CS202593B2 - A method for producing 9-fluoropropednisolone derivatives - 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 invention relates to a process for the production of new derivatives of 9-fluoroprednisolone. It also relates to pharmaceutical preparations containing these active substances.

9-Fluoroprednisolone (9a-fluoro-11/j,17a,21-trihydroxy-1,4-pregnadiene-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 used for the local treatment of inflammatory diseases because it has very strong systemic effects.

It has been discovered that hitherto unknown derivatives of 9-fluoroprednisolone are only weakly effective systemically, but when used topically they have a surprisingly strong anti-inflammatory effect, which often surpasses the most effective corticosteroids available commercially.

New derivatives of 9-fluoroprednisolone have the general formula I

» where

R1 represents an alkanoyl group having 1 to 8 carbon atoms or a benzoyl group, and

X represents a fluorine atom, a chlorine atom or an alkanoyloxy group having 3 to 8 carbon atoms.

The alkanoyl group R1 containing 1 to 8 carbon atoms and the alkanoyloxy group X containing 3 to 8 carbon atoms is to be understood as a group derived from carboxylic acids with an open or cyclic chain that is straight or branched, such as, for example, derived from butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethylacetic acid, caproic acid, tert-butylacetic acid, cyclopentylcarboxylic acid, cyclohexylcarboxylic acid or caprylic acid, or optionally from formic acid, acetic acid or propionic acid.

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

Derivatives of 9-fluoroprednisolone of the general formula I and X representing a chlorine atom are, for example, the following compounds:

17α1-acetoxy-21-chloro-9β-fluoro-115-hydroxy-15-pregnadiene-S20-dione

21-Chloro-9α-fluoro-11S'-hydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione,

17"-butyryloxy-21-chloro-9"-fluoro-Hj3-hydroxy-1,4-pregnadiene-3,20-dione,

21-chloro-9a-fluoro- _11i 3-hydroxy-17a-isobutyryloxy-1,4-pregnadiene-3,20-dione,

21-chloro-9α-fluoro-11/3-hydroxy-17α-isobutyryloxy-1,4-pregnadiene-3,20-dione and

17α-benzoyloxy-21-chloro-9α-fluoro-113-hydroxy-1,4-pregnadiene-3,20-dione.

Derivatives of 9,21-difluoroprednisolone of general formula I are, for example, the following compounds:

17ft-acetoxy-9a,21-difluoro-11(3-hydroxy-1,4-pregnadiene-3,20-dione,

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

17α-butryloxy-9α,21-difluoro-113-hydroxy-1,4-pregnadiene-3,20-dione or

9 io,21-difluoro-11β-hydroxy-17α-isobutyryloxy-1,4-pregnadiene-3,20-dione.

The 9-fluoroprednisolone derivatives of the general formula I, wherein X represents an alkanoyloxy group, are preferably those in which the radicals R1 and X together have 5 to 14 carbon atoms. Such fluoroprednisolone derivatives are, for example:

17 ₍ α-acetoxy-9α-fluoro-11/2-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione 17α-acetoxy-21-butyryloxy-9α-fluoro-11/3-hydroxy-1,4-pregnadiene-3,20-dione,

,

21-butyryloxy-9a-fluoro-11/3-hydroxy-17o1-valeryloxy-1,4-pregnadiene-3,20-dione,

17α-benzyloxy-21-butyryloxy-9α-fluoro-11/3-hydroxy-1,4-pregnadiene-3,20-dione, 1a-fluoro-11/1-hydroxy-1/1-diisobutyryloxy-1,4-pregnadiene-3,20-dione and

3-Fluoro-11,5-hydroxy-11,11-divaleryloxy-1,4-pregnadiene-3,20-dione.

The new derivatives of 9-fluoroprednisolone can be prepared according to a method known per se, which consists in halogenating or esterifying the 9-fluoro derivative of the general formula II at position 21.

where

Ri has the above meaning.

The process of the invention can be carried out under the conditions described in U.S. 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 U.S. Patent No. 3,152,154 and in 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 compounds of general formula II consists in esterifying the 21-hydroxy group with a sulfonic acid, preferably methanesulfonic acid or p-toluenesulfonic acid, and finally removing the sulfonic acid group.

