CS199512B2 - Method of producing corticoids - Google Patents

Description

The invention relates to a process for the production of new corticoids.

Preferred topically highly active corticoids with minor systemic side effects, for example betamethasone, difluorocortolone or fluocinide, are substituted at the 6-and / or 16-position of the steroid structure. Their synthesis is therefore very expensive, which is of no significance due to the increasing difficulty of obtaining appropriate starting products for the synthesis of corticoids in sufficient quantities and the high cost of the active substances that burden corticoid-containing therapeutic specialties.

Among the synthetically substantially more easily prepared corticosteroids which are in the 6- and 16-unsubstituted positions, it has not been possible to date, despite the intense effort to find an active substance which exhibits the same good spectrum of activity as the above-mentioned compounds.

It has now been found that the hitherto unknown, at the 6- and 16-unsubstituted corticoids have surprisingly potent anti-inflammatory activity when topically applied, which often outperforms the most effective commercially common corticoids, and that these corticoids cause only minor systemic side effects.

These new corticoids have the general formula I

in which

X represents a β-1-hydroxymethylene group, a β-fluoromethylene group or a carbonyl group,

Y represents a fluorine atom, a chlorine atom or an acyloxy group having 1 to 10 carbon atoms, and

R 1 represents an acyloxy group having 1 to 10 carbon atoms.

Suitable acyloxy groups R 1 and Y are, for example, formyloxy, acetoxyl, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, dimethylacetoxyl, trimethylacetoxyl, hexanoyloxy, cyclopentylcarbonyloxyl, cyclopentylcarbonyloxy a cinamoyloxy group, an octanoyl group, a succinyloxy group, a 2-benzoyloxypropionyloxy group or an adamantoylcarboxylic acid group.

Particularly preferred acyloxy groups R 1 and Y are alkanoyloxy groups having 1 to 6 carbon atoms and benzoyloxy groups.

The novel corticosteroids are produced by the known method of the 21-hydroxyl group of the corticosteroid of formula II

in which

X is as defined above and

R 1 denotes an acyl group having 1 to 10 carbon atoms, esterifies or exchanges for a fluorine or chlorine atom, and optionally oxidizes the present N -hydromethylene group X to a carbonyl group.

The substitution of the hydroxyl group at the 21-position with the fluorine atom or the chlorine atom of the invention can be carried out under the conditions known from U.S. Patent No. 3,721,686.

The esterification of the hydroxyl group at the 21-position and the optionally connected oxidation of the hydroxyl group at the 11-position proceed according to known methods, which are shown in TABLE 1.

The results of the vasoconstriction test are described, for example, in U.S. Patent No. 3,828,083.

The corticoids produced according to the invention have, as already mentioned, a strong anti-inflammatory activity when topically applied, but are only very poorly effective in systemic application.

The local anti-inflammatory activity of corticoids can be determined by a known vasoconstriction test.

On the backs of the test subjects (volunteers), they stratify the stratum corneum 20 times over each other with scraps of 2 µm wide tesafilm, causing significant hypermia.

50 mg of butter preparations are applied to the marked 4 cm ² patches inside the stripped perimeter. Butter-free base without active substance serves as zero value (blank).

The color value of the untreated skin is designated as 100, the torn skin as 0. The color value of the skin in which the vasoconstriction is evaluated is evaluated accordingly in the range of 0 to 100.

The following Table I shows the mean values from investigations of different test subjects and different back countries.

6α, 9α-difluoro-11β-hydroxy-16α-methyl-21-valeryloxy-1,4-pregnadien-3,20-dione (difluorotortolone-2-valerianate) was used as reference in these investigations.

The table shows that the compounds of the invention exhibit excellent anti-inflammatory activity even at extreme dilutions.

