DE2645105C2 - Derivatives of 9-chlorprednisolone, process for their preparation and pharmaceutical preparation containing them - Google Patents

Description

, iv? wherein R _{3 is} a hydrogen atom or an alkyl group having 1 to 7 carbon atoms or a pbenyl

Ii; group and R _{2 represent} an alkyl group containing 1 to 4 carbon atoms, cleaves hydrolytically,

p or

ρ d) for the preparation of 9-chlorprednisolone derivatives of the general formula I with X meaning

te of a chlorine atom, an alkanoyloxy group or a benzoyloxy group, a 9-chloro derivative of the general

ϊ | my formula Ia

I.

Ϊ ^H0 A

where R | has the abovementioned meaning, chlorinated or esterified in the 21 position.

3. Pharmaceutical preparation, characterized in that it is a 9a - chlorprednisolone derivative as active ingredient according to claim 1 contains.

The invention relates to the subject matter characterized in the patent claims.

The 9-chlorprednisolone (= 9a-chloro-llj &, 17 «, 21-trihydroxy-1,4-pregnadiene-3,20-dione) has been around for a long time known. (J. Amer. Chem. Soc, 77,1955,4181). This corticosteroid is used as an active ingredient in pharmaceutical preparations, which are used for the topical treatment of inflammatory diseases, unsuitable because it is very strong systematic Has effects.

It has been found that hitherto unknown derivatives of 9-chlorprednisolone are systematically almost ineffective are, but surprisingly when applied topically: have a strong anti-inflammatory effect, which usually exceeds that of the most effective commercial corticoids.

The new 9-chlorprednisolone derivatives contain R as the alkanoyloxy group or X as the alkanoyloxy group in each case 1 to 8 carbon atoms, for example a group which is different from a straight-chain or branched one Fatty acids, such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, Valeric acid, isovaleric acid, trimethyl acetic acid, caproic acid, tert-butyl acetic acid or caprylic acid.

Particularly preferred alkanoyl groups R, and alkanoyloxy groups X are those which differ from a 2 to 6 Derive alkanecarboxylic acid containing carbon atoms.

The process according to the invention for the preparation of the 9-chlorprednisolone derivatives according to the process variants a, b and d can be carried out under the conditions described in U.S. Patents 3,678,034, 37 18 671 and 38 28 083 are described. The process according to the invention according to process variant c can among those in US Pat. No. 3,152,154 and in German Offenlegungsschriften 23 40 591 and 20 55 221 conditions described are carried out.

The starting compounds for the process according to the invention can, as is known, in a simple manner and can be produced in high yields from prednisolone, which in turn is relatively easily synthesized from diosgenin can be. This has the consequence that the connections according to the invention with relatively little effort can be produced from diosgenin in a total yield of approx. 15%. In contrast, they are Syntheses of the well-known, highly effective corticoids from diosgenin are much more complex and the ones achieved Overall yields significantly lower (approx. 0.5 to 5%). This is in view of the growing difficulties

to procure suitable starting materials for the corticosteroid syntheses in sufficient quantities and with a view to on the high drug costs with which corticosteroid-containing drug specialties are burdened, not without Meaning.

As already mentioned, the compounds according to the invention have a when applied topically strong anti-inflammatory effectiveness, but are only very weakly effective with systemic application. The pharmacological properties of the compounds were determined using the following tests:

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

The substance to be tested is placed in an irritant consisting of 4 parts of pyridine, I part of distilled water, Dissolved 5 parts of ether and 10 parts of a 4% essential croton oil solution. Be with this test solution Felt strips attached to the insides of microscope slide tweezers, soaked and these under light Pressure applied for 15 seconds to the right ear of male rats weighing 100 to 160 g. The left ear is left untreated and is used as a comparison. Be three hours after application the animals were killed and 9 mm discs were punched out of their ears. The weight difference between the Disc of the right and that of the left ear is a measure of the formed edema.

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

B) Anti-inflammatory activity when administered subcutaneously to the rat paw

SPF rats weighing 130 to 150 g are injected with 0.1 ml of a 0.5% Mycobacterium butyricum suspension (available from the American company Difko) into the right hind paw to create a focus of inflammation. The paw volume of the rats 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. The paw volume is determined again after a further 24 hours.
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.