S is replaced by chlorine. Esterification of the 21-hydroxy group occurs, for example, when sulfonic acid chloride is reacted with compounds of the general 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 for a chlorine atom preferably occurs when the 21-sulfonic acid ester is reacted 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 easily from diosgenin. As a result, the compounds according to the invention can be prepared from diosgenin at relatively low cost in an overall yield of approximately 15%. In contrast, the synthesis of known highly effective corticoids from diosgenin is considerably more expensive and the overall yields achieved are considerably lower (about 0.5 to 5%). This is not without significance in view of the increasing difficulties in obtaining suitable starting materials for the synthesis of corticoids in sufficient quantities and in view of the expenditure on active ingredients, which makes special corticoid-containing drugs more expensive.

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

The anti-inflammatory effect is determined as follows:

Congestion is induced on human skin by spreading twenty overlapping strips of 2-centimeter-wide tape over the stratum corneum on the backs of male and female volunteers.

Approximately 50 milligrams of the preparation in the form of an ointment is applied to marked areas measuring 4 ^cm2 inside the abrasion area.

In order to obtain a comparable baseline value, relative numbers were used because the color of untreated skin, as well as the redness of the congested area, is different for each person.

The color value of untreated leather is given as 100 and the color value of abraded leather as

0.

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

Vasoconstriction of minor, moderate and major degree is assessed with a value corresponding to 0 to 100.

The following table shows the average values that were found during tests of various observed individuals and from different areas of the back.

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

SPF rats weighing 130 to 150 g are injected into the right hind paw with 0.1 ml of a 0.5% suspension of Mycobacterium butyricum (available from Difco, USA) to induce inflammation. The paw volume of the rats is measured before injection and again 24 hours after injection to determine the extent of edema. Finally, rats are orally administered different amounts of test substances. After another 24 hours, the paw volume is measured again.

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

The results obtained from the above tests are shown in the following table.

Table

Number Substance

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

Adjuvant edema test EDso (mg/kg)

I 6α,9α-difluoro-lljS-hydroxy-21- -valeryloxy-1,4-pregnadiene- 3,20-dione (difluorocortolone valerate ] 0.1 0.001 0.00001 58 54 32 68 66 36 0.04 II 21-acetoxy-9a-fluoro-lljS-hydroxy- 0.1 55 66 17'-valeryloxy-1,4-pregnadiene- 0.001 52 63 3.8 -3,20-dione (DOS 20 55 221) 0.00001 31 42 III 17α-acetoxy-9α-fluoro-II./3-hydroxy- 0.1 67 78 -21-hexanoyloxy-1,4-pregnadiene- 0.001 60 74 7.7 -3,20-dione 0.00001 23 36 IV 17α-acetoxy-9α-fluoro-IIH-hydroxy- 0.1 57 74 -21-trimethylacetoxy-1,4-pregnadiene- 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-pregnadiene 0.001 58 76 5.0 -3,20-dione 0.00001 39 47 VI 21-butyryloxy-9α-fluoro-11/3-hydroxy- 0.1 62 83 -17'-propionyloxy-1,4-pregnadiene- 0.001 58 76 5.7 -3,20-dione 0.00001 43 47 VII 9α-Fluoro-11S-hydroxy-17α-propionyloxy-0.1 60 75 -21-valeryloxy-1,4-pregnadiene- 0.001 57 76 6.0 -3,20-dione 0.00001 40 43 VIII 17α-benzyloxy-9α-fluoro-11β-hydroxy- 0.1 62 78 -21-propionyloxy-1,4-pregnadiene- 0.001 59 70 above 10 -3,20-dione 0.00001 40 43 IX 17α-benzyloxy-21-butyryloxy-9"- 0.1 68 82 -fluoro-1173-hydroxy-1,4-pregnadiene- 0.001 67 80 above 10 -3,20-dione 0.00001 51 58 X 17a-benzoyloxy-21-chloro-9a- 0.1 60 72 -fluoro-11(3-hydroxy-1,4-pregnadiene- 0.001 56 64 above 10 -3,20-dione 0.00001 43 45

Similar results are obtained when the systemic effect of the 9-fluoroprednisolone derivatives according to the invention is determined using the known thymolysis test or the known sodium and potassium retention test.

The new compounds are suitable in combination with carriers customary in galenic pharmacy for the local treatment of contact dermatitis, eczema of various types, neurodermatoses, erythroderma, burns, Pruritis vulvae et ani, rosacea, Erythematodes cutaneus, psoriasis, lichen planus and verrucous lichen and similar diseases.