Conc. in% Vasoconstriction after h 8 h

AND 6a, _{9a-difluoro-1!} I-hydroxy-16a-methyl-21- -valeryloxypregnadien-3,20-dione 9.00001 33 o / o 36% II 17α-benzoyloxy-11β-hydroxy-21-trime- thylacetoxy-1,4,8 (9) -pregnatriene-3,20-dione 0.00001 30% 33% III 17α-Acetoxy-21-chloro-11 (3-hydroxy-1,4,8 (9) -pregnatrene-3,20-dione 0.00001 42% 42 o / o IV 21-chloro-110-hydroxy-17α-propionyloxy- -1,4,8 (9) -pregnatriene-3,20-dione 0.00001 47% 45% in 17 (3-Benzoyloxy-21-chloro-11/5-hydroxy-1,4,8 (9) -pregnatriene-3,20-dione 0.00001 52 O / o ' 64%

The systemic activity of the compounds of the invention was determined by the thymolysis assay as follows:

SPF rats weighing 70 to 110 g are adrenalectomized under ether anesthesia; Six animals each consist of a test group, which is administered a perorally defined amount of test substance for three days. On day four, the animals are sacrificed and the weight of their thymes is determined. Control animals are treated in the same way, but they receive a mixture of benzyl benzoate with castor oil without the test substance. From the weight of the thymes thus obtained, the amount of test substance at which 50% thymolysis is observed is determined in the usual manner.

Furthermore, systemic efficacy was tested using the adjuvant swelling model test as follows:

SPF rats weighing 130-150 g are injected into the right hind limb to induce an inflammatory lesion. 0.1 ml of a 0.5% suspension of mycobacterium butyricum. The volume of rat limbs is measured prior to injection; 24 hours after injection, the limb volume is again measured to determine the extent of swelling. Thereafter, the rats are orally treated with a varying amount of the test substance dissolved in a mixture of 29% benzyl benzoate and 71% castor oil. After a further 24 hours, the limb volume is again determined.

Control animals were treated in the same manner except that they were injected with a mixture of benzyl benzoate and castor oil without the test substance.

From the obtained limb volumes, the amount of test substance required to achieve 50% healing of the paw edema is determined in a conventional manner.

Difluorocortolone-21-valerianate was again used as a reference in these tests.

The results obtained in this test are given in Table 2 below.

The results show that the compounds produced according to the invention have only minor systemic side effects.

TABLE 2

Thymolysis and adjuvant swelling test results

. number Thymolysis ED 50 mg / kg Adjuvant model test. ED50 mg / kg AND 6α, 9α-difluoro-11β-hydroxy-16α-methyl-21- -valeryloxy-1,4-pregnadien-3,20-dione 0.03 0.3 II 17α-Benzoyloxy-11β-hydroxy-21-tri-methyl-acetoxy-1,4,8 (9) -pregnatriene-3,20-dlonone 5.5 10 III 17α-acetoxy-21-chloro-11/3-hydroxy- -1,4,8 (9) -Pregnatriene-3,20-dione 3.6 3.6 IV 21-chloro-11β-hydroxy-17α-propionyloxy-1, 4,8 (9) -pregnatriene-3,20-dione 2,0 2,0 in 17α-Benzoyloxy-21-chloro-11β-hydroxy-1,4,8 (9) -propylnatriene-3,20-diori 1.0 1.0

The novel compounds are suitable in combination with carriers customary in galenic pharmacy, for the topical treatment of contact dermatitis, eczema of various species, neurodermatoses, erythrodermia, burns, pruritis vulvae et al, as well as other diseases: rosacea, erythematosus cutaneus, psoriasis, lichen ruber planus at verrucosus and similar skin diseases. .

The manufacture of medicament specialties is carried out in the usual manner by which the active substances are converted, with suitable additives, into the desired dosage forms, for example solutions, lotions, ointments, creams or patches. In such formulations, the concentration of active ingredient is dependent on the dosage form. For lotions and ointments a concentration of active compound of 0.001 to 1% is preferably used.

In addition, the novel compounds, optionally in combination with conventional carriers and excipients, are also good for the manufacture of inhalants which can be used to treat allergic respiratory diseases such as bronchial asthma or rhinitis.

The following examples serve to illustrate the invention.