From the paw volumes obtained, the amount of test substance is determined in the usual way, soft is required to achieve 50% healing of the paw edema.

C) Thymolytic effect after subcutaneous application

SPF rats weighing 70 to 110 g are adrenalectomized under ether anesthesia. 6 animals form each a test group, each of which is given a defined amount of test substance orally over a period of 3 days. On the fourth day the animals are sacrificed and their Thy .nus weight is determined. The control animals are in the Treated in the same way, but obtained a benzyl benzoate-castor oil mixture without test substance. From the obtained thymus weights is determined in the usual way the amount of test substance at which a 50% Thymolysis is observed.

The comparative substances used in these tests were the structurally analogous 9-chlorprednisolone and its 21-acetate as well as beclomethasone-P ^ l-dipropionate (= 9ur-chloro-11 ^ -hydroxy-16 _/ β-methyl-17u ', 21-dipropionyIoxy-1 , 4-pregnadiene-3,20-dione).

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

No substance

I 9ff-chlorine-l l> S, 17ur, 21-trihydroxy-1,4-pregnadiene-3,20-dione

II 21-acetoxy-9ff-chloro-l l / ^ nff-dihydroxy-l ^ -pregnadiene-3,20-dione

III 9a - chloro-lljß-hydroxy-16 ./? -Methyl-17a ', 21-dipropionyloxy-1,4-pregnadiene-3,20-dione

IV Ha-acetoxy ^ a-chloro-1 ljS, 21-dihydroxy-1,4-pregnadiene-3,20-dione

V 9ff-ChloΓ-ll / ?, 21-dihydroxy-17 / ^ pΓopionyIoxy-1,4-pregnadiene-0.45
3,20-dione

VI 21-Acetu ': y-9e-chlor-l lyMiydroxy-nar-propionyloxy-l ^ - pregnadiene-3,20-dione

ED50 in mg / kg
A) rat
eartcst B) adjuvant
Edema test C) Ti-.ymo
lyseiest 1.4
1.5 6.3
6.0 0.4
0.6 1.4 > 30 2.0 0.16 > 30 9.5 0.45 30th 4.8 0.026 25th 4.8

continuation

No. Substance ED50 in mg / kg

A) RuItCn- B) Adjuvant- C) Ihymoohrlcst Edema test lysclcst

VII 2l-Acctoxy-l7tf-benzoyloxy-9tf-chloι ■ -lI / ^ - hyαΓo.xy-l, 4- 1,5 > 3ü 3.2 pregnadiene-3.20-dione

VIII IVff-Benzoyloxy ^ a-chloro-ll.ß-hydroxy ^ l-propionyloxy-l ^ - 1.5 > 30 5.0 pregnadiene-3.20-dione

IX ^ l-dichloro-lljS-hydroxy-iTa-propionyloxy-l ^ -pregnadiene-0.09 28 4.6 J, 20-dione

Similar results are obtained if one considers the pharmacological effectiveness of the invention 9-chlorprednisolone derivatives with the help of the well-known vasoconstriction test or the well-known sodium potassium retention tests determined.

The new compounds are suitable in combination with the carriers customary in galenic pharmacy for the local treatment of contact dermatitis, various types of eczema, neurodermatoses, Erythnxlermic, burns. Pruritis vulvae et ani, rosacea, cutaneous erythematosus, psoriasis, Liehen ruber planus et verrucosus and similar skin diseases.

The pharmaceutical specialties are produced in the usual way by mixing the active ingredients with suitable Additives in the desired form of application, such as: solutions, lotions, ointments, creams or pilasters. In the pharmaceuticals formulated in this way, the concentration of the active substance depends on the form of application addicted. For lotions and ointments, an active ingredient concentration of 0.001% to 1% is preferred used.

In addition, the new compounds are optionally in combination with the customary carriers and Hill'sstolTe are also well suited for the production of inhalants, which are used in the therapy of allergic Respiratory diseases such as bronchial asthma or rhinitis can be used.

