DE2855465A1 - 17-Alpha-hydroxy-corticoid derivs. substd. by acetal or thio:acetal - antiinflammatories with greater topical activity than unsubstituted cpds. - Google Patents

Abstract

(A) Corticoids of formula (I) are new (the bonds ---- are single or double; X is H, F, Cl or Me; Y is H and Z is H, F or Cl, or Y and Z together form a C-C bond; V is beta-hydroxymethylene, beta-chloromethylene or carbonyl; W is methylene, ethylidene or vinylidene; Q is O or S; R1 is 1-8C alkyl, opt. interrupted by an O atom, or is benzyl and R2 is H or 1-4C alkyl, or R1 and R2 together form trimethylene or tetramethylene; R3 is H, F, Cl or a free or sterified OH gp.). (B) Prepn. of 11 beta-hydroxysteroids of the pregnane series, substd. in the 17 alpha position by acetal gps. of formula (X) comprises fermenting a similarly substd. 11-desoxysteroid of the pregnane series with a culture of Curvularia (pref. Curvularia lunata). (I) are antiinflammatories with a topical activity greater than that of the previously known 17 alpha-hydroxycroticoids and 17 alpha-hydroxycorticoids in which the 17 alpha-gp. has been esterified.

Description

New corticoids, procedures for theirs

Manufacture, their use and pharmaceuticals containing these corticoids preparations The invention concerns new corticosteroids, procedures too their manufacture, their use and pharmaceuticals containing these corticoids Preparations.

It has long been known that one has anti-inflammatory effects lra-hydroxycorticoids can increase their topical effectiveness by using their Esterified 17-hydroxy group. (Compare this with the overview presentation by Thomas L. Popper and Arthur S. Watnick, "Antiinflammatory Steroids in Antiinflammatory Agents "Volume 1, Academic Press, New Kork, San Francisco, London (1974) pages 268-271).

It has now been found that the topical effectiveness and / or the Dissociation between desired topical anti-inflammatory efficacy and undesirable systemic effectiveness can be increased if the hydrogen atom which the 17a-hydroxyl groups of these corticoids not through an ester but through substituted an acetal radical or a thioacetal radical.

The invention thus relates to new corticoids of the general formula I according to claim 1 and in particular those characterized in claims 2 to 64 and 71 Corticosteroids.

The new corticoids of the general formula I according to claim 1 can as substituent R1 a straight-chain or branched chain 1 to 8 or preferably Carrying alkyl radicals containing 1 to 6 carbon atoms. Examples of such alkyl radicals are the methyl radical, the ethyl radical, the propyl radical, the isopropyl radical, the butyl radical, the isobutyl radical, the tert-butyl radical, the pentyl radical, the isopentyl radical, the hexyl radical, the heptyl radical or the octyl radical. The alkyl radical of the substituent R1 can, however also be interrupted by an oxygen atom.

Such radicals are, for example, the 2-methoxyethoxy radical, the 3-Hethoxypropyloxyrest or the 2-Äthoxyäthoxyrest.

The corticoids of the general formula I an al'yl group containing 1 to 4 carbon atoms, such as the methyl group, carry the ethyl group, the propyl group, or the butyl group.

Noteworthy are those corticoids of general formula I in those R2 represents a hydrogen atom, since these cannot form mixtures of diastereomers.

The onset of action and the duration of action of the new corticoids as well their solubility in physiologically compatible solvents are just like b.ei the known corticoids in particular depending on whether and, if necessary, with which acid a hydroxyl group in the 21-position is esterified.

Acyloxy groups are preferably used as esterified 21-hydroxy groups R3 with 1 to 16 carbon atoms in the acyl radical, sulfate groups or phosphate groups in Consideration. Suitable acyloxy groups are, for example, those which differ from straight-chain or branched, saturated or unsaturated aliphatic mono- or dicarboxylic acids derive which in the usual way, for example by hydroxyl groups, amino groups or halogen atoms may be substituted.

Furthermore, radicals of cycloaliphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids, the can also be substituted in the usual way. As suitable acyloxy groups are for example: the formyloxy, acetoxy, propionyloxy, butyryloxy, Pentanoyloxy, hexanoyloxy, octanoyloxy, undecanoyloxy, dimethylacetoxy, trimethylacetoxy, Diethylacetoxy, tert-Dutylacetoxy-, Benzoyloxy-, Phenacetyloxy-, Cyclopentylpropionyloxy, hydroxyacetoxy, monochloroacetoxy, dichloroacetoxy, trichloroacetoxy, also the dimethylaminoacetoxy, the trimethylaminoacetoxy, the diethylaminoacetoxy, the Piperidinoacetoxy-, the Nicotinoyloxy-, the -Carboxypropionyloxy- and the w -Carboxypentanoyloxy group.

The 21-acyloxy compounds can be used to produce water-soluble active ingredients with a basic nitrogen group in the acyl radical in the corresponding acid addition salts, such as the hydrochlorides, hydrobromides, sulfates, phosphates, oxalates, tartrates or maleates are convicted. Furthermore, the 21-dicarboxylic acid monoesters, as well as the sulfuric acid and phosphoric acid esters to increase the water solubility into their alkali salts, such as the sodium or potassium salts.

The new corticoids of the general formula I according to claim 1 can can be produced according to the invention by the process according to claims 65 to 69.

The method characterized in claim 65 can under conditions which are known per se (Synthesis 1975, 2786, J. Chem. Soc. 66), 1974, 431, J. Amer.

Chem. Soc. 74, (1952), 1239, U.S. Patent 3,383,394 and Angew. Chemistry, 90, (1978), 289).

For example, the steroids of the general formula II with an acetal of the general formula III in the presence of acidic catalysts, such as, for example, perchloric acid, p-toluenesulfonic acid or, advantageously, phosphorus pentoxide realize. This reaction can take place in the absence or in the presence of other solvents of inert solvents (chloroform, ethylene chloride, tetrachloroethane, carbon tetrachloride, Toluene, diethyl ether, tetrahydrofuran, dioxane, etc.). The reaction is usually at a reaction temperature between 200 C Carried out up to +500 C and is particularly suitable for the first production of such steroids of the general formula I with R2 meaning hydrogen.

On the other hand, you can also use the steroids of the general formula II a vinyl ether of the general formula V to implement.

This reaction is preferably carried out in one of the above-mentioned inert Solvents with the addition of acidic catalysts (perchloric acid, p-toluenesulionic acid, Methanesulfonic acid etc.) carried out. The reaction is preferably carried out at one Reaction temperature from -20 ° C to 1000 C.

You can also use the steroids of the general formula II with a Implement α-halogen ethers of the general formula IV.

This reaction can, for example, in an inert polar solvent, such as acetonitrile, dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide or hexamethylphosphoric triamide with the addition of basic catalysts, such as e.g. silver oxide, triethylamine or diisopropylethylamine are preferably carried out the reaction takes place at a reaction temperature of 200 C to +1000 C.

The corticosteroids of the general arise during the above-mentioned conversions Formula I with Q meaning an oxygen atom. For the production of corticoids with Q in the meaning of a sulfur atom one can refer to the general corticoids React formula II with sulfoxides of general formula VI. This reaction can for example, be carried out so that the SulSoxid and the steroid, if desired in an inert solvent (methylene chloride, tetrachloroethane, tetrahydrofuran etc.) with the addition of anhydrides (preferably acetic anhydride) and acid catalysts (Acetic acid, boron trifluoride, etc.) at about 200 ° C to 1000 ° C.

Used as starting compounds for the process according to the invention according to claim 65 llß-hydroxycorticoids of the general formula II, it is expedient the 11ß-hydroxy group intermediate to protect their partial Avoid acetal screening. This can be done, for example, by removing the 11ß-hydroxyl group before acetalization into the corresponding nitrates, formates or trihaloacetates (In particular trifluoroacetate transferred and then after carrying out the process according to claim 65 cleaving these esters.

The esterification of the 11β-hydroxycorticoid with nitric acid can, for example with acetyl nitrate, made by mixing fuming nitric acid with acetic anhydride, be effected. After acetalization has taken place, the nitrates can then be used, for example by reaction with zinc dust in acetic acid back into the IIß-hydroxycorticoids convict.

The esterification of the 11β-hydroxycorticoids with formic acid can be carried out for example by means of formic acid-acetic anhydride using 4-dimethylaminopyridine act as a catalyst. After 17a-acetalization has taken place, the obtained IIß-formyloxycorticoids then by means of basic hydrolysis (for example by means of Sodium methylate solution) or by means of enzymatic saponification into the corresponding Transfer llß-hydroxysteroids.

The esterification of the llß-hydroxycorticoids with trihaloacetic acid - in particular trifluoroacetic acid - can be effected, for example, in the manner that the llß-hydroxycorticoids are reacted with trihaloacetic anhydride in pyridine. After 17a-acetalization has taken place, the trihalocacyl group can then be activated using Hydrolysis (for example in a lower alcohol with the addition of weakly basic Catalysts such as sodium acetate or triethylamine) split off again.

The method characterized in claim 66 can also under Conditions are carried out which are known per se (US Patent 3,678,034, 3,718,671, 3,845,085 and 3,894,063.

For example, the 9, ll-dehydrosteroids of the general Formula VII in an inert solvent (acetic acid, tetrahydrofuran, dioxane, Acetonitrile etc.) react with reagents that are in the presence of water and traces (Sulfuric acid, shospnoric acid, perchloric acid, etc.) hypochlorous in the course of the reaction Release acid, especially with reagents that form halogen cations, such as for example N-chloroacylamides (especially N-chloroacetamide) or N-chloroacylimides (Especially N-chlorosuccinimide. The main products of this reaction are the 9a-chloro-llß-hydroxycorticoids of the general formula I according to claim 1, as well as frequently the corresponding 9a, 11ß-dichlorocorticoids of the formula as by-products I.

The latter are obtained as the main products if you take the reaction below Carries out exclusion of water in the presence of hydrogen chloride as an acid.

On the other hand, one can use the epoxy ring of 9,11-epoxy steroids of the general Formula VIII, for example, in the same way with hydrogen chloride or hydrogen fluoride open by the compounds of formula IV in a with hydrogen chloride or Dissolves hydrogen fluoride saturated inert solvent and optionally in this solution additionally introduces hydrogen chloride gas. Suitable inert solvents are for example ether (diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran etc.) or chlorinated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, Tetrachloroethane etc.). During this reaction, the 9a-fluorocorticoids or 9a-chloro-11ß-hydroxycorticoids are formed of the general formula I according to claim 1.

For splitting off halogen from the 9-halogen steroids of the general Formula IX can be used, for example, in an inert solvent in the presence of radical formers (Azodiisobutyronitrile, di-tert-butyl peroxide, UV light etc.) with trialkyltin hydride (triethyltin hydride, tributyltin hydride etc.). Suitable inert solvents are, for example, ethers (diithyl ether, Glycol dimethyl ether, dioxane, tetrahydrofuran, raw hydrogen (cyclohexane, benzene, Toluene etc.), alcohols (methanol, ethanol, isopropanol etc.) or nitriles (acetonitrile Etc.). In this reaction, the 11β-hydroxycortitoids which are unsubstituted in the 9a-position are formed of the general formula I according to claim 1.

The elimination of hydrogen halide from the 9-halo-teroids of the general Formula IX takes place under the conditions which are usually used in steroid chemistry for splitting off hydrogen halide from halohydrins.

So you can, for example, the compounds of the general formula in a tertiary amine such as pyridine, lutidine or especially collidine under reflux heat. Another suitable method for splitting off hydrogen bromide is, for example the implementation of these compounds with lithium salts (lithium chloride etc.) and / or Calcium carbonate in dimethylformamide or dimethylacetamide. In these implementations the a 8-orticoids of the general formula I according to claim 1 arise.

The required for the method according to the invention according to claim 66 Starting substances of the general formulas VII to IX can be prepared in this way by treating the corresponding 17 «-hydroxysteroids under the conditions of the Claim 65 acetalized or from the 17-acetalized unsubstituted in the 9-position Corticoids by dehydrating them to the 9,11-dehydrosteroids of formula VII, attaches to the 9,11 double bond II Br, and the 9-brorasteroids obtained are the Formula IX converted into the epoxides of the formula VIII by means of bases.

The process products obtained according to claim 65a-d and claim 66 a to c can be further converted, if desired, by those in the 1,2-position saturated corticoids in the 1,2-position dehydrated, and / or an 11ß-Si-hydroxy group these compounds are oxidized to the II-oxo group and / or 21-ester groups are saponified and / or 21-hydroxy groups esterified or exchanged for fluorine atoms or chlorine atoms.

The conditions under which the cortical silk saturated in the l position can be dehydrated at the 1,2-position will be described later.

A preferred method is to bind the 21-hydroxy group with a To esterify sulfonic acid, preferably with methanesulfonic acid or p-toluenesulfonic acid and then to replace the sulfonic acid group with halogen. The esterification the 21-hydroxy group is carried out, for example, by adding a sulfonic acid chloride in Presence of an organic base such as pyridine or in the presence of aqueous alkali can act on the 21-hydroxysteroids. The exchange of the sulfonic acid group against a halogen atom is preferably carried out by treating the 21-sulfonic acid ester with a Alkali halide such as lithium chloride or potassium hydrogen fluoride in the presence a polar solvent such as dimethylformamide at a reaction temperature from 50 ° C to 1800 ° C.

Another aspect of the invention is that in the claims 67 to 69 marked process for the preparation of 11ß-hydroxysteroids with a 17a acetal radical of the formula X or of 11 11ß-hydroxycorticoids of Formula I d and their use as intermediates for the preparation of steroids of the general formula XII according to claim 70.

It is known that IIβ-hydroxysteroids are anti-inflammatory (such as the corticoids: hydrocortisone, prednisolone, dexamethasone, betamethasone, Prednyliden, Triamcinolon, Fluocinolon or Flurandrenolon) by means of a very complex multi-step partial synthesis from naturally occurring steroids (such as diosgenin) produced, which are increasingly difficult to obtain in sufficient quantities. Within the multi-stage synthesis of these compounds is the microbiological introduction the 11ß-hydroxyl group in the steroid structure is usually the most expensive and the most lossy Synthesis step.

In 1966 a process was developed to help the yield in the 11β-hydroxylation of 11-deoxy-17α-hydroxysteroids the pregnane series can be increased significantly by esterifying the 17a-hydroxy group, then hydroxylated by means of fungi of the genus Curvularia and the 11β-hydroxy-17o-acylox3steroids obtained saponified (German Patent 1,618,599).

The acylation of the 17-hydroxy group is quite expensive the yields achieved here are often unsatisfactory.

The hydrolysis of the 11β-hydroxy-17aacyloxysteroids is also difficult, since mostly by-products are formed and thus a costly and lossy purification of the products obtained, so that these are the ones required for active pharmaceutical ingredients Meet purity criteria.

In the method according to the invention according to claims 67-69 In contrast, starting steroids are used, which are obtained in good yields from the corresponding 17-Hydroxysteroids can be produced, the process products obtained can hydrolyzed rapidly and quantitatively to the corresponding 11ß, 17 "-dihydroxysteroids The steroids used according to the process can be substituted in the usual way be and / or contain double bonds.

The presence of hydroxy groups or acyloxy groups, for example in the 21 position, the presence of halogen atoms, preferably fluorine atoms, Methyl groups or ethylene groups, for example in the 6- and / or 16-position does not affect the feasibility of the method according to the invention. For the Processes according to the invention are preferably such steroids as starting compounds used, which is an oxo group in the 5-position and a double bond in the 4,5-position own.

Aside from using other output compounds, the Process according to the invention carried out under the conditions which are usually for 11β-hydroxylation of steroids with fungi of the genus Curvularia.

Fungi of the genus Curvularia suitable for hydroxylation are, for example Curvularia falcuta QM-102 H, Curvularia genticulata IFO (6284), Curvularia lunata NRRL 2380, -NERL 2434, ATCC 12017 or IFO (6286) or Curvularia maculans IFO (6292).

It should be mentioned that there are also other 11β-hydroxylating microorganisms as such of the genus Curvularia are suitable for carrying out the process, this brings generally no advantages over the method according to the invention.

Under the culture conditions normally used for these microorganisms are grown in a suitable nutrient medium with aeration, submerged cultures. Then one sets cultures the substrate (dissolved in a suitable solvent or preferably in emulsified form) and fermented until a maximum substrate conversion is reached.

Suitable substrate solvents are, for example, methanol, ethanol, Glycol monomethyl ether, dimethylformamide or dimethyl sulfoxide. The emulsification of the Substrates can, for example, be effected by micronized Form or in a water-miscible solvent (such as methanol, ethanol, acetone, Glycol monomethyl ether, dimethylformamide or dimethyl sulfoxide) dissolved under strong Turbulence in (preferably decalcified) water, which the usual Contains emulsification aids. Suitable emulsification aids are non-ionic Emulsifiers such as ethylene oxide adducts or fatty acid esters of polyglycols.

Suitable emulsifiers are the commercially available wetting agents tegin (R), TaWat (R), fween (R) and Span (R) named as examples.

The emulsification of the substrates often enables an increased substrate throughput and thus an increase in the substrate concentration. But it goes without saying other methods of enhancement are also possible in the method according to the invention of the substrate throughput as they are well known to the fermentation expert.

The optimal substrate concentration, substrate addition time and fermentation time depends on the structure of the substrate used and the type of microorganism used addicted. These sizes must, as is the case with microbiological steroid conversions is generally required, in individual cases by preliminary tests, as they are the expert are common, can be determined.

The subsequent dehydration of the # 4 steroids of the general formula I which are saturated in the 1-position can be used both by means of microbiological working methods as well as purely chemical methods will. For example, one can use the 4 steroids under the usual conditions with bacterial cultures of the genus Bacillus (for example Bacillus lentus or Bacillus sphaericus) or Arthrobacter (for example Arthrobacter simplex) in the l-position dehydrate. On the other hand, it is also possible to carry out the Al dehydrogenation in this way carry out that the # 4 steroids with the usual oxidizing agents for this reaction, such as selenium dioxide or 2,3-dichloro-5,6-dicyanobenzoquinone in inert Solvents heated.

The process products obtained can be used in a simple manner columns will.

This cleavage is carried out under the conditions which one conventionally used for hydrolysis or alcoholysis of acetals. So can you can split the connections, for example, by putting them in a lower alcohol, such as methanol or ethanol or in an aqueous organic solvent such as glycol monomethyl ether, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, Hexamethylphosphoric acid triamide, acetone with a mineral acid such as hydrochloric acid, sulfuric acid, Phosphoric acid, perchloric acid, a sulfonic acid, such as p-toluenesulfonic acid a strong acidic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, acidic ion exchangers or with a Lewis acid such as boron trifluoride, zinc chloride, zinc bromide or titanium tetrachloride implements.

The new corticoids of the general formula I according to claim 1, draw As already mentioned, topical application has a very good anti-inflammatory properties Effectiveness and they have a very favorable dissociation between the desired topical effectiveness and undesirable systemic side effect: the topical Sedation can be determined using the vasoconstriction test as follows.

The test is carried out on 8 healthy volunteers of both sexes, who had not received topical corticosteroid treatment in the past two weeks. After removing the stratum corneum up to the stratum lucidum on the back of the Test subjects (20-40 Desafilm-Ab-isse) each 0.1 g of the preparations on 4 cm Fields applied without an occulsion dressing. To avoid having the same preparation j is applied to f identical skin areas in each case in a rotating sequence applied.

The vasoconstriction is checked visually by the examiner after 4 and 8 hours assessed according to the following degrees of effectiveness: l = absolute fading, 2 = slight residual erythema, 3 = moderate erythema, redness intensity in the middle area of stripped, untreated and undamaged skin, 4 = erythema with slight lightening, 5 = no pale or worsening of the erythema.

The individual ratings are averaged.

In each test series, the diflucortolone-21-valerianate is used as a reference substance (= 6α, 9α-difluoro-11β-hydroxy-16α-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione = DFV) used.

It always becomes the difference A of in the individual test series determined mean degrees of effectiveness of DFV and test substance. Positive Deviations b show a more favorable, negative deviations show a less favorable Assessment of the test substance in comparison to DFV.

In the tables below are the test results observed listed in the treatment of the subjects with a 0.1 ppm active ingredient Preparation is achieved The systemic effectiveness of the compounds can be achieved with the help of the adjuvant edema test can be determined as follows: SPF rats weighing 130 up to 150 g 0.1 ml of a 0.5% Mycobacterium are used to generate a focus of inflammation butyricum suspension (available from the American company Difko) -in the right one Hind paw injected. The paw volume of the rats is measured before the injection. 24 hours after the injection, the paw volume is used to determine the size of the Öd6ms measured again. The rats are then administered orally or subcutaneously different amounts of the test substance - dissolved in a mixture of 29 Vo benzyl benzoate and 71 o castor oil. After a further 24 hours, the paw volume is determined again, the Control animals are treated in the same way, with the difference that; them a test substance-free benzyl benzoate-castor oil mixture is injected.

The amount is derived in the usual way from the paw volumes obtained of test substance determined which is necessary to reduce the volume by 50% to achieve the experimentally generated 'fotenoedema.

The test results obtained are listed in the tables below, the substances according to the invention being compared in each case with the structurally most analogous, previously known corticosteroids in commercial preparations. Table 1: Test results of hydrocortisone derivatives Vasoconstriction test Adjuvant edema test (mg / kg animal) No. Substance # after 4 h # after 8 H ED50 po ED50 sc 1 17α-butyryloxy-11β, 21- dihydroxy-4-pregnene-3.20-0.2 -0.3 54 13 dione (= hydrocortisone-17-butyrate) 2 11β, 21-dihydroxy-17α-methoxy- +0.3 +0.7 67 13 methoxy-pregnen-3,20-dione 3 17α-ethoxymethoxy-11β, 21-di- hydroxy-4-pregnen-3,20-dione 0.0 +0.7 14.5 4 11β, 21-dihydroxy-17α-propexy- +0.4 +0.4 approx. 10 methoxy-4-pregnene-3,20-dione 5 11β, 21-dihydroxy-17α-isoprop- +0.9 +0.5> 30 (42%) oxymethoxy-4-pregnen-3,20-dione 6 17α-butoxymethoxy-11β, 21-dihy- droxy-4-pregnen-3,20-dione +0.9 +0.6 20 7 11β, 21-dihydroxy-17α- (2'-tetra- hydropyranyloxy) -4-pregnen-3.20- +0.8 +0.6 12 dion Table 2: Test results of prednisolone derivatives Vasoconstriction test Adjuvant edema test (mg / kg animal) No. Substance # after 4 h # after 8 h ED50 po ED50 sc 8 11β, 17α, 21-trihydroxy-1,4- pregnadiene-3.20-dione -0.9 -0.8 8.6 2.6 (= Prednisolone) 9 11β, 21-dihydroxy-17α-methoxy- methoxy-1,4-pregnadiene-3.20-0.2 -0.3 9.8 dion 10 21-acetoxy-11ß-hydroxy-17α- methoxymethoxy-1,4-pregna- +0.7 +0.4> 3 (25%) diene-3,20-dione 11 21-acetoxy-11ß-hydroxy-17α- methylthiomethoxy-1,4- +0.4 +0.4 approx. 3 pregnadiene-3,20-dione 12 21-butyryloxy-11ß-hydroxy-17α- methoxymethoxy-1,4-pregnadiene- +0.2 +0.2 approx. 3 3,20-dione Table 3: Test results of 9-chlorocorticoids vasoconstriction test adjuvant edema test (mg / kg animal) No. S ubstaaz # after 4 h # after 8 h ED50 po ED50 sc 13 9α-chloro-11β-hydroxy-16β- methyl-17α, 21-dipropionyl-0.3 0.0 22 3.0 oxy-1,4-pregnadiene-3,20-dione (= Beclomethasone dipropionate) 14 21-acetoxy-9α-chloro-11ß-hydroxy- 17α-methoxymethoxy-4-pregnen- +0.4 +0.7 3.2 3,20-dione 15 21-acetoxy-9α-chloro-11ß-hy- droxy-17α-methoxymethoxy-1,4- +0.9 +1.0 approx. 1 pregnadiene-3,20-dione 16 21-acetoxy-9α-chloro-11ß-hy- droxy-17α- (2'-methoxyethoxy- +1.0 +1.3 approx. 8 methoxy) -1,4-pregnadiene-3.20- dion Table 4: Test results of 9-fluorocorticoids vasoconstriction test adjuvant edema test (mg / kg animal) No. Substance # after 4 h # after 8 h ED50 po ED50 sc 17 9α-fluoro-11β-hydroxy-16β-methyl- 17α, 21-dipropionyloxy-1,4-pregna- -0.5 -0.7 2.1 diene-3,20-dione (= Betamethasone dipropionate) 18 21-chloro-9α-fluoro-11ß-hydroxy- 16β-methyl-17α-propionyloxy-1,4- +0.5 +1.1 0, @@ pregnadiene-3,20-dione (= Clobetasol propionate) 19 21-chloro-9α-fluoro-11β-hydroxy-17α- methoxymethoxy-1,4-pregnadiene-3.20- +0.5 +0.5 1.9 dion 20 21-acetoxy-9α-fluoro-11β-hydroxy- 17α-methoxymethoxy-4-pregnen-3.20- +0.6 +0.5 2.0 dion 21 9α-fluoro-11β-hydroxy-17α-methoxy- methoxy-21-propionyloxy-1,4-pregna- +0.2 +0.7 3.0 diene-3,20-dione Table 4: Test results of 9-fluorocorticoids vasoconstriction test adjuvant edema test (mg / kg animal) No. Substance # after 4 h # after 8 h ED50 po ED50 sc 22 9α-fluoro-11β-hydroxy-17α-methoxy- +0.5 +1.0 3.0 methoxy-16ß-methyl-21-propionyloxy- 1,4-pregnadiene-3,20-dione 23 21-acetoxy-9α-fluoro-11β-hydroxy-16β- methyl-17α-methylthiomethoxy-1,4- +0.5 +0.2 approx. pregnadiene-3,20-dione Table 5: Test results of 6-fluoro-and-6-methylcorticoids Vasoconstriction test Adjuvant edema test (mg / kg animal) No. Substance # after 4 h # after 8 h ED50 po ED50 sc 24 6α-fluoro-11β, 21-dihydroxy- 16α-methyl-1,4-pregnadiene -1.1 -0.8 3.5 3,20-dione 25 6α-fluoro-11β, 21-dihydroxy- 17α-methoxymethoxy-4-pregnen- +0.1 +0.1 4.0 3,20-dione 26 11β, 17α, 21-trihydroxy-6α- methyl 1,4-pregnadiene-3.20 -0.8 -0.9 dion (= 6-methylprednisolone) 27 11β, 21-trihydroxy-17α- +0.6 +0.6 22 (1'-methoxyethoxy) -6α- methyl-4-pregnen-3,20-dione The new compounds are suitable in combination with the carriers customary in pharmaceutical pharmacy for the local treatment of contact dermatitis, eczema of the most varied types, neurodermatoses, erythroderma, burns, pruritis vulvae et ani, rosacea, erythematosus cutaneus, psoriasis, lichen planes et verrucosus and similar fIauterkranlQungen.

The production of the drug specialties takes place in the usual way Way, by combining the active ingredients with suitable additives in the desired application form, such as: solutions, lotions, ointments, creams or plasters.

The active ingredient concentration is in the pharmaceuticals formulated in this way depends on the form of application. For lotions and ointments, preferably one Active ingredient concentration of 0.001, ó to 1% used.

In addition, the new compounds are possibly in combination with the usual carriers and auxiliaries also good for the production of inhalants suitable for the therapy of allergic diseases of the respiratory tract, such as bronchial asthma or rhinitis can be used.

The new corticoids are also suitable in the form of capsules, Tablets or dragees, which preferably contain 10-200 mg of active ingredient, and orally be applied or in the form of suspensions, preferably 100-500 mg of active ingredient Contained per dose unit and administered rectally are also used to treat allergic reactions Diseases of the intestinal tract, such as ulcerative colitis and granulomatous colitis.

The following examples serve to explain the invention.

Example 1 a) 21.63 g of 3β, 21-diacetoxy-17α-hydroxy-5-pregnen-20-one are dissolved in 150 ml of anhydrous methylene chloride and 100 ml of anhydrous formaldehyde dimethyl acetal dissolved The solution is then cooled with water and a mixture of 21.6 is added to it g of phosphorus pentoxide and 43 g of kieselguhr and stirred for one hour at room temperature. The reaction mixture is then filtered and the residue is washed with methylene chloride, adds triethylamine to the filtrate until a pH value of 9 is reached and it narrows in vacuo The residue is recrystallized from methanol-methylene chloride and 22.68 g of 3β, 21-diacetoxy-17α-methoxymethoxy-5-pregnen-20-one from Melting point 182-184 ° C.

b) A 2 liter Erlenmeyer flask containing 1 liter of sterile nutrient solution 0.3, ° t yeast extract, 0.3% cornsteep liqour and 0.2% starch sugar - discontinued at pE = 7.0 - becomes dehydrogenated from ATCC with a dry culture of Flavobacterium 13 930 inoculated and shaken at 30 ° C for two days at 175 revolutions per minute.

A 500 ml Erlenmeyer flask with 85 ml of the same nutrient medium is made inoculated with 10 ml of the Flavobacterium dehydrogenans seed culture and at 30 0 C Shaken at 175 revolutions per minute for 7 hours. Then you set the culture 5 ml of a sterile solution 0.5 g of / 3β, 21-diacetoxy-17α-methoxymethoxy-5-pregnen-20-one in dimethylformamide and shake at 30.degree. C. for a further 65 hours long with 175 revolutions per minute. After fermentation, the culture is twice extracted with 100 ml of ethylene chloride, the extract concentrated in vacuo, the residue Purified by chromatography over aluminum oxide and 402 mg of 2l-hydroxy-17a-methoxymethoxy-4-pregnen-3 are obtained, 20-dione with a melting point of 152 - 1530 C.

c) A 2 liter Erlenmeyer flask containing 1 liter of sterile nutrient solution 2% glucose and 2% cornsteep liqour - adjusted to pH = 6.5 - is combined with a Washing away of a dry culture of Curvularia lunata NRRL 2380 inoculated and at Shaken at 300 C for 60 hours at 175 revolutions per minute.

A 500 ml Erlenmeyer flask with 90 ml of a sterile nutrient medium Contains 1.0% Cornsteep liqour and 1.25% soy powder - adjusted to pH = 6.2 - is inoculated with 10 ml of the Curvularia 3unata seed culture and at 300 C for 7 hours shaken for a long time at 175 revolutions per minute. Then 0.6 ml is added to the culture a sterile solution of 30 mg of 21-hydroxy-17a-methoxymethoxy-4-pregnen-3,20-dione in dimethylformamide and fermented for a further 65 hours below the specified Conditions.

The fermentation culture is worked up as described in Example 1b and receives 27 mg of llß, 2l-dihydroxy-17a-methoxymethoxy-4-pregnen-3,20-dione from the melting point 180 - 1820 c.

d) 2.5 g of 11β, 21-dihydroxy-17α-methoxymethoxy-4-pregnen-3,20-dione are dissolved in 40 ml of anhydrous methylene chloride, cooled to 00 C and within of 15 minutes under argon with a solution of 2.25 ml of titanium tetrachloride in 10 ml of methylene chloride were added. The reaction mixture is left for 90 minutes Stirring room temperature, then puts 150 ml of methylene chloride and 100 ml of saturated aqueous Sodium hydrogen carbonate solution is added, the mixture is stirred for 15 minutes, and the organic phase is separated off, washes them neutral, dries them over sodium sulfate and concentrates them in a vacuum. The residue is recrystallized from chloroform and 2.19 g of llß, 17a, 2l-trihydroxy-4-pregnen-3, 20-dione from decomposition point 2150 C.

Example 2 a) 50 g of 3β, 21-diacetoxy-17α-hydroxy-5-pregnen-20-one are with 50 mg of anhydrous p-doluenesulfonic acid and 350 ml of anhydrous methylene chloride added, cooled to Oo C and after adding 10 g of methyl vinyl ether for 4 hours at 00 C; clocks. Triethylamine is then added to the reaction until a pH value is reached of 9 is reached and constricts it in a vacuum. 58 g of 3β, 21-diacetoxy-17α- (1'-methoxyethoxy) -5-pregnen-20-one are obtained as a mixture of diastereomers with a melting point of 80 ° -1180 ° C. (A recrystallized from methanol Sample melts at 132-1340 C) b) Under the conditions of Example 1b, a Solution of 600 mg of 3β, 2l-diacetoxy-17a- (1'-methoxyethoxy) -5-pregnen-20-one Diastereomer mixture in 5 ml of dimethylformamide with a Flavobacterium dehydrogenans ATCC 13930 culture reacted, processed and 394 mg of 21-hydroxy-17- (1'-methoxyethoxy) -4-pregnen-3,20-dione are obtained as a mixture of diastereomers with a melting point of 166 - 1780 C.

c) A solution of 100 mg of 21-hydroxy-17α- (1'-methoxyethoxy) -4-pregnen-3,20-dione Diastereomer mixture in 2 ml of dimethylformamide is described under those in Example lc Conditions with a culture of Curvularia lunata NRRL 2380 fermented, processed and 105 mg of 11β, 21-dihydroxy-17 "- (1l-methoxyethoxy) -4-pregnen-3,20-dione are obtained as an oily mixture of diastereomers.

This mixture is mixed with 3 ml of methanol and 0.5 ml of 2N aqueous hydrochloric acid added and shaken for 5 hours at room temperature. Then you bet 4 ml of water are added to the mixture and neutralized with saturated aqueous sodium hydrogen carbonate solution, extracted twice with 8 ml of ethylene chloride each time, the organic Phase in a vacuum, the residue is purified by chromatography on an aluminum oxide column and receives 69 mg of 11β, 17α, 21-trihydroxy-4-pregnen-3,20-dione from the melting point 217 - 219 ° C.

Example 3 a) 10.0 g of 21-acetoxy-17α-hydroxy-4-pregnen-3,20-dione be with 13 mg of anhydrous p-toluenesulfonic acid and 130 ml of anhydrous Added methylene chloride, cooled to 0 ° C and after adding 2.3 g of methyl vinyl ether Stirred at 00 ° C. for 7 hours. The reaction mixture is worked up, as in Example 2a described and obtained 11.6 g of 21-acetoxy-17α- (1'-methoxyethoxy) -4-pregnen-3,20-dione with a melting point of 135 - 1500 C.

b) A solution of 0.1 g of 21-acetoxy-17α- (1'-methoxyethoxy) -4-pregnen-3,20-dione Diastereomer mixture in 2 ml of dimethylformamide is described under those in Example lc Fermented and processed conditions with a culture of Curvularia lunata NE2RL 2380. The llß, 21-dihydroxy-17α- (1'-methoxyethoxy) -4-pregnen-3,20-dione thus obtained is then hydrolyzed under the conditions described in Example 2c and one receives 78 mg of 11β, 17α, 21-trihydroxy-4-pregnen-3,20-dione with a melting point of 217 - 219 ° C.

Example 4 a) 10.0 g of 21-acetoxy-17α-hydroxy-4-pregnen-3,20-dione are under the conditions described in Example 3a with 2.50 g of ethyl vinyl ether reacted, worked up and 12.5 g of 21-acetoxy-17a- (1'-ethoxyethoxy) -4-pregnerl-3,20-dione are obtained as an oily mixture of diastereomers.

b) A solution of 0.1 g of 21-acetoxy-17α- (1'-ethoxyethoxy) -4-pregnen-3,20-dione Mixture in 2 ml of dimethylformamide is under the conditions described in Example lc prepared hydroxylated with Curvularia lunata NRRL 2380 and 17α- (1'-ethoxyethoxy) -11β, 21-dihydroxy-4-pregnen-3.20 is obtained dion, which, under the conditions described in Example 2c, resulted in 63 mg of 11β, 17α, 21-trihydroxy-4-pregnen-3,20-dione is hydrolyzed from melting point 216-217.5 ° C.

Example 5 a) 10.0 g of 21-acetoxy-17α-hydroxy-4-pregnen-3,20-dione are under the conditions described in Example 3a with 4.0 g of isobutyl vinyl ether reacted, worked up and 13.5 g of 21-acetoxy-17a- (l -isobutyloxyethoxy) -4-pregnen-3,20-dione are obtained as an oily mixture of diastereomers.

b) A solution of 0.1 g of 21-acetoxy-17α- (1'-isobutyloxyethoxy) 4-pregnen-3,20-dione mixture in 2 ml of dimethylformamide is under the in the example lc described conditions with Curvularia lunata NERL 2380 hydroxylated, processed and 11β-21-dihydroxy-17α- (1'-isobutyloxyethoxy) -4 pregnen-3,20-dione is obtained which under the conditions described in Example 2c to 68 mg of 11β, 17α, 21-trihydroxy-4-pregnen-3,20-dione is saponified with a melting point of 214-2160 ° C. (decomposition).

Example 6 a) 1.95 g of 21-acetoxy-17α-hydroxy-4-pregnen-3,20-dione are with 5 mg of anhydrous p-2oluenesulfonic acid, 25 ml of anhydrous methylene chloride and 3.5 ml of dihydropyran are added and the mixture is stirred at room temperature for 13 hours. The reaction mixture is worked up as described and obtained in Example 3a 2.0 g 21-acetoxy-17α- (2'-tetrahydropyranyloxy) -4-pregnen-3,20-dione as a mixture of diastereomers with a melting point of 185 - 2000 C.

b) A solution of 0.1 g of 21-acetoxy-17α- (2'-tetrahydropyranyloxyl-4-pregnen-3,20-dione GemiF in 2 ml of dimethylformamide is under the conditions as described in Example 1c, hydroxylated with Curvularia lunata NRRL 2380, processed and the 11ß, 21-dihydroxy-17a- (2 ' -tetrahydropyranyloxy) -4-pregnen-3,20-dione, which under those described in Example 2c Conditions for 72 mg of 11β, 17α, 21-trihydroxy-4-pregnen-3,20-dione of melting point 2150 C (decomposition) is hydrolyzed.

