DD238801A5 - PROCESS FOR PRODUCING NEW EPOXYSTEROIDS - Google Patents

Abstract

7a-Acylthio-9a, 11a-epoxy-20-spirox-4-ene-3,21-diones of the formula I wherein R is a lower alkanoyl and AA is the ethylene or cyclopropylene group have a high aldosterone antagonizing activity without significant sexual-specific side effects and are useful as potassium-sparing diuretics in the therapy of various forms of hyperaldosteronism. The compounds are available according to conventional methods of steroid chemistry.

Description

-2- 233 801

Field of application of the invention

The invention relates to a process for the preparation of novel epoxysteroids having valuable pharmacological properties, in particular aldosterone antagonizing and diuretic action.

The compounds according to the invention are used as medicaments, in particular for the treatment of diseases associated with disturbed mineral-water balance.

Characteristic of the known technical solutions Epoxysterodes are already known. As steroids with aldosterone antagonizing action, especially 20-spiroxane

Derivatives estimated, cf. z. B. Fieser and Fieser: Steroids; Page 708 (Reinhold Pu bl Corp., New York, 1359) and GB-PSNo. No. 1,041,543, including primarily spironolactone (7a-acetyl-thio-20-spirox-4-ene-3,21-dione generally introduced in therapy, see Merck Index, 10th Ed., 8610, page 1254; Merck and Co. Rahway, NJ, USA; 1983. However, all therapeutic agents used heretofore have a considerable disadvantage in that they always have some sexually-specific activity, which sooner or later will interfere with conventional long-term therapy - especially undesirable are disorders that are due to the antiandrogenic activity of the known antialdoneone preparations.

Object of the invention

The aim of the invention is the provision of new Epoxisteroiden which do not have the disadvantages of the known steroids.

Explanation of the essence of the invention

The Erfndung the task is based on finding new Epoxysteroide with the desired properties and a method for their preparation.

According to the invention new steroid compounds with the backbone of 20-spiroxane, namely lactones of the type

the formula

(X)

wherein R is a lower alkanoyl and -A-A- is the ethylene or cyclopropylene group and pharmaceutical compositions containing them; The compounds and compositions find therapeutic use

Warm-blooded animals, especially in humans. The compounds according to the invention are characterized by favorable biological properties. In particular

exhibit a strong aldosterone antagonizing effect by reducing the excessive levels of aldosterone

Minimize sodium retention and potassium excretion. That is why they are important as potassium-sparing diuretics Application in the treatment of diseases associated with disturbed mineral water balance, z. B. in the Treatment of heart failure, arrhythmia due to potassium deficiency, corpulmonary, liver cirrhosis, ascites Prophylaxis, diabetes mellitus and hypertension. By bioassay in dose range of about 5-50 mg / kg it was found that by introducing the 9a, 11a Epoxy group can be obtained in the molecule of spiro) olactone compounds of formula I characterized above, which

Surprisingly, they possess the full aldosterone antagonizing effect of the parent compound, without the undesirable effects

Side effect on the sex hormone balance. Thus, e.g. das7a-acetylthio-9a, 11a-epoxy-20-Spirox-4-ene

3,21-dione has an analogous strong aldosterone ^L antagonizing effect like spironolactone (peroral in Kagawa test mitaldrenalectomized male rats), whereas an anti-androgenic effect does not result in significantly increased doses in either

Experimental arrangement could be detected. In the symbol R of the above characterized Formula I, the lower alkanoyl group derives from one in steroid chemistry

customary, in particular a straight, alkanoic acid with 1-4 C atoms, especially of acetic acid.

The cyclopropylene radical as the symbol -A-A- is preferably oriented, i. which forms 15β, 16β-methylene group. Unless otherwise indicated, the term "lower", as used in the context of the definition of a A compound or a substituent, to a compound or a substituent containing not more than

4 carbon atoms.

Preferred compounds of the formula I are, for example, 7a-acetyl-thio-9a, 11a-epoxy-20-spirox-4-ene-3,21-dione, and the like

15SS, 16fl-methyl analog.

