CH630098A5 - Process for the preparation of derivatives of 9-chloroprednisolone - Google Patents

Description

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PATENT CLAIMS

Process for the preparation of new derivatives of 9-chloro-prednisolone of the formula

CH0X

i 2

c = o

HO

Gl in

R represents an alkanoyl group with 1 to 8 carbon atoms or the benzoyl group and X represents a fluorine atom, a chlorine atom, the hydroxy group, an alkanoyloxy group with 1 to 8 carbon atoms or the benzoyloxy group,

characterized in that one connects to the A'J "double bond of a compound of the formula

CH ~ X

I 2

c = o

OR

(II)

HOCl attaches.

The invention relates to a process for the preparation of new derivatives of 9-chloropropnisolone.

The 9-chloroprednisolone (= 99a-chloro-11ß, 17a, 21-trihydroxy-1,4-pregnadien-3,20-dione) has long been known (J. Amer. Chem. Soc., 77,1955,4181) . This corticoid is unsuitable as an active ingredient for pharmaceutical preparations used for the topical treatment of inflammatory diseases, since it has very strong systemic effects.

It has been found that previously unknown derivatives of 9-chloroprednisolone are systemically almost inactive, but surprisingly, when applied topically, they have a strong anti-inflammatory activity, which usually exceeds that of the most effective commercially available corticoids.

The new derivatives of 9-chloroprednisolone have the following formula CH0X

I 2

C = 0

HO

0

wherein

Ri represents an alkanoyl group having 1 to 8 carbon atoms or the benzoyl group and X represents a fluorine atom, a chlorine atom, the hydroxy group, an alkanoyloxy group having 1 to 8 carbon atoms or the benzoyloxy group.

An alkanoyl group R containing 1 to 8 carbon atoms and an alkanoyloxy group X containing 1 to 8 carbon atoms is to be understood as a group

which are derived from a straight-chain or branched fatty acid, such as, for example, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, tri-methyl acetic acid, caproic acid, tert-butylacetic acid or caprylic acid. ..

Particularly preferred alkanoyl groups R and alkanoyloxy groups X are those which are derived from an alkane carboxylic acid containing 2 to 6 carbon atoms.

Examples of 9-chloroprednisolone derivatives of the formula I with X in the meaning of a chlorine atom and fluorine atom are:

17a-acetoxy-9a, 21-dichloro-11ß-hydroxy-l, 4-pregnadiene-3,20-dione,

9a, 21-dichloro-11ß-hydroxy-17a-propionyloxy-l, 4-pregnadiene-3.20-dione,

17a-butyryloxy-9a, 21-dichloro-lß-hydroxy-1,4-pregnadiene-3,20-dione,

9a, 21-dichloro-11ß-hydroxy-17a-isobutyryloxy-l, 4-pregnadiene-3,20-dione,

17a-acetoxy-9a-chloro-21-fluoro-11ß-hydroxy-l, 4-pregnadien-3,20-dione,

9a-chloro-21-fluoro-11ß-hydroxy-17a-propionyloxy-l, 4-pregnadiene-3,20-dione,

17a-butyryloxy-9a-chloro-21-fluoro-11ß-hydroxy-l, 4-pregnadiene-3,20-dione,

17a-benzoyloxy-9a-chloro-21-fluoro-11ß-hydroxy-l, 4-pregnadiene-3,20-dione,

9a-chloro-21-fluoro-11ß-hydroxy-17a-isobutyryloxy-l, 4-pregnadiene-3.20-dione,

9a, 21-dichloro-11ß-hydroxy-17a-valeryloxy-l, 4-pregnadiene-3,20-dione and

17a-benzoyloxy-9a, 21-dichloro-lß-hydroxy-1,4-pregnadiene-3,20-dione.

9-chloro-prednisolone derivatives of the general formula I with X 'in the meaning of the hydroxyl group are, for example: 17a-acetoxy-9a-chloro-l 1β, 21-dihydroxy-l, 4-pregnadiene-3,20-dione,

9a-chloro-11ß, 21-dihydroxy-17ot-propionyloxy-l, 4-pregnadiene-3,20-dione,

17a-butyryloxy-9a-chloro-11ß, 21-dihydroxy-l, 4-pregnadien-3,20-dione,

9a-chloro-11ß, 21-dihydroxy-17a-isobutyryloxy-l, 4-pregnadiene-3.20-dione,

9a-chloro-llß, 21-dihydroxy-17a-valeryloxy-l, 4-pregnadiene-3.20-dione and 17a-benzoyloxy-9a-chloro-llß, 21-dihydroxy-l, 4-pregna-diene-3.20 -dion.