The production of special drugs is carried out in the usual way, where the active substance is converted with suitable additives into the desired application form, such as solutions, lotions, ointments, creams or patches. In the drugs prepared in this way, the concentration of the active substance depends on the application form. For lotions and ointments, a concentration of 0.001 to 1% of the active substance is preferably used.

In addition, the new compounds are optionally suitable in combination with conventional carriers and excipients for the production of inhalation preparations which can be used in the treatment of allergic respiratory diseases, such as bronchial asthma or rhinitis.

The following examples serve to illustrate the invention.

I. examples of synthesis

Example 1 aj 500 mg of pyridine tosylate evaporated twice with benzene in vacuo to dryness in 500 milliliters of benzene and 40 ml of N,N-dimethylformamide are added to 5 g of 9a-fluoroprednisolone. At a bath temperature of 130 °C, 50 ml of solvent are distilled off and 6 ml of orthoacetic acid triethyl ester are added. The remaining benzene is distilled off over 2.5 hours and, after adding 2.4 ml of pyridine, it is concentrated in vacuo. 17a,21-(1-ethoxyethylidenedioxy)-9afluoro-1L/S-hydroxy-1,4-pregnadiene-3,20-dione is isolated as a yellow oily mixture of epimers.

b) A solution of the obtained oil in 150 ml of methanol is 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. The whole is evaporated to dryness, poured into water and extracted with ethyl acetate. The organic extracts are washed with water, dried and evaporated in vacuo. 9 g of 17α-acetoxy-9α-fluoro-11(S,21-dihydroxy-1,4-pregnadiene-3,20-dione are obtained in the form of a foam.

cj 3.0 g of 17α-acetoxy-9-α-fluoro-11j3,21-dihydroxy-1,4-pregnadiene-3,20-dione in 17 ml of pyridine and 8 ml of propionic anhydride are stirred for 1.5 hours at room temperature. After precipitation with ice water, filtration is carried out, the residue is taken up in methylene chloride and, after washing and drying with sodium sulfate, evaporated. 4.9 g of the substance is isolated, which is chromatographed on 450 g of silica gel with methylene chloride and acetone with variable concentrations (0 to 15% acetone). The yield is 2.96 grams of 1/α-acetoxy-ga-fluoro-11^-hydroxy-21-propionylOxy-1,4-pregnadiene-3,20-dione.

Melting point 219°C;

[at] _D ²⁵ = + 81 °C (pyridine);

UV: £239 — 15100 (methanol).

Example 2

4.5 g of 17α-acetoxy-9α-fluoro-11β,21-dihydroxy-1,4-pregnadiene-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 is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed at varying concentrations of methylene chloride and acetone (0 to 15% acetone). The yield is 3.6 g of 17α-acetoxy-21-butyryloxy-9α-fluoro-1η|á-hydroxy-1,4-pregnadiene-3,20-dione.

Melting point 218 °C.

Example 3

1.0 g of 17α-acetoxy-9α-fluoro-11,21-dihydroxy-1,4-pregnadiene-3,20-dione is reacted analogously to Example 2 with 6 ml of valeric anhydride, instead of butyric anhydride, in 10 ml of pyridine. The yield is 680 µg of 17α-acetoxy-9α-fluoro-11,21-dihydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 213 °C.

Example 4

3.0 g of 17α-acetoxy-9α-fluoro-11(3,21-dihydroxy-1,4-pregnadiene-3,20-dione in 30 ml of pyridine are stirred with 15 ml of caproic anhydride for 1.5 hours at room temperature. The work-up is carried out analogously to Example 2. The crude product is purified by chromatography with variable concentrations of methylene chloride and acetone (0 to 12% acetone). 2.36 g of 17α-acetoxy-9α-fluoro-21-hexanoyloxy-11/3-hydroxy-1,4-pregnadiene-3,20-dione are isolated.

Melting point 222°C;

[|a] _D ²⁵ =+82° (pyridine);

UV: £239=15,500 (methanol).

Example 5

3.0 g of 17α-acetoxy-9α-fluoro-11/3,21-dihydroxy-1,4-pregnadiene-3,20-dione are 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 g of silica gel with varying concentrations of methylene chloride and acetone (0 to 12% acetone).

The yield is 2.06 g of 17α-acetoxy-9α-fluoro- ₁₁₁₃ -hydroxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione.

Melting point 227°C;

[Delta] ²⁵ = +79° (pyridine);

UV: £239=15,500 (methanol).

