DE2809732C2 - Derivatives of 9-fluorprednisolone, process for their production, and pharmaceutical preparations containing these active ingredients - Google Patents

Description

SPF rats weighing 130 to 150 g are used to create a focus of inflammation 0.1 ml of a 0.5% Mycobacterium butyncum suspension (available from the American company Difko) in the right hind paw injected. The paw volume of the rats is measured before the injection. 24 hours after After the injection, the paw volume is measured again to determine the extent of the edema. Then different amounts of the test substance are administered orally to the rats. After further The paw volume is determined again for 24 hours.

From the paw volumes obtained, the amount of test substance is determined in the usual way, which is required to achieve 50% healing of the paw edema. The results obtained in the tests mentioned are shown in the table below:

The new 9-fluorprednisolone derivatives can be prepared by the process according to claim 2 will.

The process according to the invention according to process variant a is carried out under conditions known per se carried out, preferably by the compound of formula III in a with hydrogen fluoride inert solvent converts. Suitable inert solvents are, for example, ethers (diethyl ether, diisopropyl ether, Tetrahydrofuran) organic bases such as pyridine or chlorinated hydrogen (methylene chloride.

No. substance Vasoconstriction test Results
4 hours after
8 hours Adjuvant
Edema test
ED ₅₀ Concentr. 66
75
34 78
76
31 0.07 mg / kg ¹ oa ^ ff-Difluor-l l ^ ß-hydroxy-21-valeryloxy-
1,4-pregnadiene-3,20-dione (= diflucortolone
valerianate) 0.1%
0.001%
0.00001% 74
77
45 80
72
38 2.18 mg / kg ι; 9a, 21-difluoro-ll ^ -hydroxy-16> methyl-
17ir-propionyloxy-1,4-pregnadiene-3,20-dione
(DE-OS 26 13 875) 0.1%
0.001%
0.00001% 78
82
56 72
77
60 4.72 mg / kg HI 9a, 21-difluoro-l l ^ -hydroxy-nff-propionyloxy-
1,4-pregnadiene-3,20-dione 0.1%
0.001%
0.00001%

Chloroform, carbon tetrachloride, tetrachloroethane).

The process according to the invention according to process variant b is also subject to known conditions carried out.

A preferred method for the fluorine exchange of the 21-hydroxy group of the general formula Hl consists therein, the 21-hydroxy group with a sulfonic acid, preferably with methanesulfonic acid or p-toluene-sulfonic acid to esterify and then exchange the sulfonic acid groups for fluorine. The esterification of the 21-Hydroxy group takes place, for example, by adding a sulfonic acid chloride in the presence of an organic Base, such as pvridine or in the presence of aqueous alkali, can act on the compounds of Forme 'III. Of the The sulfonic acid group is preferably replaced by a fluorine atom by changing the 21-sulfonic acid ester with an alkali fluoride such as potassium fluoride in the presence of a polar solvent such as. B. Dimethylf: -namide converts

The process according to the invention according to process variant c is also carried out under known conditions.
The orthoesters of the general formula IV are cleaved with trimethylsilyl fluoride, preferably in an inert solvent, such as a dipolar aprotic solvent (dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, hexamethylphosphoric acid triamide), an ether (diethyl ether, diisopropyl ether, tetrahydrofuran), , a chlorinated hydrocarbon (methylene chloride, chloroform, tetrachloroethane), a hydrocarbon (benzoI, toluene, cyclohexane) or a mixture of these solvents.

The starting compounds for the process according to the invention can thus be produced in a simple manner and in high yields from prednisolone, which in turn can be synthesized relatively easily from diosgenin. As a result, the compounds according to the invention can be prepared from diosgenin with relatively little effort in an overall yield of about 10%. In contrast, the syntheses of the known highly effective corticoids from Diosgsnin are much more complex and the overall yields achieved are significantly lower (approx. 0.5 to 5%). In view of the growing difficulties in obtaining suitable starting materials for corticosteroid syntheses in sufficient quantities and in view of the high costs of active ingredients with which corticosteroid-containing pharmaceutical specialties are burdened, this is not without significance.
As already mentioned, the compounds according to the invention have a strong anti-inflammatory activity when applied topically, but are only weakly active when administered systemically.