6.7-un _g . "9a., La- _E pox" -V "bi" du ", the form.l

H ₃ C ·· I

/ f γ V

"Orin -A-A- has the abovementioned meaning to which" double bond attaches a lower alkynoic acid R-SH (III), worm R has the abovementioned meaning, or

b) a corresponding 9 (1-D-unsaturated compound of the formula IV

S / v

IJ j A

/ VVvr

wherein R and -A-A-, which have the meaning given above, epoxidized the 9 (11) double bond.

The addition according to process variant a) takes place in a manner known per se: it is preferable to heat the relevant 6,7-dehydro compound (II) with a small excess of the thiocarboxylic acid (lower alkanethioic acid) of the formula (III), if appropriate under ultraviolet light irradiation and / or Acid catalysis (for example in the presence of an organic sulfonic acid, such as an aromatic sulfonic acid of the p-toluene or benzenesulfonic acid type) in a solvent, in particular a lower alkanol, preferably methanol. Although the reaction proceeds even at room temperature or slightly above it, temperatures of about 50 ⁰ C to 80 ° C are preferred; Accordingly, it is advantageous in the case of lower boiling solvent, for. B. in particular of the methanol to implement at the boiling point; the reaction temperature should not exceed about 90-100 ⁰ C. The necessary reaction times can last up to a few hours, but should be kept to a minimum for optimal results. Notably, it is reacted under an inert gas such as nitrogen or argon. In a typical process, the product formed crystallizes directly from the reaction mixture after cooling, optionally after prior addition of water and / or evaporation of excess solvent; if desired, the product can also be in the usual manner, for. B. by chromatography, isolated or purified. Due to the addition under these conditions, the desired 7a isomer predominantly arises.

The occurrence, and in particular the favorable result of the process described above, is completely surprising since it is to be expected that the sensitive epoxy ring is attacked by the acidity of the thiocarboxylic acid to be used as the reagent.

The 9a, 11a-epoxy-20-spiroxa ^: 4,6-diene-3,21-dione used as starting material is known, cf. J. Med. Chem. 6,732-735 (1963), the analogous starting materials with the methylene group in 15,16-position are accessible by analogy known per se. The starting materials of the formula III are known or accessible in a known manner. The compounds of the formula I according to the invention can also be obtained according to process variant b) by reacting in a corresponding 9 (11! -Unsaturated compound, ie a 7a-acylthio-20-spiroxa-4,9 (11) -diene-3,21 -dione of the above-defined formula IV, the 9 (11 (double bond epoxidized, i

The epoxidation of the 9 (11 (double bond) takes place in a manner known per se by treating the starting material of the formula IV with a peroxidic oxidizing agent, such as hydrogen peroxide, preferably in the presence of a nitrile, for example trichloroacetonitrile, or in particular with a peroxyacid, preferably an organic peroxyacid, for example an aliphatic peroxyacid, such as performic acid or peracetic acid, or preferably an aromatic peroxyacid. Of the latter, it is advantageous to use perbenzoic acid or a substituted perbenzoic acid, such as m-chloroperbenzoic acid, p-nitroperbenzoic acid or monoperoxyphthalic acid (perphthalic acid The reaction is carried out primarily in an inert organic solvent, for example in an alkane, such as pentane, hexane or heptane, a halogenated lower alkane, in particular methyl chloride, chloroform or 1,2-dichloroethane, or an open-chain or cyclic Et in particular diethyl ether, dioxane or tetrahydrofuran, or a suitable mixture thereof. The reaction temperature should not normally exceed one in which the spontaneous decomposition of the reactant is faster than the epoxidation reaction, especially the reaction is carried belZimmertemperatur or, preferably, below that up to about -20 ⁰ C, in particular between -10 ⁰ C to +10 ⁰ C.

Starting materials of the formula IV, if they are not known, can be prepared by analogous methods known per se, for. B. analogously to the above-described addition of a lower alkanethioic acid to 20-spiroxa-4,6,9 (11) -triene-3,21-dione, which in turn is known, cf. J. Med. Chem. 6,732-735 (1963), or in the case of a 15,16-methylene compound in a conventional manner accessible.

The pharmaceutical preparations of the present invention containing a compound of the formula I can be used in particular for the treatment of hyperaldosteronism of various forms. They contain an effective amount of the active ingredient alone or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients and, if desired, with other pharmacologically or therapeutically valuable substances, and are particularly suitable for enteral, z. As oral or rectal, or for parenteral administration.

