DE2839033A1 - 3-Oxo-pregnen-20 alpha:carboxylic acid derivs. - as antiinflammatories for topical treatment of skin diseases and for use in inhalants to treat disorders of the respiratory tract - Google Patents

Abstract

3-Oxo-pregnene-20 alpha-carboxylic acid derivs. of formula (I) and their salts with physiologically acceptable bases are new. In (I), X is an alpha-H or an alpha-halogen; Y1 and Y2 are =O or an alpha- or beta-OH gp. and H; X and Y1 may also form a C-C bond or -O-, in which case Y2 is H; Z is alkoxycarbonyl (1-8C in alkoxy gp.), or is carboxyl; underscored --- is a double bond, or when X is not H and Z is not carboxyl or methoxycarbonyl underscored --- can be a single bond. In (IV) underscored --- is a single or double bond; X is H or halogen. Y1' and Y2' together form a carbonyl gp. or Y1' is OH and Y2' is H; Z is alkoxycarbonyl (1-8C in alkoxy gp.) or is carboxyl. The use of 3-oxo-4-pregnene-20 alpha-carboxylic acid derivs. of formula (IV) and their salts with physiologically acceptable bases in pharmaceutical formulations is novel. (I) are intermediates for (IV). (I) and (IV) have an excellent antiinflammatory effect, when used topically, but are not effective when applied systemically.

Description

3-Oxo-4-pregnen-20 "-carboxylic acid-

Derivatives, their manufacture and use The invention relates to new 3-0xo-4-pregnen-20 "-carboxylic acid derivatives of the general formula I. according to claim 1, a process for their preparation according to claim 2 and pharmaceutical Preparations containing 3-oxo-4-pregnen-20 «-carboxylic acid derivatives of the general Formula IV according to claim 3 included.

Under a halogen atom X of the 3-oxo-4-pregnen-20a-carboxylic acid derivatives of the general formula I should preferably be understood as meaning a fluorine, chlorine or bromine atom will. As alkoxycarbonyl groups Z of the 3-oxo -4-pre gnen-20a-carboxylic acid derivatives of the general formula I and IV should, for example, be a methoxycarbonyl group, an Xthoxyearbonytgruppe, a Propyloxycarbonylgruppe, an Isopropyloxyearbonylgruppe, a butyloxycarbonyl group, an isobutyloxycarbonyl group, a tert. -Butyloxycarbonyl group, a pentyloxycarbonyl group, a hexylcarbonyl group, a heptyloxycarbonyl group or an octyloxycarbonyl group.

US Pat. No. 3,539,687 discloses some 3-oxo-4-pregnen-20α-carboxylic acid derivatives of the general formula IV known, namely the 11ß-hydroxy-3-oxo-4-pregnen-20 "-carboxylic acid and their methyl esters and the 3, ll-dioxo-4-pregnen-20a-carboxylic acid and their methyl esters. From the teaching of this patent it can be seen that the known 3-oxo-4-pregnen-20'-carboxylic acid derivatives Intermediate products for the synthesis of pharmacologically active steroids are. It was now found that these known 3-oxo-4-pregnen-20 "-carboxylic acid derivatives and the unknown 3-oxo-4-pregnen-20-carboxylic acid derivatives of the general formula I with X stands for a hydrogen atom, a fluorine atom and a chlorine atom and Y1 and Y2 mean an oxo group or a β-hydroxy group and a hydrogen atom when applied topically a pronounced anti-inflammatory Effective Xeit have that but at systemic application are pharmacologically ineffective.

This finding is surprising for the person skilled in the art, since the side chain these compounds lack all structural features which, according to previous experience, are lacking are necessary for the development of an anti-inflammatory horticoid effect.

The 3-oxo-4-pregnen-20-carboxylic acid derivatives of the general formula I are also often valuable intermediates for the preparation of pharmacologically effective 3-oxo-4-pregnen-20a-carboxylic acid derivatives, such as from the invention The method according to claim 2 can be seen.