The following examples serve to illustrate the invention.

I syntheses

Example I.

a) 5.0 g of 9ü-chlorine-li. / i, 17tf. 21-trihydroxy-1,4-pregnadiene-3.20-dione are treated with 500 ml of benzene, 40 ml of dimethylformamide and 500 mg of absolute pyridine tosylate. The mixture is heated, 50 ml of solvent are distilled off at a bath temperature of 130.degree. C., 60 ml of triethyl orthobenzoate are added and the remaining benzene is ^{distilled off within 2:} / _{: hours.} 2.4 ml of pyridine are added to the residue, the mixture is concentrated in vacuo and the nff ^ Ml-ethoxy-benzylidene-dioxyi ^ e-chloro-III / mydroxy-M-pregnadiene-3,20-dione is obtained as an oily crude product.

b> The crude product obtained is mixed with 150 ml of methanol, 54 ml of 0.1 η aqueous acetic acid and 6 ml of 0.1 n aqueous Sodium acetate solution is added and the mixture is refluxed for 90 minutes. The reaction mixture is then concentrated in vacuo, the residue is treated with water and extracted with ethyl acetate. the The organic phase is washed with water and concentrated in vacuo, and the residue is chromatographed Purified over a silica gel column, recrystallized from acetone-hexane, and 3.7 g of 17σ-Βεη-zoyioxy-9a-chloro-1 are obtained 1,21-dihydroxy-M-pregnadiene-3,20-dione, melting point 216 ° C (decomposition).

Example 2

0.5 g of 17 (7-BCnZOyIOXy ^ a-ChIOr-I ljS, 21-dihydroxy-1,4-pregn2diene-3,20-dione are stirred with 10 ml of formic acid for 24 hours at room temperature. The reaction mixture is then poured into Ice water, extracted with dichloromethane, washes the organic phase, dries it over sodium sulfate, concentrates it in vacuo and receives 400 mg of n ^ Benzoyioxy ^ chlor ^ l-formyloxy-ll.yS-hydroxy-M-pregnadiene ^ O-dione as glassy solidifying mass.
\ a \ i = + 58 ° (chloroform).

Example 3

17 ml of pyridine and 8.0 ml of acetic anhydride are added to 1.5 g of 17 ^ benzoyloxy-9 ^ chior-iijyi-dihydroxy-1,4-pregnadiene-3,20-dione and the mixture is ^{stirred at 0 °} C. for one hour. The reaction mixture is then poured into ice water, the precipitated product is filtered off, it is dissolved in dichloromethane, the organic phase is washed, dried with sodium sulfate and concentrated in vacuo. The residue is by means of methylene chloride-Ace-

ton gradient over a silica gel column chromatography, recrystallized from acetors-hexane and obtained 1.2 g of 21-acetoxy-17a-benzoyloxy-9α-chloro-lljö-hydΓoxy-1,4-pregnadiene-3,20-dione, melting point 221 ° C (Decomposition).

Example 4

17 ml of pyridine and 8.0 ml of propionic anhydride are added to 1.5 g of 17a-benzoyloxy-9a-chloro-ljß, 21-dihydroxy-l, 4-pregnadiene-3,20-dione and at ⁰ ° C. for one hour touched. The reaction mixture is worked up as described in Example 3 and 960 mg of 17a-benzoyloxy-9a-chloro-l l /? - hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione with a melting point of 226 ° C. is obtained (Decomposition).

Example 5

2.3 g of 17ff-benzoyloxy-9ff-chloro-1 \ ß, 2 1 -dihydroxy-1,4-pregnadiene-3,20-dione are added to 50 ml of pyridine and 25 ml of butyric anhydride and the mixture is stirred for 16 hours at room temperature. The reaction mixture is worked up as described in Example 3 and 2.0 g of na-benzoyloxy ^ l-butyryloxy ^ a-chloro-lljS-hydroxy-1,4-pregnadiene-3,2ö-dione with a melting point of 22crC (decomposition) are obtained .