Example 7 a) 50 g of 21-acetoxy-17 "-hydrogy-6-methyl-4-pregnen-5,20-dione are under the conditions described in Example 3a with 13.9 g of methyl vinyl ether reacted, worked up and 59 g of 21-acetoxy-17α- (1'-methoxyethoxy) -6α-methyl-4-pregnen-3,20-dione are obtained as amorphous mass.

b) A solution of 200 mg of 21-acetoxy-17α- (1'-methoxyethoxy) -6α-methyl-4-pregnen-3,20-dione in 0.4 ml of dimethylformamide is under the conditions described in Example lc hydroxylated with Curvularia Lunata NRRL 2380, processed and the 11β, 21-dihydroxy-17α- (1'-methoxyethoxy) -6α-methyl-4-pregnen-3,20-dione is obtained, which under the in example 2c described conditions to 15 mg llß1l7a, 2l-trihydroxy 6α-methyl-4-pregnen-3,20-dione of melting point 189-192 ° C is hydrolyzed, Example 8 a) 2.0 g of 21-acetoxy-17α-hydroxy-16β-methyl-4-pregnen-3,20-dione are with 5 mg of p-toluenesulfonic acid (anhydrous) and 25 ml of anhydrous methylene chloride added and cooled to 0 ° C. Then 0.5 g of methylarinyl ether is added to the mixture while stirring to, stir for 5 hours at 0 ° C and a further 12 hours at room temperature, works the reaction mixture as described in Example 3a and receives 2.1 g of 21-acetoxy-17α- (1'-methoxyethoxy) -16β-methyl-4-pregnen-3,20-dione as an oily mixture of diastereomers.

b) A solution of 50 mg of 21-acetoxy-17α- (1'methoxyethoxy) -16β-methyl-4-pregnen-3,20-dione Mixture in 1 ml of dimethylformamide is made under the conditions described in Example 1c nut Curvularia lunata NRRL 2380 hydroxylated, processed and the 11β, 21-dihydroxy-17α- (1'-methoxyethoxy) -16β-methyl-4-pregnen-3,20-dione is obtained, which under the conditions described in Example 2c to 32 mg of 11β, 17α, 21-trihydroxy-16β-methyl-4-pregnen-3,20-dione is hydrolyzed from melting point 204-207 ° C Example 9 a) 50 g 17a-Ilydroxy-regaen-3, 20-dione are obtained under the conditions described in Example 3a reacted with 15 g of methyl vinyl ether, prepared, and 51.2 g of 17 «- (1 @ -Nethoxyethoxy) -4-pregnen-3,20-dione with a melting point of 115-152 ° C.

b) A solution of 0.1 g of 17α- (1'-methoxyethoxy) -4-pregnen-3,20-dione in 1 ml of dimethylformamide is under the conditions described in Example lc Fermented and processed with a culture of Curvularia lunata NRRL 2380 The 11β-Hydroxy-17α- (1'-methoxyethoxy) -4-pregnen-3,20-dione thus obtained (melting point 85-1030 C) is hydrolyzed under the conditions described in Example 2c and 63 mg of 11β, 17α-dihydroxy-4-pregnen-3,20-dione of melting point are obtained 222-223.5 ° C.

Example 10 a) 50 g of 3β, 21-diacetoxy-17α-hydroxy-5-pregnen-20-one are under the conditions described in Example la in 150 ml of methylene chloride with 380 g of formaldehyde bis-glycol monomethyl ether acetal, 50 g of phosphorus pentoxide and 100 g of kieselguhr reacted, worked up and 45.8 g of 3β, 21-diacetoxy-17 are obtained a- (2'-methoxyethoxy-methoxy) -5-pre gnen-20-one with a melting point of 160-161 ° C.

b) Under the conditions described in Example 1b, 0.5 g 3β, 21-diacetoxy-17α- (2'-methoxyethoxy-methoxy) -5 pregnen-20-one with a culture implemented by Flavobacterium dehydrogenans ATCC 13930, processed and obtained 390 mg of 21-hydroxy-17α- (2'-methoxyethoxy) -4-pregnen 3,20-dione as glassy liquid.

c) Under the conditions of Example 1C, 30 mg of 21-hydroxy-17a- (2'-methox; rethoxy-methoxy) -4-pregnen-3,20-dione implemented with a culture of Curvularia lunata NRRL 2380, processed and you receives 24 mg of 11β, 21-dihydroxy-17α- (2'-methoxyethoxymethoxy) -4-pregnen-3,20-dione with a melting point of 143-147 ° C.

d) Under the conditions of Example 1d, 10 mg of 11β, 21-dihydroxy-17α- (2'-methoxyethoxy) -4-pregnen-3,20-dione reacted in 2 ml of methylene chloride and 0.01 ml of titanium tetrachloride, prepared and 8 mg of 11β, 17α, 21-trihydroxy-4-pregnen-3,20-dione from the decomposition point are obtained 2130 C.

Example 11 A 2 l Erlenmeyer flask with 500 ml of sterile nutrient solution, containing 0.1% yeast tract 0.5% cornsteep liquor 0.1% starch sugar - discontinued to pH 7.0 - is washed off with a dry culture of Arthrobacter simplex ATCC 6946 inoculated and shaken at 30 ° C for 48 hours at 190 revolutions per minute.

A 500 ml Erlenmeyer flask with 90 ml of the nutrient medium described above is inoculated with 10 ml of the Arthrobacter simplex seed culture and at 30 OC for 6 hours shaken for a long time at 165 revolutions per minute. Then 1 ml is added to the culture a sterile solution of 50 mg llß, 21-dihydroxy-17a-methoxymethoxy-4-pregnen-3, Add 20-dione in dimethylformamide and ferment for a further 42 hours.

The fermentation culture is worked on -as described in Example 1b- and receives 44.5 mg llß, 21-dihydroxy-17a methoxymethoxy-1,4-pregnadiene-3, 20-dione of melting point 229/230-231 ° C., Example 12 A 2 l Erlenmeyer flask with 500 ml sterile nutrient solution containing 1% yeast extract (Difco) 0.45% disodium hydrogen phosphate 0.34% potassium hydrogen phosphate 0.2% Tween 80 - adjusted to pH 6.7 - is used with was inoculated into a runoff from a dry culture of Nocardia globerula ATCC 9356 and shaken at 30 ° C. for 72 hours at 190 revolutions per minute.

Containing a 2 l Erlenmeyer flask with 950 ml sterile nutrient solution 2.0% Cornsteep liquor 0.3 ° h diammonium hydrogen phosphate 0.25% Tween 80 - adjusted to pH 6.5 - is inoculated with 50 ml of the Nocardia globerula seed culture and at Shaken at 30 ° C for 24 hours at 190 revolutions per minute. Then you bet the culture 5 ml of a sterile solution of 0.25 g of 11β, 21-dihydroxy-17α- (1'-methoxyethoxy) -6α-methyl-4-pregnen-3,20-dione in dimethylformamide and ferment for another 72 hours. One works the fermentation culture on - as described in Example 1b - and receives 0.21 g of 11β, 21-DhydroxJ-17a- (l'-methoxyethoxy) -6a: -methyl-1,4-pregnadiene-3, 20-dione with a melting point of 210-212 ° C.

Example 13 a) 50 g of 21-acetoxy-17a-hydroxy-4-pregnane-3,20-dione become suspended with 600 ml of formaldehyde diethylacetal and 600 ml of methylene chloride and on -30 to -40 ° C cooled. A mixture of 75 g of phosphorus pentoxide is added with stirring and added 150 g of kieselguhr and stirred at -30 ° C. for 30 hours. The solution will be filtered and neutralized with triethylamine. After the solvents have been distilled off is distilled off again with methanol and the residue is recrystallized from methanol. 35.9 g of 21-acetoxy-17a-ethoxymethoxy-4-pregnen-3, 20-dione are obtained, which after repeated Recrystallization at 137-139 OC melts.

b) A 2 liter Erlenmeyer flask containing 1 liter of sterile nutrient solution 1 96 Cornsteep liquor 1.25 ° h soy powder - adjusted to pH 6.2 - is made with a Washing away of a dry culture of Curvularia lunata NRRL 2380 inoculated and at. Shaken at 175 revolutions per minute for 72 hours at 30 ° C.

A 50 l fermenter with 29 l of a sterile nutrient medium as described above, is inoculated with 1 1 of the Curvularia lunata seed culture and 24 hours at 30 0 grown with aeration at 2 m3 per hour.

A 50 l fermenter with 36 l sterile nutrient solution as described above, is inoculated with 4 l of the Curvularia lunata pre-fermenter culture and 10 hours 30 ° C with aeration at 2 m3 per hour and stirring at 220 revolutions per minute bred. Then 10 g of 21-acetoxy-17a-ethoxymethoxy-4-pregnen-3,20-dione are added to the culture 2n 200 ml of ethylene glycol monomethyl ether. From the 10th hour the piI value will be between 6.5 and 7.0 held. After a further 4 hours, another 10 g of 21-acetoxy-17a-ethoxy-methoxy-4-pregnen-3,20-dione are added added in 200 ml of ethylene glycol monoethyl ether and a further 23 hours under the fermented conditions specified.

The fermentation culture is extracted three times with 10 1 ethylene chloride and then worked up further as described under Example 1b. You get 13.8 g of llß, 21-dihydroxy-17α-ethoxymethoxy-4-pregnen-3,20-dione of melting point 153-154 00.

Example 14 a) 25 g of 21-acetoxy-17α-hydroxy-4-pregnen-3,20-dione are suspended with 200 ml of formaldehyde dipropylacetal and 320 ml of methylene chloride and cooled to -20 oC. A mixture of 49.3 g of phosphorus pentoxide is added with stirring and 97 g of kieselguhr added and stirred at -20 ° C. for 22 hours. The solution will be filtered and neutralized with triethylamine. The methylene chloride is in vacuo distilled off and the formaldehyde dipropylacetal phase poured off from the deposited oil.

After distilling off further solvent in vacuo crystallize 19 g of 21-acetoxy-17 <x-propoxymethoxy-4 pregnen-3,20-dione, melting point 145-147 C.

b) 10 g of 21-acetoxy-17a-propoxymethoxy-4-pregnen-3,20-dione are with 1 g Tween 80 and three times the amount of water in the Dyno mill type KDL (Bachofen, Basel) ground.

This grist is sterilized with 1% H202 for at least 4 hours.

Curvularia lunata NRRL 2380 is -as described in Example 13b- grown in the shake flask and pre-fermenter and thus inoculated the main fermenter. This fermenter is set up in the same way as described in Example 13b and 10 hours grown according to the conditions also described in Example 13b. Then sets one of the culture the grist of 21-acetoxy-17a-propoxymethoxy-4-pregnen-3,20 dione and fermented for a further 44 hours, the pH value being kept between 6.4 and 6.7 will. The fermentation culture is worked up as described in Example 13b and 6.5 g of 11β, 21-dihydroxy-17α-propoxymethoxy-4-pregnen-3,20-dione vom Melting point 134 / 135-136 oC.

Example 15 a) 50 g of 21-acetoxy-17a-hydroxy-4-pregnen-3,20-dione become suspended with 500 ml formaldehyde dibutyl acetal and 500 ml methylene chloride and on -35 OC chilled. A mixture of 74 g of phosphorus pentoxide and 150 g of kieselguhr entered and stirred at -35 ° C. for 30 hours. The solution is filtered and neutralized with triethylamine. The methylene chloride is distilled off in vacuo and the formaldehyde dibutyl acetal phase is poured off from the separated oil.

After distilling off further solvent in vacuo crystallize 38.7 g of 21-acetoxy-17-butoxymethoxy-4-pregnen-3,20-dione, melting point 123.5-124.5 oC.

b) 8 g of 21-acetoxy-17a-butoxymethoxy-4-pregnen-3,20-dione are with 0.8 g of Tween 80 as described in Example 14b, ground.

Curvularia lunata NRRL 2380 is used in the shake flask as a seed culture, in the pre-fermenter and main fermenter as described in Example 13b, grown and fermented. At the 10th hour of the main fermenter, the substrate is added and Fermented for another 50 hours.

The fermentation culture is worked up as described in Example 13b and 3.7 g of 11β, 21-dihydroxy-17a-butoxymethoxy-4-pregnen-3,20-dione vom Melting point 79-81 oc.

Example 16 a) 10.60 g of 21-acetoxy-6'-fluoro-17a-hydroxy-4-pregnen-3,20-dione are dissolved in 265 ml of methylene chloride and 47.7 ml of formaldehyde dimethyl acetal. A A mixture of 7.95 g of phosphorus pentoxide and 15.9 g of kieselguhr is added in portions and the mixture was stirred for 90 minutes under nitrogen at room temperature. The solution is filtered and treated with 2.1 ml of triethylamine. The solvents are distilled off and the residue is recrystallized from methanol.