These new compounds are not only important as pharmacologically active substances. They can also be used as intermediates for the preparation of 9-chloro-prednisolone derivatives of the formula I with X in the meaning of a chlorine atom, an alkanoyloxy group or a benzoyloxy group.

9-Chlorprednisolone derivatives of the formula I with X meaning an alkanoyloxy group or a benzoyloxy group are preferably those in which the radicals R and X together have 3 to 14 carbon atoms. Such chloro-prednisolone derivatives are, for example: 17cc, 21-diacetoxy-9a-chloro-lß-hydroxy-1,4-pregnadiene-3.20-dione.

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l7 «-Aceto. \ v-9a-ch! or-l 1 fì-h vdroxv-2! -propionvloxv-1,4-presm; ì-dien-3,20-dione,

2l-Acetoxy-9a-chloro-11ß-hydroxy-17a-propionyloxy-l, 4-pregna-diene-3,2ü-dione.

17a-acetoxy-21-butyryloxy-9a-chloro-lß-hydroxy-1,4-pregna-5 diene-3,20-dione,

21-acetoxy-17a-butyryloxy-9a-chloro-1 lß-hydroxy-1,4-pregna-diene-3,20-dione,

17a-acetoxy-9a-chloro-11ß-hydroxy-21-isobutyryloxy-l, 4-pregna-diene-3,20-dione, 10

21-acetoxy-9a-chloro-11ß-hydroxy-17a-isobutyryloxy-l, 4-pregna-diene-3,20-dione.

17a-acetoxy-9a-chloro-11ß-hydroxy-21-valeryloxy-l, 4-pregnadiene-3.20-dione,

21-acetoxy-9a-chloro-11ß-hydroxy-17a-valeryloxy-l, 4-pregnadiene-i5 3.20-dione.

17a-acetoxy-21-benzoyloxy-9a-chloro-11ß-hydroxy-l, 4-pregna-diene-3,20-dione,

21 - acetoxy-17a-benzoyloxy-9a-chloro-l 1β-hydroxy-1,4-pregna-diene-3,20-dione, 20

9a-chloro-l 1 ß-hydroxy-17a, 21-dipropionyloxy-l, 4-pregnadiene-3.20-dione,

17a-butyryloxy-9a-chloro-11ß-hydroxy-21-propionyloxy-l, 4-pre-gnadien-3,20-dione,

21-butyryloxy-9a-chloro-11ß-hydroxy-17a-propionyloxy-l, 4-pre-25 gnadien-3,20-dione,

9a-chloro-11ß-hydroxy-17a-isobutyryloxy-21-propionyloxy-l, 4-pregnadiene-3,20-dione,

9a-chloro-11ß-hydroxy-21-isobutyryloxy-17a-propionyloxy-l, 4-pregnadiene-3,20-dione, 9a-chloro-11ß-hydroxy-17a-propionyloxy-21-valeryloxy-l, 4-pre- gnadien-3.20-dione,

9a-chloro-11ß-hydroxy-21-propionyloxy-17a-valeryloxy-l, 4-pre-gnadien-3,20-dione,

17a-benzoyloxy-9a-chloro-11ß-hydroxy-21-propionyloxy-l, 4-pre-35-gnadien-3,20-dione,

21-benzoyloxy-9a-chloro-lß-hydroxy-17a-propionyloxy-l, 4-pre-gnadien-3,20-dione,

17a, 2 l-dibutyryloxy-9a-chloro-l 1β-hydroxy-1,4-pregnadiene-3,20-dione, w

17a-butyryloxy-9a-chloro-lß-hydroxy-21-isobutyryloxy-l, 4-pre-gnadien-3,20-dione,

21-butyryloxy-9a-chloro-11ß-hydroxy-17a-isobutyryloxy-l, 4-pre-gnadien-3,20-dione,

17a-butyryloxy-9a-chloro-11ß-hydroxy-21-valeryloxy-l, 4-pregna- «diene-3.20-dione,

21-ButyryIoxy-9a-chloro-11ß-hydroxy-17a-valeryloxy-l, 4-pregna-diene-3,20-dione,

17a-benzoyloxy-21-butyryloxy-9a-chloro-11ß-hydroxy-l, 4-pregna-diene-3,20-dione, see above

21-benzoyloxy-17a-butyryloxy-9a-chloro-1 lß-hydroxy-1,4-pregna-diene-3,20-dione,

9a-chloro-lß-hydroxy-17,21-diisobutyryloxy-1,4-pregnadiene-3,20-dione and

9a-Chlor-11ß-hydroxy-17a, 21-divaleryloxy-l, 4-pregnadiene-3.20-55 dione.