Example 6

2.3 g of 17T-benzoyloxy-9ff-chloro-l 1> 5,21-dihydroxy-1,4-pregnadiene-3,20-dione are added to 50 ml of pyridine and 25 ml of valeric anhydride and for 16 hours at room temperature touched. The reaction mixture is worked up as described in Example 3 and 1.63 g of Na-benzoyloxy ^ a-chloro-llyJ-hydroxy-l ^ lvaleryloxy, 4-pregnadiene-3,20-dione of melting point 208 ⁰ C.

Example 7

2.3 g of 170-BCnZOyIoXy ^ a-ChIOr-1 ljß, 21-dihydroxy-1,4-pregnadiene-3,20-dione are in 50 ml of pyridine and 25 ml Trimethylacetic anhydride was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture is worked up as described in Example 3, and 1.72 g of na-benzoyloxy ^ ar-chloro-ljö-hydroxy-2 l-trimethylacetoxy-M-pregnadiene ^^ O-dione are obtained of melting point 236 ° C.

Example 8

2.3 g of 17ff-benzoyloxy-9ff-chior-ll _ / ?, 21-dihydroxy-1,4-pregnadiene-3,20-dione are mixed with 50 ml of pyridine and 25 ml of isobutyric anhydride and stirred for 16 hours at room temperature. The reaction mixture is worked up as described in Example 3, and 2.1 g of ha-benzoyloxy-α-chloro-ljS-hydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20-dione are obtained as a glassy mass.
[a] " = + 68 ° (chloroform).

Example 9

2.3 g of na-benzoyloxy ^ a-chlor-lljff ^ l-dihydroxy-l ^ -pregnadien ^^ O-dione are mixed with 50 ml of pyridine and 20 ml of isovaleric acid chloride and ^{stirred at 0 °} C. for 2 hours. The reaction mixture is worked up as described in Example 3, and 2.1 g of 17c-renzoyloxy-9a-chloro-l, S-hydroxy-21-isovaleryloxy-1,4-pregnadiene-3,20-dione with a melting point are obtained 197 ° C.

Example 10

2.3 g of Pa-benzoyloxy ^ a-chloro-ljS, 21-dihydroxy-1,4-pregnadiene-3,20-dione are added to 50 ml of pyridine and 30 ml of enanthic anhydride and the mixture is stirred for 16 hours at room temperature. The reaction mixture is poured into ice water, heated and the excess enanthic acid is removed by steam distillation. It is then extracted with dichloromethane, the organic phase is worked up as described in Example 3, and 2.03 g of na-benzoyloxy ^ a-chloro ^ l-heptanoyloxy-lljS-hydroxy-l ^ -pregnadienO ^ O-dione is obtained as an oily Product.
Mb ⁵ = + 64 ° (chloroform).

Example Il

2.3 g of na-benzoyloxy ^ a-chloro-II / J ^ l-dihydroxy-M-pregnadienO ^ O-dione are mixed with 45 ml of pyridine and 1 ml of benzoyl chloride was stirred for one hour at room temperature. The reaction mixture is worked up,

as described in Example 3 and receives 2.5 g of 17ff, 21-Diben / oyloxy-9 (/ - chk ■ '-! l.ye-hydroxy-M-pregnadiene-S ^ O-dione of melting point 221 ° C.

B e i s ρ i e I 12

a) 7.5 g of 9a-chloro-l iß, I 7 (r-2l-trihydroxy-1,4-pregnadicn-3,20-dione are reacted with triethyl orthoacetate under the conditions described in Example 1a and worked up .21- (l-ethoxy-äthylidendioxy) -9a - chlorine-l./?-hydroxy-l,4-pregnadiene-3,20-dione as an oily crude product.

b) The crude product thus obtained is reacted and worked up under the conditions described in Example 1b and 5.2 g of Hir-Acetoxy ^ a-chloro-l l //, 21-dihydroxy-l, 4-pregnadiene-3,20-dione vom Melting point 2O5 ° C (decomposition).

