4 g of 9α-fluoro-11,13,21-dihydroxy-17α-trimethylacetoxy-1,4-pregnadiene-3,20-dione were reacted with propionic anhydride to 1.2 grams of 9α- fluoro-11 + hydroxy-21-propionyloxy-17α-trimethylacetoxy-1,4-pregnadien-3,20dione.

Example 21

3.1 g of 17α-benzoyloxy-9α-fluoro-11,2,21-dihydroxy-1,4-pregnadien-3,20-dione, prepared analogously to Example 1a and 1b by reaction with triethyl orthobenzoate instead of triethyl orthoacetate of 9a -fluoropredisolone, are stirred in 30 ml of pyridine and 15 ml of propionic anhydride for 1 hour at room temperature. The treatment is carried out analogously to Example 1c. The crude product is purified on 450 g silica gel with methylene chloride and acetone of varying concentration (0-12% acetone). The yield is 1.34 g of 17α: -benzyloxy-9α-fluoro-11'-hydroxy-21-propionyloxy-1,4-pregnadien-3,20-dione.

235 ° C (dec.);

[.alpha.] _D ^{@ 25} = + 22 DEG (pyridine);

UV: ε ₂ 34-28 800 (methanol).

Example 22

3.0 g of 17α-benzyloxy-9α-fluoro-11 / 3,21-dihydroxy-1,4-pregnadien-3,20-dlone was reacted in 30 ml of pyridine and 15 ml of butyric anhydride analogously to Example 2 and it is also processed. After purification of the crude product, 450 g of silica gel with methylene chloride and acetone of varying concentration (0-12% acetone) was isolated.

1.9 g of 17? -Benzoyloxy-21-butyryloxy-9? -Fluoro-11? -Hydroxy-1? -Pregnadien-S? O-dione.

Mp 218 ° C (dec.);

[α] _D ²⁵ - + 21 ° (pyridine);

UV: 234 234 = 28,900 (methanol).

Example 23

2.8 g of 17.beta.-benzoyloxy-9.alpha.-fluoro-11,21,2-dihydroxy-1,4-pregnadien-3,20-dione was reacted analogously to Example 2, but with valeric anhydride instead of butyric anhydride and the same so it is processed. The crude product is purified on 450 grams of silica gel with methylene chloride and acetone of varying concentration (0-12 percent acetone). 1.81 g of 17α-benzoyloxy-9α-fluoro-11β / 3-hydroxy-21-valeryloxy-1,4-pregnadien-3,20-dione is obtained.

Mp 208 ° C;

[α] _D ²⁵ = + 22 ° (pyridine);

UV: 234 234 = 29,000 (methanol).

Example 24

2.1 g of 17α-benzoyloxy-90: -fluoro-11 / 3,21-dihydroxy-1,4-pregnadien-3,20-dione was reacted analogously to Example 2 with isobutyric anhydride instead of butyric anhydride and it is also processed. The crude product is chromatographed on 200 g of silica gel with methylene chloride and acetone of varying concentration (0-12 percent acetone). 1.09 g of 17α-benzoyloxy-9α-fluoro-11 H -hydroxy-21-isobutyryloxy-1,4-pregnadien-3,20-dione is obtained.

Example 25

1.8 g of 17α-benzoyloxy-9α-fluoro-11,3,21-dihydroxy-1,4-pregnadien-3,20-dione was reacted in analogy to Example 2 with trimethylacetic anhydride instead of butyric anhydride and treated accordingly and chromatographed as described in the example. 720 mg of 1α-benzyloxy-Oof-fluoro-11H-hydroxy-21-trimethylacetoxy-1,4-pregnadien-3,20-dione are isolated.

Example 26 ml of phosphoric acid hexamethylamide was stirred at 0 ° C with 1.3 ml of thionyl chloride for 30 minutes. Then 800 mg of 17α-acetoxy-9α-fluoro-11β, 3,21-dihydroxy-1,4-pregnadien-3,20-dione was added and stirred for 5.5 hours at 0 ° C. The mixture was poured into ice water, extracted with ethyl acetate, the extract washed with sodium bicarbonate, washed with water until neutral, dried with sodium sulfate and evaporated in vacuo to isolate 1 g of crude product which was purified on 65 g silica gel with methylene chloride and acetone concentration (0-15% acetone). The yield was 535 mg of 17α-acetoxy-21-chloro-9α-fluoro-11β-hydroxy-1,4-pregnadien-3,20-dione.