The new 9-chloroprednisolone derivatives are produced according to the invention by attaching to the AIJ '"double bond of a compound of the formula nTr, r i2 60

C = 0

0-

-OR,

(II)

65

where X and R | have the meaning given above. HOC1 accumulates.

The process according to the invention can be carried out under the conditions described in US Pat. Nos. 3678034, 3718671 and 3828083.

As is known, the starting compounds for the process according to the invention can be prepared in a simple manner and in high yields from prednisolone, which in turn can be synthesized relatively easily from diosgenin. The result of this is that the new compounds can be prepared from diosgenin in a total yield of approximately 15% with relatively little effort. In contrast, the syntheses of the well-known highly effective corticoids from diosgenin are much more complex and the overall yields achieved are significantly lower (approx. 0.5 to 5%). In view of the growing difficulties in procuring suitable starting products for corticoid synthesis in sufficient quantities and in view of the high active ingredient costs with which corticoid-containing pharmaceutical specialties are burdened, this is not without significance.

As already mentioned, the compounds produced according to the invention have strong anti-inflammatory activity when applied topically, but are only very weakly effective when applied systemically.

The pharmacological properties of the new compounds were determined using the following tests:

A) Anti-inflammatory activity when applied locally to the rat ear:

The substance to be tested is dissolved in an irritant consisting of 4 parts of pyridine, 1 part of distilled water, 5 parts of ether and 10 parts of a 4% essential croton oil solution. This test solution is used to impregnate felt strips that were attached to the inside of a specimen tweezers and press them lightly onto the right ear of male rats weighing 100 to 160 g for 15 seconds. The left ear remains untreated and serves as a comparison. Three hours after the application, the animals are killed and 9 mm discs are punched out of their ears. The difference in weight between the disc of the right ear and that of the left ear is a measure of the edema formed.

The dose of test substance is determined at which a 50% inhibition of edema formation is observed after three hours.

B) Anti-inflammatory activity with subcutaneous application to the rat paw:

SPF rats weighing 130 to 150 g are injected into the right hind paw to produce an inflammatory focus with 0.1 ml of a 0.5% Mycobacterium butyricum suspension (available from the American company Difko). The rat's paw volume is measured before the injection. 24 hours after the injection, the paw volume is measured again to determine the extent of the edema. The rats are then injected subcutaneously with different amounts of the test substance, dissolved in a mixture of 29% benzyl benzoate and 71% castor oil. After another 24 hours, the paw volume is determined again.

The control animals are treated in the same way, with the difference that they are injected with a test substance-free benzyl benzoate-castor oil mixture.

The amount of test substance required to achieve a 50% healing of the paw edema is determined in the usual way from the paw volumes obtained.

C) Thymolytic effect after oral application:

SPF rats weighing 70 to 110 g are adrenalectomized under ether anesthesia. 6 animals form one each

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Test group. which each receive a defined amount of test substance orally over 3 days.

On the fourth day, the animals are sacrificed and their thymus weight determined. The control animals are treated in the same way, but are given a benzyl benzoate-castor oil mixture without test substance. The amount of test substance in which 50% thymolysis is observed is usually determined from the thymus weights obtained.

In these tests, the structurally analogous 9-chloroprednisolone and its 21-acetate and the beclomethasone 17.21 dipropionate (= 9a-chloro-11β-hroxroxv-16ß-methyl-l7a.21-dipropionyloxy-l, 4-pregnadiene- 3.20-dione).

The results obtained in these tests are shown in the table below:

No.

substance

ED ^ i in mg / kg

A) Rat ear test

B) Adjuvant-edema test

C) Thymolysis test

I.