B e i s ρ i e I 13

1.0 g of l7ff-acetoxy-9 (/ - chloro-l./i,21-dihydroxy-l,4-prcgnadien-3,20-dione is mixed with 20 ml of pyridine and 5 ml Acetic anhydride is added and the mixture is stirred at room temperature for one hour. The reaction mixture is then poured in ice water, sucks the separated product off, dissolves it in dichloromethane, and washes the organic phase and constricts it in a vacuum. The residue is recrystallized from acetone-hexane and 860 mg are obtained 17cr, 2l-diacetoxy-9ä'-chloro-ljff-hydroxy-1,4-pregnadiene-3,20-dione, melting point 222 ° C (decomposition).

Example 14

Under the conditions of Example 4, 1.0 g of 17U-aceioxy-9a-chloro-l 1 ^, 2l-dihydroxy-l ^ -pregnadiene-3,20-dione is reacted with propionic anhydride, worked up and 940 mg of ne-acetoxy are obtained ^ cr-chloro-l \ ß hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione, melting point 219 ° C (decomposition).

Example 15

Under the conditions of Example 6, 1.0 g of ntf-acetoxy ^ tf-chloro-l1 ^, 21 -dihydroxy-1,4-pregnadiene-3,20-dione is reacted with valeric anhydride, and 660 mg of 17a are obtained - acetoxy-9-chloro-α 1 \ ß hydroxy-21-valeryloxy-l, 4-pregnadiene-3,20-dione of melting point 220 ⁰ C (decomposition).

Example 16

a) Under the conditions of Example 1 a, 7 g9a-chlorine-lje.ncr ^ l-trihydroxy-l ^ -pregnadiene ^^ O-dione reacted with triethyl orthopropionate, processed and obtained 17a.21- (l -. <\ thoxy-

• ^: propylidendioxy) -5a-chloro-lljff-hydroxy-1,4-pregnadiene-3,20-dione as a crude product.

b) The crude product obtained is reacted and worked up under the conditions described in Example 1b, and 2.9 g of 9a-chlorine-11, 21-dihydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione with a melting point are obtained 181 ⁰ C (decomposition).

: Example 17

Under the conditions described in Example 2, 1,2g9a-chloro-117?, 21-dihydroxy-17 <z-propionyl- so oxy-l, 4-pregnadiene-3,20-dione reacted with formic acid, processed and you get 400 mg of oily 9a-chlorine ; 21-formyloxy-11J5-hydroxy-17fl-propionyloxy-1,4-pregnadiene-3,20-dione.

ί [a]}, ⁵ = + 67 ° (chloroform).

1

£ Example 18

'. $ 700 mg of 9a-chloro-ll /, 21-dihydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione are as in Example 3

|; described reacted with acetic anhydride, prepared and obtained 32C mg of 21-acetoxy-9cr-chloro-ljß-hydro-

% xy-nff-propionyloxy-l ^ -pregnadien-S ^ O-dione of melting point 210 ° C (decomposition).

8 Example 19

% 700 mg 9ff-Ch! Or-Ilj3,2! -Dihydroxy-17u-propiony! Oxy-1, 4-pregnadiene-3,20-dione are

Il game 4 conditions described are reacted with propionic anhydride, processed and 420 mg are obtained

[ti 9a-chlorine-ll /? - hydroxy-17ar, 21-dipropiony! oxy-l, 4-pregnadiene-3,20-dione with a melting point of 215 ° C (Zcrset-

Example 20

mg of 9 ″ -chlorine-l Le ^ l-dihydroxy-Hrt-propionyloxy-l ^ -pregnadiene-S ^ O-dione are reacted under the conditions described in Example 5 with Br.ttersäureanhydrid, worked up and 360 mg of 21-butyryloxy are obtained -9ff-chloro-ll ^ -hydroxy-17II-propionyloxy-l, 4-pregnadiene-3,20-dione from Schmefrnunkt 208 ⁰ C (decomposition).

Example 21

Under the conditions of Example 6, 700 mg of Qa-chloro-lLe ^ l-dihydroxy-na-propionyloxy-l ^ - pregnadiene-3,20-dione are reacted with Vaierian anhydride, processed and 520 mg of 9a-chloro-l \ ß are obtained hydroxy-17a: propionyloxy-21-valeryloxy-l, 4-pregnadiene-3,20-dione of melting point 210 ⁰ C (decomposition).

Example 22

3.0 g of 9ff-chlorine-II; / ?, 21-dihydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione are mixed with 30 ml of pyridine and nil Ci-piunsäüieanhydrid added and stirred for 90 minutes at room temperature. The reaction mixture is worked on, as described in Example 3, and receives 2.6 g of 9a-chloro-21-hexanoyloxy-1 ljß-hydroxy-17 apropionyloxy-1 ^ -p

Example 23

Under the conditions of Example 10, 2.1 g of 9ü-chloro-11j8,21-dihydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione are obtained reacted with enanthic anhydride, processed and 1.02 g of 9a-chloro-21-heptanoyloxy-11 / ί-hydroxy-Ha-propionyloxy-M-pregnadiene-S ^ O-dione are obtained.

Example 24

Under the conditions of Example 7, 1.4 g of 9ff-ChloΓ-llJ, 21-dihydroxy-17ff-propionyloxy-1,4-pregnadiene-3,20-dione are reacted with trimethylacetic anhydride, and 670 mg of 9 <r- Chlorine-l \ ß hydroxy-nff-propionyloxy ^ l-trimethylacetoxy-l ^ -pregnadien-S ^ O-dione.

Example 25

a) Under the conditions of Example 20, 25 g of llj (U7a, 21-trihydroxy-1,4-pregnadiene-3,20-dione are added Butyric anhydride is converted and 23.1 g of 21-butyryloxy-1,13,17a-dihydroxy-1,4-pregnadiene-3,20-dione are obtained.

b) 100 ml of 5% ethereal methyllithium solution are added ^{dropwise under argon at 0 °} C. to a suspension of 24 g of copper (l) chloride in 480 ml of absolute tetrahydrofuran. Then the mixture is cooled to -30 ^& C and treated with a solution of 22.3 g 21-BuΓyryloxy-llyß, 17 <^ dihydroxy-l, 4-pregnadiene-3,20-dione. The mixture is stirred for 4 hours until the 1, 18-hydroxy-17ar, 21- (1-hydroxy-butylidenedioxy) -l, 4-pregnadiene-3,20-dione formed has rearranged. The reaction mixture is then aqueous Add ammonium chloride solution, extranate with methylene chloride, wash the organic phase, concentrate it in vacuo and obtain 20.3 g of ne-butyryloxy-lljS ^ l-dihydroxy-l ^ -pregnadiene-S ^ O-dione as a crude product.

c) Under the conditions of Example 3, 20 g of the crude product obtained are reacted with acetic anhydride, prepared and 14.2 g of 21-acetoxy-17α-butyryloxy-lLβ-hydroxy-1,4-pΓegnadiene-3,20-dione are obtained.

d) 5.4 ml of methanesulphonic acid chloride are added to a solution of 10 g of 21-acetoxy-17ffbutyryloxy-II / I-hydroxy-1,4-pregnadiene-3,20-dione at room temperature added dropwise to 50 ml of dimethylformamide and 11 ml of pyridine. The reaction mixture is stirred for two hours at 85 ° C., after cooling it is poured into ice water, works on as described in Example 3 and receives 6.5 g of 21-acetoxy-17a-butyryloxy-1,4,9 (l I) -pregnadiene-3,20-dione as a raw 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. 42 ml of a 10% strength aqueous perchloric acid solution are then added dropwise to ^{the mixture at 20 ° C. over a period of 10 minutes, the mixture is stirred for 3 hours at 20 °} C. and poured into a solution of 2.5 g of sodium hydrogen sulfite in 400 ml of water. The precipitated product is filtered off with suction, as described in Example 3, worked up and 3.1 g of 21-acetoxy-17α · -butyΓyloxy-9ύr-chloro-lljß-hydΓoxy-1,4-pΓegnadiene-3,20-dione are obtained.