7.6 g of 21-acetoxy-6a-fluoro-17a-methoxymethoxy-4-pregnen-3,20-dione are obtained from melting point 161-167 OC.

b) Curvularia lunata NRRL 2380 is -as described in Example 13b- Grown in the shake flask, pre- and main fermenter. At the 10th hour of the main fermenter 5 g of 21-acetoxy-6a-fluoro-17a-methoxymethoxy-4-pregnen-3,20-dione in 100 ml of ethylene glycol monomethyl ether added. The pH will be from this point in time held between 6.5 and 7.0. At the 14th hour, another 5 g of 21-acetoxy-6α-fluoro-17α-methoxymethoxy-4-pregnen-3,20-dione are added added in 100 ml of ethylene glycol monomethyl ether and fermented for a further 26 hours.

The fermentation culture is worked up as described in Example 13b and 4.2 g of 11β, 21-dihydroxy-6α-fluoro-methoxymethoxy-4-pregnen-3,20-dione are obtained from a melting point of 190-192 ° C. Example 17 a) 43 g of 3β, 21-diacetoxy-17α-hydroxy-16β-methyl-5-pregnen-20-one are dissolved in 800 ml of formaldehyde dimethyl acetal and cooled to -15 ° C. In portions a mixture of 43 g of phosphorus pentoxide and 86 g of kieselguhr is introduced and the mixture was stirred at about -15 ° C. for 15 hours. The solution is filtered with triethylamine neutralized and the solvents are distilled off in vacuo. The residue will Recrystallized with methanol, 31.5 g of 3β, 21-diacetoxy-17α-methoxymethoxy-16β-methyl-5-pregnen-20-one are obtained from melting point 117-118 OC, b) Flavobacterium dehydrogenans ATCC 13930 is like in example 1 b), grown and fermented. At the 7th hour one sets the culture 4 ml of a sterile solution of 0.2 g of 3 [beta], 21-diacetoxy-17a-methoxymethoxy-16 [beta] -methyl-5 -pregnen-20-one in dimethylformamide and shake for another 65 hours.

After fermentation has taken place, the culture is as in Example 1 b) described, worked up and 163 mg of 21-hydroxy-17a-methoxymethoxy-16ß-methy are obtained L- 4-pregnen- 3, 20-dione with a melting point of 126j128-129 oC.

c) Curvularia lunata NHRL 2380 is cultivated as in Example 1 c) and fermented. At the 7th hour of the culture 1 ml of a sterile solution of 50 mg of 21-hydroxy-17α-methoxymethoxy-16β-methyl-4-pregnen-3,20-dione in dimethylformamide added and fermented for another 65 hours.

The fermentation culture is worked up as described in Example 1 b) and 34.5 mg of 11β, 21-dihydroxy-172-methoxymethoxy-16β-methyl-4-pregnen-3,20-dione are obtained of melting point 204 / 205-206 ° C.

Example 18 3 g of llß '21-dihydroxy-17a-methoxymethoxy-4-pregnene-3,20-dione are mixed with 5 ml of acetic anhydride in 20 ml of pyridine and 5 hours at room temperature touched. After precipitation in 200 ml of ice water, it is suctioned off and 3.23 g of 21-acetoxy-11ß-hydroxy-17 "-methoxymethoxy-4-pregnen-3,20-dione are obtained, which melts after recrystallization from acetone at 172-177 ° C.

Example 19 4 g of 11β-21-dihydroxy-17α-methoxymethoxy-4-pregnen-3,20-dione are mixed with 8 ml of propionic anhydride in 25 ml of pyridine and 105 minutes at Room temperature stirred. After precipitation in 500 ml of ice water until the cleavage Stirred anhydride, filtered off with suction and 4.43 g of IIβ-hydroxy-17α-methoxymethoxy-21-propionyloxy-4-pregnen-3,20-dione are obtained, which melts at 119-121 ° C after recrystallization from methanol.

Example 20 4 g of 11β, 21-dihydroxy-17α-methoxymethoxy-4-pregnen-3,20-dione 9 ml of nutric acid anhydride are added to 25 ml of pyridine and Stirred for 105 minutes at room temperature. After precipitation in 500 ml of ice water becomes three Stirred for hours, filtered off with suction and 4.55 g of 21-butyryloxy-11ß-hydroxy-17a-methoxymethoxy-4-pregnen-3,20-dione are obtained, which melts after recrystallization from methanol at 140-142 OC.

Example 21 4 g ll3, 21-dihydroxy-17a-methoxymethoxy-4-pregnen-3,20-dione are in 25 ml of pyridine with 11 ml of trimethylacetic anhydride and 100 mg of 4-dimethylaminopyridine offset. After six hours at room temperature, ice water is added with methylene chloride extracted and this with aqueous acetic acid, sodium hydrogen carbonate solution and Washed water, dried with sodium sulfate and the solvent was distilled off in vacuo. 4.8 g of 11β-hydroxy-17α-methoymethoxy-2ltrimethylacetoxy-4-pregnen-3,20-dione are obtained, which melts after recrystallization from methanol at 182-184 OC.

Example 22 5 g of llβ, 21-dihydroxy-17α-methoxymethoxy-1,4-pregnadiene-3120-dione are mixed in 30 ml of pyridine with 8 ml of acetic anhydride and 1.5 hours at Stirred at room temperature. After precipitation in 300 ml of ice water, the mixture is filtered off with suction and 5.08 is obtained g of 21-acetoxy-11ß-hydroxy-17a-methoxymethoxy-1,4-pregnadiene-3,20-dione, which after recrystallization from methanol and some methylene chloride at 214 OC melts.

Example 23 1 g llβ, 21-dihydroxy-17-methoxymethoxy-1,4-pregnadiene-3,20-dione are mixed in 6 ml of pyridine with 2 ml of butyric anhydride and 1.5 hours at Room temperature stirred.

After precipitation in ice water, the mixture is stirred for two hours and filtered off with suction and 1.11 g of 21-Dutyryloxy-11ß-hydroxy-17a-methoxymethoxy-1,4-pregnadiene-3,20-dione are obtained, which melts at 182 ° C after recrystallization from methanol with a little methylene chloride.

Example 24 0.32 g of pyridine chlorochromate are mixed with 2 ml of anhydrous Methylene chloride is added and, with stirring, a solution of 0.45 g of 21-acetoxy-11ß-hydroxy-17a: methoxymethoxy-4-pregnen-3,20-dione added in 7 ml of methylene chloride. After 4 hours at 20 OC it is suctioned off through kieselguhr, washed with methylene chloride / diethyl ether 1: 1, mixed with a few drops of methanol and the solvent is distilled off in vacuo.

The residue is stirred with water and filtered off with suction. Recrystallization from methanol gives 0.28 g of 21-acetoxy-17a methoxymethoxy-4-pregnen-3,11,20-trione from melting point 160-161 00.

Example 25 6 g of cortisone acetate are dissolved in 120 ml of formaldehyde dimethyl acetal and 120 ml of methylene chloride dissolved and while cooling with ice with a mixture of 12 g phosphorus pentoxide and 24 g kieselguhr were added. After 4.5 hours of stirring, it is filtered, neutralized with triethylamine and the solvent was distilled off in vacuo. Of the The residue is chromatographed on silica gel using mixtures of toluene and ethyl acetate and 3.85 g of 21-acetoxy-17'-methoxymethoxy-4-pregnen-3,11,20-trione are obtained, the after recrystallization from methanol melts at 160-161 oC.

Example 26 a) 2 g of 21-acetoxy-11β-hydroxy-17α-methoxymethoxy-4-pregnen-3,20-dione are dissolved in 20 ml of pyridine and mixed with 016 ml of thionyl chloride while cooling with ice. After 30 minutes, it is precipitated in ice water and filtered off with suction. 1.76 g of 21-acetoxy-17α-methoxymethoxy-4,9 (11) -pregnadiene-3,20-dione are obtained, after recrystallization from methanol with a little methylene chloride at 194-196 ° C melts.

b) 5.0 g of 21-acetoxy-17a-methoxymethoxy-1y, 9 (11) -pregnadiene-3,20-dione are suspended in 50 ml of tetrahydrofuran and at + 20 ° C with 20.56 ml of 1N perchloric acid and 5.14 g of N-bromosuccinimide are added. It is stirred for 15 minutes.

The reaction mixture is dissolved in a solution of 5.14 g of sodium sulfite and 350 ml of ice water precipitated. The crystals are filtered off with suction, neutral with water washed and the still moist crystals are recrystallized from methanol / water. 5.0 g of 21-acetoxy-9a-bromo-11β-hydroxy-17α-methoxymethoxy-4-pregnen-3,20-dione are obtained with a melting point of 130-131 ° C.

c) 51.8 g of 21-acetoxy-9a-bromo-11ß-hydroxy-17a.methoxymethoxy-4-pregnen-3,20-dione are suspended in 516 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 oC in 5180 ml Ice-water pleases. The crystals are filtered off, washed with water and with + 20 0 dried. 41.75 g of 21-acetoxy-9β, 11β-epoxy-17amethoxynethoxy-4-pregnen-3,20-dione are obtained obtained, which melts after recrystallization from methanol at 138-139.5 5 ° C.

d) 1.0 g of 21-acetoxy-9β, 11β-epoxy-17α-methoxymethoxy-4-pregnen-3.20-dione is dissolved in 10 ml of methylene chloride and cooled with ice water. In slow stream Hydrochloric acid gas, dried over sulfuric acid, is passed in until the thin-layer chromatogram no source material is available. The reaction mixture is dissolved in 120 ml of 1% strength Sodium bicarbonate solution precipitated. The methylene chloride phase is separated with water washed neutral, dried and concentrated to dryness. 1.1 g of 21-acetoxy-9achlor-11β-hydroxy-17α-methoxymethoxy-4-pregnen-3,20-dione are obtained, which shows a melting point of 194.5 ° C. after recrystallization.

Example 27 5.0 g of 21-acetoxy-17α-methoxymethoxy-4,9 (11) -pregnadiene-3,20-dione are suspended in 50 ml of tetrahydrofuran and at + 20 ° C. with 20.56 ml of 1N perchloric acid and 2.78 g of N-chlorosuccinimide are added. It is stirred for 24 hours, with still 3.52 ml of 70% perchloric acid are added. The reaction mixture becomes a solution precipitated from 5.14 g of sodium sulfite and 350 ml of ice water. The crystals are sucked off, Washed neutral with water, and the moist crystals are made from methanol / water recrystallized. 1.5 g of 21-acetoxy-9α-chloro-11β-hydroxy-17α-methoxy are obtained methoxy-4-pregnen-3,20-dione, which after crystallization from ethyl acetate and acetone melts at 189-192 oC.

Example 28 10 g of 9α-fluorohydrocortisone acetate are in 67.4 ml of methylene chloride and 134.8 ml of methylal dissolved and with an ice Methanol bath chilled. 10 g of phosphorus pentoxide are mixed with 20 g of kieselguhr in this solution entered and stirred at -150c for 5 hours. The solution is filtered and with Triethylamine neutralized. After the distillation of the solvent is again distilled off with methanol and the residue crystallized from methanol. By Chromatography on silica gel with methylene chloride +. The products are 5% methanol separated, and receives 3.28 g of 21-acetoxy-9a-fluorine-1, 17 "-dimethoxymethoxy-i-pregnen-3,20-dione with a melting point of 132-134 ° C., 0.56 g of 21-acetoxy-Sa-fluoro-11ß-hydroxy-17a-methoxymethoxy-4-pregnen-3, 20-dione with a melting point of 211-214 oC and 0.79 g of 21-acetoxy-9α-fluoro-17α-hydroxy-11β-methoxymethoxy-4-pregnen-3,20-dione with a melting point of 196-199 ° C.

Example 29 5.0 g of 21-acetoxy-9a-chloro-11ß-hydroxy-17a-methoxymethoxy-4-pregnene-3,20-dione are suspended in 10 ml of methylene chloride and 20 ml of methanol and cooled to + 3 ° C. A solution of 0.31 g of potassium hydroxide in 11 ml of methanol is added dropwise in 5 minutes and stirred for 80 minutes. The reaction mixture is neutralized with 0.34 ml of glacial acetic acid and precipitated in 350 ml of water. The crystals are filtered off with suction and dried. Man receives 2.32 g of 9α-chloro-11β, 21-dihydroxy-17α-methoxymethoxy-4-pregnen-3,20-dione, which, after recrystallization from methanol / methylene chloride, has a melting point of 188-189 ° C shows.

Example 30 a) A solution of 5.0 g of prednisolone 21 acetate in 25 3 ml of trifluoroacetic anhydride are added dropwise to ml of pyridine at -15 ° C and stirred for 10 minutes at -10 oC.

It is poured into an ice-water-sodium chloride solution and filtered the Precipitation from. The residue is taken up in methylene chloride and washed neutral and, after drying over sodium sulfate, concentrated in vacuo. Yield 6.3 g of 21-acetoxy-17ahydroxy-11β-trifluoroacetoxy-1,4-pregnadiene-3,20-dione.

b) 3.0 S of the above crude product are in a mixture overnight from 25 ml of dimethyl sulfoxide, 15 ml of acetic anhydride and 4.8 ml of glacial acetic acid at room temperature touched. The reaction solution is added to a 10% strength sodium carbonate solution and the precipitate is filtered off. The residue is dissolved in methylene chloride and works up as usual after neutral washing. After chromatography on 350 mg of silica gel with a methylene chloride-acetone gradient (o -8% acetone) isolated 2.83 g of 21-acetoxy-17a-methylthiomethoxy-11ß-trifluoroacetoxy-1,4-pregnadiene-3,20-dione.

c) 1.5 g of 21-acetoxy-17a-methylthiomethoxy-11ß-trifluoroacetoxy 1,4-pregnadiene-3,20-dione are stirred in 38 ml of methanol and 1.9 ml of triethylamine for 4 hours at room temperature. The crude product is purified on 300 g of silica gel with a methylene chloride-acetone gradient (0 - 8% acetone) and isolated 1.2 g of 21-acetoxy-11ß-hydroxy-17 "-methylthiomethoxy-1,4-pregnadiene-3,20-dione, Melting point 155 ° C.

Example 31 a) 20.0 g of 21-acetoxy-9a-fluoro-11ß, 17-dihydroxy-4-pregnen-3,20-dione are analogous to Example 30 a) with trifluoroacetic anhydride to 23.6 g of 21-acetoxy-9α-fluoro-17α-hydroxy-11β-trifluoroacetoxy-4-pregnen-3,20-dione implemented.

b) 3.0 g of the above crude product are treated analogously to Example 30 b) with dimethyl sulphide, acetic anhydride and glacial acetic acid.

The crude product is purified on 300 g of silica gel with a Methylene chloride-acetone gradients (0 - 8% acetone).

Yield 2.58 g of 21-acetoxy-9α-fluoro-17α-methylthiomethoxy-11β-trifluoroacetoxy-4-pregnen-3,20-dione in 28 ml of methanol with 1.4 ml of triethylamine analogous to Example 30 c) to mid cleans the Crude product on 100 g of silica gel with a methyl chloride-acetone gradient (0 - 12 X acetone). Yield 914 mg of 21-acetoxy-9α-fluoro-11β-hydroxy-17α-methylthiomethoxy-4-pregnen-3,20-dione. Melting point 193 ° C., Example 32 a) A suspension of 6.0 g of 21-acetoxy-17α-hydroxy-1,4,9-pregnatriene-3,20-dione in 46 ml of anhydrous acetonitrile is mixed with 11.5 ml of methoxyethoxymethyl chloride and 11.5 ml of diisopropylethylamine were added and the mixture was stirred at 30 ° C. for 7.5 hours. After Ice water precipitation, the precipitate which is sucked off is dissolved in methylene chloride, neutral washed and concentrated after drying. The: Purification of the reaction product takes place on 800 g of silica gel with a hexane-ethyl acetate gradient (0-30% ethyl acetate).

Yield 4.9 g of 21-acetoxy-17α- (1,3,6-trioxaheptyl) -1,4,9-pregnatriene-3,20-dione. Melting point 140 ° C., b) A solution of 1.0 g of 21-acetoxy-17α- (1,3,6-trioxaheptyl) -1, 4,9-pregnatriene-3,20-dione in 10 ml of dioxane is mixed with 900 mg of N-chlorosuccinimide and 5 ml of a 10% perchloric acid offset. The mixture is stirred for 3.5 hours at room temperature and added to ice-water-common salt-sodium hydrogen sulfate solution. It is filtered off and the residue is taken up in methylene chloride and washed neutral and concentrated after drying over sodium sulfate.

The crude product is applied to 100 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone).

Yield 760 mg of 21-acetoxy-9α-chloro-11β-hydroxy-17α- (1,3,6, trioxaheptyl) -1,4-pregnadiene-3,20-dione (Melting point 204 ° C.), and 180 mg of 21-acetoxy-9a, 11β-dichloro-17a-11,3,6-trioxaheptyl) -1, 4-pregnadiene-3,20-dione {Melting point 148 ° C).

Example 33 a) 4.0 g of 21-acetoxy-17α-hydroxy-1,4,9-pregnatriene-3,20-dione are in 28 ml of anhydrous methylene chloride and 18 ml of Formaldihyddimethylacetal dissolved and in portions with a mixture of 6.0 g of kieselguhr W 20 and 3.0 g of phosphorus pentoxide offset. The mixture is stirred for 45 minutes at room temperature, suction filtered and the eluted Residue again with methylene chloride, which contains 3 - 5% triethylamine. The raw product is applied to 750 g of silica gel with a methylene chloride-acetone gradient (0 - 12% acetone) cleaned. Yield 3e3 g of 21-acetoxy-17z-methoxymethoxy-1,4,9-pregnatriene-3,20-diene Melting point 160 ° C.

b) 1.6 g of 21-acetoxy-17α-methoxymethoxy-1,4,9-pregnatriene-3120-dione are dissolved in 16 ml of dioxane and mixed with 1.5 g of N-chlorosuccinimide. After drop by drop Addition of 8 ml of 10% aqueous perchloric acid is stirred for 3 hours at room temperature continue and add to an ice-water-common salt-sodium hydrogen sulfite solution. Filter and works up analogously to Example 2. The crude product is purified on 175 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). Yield 1.1g of 21-acetoxy-9α-chloro-11β-hydroxy-17α-methoxymethoxy-1,4-pregnadiene-3,20-dione, (melting point 224 C), and 250 mg of 21-acetoxy-9a, llßdichlor-17a-methoxymethoxy-lt4-pregnadiene-3,20-dione, Melting point 162 00.

Example 34 a) 1.8 g of 21-acetoxy-17a- (1,3,6-trioxaheptyl) -1,4,9-pregnatriene-3,20-dione are dissolved in 18 ml of dioxane and treated with 1.6 g of N-bromosuccinimide. After drop by drop 8.5 ml of 10% strength aqueous perchloric acid are added and the mixture is stirred for 30 minutes at room temperature continue and add to an ice water-common salt-sodium hydrogen sulfite solution. The work-up is carried out analogously to Example 5. 2.3 g of crude 21-acetoxy-9a-bromo-11ß-hydroxy-17- (1,3,6-trioxaheptyl) -1,4-pregnadiene-3 are obtained, 20-dione.

b) 2.0 g of the above crude product are dissolved in 20 ml of hexamethylphosphoric triamide dissolved and stirred with 2.4 g of lithium chloride for 0.5 hours at a bath temperature of 80 oC. After the ice-water-common salt precipitation, it is filtered off and worked up as usual. The crude product is purified on 350 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield 570 mg of 21-acetoxy-11β-hydroxy-17a- (1,3,6-trioxaheptyl 1,4,8-pregnatriene-3,20-dione. Melting point 170 00.

Example 35 a) 3.2 g of tristriphenylphosphine rhodium (I) chloride are used dissolved in a mixture of 100 ml of methanol and 300 ml of benzene and pre-hydrogenated for 1.5 hours. After adding 4.0 g of 21-acetoxy-17α-methoxymethoxy-1,4,9-pregnatriene-3,20-dione hydrogenation is continued for 6.5 hours under normal pressure. The solution is concentrated on a rotary evaporator and purifies the residue on 400 g of silica gel with a methylene chloride-acetone gradient (Q - 12% acetone). Yield 2.1 g of 21-acetoxy-17α-methoxymethoxy-4,9-pregnadiene-3,20-dione.

b) Analogously to Example 33 b), 1.1 g of 21-acetoxy-17a-methoxymethoxy-4, -9-pregnadiene-3, 20-dione with N-chlorosuccinimide and Treated perchloric acid. To after purification, 430 mg of 21-acetoxy-9α-chloro-11β-hydroxy-17α-methoxymethoxy-4-pregnen-3,20-dione are isolated. Melting point 195 00.

Example 36 a) 17.5 g of 21-chloro-17α-hydroxy-4,9-pregnadiene-3,20-dione are reacted analogously to Example 33 a) with 236 ml Formaldihyddi methyl acetal and worked up. The crude product is purified on 2.25 kg of silica gel with a methylene chloride-acetone gradient (o - 4% acetone). Yield 7.6 g of 21-chloro-17α-methoxymethoxy-4,9-pregnadiene-3,20-dione.

Melting point 152 00.

b) 1.8 g of 21-chloro-17α-methoxymethoxy-4,9-pregnadiene-3,20-dione are treated analogously to Example 33 b) with N-chlorosuccinimide and perchloric acid. The crude product is applied to 100 g of silica gel with a methylene chloride-acetone gradient (0-10% acetone). 126 mg of 9 ", 21-dichloro-11β-hydroxy-17α-methoxymethoxy-4-pregnene-3,20-dione are isolated. Melting point 197 ° C (decomposition).

Example 37 a) 3.0 g of 21-fluoro-17'-hydroxy-1,4,9-pregnatriene-3,20-dione are reacted analogously to Example 33 a) with 14 ml Formaldihyddimethylacetal. Worked up is under the conditions described in Example 4. The raw product is cleaned on 450 g of silica gel with the methylene chloride-acetone gradient (0-8% acetone). yield 1.5 g of 21-fluoro-17'-methoxymethoxy-1,4,9-pregnatriene-3,20-dione.

b) Under the conditions of Example 33 bt, 500 mg of 21-fluoro-17a-methoxymethoxy-1,4,9-pregnatriene-3-, 20-dione are obtained with N-chlorosuccinimide and perchloric acid reacted. According to the already described Working-up instructions and purification on silica gel, 420 mg of 9 «-chloro-21-fluoro-11ß-hydroxy-17a-methoxymethoxy-1,4-pregnadiene-3,20-dione are isolated. Melting point 245 ° C.

Example 38 a) 1.0 g of 17a-hydroxy-1,4,9-pregnatriene-3,20-dione become reacted under the conditions of Example 33 a3 with formaldehyde dimethyl acetal. 823 mg of 17a-methoxymethoxy-1,4,9-pregnatriene-3,20-dione are isolated as a crude product.

b) 823 mg of the above crude product are analogous to Example 33 b) with N-chlorosuccinimide and perchloric acid treated and worked up under the conditions described there and cleaned. Yield 410 mg of 9a-chloro-11ß-hydroxy-17a-methoxymethoxy-1,4-pregnadiene-3,20-dione. Melting point 227 ° C., Example 39 a) Analogously to Example 34 a), 1.0 g of 21-fluoro-17a-methoxymethoxy-1,4,9-pregnatriene-3,20-dione is used treated with 900 mg of N-bromosuccinimide and 5 ml of a 10% strength aqueous perchloric acid. 1.1 g of 9a-bromo-21-fluoro-11β-hydroxy-17a-methoxymethoxy-1,4-pregnadiene-3,20-dione are isolated.

b) 1.1 g of the crude 9a-bromo-21-fluoro-11ß-hydroxy-17a-methoxymethoxy-1,4-pregnadiene-3,20-dione are with 1.4 g of lithium chloride analogous to Example 34 b) to 21-fluoro-11ß-hydroxy-17amethoxymethoxy-1,48-pregnatriene-3,20-dione implemented.

Yield 490 mg. Melting point 218 ° C.

Example 40 a) 3.3 g of 21-chloro-17a-hydroxy-1,4,9-pregnatriene-3,20-dione are reacted with Formaldihyddimethylacetal under the conditions of Example 33 a). 2.4 g of 21-chloro-17α-methoxymethoxy-1,4,9-pregnatriene-3,20-dione are isolated.

b) 1.4 g of 21-chloro-17-methoxymethoxy-1,4,9-pregnatriene-3,20-dione are treated with N-bromosuccinimide analogously to Example 34 a) and isolates 1.7 g of 9a-bromo-21-chloro-IIß ~ hydroxy-17'-methoxymethoxy-1,4-pregnadiene-3,20-dione as crude product.

c) 1.7 g of 9a-bromo-21-chloro-11ß-hydroxy-17a-methoxymethoxy-1,4-pregnadiene-3,20-dione are used under the conditions of Example 34 b) with 2.1g lithium chloride. The crude product is applied to 300 g of silica gel with a methylene chloride-acetone gradient (o - 8% acetone) purified. Yield 530 mg of 21-chloro-11ß-hydroxy-17a-methoxymethoxy-1,4,8-pregnatriene-3,20-dione. Melting point 166 ° C.

Example 41 a) Analogously to Example 38, 7.6 g of 21-fluoro-17a-hydroxy-4,9-pregnadiene-3,20-dione are prepared and 68 ml of formaldehyde di methyl acetal 3.4 g of 21-fluoro-17a-methoxymethoxy-4,9-preg nadiene-3,20-dione.

b) 1.4 g of 21-fluoro-17a-methoxymethoxy-4,9-pregnadiene-3,20-dione are obtained under the conditions of Example 36 b) treated with N-chlorosuccinimide and perchloric acid. The raw product is cleaned 100 g silica gel with a methylene chloride-acetone gradient (0-10 °% acetone). Yield 380 mg of 9a-chloro-21-fluoro-11ß-hydroxy-17a-methoxymethoxy-4-pregnene-3,20-dione. Melting point 214 C. (dec.) Example 42 a) In a mixture of 100 ml of pyridine and 12 ml of trifluoroacetic anhydride are 20.0 g of 9α-fluoro-11β, 17α-dihydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione at -10 ° C given and stirred at -10 ° C for 10 minutes. Filtered after the ice water precipitation one off and the residue is taken up in methylene chloride. After washing and drying the organic solution is concentrated in vacuo, 22.0 g of 9-fluoro-17a-hydroxy-21-propionyloxy-lln trifluoroacetoxy-1,4-pregnadiene-3,20-dione isolated.

b) 22.0 g of the above crude product are under the conditions of Example 33 a) reacted with 90 ml of formaldehyde dimethyl acetal, 9α-fluoro-17α-methoxymethoxy-21-propionyloxy-11β-trifluoroacetoxy-1,4 pregnadiene-3,20-dione isolated as a crude product.

c), The crude 9α-fluoro-17α-methoxymethoxy-21-propionyloxy-11β-trifluoroacetoxy-1,4-pregnadiene-3,20-dione is dissolved in 500 ml of methanol and after addition of 25 ml of triethylamine, the mixture is stirred for 30 minutes Room temperature further. The reaction solution is concentrated to dryness in vacuo and the residue is chromatographed on 2.25 kg of silica gel with a methylene chloride-acetone gradient (0-12% acetone).

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

Example 543 ar Under the conditions of Example 42 a) becomes 1.0 g of 21-butyryloxy-9a-fluoro-11ßl17-dihydroxy-1,4-pregnadiene-3,20-dione with trifluoroacetic anhydride implemented and worked up. 0.9 g of 21-butyryloxy-9a-fluoro-17α-hydroxy-11β-trifluoroacetoxy-1,4-pregnadiene-3,20-dione is isolated.

b) 800 mg of the above crude product are analogous to Example 42 b) with 3.6 treated m7 Formaldihyddimethylacetal. After the aura heating, you get 1.1 p crude 21-butyryloxy-9α-fluoro-17-methoxymethoxy-11β-trifluoroacetoxy-1,4-pregnadiene-3,20-dione.

c) 1.1 g of crude 21-butyryloxy-9α-fluoro-17α-methoxymethoxy-11β-trifluoroacetoxy-1,4-pregnadiene-3,20-dione are reacted with triethylamine as in Example 42 b).

The crude product is chromatographed on 75 g of silica gel with a Methylene chloride-acetone gradient (0-15% acetone).

Yield 540 mg of 21-butyryloxy-9α-fluoro-11β-hydroxy-17α-methoxymethoxy-1,4-pregnadiene-3,20-dione. Melting point 2470C.

Example 44 2.0 g of 21-butyryloxy-9α-fluoro-17α-hydroxy-1,4-pregnadiene-3,11,20-trione are reacted and worked up analogously to Example 33 a) with 9 ml of formaldehyde dimethyl acetal. The crude product is purified on 300 g of silica gel with a methylene chloride-acetone gradient (0-10% acetone. Yield 2.07 g of 21-butyryloxy-9a-fluoro-17a-methoxymethoxy-1,4-pregnadiene-3,11,20-trione. Melting point 192 OC.

Example 45 Analogously to Example 32, 700 mg of 21-butyryloxy-9a-fluoro-17α-hydroxy-1,4-pregnadiene-3,11,20-trione are obtained reacted with 1.54 ml of methoxyethoxymethyl chloride. The crude product is applied to 135 g of silica gel with a methylene chloride-acetone gradient (0 - 5% Acetone3 purified. Yield 430 mg of 21-butyryloxy-9a-fluoro 17α- (1,3,6-trioxaheptyl) -1,4-pregnadiene-3,11,20-trione.

Melting point 126 t.

Example 46 a) 15.2 g of 9α-fluoro-11β, 17α-dihydroxy-16β-methyl-21-propionyloxy-1,4-pregnadiene-3,20-dione are treated, prepared from 9α-fluoro-11β, 17α, 21-trihydroxy-16β-methyl-1,4-pregnadiene-3,20-dione and propionic anhydride, with 9.1 ml of trifluoroacetic anhydride analogous to the example 42 a). 15.4 g of 9α-fluoro-17′-hydroxy-16β-methyl-21-propionyloxy-11β-trifluoro are obtained acetoxy-1,4-pregnadiene-3,20-dione.

b) 15.4 g of the above crude product are under the conditions of Example 42 b) with formaldehyde dimethyl acetal to give 9α-fluoro-17α-methoxymethoxy-16β-methyl-21-propionyloxy-11β-trifluoroacetoxy-1,4-pregnadiene-3,20-dione implemented.

Yield 16.9 g of the crude product.

c) The solution of the crude 9a-fluoro-17a-methoxymethoxy-16ß-methyl-21-propionyloxy-11ß-trifluoroacetoxy-1,4-pregnadiene-3,20-dione in 250 ml of methanol is treated analogously to Example 42 c) with 30 ml of triethylamine. After working up, the crude product is purified on 1.5 kg of silica gel with a methylene chloride-acetone gradient (o - 10% acetone). Yield 9.6 g of 9α-fluoroIIIβ-hydroxy-17α-methoxymethoxy-16β-methyl-21-propionyloxyl, 4-pregnadiene-3,20-dione. Melting point 169 ° C., Example 47 600 mg of 9α-fluoro-11β-hydroxy-17'-methoxymethoxy-16β-methyl-21-propionyloxy-1,4-pregnadiene-3,20-dione are with 500 mg tristriphenylphosphine rhodium (I) chloride under the conditions of Example 35 a) hydrogenated and worked up. According to the chroniatography of the crude product on 65 g silica gel with a methylene chloride-acetone gradient (0 - 10 ° Zo acetone) 347 mg of 9α-fluoro-11β-hydroxy-17α-methoxymethoxy-16β-methyl-21-propionyloxy-4-pregnen-3,20-dione are isolated. Melting point 165 ° C.

Example 48 A suspension of 6.9 g of 9α-fluoro-11β-hydroxy-17α-methoxymethoxy-16β-methyl-21-propionyloxy-1,4-pregnadiene-3,20-dione in 80 ml of methanolic Ci, 2 N potassium hydroxide solution, the mixture is stirred at 0 ° C. for 45 minutes. It is neutralized with 10% acetic acid and obtained after the ice water precipitation and working up a crude product, the 450 g of silica gel with a methylene chloride-acetone gradient (O - 20% acetone) is purified. Yield 4.1 g of 9α-fluoro-11β, 21-dihydroxy-17α-methoxymethoxy-16β-methyl-1,4-pregnadiene-3,20-dione. Melting point 220 ° C.

Example 49 a) A solution of 1.7 g of 9α-fluoro-11β, 21-dihydroxy-17α-methoxymethoxy-16β-methyl-1, 4-pregnadiene-3,20-dione in 17 ml of pyridine is added with 2.04 g of tosyl chloride for 1 hour Room temperature stirred. After the ice water precipitation, the precipitate is in methylene chloride recorded and processed as usual.

The crude product is purified on 135 g of silica gel with a methylene chloride-acetone gradient (0-10% acetone). Yield 876 mg of 9α-fluoro-11β-hydroxy-17α-methoxymethoxy-16β-methyl-21-tosyloxy-1,4-pregnadiene-3,20-dione.

b) 876 mg of the above product are dissolved in 17 ml of hexamethylphosphoric triamide stirred with 880 mg lithium chloride for 1 hour at 80 oC. One gives on ice water and the precipitate is filtered off. After the usual work-up, it is crystallized the crude product from liexane / acetone to. Yield 485 mg of 21-chloro-9a-fluoro-11β-hydroxy-17α-methoxymethoxy-16β-methyl-1,4-pregnadiene-3,20-dione. Melting point 204 OC.

Example 50 a) A suspension of 11.2 g of 9 ″ -fluoro-11β-hydroxy-17 ″ -methoxamethoxy-21-propionyloxy-1,4-pregnadiene-3,20-dione 129 ml of a methanolic 0.2 N potassium hydride solution are added. One stirs 1 hour at room temperature and works up as described in Example 48. To the chromatography on 1.5 kg of silica gel with a methylene chloride-acetone degree ducks (0 - 35% acetone) are isolated 7.5 5 g of 9a-fluoro-11ß, 21-dihydroxy-17a-methoxymethoxy-1, 4-pregnadiene-3, 20-dione.

b) Analogously to Example 49a, 1.0 g of the above raw product is made with 2.0 g of tosyl chloride implemented. The crude product is purified on 200 g of silica gel with a methylene chloride-acetone gradient (O - 10% acetone). Yield 886 mg of 9α-fluoro-11β-hydroxy-17'-methoxymethoxy-21-toxyloxy-1,4-pregnadiene-3,20-dione.

c) 886 mg of 9a-fluoro-11ß-hydroxy-17a-methoxymethoxy-21-toxyloxy 1,4-pregnadiene-3,20-dione are treated with lithium chloride under the conditions of Example 49 b) and worked up. The purification is carried out by recrystallization from acetone / hexane. yield 392 mg of 21-chloro-9a-fluoro-11ß-hydroxy-17a-methoxymethoxy 1,4-pregnadiene-3,20-dione. Melting point 225 OC.

Example 51 a) 20.0 g of 21-acetoxy-9α-fluoro-11β, 17-dihydroxy-4-pregnen-3,20-dione are used analogous to Example 42 a) with 12 ml of trifluoroemic anhydride to 21-acetoxy-9 "-fluoro-17" -hydroxy-11B-trifluoroacetoxy-4-pregnen-3,20-dione around.

b) 5.0 g of the above crude product are analogous to Example 33 a) with 22.5 ml Formaldihyddimethylacetal into the 21-acetoxy-9-fluoro-17-methoxymethoxy-11ß-trifluoroacetoxy-4-pregnen-3,20-dione converted. Yield 5.3g.

c) 5.3 g of 21-acetoxy-9a-fluoro-17a-methoxymethoxy-11ß-trifluoroacetoxy-4-pregnen-3,20-dione are treated with triethylamine analogously to Example 42 c). The raw product is cleaned on 500 g of silica gel with a methylene chloride-acetone gradient (0-8% acetone). Yield 560 mg of 21-acetoxy-9a-fluoro-11β-hydroxy-17α-methoxymethoxy-4-pregnen-3,20-dione.

Melting point 213 00.

Example 52 1.0 g of 21-butyryloxy-9a-fluoro-11ß-hydroxy-17a-methoxymethoxyl, 4-pregnadiene-3,20-dione are with 800 mg tristriphenylphosphine rhodium (I) chloride under the conditions of Example 35 a) hydrogenated and worked up. After the crude product has been chromatographed on 100 g of silica gel with a methylene chloride-acetone gradient (0 - 10% acetone) 620 mg of 21-butyryloxy-9-fluoro-11ß-hydroxy-17-methoxymethoxy-4-pregnene-3,20-dione are isolated. Melting point. 183 00.

Example 53 a) Analogously to Example 48, 28.0 g of 21-acetoxy-9α-fluoro-11β-hydroxy-17α-methoxymethoxy-4-pregnen-3,20-dione are obtained with methanolic 0.2 N potassium hydroxide solution to 9α-fluoro-11β, 21-dihydroxy-17α-methoxymethoxy-4-pregnen-3,20-dione saponified b) A solution of 500 mg of 9α-fluoro-11β, 21-dihydroxy-17α-methoxymethoxy-4-pregnen-3,20-dione in 5 ml of pyridine is mixed with 7.5 11 n-valeric anhydride for 1 hour at room temperature touched. After ice water precipitation, it is filtered off and worked up as usual. That The crude product is poured onto 400 g of silica gel with a hexane-ethyl acetate gradient (0-30%) % Ethyl acetate). Yield 235 mg of 9α-fluoro-11β-hydroxy-17α-methoxymethoxy-21-valeryloxy-4-pregnen-3,20-dione. Melting point 181 ° C.