Example 10 10 g of 11 / 3,17a, 21-trihydroxy-1,4,8-, pregnatriene-3,20-dione are stirred in 100 ml of pyridine with 50 ml of butyric anhydride at room temperature for 2 hours. It is taken up in ice water, filtered and the washed residue is taken up in methylene chloride. After washing and drying, the organic solution is evaporated in vacuo. The yield of crude product was 12.1 g, which was recrystallized from acetone / be199512 xane to give 8.9 g of 21-butyryloxy-11 ₍ η 17α-dihydroxy-1,4,8-pregnatriene-3,20-dione).

(b) To a suspension of 3 g of cuprous iodide in 60 ml of dry tetrahydrofuran, 12.5 ml of a 5% methyllithium solution in ether are added dropwise under argon at 0 ° C. The yellow mixture was cooled to -30 ° C and a solution of 2.8 g of 21-butyryloxy-11,17a-dihydroxy-1,4,8-pregnatriene-3,20-dione in 50 ml dry tetrahydrofuran was added. Stir for 3-4 hours at this temperature and quench excess reagent with aqueous ammonium chloride solution. After extraction with methylene chloride, the organic solution was washed, dried with sodium sulfate and evaporated in vacuo. The yield of crude product is 2.5 g of 17α-butyryloxy-11 (S, 21-dihydroxy-1,4,8-pregnatriene-3,20-dione).

c) 2.5 g of crude 17? -butyryloxy-11 / 3,21-dihydroxy-1,4,8 (9? -pregnatriene-3,20-dione) was stirred in 25 ml of pyridine overnight with 3 g of p- After precipitation with ice water, it is extracted with methylene chloride, the extracts are washed with water and, after drying over sodium sulphate, concentrated in vacuo to yield 2.3 g of crude product which is purified on 250 g of silica gel with methylene chloride / acetone gradient (0-15% acetone). Yield 1.5 g of 17α-butyryloxy-11β-hydroxy-21-p-toluenesulfonyloxy-1,4,8-pregnatriene-3,20-dione.

d) 1.5 g of 17α-butyryloxy-11/3-hydroxy-21-p-toluenesulfonyloxy-1,4,8-pregnatriene-3,20-dione in 30 ml of hexamethylphosphoric triamide were stirred with 5 g of lithium chloride for 4 hours. at 70 ° C bath temperature. Pour into ice water, filter and wash the washed residue into methylene chloride. The organic solution was washed with water, dried over sodium sulfate and concentrated in vacuo. Yield of crude product: 1.3 g, which is purified on 140 g of silica gel with a gradient of hexane and ethyl acetate (0 to 50% ethyl acetate). Yield 720 mg of 17α-butyryloxy-21-chloro-11H-hydroxy-1,4,8-pregnatriene-3,20-dione.

Example 2

a) 10 g of 11 / 3,17a, 21-trihydroxy-1,4,8-pregnatriene-3,20-dione were treated in analogy to Example 1 with n-valeric anhydride to give 11 / β, 17a-dihydroxy-21 -valeryloxy-1,4,8-pregnatriene-3,20-dione. Yield of crude product 11.5 g, which is recrystallized from acetone and hexane. Yield 8.2 g.

b) Analogously to Example 1b), 5 g of 11β / 3,17α-dlhydroxy-21-valeryloxy-1,4,8-pregatriene-3,20-dione was converted by lithium dimethyl ethyl acetate to 11β, 21-dlhydroxy-17α-valeryloxy-1,1,1-pregnatriene-3,20-dione. 4,8-pregnatriene-3,20-dione. Yield of crude product 3.5 g.

c) 3.5 g of the above crude product 9e was treated analogously to Example 1c] to give 11 (S) -hydroxy-na-valeryloxy-1,4-p-toluenesulfonyloxy-1,4,8-pregnatriene-,203,20-dione. Yield of crude product 3.2 g, which are chromatographed on 360 g silica gel with methylene chloride and acetone gradient (0-15% acetone). Yield 1.9 g of 11 N -hydroxy-21-p-toluenesulfonyloxy-17α-valeryloxy-1,4,8-pregnatriene-3,20-dione.

d) 1.9 g of the above p-toluenesulfonate was converted, as in Example 1d, with lithium chloride into the corresponding 21-chloro compound. Yield of crude product 1.8 g, which is purified on 200 g of silica gel with a gradient of hexane and ethyl acetate (0 to 50% ethyl acetate). Yield 1.1 g of 21-chloro-11, d-hydroxy-17α-valeryloxy-1,4,8-pregnatriene-3,20-dione.