The process according to the invention according to process variant a of claim 2 is carried out in a manner known per se by the compounds of the general Formula II by means of a microorganism culture capable of II-hydroxylation in hydroxylated at the ll-position. Suitable microorganism cultures are, for example the fungal cultures of the genera Curvularia, Cunninghamella capable of llß-hydroxylation and the fungal cultures of the genera Aspergillus capable of II'-hydroxylation, Sclerotium, Glomerella, Trichothecium, Absidia or Rhizopus such as: Curvularia lunata (NRRL 2380), Cunninghamella blakesleana (ATCC 8688b), Cunninghamella bertholletiae (NRRL 1378), Cunninghamella verticillata CATCC 8983), Cunninghamella elegans (ATCC 9245), Aspergillus ochraceus (NRRL 405), Aspergillus niger (NRRL 3228), Sclerotium hydrophilum (IFO 5293), Glomerella cingulata (ATCC 10 534), Trichothecium roseum (ATCC 8685), Absidia orchidis (ATCC 6811) and Rhizopus stolonifer CATCC 6227b).

Under the culture conditions commonly used for these microorganisms are grown in a suitable nutrient medium with aeration, submerged cultures. The substrate is then dissolved in a suitable solvent for the cultures to and ferment until a maximum substrate conversion is reached.

Suitable substrate solvents are, for example, methanol, methanol, Glycol monomethyl ether, dimethylformamide or dimethyl sulfoxide.

The optimal substrate concentration, substrate addition time and fermentation time is used on the structure of the sub.

strates and the type of microorganism used.

pending. 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 dehydration of the compounds of the general formula III according to Process variant b of claim 2 can also be used in a manner known per se be carried out, for example, by making these compounds through reaction with nethanesulphonic acid chloride or p-2oluenesulphonic acid chloride in the corresponding Sulphonic acid ester and converted by treatment with weak bases such as sodium acetate converted into the corresponding 9, 11 steroids.

Surprisingly, this dehydration can also be done in that way carry out that the compounds of general formula III in an inert Solvents (such as benzene, toluene or xylene) with mineral acids (sulfuric acid, Phosphoric acid or hydrochloric acid).

The 9 (1l) steroids produced in this way can be used in a manner known per se Way, add HOC1 or HOBr, for example by touching them in the presence of Water and mineral acids such as sulfuric acid or perchloric acid N-chloroacylamide, N-chloroacylimide, N-bromoacylamide or N-bromoacylimide (for example N-chloroacetamide, N-bromoacetamide, N-chlorosuccinimide or N-bromosuccinimide) leaves.

The 9 ″ -chlorine and 9 ″ -bromine compounds obtained can in per se be converted into the corresponding 9,11R-epoxy compounds in a known manner (for example by treating with bases such as sodium hydroxide? Potassium carbonate, sodium acetate or Potassium acetate 'which is then reacted with Hydrogen fluoride or hydrogen chloride into the ultimately desired 9 «-fluoro- or 9a-chloro steroids being transformed.

Contain those prepared according to process variant a or b according to claim 2 Compounds a 20a-hydroxymethylene group, this is for example with chromium (VI) -oxyd-sulfuric acid with simultaneous oxidation of any II-hydroxyl group that may be present converted into the corresponding 3-oxo-4-pregnen-20 "-carboxylic acid.

The 10-oxosteroids obtained can then, if desired, be added to the corresponding llß-hydroxy compounds are reduced, for example by reduction with sodium borohydride.

The subsequent dehydration of the In the l-position saturated 4 ~ steroids of the general formula 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 genera Bacillus (for example Bacillus lentus or Bacillus sphaericus) or Arthrobacter (for example Arthrobacter simplex) in the Dehydrate l position. On the other hand, it is also possible to use Al dehydrogenation carry out in such a way that the A4 steroids with the usual for this reaction Oxidizing agents such as selenium dioxide or 2,3-dichloro-5,6-dicyanobenzoquinone heated in inert solvents.

The working methods with which one can remove the free acids if necessary converted into their salts or esters or existing esters optionally saponified, are known to those skilled in the art (e.g., from U.S. Patent 3,824,260).

Due to their anti-inflammatory effectiveness, they are suitable 3-Oxo-4-pregnen-20 "-carboxylic acid derivatives of the general formula IV in combination with those in the galenic Pharmacy usual carrier means for local treatment of contact dermatitis, various types of eczema, neurodermatoses, Erythroderma, burns, pruritis vulvae et ani, rosacea, erythematosus cutaneus, Psoriasis, lichen planus et verrucosus and similar skin diseases.

The production of the pharmaceutical 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. In In the pharmaceuticals formulated in this way, the concentration of the active substance depends on the form of administration addicted.

In the case of lotions and ointments, an active ingredient concentration is preferred used from 0.001% to 1%.

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 following examples serve to illustrate the invention Procedure.

Example 1 a) 200 g of 20a-hydroxymethyl-4-pregnen-3-one are in 1.5 Liters of acetone suspended and for this purpose 300 ml of Jones reagent at 15-20 ° C. with stirring (133.5 g CrO3 in 100 ml conc.

Suspended H2S04 and made up to 500 ml with H2O). Afterward is stirred for 6 hours at room temperature and the reaction mixture in 5 liters Poured ice water. The precipitated crystals are sucked off, still feasting once in water, soaks up again, washes neutral with water and dries in Vacuum drying cabinet.

Yield: 197 g, melting point: 260-262 ° C. After crystallization from acetone The pure 3-oxo-4-pregnen-20a-carboxylic acid melts at 283-285 ° C.

b) A 2 l Erlenmeyer flask that holds 500 ml of a 30 minute at 1200 C nutrient solution of 1 O / o Cornsteep liquor and 1.25 C, sterilized in an autoclave, Soy powder adjusted to pH 6.2 is contained with a lyophil culture of Curvularia lunata (NRRL 2380) and 72 hours at 30 ° C on a rotary shaker shaken. This preculture is used to inoculate a 20 l fermenter that holds 14 liters a medium of the same composition sterilized at 1210 C and 1.1 atm as the preculture contains. With the addition of Silicon SH as an antifoam agent at 290 C with aeration (10 1 / min.), 0.7 atmospheric pressure and stirring (220 rpm.) 24 Hours germinated.

Then 1.8 liters of the culture broth are used under sterile conditions in a 28 liter sterile culture medium.

50 l fermenter filled with the same composition and transferred under grown under the same conditions. After 12 hours, 15 g of 3-oxo-4-pregnene-20a-carboxylic acid are obtained dissolved in 250 ml of dimethylformamide, added and stirred and aerated further. After a contact time of 48 hours, the fermenter contents are acidified with semi-conc. HCl to pH 5 twice with 20 l of methyl isobutyl ketone each time, and the extracts are combined and evaporated at 500 a bath temperature in a vacuum. The residue is through two hours Stirring, washed silicone- and lipoid-free with hexane and finally with activated charcoal Recrystallized ethyl acetate.

7.6 g of β-hydroxy-3-oxo-4-pregnene-20′-carboxylic acid are obtained Melting point 258-240 ° C.

Example 2 a 1) A 2 l Erlenmeyer flask that holds 1 liter for 30 minutes Nutrient solution made of 3.0% glucose, 1.0% cornsteep, sterilized in an autoclave at 1200 C, Contains 0.2% NaN03, 0.1% EH2HP04, 0.05% MgS04, 0.002% FeSO4 and O, Oj EC1 inoculated with a lyophilic culture of Aspergillus o.chraceus (NRRL 405) and 72 hours shaken at 300 C on a rotary shaker. This preculture is then used inoculated a 50 l fermenter, which sterilized 30 l of one at 1220 C and 1.1 atm Nutrient medium, consisting of 1% starch sugar and 1% soybean meal. Under Silicon SH is added as an antifoam agent at 290 C with ventilation (10 l / min. 7 0 ,? Atü pressure and stirring (220 rpm) germinated for 12 hours. After that there will be a solution of 6 g of 20-hydroxymethyl-4-pregnen-3-one was added to 200 ml of ethanol and the mixture was stirred further and ventilated. After 18 hours of contact time, the contents of the Bermenter are twice each 10 1 of methyl isobutyl ketone and the combined extracts at 500 C bath temperature evaporated in vacuo. The residue is taken up in methanol, the undissolved Separated silicone oil, the solution concentrated to dryness and passed over a gradient column Chromatographed on silica gel (gradient: 5 1 hexane - 2.5 1 hexane / 2.5 1 acetone). The main fraction is made up of ethyl acetate / isopropyl ether crystallized. 4.2 g of 11-hydroxy-20a-hydroxymethyl-4-pregnen-3-one with a melting point of 159-160 ° are obtained å.

a 2) A 2 liter Erlenmeyer flask that holds 500 ml of a 30 minute at 1200 C nutrient solution, sterilized in an autoclave, consisting of 1% Cornsteep liqour, 1% soy powder and 0.005 r soybean oil, adjusted to pH 6.2, is made with a lyophil culture of Curvularia lunata (NRRL 2380) and 72 hours at 300 C on a rotary shaker shaken. This preculture is used to inoculate a 20 liter fermenter, the 14 liter a medium sterilized at 1210 C and 1.1 atmospheres from 1% Cornsteep liqour, 0.5 Contains% starch sugar and 0.005% soybean oil, adjusted to pH 6.2. With an encore Silicon & I as an anti-foam agent is applied at 290 C with ventilation (10 1 / min.) 0, 7 atmospheres pressure and stirring (220 rpm) germinated for 24 hours.

1 liter of the culture broth is poured into 14 l of a Medium sterilized as above from 1% Cornsteep liqour, 1.25% soy powder and 0.005 % Soybean oil transferred and grown under the same conditions.

After 12 hours, a solution of 3g of 20a-xydroxymethyl-4-pregnen-3-one added in 50 ml of dimethylformamide and stirred and aerated further. After a Contact time of 42 hours is the fermenter contents twice with 10 1 methyl isobutyl ketone stirred and the extract evaporated at 50 ° C bath temperature in vacuo. The residue is taken up in methanol, the undissolved silicone oil is deposited and the solution again concentrated to dryness in vacuo. To remove by-products, the oily residue by means of the linear eluent gradient en methylene chloride-acetone chromatographed on a silica gel column and then recrystallized from acetone / hexane. 1.3 g of 11β-hydroxy-20α-hydroxymethyl-4-pregnen-3-one with a melting point are obtained in this way 135-1370 0.

b) 10 g of II "-hydroxy-20" -hydromethyl-4-pregnen-3-one are in 200 ml Dissolve acetone and add 30 ml Jones reagent (133.5 g CrO3 in 100 ml conc. Suspended H2S04 and made up to 500 ml with H2O) was added dropwise. One stirs another 5 hours and then pour into 1 l of ice water. The unusual product is suctioned off, washed neutral with water and dried in a vacuum drying cabinet. This gives 9 g of 3,11- »ioxo-4-pregnen-20a-carboxylic acid with a melting point of 236-239 ° a.

The same compound is obtained under the same oxidation conditions when using 11β-hydrox; sr-20'-hydrox; ymethyl-4-pregnen-3-one.

c) 20 g of 3,11-dioxo-4-pregnen-20α-carboxylic acid are in 600 ml Methanol containing 1% water, dissolved and with stirring at room temperature in the Over the course of one hour, 20 g of powdered sodium borohydride were added in small portions. Then the reaction solution is concentrated to 200 ml and poured into 1 liter of water stirred in.

It is now acidified to pH 5 with dilute HCl and the precipitated product is sucked off finely crystalline precipitate.

After washing and drying, 18 g of β-Hydro} 7-3-oxo-4-pregnene-20′-carboxylic acid are obtained from melting point 235-239 ° C.

Example 3 a) 100 g of 20-hydroxymethyl-1,4-pregnadien-3-one are in 1 liter of acetone suspended and 200 ml of Jones reagent (133.5 g of CrO3 in 100 ml of conc. Suspended H2S04 and made up to 500 ml with H2O) was added dropwise with stirring, whereby the temperature is kept below 200 C by external cooling. After 2 hours The reaction mixture is then stirred into 4 1 of ice water which has precipitated out Raw product sucked off, washed neutral and off Acetone in the presence recrystallized from A-Eohle. 92.9 g of 3-oxo-1,4-pregnadiene-20α-carboxylic acid are obtained from melting point 23623? O C.

b) 7.5 g of 3-oxo-1,4-pregnadiene-20a-carboxylic acid are obtained under the conditions of Example 1b in a 50 l permenter filled with 30 l of a Curvularia lunata culture, Fermented for 70 hours. The pH is then adjusted to 6, extracted with methyl isobutyl ketone, evaporate the extract to dryness in vacuo and purify the residue by chromatography on a silica gel column using the solvent gradient hexane / acetone. After crystallization 2.1 g of 11β-hydroxy-3-oxo-1,4-pregnadiene-20α-carboxylic acid are obtained from ethyl acetate with a melting point of 241-242 ° C.

Example 4 A solution of 3.6 g of β-hydroxy-3-oxo-4-pregnene-20acarboxylic acid in 75 ml of dimethylformamide, after adding 2.5 g of silver oxide and 3.6 ml of butyl bromide Heated to the boil for 30 minutes. The reaction mixture is then brought to room temperature cooled, filtered and stirred into ice water. The precipitate formed is suctioned off, dissolved in chloroform, the chloroform solution washed neutral, over Na2SO4 dried, evaporated to dryness in vacuo and the residue from isopropyl ether recrystallized.

3.1 g of butyl 11β-hydroxy-3-oxo-4-pregnen-20α-carboxylate are obtained with a melting point of 155156O C.

Example 5 900 mg of 11β-hydroxy oxo-1,4-pregnadiene-20α-carboxylic acid are dissolved in 10 ml of acetone and 3 ml of Jones reagent (133.5 g of Cr0 in 100 ml conc. Suspended H2S04 and made up to 500 ml with H2O) was added dropwise. It is stirred for another hour and then poured into ice water. The unusual one Product is filtered off with suction, washed neutral, dried and made from hexane / acetone recrystallized. 800 mg of 3,11-dioxo-1,4-pregnadiene-20a-carboxylic acid with a melting point of 225-227 ° are obtained C.

Example 6 A 2 liter Erlenmeyer flask containing 500 ml of a 30 minute 1200 C in an autoclave sterilized nutrient solution of 1.5 7o peptone, 1.2% cornsteep and 0.2% MgS04, adjusted to pH 6.5, is with a lyophil culture of Bacillus lentus (ALSO 13805) inoculated and 24 hours at 300 G on a rotary shaker shaken. A 20 l fermenter is inoculated with this preculture, which is filled with 14 l a liquid nutrient medium made of 0.1% yeast extract, sterilized at 1210 C and 1.1 atmospheres, 0.5 o / o cornsteep and 0.05% starch sugar, adjusted to pH 7, is filled. To Addition of Silicon SH as an antifoam is now at 290 C with ventilation and Stirring germinated. The substrate is added after a growth phase of 6 hours in the form of a solution of 3 g of 11β-Hydroxy-3-oxo-4-pregnen-20crcarboxylic acid methyl ester in 100 ml of dimethylformamide. After 34 hours of contact time, the fermenter content becomes extracted twice with 10 1 methyl isobutyl ketone each time and the extract was evaporated in vacuo. The residue is washed with hexane to remove the silicone oil and then washed recrystallized from methylene chloride / acetone. 2.4 g of IIβ-hydroxy-3-oxo-1 are obtained Methyl 4-pregnadiene-20'-carboxylate, melting point 226-227 ° C.

Example 7 15 g of IIβ-hydroxy-3-oxo-4-pregnene-20α-carboxylic acid become suspended in 500 ml of benzene, 40 ml of conc. HC1 was added and refluxed for 4 hours heated to boiling. The aqueous phase is then separated off in a separating funnel, gives another 40 ml conc. EC1 is added and the mixture is refluxed for a further 4 hours. Afterward the solution is stirred into 3 l of ice water, extracted with ethyl acetate and the ethyl acetate solution in the Concentrated vacuum until the beginning of crystallization. The precipitated crystals is sucked off and dried. 13 g of 3-oxo-4,9 (II) -pregnadiene 20 "-carboxylic acid are obtained with a melting point of 233-235 ° C.

Example 8 1.5 g of 3-oxo-4,9 (11) -pregnadiene-20a-carboxylic acid are used in Dissolved 30 ml of tetrahydrofuran and 12 ml of 1-N-perchloric acid under nitrogen at room temperature added dropwise. Then 2.3 g of N-bromosuccinimide are added in portions and the mixture is stirred 30 minutes after and mixed with a solution of 2.2 g of sodium sulfite in 300 ml Ice water. The precipitated oily product is extracted with chloroform, the chloroform phase washed with water, dried and concentrated to dryness.

After crystallization from acetone / isopropyl ether, 1.2 g of 9-bromo-11β-hydroxy-3-oxo-4-pregnene-20α-carboxylic acid are obtained with a melting point of 137-138 ° C.

Example 9 200 mg of 9 ″ -Bromo-1β-hydro-3-oxo-4-pregnene-20 ″ -carboxylic acid are mixed with 370 mg of anhydrous potassium acetate and 2.3 ml of ethanol and under Nitrogen heated to boiling for 2 hours. Then cool down to room temperature, stirs in ice water and extracted with ethyl acetate. The ethyl acetate phase is washed neutral, dried over Na2S04 and concentrated to dryness. The oily residue crystallizes one from ether and receives 120 mg of 9,11ß-epoxy-3-oxo-4-pregnen-20a-carboxylic acid from Melting point 194-197 ° C.

Example 10 1.4 g of 9,11ß-epoxy-3-oxo-9ß-pregn-4-ene-20a-carboxylic acid are dissolved in 5 ml of dimethylformamide, cooled to -20 ° C and stirred at 5 ml of hydrofluoric acid were added to this temperature. It is then slowly allowed to come to room temperature heat and stir for a further 18 hours. The reaction mixture will stirred into ice water, adjusted to pH 6 with dilute sodium hydroxide solution and that precipitated crude product sucked off. For purification, it is chromatographed on a Silica gel column (gradient hexane-acetone) and the main fraction crystallizes out Isopropyl ether. 900 mg of 9α-fluoro-11β-hydroxy-3-oxo-4-pregnene-20′-carboxylic acid are obtained with a melting point of 257259O C.

Example 11 In an ice-cold solution of 1.3 g of 9,11β-epoxy-3-oxo-9βpregn-4-en-20′-carboxylic acid in 6.5 ml of methylene chloride is a slow stream of hydrogen chloride for 15 minutes initiated. The reaction solution is left to stand at 250 a for one hour. Afterward is argon for 30 minutes to remove excess hydrogen chloride by the Solution headed. It is diluted with 20 ml of methylene chloride, washed with water and dried over sodium sulfate and concentrated to dryness in vacuo. The residue is on silica gel ohromatographed. With 21-28% acetone-hexane the product is eluted and from a Recrystallized acetone-hexane mixture.

Yield: 651 mg of 9α-chloro-11β-hydroxy-3-oxo-4-pregnene-20α-carboxylic acid from melting point 228-230 ° C.

Example 12 320 mg of 9 "-chloro-11ß-hydroxy-3-o-xo-4-pregnene-20" -carboxylic acid are dissolved in a mixture of 15 ml of methanol and 15 ml of methylene chloride. Man mixed with essential diazomethane solution, made from 1.5 g nitrosomethylurea, and evaporates solvent and excess reagent in a vacuum. The residue is chromatographed on silica gel.

With 5-10% acetone-hexane, after recrystallization from acetone-hexane, 195 mg of methyl 9'-chloro-11ß-hydroxy-3-oxo-4-pregnen-20'-carboxylate are obtained from melting point 2010 C.