Example 26
a) 9.5 g of 17a-butyryloxy-II / ?, 21-dihydroxy-1,4-pregnadiene-3,20-dione crude product, prepared according to the example

25 b, are reacted under the conditions of Example 7 with trimethylacetic anhydride, processed and 6.3 g of ITir-butyryloxy-lljß-hydroxy ^ l-trimethylacetoxy-l ^ -pregnadiene-S ^ O-dione are obtained.

b) 6.0 g of nar-butyryloxy-ll ^ -hydroxy ^ l-trimethylacetoxy-l ^ -pregnadienO ^ O-dione are reacted with methanesulfonic acid chloride under the conditions of Example 25d, worked up and 3.4 g of 17ff-butyryloxy are obtained -21-trimethylacetoxy-1,4,9 (II) -pregnatriene-3,20-dione as crude product. _;

c) 3.0 g of the crude product obtained are reacted and worked up under the conditions of Example 25e and 1.1 g of nff-butyryloxy ^ a-chloro-l ljS-hydroxy ^ l-trimethylacetoxy-l ^ pregnadiene-S ^ O-dione are obtained.

Example 27 K

a) 14.1 g of 17a-butyr> 'loxy-lljff, 21-dihydroxy-1,4-pregnadiene-3,20-dione crude product, prepared according to the example 25 b, is reacted under the conditions of Example 10 with enanthic anhydride, processed and 8.2 g of na-butyryloxy ^ l-heptanoyloxy-lljß-hydroxy-l ^ -pregnadienO ^ O-dione are obtained.

b) 7.6 g of nir-butyryloxy ^ l-heptanoyloxy-ll ^ -hydroxy-l ^ -pregnadiene-S ^ O-dione are under the conditions: According to Example 25d reacted, worked up and 3.9 g of ne-butyryloxy-1-heptanoyloxy-T, 4.9 (II) -pregnatriene-3,20-dione are obtained as a raw product.

c) 3 g of the crude product thus obtained are treated with N-chlorosuccinimide under the conditions of Example 25e implemented, processed and one receives 950 mg ncr-butyryloxy ^ a-chloro ^ l-heptanoyloxy-l 1 / f-hydroy.y-1 ^ -pregnadien-S ^ O-dicn. 2 (

Example 28

a) Under the conditions of Example 25 b, 20 g of 1 l ^ nff-dihydroxy ^ l-valeryloxy-l ^ -pregnadien- 2i 3,20-dione reacted with lithium dimethyl cuprate, worked up and 18.6 g of 1 ljS, 21-dihydroxy-17arvaleryloxy-1,4-pregnadiene-3,20-dione are obtained as a raw product.

b) 18g of the crude product obtained are treated with propionic anhydride under the conditions of Example 4 implemented, processed and 10.8 g of IIjS-hydroxy ^ l-propionyloxy-nar-valeryloxy-M-pregnadiene-3,20-dione are obtained. 3C

c) 9 g lljS-Hydroxy ^ l-propionyloxy-nff-valeryloxy-M-pregnadienO ^ O-dione are used under the conditions of Example 25 d reacted with methanesulfonic acid chloride, worked up and you get 4 g of 21-propionyloxy-17a-valeryloxy-l, 4.9 ( 1 l) -pregnatrien-3,20-dione as crude product.

d) 4.0 g of the crude product obtained are reacted and worked up under the conditions of Example 25e and 1.4 g of 9c-chloro-1Jjß-hydroxy ^ l-propionyloxy-nij-valeryloxy -! ^ • pregnadäcn-S ^ Ö-dione. 3:

Example 29

a) 17.2 g lljS ^ l-dihydroxy- ^ a-valeryloxy-M-pregnadiene-. '^ O-dione crude product are sold under the conditions 4C reactions of Example 6 are reacted with valeric anhydride, processed and 9.7 g of 1 l /? - hydroxy-17a, 21 are obtained -di valery loxy-1 ^ -pregnadienO ^ O-dione.

b) 8 g of H / J-Hydroxy-172r, 21-divaleryioxy-1,4-pregnadiene-3,20-dione are under the conditions of the example Reacted with methanesulfonic acid chloride for 25 days, worked up and 4.6 g of 17a, 21-divaleryloxy-1,4,9 (1st l) -pregnatriene-3,20-dione as a crude product.

c) 4.5 g of the crude product obtained are reacted and worked up under the conditions of Example 25e and 1.8 g of 9ff-Chbr-II /? - hydroxy-17ur, 21-divaleryloxy-1,4-pregnadiene-3,20-dione are obtained.