Example 3

a) Analogously to Example 1, 12 g of 1α, 17α, 21-trihydroxy-1,4,8-pregnatriene-3,20-dione are treated with caproic anhydride. 14.1 g of 21-hexanoyloxy-11 / 3,17a-dihydroxy-1,4,8-pregnatriene-3,20-dione are isolated, which is recrystallized from acetone and hexane. Yield 11 g.

b) 3 g of 21-hexanoyloxy-110,17a-dihydroxy-1,4,8-pregnatriene-3,20-dione were converted in analogy to Example 1b) with lithium dimethyl ethyl acetate to 17a-hexanoyloxy-11 / 3,21-di) hydroxy -1,4,8-pregnatriene-3,20-dio. Yield of crude product 6.5 g.

c) Analogously to Example 1c), 6.5 g of the above crude product were treated to 17α-hexanoyloxy-11β-hydroxy-21-p-toluenesulfonyloxy-1,4,8-pregnatriene-3,20-dione.

d) In analogy to Example 1d), 3.9 g of the above p-toluenesulfonate was treated with lithium chloride. The yield of crude product was 3.2 g, which was purified on 250 g of silica gel with hexane / ethyl acetate gradient (0 to 50% ethyl acetate). Yield 2.3 g of 21-chloro-17α-hexanoyloxy-11 (3-hydroxy-1,4,8-pregnatriene-3,20-dione).

Example 4

a) 12.9 g of 11,3,17a, 21-trihydroxy-1,4,8-pregnatriene-3,20-dloin is stirred in 240 ml of pyridine with 18.5 g of cyclohexanecarboxylic acid and 12.3 g of N, N dicyclohexylcarbodiimide for hours at room temperature. After precipitation _from ice water and usual work-up, it is purified on 1.8 g of silica gel with a gradient of methylene chloride and acetone (0 to 10% acetone). 8.2 g of 21-cyclohexylcarbonyloxy-H (3,17a-dihydroxy-1,4,8-pregnatriene-3,20-dione) are obtained.

b) 7 g of 21-cyclohexylcarbonyloxy-11,17α-dihydroxy-1,4,8-pregnatriene-3,20-dione were converted in analogy to Example 1b) by lithium dimethyl ethyl acetate to 17α-cyclohexylcarbonyloxy-11,21-dihydroxy-1, 21-dihydroxy-1. , 4,8-pregnatriene-3,20-dione. Yield of crude product 5.5 g.

c) 5.5 g of the above crude product was treated analogously to Example 1c) to give 17α-cyclahexylcarbonyloxy-11β-hydroxy-21-p-toluenesulfonyloxy-1,4,8-pregnatriene-3,20-dione. Yield of crude product

4.8 g which is chromatographed on 500 g of silica gel with a gradient of methylene chloride and acetone (0 to 15% acetone). Yield 2.8 g of 17? -Cyclohexylcarbonyloxy-11? -Hydroxy-21-p-tolueinsulfonyloxy-1,4,8-pyregnatriene-3,20-dione.

d) 2.8 g of the above p-toluenesulfonate was reacted in a manner similar to Example 1d) with lithium chloride. Yield of crude product 2.3 g, which is purified on 250 g of silica gel with hexane / ethyl acetate gradient (0 to 50% ethyl acetate). Yield 1.2 g of 21-chloro-17'-cyclohexylcarbonyloxy-11/3-hydroxy-1,4,8-pregnatriene-3,20-dione.