Claims (1)

Claims 1. 3-Oxo-4-pregnen-20α-carboxylic acid derivatives of the general formula I. in which X is a hydrogen atom in the a or a halogen atom and Y1 and Y2 are an oxo group or a hydroxyl group in the a or β position and a hydrogen atom or X and Y1 are a carbon-carbon bond or an oxo group and Y2 is a hydrogen atom, in which Z represents an alkoxycarbonyl group with 1 to 8 carbon atoms in the alkoxy radical or a carboxyl group and its salts with physiologically acceptable bases and in which ..... a double bond or if X is not hydrogen and Z is not a carboxyl group or methoxycarbonyl group, it is also a single bond. 2. Process for the preparation of 3-oxo-4-pregnen-20a-carboxylic acid derivatives of the general formula I according to claim 1, characterized in that a) that for the preparation of 3-oxo-4-pregnen-20a-carboxylic acids with X in the meaning of a hydrogen atom is a compound of the general formula II where Z 'has the same meaning as Z or represents a hydroxymethylene group and ..... has the abovementioned meaning in a manner known per se by means of microorganism cultures capable of 11-hydrolysis in the II-position or b) that one for the production of 3-Oxo-4-pregnen-20 «-carboxylic acid derivatives of the general formula I in which X does not represent a hydrogen atom, a compound of the general formula III where ..... and Z 'have the abovementioned meaning dehydrated to the corresponding A steroids, optionally adding HOC1 or HOBr to them, converting the halohydrins obtained with bases into the 9, llß-epoxy steroid azides and adding HC1 or HF to these, as well as the 21α-HydroxZmethylsteroide prepared according to variant a or b with simultaneous oxidation of the II-hydroxy group to the 3,11-dioxo-4-pregnen-20'-carboxylic acids of the general formula I, optionally II-oxosteroids to the corresponding IIβ-hydroxysteroids reduced, optionally 3-oxo-4-pregnen-2Oa-carboxylic acid-I) derivatives of the general formula I which are saturated in the 1,2-position are dehydrated to the 3-oxo-l, pregnadiene-2O «-carboxylic acid-1) derivatives, and optionally acids converted into their salts or esters or esters saponified or transesterified. 3. Pharmaceutical preparations containing as active ingredient a 3-oxo-4-pregnen-20'-carboxylic acid derivative of the general formula IV in which ..... a single bond or a double bond, X a hydrogen atom or a halogen atom, and and Y2 'together a carbonyl group or a hydroxyl group and Y2' a hydrogen atom and Z an alkoxyearbonyl group with 1 to 8 carbon atoms in the alkoxy radical, or a carboxyl group and mean their salts with physiologically acceptable bases. 4. Pharmaceutical preparations containing the 11ß-hydro-3-oxo-4-pregnen-20 "-carboxylic acid as active ingredient or their salts with physiologically acceptable bases. 5. 11β-Hydroxy-3-oxo-1,4-pregnadiene-20'-carboxylic acid. 6. IIβ-Hydroxy-3-oxo-4-pregnen-20cx-carboxylic acid butyl ester. 7. 3,11-Dioxo-1,4-pregnadiene-20a-carboxylic acid 8. IIß-hydroxy-3-oxo-1,4-pregnadiene-20a-^ carboxylic acid, methyl ester. 9. 3-Oxo-4,9 (11) -pregnadiene-20a-carboxylic acid. 10. 9a-Bromo-11ß-hydroxy-3-oxo-4-pregnene-20a-carboxylic acid. 11. 9,13-epoxy-3-oxo-4-pregnen-20 "-carboxylic acid. 12. 9 "-Fluoro-11ß-hydroxy-3-oxo-4-pregnene-20a-carboxylic acid. 13. 9 "-Chlor-11ß-hydroxy-3-oxo-4-pregnene-20a-carboxylic acid. 14. 9 "-Chlor-11ß-hydroxy-3-oxo-4-pregnen-20a-carboxylic acid methyl ester. 15. Process for the preparation of 3-oxo-4-pregnen-20'-carboxylic acid-I) derivatives of the general formula I a wherein ..... and Z have the meaning given in claim 1, characterized in that a compound of the general formula III according to claim 2b is dehydrated with mineral acids.