The new compounds are suitable in combination with the carriers customary in pharmaceutical pharmacy for the local treatment of contact dermatitis, various types of eczema, neurodermatoses, Erythroderma, burns, pruritis vulvae et ani, rosacea, erythematosus cutaneus, 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 plaster. In the pharmaceuticals formulated in this way, the active substance concentration is of the api'lication form addicted. In the case of lotions and ointments, an active ingredient concentration of 0.001% to 1% is preferred 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 treatment of allergic diseases of the respiratory tract, such as bronchial asthma or rhinitis, for example.
The following examples serve to illustrate the invention.

example 1

a) A suspension of 8.7 g of 21-fluoro-17ff-hydroxy-l, 4,9 (ll) -pregnatrien-3,20-dione in 100 ml of diethylene glycol dimethyleth is mixed with 12 g of Ν, Ν-dimethylaminopyridine and 8, 8 ml of acetic anhydride were ^{stirred at 80 °} C. for 6.5 hours. The reaction mixture is diluted with methylene chloride and washed with 2N hydrochloric acid.

After steam distillation, the mixture is extracted with methylene chloride, dried over sodium sulfate and isolated after evaporation 7.9 g of 17a-acetoxy-21-fluoro-J, 4,9 (II) -pregnatriene-3,20-dione.

b) 7.6 g of 17a-acetoxy-21-fluor-1,4,9 (11) -pregnatriene-3,20-dione are dissolved in 76 ml of dioxane and mixed with 7.2 g of N-bromosucciiiimide offset. 38 ml of 10 percent aqueous perchloric acid are added dropwise and the mixture is stirred Continue for 30 minutes at room temperature and add the reaction solution to a solution of 3.5 g of sodium hydrogen sulfite in 350 ml of water. The precipitate is filtered off with suction and, after drying, 10 g of 17ur-acetoxy-9u-bromine-21 are obtained -fluoro-1 I / hydroxy-1,4-pregnadiene-3,20-dione.

c) 10 g of the above crude product is refluxed in 600 ml of ethanol with 14.0 g of potassium acetate for 2 hours at 110 ⁰ C. The reaction solution is concentrated in vacuo and poured into ice water. The precipitate is filtered off and the crude product is purified on 700 g of silica gel with a methylene chloride-acetone gradient (0-6% acetone). Yield 3.4 g of 17a-acetoxy-9, l./?-epoxy-21-fluor-l,4-pregnadiene-3,20-dione.

d.) 31 ml of a 70proz (HF) "/ pyridine solution is cooled to 6O ⁰ C and treated with a solution of 3 g 17? '- acetoxy-9,1 iy -epoxy-21 -fluoro-l, 4- pregnadiene-3,20-dione was added to 3 ml of pyridine. The reaction solution is stirred for 10 hours at -5 ° C. and then stored in the refrigerator for 3 days. It is poured into ammoniacal fresh water and the precipitate is filtered off. The crude product is purified on 350 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield 2.15 g of 17a-acetoxy-9a, 21-difluoro-1 l ^ -hydroxy-l ^ -pregnadiene ^^ O-dione. Melting point 276 ° C (dec.). [d \ o = + 16 ° (chloroform). UV: ε-, v, = 15,800 (methanol).

Example 2

a) Analogously to example la, 7.9 g of 21-fluoro-17a-hydroxy-1,4,9 (1 l) -pregn; itriene-3,20-dione and propionic anhydride are prepared 5 g of 21-fluoro-17ar-propionyioxy-l, 4,9 (l l) -pregnatrien-3,20-dione produced under the in the example I b conditions described are reacted with N-bromosuccinimide. Yield 8.5 g of 9cr-bromo-21-fluoro-11 ^ -hydroxy-17ff-propionyloxy-1,4-pregnadiene-3,20-dione.

b) 8.5 g of the above crude product are treated with potassium acetate under the conditions described in Example 1c implemented. The crude product is poured onto 700g silica gel with a methylene chloride-acetone gradient (0-6% acetone) purified. Yield 5.3 g 9.1 I ^ S-epoxy ^ l-fluoro-na-propionyloxy-l ^ -pregnadiene ^^ O-dione.