Example 5 and 2.5 g of 17.beta.-benzoyloxy-9.alpha.-chloro-11 / S, 21-dihydroxy-1,4-pregnadien-3,20ydione are stirred in 50 ml. Of hexamethylphosphoric triamide with 2.5 g. 80 ° C in a bath for 3 hours. After the usual work-up, 2.2 g of 17α-benzoyloxy-11,21-dihydroxy-1,4,8-pregnatriene-3,20-dione were isolated as a crude product.

b) To 2.2 g of the above crude product in 44 ml of pyridine, 4.4 ml of methanesulfonic acid chloride were added portionwise at 0 ° C, and then stirred at this temperature for 10 minutes. Precipitation with ice water and usual work-up gives 2.2 g of crude product which is purified on 250 g of silica gel with a gradient of methylene chloride and acetone (0-15% acetone). Yield 1.4 g of 17α-benzoyloxy-11β-hydroxy-21-methanesulfonyloxy-1,4,8-pregnatriene-3,20-dione as a foam.

(c) 1.2 g of the above methanesulfonate are stirred in 40 ml of dimethylformamide

3.8 g of potassium hydrogen fluoride for 72 hours under nitrogen at a bath temperature of 110 ° C. Precipitating with ice-water with the usual working-up gives 1.8 g of an oil which is purified on 135 g of silica gel with a gradient of methylene chloride and acetone (0 to 9% acetone). Yield 214 mg of 17α-benzoyloxy-21-fluoro-11β-hydroxy-1,4,8-pregnatriene-en3,20-dione.

Example 6

a) 15 g of 11 / 3,17a, 21-trihydroxy-1,4,8-pregnatriene-3,20-dione in 75 ml of pyridine are treated with 40 ml of propionic anhydride in a similar manner to Example 1. Yield of crude 16 2 g, which yielded 13.4 g of 11,17a-dihydroxy-21 _: propionyloxy-1,4,8-pregnatriene-3,20-dione from a mixture of acetone and hexane.

bj In analogy to Example 1b), 12 g of 11,6,17a-dihydroxy-21-propionyloxy-1,4,8-pregnatriene-3,20-dione was rearranged with lithium acetate to the corresponding 17α-acyloxy compound. Yield of crude product 10.8 g of 11 / 3,21-dihydroxy-17α-propionyloxy-1,4,8-pregnatriene-3,20-dione.

c) 10 g of crude 11 / 3,21-dihydroxy-17.alpha.-propionyloxy-1,4,8-pregnatriene-3,20-dione were converted in analogy to Example 1c) to 11/3-hydroxy-17.alpha.-propionyloxy-21. - p-toluenesulfonyloxy-1,4,8-pregnatriene-3,20-dlon. Yield 7.2 g.

d) 7 g of said p-toluenesulfonate in dimethylformamide were reacted similarly as in Example 5 with potassium fluoride and purified. Yield 1.2 g of 21-fluoro-11β-hydroxy-17α-propionyloxy-1,4,8-pregnatriene-3,20-dione. Mp 238 ° C.

Example 7

700 mg of 21-fluoro-11,6-hydroxy-17α-propionyloxy-1,4,8-pregnatriene-3,20-dione was oxidized with chromium oxide. Yield 530 mg of 21-fluoro-17α-propionyloxy-1,4,8-pregnatriene-3,11-20-trione.

EXAMPLE 8 a) 10 g of 11 / 3,17a, 21-trihydroxy-1,4,8-pregnatriene-3,20-dione are similarly converted into triethyl orthoacetic acid triethyl ester, followed by hydrolysis, to 18.5 g of 17? acetoxy-11 / 3,21-dihydroxy-1,4,8-pregnatriene-3,20-dione.

b) 1 g of crude 17α-acetoxy-11 / 3,21-dihydroxy-1,4,8-pregnatriene-3,20-dione in 6 ml of pyridine was stirred at room temperature with 3 ml of acetic anhydride for 1 hour. After the usual work-up, 0.9 g of crude product is isolated, which is purified on 100 g of silica gel with a gradient of methylene chloride and acetone (0 to 12% acetone). Yield 420 mg 17a, 21-diacetoxy-11/3-hydroxy-1,4,8-pregnatriene-3,20-dione. Melting point 220 ° C.