Without a more specific specification, the term "active substance" throughout the text below to understand a compound of formula I, as defined above.

The present invention relates in particular to pharmaceutical compositions containing as active ingredient at least one compound of the formula I according to the invention in the form of a sterile and / or isotonic aqueous solution, or in admixture with at least one solid or semisolid carrier.

The present invention also relates to medicaments, and in particular medicaments in the form of dosage units which contain at least one of the compounds according to the invention, alone or in admixture with one or more excipients, in particular those in solid form.

In particular, the invention relates to medicaments in the form of tablets (including lozenges, granules and lozenges), dragees, capsules, pills, ampoules, dry vials or suppositories containing the above defined active ingredient alone or in admixture with one or more excipients.

As a particular form of these pharmaceutical compositions and pharmaceutical compositions according to the invention are also those which, in addition to an aldosterone antagonizing compound of the formula I according to the invention (which is referred to in this context as component A), nor a nonspecific with respect to electrolytes diuretic component B. ,

As such, with respect to non-specific diuretic component B electrolyte excretion, conventional "classical" diuretics or mixtures thereof are contemplated which increase diuresis by renal as well as extrarenal action on tissue, particularly those having inhibitory effect on reabsorption in the tubule. A detailed list of suitable diuretics of this type is found, for example, in US Patent 4,261,985, particularly suitable as the eggtrolyte non-specific component B are benzothiadiazine derivatives such as thiazides and hydrothiazides, furthermore benzenesulfonamides, phenoxyacetic acid Benzofuran-2-carboxylic acids, and 2,3-dihydrobenzofuran-2-carboxylic acids The electrolyte-nonspecific component B may consist of a single active substance or a suitable combination of several active substances, wherein the active substances may also belong to more than one of the mentioned substance groups beso In addition, the following conventional diuretics are considered as component B: 1-oxo-3- (3-sulfamyl-4-chlorophenyl) -3-hydroxyisoindoline, e-chloro-T-sulfamyl-S 1 -dihydro-1-hydroxybenzene benzothiadiazine-i-dioxide, S-cyclopentyimethyl-e-chloro-y-sulfamyl-S-dihydro-1'-benzothiadiazine-ii-dioxide, 4- (2-methylenebutyryl) -2,3-dichlorophenoxyacetic acid, 4-thenoyl-2, 3-dichloro-phenoxyacetic acid, (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid, 2-chloro-4-furfurylamino-5-carboxybenzene-sulfonamide, 2-phenoxy 3-Butylamino-5-carboxybenzenesulfonamide and 2-phenoxy-3- [3- (1-pyrrolyl) -propyl] -5-carboxybenzenesulfonamide.

In such pharmaceutical compositions and pharmaceutical compositions of the invention, the ratio of the component azure component B, based on the respective mean effective dose, is about 4: 1 to about 1: 4, preferably about 3: 2 to about 2: 3. Since the mean effective dose of each specific component is a known value or easily detectable by known pharmacological test methods, it will be readily apparent to those skilled in the art within the limits set forth above, a suitable ratio of both components to each patient according to their specific ailment, general health, individual responsiveness, and age , as well as its gender, to prescribe. For example, such combination preparations per dose unit contain 15 to 150 mg, in particular 20 to 100 mg of a compound of the formula I as component A and, as component B, for example 10-100 mg, in particular 25-50 mg of 2-chloro-5- [3-hydroxy-1 -oxo-isoindolyl- (3)] - benzenesulfonamide or 4- (2-methylene-butyryl) -2,3-dichlorophenoxyacetic acid, 5-50mg, especially 12-25mg of e-chloro-T-sulfamyl-S-dihydric triazobenzothiadiazine-IJ -dioxide or 2-chloro-4-furfurylamino-5-carboxybenzenesulfonamide, 2-20 mg, in particular 5-10 mg of 2-phenoxy-3- [3- (1-pyrrolyl) -propyl] -5-carboxybenzenesulfonamide, 0.1-1, 0mg, in particular 0.25-0.5 mg of S-cyclopentylmethyl-δ-chloro-y-sulfamyl-S ^ -dihydro-i ^^ - benzothiadiazine-iji-dioxide or 2-phenoxy-3-butylamino-5-carboxybenzolfonamide, 100- 400mg, especially 200mg4-thenoyl-2,3-dichlorophenoxyacetic acid and 5-25mg, especially 10mg of racemic (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid, or half an amount the laevo form of this acid.

For the treatment of edema in a moderately severe case, for example, 1-3 doses are taken daily containing the active ingredients in amounts by weight which are at the higher limit of the above-mentioned particularly preferred dosage; a moderate case of essential hypertension is z. B. treated with 1-3 dose units whose active ingredient content is at the lower most preferred quantity limit.

The term "drug" is used to refer to individual discrete portions of uniform composition suitable for medical administration The term "drug in the form of dosage units" is used throughout this specification to refer to individual discrete portions of uniform composition which are known for use in the art are suitable for medical administration and each containing a specific amount of the erfinduhgsgemäßen active ingredient, which corresponds to about 0.05 to about 2, preferably about 0.1 to about 1 daily dose. !

The excipients for use in the pharmaceutical compositions (e.g., granules) for the preparation of tablets, dragees, capsules and pills are e.g. the following:

a) diluent, e.g. Starch, sugars (such as lactose, glucose and sucrose), mannitol, sorbitol and silicic acid,

b) binders, e.g. Carboxymethylcellulose and other cellulose derivatives, alginic acid and its salts (such as sodium alginate), gelatin, and polyvinylpyrrolidone,

c) moisture regulators, e.g. Glycerol, "" ~

d) disintegrants, e.g. Agar-agar, calcium carbonate and sodium bicarbonate,

e) retarding agents for slowing up ingestion of the active ingredient, e.g. Paraffin,

f) accelerator of absorption, z. B. quaternary ammonium compounds,

g) surface-active agents, e.g. Cetyl alcohol and glycerol monostearate, h) adsorbents, e.g. Kaolin and bentonite,

i) flow regulators and lubricants, e.g. Talc, calcium stearate, magnesium stearate and solid polyethylene glycols. These and similar excipients may also serve several of the above purposes.

The tablets, dragees, capsules and pills containing the abovementioned pharmaceutical compositions according to the invention can be provided with the usual coatings and sheath materials to which, if desired, dyes or pigments, for. B. for identification or identification purposes, be admixed. These coatings may also have such a composition which allows a slow release of the active ingredient; for this purpose are z. As waxes and cellulose preparations, such as acetyl cellulose phthalate, or hydroxypropylmethyl cellulose phthalate suitable. These compositions can also be processed into the form of the microcapsules.

The pharmaceutical compositions of the invention preferably contain from about 0.1 to about 99.5, more preferably from about 1 to about 90% by weight of the active ingredient.

The recommended daily dose of the active ingredient of formula I for a 75kg warm-blooded animal is about 30-300mg, preferably 50-150mg, but may well exceed these limits depending on species, age and individual responsiveness both down and up.

The preparation of the abovementioned pharmaceutical compositions, preparations, medicaments and medicaments in the form of dosage units according to the invention is carried out by means of conventional production methods known per se in the pharmaceutical industry, e.g. by means of customary mixing, granulating, tabletting, coating, dissolving and lyophilization processes, if desired working under aseptic conditions or sterilizing an intermediate product or a finished product.

The present invention also relates to the use of the compounds of the formula I for the control of various forms of hyperaldosteroism in humans and other warm-blooded animals, as well as a corresponding therapeutic method which comprises administering an effective dose of at least one of the active compounds according to the invention alone or together with one or more Carriers or in a drug form is characterized. The active compounds according to the invention are enterally, z. B. rectally or especially orally, or parenterally, such as in particular administered intravenously. A particular implementation of the present invention healing method is characterized in that the inventive compound of formula I as the aldosterone antagonizing steroid component A, and with respect to the electrolyte excretion nonspecific diuretic component (component B) simultaneously or together, in particular in the form of corresponding pharmaceutical composition or a drug.

Ausführungsbeispiei

The invention is explained in more detail below with reference to some examples.

In the following examples, which further illustrate the invention without limiting it, the temperatures are Celsius degrees indicated. All melting points are uncorrected.

Example 1: A solution of 6.5 g of 9a, 11a-epoxy-20-spiroxa-4,6-diene-3,2-dione in 275 ml of methanol and 11 ml of thioacetic acid is refluxed under argon for 3.5 hours About Ve concentrated by distilling off the solvent at atmospheric pressure, and cooled. The reaction product, which crystallized from the mixture, is filtered off with suction, and the residue obtained by concentration of the mother liquor is chromatographed on silica gel. Elution with a mixture of hexane-acetone (3: 1 (gives a further uniform portion of the desired product.) The resulting 7a-acetylthio-9a, 11a-epoxy-20-spirox-4-ene-3,21-dione becomes Methylene chloride-methanol crystallized, mp 224 (sintering) 242 ^° C. (decomposition).

An alternative isolation of the end product can be carried out as follows: The reaction mixture obtained by the above-described method is diluted while still hot with 10 ml of water and concentrated under argon at atmospheric pressure until 190 ml of distillate are collected processed as described above. j

In an analogous manner, the thioacetic acid can be replaced by thiopropionic or thiobutyric acid and the following compounds can be obtained: i

a) 7a-propionylthio-9a, 11a-epoxy-20-spirox-4-ene-3,21-dione (amorphous), respectively

b) 7a-Butyrylthio-9a, 11a-epoxy-20-spirox-4-ene-3,21-dione (amorphous).

Example 2: In an analogous manner as described in Example 1, 9α, 11α-γροχγ-15β, 16β-methylene-20-spiroxa-4,6-diene-3,21-dione is reacted with thioacetic acid in methanol and according to alternative b ) processed, thus 7a-acetylthio-9a, 11a-epoxy-15SS, 16ss-methylene-20-Spirox-4-ene-3,21-dione, mp. 268 ⁰ C (sintering) .292 ° C (decomposition) is obtained. The starting 9a, 11a-epoxy-15β, 16β-methylene-20-spiroxa-4,6-diene-3,21-dione can be prepared as follows:

a) A solution of 20 g of 17a, 20, 20,21-bismethylenedioxypregn-5-en-3β, 11β-diol in 150 ml of pyridine and 150 g of acetic anhydride is refluxed for 1 hour. The cooled reaction solution is poured onto 3 000 g ice flakes with stirring and stirred until thawing. The precipitate is filtered off with suction and dried in air; the crude 3β, 11β-diacetoxy-17a, 20; 20,21-bis-methylenedioxy-pregn-5-ene widened / worked up without purification.

b) 20.3 g of air-dried 3,11-diacetate is under external cooling with ice water with stirring in portions in 71 ml of a

The solution is introduced by passing, at about OX, of 141 g of gaseous hydrogen fluoride-a solution consisting of

100 ml of isopropyl alcohol, 48 g of urea and 9.6 ml of water are prepared in advance.

The reaction mixture is stirred under ice-water cooling for 1 hour, poured cautiously into an ice-cold solution of 142 g of sodium sulfite in 1015 ml of water and stirred for 20 minutes. The mixture is extracted with ethyl acetate and washed successively with saturated sodium chloride solution, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again with dilute sodium chloride solution, dried and evaporated in a water-jet vacuum. The residue is chromatographed on a 100-fold amount by weight of silica gel. Elution with a mixture of methylene chloride-acetone (95: 5) gives uniform fractions which, after once recrystallizing from methylene chloride-methanol-ether 3β, 11β-diacetoxy-17α, 21-dihydroxypregn-5-en-20-one of melting point ! 231 ° -233 ° C.

c) A solution of 13.8 g of the latter compound in 207 ml of dioxane is mixed with 69 g of finely divided manganese dioxide and boiled for 3 hours at reflux. After cooling to room temperature, the solid portion is removed by suction filtration and washed well with chloroform. The filtrate is evaporated, dissolved in methylene chloride and filtered through a 10-fold weight amount of neutral alumina. By evaporation of the solvent crystalline 3ß, 11 ß-diacetoxyandrost-5-en-17-one is obtained, which melts after a single recrystallization from methylene chloride-petroleum ether at 177 ⁰ C-179 ⁰ C.

d) A mixture of 7.5 g of 3β, 11β-diacetoxy-androst-5-en-17-one and 150 mg of p-toluenesulfonic acid in 450 ml of benzene and 7.5 ml of ethylene glycol is refluxed for 16 hours on the water separator. After cooling, the solution is diluted with ethyl acetate and washed immediately with 225 ml of ice-cold saturated sodium chloride solution. The organic phase, after drying in a water-jet vacuum, is evaporated and the oily 3β, 11β-diacetoxy-17,17-ethylenedioxy-androst-5-ene used for the next step without purification.

e) To a stirred suspension of 2.35 g of lithium aluminum hydride in 95 ml of tetrahydrofuran at the internal temperature of 5 ° -10 ⁰ C, a solution of 4.7 g of βß, 11ß-diacetoxy-17,17-ethylenedioxy-androst-5-ene in 140 ml of tetrahydrofuran was added dropwise, rinsed with 9rnl tetrahydrofuran, and the mixture was refluxed for 12 hours. The reaction mixture is at an internal temperature of max. 5 ° C by careful dropwise addition of a mixture of 9 ml of tetrahydrofuran and 14 ml of ethyl acetate and then a mixture of 9 ml of tetrahydrofuran and 14ml of water and decomposed after addition of 70 g of anhydrous sodium sulfate for 30 minutes without cooling. Solid portions are removed by suction filtration through a kieselguhr layer (washing with tetrahydrofuran), and the filtrate is concentrated in a water-jet vacuum. The amorphous residue is chromatographed on a 50-fold amount by weight of silica gel. Elution with a mixture of methylene chloride-acetone (93: 7) and evaporation of the solvent is uniform 17,17-ethylenedioxy-androst-5-en-3.beta. obtained 11.beta.-diol which after one reprecipitation from fvlethylenchlorid ether at 123 ⁰ C-125 ° C melts.

f) To a solution of 16.8 g of 17,17-ethylenedioxy-androst-5-en-3β, 11β-diol in 102 ml of tetrahydrofuran is added 36.3 g of pyridine hydrobromide perbromide and stirred at room temperature for 2½ hours. The mixture is mixed with 2S, 9g sodium iodide, stirred for a further 30 minutes, successively treated with a solution of 36.3 g of sodium thiosulfate in 50.4 ml of water and with 100 ml of pyridine and stirred again at room temperature for 2 hours. The reaction mixture is diluted with 100 ml of water and concentrated in a water-jet vacuum at about 45 ⁰ C. The residue is taken up in ethyl acetate and washed successively with saturated brine, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again with saturated sodium chloride solution and dried over sodium sulfate. By distilling off the solvents in a water-jet vacuum results in an amorphous residue of crude 16a-bromo-17,17-ethylenedioxy-a ndrost-5-en-3ß, 11ß-diol. The crude product obtained (13g) is dissolved in 143 ml of dimethyl sulfoxide, in the course of 30 minutes at 45 ⁰ C with stirring with a mixture of 7g potassium tert-butoxide in 13ml dimethyl sulfoxide and stirred for 20 hours at 5O ⁰ C (bath temperature). The mixture is cooled to room temperature, diluted with about 1300 ml of a saturated ammonium chloride solution and taken up in ethyl acetate; The organic phase is washed three times with a saturated saline solution and dried over sodium sulfate. By distilling off the solvents in a water-jet vacuum amorphous 17,17-ethylenedioxy-androsta-5,15-diene-3ß, 11ß-diol is obtained, the purity of which is sufficient for further processing.

g) A solution of 800 mg of 17,17-ethylenedioxy-androsta-5,15-diene-3β, 11β-diol in 40 ml of acetone is treated with 4 ml of a solution of 100 mg of p-toluenesulfonic acid in 10 ml of water and stirred for 6 hours at room temperature. After dilution with 40 ml of water, the acetone is distilled off in a water-jet vacuum, the oily residue is taken up in chloroform and washed with ice-cold saturated sodium bicarbonate solution. After evaporation of the organic solvents, amorphous 3β, 11β-dihydroxyandrosta-5,16-dien-17-one is obtained, which can be used without further purification for the next step.

h) Dimethylsulfoxide (64 ml) under nitrogen atmosphere with 1.52 g of 55-60% sodium hydride (as a mineral oil suspension) and 7.57 g Trimethylsulfoxoniumjodid added and first for 30 minutes at room temperature and then for a further 30 minutes at an outside temperature of 34 ° C-40 ° C stirred. The mixture, cooled to room temperature, is added with 8 g of 3β, 11β-dihydroxyandrosta-5,15-dien-17-one and rinsed with 26 ml of dimethyl sulfoxide. The reaction mixture is stirred at room temperature for 3 hours, poured into 1 liter of ice cold saturated brine, rinsed with a little methyl alcohol and water, acidified with dilute hydrochloric acid and stirred for 30 minutes. The deposited oil is taken up in ethyl acetate and the organic phase washed successively with saturated brine, ice-cold dilute sodium hydroxide solution and again with saturated brine. After drying, the solvents are evaporated in a water jet vacuum and the resulting amorphous 3β, 11β-dihydroxy-15β, 16β-methylene-androst-5-en-17-one is subjected to subsequent acetylation without purification.

i) A solution of 7.9 g of 3β, 11β-dihydroxy-15β, 16β-methylene-androst-5-en-17-one in 39.5 ml of pyridine and 39.5 ml of acetic anhydride is allowed to stand at room temperature for 5 hours, with 800 ml of ice water diluted and extracted after standing for one hour with ethyl acetate. The organic phase is washed successively with saturated brine, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again with saturated brine, dried and concentrated in a water-jet vacuum. Chromatography of the crude product on a 30 weight percent silica gel and elution with a mixture of methylene chloride-acetone (98: 2) gives 3β-acetoxy-11β-hydroxy-15β, 16β-methylene-androst-5-en-17-one , which after a single redissolution of methylene chloride-ether petroleum ether at

209 ° C-211 ° C melts. _ _

j) A solution of 1.75 g of S, S-acetoxy-Hβ-hydroxy-ISβ-β-methylsandrost-S-en-n-one in 10.5 mL of dimethylformamide and 3.5 mL of γ-collidine is treated with 2.6 mL of a 5 weight solution. % Sulfur dioxide in methanesulfonyl chloride and stirred for 20 minutes, while allowing the internal temperature to rise to about 45 ⁰ C. The mixture together with the precipitate precipitated is poured into 17.5 ml of ice water with stirring and stirred for a further 10 minutes. The precipitated oil is taken up in ethyl acetate and washed successively with saturated brine, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again with saturated brine. After evaporation of the solvent results thin-layer chromatography uniform 3ß-acetoxy-15ß, 16ß-methylene-androsta-5,9 (11) dien-17-one, which is further processed without purification.

k) A solution of 5.2 g of 3β-acetoxy-15β, 16β-methylene-androsta-5,9 (11) -dien-17-one in 127.5 ml of tetrahydrofuran is added under ice-water cooling with 1.78 g of lithium wire (pieces of approx. 5 mm length) and then within 10 minutes with a solution of 12.75 ml of cyclic ethylene acetal of the ß-chloropropionaldehyde [2- {3-chloropropyl) -1,3-dioxolane] in 12.75 ml tetrahydrofuran added dropwise and then for one hour under ice cooling and Stirred for 16 hours at room temperature. The reaction mixture is mixed with 330 ml of ethyl acetate and stirred for 45 minutes, diluted with more ethyl acetate, washed successively with saturated brine, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again with saturated brine, dried and concentrated in a water-jet vacuum. The oily crude product is dissolved in a mixture of toluene-ethyl acetate (90:10) and filtered through a 10-fold amount by weight of silica gel. The filtrate provides after evaporation of the solvent 4.84g amorphous substance. This is dissolved in 363 ml of chloroform, mixed with 242g of acidic alumina (activity level 1) and stirred for 2V2 hours at reflux temperature, diluted with a further 363 ml of chloroform and stirred for a further 5 minutes and cooled. The mixture is sucked on diatomaceous earth, washed the filter cake with chloroform, and the filtrate concentrated in a water-jet vacuum. The resulting crude 21-carbaldehyde (4g) is dissolved in 20rnl methylene chloride and 80 ml of acetone, at 5 ⁰ C for 5 minutes with 8 ml of an SN-ChromlVIJ-sulfuric acid solution and stirred for 45 minutes under ice cooling. The mixture is diluted with 80 ml of ice-cold water, stirred for 10 minutes without cooling and extracted with methylene chloride. The organic phase is washed with ice-cold saturated sodium bicarbonate solution and dried. By distilling off the solvent! In a water-jet vacuum gives crystalline crude product, which is filtered in a solution in methylene chloride through a 5-fold weight of neutral alumina. By distilling off the solvent from the main fraction, crystals are obtained which, after once recrystallizing from methylene chloride-ether, the 3β-acetoxy-15β, 16β-methylene-20-spiroxa-5,9 (11) -diene-21-one of mp 241 ° C-243 ° C deliver.