c) As in Example Id, 5.0 g of 9.1 l3-epoxy-21-fluoro-17ff-propionyloxy-l, 4-pregnadiene-3,20-dione are treated with 70%. (HF) „/ pyridine solution. The reaction product is purified on 700 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield 3.98 g of 9a ', 21-difluoro-11j8-hydroxy-17opropionyloxy-1,4-pregnadiene-3,20-dione. Mp 214 ⁰ C. [a] "= + 15 ° (chloroform) UV:. F, = 15 800 _{(Methanol)?..}

Example 3

a) Treating 20.0 g of 17a-butyryloxy-21-fluoro-1,4,9 (1 l) -pregnatriene-3,20-dione, prepared analogously to the example

la from 21-fluoro-17ß-hydroxy-1,4,9 (1 l) -pregnatrien-3,20-dione and butyric anhydride, with N-bromosuccinimide analogous to example Ib. Yield 24.9 g of 9ff-bromo-17ur-butyryloxy-21-fluoro-lje-hydroxy-1,4-pregnadiene-3,20-dione.

b) The above crude product is treated with potassium acetate under the conditions described in Example 1c. 16.1 g of 17a-butyryloxy-9, l lyS-epoxy ^ l-fluoro-M-pregnadienO ^ O-dione are isolated.

c) Analogously to Example Id, 15.1 g of 17a-butyryloxy-9, lljö-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione are added 70 percent (HF) „/ pyridine solution treated. The crude product is applied to 1.5 kg of silica gel with a methylene chloride-acetate gradient (0-15% acetone). 13.4 g of 17a-butyryloxy-9ur, 21-difluoro-

I! / - hydroxy-1,4-pregnadiene-3,20-dione. Melting point 126 ° C. [a] ^: _D ^s = + 11 ° (chloroform). UV: ε _2Μ = 15,300 (methanol).

Example 4

a) Analogously to example la, 9.0 g of 21-fluoro-l 7u-hydroxy-1,4,9 (1 l) -pregnatriene-3,20-dione and valeric anhydride are prepared 7.1 g of 21-fluoro-17a-valeryloxy-1,4,9 (1 l) -pregnatriene-3,20-dione produced analogously to Example Ib treated with N-bromosuccinimide. Yield 8.7 g of 9ff-bromo-21-fluoro-l l ^ -hydroxy-pir-valeryloxy-

b) 6.0 g of the above crude product are reacted with potassium acetate as in Example Ic. After cleaning the Reaction product on 700 g of silica gel with a methylene chloride-acetone gradient (0-5% acetone) 4.2 g of 9.1 ljß-epoxy ^ l-fluoro- ^ ü-valeryloxy-l / l-pregnadienO ^ O-dione are obtained.

c) Analogously to Example Id, by reacting 3.8 g of 9.1 ljS-epoxy-2 l-fluoro-na-valeryloxy-l ^ -pregnadiene-3,20-dione with a 70 percent. (HF) "/ pyridine solution 3.1 g of 9a, 21-difluoro-II / hydroxy-Pff-valeryloxy-1 ^ -pregnadienO ^ O-dione, which after cleaning on 450 g of silica gel with a methylene chloride-acetone Gradients (0-15% acetone) can be obtained. Melting point 139 ° C. [a] ⁷ _D ⁵ = + 10 ° (chloroform). UV: f, ₃ , = 15,800 (methanol).