Example 1 9

2.5 g of crude 17α-iacetoxy-11 / 3,21-dihydroxy-1,4,8-pregnatriene-3,20-dione was stirred in 25 ml of pyridine with 12 ml of valeric anhydride overnight at room temperature. After the usual work-up, the crude product is purified on 500 g of silica gel with a gradient of methylene chloride and acetone (0-12% ace).

189512 ton). Yield 1.1 g of 17α-acetoxy-11H-hydroxyoxy-21-valeryloxy-1,4,8-pregnatriene-3,20-dione.

He did

As in Example 9, 2.1 g of crude 17α-acetoxy-11 / 3,21-dihydroxy-1,4,8-pregnatriene-3,20-dione were reacted in 25 ml of pyridine with 12 ml of trimethylacetic anhydride. . The crude product is purified on 400 g of silica gel with methylene chloride-acetone (0-12% acetone al. Are isolated 850 mg of 17a-acetoxy-l, _{1-d-hydroxy-21-trimethylacetoxy-l,} 4,8-pregnatriene-3,20 -dionu.

Example 11 g of 11 / 3,17a, 21-trihydroxy-1,4,8-pregnatriene-3,20-dione was reacted in analogy to Example 8 with triethyl orthopropionate and then subjected to hydrolysis. Purify 5 g of the crude product on 600 g of silica gel with hexane-ethyl acetate gradient (0 to 100% ethyl acetate). Yield 2.1 g of 11 / 3,21-dihydroxy-17α-propionyloxy-1,4,8-pregenetrien- 3,20-dione, m.p. 216 ° C.

Example 12

1.2 g of purified 11 (3,21-dihydroxy-17α-propionyloxy-1,4,8-pregnatrieh-3,20-dione) are stirred at room temperature with 10 ml of formic acid for 24 hours. After filtration, the residue was dissolved in methylene chloride and the solution was washed neutral with sodium bicarbonate and water, dried, concentrated, and 415 mg of 21-formyloxy-11 / S-hydroxy-17α-propionyloxy-1,4,8-pregnatriene was isolated. 3,20-dione;

Example 13

700 mg of crude 11 / S, 21-dlhydroxy-17α-propionyloxy-1,4,8-pregnatriene-3,20-dione was treated with acetic anhydride in a similar manner as in the example. 700 mg of crude product is isolated, which is purified on 800 g of silica gel with a gradient of methylene chloride and acetone (0 to 12% acetone). Yield: 385 mg of 21-acetoxy-l _{J-hydroxy-17a-propionyloxy-l,} 4,8-pregnatriene-'3,20-dione. Melting point 213 ° C.

Example 14

1.5 g of crude 11 / 3,21-dihydroxy-17α-propionyloxy-1,4,8-pregnatriene-3,20-dione in ml pyridine was treated with 5 ml propionic anhydride for 1 hour at room temperature. After the usual work-up, a crude product yield of 1.4 g is obtained which is chromatographed on 160 g of silica gel with a gradient of methylene chloride and acetone (0 to 12% acetone). 620 mg of 11β-hydroxy-17α, 21-dipropionyloxy-1,4,8-pregnatriene-3,20-dione are isolated. Mp 191 ° C. Example 15

1.1 g of crude 11 (3,21-dihydroxy-17α-propionyloxy-1,4,8-pregnatriene-3,20-dione is stirred in 12 ml of pyridine with 6 ml of butyric anhydride overnight at room temperature. The crude product obtained is purified on 120 g of silica gel with a gradient of methylene chloride and acetone (0-12% acetone) to yield 510 mg of 21-butyryloxy-11β-hydroxy-17α-propionyloxy-1,4,8-pregnatriene-3,20-dione Melting point: 163 ° C.

Example 16

Analogously to Example 9, the reaction was carried out on

1.3 g of 11 ₍ 3,21-dihydroxy-17α-propionyloxy-1,4,8-pregnatriene-3,2Q-dione in 15 ml of pyridine, 8 ml of n-valeric anhydride. The crude product yield 2.5 g is purified on 200 g of silica gel with a gradient of methylene chloride and acetone (0 to 12% acetone) 535 mg of 11β-h, hydroxy-17α-propionyloxy-21-valeryloxy-1,4,8-pregnatriene-3,20-dione is isolated. 147 ° C.