9a-chloro-l 1β, 17a, 21-trihydroxy-l, 4-pregnadiene-3,20-dione

1.4

6.3

0.4

II

21 - Acetoxy-9a-chloro-11β, 17a-dihydroxy-1,4-pregnadiene-3,20-dione

1.5

6.0

0.6

III

9 "-Chlor-11ßhydroxy-16ß-methyl-17a, 21-dipropionyloxy-l, 4-pregnadien-3,20-dione

1.4

> 30

2.0

IV

17a-acetoxy-9a-chloro-11ß, 21-dihydroxy-l, 4-pregnadiene-3,20-dione

0.16

> 30

9.5

V

9a-chloro-11ß, 21dihydroxy-17a-propionyloxy-l, 4-pregnadiene-3,20-dione

0.45

30th

4.8

VI

21 - Acetoxy-9a-chloro-11β-hydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione

0.026

25th

4.8

VII

21-Acetoxy-17a-benzoyloxy-9a-chloro-11β-hydroxy-1,4-pregnadiene-3,20-dione

1.5

> 30

VIII

17a-benzoyloxy-9a-chloro-11ß-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione

1.5

> 30

. Similar results are obtained if the pharmacological activity of the 9-chloroprednisolone derivatives which can be prepared according to the invention is determined with the aid of the known vasoconstriction test or the known sodium-potassium retention test. 35

The new compounds are suitable in combination with the vehicles commonly used in pharmaceutical pharmacy for the local treatment of contact dermatitis, various types of eczema, neurodermatoses, erythroderma, burns, pruritis vulvae et ani, rosacea, erythematode cutaneus, Psoria-40 sis. Lies ruber planus et verrucosus and similar skin diseases.

The pharmaceutical specialties can be produced in the usual way by converting the active ingredients into the desired application form, for example: 45 solutions, lotions, ointments, creams or plasters, with suitable additives. In the pharmaceuticals formulated in this way, the active substance concentration depends on the form of administration. In the case of lotions and ointments, an active substance concentration of (), (! Ul% to 1%) is preferably used

In addition, the new compounds, if appropriate in combination with the usual carriers and auxiliaries, are also well suited for the production of inhalants which can be used for the therapy of allergic diseases of the respiratory tract, such as bronchial asthma or rhinitis 55.

The following examples serve to explain the invention.

Example 1 50

a) 25 g 1 lß, 17a, 21-trihydroxy-l, 4-pregnadiene-3,20-dione are reacted with butyric anhydride, processed and 23.1 g21-butyryloxy-llß, 17a-dihydroxy-l, 4-pregnadiene are obtained -3.20-dion.

65

b) In a suspension of 24 g of copper (I) chloride in 480 ml of absolute tetrahydrofuran, 100 ml of 5% ethereal methylene chloride solution are added dropwise under argon at 0 ° C. Then you cool it

Mixture to -30 ° C and a solution of 22.3 g of 21-butyryloxy-1 let. 17a-dihydroxy-1,4-pregnadiene-3,20-dione. The mixture is stirred for 4 hours until the 1ß-hydroxy-17a, 21- (l-hydroxybutylidenedioxy) -l, 4-pregna-diene-3,20-dione that is formed is rearranged. Then aqueous ammonium chloride solution is added to the reaction mixture, extracted with methylene chloride, the organic phase is washed, concentrated in vacuo and 20.3 g of 17a-butyryloxy-11, 21-dihydroxy-1,4-pregnadiene-3.20- are obtained. dion as a raw product.

c) 20 g of the crude product obtained are reacted with acetane hydride, processed and 14.2 g of 21-acetoxy-17a-butyryloxy-1-beta-hydroxy-1,4-pregnadiene-3,20-dione are obtained.

d) 5.4 ml of methanesulfonic acid chloride are added dropwise at room temperature to a solution of 10 g of 21-acetoxy-17a-butyryloxy-11ß-hydroxy-l, 4-pregnadiene-3,20-dione in 50 ml of dimethylformamide and 11 ml of pyridine. The reaction mixture is stirred at 85 ° C. for two hours, poured into ice water after cooling, worked up as described in Example 3 and 6.5g21-acetoxy-17a-butyryloxy-1,4,9 (II) - is obtained. pregnatrien-3,20-dione as a crude product.

e) 6 g of the crude product thus obtained are suspended in 80 ml of dioxane, and 5.6 g of N-chlorosuccinimide are added. Then, within 10 minutes at 20 ° C, 42 ml of a 10% aqueous solution of perchloric acid is dropped into the mixture, stirred for 3 hours at 20 ° C, and poured into a solution of 2.5 g of sodium bisulfite in 400 ml of water. The product which has separated out is filtered off with suction, processed as described in Example 3, and 3.1 g of 21-acetoxy-17a-butyryloxy-9a-chloro-11β-hydroxy-1.4-pregnadiene-3.20-dione are obtained. Melting point 215 ° C.

Example 2

a) 9.5 g of 17a-butyryloxy-lß, 21-dihydroxy-l, 4-pregnadiene-3.20-dione crude product, prepared according to example lb, are reacted with trimethylacetic anhydride, processed and obtained

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6.3 g of 17a-butyryloxy-1-beta-hydroxy-21-trimethylacetoxy-1, 4-pre- conditions of Example le were reacted, processed and gnadien-3,20-dione. receives 1.8 g of 9a-chloro-11ß-hydroxy-17a, 21-divaleryloxy-l, 4-pregna-

dien-3.20-dione. Melting point 254 ° C.

b) 6.0gl7a-butyryloxy-11β-hydroxy-21-trimethylacetoxy-1,4-

pregnadiene-3,20-dione are, according to example ld, with methanesulfs example 5

Fonic acid chloride reacted, processed and 3.4 g of 17a are obtained. A) A suspension of 5.6 g of 21-fluoro-17a-hydroxy-1,4,9 (11) -butyryloxy-21-trimethylacetoxy-1,4,9 (1 l) -pregnatrien-3.20- pregnatrien-3.20-dione in 80 ml diethylene glycol dimethyl ether dione as a crude product. is mixed with 10 g of N, N-dimethylaminopyridine and 6.4 ml of acetane

Drid stirred at 80 ° C for 6.5 hours. The reaction mixture is c) 3.0 g of the crude product obtained are diluted under the io with methylene chloride and washed with 2N hydrochloric acid. Conditions of Example le implemented, processed and after steam distillation, the mixture is extracted with methy-obtainable, lgl7a-butyryloxy-9a-chloro-11ß-hydroxy-21-trimethyl-lene chloride, dried over sodium sulfate and isolated after the acetoxy-1,4,4 pregnadien-3,20-dione. Melting point 259 ° C. Evaporation 6.7g 17a-acetoxy-21-fluoro-l, 4.9 (ll) -pregnatrien-

3.20-dione.

Example 3 15

a) 14.1 g of 17a-butyryloxy-11ß, 21-dihydroxy-l, 4-pregnadiene- b) 2 g of the above crude product are dissolved in 20 ml of dioxane treated analogously to Example le with N-chlorosuccinimide. The enanthic anhydride is reacted, processed and 8.2 is obtained. The reaction product is purified on 220 g of silica gel with g of 17a-butyryloxy-21-heptanoyloxy-11ß-hydroxy-l, 4-pregnadiene - a methylene chloride-acetone gradient (0-10% Acetone). 3.20-dion. 20 yield l, 3gl7a-acetoxy-9a-chloro-21-fluoro-11ß-hydroxy-l, 4-

pregnadien-3,20-dione. Melting point 232 ° C (dec.). [a] n = + 52 °

b) 7.6g 17a-butyryloxy-21-heptanoyloxy-11ß-hydroxy-1,4- (chloroform). UV: £ 139 = 15100 (methanol). pregnadiene-3,20-dione are reacted under the conditions of Example ld, processed and 3.9 g of 17a-Example 6 are obtained. Butyryloxy-21-heptanoyloxy-1,4,9 (ll) -pregnatrien-3,20-dione 25 2g21-fluoro-17a-propionyloxy-l, 4.9 (ll) -pregnatrien-3.20-as a crude product. dione, prepared analogously to Example 5a from 21-fluoro-17a-hydroxy

1,4,9 (1 l) -pregnatrien-3,20-dione and propionic anhydride,

c) 3 g of the crude product thus obtained are reacted under the conditions of Example le with N-chlorosuc conditions of Example le with N-chlorosuccinimide, reacted cinimid. The crude product is prepared on 220 g of silica gel and 950 mg of 17a-butyryloxy-9a-chloro-21-30 is obtained in a methylene chloride-acetone gradient (0-10% acetone) heptanoyloxy-11ß-hydroxy-l, 4-pregnadiene- 3.20-dione. cleaned. Yield 1.24 g of 9a-chloro-21-fluoro-11ß-hydroxy-17a

propionyloxy-1,4-pregnadiene-3,20-dione. Melting point 221 ° C Example 3 (dec.). [a] d = + 48 ° (chloroform). UV: e2.-w = 15500 (methanol).

a) Under the conditions of Example 1b, 20 g

1 lß, 17a-Dihydroxy-21-valeryloxy-l, 4-pregnadien-3,20-dione with 35 Example 7

Lithium dimethyl cuprate reacted, processed and obtained 1.5 g of 17a-butyryloxy-21-fluoro-l, 4.9 (1 l) -pre-

18.6 g llß, 21-dihydroxy-17a-valeryloxy-l, 4-pregnadiene-3.20-gnatrien-3.20-dione, prepared analogously to Example 5a from 21-fluorodione as the crude product. 17a-hydroxy-l, 4,9 (ll) -pregnatrien-3,20-dione and butyric acid

hydride, with N-chlorosuccinimide analogous to example le. The Reini-

b) 18 g of the crude product obtained are reacted with propionic acid 40 g of the crude product on 150 g of silica gel with a reanhydride, processed and 10.8 g of 1 lß-methylene chloride-acetone gradient (60-10% acetone). From Hvdroxy-21-propionyloxy-17a-valeryloxy-l, 4-pregnadiene-3.20-loot 840 mg of 17a-butyryloxy-9a-chloro-21-fluoro-l lß-hydroxy-1,4-dione. pregnadien-3,20-dione.

c) 9glß-hydroxy-21-propionyloxy-17a-valeryloxy-l, 4-pre-45

Gnadiene-3,20-dione are made under the conditions of Example 8

1 d reacted with methanesulfonic acid chloride, processed and analogous to Example 5a, 5 g of 21-fluoro-17a-hydroxy-

4.9g21-propionyloxy-17a-valeryloxy-l, 4.9 (ll) -pre-l, 4.9 (ll) -pregnatrien-3.20-dione and isobutyric anhydride 4.8 are obtained

gnatrien-3,20-dione as a crude product. g21-fluoro-17a-isobutyryloxy-l, 4,9 (ll) -pregnatrien-3,20-dio'n so, which, under the conditions of Example le, with N-chlorosuc-

d) 4.0 g of the crude product obtained are reacted under the 'cinimid. The crude product is reacted to 350 g of conditions from Example le, processed and silica gel with a methylene chloride-acetone gradient is obtained 1.4 g of 9a-chloro-11β-hydroxy-21-propionyloxy-17a-valeryl- (0-10% acetone ) cleaned. Yield 3.5 g of 9a-chloro-21-fluorine

oxy-1.4-pregnadiene-3.20-dione. Melting point 242 ° C. 1 lß-hydroxy-17a-isobutyryloxy-l, 4-pregnadiene-3,20-dione.

55

Example 4

a) 17.2 g llß, 21-dihydroxy-17a-valeryloxy-l, 4-pregnadiene

3.20-dione crude product are reacted with valeric anhydride.

sets, processed and 9.7 g of 11β-hydroxy-17a, 21- ^,

divaleryloxy-l, 4-pregnadiene-3,20-dione. 60 pharmaceutical preparations

A. Composition of an ointment b) 8 g of 1 lß-hydroxy-17a, 21-divaleryloxy-l, 4-pregnadiene-3.20-0.03% 21-acetoxy-9a-chloro-11ß-hydroxy-17a-propionyloxy- 1, 4-dione under the conditions of Example ld with pregnadiene-3,20-dione

Methanesulfonic acid chloride reacted, processed and 2.50% allercurhexachlorophenate, micronized, particle size obtained 4.6 g 17a, 21-divaleryloxy-l, 4.9 (ll) -pregnatrien-3.20-dione 65 approx. 8 u. (Allercur = registered trademark for 1-p-chloro as a crude product. Benzyl-2-pyrrolidyl-methyl-benzimidazole)

6.00% Hostaphat KW 340 (R) (tert. Ester from O-phosphoric acid c) 4.5 g of the crude product obtained are under the and wax alcohol tetra-glycol ether)

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0.10% sorbic acid

10.00% neutral oil (Migloyol 812 (R |)

3.50% steary alcohol

1.50% wool fat, anhydrous DAB 6

76.36% demineralized water

B. Preparation of an inhalation agent 1,000 g micronized 21-acetoxy-9a-chloro-11ß-hydroxy-17a-propionyloxy-l, 4-pregnadiene-3,20-dione (average grain size less than 7 n and 39,000 g of ground lactose are mixed, s A dose of 20 mg inhalant is used per inhalation.

M