45 example! 5

a) Under the conditions described in Example la, 8.9 g of 2 l-fluoro-17ff-hydroxy-1,4,9 (l I) -pregnatriene-3,20-dione are prepared and caproic anhydride 7.3 g of 21-fluoro-17ff-hexanoyloxy-1,4,9 (II) -pregnatriene-3,20-dione here, which are reacted analogously to Example Ib with N-bromosuccinimide. Yield 8.2 g of 9-bromo-21-fluoro-17 <z-hexanoyloxy-1 l / f-hydroxy-M-pregnadienO ^ O-dione.

b) As in Example Ic, 8.0 g of the above crude product are treated with potassium acetate and the crude product is purified with a methylene chloride-acetone gradient (0-5% acetone). 5.8 g of 9.1 l / f-epoxy-21-fluoro-17ff-hexanoyloxy-1,4-pregnadiene-3,20-dione are isolated.

c) 3.2 g of 9, llj3-epoxy-21-fluoro-17Er-hexanoyloxy-1,4-pregnadiene-3,20-dione are, as described in Example Id, with a 70 per cent. (HF) „/ pyridine solution treated. The reaction product is purified on 350 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield 2.6 g of 9a, 2l-difluor-17tf-hexanoyloxy-ll./?-hydroxy-l,4-pregnadiene-3,20-dione.

B e i s ρ i e 1 6

a) Analogously to example la, 6.2 g of 21-fluorine-17ff-isobutyryloxy- 1,4,9 (II) -pregnatriene-3 _v 20-dione, which are reacted with N-bromosuccinimide analogously to Example Ib. Yield 6.9 g of 9ff-bromo-2! -fluor-1 JjÖ-hydroxy-17ir-isobutyryloxy-1,4-pregnadiene-3,20-dione.

b) 6.0 g of the above crude product are reacted with potassium acetate as in Example Ic and the reaction product is purified on 600 g of silica gel with a methylene chloride-acetone gradient (0-5% acetone). You get 4.1 g 9, ll /? - epoxy-21-fluoro-17a-isobutyryIoxcy-1,4-pregnadiene-3,20-dione.

c) 3.5 g of 9.1 l ^ -Epoxy ^ l-fluoro-lTff-isobutyryloxy-M-pregnadienO ^ O-dione are left in analogy to Example 1d a 70 percent (HF) „/ pyridine solution react. The crude product is on 400 g of silica gel with a methylene chloride-acetone gradient (0-15% Acetone). Yield 2.9 g of 9a, 21-difluoro-l I> hydroxy-I7a - isobutyryloxy-1,4-pregnadiene-3,20-dione.

Example 7

a / 8.0 g of 21-fluorine - ^ - hydroxy-1,4,9 (1 l) -pregnatriene-3,20-dione are added to a mixture of 80 ml of isovaleric acid and 32 ml of trifluoroacetic anhydride and then added for 2.5 hours stirred at 80 ⁰ C.

ίο You put on warm water to destroy the excess anhydride, then you extract with

Methylene chloride. After neutralizing with lproz. Pyridine / water and drying over sodium sulfate one evaporates in a vacuum. The substance is dissolved in a small amount of pyridine, poured into ice water and neutralizes the pyridine with dilute hydrochloric acid. After the usual work-up, 5.8 g of 21-fluoro-17a-isovaleryloxy-1 are isolated , 4,9 (11) -pregnatriene-3,20-dione.

b) 5.3 g of 21-fluoro-17a-isovaleryloxy-1,4,9 (1 l) -pregnatriene-3,20-dione are treated analogously to Example Ib with N-bromosuccinimide treated. 6.2 g of 9a-bromo-21-fluoro-1 ljS-hydroxy-nff-isovaleryloxy-l ^ -pregnadiene-3,20-dione are obtained.

c) 6.0 g of the above crude product are reacted with potassium acetate as in Example Ic. The reaction product is purified on 600 g of silica gel with a methylene chloride-acetone gradient (0-5% acetone).

Yield 3.7 g of 9,11,0-epoxy-21-fluoro- ^ ff -isovaleryloxy-M-pregnadienO ^ O-dione.

d) Under the conditions of Example Id, 3 g of 9.1 ljß-epoxy-21 -fluoro-nu-isovaleryloxy-l ^ -pregnadiene-3,20-dione with a 70%. (HF) „/ pyridine solution react. The crude product is purified on 300 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone) Yield 2.1 g of 9, 21-difluoro-1 \ ß- hydroxy-na-isovaleryloxy-M-pregnadienO ^ O- dion.