Example 1 7

1.6 g of 11 / 3,21-dihydroxy-17α-propionyloxy-1,4,8-pregnatriene-3,20-dione are stirred in 30 ml of pyridine with 15 ml of caproic anhydride at room temperature for 1.5 hours. . After precipitation with ice water and usual work-up, 3.1 g of crude product are isolated, which is chromatographed on 300 g of silica gel with a gradient of methylene chloride and acetone (0-12% acetone). Yield 1.23 g of 21-hexanoyloxy-11, .alpha.-hydroxy-17.alpha.-propionyloxy-1,4,8-pregnatrine-3,20-dione. Melting point 162 ° C.

Example 18

1.5 g of crude 11 ₁ S, 21-dihydroxy-17α-propionyloxy-1,4,8-pregnatriene-3,20-dione are stirred in 15 ml of pyridine with 10 ml of enanthic anhydride at room temperature overnight. After the usual treatment, the excess enanthic acid is removed by steam distillation. The crude product is chromatographed on 300 g of silica gel with a gradient of methylene chloride and acetone (0-12% acetone), and 680 mg of 21-heptanoyloxy-11/3-hydroxy-17α-propionyloxy-1,4,8-pregnatriene-3,20- ^is isolated. dionu.

Example 19

1.9 g of crude 11 / 3,21-dihydroxy-17α-propionyloxy-1,4,8-pregnatriene-3,20-dione were treated similarly to Example 10 with trimethylacetic anhydride. The crude product is chromatographed on 400 g of silica gel with a gradient of methylene chloride and acetone (0-12% acetone). Yield: 620 mg 11/3-hydroxy-17.alpha.-propionyloxy-21-tri methylacetoxy ^i-l, 4,8-pregnatrieh-3,20-dione.

Example 20

1.4 g of crude 17α-butyryloxy-11 / 3,21-dihydroxy-1,4,8-pregnatriene-3,20-dione were treated analogously to Example 8 with acetic anhydride. The crude product was chromatographed on 250 g of silica gel with methylene chloride and acetone gradient (0-12% acetone) to give 785 mg of 21-acetoxy-17α-butyryloxy-11 / S-hydroxy-1,4,8-pregnatriene-3.20 -dionu.

Example 21

1.2 g of 17α-butyryloxy-11β, 21-dihydroxy-1,4,8-pregnatriene-3,20-dione were treated with trlmethylacetic anhydride in a similar manner to Example 19. Purification was achieved on 200 g of silica gel with a gradient of methylene chloride and acetone (0-12% acetone). Yield: 345 mg of 17.alpha.-butyryloxy-l / 3-hydroxy-21-tri methylacetoxy ^i-l, 4,8-pregnatriene-3,20-dione.

Example 22

Analogously to Example 17, 900 mg of 17α-butyryloxy-11 / 3,21-dihydroxy-1,4,8-pregnatriene-3,20-dione is reacted with caproic anhydride. The crude product is chromatographed on 150 g of silica gel with a gradient of methylene chloride and acetone (0-12% acetone) and 410 mg of 17α-hutyryloxy-21-hexanoyloxy-11/3-hydroxy-1,4,8-pregnatriene-3,20 is isolated. -dionu.

Example 23

As in Example 14, 1.1 g of crude 11,13,21-dihydroxy-17α-valeryloxy-1,4,8-pregnatriene-3,20-dione is reacted with propionic anhydride and the crude product is purified on 160 g of silica gel gradient of methylene chloride - and acetone (0 to 12% acetone). Yield: 562 mg of 11β-hydroxy-21-propionyloxy-17α-valeryloxy-1,4,8-pregnatriene-3,20-dione.

Example 24

In a similar manner to Example 16, 1 g of crude 11 (3,21-dihydroxy-17α-valeryloxy-1,4,8-pregnatriene-3,20-dione) is reacted with n-valeric anhydride. g of silica gel with a gradient of methylene chloride and acetone (0 to 12% acetone) gave 490 mg of 11 (S-hydroxy-17a, 21-divaleryloxy-1,4,8-pregnatriene-3,20-dione).