Melting point 265 ° C (dec.);

[α] _D ²⁵ = + 101 ° (pyridine);

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

Example 27

1.2 g of 9α-β1-η-11 (3,21-dibydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione) are reacted with thionyl chloride in phosphoric acid hexamethylamide analogously to Example 26. Crude product The residue was chromatographed on 150 g of silica gel with methylene chloride and acetone at varying concentrations (0-15% acetone) to give 860 mg of 21-chloro-9'-fluoro-11,3-hydroxy-17-t-propionyloxy-1,4-pregnadien- 3,20-d'one.

Mp 229 ° C (dec.);

[α] D ²⁵ = + 98 ° (pyridine);

UV: 239 239 = 15,900 (methanol).

Example 28

950 mg of 9α-fluoro-11 / 3,21-dihydroxy-17α-isobutyryloxy-1,4-pregnadien-3,20-dione were treated analogously to Example 26 with thionyl chloride in hexamethylammonium phosphate. The crude product is purified on 120 g of silica gel with methylene chloride and acetone at varying concentrations (0-15% acetone). Yield: 520 mg of 21-chloro-9 alpha-fluoro-l _l 3-hydroxy-17a-isobutyryloxy-l 4_pregnadiene-3,20-dione. Mp 216 ° C.

Example 29

2.5 g of 17α-benzoyloxy-9'-fluoro-11 / 3,21-dihydroxy-1,4-pregnadien-3,20-dione was reacted as in Example 26 and the crude product was purified on 250 g of silica gel with methylene chloride. and acetone at varying concentrations (0-12% acetone). The yield was 1.1 g of 17α-benzoyloxy-21-chloro-9α-fluoro-11β-hydroxy-1,4-pregnadien-3,20-dione.

Mp 256 ° C (dec.);

[α] _D ²⁵ = + 15 ° (pyridine);

UV:? 23? = 28 600 (methanol).

II. Pharmaceutical preparations

Example A

Ointment composition

0.03% 9'-fluoro-11β-hydroxy-17α, 21-dipropionyloxy-1,4-pregnadien-3,20-dione

2.50% Allercurhexachlorophenate [micronized, particle size about 8 μνη (Allercur = + registered trademark for 1-p-chlorobenzyl-2-pyrrolidylmethylbenzimidazole)]

6,00% tartaric acid orthophosphoric ester and tetraglycol ether alcohol contained in wax (Hostaphatu KW 340 ^(R) )

0,10% sorbic acid

10.00% neutral oil (Migloyol 812 ^{, R)} )

3.50% stearyl alcohol

1.50% Wax of anhydrous sheep wool (DAB 6)

76.36% desalinated water

Example B

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 mixed with 39,000 g of ground lactose.

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

SUBJECT

Claims (3)

SUBJECT A process for the preparation of 9-fluoropredisolone derivatives of the general formula I wherein R1 represents an alkanoyl group with C 1 to C 8 or benzoyl; and X represents a fluorine atom, a chlorine atom or a C3 -C8 alkanoyloxy group, characterized in that the 9-fluoro derivative of the general formula is halogenated or esterified in a manner known per se at the 21-position II where R1 is as defined above. YNÁLEZU 2. The process of item 1 for the preparation of 9-fluoro-prednisolone derivatives of the general formula I wherein R 1 is as defined in item 1 and X is chlorine or C 3 -C 8 alkanoyloxy, characterized in that the 9-fluoro derivative of the general formula is halogenated or esterified in a manner known per se at position 21 wherein: Ri is as defined in point 1. 3. A process according to claim 1 for the preparation of 9-fluoro-prednisolone derivatives of the formula I as defined in item 1 and is a fluorine atom, characterized in that the 9-fluoro derivative of formula II is halogenated or esterified in a manner known per se. • viroirafla, np, plant 7, Most