Claims (1)

Claims 1. Corticoids of the general formula I wherein the bonds ..... single bonds or double bonds, X a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, Y a hydrogen atom and Z a hydrogen atom, a fluorine atom or a chlorine atom or Y and Z together a carbon-carbon bond, a ß -Hydroxymethylene group, a ß-chloromethylene group or a carbonyl group, W a methylene group, an ethylidene group or a vinylidene group, Q an oxygen atom or a sulfur atom, R1 an alkyl group containing 1 to 8 carbon atoms, optionally interrupted by an oxygen atom, or a benzyl group and R2 a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms or and R2 together denote a trimethylene group or a tetramethylene group and R3 denotes a hydrogen atom, a fluorine atom, a chlorine atom or a free or esterified hydroxyl group. 2. Corticoids of the general formula Ia in which W, Q, R1, R2 and R3 are as defined in claim 1 and X is a hydrogen atom, a fluorine atom or a methyl group and Z1 is a hydrogen atom, a fluorine atom or a chlorine atom. 3. Corticoids of the general formula Ib wherein X ', Z', W, Q, R1, R2 and R3 have the meaning given in claim 2. 4. Corticoids of the general formula I c wherein X ', W, Q, Q, R1 and R3 have the meaning given in claim 2. 5. Corticoids according to claim 2 to 4, characterized in that the symbol X 'of the general formula means a hydrogen atom. 6. Corticoids according to claim 2, 3 and 5, characterized in that the symbol Z 'of their general formula Means hydrogen atom 7. Corticoids according to claim 2> 3 and 5, characterized in that the symbol Z 'in its general formula denotes a fluorine atom or a chlorine atom. 8. Corticoids according to claim 1 to 7, characterized in that the symbol W of their general formula means a methylene group. 9. Corticoids according to claim 1 to 8, characterized in that the symbol Q in their general formula means an oxygen atom 10. Corticoids according to claim 1 to 8, characterized in that the symbol Q is their general Formula means a sulfur atom. 11. Corticoids according to claim 1 to 10, characterized in that the symbol R2 in their general formula denotes a hydrogen atom. 12. Corticoids according to claim 1 to 11, characterized in that the symbol R2 of their general formula contains 1 to 6 carbon atoms Means alkyl group. 13. Corticoids according to claim 1 to 12, characterized in that the symbol R3 of their general formula is a hydroxyl group or 1 to 8 carbon atoms Means containing acyloxy group. 14. Corticoids according to claim 1 to 12, characterized in that the symbol R3 in their general formula denotes a fluorine atom or a chlorine atom. 15. 11β, 21-dihydroxy-17α-methoxymethoxy-4-pregnene-3,20-dione, 16. 11β, 21-dihydroxy-17α- (1'-methoxyethoxy) -4-pregnene-3.20 dione, 17. 17α- (1'-ethoxy-ethoxy) -11β, 21-dihydroxy-4-pregnen-3,20-dione, 18. 11ß, 21-dihydroxy-17α- (1'-isobutyloxy-ethoxy) -4-pregnen-3,20-dione, 19. llß, 21-dihydroxy-17a- (2'-tetrahydropyranyloxy) -4-pregnen-3, 20-dione, 20. llß, 21-dihydroxy-17 "- (1'-methoxyethoxy) -6a-methyl-4-pregnen-3,20-dione, 21. llß, 21-dihydroxy-17a- (1'-methoxyethoxy) -16 [beta] -methyl-4-pregnen-3,20-dione, 22. llß-Hydroxy-17a- (1'-methoxyethoxy) -4-pregnen-3,20-dione, 23.11ß, 21-dihydroxy-17α- (2'-methoxyethoxymethoxy) -4-pregnen-3,20- dion, 24. llß, 21-dihydroxy-17a-methoxy-1,4-pregnadiene-3,20-dione, 25. llß, 21-dihydroxy-17a-(1'-methoxyethoxy) -6a-methyl-1, 4-pregnadiene-3,20-dione, 26. llß, 21-dihydroxy-17 "-ethoxymethoxy-4-pregnene-3,20-dione, 27. llß, 21-dihydroxy-17a-propoxysethoxy-4-pregnene-3,20-dione, 28. llß, 21-dihydroxy-17a-butoxymethoxy-4-pregnen-3,20-dione, 29. llß121-dihydroxy-6a-fluoro-17a-methoxyeethoxy-4-pregnen-3,20-dione, 30 llß, 21-dihydroxy-17a-methoxymethoxy-16ß-methyl-4-pregnen-3,20-dione, 31. 21-acetoxy-11ß-hydroxy-17a-methoxymethoxy-4-pregnen-3,20-dione, 32. llß-Hydroxy-17a-methoxymethoxy-21-propionyloxy-4-pregnen-3,20-dione, 33. 2l-Butyryloxy-Llß-hydroxy-17-methoxymethoxy-4-pregnen-3,20-dione, 34. llß-Hydroxy-17a-methoxymethoxy-21-trimethylacetoxy-4-pregnen-3,20-dione, 35.21-acetoxy-11ß-hydroxy-17a-methoxymethoxy-1,4-pregnadiene-3,20-dione, 36.21-butyryloxy-11ß-17a-methoxymethoxy-1,4-pregnadiene-3,20-dione, 37. 21-acetoxy-17a-methoxymethoxy-4-pregnen-3,11,20-trione, 38.21-acetoxy-9a-chloro-11ß-hydroxy-17a-methoxymethoxy-4-pregnen-3,20-dione, 39. 21-acetoxy-9a-fluoro-11ß-hydroxy-17 "-methoxymethoxy-4-pregnen-3,20-dione, 40. 9a-chloro-11ß, 21-dihydroxy-17a-methoxymethoxy-4-pregnen-3,20-dione, 41.21-acetoxy-11ß-hydroxy-17α-methylthiomethoxy-1,4-pregnadiene-3,20-dione, 42. 2l-acetoxy-9a-fluoro-11ß-hydroxy-17a-methylthiomethoxy-4-pregnen-3,20-dione, 43. 21-acetoxy-9a-chloro-17 "- (2'-methoxyethoxymethoxy) -1,4-pregnadiene-3,20-dione, 44. 21-acetoxy-9a, 11B-dichloro-17 "- (2'-methoxyethoxymethoxy) -1,4-pregnadiene-3,20-dione, 45. 21-acetoxy-9α-chloro-11β-hydroxy-17α-methoxymethoxy-1,4-pregnadiene-3,20-dione, 46. 21-Acetoxy-9 ", 11ß-dichloro-17ff-methoxymethoxy-1,4-pregnadiene-3,20-dione, 47. 2L-acetoxy-11ß-hydroxy-17a- (2'-methoxy-ethoxymethoxy) -1, 4,8-pregnatrien-3, 20-dione, 48.9a, 21-dichloro-11ß-hydroxy-17 "-methoxymethoxy-4-pregnen-3,20-dione, 49. 9α-chloro-21-fluoro-11β-hydroxy-17α-methoxy-1,4-pregnadiene-5, 20-dione, 50.9a-chloro-11ß-hydroxy-17a-methoxymethoxy-1,4-pregnadiene-3,20-dione, 51.21-fluoro-11ß-hydroxy-17a-methoxymethoxy-1,4,8-pregnatriene-3, 20-dione, 52. 21-chloro-11β-hydroxy-17α-methoxymethoxy-1,4,8-pregnatriene-3,20-dione, 53. 9 "-Chlor-21-fluoro-IIR-hydroxy-17a-methoxymethoxy-4-pregnen-3, 20-dione 54.9α-fluoro-11β-hydroxy-17α-methoxymethoxy-21-propionyloxy-1,4-pregnadiene- 3,20-dione, 55. 21-butyryloxy-9α-11β-hydroxy-17α-methoxymethoxy-1,4-pregnadiene-3,20-dione, 56. 21-butyryloxy-9a-fluoro-17a-methoxymethoxy-1,4-pregnadiene-3,11,20-trione, 57. 2l-butyryloxy-9a-fluoro-17a- (2'-methoxy-ethoxymethoxy) -1,4-pregnadiene-3,11,20-trione, 58.9 "-Fluoro-11ß-hydroxy-17a-methoxymethoxy-16ß-methyl-21-propionyloxy-1,4-pregnadiene-3,20-dione, 59. 9α-fluoro-11β-hydroxy-17α-methoxymethoxy-16β-methyl-21-propionyloxy-4-pregnen-3,20-dione, 60. 9α-fluoro-11β, 21-dihydroxy-17α-methoxymethoxy-16β-methyl-1,4-pregnadiene-3,20-dione, 61. 21-chloro-9a-fluoro-11ß-hydroxy-17a-methoxymethoxy-16ßmethyl-1,4-pregnadiene-3,20-dione, 62. 21-butyryloxy-9a-fluoro-11ß-hydroxy-17a-methoxymethoxy-4-pregnen-3,20-dione, 63. 9a-fluoro-IIE-hydroxy-17 "-methoxymethoxy-2l-valeryloxy-4 pregnen-3,20-dione, 64. Pharmaceutical Preparations, characterized by a content of 1 to 3 corticoids according to claim 1 to 63 and 71. 65. A process for the preparation of corticoids of the general formula I according to claim 1, characterized in that a 17a-hydroxysteroid of the general formula II is used in a manner known per se in which ....., X, Y, Z, V, W have the meaning given in claim 1 and R'3 denotes a hydrogen atom, a fluorine atom, a chlorine atom or an esterified hydroxyl group, if desired after intermediate protection of an ILß-hydroxyl group, a) with an acetal of the general formula III R2HC (OR1) 2 (III), in which R1 and R2 have the meaning given in claim 1, or b) with an a-halogen ether of the general formula IV Hal -R2CH-OR1 (IV ), wherein R1 and R2 have the meaning given in claim 1 and Hal represents a chlorine atom, a bromine atom or an iodine atom, or c) with a vinyl ether of the general formula V R'2CH = CH-OR1 (V), wherein R1 is the has the meaning given in claim 1 and R'2 represents a hydrogen atom or an alkyl radical containing one to three carbon atoms, or d) with a sulfoxide of the general formula VI R2CH2S ° R1 (VI), wherein R1 and R2 are those mentioned in claim 1 Have meaning implements, and possibly the according to Va riante a to d obtained, in the 1 and 2 position saturated corticoids dehydrated in the 1,2-position, and / or an 11ß-hydroxyl group oxidized to the oxo group, and / or 21-ester groups saponified and / or 21-hydroxyl groups esterified or against Exchanges fluorine atoms or chlorine atoms. 66. A process for the preparation of corticoids of the general formula I according to claim 1, characterized in that in a manner known per se a) a 9, ll-dehydrosteroid of the general formula VII in which .....,, X, W, Q, R1 ', R2 and R3 have the meaning given in claim 1, chlorine or hypochlorous acid is added, or b) the epoxy ring of a 9,11-epoxy steroid of the general formula VIII in which ....., X, Q, Q, Q, R1, R2 and R3 have the meaning given in claim 1 with hydrogen fluoride or hydrogen chloride opens, or c) from a 9-halostsroid of the general formula IX wherein ....., X, W, Q, R1, R2 and R3 have the meaning given in claim 1 and Z "represents a chlorine atom or a bromine atom,%" or SITZ "eliminates, and optionally those according to variant a to c The 1,2-position saturated corticoids obtained are dehydrated in the 1,2-position, and / or an 11β-hydroxyl group is oxidized to the oxo group, and / or 21-ester groups are saponified and / or 21-hydroxy groups are esterified or against fluorine atoms or chlorine atoms exchanges. 67. Process for the preparation of in the 7a-position by an acetal radical of the general formula X. in which R1 and R2 have the meaning given in claim 1, substituted IIβ-hydroxysteroids of the pregnane series, characterized in that a II-deoxysteroid of the pregnane series which is similarly substituted in the 17-position or its 21-ester with the aid of fungal cultures of the genus Curvularia fermented. 68. Process for the preparation of IIβ-hydroxysteroids of the general formula Id wherein .....,, X, W, Q, R1 and R2 have the meaning given in claim 1 and R4 represents a hydrogen atom or a hydroxyl group, characterized in that a II-deoxysteroid of the general formula XI wherein X, W, Q, Rl and R2 have the abovementioned meaning and R4 represents a hydrogen atom, a hydroxyl group or an alkanoyloxy group containing 1 to 6 carbon atoms fermented with fungal cultures of the genus Curvularia, and the compounds of the formula I d obtained with the meaning of a Single bond optionally dehydrated in the 1,2-position. 69. The method according to claim 67 and 68, characterized in that the fermentation is carried out with the aid of fungal cultures of the species Curvularia lunata. 70. Use of IIß-hydroxysteroids of the general formula I d according to claim 68 for the preparation of steroids of the general formula XII wherein .....,, X, W and R4 have the meaning given in claim 68. 71. 21-chloro-9a-fluoro-11ß-hydroxy-17a-methoxymethoxy 1,4-pregnadiene-3,20-dione.