Example 25

Analogously to Example 8, 1 g of crude 17α-benzoyloxy-11 (3,21-dihydroxy-1,4,8-pregnatriene-3,20-dione) is acetylated and the crude product is purified on 120 g of silica gel with a gradient of methylene chloride and acetone (0 to 20 g). Yield: 672 mg of 21-acetoxy-17.alpha.-benzoyloxy-11/3-hydroxy-1,4,8-pregnatriene-3,20-dione, m.p. 215 DEG C. (dec.).

Example 1 a d 2 6

Analogously to Example 10, the reaction is carried out

1.2 g of crude 17α-benzoyloxy-11 (3,21-dihydroxy-1,4,8-pregnatriene-3,20-dione with trimethyl acetic anhydride) The crude product is purified on 160 g of silica gel with a gradient of methylene chloride and acetone (0 to 12). Yield: 743 mg of 17? -benzoyloxy-1- (3-hydroxy-21-trimethylacetoxy-1,4,8-pregnatripin-3,20-dione; mp 135 ° C).

Example 1 a d 2 7

As in Example 17, 1.3 g of crude 17α-beinzoyloxy-11 / 3,21-dihydroxy-1,4,8-pregnatriene-3,20-dione was reacted with caproic anhydride. The crude product is chromatographed on 120 g of silica gel with a gradient of methylene chloride and acetone (0-12% acetone). 790 mg of 17α-benzoyloxy-21-hexanoyloxy-11 (S-hydroxy-1,4,8-pregnatriene-3,20-dione) is isolated.

Example 1 a d 2 8

Oxidation of 700 mg of 17α-acetoxy-11, d-hydroxy-21-trimethylacetoxy-1,4,8-pregnatriene-3,20-dione with chromium oxide gave the crude product which was chromatographed on 120 g silica gel with a gradient of methylene chloride and acetone (0). to 12% acetone) to give 384 mg of 17α-acetoxy-21-trimethylacetoxy-1,4,8-pregnatriene-3,11-20-trioin.

Example29

After oxidation of 850 mg of 11 (3-hydroxy-17α, 21-dipropionyloxy-1,4,8-ipregnatriene-3,20-dione with chromium trioxide), the crude product obtained is purified on 120 g of silica gel with a gradient of methylene chloride and acetone (0 to 12%). Yield: 565 mg of 17a, 21-dipropionyloxy-1,4,8-pregnatriene-3,11,20-trione.

Example 1 a d 3 0

After oxidation of 900 mg of 17α-butyryloxy-21-hexanoyloxy-11β-hydroxy-1,4,8-pregnatriene-3,20-dione with chromium oxide, the crude product obtained is chromatographed on 120 g of silica gel with a gradient of methylene chloride and acetone (0 to 12). % acetone). 715 mg of 17α-butyryloxy-1,4,8-pregnatriene-3,11-20-trioma is isolated.

Example 31

After oxidation of 1 g of 21-aceitoxy-17α-benzoyloxy-11/3-hydroxy-1,4,8-pregnatriene-3,20-dione with chromium trioxide and after purification on 120 grams of silica gel with a gradient of methylene chloride and acetone (0 to 12%) (acetone) was isolated 840 mg of 21-acetoxy-17'-benzoyloxy-1,4,8-pregnatriene-3,11,20-trione, which was recrystallized from acetone and hexane. Mp 249 ° C (dec.).

Claims (1)

SUBJECT Process for the preparation of corticolds of the general formula I Wherein the 21-hydroxyl group of a corticoid of formula (II) in which: X represents a β-hydroxymethylene group, a β-fluoromethylene group or a carbonyl group, Y represents a fluorine atom, a chlorine atom or an acyloxy group having 1 to 10 carbon atoms and R 1 represents an acyloxy group having 1 to 10 carbons in which X is as defined above and R 1 represents an acyl group having 1 to 10 carbon atoms, esterified or exchanged for a fluorine or chlorine atom, and optionally the β-hydroxymethylene group X present is oxidized to a carbonyl group. SmrofrailB, a. P., Aved 7, Mnt