Example 30

ml Mexamethylphosphorsäuretriamid are added at 0 ⁰ C with 1.3 ml of thionyl chloride and stirred for 30 minutes. Then added to the mixture 800 mg of 17a-acetoxy-9 "-chloro-l ^ 1, 21 dihydroxy-1,4-pregnadiene-3,20-dione are added and stirred for an additional 5 ¹ / h at 0 ⁰ C.

The reaction mixture is worked up as described in Example 3 and 540 mg of 17a-acetoxy-9a, 21-dichloro-1 are obtained l> 8-hydroxy-1,4-pregnadiene-3,20-dione, melting point 222 ° C (decomposition).

Example 31

Under the conditions of Example 30, 1.2 g of 9o-chlorine-l 1 ^ -21-dihydroxy-na-propionyloxy-1,4-pregnadiene-3,20-dione are reacted with thionyl chloride, and 860 mg of 9 are obtained «, 21-dichloro-1 \ ß hydroxy-l7a-propionyloxy-1,4-pregnadiene-3,20-dione with a melting point of 232 ° C.

Example 32
Under the conditions of Example 30, 8.5 g of 17a-benzoyloxy-9fl-chloro-l l ^, 2l-dihydroxy-l, 4-

pregnadiene-3,20-dione converted, processed and 4.1 g of 17a-benzoyloxy-9ir, 21-dichloro-1 l /? - hydroxyl, 4-pregnadiene-3,20-dione with a melting point of 220 ^° C. are obtained.

5 II Pharmaceutical Preparations

Example 1 Composition of an ointment |

0.03% 21-acetoxy-9ff-chloro-II> hydroxy-17ff-propionyloxy-1,4-pregnadiene-3,20-dione 2.50% Allercur hexachlorophenate, micronized, particle size approx. 8 μ (Allercur = registered trademark for l-p-chlorobenzyl ^ -pyrrolidyl-methyl-benzimidazole)

6.00% Hostaphat KW 340 ^IRl (tert. Ester of O-phosphoric acid and wax alcohol tetra-glycol ether) 15 0.10% sorbic acid

10.00% neutral oil (Migloyol 812 ^(RI ) 3.50% stearyl alcohol 1.50% wool fat, anhydrous DAB 76.36% demineralized water

Example 2

si Manufacture of an inhalant |

1,000 g of micronized 21-acetoxy-9a-chloro-ll ^ S-hydroxy-17a'-propionyloxy-1,4-pregnadiene-3,20-dione (mean Grain size smaller than 7 μ) and 39,000 g of milled lactose are mixed. A dose of 20 mg inhalation agent is required per inhalation! applied.

10

Claims (2)

Patent claims: 1. Derivatives of 9-chloro prednisolone of the general formula I CH ₂ X HO (D R _{1 represents} an alkanoyl group having 1 to 8 carbon atoms or a benzoyl group, and X represents a chlorine atom, a hydroxyl group, an alkanoyloxy group having 1 to 8 carbon atoms or a benzoyloxy group. 2. Process for the preparation of derivatives of 9-chlorprednisolone of the general formula I CH ₂ X HO R, denotes an alkanoyl group having 1 to 8 carbon atoms or a benzoyl group and X represents a chlorine atom, a hydroxyl group, an alkanoyloxy group with 1 to 8 carbon atoms, characterized in that one in a known manner a) to the ^ '''double bond of a compound of the general formula II CH ₂ X (Π) wherein X and Rj have the abovementioned meaning, HOCl attaches, or b) the epoxy ring of a compound of the general formula III CH ₂ X (HD gj opens with hydrogen chloride, or % c) for the preparation of 9-chlorprednisolone derivatives of the general formula I with X meaning jg a hydroxyl group, an orthoester of the general formula IV OR ₂ 'ß HO ν y \ r / \ U K.3