DE1175668B - Process for the production of 9ª ‡, 11ª ‰ -dihalogen compounds of the pregnane or androstane series - Google Patents

Description

Process for the preparation of 9a, llß-dihalogen compounds of the pregnan- or androstane series The invention relates to a method for the production of 9a, Ilfl-dihalogenosteroids the pregnane or androstane series.

The end compounds which can be prepared according to the invention necessarily contain halogen on the 9- and 11-position carbon atom as well as a keto group in the 3-position and a keto group in the 20-position in the pregnane series. The compounds which can be prepared according to the invention preferably contain one or more unsaturated sites in ring A. Further substituents or functional groups can be present at other sites on the molecule. 20-keto-17,21-diol compounds of the pregnane series preferably have a 1,4-diene system in ring A, but the monoenes are the preferred therapeutically active compounds among the progesterone derivatives. Hydroxyl or ester groups can be present on carbon atoms 16, 17 and / or 21, lower alkyl groups, for example on carbon atoms 2, 6 or 16, or halogen substituents at various positions, e.g. B. at carbon atoms 6, 17, 21.

Similar substituents may be present in the compounds of the androstane series, with the exception, of course, of those located on the carbon atoms of the side chain. However, the 9,11-dihaloandrostanes and their analogs with an unsaturated ring A can have 17 substituents on the carbon atom, for example 0, (H, flOH) or lower alkyl (flOH).

As will be described in detail below, the novel dihalogen compounds which can be prepared according to the invention can preferably be obtained by using a 3-keto-4,9 (I 1) -pregnadiene or 3-keto-1,4,9 (I 1) -pregnatriene (or the appropriately substituted androstane) is reacted with a suitable halogenating agent. Preliminary experiments have shown that also esterified corresponding 9a-halo-11 a-hydroxy compounds, preferably halogen-9a-a- 1 in the form of its 1 1-tosylate or -Mesylates, or corresponding 1 or -1 ISS amino compounds under the conditions of the inventive method in its 9a, 11 can be converted ß-dihalo derivatives. In the pregnancy series it is advantageous that all the desired substituents are present and that the halogenation is the last step. This does not exclude saponifications or esterifications following the halogenation. This also does not exclude the conversion of a 3-keto-J4-pregnadiene into a 3-keto-A1,4-pregnadiene. Intermediate transformations such as hydroxylation, alkylation and the like can be carried out on the substance which has already been dihalogenated.

In the process according to the invention, the starting compounds can have a plurality of double bonds, for example an A ', A4 or Z11,4 bond in addition to the A9 (11) bond; however, the halogenation process is selective so that only the 9,11 double bond is attacked. The 9,11-unsaturated starting materials for the dihalopregnanes prepared according to the invention are known in some cases, for example. B. the 21-acetate of 4,9 (I1) -pregnadiene-17a, 21-diol-3,20-dione, its 1-dehydro analogue and the 21-acetate of 16a-acetoxy - 4,9 (11) - pregnadiene - 17 a, 21 - diol - 3, 20 - dione. Other 4,9 (I1) -pregnadienes can be prepared from the corresponding 4-pregnenes with a hydroxyl group in the 11-position by reaction, for example, with methanesulfonyl chloride in the presence of pyridine, phosphorus oxychloride in pyridine or concentrated aqueous hydrochloric acid by heating in benzene ether under reflux . Similarly, 1A9 (I1) -Pregnatrienes, which serve as starting compounds, can be prepared from the corresponding 11 -hydroxy-1,4-pregnadienes or by A'-dehydrogenation of the 4,9 (I1) -Pregnadienes. For the production of the substances not halogenated in positions 9a and Ilß, which are mentioned in the description, i. H. Protection is not sought in the context of the present invention for the preparation of the starting materials of the process according to the invention.

The halogenating agents used for the process according to the invention can be classified as follows: 1. molecular homatomic halogens, such as chlorine or bromine; 2. Molecular halogen donors such as the addition compounds pyridine bromide perbromide, dioxan dibromide, iodobenzene dichloride and p-iodotoluene dichloride, 3. mixed halogen molecules or heteroatomic halogens, such as iodine monochloride, 4. a mixture of reagents that contain a positive compound such as N or a molecular halogen donor such as -Chlorosuccinimide, N-bromoacetamide, dimethyl-N, N-dibromohydantoin or N-iodosuccinimide, and a halogen ion. dps is as or more electronegative than the positive halogen donor mentioned above. The term "positive halogen donor" will be explained later. Examples of such mixtures are lithium chloride and N-chlorosuccinimide, lithium chloride and chlorine, potassium fluoride or hydrogen fluoride and N-bromoacetamide, hydrogen bromide and N-bromoacetamide, potassium fluoride and N-iodosuccinimide, hydrogen chloride, lithium chloride and N-chlorosuccinimide; 5. Fluorinating agents, such as lead tetrafluoride or lead dioxide with hydrogen fluoride, which are described in more detail below.

It can be assumed that when the 9 (11) double bond is halogenated, the reaction takes place either sequentially or simultaneously as a result of the influence of a positive halogen ion with a negative halogen ion. The positive halogen ion, which results from a heteropolar cleavage of a halogen molecule or from an N-haloamide, finally attaches itself to carbon atom 9 , while the negative ion goes to carbon atom 11. In a reaction vessel in which there is, for example, N-bromoacetamide and hydrogen fluoride, the product would be a 9'-bromo-IL3-fluorine compound.

The molecular halogens, molecular halogen donors or mixed halogens such as chlorine, bromine, iodobenzene dichloride, iodine monochloride ... used for the process according to the invention can be used in the commercially available form; in that case they are added directly to the reaction mixture either alone or in a suitable solvent such as acetic acid or tetrahydrofuran. The desired halogen or halogen mixture can also be added in situ by adding 0.9 to 1.2 equivalents, based on the amount of steroid, of a positive halogen donor, such as N-bromosuccinimide, to a reaction mixture which has an equally strong or stronger electronegative halogen ion such as the added halogen contains. This halogen anion can be provided by a hydrohalic acid or a suitable salt such as sodium bromide, lithium chloride, potassium fluoride, or mixtures of an acid and a corresponding salt. When a hydrohalic acid is the source of the halogen anion, approximately theoretical amounts are generally used, while a halogen salt can be present in large excess as the source of anions. Such an excess of anions is often useful when it is desired to increase the yield and purity of a given reaction. A source of halogen ions can also be used in reactions using a mixed halogen molecule; in the case of a source of the more electronegative anion is used, d. H. a suitable chloride salt, or hydrogen chloride, would be used in halogenation with iodine monochloride.

From the above it appears that there are a number of equivalent methods by which the same connection can be made. For example, a 9a.Ilß dichloro compound can be prepared using the following reagents and combinations: 1. chlorine and lithium chloride in acetic acid, 2. N-chlorosuccinimide and lithium chloride in glacial acetic acid, 3. sodium chloride and N-chlorosuccinimide in glacial acetic acid along with Hydrogen chloride in tetrahydrofuran; 4. Chlorine alone in glacial acetic acid or, preferably, in the presence of lithium chloride; 5. Iodobenzene dichloride in moist acetic acid.

For each reaction, the choice of solvent depends on the Solubility and reactivity of the reagents in the particular process.

The dihalogenation of the 9 (I1) position is generally carried out in a suitable solvent at temperatures between 5 and 50 ° C. with reaction times of 30 minutes to 24 hours, these again depending on the reactivity of the reagents. The preferred reaction conditions using the halogenating agents described above require glacial acetic acid as the sole or major solvent when the reaction is carried out at room temperature for about 2 hours. Other solvents can be used alone or in conjunction with acetic acid. Such solvents are the lower aliphatic acids such as acetic or diethyl acetic acid, halogenated hydrocarbons such as methylene chloride or chloroform, saturated ethers such as tetrahydrofuran and dioxane, other inert solvents such as dimethyl sulfoxide, and suitable mixtures of these solvents.

It has been found that under certain circumstances the halogenation of the 9 ( 11) bond is favored when it is carried out in a non-reactive solvent such as methylene chloride, chloroform or carbon tetrachloride to which an organic base such as pyridine has been added . Other basic agents that can be used are tertiary amines, such as trimethylamine, triethylamine, and preferably aromatic tertiary amines, such as dimethylaniline, lutidine, collidine and other substituted pyridines. The concentration of the tertiary amine can be up to 80 moles per mole of A9 (I1) steroid, but is preferably less than 20 molar equivalents.

The use of a tertiary amine in a chlorinated hydrocarbon solvent is particularly valuable when halogenating a steroid with a 17-position hydroxyl group, particularly the androstane series. An androstane with a secondary hydroxyl group in the 17-position, for example 4,9 (11) -androstadien- 1 7ß-ol-3-one, tends to be halogenated in acetic acid with, for example, N-chlorosuccinimide and hydrogen chloride, in addition to the Addition of halogen in the 9- and 11-positions on the 17-position hydroxyl group to be esterified, whereby a mixture of 9,11-dihaloandrostene-17β-ol-3-one and its 17-acetate is formed. On the other hand, when the aforementioned androstadiene is halogenated with the same reagent in carbon tetrachloride solution in the presence of about 1.1 molar equivalents of pyridine, nearly theoretical amounts of 9,11-dihalo-17β-hydroxyandrostadiene are obtained without contamination by 17-acetate. In addition, androstanes with a 17 tertiary hydroxyl group such as 17a-methyl-4,9 (I 1) -androstadien-17ß-ol-3-one tend to rearrange and / or dehydrate in the presence of any strong acid. Thus, the aforementioned androstadiene is not only halogenated at carbon atoms 9 and 11 when exposed to a commonly used halogenation medium such as acetic acid, but rearranges and becomes dehydrated to form a product mixture that is difficult to separate and purify. When carbon tetrachloride-pyridine is used as the solvent, 9a, 11ß-dihalo-17a-methyl-4-androsten-17ß-ol-3-one is formed as essentially the only product in high yield and high purity.

Similarly, 17a-hydroxyprogesterones are preferably used in halogenated in a basic medium instead of in an acidic medium, creating competing Dehydration and rearrangement reactions are excluded.

The method with a halogenated hydrocarbon as solvent in a basic medium is advantageous in the halogenation of pregnanes the corticoid series, for example of 4,9 (I1) -Pregnadiene-17a, 21-diol-3,20-dione-21-acetate, applied. For example, halogenation of the aforementioned pregnadiene provides with chlorine in acetic acid some 9a, llß-dichloro-4-pregnen-17a, 21-diol-3,20-dione-21-acetate, but with reduced yield, possibly due to 2,6-dichlorination and 2,6,9,11-tetrachlorination. However, when using carbon tetrachloride as a solvent and pyridine is added, an almost theoretical yield of 9a, llß-dichloro-4-pregnen-17a, 21-diol-3,20-dione-21-acetate is obtain.

This aforementioned modification of the halogenation process is generally carried out in a substantially anhydrous halogenated hydrocarbon solvent, such as carbon tetrachloride, chloroform and the like, with a halogenating agent of the type described above in amounts preferably between 1 and 1.2 molar equivalents per mole 9 (I1) -Dehydrosteroid is used- A rabbit- such as Pvridine- is added in quantities of 0.1 to 80 molar equivalents per mole of 9 (11) -Dehydrosteroid. The reaction can be carried out in the temperature range from about -40 to about + 50 ° C., preferably in the range from -25 to + 25 ° C., in the course of 30 minutes to 18 hours. In general, A9 (11) binding in a steroid can be accomplished in a shorter time and at lower temperatures than required for nuclear halogenations.

The halogenation procedures described above are generally applicable to the conversion of an A9 (11) steroid to a 9a, llp dihalogen function. However, except when fluorinating agents are used, the substances prepared by these methods may have a halogen selected from the group formed from Cl, Br or I on carbon atom 9 and a halogen selected from the group formed from F, Cl or Br on carbon atom 11 , provided that in the case of heterohalogenation, the more electronegative atom appears on carbon atom 11 . Therefore, these methods are for the production of halogen combinations, such as 9a, Ilfl-dichlor, 9a, Ilfl-dibrom, i 9a-chloro-Ilfl-fluor, 9a-bromo-Ilfl-chlor, 9a-iodo-] Iß-chlorine, 9a -Iodine-Ilß-bromine, suitable.

Slight modifications to the process are required to effect halogenation in which the more electronegative atom goes to carbon atom 9.

These compounds, including the 9,11-difluoro analogs, can also either from an A9 (11) -dehydropredecessor or from a 9a-halo-11 -hydroxypriorecessor the choice depending on the halogen atoms present in the final product should be present.

For example, there are several ways to prepare difluorine compounds. You can start from an A9 (11) -Pregnen, such as a 1,4,9 (11) -Pregnatrien-17a, 21-diol-3,20-dione-21-acetate, and allow a suitable fluorinating agent to act on this leading to the corresponding 9a, 11 fl-difluoro analogue. As mentioned above, agents such as lead tetrafluoride or lead dioxide in conjunction with hydrogen fluoride are useful for this conversion. Other fluorinating agents such as antimony pentafluoride, iodoheptafluoride, and bromine trifluoride can be used in a similar manner.

The fluorination is usually carried out in an inert solvent such as Chloroform, methylene chloride, tetrahydrofuran and the like, at low temperatures, generally carried out at -20 to -30'C.

An inversion of configuration at carbon 11 apparently takes place in the direct exchange of an esterified 1 1 -ständigen hydroxyl group. Therefore, it is necessary to give a 1 to obtain Eat-halogen compound in this way, a-hydroxyl function assume a 11th The replacement of the 11 ap-toluenesulfonyloxy group by halogen is effected by reaction with a suitable halogen ion source in an inert solvent. For example, the treatment of 11 ap-toluenesulfonate des 9a-fluoro-1,4-pregnadien-Iia, 17a, 21-tri-5 ol-3,20-dione-21-acetate with lithium chloride in dimethyl sulfoxide or dimethylformamide 9a-fluoro -11 ß-chloro- 1, 4-pregnadiene- 17 a, 21-diol-3,20-dione-21-acetate formed. The corresponding 9a-chloro-1β-bromine compound is obtained in a similar manner by starting from a 9a-chloro-Ila-p-toluenesulfonate and treating this with lithium bromide in dimethyl sulfoxide. In this way, 9a-chloro-1,4-pregnadiene-11 a, 17 a, 21 - triol -3, 20 - dione -11-p- toluenesulfonate-21-acetate becomes the compound 9a-chloro- 11 fl-bromine - 1,4-pregnadiene-17a, 21-diol-3,20-dione-21-acetate obtained.

Halogen can be also introduced by a 11 a-amino function is reacted with a nitrosyl halide or an amino group Ilfl-treated with an alkyl nitrite and then reacting with a hydrogen halide acid.

Thus, a 9α-fluoro-11a-aminopregnane can be treated with a suitable nitrosyl halide, for example nitrosyl chloride, the corresponding 9a-fluoro-11ß-chlorine compound being obtained. The same compound is obtained by treating the ILβ-aminoepimer with an alkyl nitrite and hydrogen chloride, for example ethyl nitrite, in combination with hydrogen chloride. A small amount of the Ila-chlorepimer is formed in both reactions and can easily be removed by chromatographic separation using standard procedures. The 11 -fluoro and 11 -broman analogs can be prepared in a similar manner using nitrosyl fluoride and nitrosyl bromide, respectively, in the reaction described above.

In a similar manner, a 1 β-amino function can be converted into a 1 β-fluoro group with an alkyl nitrile and hydrogen fluoride.

The saturated 9,11- dihalo-3-ketones obtained according to the process can be converted into the corresponding 4-pregnene and / or 1,4-pregnadiene compounds by known processes. For example, bromination with 1 mole of bromine gives the 4-bromo analogue which, after debromination with lithium chloride in dimethylformamide, gives the corresponding 3-keto-4-pregnen. The corresponding 3-keto-1,4-pregnadiene is obtained by microbiological dehydration of the 4-pregnancy with a microorganism such as Corynebacterium simplex. However, the 3-keto-1,4-diene can also be obtained by allowing 2 mol of bromine to act on the 3-ketopregnane and then didehydrohalogenation. An existing bismethylenedioxy protective function is removed by treatment with aqueous acid, such as. B. with 600 / () formic acid removed.

From the above it can be seen that there are a number of different methods of making the connections. For example, a 9a, 11ß-difluoro compound can be prepared by using, for example, the following starting materials and reagents: 1. an A9 (I1) steroid and lead tetrafluoride, 2. an A9 (11) steroid and iodosobenzene diacetate and hydrogen fluoride; 3- a 9a-fluoro-Ila-hydroxysteroid, preferably in the form of its 11-methanesulfonate or 11-p-toluenesulfonate, and lithium fluoride in dimethyl sulfoxide; 4. a 9a-fluoro-Ila-amino-pregnen and nitrosyl fluoride or 5. a 9a-fluoro-ILß-aminopregnen and ethyl nitrite and hydrogen fluoride. Halogen other than fluorine can be introduced at carbon atom 11 by analogous means.

9a obtained in the method outlined above, 11 fl-dihalo-21 may be chemically saponified esters either by application of dilute acid or base or by microbiological methods into the corresponding alcohols. However, a hydroxyl group, if it is present in the new compounds, can also be esterified using standard methods.

In the previous part of the description are the halogenation reactions on compounds of the Pregnan series have been explained. These are only exemplary Embodiments, because similar transformations can also be used for A9 (I1) steroids Androstane series can be made.

In detail, the new 9,11-dihaloandrostanes (including androstenes and androstadienes) which can be prepared according to the invention are produced either by halogenation of a corresponding 9,11-dehydro compound, as described above, or by oxidative degradation of a corresponding 9a, llß-dihalo-prepregnane, which is a20-keto- 17,21-dihydroxy side chain has prepared. Accordingly, 1,4,9 (I1) -androstatriene-3,17-dione gives after treatment with N-chlorosuccinimide, hydrogen chloride and lithium chloride in acetic acid 9a, IIfl-dichloro-1,4-androstadiene-3,17-dione. In a similar manner, other dihaloandrostanes are prepared by appropriate halogenation as previously described. But it can also be a 9a, 11-ß Dihalogenpregnan-17a, 21-diol-3,20-dione by oxidation with Natriumwismuthat to a corresponding 17-Ketoandrostan be reduced. For example, 6 a - methyl - 9 a - chlorine - 11 ß - fluorine - 1, 4 - pregnadiene-17a, 21-diol-3,20-dione after oxidation with sodium bismuthate gives 6a-methyl-9a-chloro-ILß-fluorine -1,4-androstadiene-3,17-dione.

For example, B. 17a-Methyl-1,4,9 (I 1) -androstatrien-17.beta.-ol-3-one-1 7-propionate by reaction with N-bromoacetamide and hydrofluoric 9a-bromo-Ilfl-fluoro-17a-methyl- 1,4-androstadien-17fl-ol-3-one-17-propionate. Similarly, a 6a-methyl-9 (I1) -dehydro- or 6 (, i-fluoro-9 (I1) -dehydro-androstene can be halogenated to the corresponding 6a-methyl- or 6a-fluoro by the methods previously described -9a, llß-dihalo androstane derivative.

It has been found that the esterification of the hydroxyl function on carbon atom 17 of the 9,11-dihalo-17-hydroxyandrostanes leads to a prolongation of the physiological effect. Esterification takes place according to known processes, for example with acetic anhydride in pyridine or acetic acid in the presence of trifluoroacetic anhydride. Treatment with other lower alkanoic anhydrides in pyridine or with the free lower alkanoic acids in the presence of trifluoroacetic acid leads in a similar manner to the corresponding esters, such as propionate, butyrate or caproate.

The physiological effect of the compounds which can be prepared according to the invention depends on their particular structure, i. H. whether they belong to the pregnane or androstane series, as well as the type of substituent in the side chain.

In the Pregnan series, the 9,11-dihalogen compounds with a 20-keto-17,21-dihydroxy group (or their ester derivatives) have an adrenocortical effect. In particular, they are powerful anti-inflammatory agents that have a minimum of somatic effects. The preferred compounds in this group are 3-keto-1,4-pregnadienes of the following structural formula and their 1,2-dihydro analogs, where X and Y are halogen, R is hydrogen or the acyl group of lower alkanoic acids, dibasic organic acids with up to 8 carbon atoms or inorganic acyl radicals, such as phosphate or sulfate, A is hydrogen or methyl, B is hydrogen, Halogen or methyl and D is hydrogen, lower α-alkyl, lower β-alkyl, α-hydroxy or lower α-alkanoyloxy or in connection with the 17-position hydroxyl group is a 16,17-alkylidenedioxy function, as shown below: in which R 'and R "are hydrogen or lower alkyl. Examples of the group R are radicals such as acetate, propionate, cyclopentyl propionate, t-butyl acetate, hemisuccinate, hemiphthalate, sulfobenzoate and the like the formation of water-soluble sodium salts The bonds indicated by wavy lines mean both a- and ß-configuration.

The 1,2-dihydro analogs of the compounds of Formula I that are the 3-keto-A4-pregnene, also show a beneficial therapeutic effect, but to a lesser extent. The monoenes are mainly used for the production of the preferred dienes can be used and can be introduced according to known methods an A 'bond can be converted into this.

As mentioned above, the new 9,11 -dihalo compounds falling under Formula 1 are powerful anti-inflammatory agents which advantageously do not exhibit salt retention. That these compounds have anti-inflammatory activity is surprising in and of itself, taking into account the fact that these compounds are almost negligible as dihalogenated derivatives of Reichstein's compound S (4-pregnen-17a, 21-diol-3,20-dione), an adrenal steroid pharmacological activity, and bearing in mind that it has never been previously established that a steroid compound devoid of oxygen at the carbon atom has any significant anti-inflammatory activity. In addition, the fact that the compounds that can be prepared according to the invention show no salt retention is in contrast to what can be seen in view of the preceding information, according to which the presence of a 9a halogen in a steroid molecule is usually synonymous with the compound acquiring salt activity, should expect. Thus causes in the case of prednisone and prednisolone which - both as an anti-arthritic steroids are common with negligible salt retention far ', the introduction of a 9a-fluoro share that these compounds have such salt retention that the 9a-fluoro analogs for anti-inflammatory therapy by oral or parenteral Ways become unusable.

In the treatment of inflammatory diseases, show the invention manufacturable dihalocorticoids greater activity and a longer duration of action than prednisolone acetate, while it is advantageously a negligible one Show salt retention. For example, 9a, Ilfl-dichloro-17a, 21-dihydroxy-1,4-pregnadiene-3,20-dione 20 times as effective as prednisolone 21 acetate when it was tested on the granuloma bag is measured. In addition, studies show the duration of activity versus Eosinophils that at the same doses, the 21-acetate of the aforementioned dichloropregnadienes 21/2 times as long as prednisolone acetate retains 80% of its initial activity.

The compounds which can be prepared according to the invention are particularly valuable in human therapy when they are used locally to remove inflammation and burns, and in the treatment of atopic dermatitis (allergic eczema, food eczema, infantile eczema, nummular eczema, eczematoid dermatitis, puritus with lichenification) Neurodermatitis), contact dermatitis caused by plants (root toxins) and other substances. When the compounds that can be prepared according to the invention are applied topically to humans, they show a significantly increased activity compared to other topically applied steroids and at the same time do not induce any somatic effects. This is unexpected in view of the somatic effects suffered by patients using ointments containing 9a-halogenated compounds such as 9a-fluorohydrocortisone. The compounds prepared according to the invention have been found to be locally effective at smaller doses than heretofore used by other steroids, and they have also been found to be effective in cases unresponsive to other corticosteroids. Medicinal products which can be used and which contain 0.1 to 0.51% of the compounds which can be prepared according to the invention are preferably used.

When the dihalocorticoids of the formula I which can be prepared according to the invention are administered intravenously in humans, they produce the effects which are usually similar to those of the corticoids. This is why they are valuable therapeutics to be administered intravenously for acute adrenal crises, acute surgical cases and acute "stress" conditions. The parenteral compositions can contain the therapeutically active compounds which can be prepared according to the invention, dissolved or suspended in a non-toxic, liquid carrier, for example in diethylacetamide and salt or dextrose and salt. The dose can vary between 5 and 25 mg and depends on the severity of the crisis; it can be given in a single injection or by a slow drip method.

The halogenated pregnenes and pregnadienes which can be prepared according to the invention are also valuable therapeutic agents for veterinary use, in particular in smaller animals. When treating pain in small animals caused by Inflammatory diseases, practice the compounds that can be prepared according to the invention several times greater effect than prednisone and prednisolone and are much less more catabolic than the latter compounds.

In addition to the aforementioned compounds of the pregnane series, which have a 20-keto-17a, 21-dihydroxy side chain, there are 9,11-dihalogen compounds which can be regarded as derivatives of progesterone. These valuable therapeutic compounds exhibit beneficial progestational effects and, accordingly, are useful in the treatment of functional dysmenorrhea, premenstrual tension, and pregnancy maintenance. These new progestins can be illustrated by the 3-keto-J4-monoene with the following structural formula: together with the A'-dehydroanalogues, 19-noranalogues and l (2) -dehydro-4,5-dihydroanalogues, where X and Y are halogen, B hydrogen, halogen or methyl, V hydrogen, methyl, hydroxy, lower alkanoyloxy, chlorine and bromine and Z are hydrogen or halogen, preferably fluorine or iodine. Other substituents can be present on the core, for example alkyl on carbon atoms 2 or 16.

Of the compounds described above, the monoenes, i. H. 3-Keto-, 14-pregnene are preferred because they show the advantageous physiological properties to a greater extent.

These new progestins are physiologically effective both on the oral as well as parenteral routes. They are especially free of androgens, and estrogens corticoid effects. Considering their usability, to be threatening or habitual To prevent miscarriages, these progestins have both great value in breeding as well as small animals. As stated earlier, these progestins are made through the general halogenation processes described, for example halogenation a corresponding 9 (1: 1) -dehydro precursor prepared.

The 17a-oxy compounds of the formula 11 are preferably used therapeutically in the form of a lower alkanoyl ester. The ester group can be present before the halogenation, or the halogenation can also be carried out on a 17-hydroxy-9,11-dehydroprogestin with subsequent esterification of the 17-position hydroxyl group.

Although the compounds represented by Formula II are generally progestationally active, those having a hydroxyl group on carbon 17 and a halogen atom on carbon 21 are valuable as anti-inflammatory agents.

The compounds which can be prepared according to the invention also include the 9,11 -dihalogen compounds of the androstane series, which are useful anabolic and / or androgenic agents. These new new 9,11-dihalogenated androstanes, including their .11-, 14-, -11.-4- and, 14-19-nor analogs, can be represented by the following general formula where X and Y are halogen, B is hydrogen, halogen or lower alkyl, D is hydrogen or alkyl, and R # O; H, ßOR 'or lower alkyl, FLOR' means, while R 'means H or a lower alkanoyl radical.

The new dihalogen compounds of the androstane series show increased androgenic and / or anabolic activity. The ratio of anabolic to androgenic activity can be changed and depends on the particular halogen combination on carbon atoms 9 and 11 . With 9 a, 11 ß - dichloro - 1, 4 - androstadien - 17 fl - ol - 3 - one-17-propionate, a high degree of both androgenic and anabolic properties is observed, while with 9a-bromo-ILß-fluorine -1,4-androstadien-17ß-ol-3-one-17-propionate there is a marked decrease in androgenic activity and a marked increase in anabolic activity compared with dichloro compounds. The 9a-bromo-11 fl-fluorine compound and similarly halogenated androstanes are accordingly valuable for geriatric therapy, the treatment of metabolic changes in adolescents, post-surgical therapy, the treatment of severe infections and dehabilitating diseases, and for the treatment of similar cases in which Anabolism and constructive metabolism without the androgenic activity usually associated with anabolic agents are desired.

The process can be prepared according 9,1-dichloro 1 show increased androgenic activity, without having lost the anabolic activity, and are thus useful in the treatment of severe hypogonadism, benign prostatic hypertrophy, dysmenorrhea and similar cases where androgenic agents are displayed.

The dihaloandrostanes which can be prepared according to the invention are preferably administered orally in the form of tablets, capsules or the like. The dosage for adults can vary between 10 and 20 mg, while for adolescents doses of 0.5 mg up to the adult amount may be used depending on the nature and severity of the particular case and the age of the child.

In summary, new processes for the preparation of 9a, llfl-dihalogen compounds of the pregnane and androstane series have been described here. The term "pregnane" and "androstane" quite broadly in the description and claims, d. i.e., it includes the unsaturated analogs such as the A4 or Al, 4- (and the like) -dehydro compounds as well as the 19-nor-A4 analogs. The inventively produced principal novel compounds that are therapeutically valuable in itself, or have value as intermediates, may be regarded as compounds of the androstane and pregnane series which possess a 3-keto group and a 9,1-1 Dihalogenfunktion. Structurally, all of these compounds can be replaced by the 3-ketosteroids of the formula: including their A'-dehydro, A4-dehydro, A1,4-bisdehydro and 19-nor-A4-dehydro analogs, where A is hydrogen or lower alkyl, B is hydrogen, lower alkyl or halogen, D is hydrogen, lower Denotes alkyl, hydroxy or lower alkanoyloxy, X and Y are halogen and Q denotes the following grouping: in which Z = H, OR or halogen, R = H or acyl and V = H, halogen, OR, lower alkyl or together with D, when D is a-hydroxyl, means a lower alkylidenedioxy group.

The following examples explain the process according to the invention.

Example 1 9a-Bromo- 11 fl-chloro-1,4-pregnadiene- 1 7a, 2 1 -diol-3,20-dione-21-acetate A solution of 1,0g 1,4,9 (I1) -Pregnatriene -17a, 21-diol-3,20-dione-21-acetate in 40 cc of carbon tetrachloride and 1 cc of pyridine is treated with 0.395 g of N-bromoacetamide and then with 0.104 g of anhydrous hydrogen chloride dissolved in 1 cc of tetrahydrofuran. The reaction mixture is stirred at room temperature for 3 hours and poured into ice-water. The mixture is filtered and the precipitate is washed with dilute hydrochloric acid and then with water to give 1.23 g of the crude product. Recrystallization from acetone-hexane gives pure 9a-bromo-Ilfl-chloro-1,4-pregnadiene-17a, 21- diol 3,20-dione-21-acetate; M.p. 190 to 195 ° C (decomposition); [a] -D = + 172 0 (dioxane), A CII., OH = 239 mp., rnax E = 14,500.

Example 2 9a, 11 ß-dichloro-1,4-pregnadiene- 1 7a, 21-diol-3,20-dione-21-acetate A solution of 1,0g 1,4,9 (11) -pregnatriene-17a, 21-diol-3,20-dione-21-acetate and 5.0 g of lithium chloride in 40 cc of glacial acetic acid is reacted with 0.410 g of N-chlorosuccinimide and then with 0, 104 g of anhydrous hydrogen chloride, which is dissolved in 2.5 cc of tetrahydrofuran, treated. The reaction mixture is stirred for 2 hours and poured into ice-water. The crude product is filtered and washed with water to 1 to give 12 g of solid material which is recrystallized from acetone-hexane and substantially pure 9a, LLSs-dichloro-1,4-pregnadiene-17a, 21-diol-3, 20-dione-21-acetate provides; M.p. 246 to 253 ° C (decomposition); [a1- ' D5 = +162'(dioxane); 2. cm'a'xOH - 237 m # L, E = 15,000.

The compound of this example can also be obtained by treating a solution of 1.0 g of 1,4,9 (1 1) -Pregnatriene-17a, 21-diol-3,20-dione-21-acetate and 5.0 g of lithium chloride in 40 cc of glacial acetic acid can be prepared with a solution of 203 mg of anhydrous chlorine in 5 cc of tetrahydrofuran and then stirred at room temperature for 3 hours; Work-up and physical constants as above. Example 3 9a-bromo- 11 fl-fluoro-1,4-pregnadiene- 1 7a, 2 1 -diol-3,20-dione-21-acetate A. To a solution of 1.0 g 1,4,9 ( 11) -Pregnatrien-17a, 21-diol-3,20-dione-21-acetate and 6, Og potassium fluoride in a mixture of 40 cem diethylacetic acid and 20 cc tetrahydrofuran are added 0.395 g N-bromoacetamide. The reaction mixture is stirred at room temperature for 20 hours, poured into ice-water and extracted with methylene chloride. The extracts are washed in sequence with sodium bicarbonate solution and water and then dried over anhydrous magnesium sulfate. The solvent is then evaporated to an oily residue which, after trituration with ether, yields 1.1 g of the crude product of this example. Chromatography on silica gel (100: 1) and elution with 50% ether-hexane yields 9a - bromine - 1 Iß - fluorine - 1,4 - pregnadiene - 17a, 21 - diol-3,20-dione-21-acetate, the is recrystallized from acetone-hexane, A CH-OH = 239 mp .. The compound max of this example can also be obtained by treating 1,4,9 (I1) -Pregnatrien-17a, 21-diol-3,20-dione- acetate with N-bromoacetamide in diethyl acetic acid containing anhydrous hydrogen fluoride, and isolating and purifying the 9a-bromo-Ilß-fluoropregnadiene thus obtained in the same manner as described above.

However, the compound of this example can also be prepared in the manner described in Parts B and C below.

B. A solution of 1.0 g of 4,9 (1 1) -Pregnadien- 1 7a, 21-diol-3,20-dione-21-acetate and 2.0 g of hydrogen fluoride, or 6.0 g of potassium fluoride in 40 cc Diethyl acetic acid and 20 cc of tetrahydrofuran are reacted with 0.395 g of N-bromoacetamide and the crude product is isolated as described in Example 3, A. The Rohpiodukt is then chromatographed on silica gel with 40% ethyl ether - hexane eluted fraction is crystallized from acetone-hexane and delivers 9a-bromo-1-Eat fluoro-4-pregnene-17a, 21-diol-3,20-dione -21-acetate; AcH, OH = 243m Max #LC. 9a - bromine - 1 Iß - fluorine - 4 - pregnen - 17a, 21 - diol-3,20-dione-21-acetate is then subjected to the action of the microorganism Corynebacterium simplex as follows: A solution of 1 g of yeast extract (known under the Trade name "Difco") in 11 tap water, the pH of which is adjusted to 6.9 , is distributed among ten 300 cc Erlenmeyer flasks, and an ose full, 2 cc, Corynebacterium simplex is added to each flask. The suspensions formed are incubated on a shaker at 30 ° C. for 18 hours. 1 / 2g of 9a-bromo-Ilfl-fluoro-4-pregnen-17a, 21-diol-3,20-dione-21-acetate is dissolved in 25 cc of acetone and the resulting solution evenly on the ten flasks with the 18-hour growth of Corynebacterium simplex distributed. The culture, which contains the 9a-bromo-ILß-fluoro-4-pregnen-17a, 21-diol-3,20-dione-21-acetate, is then incubated at 30 ° C. for 24 hours. After 24 hours the contents of the flasks are combined and extracted with a total of 3 liters of chloroform. The crude chloroform extract of the conversion is then concentrated to a residue which is crystallized from methylene chloride-hexane to give 0.35 g of crystalline solid, mp. 167 to 172'C are obtained. Recrystallization from the same solvent mixture gives 9a-bromo-ILß-fluoro-1,4-pregnadiene-17a, 21-diol-3,20-dione-21-acetate with the above constants. Example 4 9a, Ilfl-dibromo-1,4-pregnadiene-17a, 21-diot-3,20-dione-21-acetate To a solution of 1.0 g of 1,4,9 (11) -pregnatriene-17a , 21-diol-3,20-dione-21-acetate in 40 cem methylene chloride is added dropwise at O'C a solution of 420 mg bromine in 5 cc methylene chloride. The reaction mixture is stirred for 1 hour at O'C Ge, then diluted with methylene chloride, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The remaining CU is dissolved in acetone, treated with decolorizing charcoal and crystallized from acetone-hexane to give 9a, Ilfl-dibromo-1,4-pregnadiene-17a, 21-diol-3,20-dione-21-acetate; M.p. 142 to 146'C (decomposition), [a] 211 # + 185 ' (dioxane); Cli IIIH 1-40 in E- 14 200.

The compound of this example is also obtained by a solution of 1,4,9 (I1) -Pregnatrien-17a, 21-diol-3,20-dione-21-acetate in glacial acetic acid with N-bromoacetamide and hydrogen bromide is treated.

Example 5 9a, llß-dichloro-4-pregnen-17a, 21-diol-3,20-dione-21-acetate A solution of 1,04,9 (I1) -pregnadiene-17a, 21-diol-3, 20-dione-21 acetate and 5.0 g of lithium chloride in 40 cc of glacial acetic acid are treated with a solution of 200 mg of chlorine gas in 3 cc of tetrahydrofuran according to the modified procedure of Example 2. Crystallization of the crude product from acetone - hexane gives 9a, Ilfl-dichloro-4-pregnen-17a, 21-diol-3,20-dione-21-acetate; ircnaHx'OH = 24OmtL; F.230 to 232'C (with decomposition).

Example 5a 9a, 11 beta-dichloro-1,4-pregnadiene 1 7a, 21-diol-3,20-dione 1 g 1,4,9 (I1) -Pregnatrien-] 7a, 21-diol-3,20 -dione; Mp 220 to 228'C (decomposition),;. .CH.OH = 238 m £ #, Max E = 15 500, was as described with chlorine gas and lithium chloride in glacial acetic acid solution in Example 2 treated. The obtained product is crystallized from acetone to obtain 9a, llß-dichloro-1,4-pregnadiene-17a, 21-diol-3,20-dione; M.p. 238 to 241 ° C (decomposition); + 134 '(pyridine); 2 l H3 Max ' = 237 m # t; E # 15 400. Example 6 9a, 1 β-dichloro-1,4-androstadiene-3,17-dione A. To a solution of 1.32 g of 1,4,9 (1: 1) -androstatriene-3.17 -dione and 5.0 g of lithium chloride in 60 cc of diethyl acetic acid, which is stirred at room temperature, 686 mg of N-chlorosuccinimide and immediately thereafter 5 cc of normal aqueous hydrochloric acid are added. Stirring is continued for 17 hours at room temperature and the reaction mixture is then poured into saturated aqueous sodium carbonate solution. The resulting mixture is extracted with methylene chloride and the extracts are washed with water, dried with magnesium sulfate and evaporated in vacuo to obtain the crude product. Crystallization from acetone-hexane gives 9a, llp-dichloro-1,4-androstadiene-3,17-dione -, Schnip. 227 to 231 ° C (decomposition); H, [al " 173 ' (dioxane); i'.."# 235 mu, E = 15,600. M B. However, the compound of this example can also be prepared as follows: To a solution of 9a, Ilfl-dichloro 1,4-pregnadiene-] 7a, 21-diol-3,20-dione (1.0g), the compound of Example 11, in 50% aqueous acetic acid (800ccm) is added sodium bismuthate (18g) and the suspension at room temperature Stirred for 20 hours. The reaction mixture is then filtered and methylene chloride is added to the filtrate. Water is added to the mixture obtained and the organic phase is separated off, washed with water, then with 100% aqueous sodium bicarbonate solution and finally with water. The methylene chloride solution is then dried with magnesium sulfate and evaporated in vacuo to give the crude product. Crystallization from methylene chloride-hexane gives 9a, Ilfl-dichloro-1,4-androstadiene-3,17-dione.

Example 7 9a-Bromo-1β-fluoro-1,4-androstadiene-3,17-dione To a solution of 1.0 g of 1,4,9 (1: 1) -androstatriene-3,17-dione in 50 cc Diethyl acetic acid, which is stirred and contained in a polyethylene bottle at room temperature, is added to a solution of 1.35 g of hydrogen fluoride in 5 cc of chloroform-tetrahydrofuran solution (1: 2) and then 535 mg of N-bromoacetamide. Stirring is continued for 17 hours at room temperature and the solution is then poured into 500 cc of 10% aqueous sodium bicarbonate solution. The mixture is extracted with methylene chloride and the extracts are washed with water, dried with magnesium sulfate and evaporated in vacuo to give 1.21 g of the crude product (91%). Crystallization from acetone - hexane gives 9a-bromo- 11 ß-fluoro-1,4-androstadiene-3,17-dione; M.p. 194 to 196 ° C (decomposition); [al, 118 ' (dioxane); E = 14,000.

Example 8 9a, 11β-dichloro-1,4-androstadien-17fl-ol-3-one To a solution of 1.0 g 1,4,9 (11) -androstatrien-17fl-ol-3-one in carbon tetrachloride (50 cem) and pyridine (0.8 ccm), which is stirred, is added at -20'C N-chlorosuccinimide (520 mg) and a solution of hydrogen chloride (140 mg) in tetrahydrofuran (1.4 ccm). Stirring is continued at −20 ° C. for 15 minutes, and then the reaction mixture is allowed to assume room temperature for a further 15 minutes. Methylene chloride (50 cc) is added and the solution is washed successively with sodium thiosulphate solution, water, 10 percent sodium bicarbonate solution and finally with water, dried over magnesium sulphate, filtered and evaporated in vacuo to a residue which is crystallized from methylene chloride-hexane to give 9a, To obtain Ilfl-dichloro-1,4-androstadien-17fl-ol-3-one, A CH.OH = 237 m # t; max E = 15,300; F., 205 to 210 ° C. Example 9 9a-bromo-1β-chloroprogesterone 490 mg of N-bromoacetamide are added to a solution of 1.005 g of 4.9 (1 l) -pregnadiene-3,20-dione and 4.0 g of lithium chloride in 50 cc of glacial acetic acid -The mixture is stirred at room temperature and a slow stream of gaseous = hydrogen chloride is passed over the surface until the surface begins to darken (10 to 30 seconds). The hydrogen chloride gas is removed and the solution is stirred in the dark at room temperature for about 10 minutes. The solution is poured into ice-water with stirring and the solid obtained is filtered, washed with water and crystallized from methylene chloride-pentane in order to obtain 9α-bromo-1β-chloroprogesterone, melting point 111 to 113 ° C. (decomposition); E = 15,900; [a] " +226 ' (chloroform).

Example 10 9a-bromo-1β-fluoroprogesterone To a solution of Ig 4,9 (I1) -Pregnadiene-3,20-dione and 483 mg N-bromoacetamide in 30cc acetic acid a solution of about 50O mg hydrogen fluoride in 20 cc acetic acid is added. The solution is stirred for 2 hours at room temperature, then poured into ice-water with stirring. A resinous precipitate forms from which the aqueous solution is decanted. The precipitate is then dissolved in acetone-ether and filtered through a column of synthetic magnesium silicate (known under the trade name Florisil) in ether. The eluted material is combined, the ether is removed in vacuo and the precipitate obtained is triturated with pentane-ether, then crystallized from methylene chloride-pentane to obtain 9a-bromo-ILß-fluoroprogesterone , m.p. 145 to 150 ° C (decomposition); F, = 15200; [al + 170 ' (chloroform).

Example 11 9a, 11 beta-dichloro-1,4-pregnadiene-3,20-dione A solution of 1 g 1,4,9 (1 1) -pregnatriene-3,20-dione in 40 cc of acetic acid with 490 mg 95% N-chlorosuccinimide in the presence of hydrogen chloride and lithium chloride according to the method of Example 2 reacted. The precipitated with water solid is crystallized from acetone-hexane to afford 9a, 11 beta-dichloro-1,4-pregnadiene-3,20-dione to obtain: mp 198 to 208'C (decomposition);. 237 mp .; [a]. = + 184 '(chloroform). Example 12 9a-chloro-1β-fluoro-1,4-pregnadiene-3,20-dione To a solution of. 500 mg 1,4,9 (11) -Pregnatrien-3,20-dione in 20 ccm carbon tetrachloride and 3 cc pyridine are a solution of 860 mg hydrogen fluoride in 1.5 cern a mixture of tetrahydrofuran and chloroform and then 230 mg N -Chlorsuccinimide added. The reaction mixture is diluted with enough methylene chloride to give a solution and is stirred for 48 hours at room temperature, then poured into aqueous sodium carbonate. The crude mixture is extracted with methylene chloride, the organic extracts are combined, washed with water, dilute hydrochloric acid and finally with water. The solution. is then dried over magnesium sulfate, filtered and evaporated to a residue which is triturated with ether, filtered and crystallized from acetone-hexane to give 9a-chloro-Ilß-fluoro-1,4-pregnadiene-3,20-dione : M.p. 215 to 220 ° C; ; E = 15100; [al "= + 141 '(chloroform).

Example 13 6β-Methyl-9a-chloro-1β-fluoro-1,4-pregnadiene-3,20-dione To 500 mg of 6P-methyl-1,4,9 (I 1) -pregnatriene-3,20-dione 215 mg of N-chlorosuccinimide in 25 cem of diethyl acetic acid and then a solution of 620 mg of hydrogen fluoride in 3.2 cem of a mixture of tetrahydrofuran and chloroform are added. The reaction mixture is stirred at room temperature for 48 hours; then it is poured into aqueous sodium carbonate solution. The mixture is extracted with methylene chloride, the organic extracts are combined and evaporated to a residue which is chromatographed on silica gel. The product eluted with 25% ether-in-hexane is crystallized from methylene chloride-hexane to obtain 6β-methyl-9α-chloro-ILβ-fluoro-1,4-pregnadiene-3,20-dione. Example 14 9a-Bromo-1β-chloro-17a-hydroxyprogesterone-17-acetate 1 g of 17a-hydroxy-4,9 (I1) -pregnadiene-3.20-dione-17-acetate and 4 g of lithium chloride are dissolved in 50 cc of glacial acetic acid and added 42Omg N-bromoacetamide. The mixture is stirred at room temperature and a slow stream of gaseous hydrogen chloride is passed over the surface until the solution begins to darken (10 to 30 seconds). The hydrogen chloride gas is removed and the solution is stirred in the dark at room temperature for about 10 minutes. The solution is poured into ice-water with stirring, and the resulting solid is filtered off, washed with water and crystallized from acetone-hexane to obtain 9a-bromo-Ilfl-chloro-17a-hydroxyprogesterone-17-acetate; Mp. 124 to 129'C (decomposition). [al, # - # - 142 '(Chloroforrn); ic "-II" = 242m # t; E = 15600th Max Example 15 9a-bromo-11 beta-fluoro-1 7a-hydroxyprogesterone 17-acetate To a solution of of 1 g of 17a-hydroxy-4,9 (I 1) -pregnadiene-3,20-dione-17-acetate and 425 mg of N-bromoacetamide in 50ccm of diethyl acetic acid is a solution of 500 mg of hydrogen fluoride in 4.7 cc of chloroform-tetrahydrofuran added. The solution is stirred for 2 hours at room temperature, then poured into ice-water with stirring. The acid is neutralized by adding sodium carbonate and a resinous precipitate is formed from which the aqueous solution is decanted. The precipitate is then dissolved in methylene chloride and the solution is washed with 5% strength aqueous sodium hydroxide and then with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue obtained is triturated with pentane, filtered and crystallized from methylene chloride-pentane. to obtain 9a-bromo-ILß-fluoro-17a-hydroxyprogesterone-17-acetate; M.p. 176 to 180 ° C (decomposition); A1c11-011 = 240 m # t, E = 16 100; Max [al # = + g1 ' (chloroform). Example 16 9a, 1 β-dichloro-17a-hydroxy-1,4-pregnadiene-3.2 "ion-17-acetate 1 g of 17a-hydroxy-1,4,9 (1 1) -pregnatriene-3.20- dione-17-acetate is reacted with 395 mg of N-chlorosuccinimide in the presence of hydrogen chloride and lithium chloride to obtain 9allß-dichloro-17'-hydroxy-1,4-pregnadiene 3,20-dione-17-acetate, Max Ac "#"H# 237 mIL, E = 15,300 ; m.p. 230 to 235'C (decomposition); [al #, = + 115 ' (chloroform).

The compound of this example can also be prepared as follows, 17a-hydroxy-1,4,9 (I 1) -prepatrien-3,20-dione is reacted with 220 mg of chlorine gas in carbon tetrachloride in the presence of pyridine to give 9a, llß- To obtain dichloro-17a-hydroxy-1,4-pregnadiene-3,20-dione; Mp. 235 to 239'C (decomposition), Ac "-OH 238 mp .; E = 15,000; [a]" = + 129 '(ChWomax form. Example 17 9a-Bromo-Ilß-fluoro-17a- hydroxy-19-norprogesterone In the manner described in Example 14, 250 mg of 17a-hydroxy-19-nor-4,9 (I 1) -pregnadiene-3,20-dione with 110 mg of N-bromoacetamide in 50 cc of diethyl acetic acid and a solution of 25Omg hydrogen fluoride in 2cc of a chloroform-tetrahydrofuran mixture (1: 2) reacted and the product obtained is isolated and purified, to afford 9a-bromo-19-nor-progesterone to obtain 1-fluoro-17a-hydroxy-Eat.

Claims (2)

Claims: 1. A process for the preparation of 9a, 11ß-dihalogen compounds of the pregnane or androstane series, characterized in that a corresponding 9,1 1-dehydro compound, esterified 9 "-halogen-Ila-hydroxy compound, preferably in the form of its 11-tosylate or -Mesylates, or a corresponding 9a-halo-Ila- or 9a-halo-Ilß-amino compound of the pregnane or androstane series, if necessary with temporary protection of groups sensitive to halogenation in an inert solvent with a halogenating agent, the halogenating agent used being a can cause inversion of configuration at the 1 1-position of the starting compound, and in that then, if desired, 9a thus obtained, 1 ISS dihalo compound in a conventional manner and in any order in l dehydrated (2) position and / or, if desired, if it belongs to the Pregnan series, according to methods known per se by oxidative degradation of the 1 7-position side chain converted into the corresponding compound of the androstane series and / or, if desired, saponified at least one ester group present and / or esterified at least one hydroxyl group present in a known manner. 2. The method of claim 1, characterized denotes Ge, that -androsten a 3-keto-9 (I 1) or a 3,20-diketo-9 (I 1) -pregnen or its 19-nor-analogs can be unsaturated in ring A, can be substituted in the core and in the side chain by lower alkyl, hydroxy, acyloxy or halogen groups, in particular a 9,11 -dehydrosteroid of the following structural formula and its A'-dehydro, A4-dehydro, AI, 4-BiS-dehydro and 19-nor-A4-dehydro analogs are used as starting compounds, in which A is hydrogen or a lower alkyl group, B is hydrogen, a lower alkyl group or halogen, D is hydrogen, a lower alkyl group, hydroxyl or a lower alkanoyloxy group and Q is the radical denotes where R is hydrogen or an acyl radical, V = H, OR, a lower alkyl radical or halogen and Z # is H, OR or halogen. 3. The method according to claim 1 and 2, characterized in that the halogenating agent provides a positive halogen ion and a negative halogen ion, the sum of the atomic weights of these ions being greater than 38 but less than 253 . 4. The method according to claim 1 to 3, characterized in that the halogenating agent used is molecular halogen of the same atom, molecular heteroatomic halogen, addition compounds of molecular halogen, N-haloamides in connection with a halide, heavy metal polyfluorides or heavy metal oxides in connection with hydrogen fluoride. 5. The method according to claim 1, characterized in that a steroid of the 3,20-diketo-A9 (I1) -Pregnen- oder3-keto-A9 (I1) -androstenzeile with molecular halogen with a molecular weight greater than 38 and is less than 253 , with an N-haloamide mixed with a halide, the halogen in the halide being at least as electronegative as the halogen in the N-haloamide and the sum of the atomic weights of these halogens being greater than 38 and less than 253 , or with addition compounds of molecular halogen. 6. The method according to claim. 1 to 5, characterized in that the solvent used is a lower alkanoic acid, in particular acetic acid, a halogenated hydrocarbon in the presence of a tertiary base, in particular a chlorinated methane in the presence of pyridine. 7. The method according to claim 6, characterized in that the halogenation is carried out with chlorine. 8. The method according to claim 1 to 7, characterized in that the halogenating agent contains N-chlorosuccinimide, lithium chloride and hydrogen chloride. 9. The method according to claim 1 to 8, characterized in that the halogenating agent contains chlorine and lithium chloride.