Example 6

5.0 g of 9a-fluoro-11(S,21-dihydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione prepared from 9a-fluoroprednisolone analogously to Examples 1a and 1b by reaction with orthopropionic acid triethyl ester instead of orthoacetic acid triethyl ester are stirred in 50 ml of pyridine with 25 ml of propionic acid anhydrides for 2 hours at room temperature. The work-up is carried out as described in Example 2. 4.8 g of the crude product are purified on 450 g of silica gel at varying concentrations of methylene chloride and acetone (0 to 15% acetone). The yield is 4.62 g of 9a-fluoro-11(S,21-dipropionyloxy-1,4-pregnadiene-3,20-dione.

Melting point 191°C;

[|a] _D ²⁵ =+51°, (chloroform);

UV: £239 = 15,700 (methanol).

Example 7

5.0 g of 9a-fluoro-11/5,21-dihydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione are reacted analogously to Example 2 with butyric anhydride. The crude product is chromatographed on 450 g of silica gel with varying concentrations of methylene chloride and acetone (0 to 12% acetone). 4.93 grams of 21-butyryloxy-9a-fluoro-11/3-hydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione are isolated.

Melting point 179°C;

[)a] _D ²⁵ =' + 51° (chloroform);

UV: £239=15,700 (methanol).

Example 8 g of 9α-fluoro- _11α -11,21-dihydroxy-17α-propionyloxy-1,4-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 to 15% acetone). The yield is 5.03 g of 5α-fluoro-11α-hydroxy-17α-propionyloxy-21-valeryloxy-1,4-pregnadiene-3,20-dione.

Melting point 190°C;

[ia] _D ²⁵ —+54° (chloroform);

UV: £239=15,800 (methanol).

Example 9

5.0 g of 9α-fluoro-11β-3,21-dihydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione are reacted analogously to that described in Example 2 with caproic anhydride instead of butyric anhydride. The crude product weighing 5.8 g is purified on 700 grams of silica gel with methylene chloride and acetone of varying concentrations (0 to 12 percent acetone). 4.32 g of 9α-fluoro-21-hexanoyloxy-18-hydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione are isolated.

Melting point 208°C;

[/a] _D ²⁵ —+52° (chloroform);

UV: £239=15,900 (methanol).

Example 10

5.0 g of 9α-fluoro-11[3,21-dihydroxy-17[alpha]-propionyloxy-1,4-pregnadiene-3,20-dione are reacted and worked up as in Example 2 with trimethylacetic anhydride instead of butyric anhydride. 5.9 g of the crude product are chromatographed on 450 g of silica gel at varying concentrations of methylene chloride and acetone (0 to 12% acetone). The yield is 2.23 g of 9α-fluoro-11[3,21-hydroxy-17[alpha]-propionyloxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione.

Melting point 214 °C;

[(a[ _D ²⁵ =+53° (chloroform);

UV: £239=15,700 (methanol).

They applied

a) 25 g of 9a-fluoroprednisolone are stirred overnight at room temperature 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 is 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 variable concentrations (0 to 15% acetone). The yield is 23.1 g of 21-butyryloxy-9a-fluoro-11/S,17a-dihydroxy-1,4-pregnadiene-3,20-dione.

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

c) 2.0 g of 17α-butyryloxy-9,α-fluoro-11/3,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted analogously to example 1c with propionic anhydride, the product is worked up and purified. 1.4 g of 17α-butyryloxy-9α-fluoro-11/3-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione are isolated. Melting point 146 degrees Celsius.

Example 12

1.5 g of 17α-butyryloxy-9α-fluoro-11β-dihydroxy-1,4-pregnadiene-3,20-dione are reacted analogously to Example 2 with valeric anhydride instead of butyric anhydride to give 17α-butyryloxy-9α-fluoro-11β-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 220 °C.

Example 13

1.4 g of 17a-butyryloxy-9a-fluoro-11/3,21-dihydroxy-1,4-pregnadiene-3,20-dione are stirred in 15 ml of pyridine and 10 ml of enanthic anhydride overnight at room temperature. The mixture is then poured into ice water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated in vacuo. Excess enanthic acid is removed from the residue by steam distillation. The crude product is chromatographed on 250 g of silica gel with methylene chloride and acetone of average concentration (0 to 12% acetone). 790 mg of 17a-butyryloxy-9a202593 are isolated.

of -fluoro-21-heptanoyloxy-1/3-hydroxy-1,4-pregnadiene-3,20-dione.