Example 8

a) As described in Example la, 8.7 g of 21-fluoro-17ff-hydroxy-1,4,9 (ll) -pregnatriene-3,20-dione and trimethylacetic anhydride are converted into 6.3 g of 21-fluoro-17a- trimethylacetoxy-1,4,9 (11) -pregnatriene-3,20-dione implemented, which is treated analogously to Example Ib with N-bromosuccinimide. After the usual work-up, 6.5 g of 9 a ⁱ -Bromo-21-Nuor-IIjS-hydroxy-17a'-trimethylacetoxy-1,4-pregnadiene-3,20-dione are isolated.

b) 6.0 g of the above crude product are reacted with potassium acetate as in Example Ic and the crude product is purified on 600 g of silica gel with a methylene chloride-acetone gradient (0-5% acetone). Yield 3.1g 9,11 / -Epoxy-21-fluoro-na-trimethylacetoxy-1 ^ -pregnadiene-S ^ O-dione.

c) Analogously to Example Id, one prepares from 3.0 g of 9.1 l ^ -epoxy ^ l-fluoro- ^ ff-trimethylacetoxy-l ^ -pregnadienO ^ O-dione by reaction with a 70 per cent. (HF) n / pyridine solution 1.9 g of 9a, 21-difluor-1 ^ -hydroxy-17ff-trimeihyi-aceioxy-1,4-pregnadiene-3,20-dione after cleaning on 300 g of gravel egg with a methylene chloride-acetone gradient (0-15% acetone) can be obtained.

Claims (3)

Patent claims:
1. Derivatives of 9-Fluorprednisolons of the general formula I. HO c-OR, wherein R, denotes an alkanoyl radical with up to 6 carbon atoms. 2. Process for the preparation of 9-fluorprednisolone derivatives according to claim 1, characterized in that that one in a known manner a) the epoxy ring of a compound of general formula II OD b) wherein R _{1 has} the meaning given in claim 1, opens with hydrogen fluoride, or the 21-hydroxy group of a 9-fluorine derivative of the general formula III CH ₂ OH HO (III) wherein R, has the abovementioned meaning exchanges for fluorine or c) an orthoester of the general formula IV OR ₂ ^H0 (IV) wherein R, an alkyl radical having a maximum of 5 carbon atoms, and R _{: represent} an alkyl group containing 1 to 4 carbon atoms, cleaves with trimethylsilyl fluoride. 3. Medicaments, characterized in that they are one or two compounds according to the active ingredient Claim 1 received. The invention relates to new derivatives of 9-FluorprednisoIons, according to claim 1, a process for their preparation, and pharmaceutical preparations containing these active ingredients. 9-Fluorprednisolone (= 9α-FluoΓ-ll / ?, I7ύr, 21-thihydΓoxy-l, 4-pΓegnadien-3,20-dione) has been around for a long time known. (J. Amer. Chem. Soc, 77,1955,4181). This kort! Koid is used as an active ingredient for pharmaceutical preparations,! O which are used for the topical treatment of inflammatory diseases, unsuitable as it is very strong systemic Has effects It has been found that hitherto unknown derivatives of 9-fluorprednisolone have only weak systemic effects are, but surprisingly, when applied topically, have a strong anti-inflammatory activity which usually outperforms that of the most effective commercial corticosteroids. The anti-inflammatory effectiveness was determined as follows: On human skin, the following Way creates hyperemia. On the back of voluntary male and female test persons was placed on top of each other by 20 times applied tear-offs with a 2 cm wide scotch tape dissect the stratum corneum and thus a pronounced Generates hyperemia About 50 mg of the ointment preparations were applied to marked 4 cm ^{2 fields within the stripped area.} In order to obtain comparable starting values, relative numbers were used as the color of the untreated Skin as well as the reddening of the hyperemic Bf-oak varies from person to person. The color value of the untreated skin was set as 100, that of the stripped skin as 0. The skin color value of the skin in vasoconstriction (100) was determined by forming a ratio. Minor, moderate, and major vasoconstriction were rated between 0 and 100, respectively. The table below shows the mean values obtained from examinations of the various test subjects and come from different back regions. The sysiemic effectiveness of the compounds was determined using the adjuvant edema test as follows: