FI70718C - FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT ANVAENDBARA KORTIKOIDER - Google Patents

Description

1 70718

A process for the preparation of new therapeutically useful corticoids

Separated from Patent Application No. 5909040

The invention relates to a process for the preparation of novel corticoids of formula I.

10 ch2r3 t = 0 i2 HO - - - "OÖHQR1 • i * X — T4 15 (I),

Z

X

Wherein the bond .. represents a single bond or a double bond, X is hydrogen, fluorine or methyl, Y is hydrogen and Z is hydrogen, fluorine or chlorine, or Y and Z together form a carbon-carbon bond and Q is oxygen or sulfur, R 1 is an alkyl group or a benzyl group having 1 to 8 carbon atoms, optionally truncated by an oxygen atom, and R 2 is hydrogen or an alkyl group having 1 to 4 carbon atoms, or R 1 and R 2 together represent a trimethylene group or a tetramethylene group, R 1 is hydrogen, fluorine, chlorine or free or esterified 2 70718 hydroxy group and is hydrogen or methyl.

It has long been known that the potency of the anti-inflammatory effect of 17β-hydroxycorticoids when applied topically can be enhanced by esterifying their 17-hydroxy group. (See General L. Thomas Popper and Arthur S. Watnick, "Anti-Flammatory Steroids in Anti-Flammatory Agents," Volume 1, Academic Press, New York, San Francisco, London (1974) pp. 268-271).

It has now been found that when applied topically, and / or the distribution of the desired local anti-inflammatory effect and undesired systemic effect, can be further enhanced by replacing the hydrogen atom of the 17α-hydroxy groups of these corticoids not with an ester but with an acetal residue or thioacetal residue.

The substituents of the new corticoids of the formula I can be a straight-chain or side-chain alkyl group f having 1 to 8, preferably 1 to 6 carbon atoms. Such are alkyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl groups. However, the R 1 alkyl group of the substituent may also be cleaved by an oxygen atom. Such groups include, for example, 2-methoxy-25 ethoxy, 3-methoxypropyloxy and 2-ethoxyethoxy.

As substituents for the corticoids of the formula I, R 2 can be an alkyl group having 1 to 4 carbon atoms, such as, for example, a methyl, ethyl, propyl or butyl group. Of note are the cort-30 moles of formula I, wherein R 2 corresponds to a hydrogen atom, as these cannot form diastereomeric mixtures.

The onset and duration of action of the new corticoids, as well as their solubility in physiologically acceptable solvents, depend as well as known corticoids, in particular whether the hydroxy group in the 21-position is esterified and, if so, with which acids it is esterified.

As esterified 21-hydroxy groups, R3 is mainly acyloxy groups having 1 to 16 carbon atoms in the acyl group, sulfate groups or phosphate groups. Suitable acyloxy groups are, for example, groups which are derivatives of straight-chain or side-chain saturated or unsaturated aliphatic mono-10 or dicarboxylic acids, in which, for example, hydroxy groups, amino groups or halogen atoms can be substituted as usual.

Also suitable as acyloxy groups are residues of cycloaliphatic, aromatic, aromatic-aliphatic-mixed acids or heterocyclic acids, which may also have customary substituents. Suitable acyloxy groups include, in particular: formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, octa-20-yloxy, undecanoyloxy, dimethylacetoxy, trimethylacetoxy, diethylacetoxy, tert-acetoxy, tert-butyl. , benzoyloxy7, phenacetylethoxy, cyclopenylpropionyloxy, hydroxyacetoxy, monochloroacetoxy, dichloroacetoxy, trichloroacetoxy, further dimethylaminoacetoxy, trimethylaminoacetoxy-, diethylaminoacetoxy-, diethylaminoacetoxy, piperidine, piperidino and a N-carboxypentanoyloxy group.

To prepare water-soluble active ingredients, 21-acyloxy compounds having a basic nitrogen group in the acyl residue can be converted into the corresponding acid addition salts, such as, for example, hydrochlorides, hydrobromides, sulfates, phosphates, oxalates, tartrates or maleates. Furthermore, 21-dicarbon-35 acid monoesters, as well as sulfuric acid and phosphoric acid esters, can be converted to their alkali metal salts, such as sodium or potassium salts, to improve water solubility.

The process according to the invention for the preparation of novel corticoids of the formula I is characterized in that A) 17 X.-hydroxy steroid of the formula (II) CH R '10 C = O

H0 ^, JU - - o 0H

is (II) 'O' 'γ' '

X

20 where ..,. , X, Y, Z and are as defined above and R 1 is hydrogen, fluorine, chlorine or an esterified hydroxy group, is reacted in a manner known per se, if desired after temporary protection of the 11β-hydroxy group, with a) an acetal of the formula (III) r 2hc (or 1) 2 (III), wherein R 1 and R 2 are as defined above, or b) with an X-haloether of formula (IV)

Hal-R2CH-OR1 (IV), wherein R1 and R2 are as defined above and Hal 35 is chlorine, bromine or iodine, or

II

C) with a vinyl ether of formula (v) R '2CH = CH-OR · ^ (V), wherein R' is as defined above and R'2 is hydrogen or an alkyl group having 1 to 3 carbon atoms, or d) with a sulphoxide of formula (VI), wherein R 2 and R 2 are (VI) in which R 1 and R 2 are as defined above, or B) in a manner known per se to a) a 9,11-dehydrosteroid of formula (VII) CH-R-, I 2 3 i = o R2! L_ - - - OCFIQR1 20 .......— ^ <VII) '0' "'-s' '' 25 * where ..., X, Q, R ^, R2 / R ^ and R ^ have the same meaning as above, chlorine or subchloric acid is added, or b) a 9,11-epoxysteroid of formula (VIII) CH2R3 30! R9 C = O! z ___ OCHQR-j ^ JJ (VIII), 35 (Jj ·· · · -: '

X

6 70718 wherein ...., X, Q, R 1, 1 * 2, R 2 and R 2 are as defined above, an epoxy ring with hydrogen fluoride or hydrogen chloride, or c) a halogen steroid of formula (IX)

5 CH R

I h c = o | H ° R "° CHQR1 i 10 · γ" · '-ν (IX> - z "|

oVyJ

i t

X

15 where. . . . , X, Q,, # 2 'R3 and R4 are as defined above and Z "is chlorine or bromine, is cleaved by Z" or HZ ", and, if desired, the resulting corticoids having a saturated 1,2-position, 1.2 the position is dehydrated, and / or the 20β-hydroxy group is oxidized to an oxo group, and / or the 21-ester groups are saponified and / or the 21-hydroxy groups are esterified or exchanged for fluorine atoms or chlorine atoms.

The methods of Δ) can be performed under conditions known per se (Synthesis 1975, 2786, J. Chem. Soc. 66, 1974, 431, J. Amer. Chem. Soc. 74, (1952), 1239, U.S. Pat. patent 3,383,394 and Angew, 90, (1978), 289).

Thus, for example, steroids of formula (II) may be reacted a) with an acetal of formula (III) in the presence of acidic catalysts such as perchloric acid, p-toluenesulphonic acid or suitably phosphorus pentoxide. This reaction can be carried out without using another solvent or in the presence of neutral solvents (chloroform, methylene chloride, tetrachloroethane, tetrachloromethane, toluene, diethyl ether, tetrahydrofuran, dioxane, etc.). The reaction is usually carried out at a reaction temperature of -20 ° C to + 50 ° C and is particularly suitable for the preparation of steroids of formula (I) in which R e represents hydrogen.

On the other hand, steroids of formula (II) may also be reacted c) with a vinyl ether of formula (V). This reaction is carried out closest to one of the above-mentioned neutral solvents by adding acid catalysts (perchloric acid, p-toluenesulfonic acid, methanesulfonic acid, etc.). The reaction preferably takes place at a reaction temperature of -20 ° C to + 100 ° C.

Furthermore, steroids of formula (II) may also be reacted b) with a β-halogen ether of formula (IV). This reaction can be carried out, for example, in a neutral polar solvent such as acetonitrile, dimethylformamide, N-methyl-lipyrrolidone, or hexamethylphosphoric acid triamide by adding basic catalysts such as, for example, silver oxide, triethylamine or diisopropylethyl. The reaction preferably takes place at a reaction temperature of -20 ° C to + 100 ° C.

The above reactions give rise to corticoids of formula (I) in which Q represents an oxygen atom. To prepare corticoids in which Q represents a sulfur atom, the corticoids of formula (II) may be reacted with d) sulfoxides of formula (VI). This reaction can be carried out, for example, by reacting a sulfoxide and a steroid, if desired, in a neutral solvent (methylene chloride, tetrachloroethane, tetrahydrofuran, etc.) by adding anhydrides (mainly acetic anhydride) and acid catalysts (acetic acid, boron trifluoride, etc.) at about 20 ° to + 100 ° C.

7071 8

If hydroxycorticoids of formula (II) are used as starting compounds in A), it is expedient to protect the 11/5-hydroxy group temporarily in order to prevent its partial acetal-5 coupling. This can be done, for example, by converting the γ-hydroxy group into the corresponding nitrates, formates or trihaloacetates (especially trifluoroacetates) before acetalization, and after carrying out the process according to A) this ester is cleaved, e.g., esterification of 11β-hydroxycorticoids with nitric acid can be carried out. with gun-style nitrate prepared by mixing fuming nitric acid with acetic anhydride. After acetalization, the nitrates can then be converted again, for example by reaction with zinc dust in acetic acid, to 11β-hydroxycorticoids.

The esterification of 11β-hydroxycorticoids with formic acid can be carried out, for example, with formic acid-acetic anhydride using 4-dimethylaminopyridine as catalyst. The 1-formyloxycorticoids obtained after 17 PC acetalization can then be converted to the corresponding 11/5 hydroxy steroids by basic hydrolysis (e.g. with sodium methylate solution) or by enzymatic saponification.

The esterification of 11/5-hydroxycorticoids with trihaloacetic acid - in particular trifluoroacetic acid - can be carried out, for example, by reacting 11/9-hydroxycorticoids with trihaloacetic anhydride in pyridine. After 17 * E-acetalization, the trihaloacyl group can then be cleaved again by hydrolysis (e.g., in a low molecular weight alcohol with the addition of weakly basic catalysts such as sodium acetate or triethylamine).

li 5 70718

The methods of B) can also be carried out under conditions known per se (U.S. Patents 3,678,034, 3,718,671, 3,845,085 and 3,894,063). Thus, for example, a) 9,11-dehydro-5 steroids of formula (VII) can be reacted in a neutral solvent (acetic acid, tetrahydrofuran, dioxane, acetonitrile, etc.) with reagents such as water and acids (sulfuric acid, phosphoric acid, in the presence of perchloric acid, etc.) during the reaction, light decomposes with the alichloroacid, in particular halogen cation-forming reagents such as, for example, N-chloroacylamides (especially N-chloroacetamide) or N-chloroacylimides (especially N-chlorosuccinimide). In this reaction, the 9-L-chloro-11β-hydroxycorticides of formula (I) are obtained as main products, as are the corresponding 9β, 11β-dichlorocorticoids of formula I, often as by-products. The latter are obtained as main products if the reaction is carried out protected with water in the presence of hydrogen chloride as an acid.

On the other hand b) the epoxy ring of the 9,11-epoxysteroids of formula (VIII) can be opened with hydrogen chloride or hydrogen fluoride, e.g. by dissolving the compounds of formula (IV) in a neutral solvent saturated with hydrogen chloride or hydrogen fluoride and optionally introducing further chlorine -vetykaasua. Suitable neutral solvents are, for example, ethers (diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, etc.) or chlorinated hydrocarbons (methylene chloride, chloroform, tetrachloromethane, tetrachloroethane, etc.). In this reaction, M-fluoro or 9β-chloro-11β-hydroxycorticoids of formula (I) are formed.

In step c) to cleave halogen of the 9-halo steroids of formula 35 (IX), these can be reacted, e.g., in a neutral solvent in the presence of radical generators (azodiisobutyronitrile, di-tert-butyl peroxide, UV light, etc.) as trialkyltin hydride triethylhydride , tri-5-butyltin hydride, etc.). Suitable neutral solvents are, for example, ethers (diethyl ether, Glycolide dimethyl ether, dioxane, tetrahydrofuran, hydrocarbons (cyclohexane, benzene, toluene, etc.), alcohols (methanol, ethanol / isopropanol, etc.) or nitriles (in acetonitrile, etc.). I) 11β-hydroxycorticoids having no substituents at the 9β position.

The cleavage of hydrogen halide from the 9-halo steroids of formula (IX) occurs under conditions commonly used in steroid chemistry to cleave hydrogen halide from halohydrins. Thus, for example, compounds of formula (IX) may be heated to reflux in a tertiary amine such as pyridine, lutidine or especially collidine.

Another suitable method of cleaving hydrogen bromide is, for example, the reaction of these compounds with lithium salts (lithium chloride, etc.) and / or calcium carbonate in dimethylformamide or dimethylacetamide. In these g reactions, za-corticoids of formula (I) are formed.

The starting materials of the formulas (VII) to (IX) used in B) of the process according to the invention can be prepared by acetalizing the corresponding 17β-hydroxy steroids under the conditions of A) or from 17-acetalized corticoids having no 9-position no substituents, by dehydrating these to 9,11-dehydrosteroids of formula (VII), attaching HBr to the 9,11-double bond, and converting the resulting 9-bromisterolites of formula (IX) with bases of formula (VIII) epoxides according to

li 7 071 8

The compounds obtained can, if desired, be further converted by dehydration of the 1,2-position of the saturated corticoids and / or by oxidation of the 11β-hydroxy group of these compounds to the 11-oxo group, and / or by saponification of the 21-ester groups and / or by esterifying the 21-hydroxy groups or exchanging them for fluorine atoms or chlorine atoms.

The conditions under which the 1,2-position of corticoids having a saturated 1,2-position can be de-10 hydrated will be described in the section below.

The preferred method is to esterify the 21-hydroxy group with a sulfonic acid, mainly methanesulfonic acid or p-toluenesulfonic acid, and then convert the sulfonic acid group to halogen. The esterification of the 21-hydroxy group 15 takes place, for example, by allowing the sulfonic acid chloride to act on the 21-hydroxysteroids in the presence of an organic base such as pyridine or in the presence of an aqueous alkali. The exchange of the sulfonic acid group for the halogen atom takes place mainly by reacting 21-sulfonic acid esters with an alkali metal halide such as lithium chloride or potassium hydrogen fluoride in the presence of a polar solvent such as dimethylformamide at a reaction temperature between 50 ° C and 180 ° C.

The novel corticoids of formula (I) have a very good anti-inflammatory effect and the distribution between the effectiveness of their desired local effect and the undesirable systemic side effect is very advantageous.

30 The effectiveness of a local effect can be determined by a vasoconstriction test as follows.

The experiment is performed using two groups of eight experimental animals of both sexes that have not been treated topically with corticosteroids in the last two weeks 12 7071 8. After removal of the stratum corneum from the back of the experimental animals -

Stratum lucidum (20-40 Thesaurus strips), a batch of 0.1 g is applied to these 2 sites on 4 cm areas without occlusive dressing. To avoid application of the same preparation to the same areas of the skin, the application is performed in a rotational order.

The experimenter assessed vasoconstriction visually after 4 and 8 hours using the following effect rating scale: 1 = complete brightness, 2 = slight residual redness, 3 = moderate redness, redness intensity between torn, untreated and undamaged skin, 4 - , among minor 15 light spots, 5 = no light spots or intensified redness.

Individual estimates are reported.

In each series of experiments, diflucortolone-21-valerianate (= 6, 9, 9, difluoro-11/9-20 hydroxy-16 * icmethyl-21-valeryloxy-1,4-pregnadiene-3,20-dione = DFV).

In each case, the difference between the mean potencies of DFV and the test substance reported in the private series shall be reported Λ. Positive Δ differences indicate that the test substance is judged to be more favorable than DFV, negative differences indicate that the test substance is judged to be less favorable than DFV.

The following tables show the observed experimental results obtained by treating the experimental subjects with a preparation containing 0.1 ppm of active ingredient.

The systemic efficacy of the compounds can be determined by the excipient swelling test as follows: 35 SPF rats weighing 130-150 g, 7071 8 are injected with 0.1 ml of 0.5% Mycobacterium butyricum suspension (available from the American company Difko) at the right back to induce inflammatory foci. -käpälään. Prior to injection, rat paw-5 volumes are measured. At 24 hours after injection, paw volumes are remeasured to determine the amount of swelling. Rats are then orally or subcutaneously administered varying amounts of test substance - dissolved in a mixture of 10% benzyl benzoate and 71% castor oil.

After the next 24 hours, the paw volumes are measured again.

Control animals are treated in the same manner, except that they are injected with a benzyl benzoate-castor oil mixture which does not contain the test substance.

From the paw volumes obtained, the amount of test substance required to reduce the swelling of the paws caused by the test by 50% is determined in the usual manner.

The following tables show the test results obtained, in which the substances according to the invention are compared with structurally analogous corticoids contained in commercial preparations.

7071 8

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tl 7071 8 19

In the galenic pharmacy, the new compounds are suitable for the treatment of contact dermatitis, a wide variety of herbs, neurological skin disorders, skin erythema, burns, pubic and anal itching, erythema and redness, dermatitis, dandruff,

Special medicaments are prepared in the customary manner by bringing the active ingredients into the desired form of application with suitable additives, such as, for example, solutions, lotions, ointments, creams or patches. The active ingredient concentration of the drugs thus formulated depends on the form of application. The concentration of active ingredient used in washing liquids and ointments is mainly between 0.001 and 1%.

In addition, the novel compounds, possibly in combination with conventional carriers and excipients, are also suitable for the preparation of highly inhalable substances which can be used for the treatment of allergic diseases of the respiratory tract, such as, for example, asthma or nasal catarrh.

The new corticoids are also still suitable in the form of capsules, tablets or granules containing mainly 10-200 mg of active ingredient and applied orally or in the form of suspensions containing mainly 100-500 mg of active ingredient per dosage unit and applied rectum, including 30 intestinal allergic diseases such as

For the treatment of colitis sulcerosa and Kolitis granulomatosa.

The following examples are intended to illustrate the invention.

2o 7071 8

Example 1 21-Acetoxy-17,11-methoxymethoxy-4-pregnene-3,11,20-trione 6 g of cortisone acetate are dissolved in 120 ml of 5 formaldehyde dimethyl acetal and 120 ml of methylene chloride and a mixture of 12 g of phosphorus pentoxide and 24 g of phosphorus pentoxide is added under ice-cooling. g of milk. After stirring for 4.5 hours, the mixture is filtered, neutralized with triethylamine and the solvents are distilled off in vacuo. The residue is chromatographed on diatomaceous earth with toluene-acetic acid-ethyl ester mixtures to give 3.85 g of 21-acetoxy-17o <-methoxymethoxy-4-pregnene-3,11,20-trione, which melts at 160-161 ° C after recrystallization from methanol. Example 2 21-Acetoxy-9-chloro-11β-hydroxy-17β - (methoxymethoxy-4-pregene-3,20-dione a) 2 g of 21-acetoxy-11β-hydroxy-17α -methoxy-methoxy-4-pregnene-3,20-dione is dissolved in 20 ml of pyridine and, under ice-cooling, 0.6 ml of thionyl chloride are added. After 30 minutes, precipitate in ice-water and filter. 1.76 g of 21-acetoxy-17 * 6-methoxymethoxy-4,9 (11) -pregnadiene-3,20-dione are obtained, which melts at 194-196 ° C after recrystallization from methanol and a small amount of methylene chloride.

b) 5.0 g of 21-acetoxy-17α-methoxymethoxy-4,9 (11) -pregnadiene-3,20-dione are suspended in 50 ml of tetrahydrofuran and 20.56 ml of 1-norm are added at + 20 ° C. .

30 perchloric acid and 5.14 g of N-bromosuccinimide. It is then stirred for 15 minutes. The reaction mixture is precipitated in a solution of 5.14 g of sodium sulfite and 350 ml of ice water. The crystallization is filtered off, washed with water until neutral and the still moist crystallization is recrystallized from methanol / water. 5.70 g of 21-acetoxy-9α-bromo-11β-hydroxy-17β-methoxymethoxy-4-pregnene-3,20-dione with a melting point of 130-131 ° C are obtained. .

c) 51.8 g of 21-acetoxy-9e6-bromo-1β-hydroxy-5,17β-methoxymethoxy-4-pregnene-3,20-dione are suspended in 518 ml of ethanol and 45.3 g of anhydrous potassium acetate are added. The mixture is refluxed for one hour and, after cooling to + 20 [deg.] C., 5180 ml of ice-water mixture are precipitated. The crystal is filtered off, washed with water and dried at + 20 ° C. 41.75 g of 21-acetoxy-9β, 11β-epoxy-17β-methoxymethoxy-4-pregnene-3,20-dione are obtained, melting at 138-139.5 ° C after recrystallization from methanol: in.

D) 1.0 g of 21-acetoxy-9H-1,3-epoxy-17e6-ethoxymethoxy-4-pregene-3,20-dione is dissolved in 10 ml of methylene chloride and cooled with ice water. Hydrochloric acid gas dried over sulfuric acid is introduced slowly into the solution until the plate chromatogram shows that no starting material is present. The reaction mixture is precipitated in 120 ml of 1% sodium hydrogen carbonate solution. The methylene chloride phase is separated off, washed neutral with water, dried and evaporated to dryness. 1.1 g of 21-acetoxy-9,4-chloro-11β-hydroxy-17β-methoxymethoxy-4-pregnene-3,20-dione with a melting point of 194.5 ° C after recrystallization are obtained.

Example 3 21-Acetoxy-9et-chloro-11β-hydroxy-17β-methoxy-methoxy-4-pregnene-3,20-dione 0.5 g of 21-acetoxy-170β-methoxymethoxy-4,9 (11) - pregnadiene-3,20-dione is suspended in 50 ml of tetrahydrofuran and 20.56 ml of 1-norm are added at + 20 ° C. perchloric acid and 2.78 g of N-chlorosuccinimide. After stirring for 74 hours, a further 3.52 ml of 70% perchloric acid are added over a period of 35 hours.

The reaction mixture is precipitated in a solution of 5.14 g of sodium sulfite and 350 ml of ice water. The crystallization is filtered off, washed neutral with water, and the wet crystallization is recrystallized from a methanol / water mixture. 1.5 g of 21-acetoxy-9β-chloro-11β-hydroxy-17β-methoxymethoxy-4-pregnene-3,20-dione are obtained, which, after recrystallization from ethyl acetate and acetone, melts 189 -192 ° C.

Example 4- 21-Acetoxy-9H-fluoro-11β, 17? -Dimethoxymethoxy-10 4-pregnene-3,20-dione 10 g of 9e-fluorohydrocortisone acetate are dissolved in 67.4 ml of methylene chloride and 134.8 ml of methylate and cooled in an ice-methanol bath.

To this solution is added 10 g of phosphorus pentoxide mixed with 20 g of diatomaceous earth and then stirred at -15 ° C for 5 hours. The solution is filtered and neutralized with triethylamine11a. After distilling off the solvent, distill once more using methanol and the residue is crystallized from methanol. The products are separated by chromatography on silica gel with methylene chloride + 5% methanol to give 3.28 g of 21-acetoxy-90-fluoro-1,17 ° -dimethoxymethoxy-4-pregene-3,20-dione with a melting point of 132- 134 ° C, 0.56 g of 21-acetoxy-9-oc-fluoro-N 3 -hydroxy-17β-methoxymethoxy-25 4-pregnene-3,20-dione with a melting point of 211-214 ° C and 0, 79 g of 21-acetoxy-9-trifluoro-17β-hydroxy-11β-methoxymethoxy-4-pregnene-3,20-dione, m.p. 196-199 ° C.

Example 5 30 9'-Chloro-11β, 21-dihydroxy-17β-methoxymethoxy-4-pregnene-3,20-dione 5.0 g of 21-acetoxy-9α-chloro-11H-hydroxy-17 N-methoxymethoxy-4-pregnene-3,20-dione is suspended in 10 ml of methylene chloride and 20 ml of methanol and cooled to + 3 ° C. Within 5 minutes, a solution of 0.31 g of potassium is added dropwise.

»I

23 7071 8 hydroxide in 11 ml of methanol and then stirred for 80 minutes. The reaction mixture is neutralized with 0.34 ml of glacial acetic acid and mixed with 350 ml of water. The crystallization is filtered off and dried. 2.32 g of 5 9 <4 -chloro-11 / 3,21-dihydroxy-17® <-methoxymethoxy-4-pregnene-3,20-dione are obtained, having a melting point of 188-189 after recrystallization from methanol-methylene chloride. ° C.

Example 6 21-Acetoxy-11/5-hydroxy-17β-methylthiomethoxy-1,4-pregnadiene-3,20-dione a) to a solution of 5.0 g of prednisolone-21-acetate in 25 ml pyridine, is added dropwise at -15 ° C by dropwise addition of 3 ml of trifluoroacetic anhydride and stirred for 10 minutes at -10 ° C. This is added to ice-water-brine and the precipitate is filtered off. The residue is dissolved in methylene chloride, washed neutral and, after drying over sodium sulfate, evaporated to dryness in vacuo. Yield 6.3 g of 21-acetoxy-20-si-17β-hydroxy-11β-trifluoroacetoxy-1,4-pregnadiene-3,20-dione.

b) 3.0 g of the above crude product are stirred at room temperature overnight in a mixture of 25 ml of dimethyl sulfoxide, 15 ml of acetic anhydride and 4.8 ml of glacial acetic acid. The reaction solution is added to 10% sodium carbonate solution and the precipitate is filtered off. The residue is dissolved in methylene chloride and, after washing to neutral, proceed as usual. After chromatography, using 350 mg of silica gel and mixtures of methylene chloride-acetone (0-8% acetone), 2.83 g of 21-acetoxy-17β-methylthiomethoxy-11β-trifluoroacetoxy-1,4-pregna-diene are isolated. -3, 20-dione.

c) A mixture of 1.5 g of 21-acetoxy-17β- [3-yl] thiomethoxy-1β-trifluoroacetoxy-1,4-pregnadi-24 7071 8 ene-3,20-dione in 38 ml of methanol and 1 , 9 ml of triethylamine, are stirred for 4 hours at room temperature.

The crude product is purified on 300 g of silica gel with 5 methylene chloride-acetone mixtures (0-8% acetone) and 1.2 g of 21-acetoxy-11H-hydroxy-17α-methylthioethoxy-1,4-pregnadiene-3,20-acetone are isolated. dione, melting point 155 ° C.

Example 7 21-Acetoxy-9β-fluoro-11β-hydroxy-17et-methylthiomethoxy-4-pregene-3,20-dione a) 20.0 g of 21-acetoxy-9-ethyl -fluoro-11β-17β-dihydroxy-4-pregnene-3,20-dione is reacted according to Example 6a) with trifluoroacetic anhydride to give 23.6 g of 15-oxy-21β-fluoro-17α-hydroxy-11 3-trifluoroacetoxy-4-pregnene-3,20-dione.

b) 3.0 g of the above crude product are treated according to Example 6b) with dimethyl sulfoxide, acetic anhydride and glacial acetic acid. The crude product 20 is purified on 300 g of silica gel with methylene chloride-acetone mixtures (0-8% acetone).

The resulting 58.5 g of 21-acetoxy-9-fluoro-17β-methylthiomethoxy-1-trifluoroacetoxy-4-pregnene-3,20-dione is reacted in 28 ml of methanol with 1.4 ml of triethylamine of Example 6c). and the crude product is purified on 100 g of silica gel with methyl chloride-acetone mixtures (0-12% acetone). Yield 914 mg of 21-acetoxy-9α-fluoro-11β-hydroxy-17α-methylthiomethoxy-4-pregnene-3,20-dione. Melting point 193 ° C.

Example 8 21-Acetoxy-90β-chloro-1H-hydroxy-17o (r (1,3,6-trioxaheptyl-1,4-pregnadiene-3,20-dione and 21-acetoxy-9H-11,11) N-dichloro-17β (r (1,3,6-trioxaheptyl) -1,4-pregnadiene-3,20-dione 35 a) To a suspension of 6.0 g of 21-acetoxy-17α-hydroxy-1 , 4,9-pregnatriene-3,20-dione in 46 ml of aqueous acetonitrile, 11.5 ml of methoxyethoxymethyl chloride and 11.5 ml of diisopropylethylamine are added and the mixture is stirred for 7.5 hours. After precipitation with ice water, the separated precipitate is dissolved in methylene chloride, washed neutral and evaporated to dryness after drying, and the reaction product is purified on 800 g of silica gel with hexane-ethyl acetate mixtures (0-30% ethyl acetate). , 9 g of 21-acetoxy-17α- (1,3,6-trioxaheptyl) -1,4,9-pregnatri-10-ene-3,20-dione, melting point 140 ° C.

b) To a solution of 1.0 g of 21-acetoxy-17β- (1,3,6-trioxaheptyl) -1,4,9-pregnatriene-3,20-dione in 10 ml of dioxane is added 900 mg of N-chlorosuccinate. -ni-imide and 5 ml of 10% perchloric acid. The mixture is stirred for 3.5 hours at room temperature and the mixture is added to an ice-water-brine-sodium hydrogen sulfate solution. Filter and dissolve the residue in methylene chloride, wash until neutral and evaporate to dryness after drying over sodium sulphate. The crude product is purified on 100 g of silica gel with methylene chloride-acetone (0-15% acetone).

Yield 760 mg of 2'-acetoxy-9H-chloro-11H-hydroxy-17-N- (1,3,6-trioxaheptyl) -1,4-pregnadiene-3,20-dione (melting point 204 °) C), and 180 mg of 21-acetoxy-25,9,11,9-dichloro-17β- (1,3,6-trioxaheptyl) -1,4-pregadienene-3,20-dione (melting point 148 ° C).

Example __9_ 21-Acetoxy-9β-chloro-11β-hydroxy-17,4-methoxy-methoxy-1,4-pregnadiene-3,20-dione and 21-30-acetoxy-9β, 11β-dichloro-17 N-methoxymethoxy-1,4-pregnadiene-3,20-dione a) Dissolve 4 g of 21-acetoxy-17,6-hydroxy-1,4,9-pregna-triene-3,20-dione in 28 ml of: anhydrous methylene chloride and 18 ml of formaldehyde dimethyl-35 cetal and a mixture of 6.0 g of Kieselgur W 20 and 3.0 g of phosphorus pentoxide is added portionwise.

26 7071 8

It is then stirred for 45 minutes at room temperature, filtered and the residue is eluted once more with methylene chloride containing 3-5% of triethylamine. The crude product is purified on 750 g of silica gel with methylene chloride-acetone mixtures (0-12% acetone).

Yield 3.3 g of 21-acetoxy-170β-methoxymethoxy-1,4,9-pregnatriene-3,20-dione, m.p. 160 ° C.

b) 1.6 g of 21-acetoxy-17c (.-methoxymethoxy-1,4,9-pregnatriene-3,20-dione) are dissolved in 16 ml of dioxane-10 and 1.5 g of N-chlorosuccinimide are added. is added dropwise to 8 ml of a 10% aqueous solution of perchloric acid, stirred for a further 3 hours at room temperature and the mixture is added to an ice-water-brine-sodium hydrogen sulphite solution, filtered and further treated as in Example 2. The crude product is purified on 175 g of silica gel with methylene chloride. -acetone mixture (0-12% acetone) Yield 1.1 g of 21-acetoxy-9H-chloro-11β-hydroxy-17β-methoxymethoxy-1,4-pregadiene-3,20-dione (melting point 224 ° C), and 250 mg of 21-acetoxy-dichloro-17α-methoxymethoxy-1,4-pregnadiene-3,20-dione, melting point 162 ° C.

Example 10 21-Acetoxy-11β-hydroxy-17α- (1,3,6-trioxaheptyl) -1,4,8-pregnatriene-3,20-dione 25 a) 1.8 g of 21-acetoxy 17 Jr (1,3,6-trioxaheptyl) -1,4,9-pregnatriene-3,20-dione are dissolved in 18 ml of dioxane and 1.6 g of N-bromosuccinimide are added.

After adding dropwise 8.5 ml of a 10% aqueous solution of perchloric acid, the mixture is further stirred for 30 to 30 minutes at room temperature, and the mixture is added to an ice-water-brine-sodium hydrogen sulfite solution. Further processing is performed according to Example 5. 2.3 g of crude 21-acetoxy-9? -Bromo-1-hydroxy-17o4- (1,3,6-trioxaheptyl) -1,4-pregnadiene-3,20-dione are obtained.

277071 8 b) 2.0 g of the above crude product are dissolved in 20 ml of hexamethylphosphoric acid triamide and the solution is stirred for 0.5 hours at a bath temperature of 80 ° C with 2.4 g of lithium chloride. After precipitation with ice-water-boiling-5a, the mixture is filtered and further processed as usual. The limb product is purified on 350 g of silica gel with methylene chloride-acetone mixtures (0-15% acetone). Yield 570 mg of 21-acetoxy-11β-hydroxy-17,6- (1,3,6-trioxaheptyl) -10 1,4,8-pregnatriene-3,20-dione. Melting point 170 ° C.

Example 11 21-Acetoxy-9-chloro-11β-hydroxy-17-methoxy-methoxy-4-pregnene-3,20-dione a) 3.2 g of tris-triphenylphosphine rhodium (I) -15 chloride are dissolved in the mixture. with 100 ml of methanol and 300 ml of benzene and prehydrated for 1.5 hours.

After adding 4.0 g of 21-acetoxy-17β-methoxymethoxy-1,4,9-pregnatriene-3,20-dione, it is further hydrogenated for 6.5 hours under normal pressure. The solution is concentrated on a rotary evaporator and the residue is purified on 400 g of silica gel with methylene chloride-acetone (0-12% acetone). Yield 2.1 g of 21-acetoxy-17α-methoxymethoxy-4,9-pregnadiene-3,20-dione.

b) 1.1 g of 21-acetoxy-17β-methoxymethoxy-4,9-pregnadiene-3,20-dione are treated according to Example 9b) with N-chlorosuccinimide and perchloric acid. After purification, 430 mg of 21-acetoxy-9α-chloro-11β-hydroxy-17β-methoxy-methoxy-4-pregnene-3,20-dione are isolated. Melting point 195 ° C.

30 Example 12

O, N-dichloro-11β-hydroxy-17β (methoxymethoxy-4-pregnene-3,20-dione) 17.5 g of 21-chloro-17β-hydroxy-4,9-pregnadiene-3, The 20-dione is reacted with 236 ml of form-35 aldehyde dimethyl acetal and further treated according to Example 9 a).

28 7071 8

The crude product is purified on 2.25 kg of silica gel with methylene chloride-acetone mixtures (0-4% acetone). Yield 7.6 g of 21-chloro-17β-methoxymethoxy-4,9-pregnadiene-3,20-dione. Melting point 152 ° C.

B) 1.8 g of 21-chloro-170β-methoxymethoxy-4,9-pregadiene-3,20-dione are treated according to Example 9b) with N-chlorosuccinimide and perchloric acid. The crude product is purified on 100 g of silica gel with methylene chloride-acetone mixtures (0-10% acetone). 126 mg of 9α, 21-dichloro-11β-hydroxy-17β-methoxymethoxy-4-pregnene-3,20-dione are isolated. Melting point 197 ° C (decomp.).

Example 13 9et-Chloro-21-fluoro-11H-hydroxy-17α-methoxy-15-methoxy-1,4-pregnadiene-3,20-dione a) 3.0 g of 21-fluoro-17α-hydroxy 1,4-Pregna-triene-3,20-dione is reacted according to Example 9a) with 14 ml of formaldehyde dimethyl acetal. Further work-up takes place under the conditions described in Example 4. The crude product is purified on 450 g of silica gel with methylene chloride-acetone mixtures (0-8% acetone). Yield 1.5 g of 21-fluoro-17β-methoxymethoxy-1,4,9-pregnatriene-3,20-dione.

b) 500 mg of 21-fluoro-17β-methoxymethoxy-1,4,9-25 pregnatriene-3,20-dione are reacted with N-chlorosuccinimide and perchloric acid under the conditions of Example 9b). After the work-up instructions already described and the purification on silica gel, 420 mg of 9 * 4-chloro-21-fluoro-11H-hydroxy-17o4-methoxide-1,4-pregnate are isolated. en - 3,20-dione. Melting point 245 ° C.

Example 14 9 Urine-1-hydroxy-17β-methoxymethoxy-1,4-pregnadiene-3,20-dione 35 a) 1.0 g of 17β-hydroxy-1,4,9-pregnatriene-3 , 20-dione is reacted under the conditions of Example 9a) with formaldehyde dimethyl acetal. 82 mg of 17β-methoxymethoxy-1,4,9-pregnatriecni-3,20-dione are isolated as a crude product.

b) 823 g of the above crude product are treated in accordance with Example 9 b) with N-chlorosuccinimide and perchloric acid, and further treatment and purification of the product are carried out under the conditions described therein. Yield 410 mg of 9β-chloro-11β-hydroxy-17α (methoxymethoxy-1,4-pregnadiene-3,20-dione. Su-10 mp 227 ° C.

Example 1 21-Fluoro-1-hydroxy-17α-methoxymethoxy-1,4,8-pregnatriene-3,20-dione a) 1.0 g of 21-fluoro-17β-methoxymethoxy-1 The 1,4,9-pregnatriene-3,20-dione is treated under the conditions of Example 10 a) with 900 mg of N-bromosuccinimide and 5 ml of a 10% aqueous solution of perchloric acid. 1.1 g of 9et-bromo-21-fluoro-1H-hydroxy-17α-methoxymethoxy-1,4-pregna-20-diene-3,20-dione are isolated.

b) 1.1 g of crude 9α-α-bromo-21-fluoro-11β-hydroxy-17β-methoxymethoxy-1,4-pregnadiene-3,20-dione are reacted according to Example 10 b) 1.4 with g of lithium chloride to 21-fluoro-11β-hydroxy-17α-methoxymethoxy-1,4,8-pregnatriene-3,20-dione. I get to 490 mg. Melting point 218 ° C.

Example 16 21-Chloro-H / 3-hydroxy-170β-methoxymethoxy-1,4,8-pregnatriene-3,20-dione 30 a) 3.3 g of 21-chloro-17α-hydroxy-1,4, 9-pregna triene -3,20-dione is reacted with formaldehyde dimethyl acetal under the conditions of Example 9a). 2.4 g of 21-chloro-17α-methoxymethoxy-1,4,9-pregnatriene-3,20-dione are isolated.

B) 1.4 g of 21-chloro-17β-methoxymethoxy-1,4,9-pregnatriene-3,20-dione are treated according to Example 10a) with N-bromosuccinimide and isolated as a crude product 1 7.7 g of 9o-bromo-21-chloro-5H-hydroxy-17et-methoxymethoxy-1,4-pregnadiene-3,20-dione.

c) 1.7 g of 9-hydrobromo-21-chloro-11H-hydroxy-17β-methoxymethoxy-1,4-pregnadiene-3,20-dione are reacted under the conditions of Example 10 b) with 2.1 g of 10 with lithium chloride. The crude product is purified on 300 g of silica gel with methylene chloride-acetone mixtures (0-8% acetone). Yield 530 mg of 21-chloro-11β-hydroxyl-17,76-methoxymethoxy-1,4,8-pregnatriene-3,20-dione. Melting point 166 ° C.

Example 17 9e-Chloro-21-fluoro-11H-hydroxy-17β-methoxy-methoxy-4-pregnene-3,20-dione a) 7.6 g of 21-fluoro-17e ( rhydroxy-4,9-pregadiene-3,20-dione and 68 ml of formaldehyde dimethyl acetal are prepared according to Example 14 with 3.4 g of 21-fluoro-17α-methoxymethoxy-4,9-pregnadiene-3,20-dione .

b) 1.4 g of 21-fluoro-17-methoxymethoxy-4,9-pregnadiene-3,20-dione are treated under the conditions of Example 12 b) 25 with N-chlorosuccinimide and perchloric acid. The crude product is purified on 100 g of silica gel with methylene chloride-acetone mixtures (0-10% acetone). Yield 380 mg of 9-chloro-21-fluoro-11β-hydroxy-17eC-methoxymethoxy-4-pregnene-3,20-dione. Melting point 214 ° C (decomposed).

Example 18 9α-Fluoro-11H-hydroxy-17α-methoxymethoxy-21-propionyloxy-1,4-pregnadiene-3,20-dione a) To a mixture of 100 ml of pyridine and 12 ml of trifluoroacetic anhydride is added -10 At 31 ° C 71.071.0 g of 9-fluoro-11,17,4-dihydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione and then stirred for 10 minutes at -10 ° C. After precipitation in ice water, the mixture is filtered and the residue is dissolved in methylene chloride. After washing and drying the organic solution is evaporated to dryness in vacuo to give 22.0 g of 9-fluoro-17β-hydroxy-21-propionyloxy-11,6-trifluoroacetoxy-1,4-pregnadiene-3, 20-diol-ketone.

10 b) 22.0 g of the above crude product are reacted under the conditions of Example 9 a) with 90 ml of formaldehyde dimethyl acetal to isolate 9α-fluoro-17α-methoxymethoxy-21-propionyloxy-11β-trifluoro-15 acetoxy-1,4-pregnadiene-3,20-dione.

c) The crude fluoro-17β-methoxy oxy-21-propionyloxy-11β-trifluoroacetoxy-1,4-pregnadiene-3,20-dione is dissolved in 500 ml of methanol and, after adding 25 ml of triethylamine, stirred for 20 hours. another 30 minutes at room temperature. The reaction solution is evaporated to dryness in vacuo and the residue is chromatographed on 2.25 kg of silica gel with methylene chloride-acetone mixtures (0-12% acetone).

Yield 12.3 g of 9β-fluoro-11/6-hydroxy-17 ° C-methoxymethoxy-21-propionyloxy-1,4-pregnadiene-3,20-dione. Melting point 241 ° C.

Example 19 21-Butyryloxy-9 * (rf fluoro-hydroxy-17oE-methoxymethoxy-1,4-pregnadiene-3,20-dione 30a) 1.0 g of 21-butyryloxy-9o (-fluoro-11/3, 17-Dihydroxy-1,4-pregnadiene-3,20-dione is reacted with trifluoroacetic anhydride and further treated under the conditions of Example 18 a). 0.9 g of 21-butyryloxy-9,4-fluoro-35β-hydroxy-11/6 -trifluoroacetoxy-1,4-pregnadiene-7071 8 3/20-dione are isolated.

b) 800 mg of the above crude product are treated according to Example 18 b) with 3.6 ml of formaldehyde dimethyl acetal. After further work-up, 1.1 g of crude 21-butyryloxy-90-fluoro-17o (.-Methoxymethoxy-N, N-trifluoroacetoxy-1,4-pregnadiene-3,20-dione) are obtained.

c) 1.1 g of crude 21-butyryloxy-9β, fluoro-17,4-methoxymethoxy-11H-trifluoroacetoxy-1,4-pregnadiene-10,20-dione are reacted according to Example 18 b) with triethylamine. with. The crude product is chromatographed on 75 g of silica gel with methylene chloride-acetone mixtures (0-15% acetone). Yield 540 mg of 21-butyryloxy-9eC-fluoro-11β-hydroxy-17β-methoxymethoxy-1,4,4-pregnadiene-3,20-dione. Melting point 247 ° C.

Example .20_ 2 1-Butyryloxy-9H-fluoro-17β-methoxymethoxy-1,4-pregnadiene-3,11,20-trione 2.0 g of 21-buryryloxy-9H-fluoro-17β -hydroxy-1,4-pregnadiene-3,11,20-trione is reacted with 9 ml of formaldehyde dimethyl acetal and further treated according to Example 9 a). The crude product is purified on 300 g of silica gel with methylene chloride-acetone mixtures (0-10% acetone). Yield 2.07 g of 21-bu-25yryloxy-9β-fluoro-170β, methoxymethoxy-1,4-pregnadiene-3,11,20-trione. Melting point 192 ° C.

Example 21 21-Butyryloxy-9-fluoro-17-ol - (1,3,6-trioxaheptyl) -1,4-pregnadiene-3,11,20-trione 30,700 mg of 21-butyryloxy-9 Fluoro-17α-hydroxy-1,4-pregnadiene-3,11,20-trione is reacted according to Example 8 with 1.54 ml of methoxyethoxymethyl chloride. The crude product is purified on 135 g of silica gel with methylene chloride-acetone mixtures (0-5% acetone). Yield 430 mg of 21-butyryloxy-9β-fluoro-17α- (1,3,6-trioxaheptyl) -1,4-pregnadiene-3,11,20-trio-

II

7071 8 nia. Melting point 126 C.

Example 22 9α-fluoro-11β-hydroxy-17α-methoxymethoxy-16β-methyl-21-propionyloxy-1,4-pregnadiene-5,20-dione a) 15.2 g of 9β-fluoro-ββ, 17β-dihydroxy-16β-methyl-21-propionyloxy-1,4-pregnadiene-3,20-dione, prepared from 9-fluoro-11β, 17β, 21-trihydroxy-16β-methyl- 1,4-pregnadiene-3,20-dione and propionic anhydride, is treated according to Example 18 a) with 9.1 ml of trifluoroacetic anhydride. 15.4 g of 9 - (- fluoro-17α-hydroxy-16β-methyl-21-propionyloxy-1-trifluoroacetoxy-1,4-pregna-diene-3,20-dione are obtained.

15 b) 15.4 g of the above crude product are reacted with formaldehyde dimethyl acetal under the conditions of Example 18 b) with 9-fluoro-17β-methoxymethoxy-16β-methyl-21-propionyloxy-11β-trifluoroacetoxy-1,4- -pregnadiene-3,20-dione.

Yield 16.9 g of crude product.

c) A solution of crude% 1r fluoro-170, t * methoxymethoxy-16β-methyl-21-propionyloxy-1-trifluoroacetoxy-1,4-pregnadiene-3,20-dione in 250 ml of methanol is treated as in Example 18 c) with 30 ml of triethylamine. After further work-up, the crude product is purified on 1.5 kg of silica gel with methyl i-chloride-acetone mixtures (0-10% acetone). Yield 9.6 g of 9β-fluoro-11β-hydroxy-17β-methoxymethoxy-16β-methyl-21-propionyloxy-1,4-pregnadiene-3,20-dione.

Melting point 169 ° C.

Example 23 9 N, N-fluoro-11β-hydroxy-17α (-methoxymethoxy-16β-methyl-21-propionyloxy-4-pregnene-3,20-dione 35,600 mg of 9β-fluoro-11β-hydroxy -17α4-methoxime-34,7071 8 Tox-16β-methyl-21-propionyloxy-1,4-pregnadiene-3,20-dione is hydrogenated with 500 mg of tris-triphenylphosphine rhodium (I) chloride and treated in the same manner as in Example 11a. ). After chromatography of the crude product on 65 g of silica gel with methylene chloride-acetone mixtures (0-10% acetone), 347 mg of 9β-fluoro-11β-hydroxy-17α-ethoxymethoxy-16-methyl-21-propionyloxy-4 -pregnene-3,20-dione. Melting point 165 ° C.

Example 24 9-fluoro-11,21-dihydroxy-17α- (methoxymethoxy-16H-methyl-1,4-pregnadiene-3,20-dione A suspension of 6.9 g of 9 '(4-fluoro-11 N-hydroxy-17α-methoxymethoxy-16β-methyl-21-propionyl-15-hydroxy-1,4-pregnadiene-3,20-dione in 80 ml of a 0.2 N solution of potassium hydroxide in methanol, stirred for 45 minutes At 0 [deg.] C. After precipitation with 10% acetic acid and ice water and further work-up, the crude product is obtained, which is purified on 450 g of 20 g of silica gel with methylene chloride-acetone mixtures (0-20% acetone) Yield 4.1 g 9 * lrf chloro-11β, 21-dihydroxy-17-ol, methoxymethoxy-16β-methyl-1,4-pregnadiene-3,20-dione Melting point 220 ° C.

Example 25 21-Chloro-9β-fluoro-11β-hydroxy-17β-methoxymethoxy-16β-methyl-1,4-pregnadiene-3,20-dione a) a solution in which 1.7 g of 9β-fluoro-11β, 21-dihydroxy-17β-methoxymethoxy-16β-methyl-1,4-pregna-diene-3,20-dione in 17 ml of pyridine are stirred For -30 n at room temperature with 2.04 g of tosyl chloride. After precipitation with ice water, the precipitate is dissolved in methylene chloride and further worked up as usual. The crude product is purified on 135 g of silica gel with methylene chloride-acetone mixtures (0-10% acetone). Yield 876 mg of 9β-fluoro-11β-hydroxy-17α-remo-357071 8 cimethoxy-16β-methyl-21-tosyloxy-1,4-pregnadiene-3,20-dione.

b) 876 mg of the above product are stirred for 1 hour at 80 [deg.] C. in 17 ml of hexamethylphosphoric acid triamide with 880 mg of lithium chloride. The mixture is poured into ice water and the precipitate is filtered off. After the usual work-up, the crude product is recrystallized from hexane-acetone. Yield 485 mg of 21-chloro-9β-fluoro-11β-hydroxy-17β-methoxy oxy-10,16β-methyl-1,4-pregnadiene-3,20-dione. Melting point 204 ° C.

Example 2 6-21-Chloro-9β-fluoro-11/5-hydroxy-17α-4-methoxymethoxy-1,4-pregnadiene-3,20-dione 15 a) To a suspension of 11.2 g of 9β / 7-Fluoro-11β-hydroxy-17β-methoxymethoxy-21-propionyloxy-1,4-pregnadiene-3,20-dione is added 129 ml of 0.2-norm. methanolic solution of potassium hydroxide. Stir for 1 hour at room temperature and work up as described in Example 24. After chromatography on 1.5 kg of silica gel with methylene chloride-acetone mixtures (0-35% acetone), 7.5 g of 9 <jE-fluoro-11 / ¾, 2 l -dihydroxy-17 JLrmethoxy are isolated. ime toxi-1,4-pregnadiene-3,20-dione.

B) 1.0 g of the above crude product is reacted according to Example 25a with 2.0 g of tosyl chloride. The crude product is purified on 200 g of silica gel with methylene chloride-acetone mixtures (0-10% acetone). Yield 886 mg of 9β-fluoro-11H-hydroxy-17β-methoxy-30-methoxy-21-tosyloxy-1,4-pregnadiene-3,20-dione.

c) 886 mg of 9β-fluoro-11β-hydroxy-17β-methoxy-methoxy-21-tosyloxy-1,4-pregnadiene-3,20-dione are treated with lithium chloride and further treated in the same manner as in Example 25 b). conditions. Purification is by recrystallization from acetone / hexane. Yield 392 mg of 21-chloro-9β-fluoro-lift-hydroxy-17 ° C-methoxymethoxy-1,4-pregnadiene-3,20-dione. Melting point 225 ° C.

Example 27 21-Acetoxy-906-fluoro-11/0-hydroxy-17α-methoxymethoxy-4-pregnene-3,20-dione a) 20.0 g of 21-acetoxy-9H-fluoro-11 Η 5,17-dihydroxy-4-pregnene-3,20-dione is reacted according to Example 18 a) with 12 ml of trifluoromethylic anhydride with 21-acetoxy-9α-fluoro-170β-hydroxy-11 N-trifluoroacetoxy-4-pregnene-3,20-dione.

b) 5.0 g of the above crude product are converted according to Example 9 a) with 22.5 ml of formaldehyde dimethyl acetal 21-acetoxy-9H-fluoro-17β-methoxymethoxy-11β-trifluoroacetoxy-4-pregnene-3 , 20-dione. Yield 5.3 g.

c) 5.3 g of 21-acetoxy-9 * i-fluoro-170 (> - methoxy-methoxy-1 H -trifluoroacetoxy-4-pregnene-3,20-dione are treated according to Example 18 c) with triethylamine 20. The crude product is purified on 500 g of silica gel with methylene chloride-acetone (0-8% acetone).

Yield 560 mg of 21-acetoxy-9 '(- fluoro-11β-hydroxy-17,11-methoxymethoxy-4-pregnene-3,20-dione.

Melting point 213 ° C.

Example 28 9H-Fluoro-11β-hydroxy-17β-methoxymethoxy-21-valeryloxy-4-pregnene-3,20-dione a) 28.0 g of 21-acetoxy-9β-fluoro-1β -hydroxy-17β-methoxymethoxy-4-pregnene-3,20-dione is saponified according to Example 24 with a methanolic solution of 0.2 M potassium hydroxide in 9-fluoro-11β, 21-dihydroxy-17β-methoxymethoxy-4- pregnene-3,20-dione.

b) A solution of 500 mg of 9β-fluoro-11β, 21-dihydroxy-17α-methoxymethoxy-4-pregnene-3,20-dione in 5 ml of pyridine is stirred for one hour at room temperature.

at 7.5 with n-valeric anhydride. After precipitation with ice water, the precipitate is filtered off and further worked up as usual. The crude product is purified on 400 g of silica gel with hexane-ethyl acetate mixtures (0-30% ethyl acetate). Yield 235 mg of 9β-fluoro-11β-hydroxy-17α-methoxymethoxy-21-valeryloxy-4-pregnene-3,20-dione. Melting point 181 ° C

Example 29 17β-Ethoxymethoxy-11β, 21-dihydroxy-1,4-pregadiene-3,20-dione a) 10.0 g of prednisolone-21-acetate are dissolved in a mixture of 40 g of 4-dimethylaminopyridine and 500 g of ml of methylene chloride, cool to -15 ° C and add 25 ml of acetic anhydride. Within 10 minutes, 10 ml of formic acid are added dropwise and stirring is continued for 135 minutes at -10 to -15 ° C. The solution is extracted with water, 4% hydrochloric acid and sodium hydrogen carbonate solution. The organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. The residue is recrystallized from methanol by adding a little methylene chloride to give 9.34 g of 21-acetoxy-1-formyloxy-17β-hydroxy-1,4-pregnadiene-3,20-dione, m.p. 221-223 ° C.

B) 5.0 g of 21-acetoxy-11H-formyloxy-17β-hydroxy-1,4-pregnadiene-3,20-dione are dissolved in 150 ml of methylene chloride and 30 ml of formaldehyde diethyl acetal and cooled. 0 ° C. With stirring, a mixture of 5 g of phosphorus pentoxide and 10 g of diatomaceous earth is added and stirred for 2.5 hours in an ice bath. The mixture is filtered, washed with methylene chloride and the pH is adjusted to 9 with triethylamine. After distilling off the solvents, 10.5 g of crude 21-acetoxy-17α-ethoxymethoxy-11/9-formyloxy-1,4-pregnadiene-3,20-35 are obtained. dione as a semi-solid mass.

36 7 0 7 1 8 c) 0.34 g of crude 21-acetoxy-17α-ethoxymethoxy-11β-formyloxy-1,4-pregnadiene-3,20-dione is dissolved in 13 ml of methanol and the solution is added to the solution under argon. with 0.126 g of sodium hydrogen carbonate in 1.32 ml of water at 60 ° C. The mixture is heated at reflux for 10 minutes, cooled, water is added and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate, evaporated to dryness and the residue is chromatographed on silica gel with toluene-ethyl acetate mixtures. 0.1 g of 11 .mu.l of ethoxymethoxy-1,1'-dihydroxy-1,4-pregnadiene-3,2-dione with a melting point of 149.5-152 [deg.] C. is obtained.

Example 30 21-Acetoxy-17α-ethoxymethoxy-9α-chloro-1-hydroxy-4-pregnene-3,20-dione a) 9.0 g of 21-acetoxy-17α-hydroxy-4,9 (11 ) pregadiene-3,2-dione is dissolved in 72 ml of formaldehyde diethyl acetal and 280 ml of methylene chloride and cooled to 0 ° C. With stirring, a mixture of 9.0 g of phosphorus pentoxide and 18 g of diatomaceous earth is added and stirred for 2.5 hours in an ice bath. The mixture is filtered and washed with methylene chloride. The pH of the solution is adjusted to 9 with triethylamine, concentrated and the residue is chromatographed on silica gel with toluene-ethyl acetate-25 mixtures. 5.93 g of 21-acetoxy-17α-ethoxymethoxy-4,9 (11) -pregnadiene-3,20-dione with a melting point of 167-169 ° C are obtained.

b) 5.8 g of 21-acetoxy-17α-retoxymethoxy-4,9 (11) -pregnadiene-3,20-dione are reacted under the conditions mentioned in Example 30b, without recrystallization, to give 7.6 g of crude 21-acetoxy-17β-ethoxymethoxy-9β-bromo-11α-hydroxy-4-pregene-3,2-dione as a glass.

c) 7.6 g of crude 21-acetoxy-17β-ethoxymethoxy-35,9β-bromo-11β-hydroxy-4-pregnene-3,20-dione are reacted under the conditions mentioned in Example 24c and the crude product the methanol solution is filtered using silica gel. 5.49 g of crude 21-acetoxy-17 * 4-recoxymethoxy-9-epoxy-4-pregnene-3,20-dione are obtained as an amorphous substance.

d) 5.4 g of crude 21-acetoxy-17β-ethoxymethoxy-9β-N-epoxy-4-pregnene-3,20-dione are reacted under the conditions mentioned in Example 24d. The crude product is chromatographed on silica gel with toluene-vinegar. -10 ester mixtures to give 1.78 g of 21-acetoxy-17β-ethoxymethoxy-9 * (.-Chloro-11β-hydroxy-4-pregnene-3,20-dione, m.p. 148-151 ° C). .

Example 31 31β, 21-Dihydroxy-17β-hexyloxymethoxy-4-15 pregnene-3,20-dione a) 6.0 g of hydrocortisone-21-acetate-II-formate are dissolved in 150 ml of methylene chloride. and 63 g of formaldehyde hexyl acetal and cooled to 10 ° C. Protected by argon, a mixture of 6 g of phosphorus pentoxide and 12 g of diatomaceous earth is added portionwise and the mixture is stirred for one hour at 10 ° C and for one hour at 15 ° C. The mixture is filtered, washed with methylene chloride and the pH is adjusted to 8 with triethylamine. The methylene chloride is evaporated off in vacuo and the residue is cooled in an ice bath. The solution is decanted off the separated oil and chromatographed on silica gel with toluene-ethyl acetate mixtures. 4.2 g of 21-acetoxy-11H-formyloxy-17β, hexyloxy oxy-4-pregene-3,20-dione are obtained, melting at 110 DEG C. after crystallization from pentane. :in.

b) 0.38 g of 21-acetoxy-11β-formyloxy-17β-hexyloxymethoxy-4-pregnene-3,20-dione is reacted under the conditions described in Example 29c to give 0.1 g of 11β-1,2,2-dihydroxy -17E-hexyloxy-35-methoxy-4-pregnene-3,20-dione.

40 7071 8

Example 32_17β-Benzyloxymethoxy-11β, 21-dihydroxy-4-pregnene-3,20-dione a) 6.0 g of hydrocortisone-21-acetate-11-form-5 -ate are dissolved in 150 ml of methylene chloride and 65 g to formaldehyde dibenzyl acetal, and a mixture of 6 g of phosphorus pentoxide and 12 g of diatomaceous earth is added portionwise in a water bath at room temperature with stirring under argon. After 4 hours, the mixture is filtered, washed with methylene chloride and the pH is adjusted to 8 with triethylamine. The methylene chloride is evaporated off in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate mixtures. 3.0 g of 21-acetoxy-17α-benzyloxime-15-toxo-11β-formyloxy-4-pregnene-3,20-dione are obtained.

b) 0.38 g of 21-acetoxy- [17? -benzyloxymethoxy-11β-formyloxy-4-pregnene-3,20-dione is reacted under the conditions described in Example 29c to give 0.11 g of 170β-benzyloxymethoxy-11β-dione. , 21-di-20 hydroxy-4-pregnene-3,20-dione.

Example 33 21-Acetoxy-11β-hydroxy-17e (methoxymethoxy-16-methylene-4-pregnene-3,20-dione 3,0 g 11β, 21-dihydroxy-17β (methoxymethoxy) 16-Methylene-4-pregnene-3,20-dione is dissolved in 12 ml of pyridine at + 20 [deg.] C. and 2.37 ml of acetic anhydride are added, and the reaction mixture is then stirred for 2 hours at -20 [deg.] C. and After crystallization from ethyl acetate, 2.74 g of 21-acetoxy-UA-hydroxy-17β (rme-toxomethoxy-16-ol) are precipitated, washed with water and dried. methylene-4-pregnene-3,20-dione with a melting point of 166-167 ° C.

Claims (8)

A process for the preparation of novel therapeutically useful corticoids of formula (I) FH 2 R 3 R 2 ° OCHQR; 10. X ............ (T) 'Z 15 where x is a bond. represents a single bond or a double bond, X is hydrogen, fluorine or methyl, Y is hydrogen and 20. is hydrogen, fluorine or chlorine, or Y and Z together form a carbon-carbon bond and Q is oxygen or sulfur, R1 is 1- An alkyl group or benzyl group having 8 carbon atoms, optionally truncated by an oxygen atom, and R 2 is hydrogen or an alkyl group having 1 to 4 carbon atoms, or R 1 and R 2 together represent a trimethylene group or a tetramethylene group, R 1 is hydrogen, fluorine, chlorine or a free or esterified hydroxy group and R 2 is hydrogen or methyl, characterized in that 42 7 071 8 A) 17 <> S-hydroxy asteroid of formula (II) CH 2 R 7 c = o HO 2 - - ° H 5 ID, zs 'io! X wherein ...., X, Y, Z and have the same meaning as above and R' ^ is hydrogen, fluorine, chlorine or an esterified hydroxy group, is reacted in a manner known per se, if desired 11 / ^ after temporary protection of the hydroxy group, a) with an acetal of formula (III) r2hc (or1) 2 (III), wherein R1 and R2 are as defined above, or b) with an X-halo ether of formula (IV) Hal-R 2 CH-OR 1 (IV), wherein R 1 and R 2 are as defined above and Hal is chlorine, bromine or iodine, or c) with a vinyl ether of formula (V) R'2CH = CH-ORj ^ (V) wherein R1 is as defined above and R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms, or d) a sulfoxide having formula (VI) r2ch2sor1 (VI), wherein R1 and R2 have the same meaning as above, or li 43 7071 8 B) in a manner known per se a) to a 9,11-dehydrosteroid of the formula CH-R, I 2 3 c = o I l 5 t ^ A- ~ -0C »QR1 10 -, X where ...., X, Q,, R2 / R ^ and R ^ have the same meaning as above, chlorine or alachloric acid is added, or 15 b) opened A 0.1-epoxysteroid of formula (VIII) 9H 2 R 3 p I, 2 C = O, -OCHQR 1 Π / R 4; ^. [..... "(VITI), f Ti 25 wherein ♦..., X, Q, R 1, R 2, R 3 and R 2 are as defined above, an epoxy ring with hydrogen fluoride or hydrogen chloride, or c) a halogen steroid having formula (IX) CH-R I R2 30 C = 0 HO I _ .. .. OCHQR,: f 'R4 -------- (IX)' z "3 5 X 44 7 0 71 8 where ...., X, Q, R R 2, R 2, R 2 and are as defined above and Z "is chlorine or bromine, cleaved Z" or H 2 ", and, if desired, the 1,2-position of the obtained corticoids having a saturated 1,2-position is dehydrated, and / or The 11β-hydroxy-5 group is oxidized to an oxo group, and / or the 21-ester groups are saponified and / or the 21-hydroxy groups are esterified or exchanged for fluorine atoms or chlorine atoms. 11 45 7071 8 For the preparation of corticosteroids in the form of a corticosteroid with formula (I) 5 f2 ** 3? 2 C = 0 I | __ OCHQR, 1 ”y ^ tvT '" R4. Ϊ. · ---- (X), · ρκγ lk 15 color bindningen .... betecnar en en publicindning eller dubbelbindning, X är väte, fluor eller methyl, Y är väte , ooh Z är väte, fluorine ell chlorine, eller Y and Z bildar gemensamt en kol-kolbindning, och Q är en syre eller svavel, ären 1-8 kolatomer innehällande, optionuellt av en 20 syreatom avbruten alkylgrupp, eller en benzylgrupp och R2 with the addition of 1-4 alkyl groups with R 1 and R 2 and R 2 is attached to a trimethylene group with a tetramethyl group, with the addition of fluorine, chlorine or a free or fatty acid hydroxy group with an R 2 and an alkyl group, 25 parts of the reaction group ) in the presence of 17 · 4-hydroxysteroids of formula (II) CH2R, 3 30 Y = 0 Jkr --- OH _R4 (II), Y 1 rz 3 5 -vk J 0 X 46 7071 8 color ...., X, Y, Z and the same column as the ovan and R '^ är väte, fluorine, chlorine or a hydroxyl group, if any of the following is used to give 11 hydroxyl groups 5 a) with acetal of formula (III) r2hc (or1) 2 (III), color Rx and R2 as the same as above, or b ) with a halogenated formulation (IV) 10 Hal-R2CH-OR1 (IV), color R1 and R2 in which the sample is oval and halogen is chlorine, bromine or iodine, or c) with a vinyl ether with formula (V) 15 R'2ch = CH-OR1 (V), color R ^ betecknar samma som ovan och and R'2 is used as an alkyl group with 1-3 cholaters, or d) with a sulfoxide from formula (VI), 20 r2ch2sor1 (VI) ), color R ^ and R2 betecknar samma som ovan, eller B) pä i och för sig känt sätt a) account en 9,11-dehydrosteroid med formuleln (VII) 25 CH-R, I? 2 C = 0 Iz OCHQR ^ 30 JT '(VII)' 35 X