Example 4

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

Example 15

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

b) 2 g of 9α-fluoro-11β,17α-dihydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione are rearranged analogously to Example 11b using lithium dimethyl cuprate to give 1.86 g of 9α-fluoro-11β,21-dihydroxy-17β-valeryloxy-1,4-pregnadiene-3,20-dione.

c) 1.8 g of 9α-fluoro-11/,21-dihydroxy-17α-valeryloxy-1,4-pregnadiene-3,20-dione are reacted analogously to Example 2, but with propionic anhydride instead of butyric anhydride, to give 920 milligrams of 9α-fluoro-11/3-hydroxy-21-propionyloxy-17α-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 206°C.

Example 16

3.4 g of 9a-fluoro-11/1,21-dihydroxy-17a-valeryloxy-1,4-pregnadiene-3,20-dione are treated with butyric anhydride in the same manner as in Example 2 and further worked up in the same manner. 1.96 g of 21-butyryloxy-9a-fluoro- _11/ 3-hydroxy-17a-valeryloxy-1,4-pregnadiene-3,20-dione are isolated. Melting point 234 °C.

Example 17

A solution of 2.0 g of 9α-fluoro-11(3,21-dihydroxy-17α-valeryloxy-pregnadiene-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 off and dissolved in methylene chloride. The solution is washed with water, dried and evaporated in vacuo. The remaining 1.96 g of crude product is chromatographed on 200 g of silica gel with methylene chloride and acetone at variable concentrations (0 to 12% acetone). The yield is 1.58 g of 9α-fluoro-21-hexanoyloxy-11/-hydroxy-17α-valeryloxy-1,4-pregnadiene-3,20-dione.

Example 18

a) 12 g of 9α-fluoroprednisolone are reacted analogously to Example 11a, but with isobutyric anhydride instead of butyric anhydride, to give 10.4 g of 9α-fluoro-H0,17-dihydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20-dione.

b) 10 g of 9α-fluoro-11β,17α-dihydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20-dione are rearranged analogously to Example 11b using lithium dimethyl cuprate to give 6.9 g of 9α-fluoro-11β,17α-dihydroxy-17α-isobutyryloxy-1,4-pregnadiene-3,20-dione.

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

E x a m p l e 1 9

1.2 g of 9a-fluoro-11(3,21-dihydroxy-17a-isobutyryloxy-1,4-pregnadiene-3,20-dione are reacted with butyric anhydride, treated and chromatographed similarly to Example 2. 670 mg of 21-butyryloxy-9a-fluoro-11(S-hydroxy-17a-isobutyryloxy-1,4-pregnadiene-3,20-dione are isolated.

Example 20

a) 5.0 g of 9α-fluoro-11/3,17α-dihydroxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione are rearranged analogously to Example 11b using lithium dimethyl cuprate to give 3.4 g of 9α-fluoro-11/5,21-dihydroxy-17α-trimethylacetoxy-1,4-pregnadiene-3,20-dione.

b) 2.4 g of 9α-fluoro-11+hydroxy-17α-trimethylacetoxy-1,4-pregnadiene-3,20-dione are reacted with propionic anhydride analogously to Example 1c to give 1.2 grams of 9α-fluoro-11+hydroxy-21-propionyloxy-17α-trimethylacetoxy-1,4-pregnadiene-3,20-dione.

Example 21

3.1 g of 17a-benzoyloxy-9a-fluoro-11j3,21-dihydroxy-1,4-pregnadiene-3,20-dione, prepared analogously to Examples 1a and 1b by reacting with orthobenzoic acid triethyl ester instead of orthoacetic acid triethyl ester from 9a-fluoroprednisolone, are stirred in 30 ml of pyridine and 15 ml of propionic anhydride for 1 hour at room temperature. The work-up is carried out analogously to Example 1c. The crude product is purified on 450 g of silica gel with methylene chloride and acetone of variable concentration (0 to 12% acetone). The yield is 1.34 g of 17a:-benzyloxy-9a-fluoro-11j-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione.

Melting point 235 °C (decomposition);

[ia] _D ²⁵¹ =+22° (pyridine);

UV: 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 are reacted in 30 ml of pyridine and 15 ml of butyric anhydride analogously to Example 2 and worked up in the same way. After purification of the crude product with 450 g of silica gel with methylene chloride and acetone of variable concentration (0 to 12% acetone) the product is isolated.

