CH616691A5 - Process for the preparation of steroid compounds and their use. - Google Patents

Description

The invention relates to a method for producing compounds of the Pregnan and Androstan series, which improve

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show anesthetic properties, as well as the use of compounds produced by the process.

It has long been known that a number of steroids have a depressing effect on the central nervous system and pharmacodynamically as anesthetics or hypnotics. These compounds have been studied extensively to find anesthetics to replace such compounds as thiobentone 7 sodium (free international short name for ethyl isoamylthiobarbital sodium), which are generally used but have certain hazards and disadvantages. From the literature it can be seen that a large number of steroid compounds have been investigated in this regard. Summaries and discussions of the work carried out in this regard are e.g. in: "Methods in Hormone Research" (Edited by Ralph I. Dorfman, Vol. III Part A, Academic Press, London and New York, 1964, pp. 415-475); H. Witzel, Z. Vitamin hormone fermentation research. 1959, 10.46-74; H. Selye, Endocrinology, 1942,30,437-453; S.K. Figdor et al., J. Pharmacol. Exptl. Therap., 1957, 119, 299-309 and Atkinson et al., J. Med. Chem. 1965, 8, 426-432.

A review of the literature shows that anesthetic steroids generally have low activity and / or long induction periods. A large number of undesirable side effects, such as paraesthesia and venous damage, have been found when using such compounds. Steroids which have anesthetic properties which have been described hitherto are generally relatively simple prognane derivatives which are frequently hydro-xylated in the 3-position, in which in general, the 3β-hydroxy compounds were preferred compared to the 3 a-hydroxy compounds.

It has now been found that certain 3a-oxygen-containing steroids of the Pregnan and Androstan series, which are described in more detail below, show remarkable anesthetic or anesthetic properties and can therefore be an active ingredient for pharmaceutical compositions with which anesthesia or in appropriate dosage, a sleep aid or sedative effect can be caused. The term "pharmaceutical" as used herein encompasses both human and veterinary medicine.

The invention now relates to a process for the preparation of 3β-substituted steroid compounds of the formula I.

c = o

HO

(I)

H

in which mean:

R2 is an alkyl group with 2 to 6 carbon atoms;

R4 represents a hydrogen atom, a hydroxyl group or an epoxy group or carbon-carbon bond connected to the 9-position;

R5 is a hydrogen atom when R4 is a hydrogen atom or an epoxy group or carbon-carbon bond linked to the 9-position; or an alkyl group having 1 to 6 carbon atoms or an allyl group when R4 is a hydroxy group; or R4 and R5 together are an oxo group when R7 is a methyl group;

R6 represents a hydrogen or halogen atom or a methyl group;

R6A is a hydrogen atom or, when R6 is a methyl group, a methyl group;

R7 is a methyl group or an alkoxy group having 1 to 6 carbon atoms;

and which may have a double bond in the 8 (9) position. The process according to the invention is characterized in that a corresponding compound of the formula I which has a 3-spiro-oxirane group instead of the a-hydroxy group and the β-alkyl group in the 3-position, optionally with intermediate protection of the 20-oxo group when R7 is a methyl group, with a complex metal hydride or a metal alkyl compound having 1 to 5 carbon atoms.

The invention furthermore relates to the use of compounds of the formula I which have an 11-hydroxy group and have been prepared by the process according to the invention for the preparation of corresponding compounds in which R4 and R5 together represent an oxo group by oxidation of the starting compound.

The term "low" as used hereinafter with respect to the alkyl or alkoxy groups means that the groups in question have 1 to 6 carbon atoms. Applied to the acyl groups, this expression means

that the acyl group has 2 to 6 carbon atoms.

The compounds of the general formula given above are excellent anesthetics and bring about the anesthetic effect within short induction times, the anesthetic effect generally occurring immediately with a suitable dosage. The compounds thus represent excellent anesthetics with which an anesthetic effect, e.g. B. to be maintained by an inhalation anesthetic such as ether, halothane, nitrous oxide, trichlorethylene, etc. is induced. However, the compounds are able to maintain the anesthetic and analgesia to a sufficient extent so that various surgical operations can be performed without the use of an inhalation anesthetic.