1.9 g of 17?-benzoyloxy-21-butyryloxy-9?-fluoro-11S-hydroxy-1?-pregnadiene-S?O-dione.

Melting point 218 °C (decomposition);

[(ee] _D ²⁵ — +21° (pyridine);

UV: £234=28,900 (methanol).

Example 23

2.8 g of 17α-benzoyloxy-9α-fluoro-11β,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted analogously to Example 2, but with valeric anhydride instead of butyric anhydride and worked up in the same way. The crude product is purified on 450 g of silica gel with methylene chloride and acetone of varying concentrations (0 to 12 percent acetone). 1.81 g of 17α-benzoyloxy-9α-fluoro-11β-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione are obtained.

Melting point 208°C;

[α] _d ²⁵ = +22° (pyridine);

UV: £234 = 29,000 (methanol).

Example 24

2.1 g of 17a-benzoyloxy-9a-fluoro-11/3,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted analogously to Example 2 with isobutyric anhydride instead of butyric anhydride and worked up in the same way. The crude product is chromatographed on 200 g of silica gel with methylene chloride and acetone of varying concentrations (0 to 12 percent acetone). 1.09 g of 17a-benzoyloxy-9a-fluoro-11/j-hydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20-dione are obtained.

Example 25

1.8 g of 17a-benzoyloxy-9a-fluoro-11.3,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted analogously to Example 2 with trimethylacetic anhydride instead of butyric anhydride and are worked up and chromatographed accordingly as described in the said Example. 720 mg of 1.2a-benzyloxy-0.05-fluoro-11.5-hydroxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione are isolated.

Example 26 ml of phosphoric acid hexamethylamide is stirred at 0°C with 1.3 ml of thionyl chloride for 30 minutes. Then 800 mg of 17α-acetoxy-9α-fluoro-1113,21-dihydroxy-1,4-pregnadiene-3,20-dione are added and the mixture is stirred for 5.5 hours at 0°C. The mixture is poured onto ice water, extracted with ethyl acetate, the extract is washed with sodium bicarbonate, washed with water until neutral, dried with sodium sulfate and after evaporation in vacuo 1 g of crude product is isolated, which is purified on 65 g of silica gel with methylene chloride and acetone, at variable concentrations (0 to 15% acetone). The yield is 535 mg of 17α-acetoxy-21-chloro-9α-fluoro-1115-hydroxy-1,4-pregnadiene-3,20-dione.

Melting point 265 °C (decomposition);

[|a] _D ²⁵ =+101° (pyridine);

UV: £239 =15,800 (methanol).

Example 27

1.2 g of 9α-ί1ηοΓ-11(3,21-dihydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione are reacted with thionyl chloride in phosphoric acid hexamethylamide analogously to Example 26. The crude product is chromatographed on 150 g of silica gel with methylene chloride and acetone at variable concentrations (0 to 15% acetone). The yield is 860 mg of 21-chloro-9α-fluoro-11β-hydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione.

Melting point 229°C (decomposition);

[i«]d ²⁵ =' + 98° (pyridine);

UV: £239 =15,900 (methanol).

Example 28

950 mg of 9α-fluoro-11/3,21-dihydroxy-17α-isobutyryloxy-1,4-pregnadiene-3,20-dione are treated analogously to Example 26 with thionyl chloride in phosphoric acid hexamethylamide. Purification of the crude product is carried out on 120 g of silica gel with methylene chloride and acetone at variable concentrations (0 to 15% acetone). The yield is 520 mg of 21-chloro-9α-fluoro- ₁₁ /3-hydroxy-17α-isobutyryloxy-1,4-pregnadiene-3,20-dione. Melting point 216 °C.

Example 29

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

Melting point 256 °C (decomposition);

[α] _D ²⁵ =+15° (pyridine);

UV: λ23^=28,600 (methanol).

II. Pharmaceutical preparations

Example A

Composition of the ointment

0.03% 9'-fluoro-11|S-hydroxy-17α,21-dipropionyloxy-1,4-pregnadiene-3,20-dione

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

6.00% tert.ester of orthophosphoric acid and tetraglycol ether of 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% sheep wool wax anhydrous (DAB 6)

76.36% desalinated water

Example B

Inhalant production

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

For inhalations, doses of 20 mg of the inhalation agent are used.

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