The required degree of anesthesia can, if necessary, be maintained by repeated administration, or even continuous administration. Furthermore, the anesthetics produced by the process according to the invention lead to minor side effects compared to the steroid anesthetics described hitherto.

An important class of compounds which can be produced by the process according to the invention are compounds which have a double bond in the 8 (9) position, in particular if an oxo group is present in the 11-position, i. H. when the groups R4 and R5 together form an oxo group. Other substituents can of course also be present in the compounds of the important class mentioned above, in particular substituents of the type mentioned in the 16-position.

A particularly preferred compound which can be prepared by the process according to the invention is 3a-hydroxy-3β-methyl-5 a-pregnan-11,20-dione.

Many of the anesthetic steroid compounds described above are only slightly soluble in water. However, it has been found that these compounds can be administered parenterally in an aqueous solution of a parenteral

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compatible non-ionic surfactants can be formulated.

The non-ionic surfactants used for this purpose are the water-soluble agents, which suitably have an HLB value (hydrophilic-lipophilic balance, see J. Soc. Cosmetic Chem. 1949, pages 311-326) of at least 9, preferably at least 12 and most advantageously have at least about 13. Preferably, the surfactant's HLB is no more than about 15, although it can reach 18. The surfactant must of course be physiologically acceptable, i.e. H. do not lead to physiologically undesirable side effects in the subjects to be treated (humans or animals) at the doses used. Surfactants that can be used are the following non-ionic surfactants and classes of surfactants:

Polyoxyethylated derivatives of fatty glyceride oils (with 12 to 20 carbon atoms), e.g. B. castor oil containing 35 to 45 or up to 60 oxyethylene groups per mole of fatty oil. Polyoxyethylene ethers (which have 10 to 30 oxyethylene groups) of long chain alcohols (e.g. containing 12 to 18 carbon atoms).

Polyoxyethylene polyoxypropylene ethers containing 15 to 35 or 15 to 30 oxyethylene or oxypropylene groups. Polyoxyethylene ethers (which have 6 to 12 oxyethylene groups) of alkylphenols, the alkyl groups of which preferably contain 6 to 10 carbon atoms.

Polyoxyethylated fatty acid esters containing 15 to 30 oxyethylene groups and 12 to 18 carbon atoms in the fatty acid part of sugar alcohol anhydrides, e.g. of sorbitan hydride or mannitol hydride. Long chain (e.g. containing 10 to 16 carbon atoms) alkanoyl mono- and di-alkanol amides (whose alkanol parts contain e.g. 1 to 5 carbon atoms), e.g. Lauroyl mono and diethanol amides. Polyethylene glycol esters (which have 6 to 40 ethylene oxide units) of long chain fatty acids (e.g. containing 12 to 18 carbon atoms) e.g. Polyethylene glycol mono-oleate (e.g. containing 8 ethylene oxide units).

Examples of nonionic surfactants of the types described above that can be used include:

Cremophor EL - a polyoxyethylated castor oil that contains about 40 ethylene oxide units per triglyceride unit;

Tween 80 - polyoxyethylene sorbitan mono-oleate containing about 20 ethylene oxide units;

Tween 60 - polyoxyethylene sorbitan monostearate containing about 20 ethylene oxide units; and

Tween 40 - polyoxyethylene sorbitan mono-palmitate containing about 20 ethylene oxide units.

The term "solutions" as used herein includes liquids which have the appearance of real solutions and are therefore optically clear and capable, e.g.

to penetrate through a microporous filter, regardless of whether these solutions are real solutions in the classic chemical sense and regardless of whether they are stable or meta-stable. Thus, the steroid can be associated with micelles. Regardless of their exact physical nature, intravenous injections behave like real solutions.

The proportions in which the surfactants are used in the compositions depend on the type and concentration of the steroid contained in the final composition.

In preferred compositions, the level of surfactant is preferably at least 5% by weight, and advantageously about 10% by weight.

It has been found that a very suitable amount of surfactant is 20% by weight, although amounts of 30 and up to 50% by weight can be used. Amounts of surfactant are given as weights in relation to the total volume of the composition in metric units.

It is understood that the amount of the steroid in the aqueous solution depends on the type and amount of the surfactant used. The composition contains at least 1 mg steroid per ml and solutions can be prepared which e.g. contain up to 10 mg / ml.

In all cases, the various components are adjusted so that a clear solution is obtained.

In a preferred mode of preparation for the solutions, the steroid is first in the selected surfactant, e.g. with heating, dissolved, whereupon the resulting solution is dissolved in water. Alternatively, the steroid can be in a volatile organic solvent which advantageously has a boiling point less than about 80 ° C and which is miscible with the surfactant, such as a volatile low aliphatic ketone, e.g. Acetone or methyl ethyl ketone or a volatile halogenated hydrocarbon, e.g. Chloroform or methylene chloride. For this purpose, acetone is the most preferred solvent. The surfactant is then added to this solution and the organic solvent is removed by evaporation, e.g. by passing an inert gas stream, e.g. a nitrogen stream is removed through the solution and the resulting steroid solution in the surfactant is then mixed with water.

The solutions can also be prepared by shaking the steroid with an aqueous surfactant solution.

In all cases, simple studies enable the relative amounts of surfactant required to be determined.

The anesthetic solutions are generally administered by intravenous injection, although it is known that in certain cases, e.g. in young children, intramuscular injection is preferred.

As is common for anesthetics, the amount of steroid used to produce the anesthetic depends on the weight of the individual to be anesthetized. When administered intravenously, a dose of about 0.5 to 30 mg / kg is sufficient for the average adult to induce anesthesia, with a preferred dose being in the range of 0.7 to 20 mg / kg. The dose will of course vary to some extent with the physical condition of the patient and the depth and duration of the desired anesthetic effect. It is therefore possible to induce anesthetic durations ranging from 10 minutes to 1 hour or more by changing the dose. If it is desired to maintain a prolonged anesthetic effect, repeated doses of the solution can be used, the repeated doses generally being of the same order of magnitude or less as the original dose. Alternatively, continuous administration, e.g. with an amount of 0.09 to 14 mg / kg / min. be performed.

When the anesthetic solutions are administered intramuscularly, higher doses are generally required.

The starting compounds to be used in the process according to the invention are new. They can be made by any suitable method, e.g. following the procedure as published in: Djerassi, “Steroid Reactions”, p

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by Holden-Day, Inc., San Francisco, 1963.

The compounds of formula I in which the group R5 represents a hydroxyl group and the group R4 represents a hydrogen atom can e.g. can be prepared by stereo-specific reduction of a compound of the formula I in which R4 and R5 together denote an oxygen atom.

An alkali metal, preferably lithium or an alkaline earth metal, advantageously calcium and a suitable nitrogen base, e.g. Ammonia or a lower alkylamine, advantageously ethylamine. The reaction is suitably accomplished in a solvent, preferably in the nitrogen base used as the reducing agent.

The compounds of formula I in which the group R5 represents a lower alkyl or allyl group and the group R4 represents a hydroxy group can e.g. from the corresponding compound of the general formula I, in which R4 and R5 together denote an oxygen atom and which, if R7 denotes a methyl group, has an ethylenedioxy group in the 20-position by reaction with an alkylating or allylating agent, preferably an alkali metal alkyl or allyl compound, advantageously methyl lithium or allyl lithium. The alkylation or allylation can suitably be carried out in an aprotic organic solvent, e.g. an ether such as diethyl ether and / or tetrahydrofuran, preferably at a temperature of 0 to 100 ° C, more preferably at a temperature of 15 to 65 ° C.

Compounds of general formula I thus prepared and precursors of these compounds which have an ethylenedioxy group in the 20-position can be prepared in compounds of general formula I with a 20-0xo group using known methods, e.g. by hydrolysis in the presence of an inorganic or organic acid such as a hydrohalic acid, e.g. Hydrochloric acid, or a lower alkane carboxylic acid, e.g. Acetic acid. The hydrolysis can suitably be carried out at a temperature of 0 to 100 ° C.

The preparation of the compounds of general formula I in which the group R6 represents a 16β-methyl group can e.g. by hydrogenation of an analog ô16 compound, preferably using catalytically activated hydrogen. Suitable catalysts are e.g. Platinum metal catalysts, preferably a palladium catalyst, e.g. Palladium on activated carbon. The hydrogenation is preferably carried out in an organic solvent, e.g. a low alkanol, e.g. Methanol or ethanol or an ether solvent e.g. Tetrahydrofuran or diethyl ether, a halogenated hydrocarbon, e.g. Methylene chloride or a lower alkane carboxylic acid ester, e.g. Ethyl acetate.

The 16-methyl-16-en analogues of steroids of general formula I can be prepared by known procedures, e.g. according to the Negata et al. (Helv. Chim. Acta 1959, 42, 1399) can be prepared from the corresponding 3β-hydroxy-16-methyl-16-ene steroid. This process can generally be used to convert an analog 3β-hydroxy compound into a compound of general formula I. The 3β-hydroxy compound can thus be converted into a hydrocarbon sulfonyloxy derivative, preferably the 3β-toluosulfonyloxy derivative, which is then e.g. with a salt of a low alkanoate, e.g. Triethylammoniumacetate are implemented, so that the 3a-acyloxy compound is obtained. The 3 a-acyloxy compound can then be hydrolyzed to form the 3a-hydroxy compound.

The 20-0xo compounds of general formula I which have a 16a-methyl substituent can be obtained from the corresponding 16-unsubstituted ô16-20-0xo compounds by reaction with a metal methyl derivative such as lithium dimethyl cuprate or using a copper catalyst or methyl magnesium halide, e.g. bromide or iodide. The reaction is preferably carried out in an ether solvent, e.g. Diethyl ether.

The compounds of the general formula I in which the group R4 is an epoxy group which is bonded in the 9β-position can be prepared by known procedures. It has been found that it is suitable to remove such compounds from the corresponding 9a-halogen-11β-hydroxy compound by splitting off hydrogen halide, e.g. HBr. This elimination is preferably carried out under alkaline conditions, e.g. using an aqueous solution of an alkali metal hydroxide, e.g. Sodium hydroxide, preferably at a pH of 11 to 12.5. The reaction can be carried out at room temperature during e.g. over a period of about 15 minutes. The 9a-halo-11β-hydroxy-steroids used in this reaction, preferably the 9a-bromine compounds, can be prepared by methods known per se, e.g. can be obtained from the corresponding 9,11-dehydro compounds by reaction with a source of hypohalic acid. Suitable hypohalic acid sources include e.g. aqueous, acidic solutions of halogenating agents, e.g. N-Bromsuc-cinimid, a.

The 9,11-dehydro-steroids of general formula I can be prepared according to known procedures, e.g. by hydrogenating the corresponding 9 (11), 16-dienes, e.g. in an analogous manner to the process used above for the preparation of the 16-methyl-ô16 compounds which are used in the preparation of the available 16β-methyl compounds and as described in the Belgian patent specification 752 165 from the corresponding 3ß-hydroxy -9 (ll), 16-serve.

Compounds which have a double bond between the 8 and 9 positions and an 11-oxo group can e.g. can be obtained by dehydrohalogenation of a corresponding 9 a-halo-ll-oxo compound. The dehydrohalogenation can generally be carried out under usually mild conditions, e.g. a nitrogen-containing Lewis base, such as N, N-dimethylformamide or N, N-dimethylacetamide, preferably in the presence of an alkali metal or alkaline earth metal carbonate, preferably in the presence of calcium carbonate. The reaction can e.g. at elevated temperatures, preferably at the reflux temperature of the solvent when a solvent is used. Low temperatures can be used when using added lithium halide or calcium halide. This reaction is preferably carried out using a 3 a-acyloxy-9a-halogen-ll-oxo compound, e.g. of the 3a-acetoxy compound, and if the corresponding 3 a-hydroxy compound is to be prepared, the chosen 3a-acyloxy-5a-pregn-8-en-ll-one can e.g. with a low alkanol, e.g. Methanol or ethanol or with water, preferably in the presence of an acidic or basic catalyst, e.g. Perchloric acid. This reaction can take place at a temperature of 0 to 100 ° C.

The 9a-halogen-5a-pregnan-ll-ones used in the above reaction can be prepared according to known procedures and are preferably obtained by oxidation of the corresponding 3a-acyloxy-9a-halogen-11ß-hydroxy-5 a-pregnanes, e.g. using chromic acid, e.g. in a solvent such as acetone. These 3a-acyl-oxy-9ß-halogen-5a-pregnan-11ß-ones can suitably e.g. by reacting a compound of general formula I, wherein the group R4 is an epoxy group, which is also described in s

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which is bound to the 9β position means with a hydrohalic acid, preferably hydrochloric acid.

In the process according to the invention, the reaction of the corresponding 3-spiro-oxirane compound with a complex metal hydride leads to compounds of the formula I in which R2 denotes a methyl group. If it is desired to prepare compounds of formula I in which R2 represents an alkyl group other than methyl, the reaction is carried out with a metal alkyl compound, e.g. Lithiumdi-methyl-cuprat, by. The latter reaction is suitably accomplished in an aprotic organic solvent, preferably an ether solvent such as diethyl ether or tetrahydrofuran. In general, it is preferred to carry out the reaction at a temperature below room temperature, e.g. to be carried out at a temperature of -20 ° to + 20 ° C.

The reaction of the 3-spiro-oxirane compound with a complex metal hydride, preferably a complex aluminum hydride, e.g. Lithium aluminum hydride is preferably used in an aprotic organic solvent, e.g. an ether solvent such as diethyl ether or tetrahydrofuran. In general, when an 11-oxo group is present in the compound reacted with the complex metal hydride, this group is reduced to an 11β-hydroxy group. If compounds of the general formula I are to be prepared in which the groups R4 and R5 together represent an oxygen atom, the IIβ-hydroxy compound prepared according to the above reaction can be oxidized in a manner known per se, e.g. using chromic acid in an aqueous organic solvent, e.g. in aqueous acetone. The oxidation is preferably carried out under acidic conditions and advantageously at a temperature of 0 to 50 ° C.

It may be desirable to add any 20-0xo group in a 3-spiro-oxirane-20-oxo-pregnane compound used in these reactions, e.g. by ketal formation, e.g. with ethylene glycol.

The 3-spiro-oxi-ran compounds used in the above reactions can be prepared in a known manner. In general, these compounds can be prepared by reacting the corresponding 5a-Pregnan-3,20-dione-20-ketals, preferably the 20-ethylenedioxy compound, with a trimethylsulfoxonium halide, preferably the iodide, in the presence of an alkali metal hydride, preferably sodium hydride . The 3-spiro-oxirane compounds can also e.g. can be obtained by epoxidizing the corresponding 3-methylene compound by known methods.

Compounds in which the group R6 represents a halogen atom in the 16a position can be prepared by known procedures, e.g. from the corresponding 16-unsubstituted 5a-Pregn-16-enes by reaction with a hydrohalic acid. The reaction with the hydrohalic acid is preferably carried out in an anhydrous aprotic organic solvent, such as an ether solvent, e.g. 1,4-dioxane, diethyl ether or tetrahydrofuran. This reaction can suitably be carried out at a temperature of about 15 to 40 ° C.

Compounds having a 17β-lower alkoxycarbonyl group can be obtained according to known procedures. Such compounds are suitably prepared by adding a salt of the corresponding 17β-carboxylic acid, suitably a salt with a tertiary amine or a quaternary ammonium salt (for example a trialkylammonium salt or a tetraalkylammonium salt) with an alkylhalogen corresponding to the alcohol portion of the desired ester. nid, e.g. Methyl iodide. This reaction is suitably carried out in a solvent medium (e.g. a lower alkyl ketone such as acetone or methyl ethyl ketone) or in dimethylformamide at temperatures from 20 to 100 ° C.

In particular for the preparation of the lower alkyl esters, it has been found that it is preferred to combine the carboxylic acid with a diazoalkane, e.g. Diazomethane or diazoethane to implement. The reaction with the diazoalkane is suitably carried out in solution in an inert organic solvent, e.g. an ether such as diethyl ether or tetrahydrofuran or a lower alkanol, e.g. Methanol, the diazo compound preferably in solution in an inert organic solvent, e.g. the solvent in which it is extracted during manufacture, e.g. Diethyl ether is used. The reaction is suitably carried out at temperatures between -25 ° C and + 30 ° C.

17β-alkoxycarbonyl compounds can e.g. be prepared by reacting the corresponding 17β-carboxylic acid or a reactive derivative of this compound with an alcohol in the presence of a catalyst. Acidic catalysts, e.g. Sulfuric acid, hydrochloric acid, perchloric acid or p-toluenesulfonic acid are suitable for this purpose. Preferably the carboxylic acid is incorporated in an excess amount of the alcohol from which the ester is to be derived, e.g. Methanol, ethanol or isopropanol containing dry hydrogen chloride, preferably at an elevated temperature, e.g. under reflux temperature.

Suitable activated derivatives of the 17β-carboxyl compound include e.g. the acid halides, preferably the acid chlorides.

The reaction of the acid halides with an alcohol can be carried out in a known manner, preferably in the presence of an inert organic solvent, e.g. a halogenated hydrocarbon, e.g. Methylene chloride or chloroform, or an aromatic hydrocarbon, e.g. Benzene or an ether, e.g. Diethyl ether or tetrahydrofuran can be accomplished.

In general, the reaction is preferably carried out in the presence of an acid binding agent, e.g. a tertiary organic base such as pyridine or triethylamine or an inorganic base such as an alkali metal carbonate or bicarbonate, e.g. Sodium carbonate or sodium bicarbonate.

The reaction of the carboxylic acid halide with the alcohol can e.g. at temperatures between -10 ° C to + 110 ° C.

The acid halides used in the above reaction can be prepared in a known manner, e.g. from the corresponding 17β-carboxylic acid by reaction with a suitable halogenating agent, e.g. a thionyl, phosphoryl or oxalyl halide can be obtained. If it is desired to use the acid chlorides to prepare the esters according to the invention, thionyl chloride, phosphoryl chloride or oxalyl chloride is preferably used. The 3 a-hydroxy group is preferably protected during this reaction.

The carboxylic acids required to prepare the reaction described above can be prepared by conventional procedures, e.g. by the oxidation of the 17ß-acetyl group of a corresponding pregane. This oxidation can e.g. in solution using a hypohalo genite, e.g. B. an alkali metal or alkaline earth metal hypohalo genits as an oxidizing agent. Suitable hypohalo genites include z. B. a sodium and potassium hypochlorite, hypobromite and hypojodite.

The oxidation is preferably carried out in an aqueous or non-aqueous medium. For example, the reaction can in an aqueous, water-miscible organic solvent, e.g. a water-miscible ether, e.g. Dioxane,

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Tetrahydrofuran, diglyme or 1,2-dimethoxyethane or in a water-miscible alcohol, e.g. tert-butanol. The preferred solvent is dioxane.

The oxidation can be carried out at a temperature of from -20 ° C. to + 100 ° C., temperatures from 5 to 10 ° C. being preferred.

The following examples are intended to further illustrate the present invention without, however, restricting it. The rotation values given in the examples relate to approx. 1% (w / v) solutions in chloroform at 20 ° C. The petroleum ether used in the examples had a boiling range of 40 to 60 ° C.

Preparative thin layer chromatography was carried out on silica gel.

example 1

3 a-Hydroxy-3β-methyl-5 a-pregnan-11,20-dione

(a) (3R) -20,20-ethylenedioxy-ll-oxo-5a-pregnan-3-spiro-oxirane

A mixture of 17 mg of sodium hydride, 300 mg of trimethylsulfoxonium iodide and 2 ml of dimethyl sulfoxide was stirred for 1 hour at room temperature under nitrogen. Then 100 mg of 5a-Pregnan-3, II, 20-trion-20-ketal was added and the resulting mixture was stirred for a further 2 hours and then poured into water. The precipitated solid was collected by filtration and washed with water and dried over P2O5 in vacuo. Recrystallization from acetone / petroleum ether gave 50 mg of the title compound in the form of white needles.

F = 176-177 ° C, [<X] D + 49 °.

(b) 20,20-Ethylenedioxy-3β-methyl-5a-pregnan-3 a, 11β-diol A solution of 1.0 g of the above oxirane in 5 ml of tetrahydrofuran was added to a stirred suspension of 0.5 g Lithium aluminum hydride placed in 15 ml ether. The resulting mixture was refluxed for 2 hours, treated with saturated aqueous ammonium chloride solution and extracted with ether. The organic layer was washed with water, dried over Na2SO4 and evaporated. Recrystallization of the residue from acetone gave 0.9 g of the title compound in the form of white needles.

F = 162 ° C, [a] D + 35 °.

(c) 3a-Hydroxy-3ß-methyl-5 a-pregnan-11,20-dione A solution of 1.5 g of 20,20-ethylenedioxy-3ß-methyl-

5 a-pregnan-3 a, 11β-diol in 60 ml acetone was treated with a solution of 1.5 g potassium dichromate in 15 ml 2N sulfuric acid at room temperature for 2 hours. The mixture was then poured into water and the precipitate which had separated out was filtered off, washed in water and dried over phosphorus pentoxide in vacuo. Recrystallization from acetone / petroleum ether gave 0.75 g of the title compound in the form of white needles.

F = 175 ° C, [a] D + 116 °.

616691

Example 2

3β-ethyl-3 a-hydroxy-5 a-pregnan-11,20-dione A 2m solution of methyl lithium in 15.5 ml ether became a stirred slurry of 3.0 g copper i-iodide in 50 ml Ether added under nitrogen at -20 ° C. A solution of 1.0 g (3R) -20,20-ethylenedioxy-ll-oxo-5a-preg-nan-3-spiro-oxirane in 150 ml ether was then added to the mixture at a temperature of -20 ° C . Then the reaction mixture was allowed to stand at 0 ° C for 18 hours, then poured into a saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The extracts were washed with water, dried over Na2S04 and evaporated. Preparative thin layer chromatography and recrystallization from acetone gave 1.7 g of 3β-ethyl-20,20-ethylenedioxy-3a-hydroxy-5a-pregnan-ll-one.

F = 144 ° C, [a] D + 72.3 °.

A solution of 0.5 g of this material in 85 ml of acetone was treated with 17 ml of 2N hydrochloric acid at room temperature for 30 minutes. The solution was then poured into water and extracted with ethyl acetate. The extracts were washed with water, dried over Na2S04 and evaporated. Recrystallization of the residue from acetone gave 0.3 g of the title compound.

F = 129 ° C, [a] D + 118 °.

Example 3

3 a-hydroxy-3 ß-pentyl-5 a-pregnan-11,20-dione 20,20-ethylenedioxy-3 a-hydroxy-3 ß-pentyl-5 a-pregnan-11-one (F 106 ° C, [a] D + 62 °) was prepared in a similar manner to the corresponding 3β-ethyl compound of Example 2 using a 22% solution of butyllithium in hexane instead of a 2m methyl lithium solution in ether. Acid hydrolysis as described in Example 2 followed by recrystallization from ether / petroleum ether gave 0.14 g of the title compound.

F = 102 ° C, [a] D + 109 °.

Example 4

3 a-Hydroxy-3 ß-methyl-5 a-pregnan-20-one This material was made from 3 g of 5 a-Pregnan-3,20-dione-20-ketal via the 3 (R) -20,20-ethylenedioxy -5 ° -pregnan-3-spiro-oxirane and the 20,20-ethylenedioxy-3 ß-methyl-5 a-pregnan-3a-ol (F 139 ° C) in a similar manner to that in Example 1 for the preparation of the 3a-Hydroxy-3 ß-methyl-5 a-pregnan-11,20-dions prepared manner described. The title compound (0.6 g) was obtained in the form of white needles.

F = 189 ° C, [a] D + 103 °.

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B

Claims (11)

616 691 2. The method according to claim 1, characterized in that compounds of formula I are prepared in which R4 and R5 together represent an oxo group, R6 is a hydrogen atom and R7 is a methyl group. 2nd PATENT CLAIMS 1. Process for the preparation of 3 β-substituted steroid compounds of the formula I c = o / in which mean: R2 is an alkyl group of 2 to 6 carbon atoms; R4 represents a hydrogen atom, a hydroxyl group or an epoxy group or carbon-carbon bond linked to the 9-position; R5 is a hydrogen atom when R4 is a hydrogen atom or an epoxy group or carbon-carbon bond linked to the 9-position; or an alkyl group having 1 to 6 carbon atoms or an allyl group when R4 is a hydroxy group; or R4 and R5 together are an oxo group when R7 is a methyl group; R6 represents a hydrogen or halogen atom or a methyl group; R6A is a hydrogen atom or, when R6 is a methyl group, a methyl group; R7 is a methyl group or an alkoxy group having 1 to 6 carbon atoms; and which optionally have a double bond in the 8 (9) position, characterized in that a corresponding compound which has a 3-spiro-oxirane group instead of the a-hydroxy group and the β-alkyl group in the 3-position, if appropriate with intermediate protection of the 20-0xo group, when R7 is a methyl group, with a metal alkyl compound having 1 to 5 carbon atoms. 3. The method according to claim 1, characterized in that the starting compound is reacted with lithium dimethyl cuprate. 4. Use of compounds of the formula I prepared by the process according to claim 1, which have an 11-hydroxy group, for the preparation of corresponding compounds in which R4 and R5 together represent an oxo group, characterized in that the 11-hydroxy compound is oxidized. 5. Use according to claim 4, characterized in that one carries out the oxidation by means of chromic acid in an aqueous organic solvent. 6. Process for the preparation of 3 β-substituted steroid compounds of the formula I. C = 0 R / HO in which mean: R2 is a methyl group; R4 represents a hydrogen atom, a hydroxyl group or an epoxy group or carbon-carbon bond linked to the 9-position; R5 is a hydrogen atom when R4 is a hydrogen atom or an epoxy group or carbon-carbon bond linked to the 9-position; or an alkyl group having 1 to 6 carbon atoms or an allyl group when R4 is a hydroxy group; or R4 and R5 together are an oxo group when R7 is a methyl group; R6 represents a hydrogen or halogen atom or a methyl group; R6A is a hydrogen atom or, when R6 is a methyl group, a methyl group; R7 is a methyl group or an alkoxy group having 1 to 6 carbon atoms; and which optionally have a double bond in the 8 (9) position, characterized in that a corresponding compound of the formula I which, instead of the a-hydroxy group and the β-methyl group, has a 3-spiro-oxirane group in the 3-position has, optionally with intermediate protection of the 20-0xo group, if R7 is a methyl group, with a complex metal hydride. 7. The method according to claim 6, characterized in that compounds of formula I are prepared in which R4 and R5 together represent an oxo group, R6 is a hydrogen atom and R7 is a methyl group. 8. The method according to claim 6, characterized in that one produces 3a-hydroxy-3ß-methyl-5a-pregnan-ll, 20-dione. 9. The method according to claim 6, characterized in that the starting compound is reacted with lithium aluminum hydride. 10. Use of compounds of the formula I which have an 11-hydroxy group and are prepared by the process according to claim 6 for the preparation of corresponding compounds in which R4 and R5 together represent an oxo group, characterized in that the 11-hydroxy compound is oxidized. 11. Use according to claim 10, characterized in that one carries out the oxidation by means of chromic acid in an aqueous organic solvent.