1) To a suspension of 1.9 g of β-acetoxy-15β, 16β-methyl-20-spiroxa-5,9 (11) -dien-21-one in 26.8 ml of chloroform and 190 ml of methyl alcohol, 19 ml of a 1N sodium hydroxide solution added. The mixture is stirred for 1 hour at room temperature, diluted with 190 ml of water and extracted with a portion each of chloroform and a mixture of chloroform-iVlethanoi (90:10). The combined organic phases are concentrated after drying in a water jet vacuum and the crystalline crude product is recrystallized once from methylene chloride-ether-petroleum ether. The resulting 3β-hydroxy-15β, 16β-methylene-20-spiroxa-5,9 (11) -diene-21-one melts at 244 ° C-246 ° C.

m) From a suspension of 400 mg of 3β-hydroxy-15β, 16β-methylene-20-spiroxa-5,9 (11) -dien-21-one in 20 ml of toluene and 3 ml of cyclohexanone, 4 ml of solvent are distilled off under atmospheric pressure. It is cooled to an internal temperature of about 8O ⁰ C, mixed with 480 mg of aluminum isopropoxide and stirred for two hours under reflux. The solution is cooled to room temperature, treated with a solution of 0.4 ml of acetic acid in 0.8 ml of toluene and evaporated four times with 5 ml of water in a water jet vacuum to dryness. The oily residue is taken up in chloroform, washed successively with ice-cold dilute hydrochloric acid, water, ice-cold sodium hydroxide solution and water again, the organic phase dried and evaporated in a water-jet vacuum. The amorphous crude product is applied to a 50-fold amount by weight of silica gel and with a mixture of methylene chloride-acetone (98: 2) chromatographies. The obtained 15SS, 16ss-methylene-20-spiroxa-4,9 (11) -diene-3,21-dione melts after one reprecipitation from methylene chloride-ether-petroleum ether at 172 ° C-174 ⁰ C.

option A

An) A solution of 3.27 g of 15β, 16β-methylene-20-spiroxa-4,9 (11) -diene-3,21-dione in 16.35 ml of dioxane and 6.54 ml of trimethyl orthoformate is added with 0.654 ml of a solution of 900 mg p-Toluenesulfonic acid in 10 ml of dioxane and 2 ml of ethyl alcohol, stirred for 4 hours at room temperature, poured into 430 ml of an ice-cold 0.2 N sodium hydroxide solution with stirring and stirred intensively for 15 minutes. The precipitate is filtered off with suction, washed with water and dried on a suction filter. The crude 3-ethoxy-15β, 16β-methylene-20-spiroxa-3,5,9 (11) -triene-21-one obtained is dissolved in 105 ml of acetone and washed successively with a solution of 1.13 g of sodium acetate (trihydrate). in 8.84 ml of water and, with cooling to -5 ° C, treated with 1.55 g of N-bromoacetamide and 1.13 ml of acetic acid. The mixture is stirred for 30 minutes at an internal temperature of about -3 ° C and then for 15 minutes without cooling, with a solution of 0.88 g of potassium iodide in 17.7 ml of water and a solution of 5.58 g of sodium thiosulfate in 17.7 ml of water added successively, stirred for a further 5 minutes and diluted with 88 ml of water. The mixture is extracted with chloroform and the organic phase is washed with ice-cold saturated sodium bicarbonate solution. By drying and concentrating the organic phase, the amorphous residue is obtained, which is dissolved in 78 ml of dimethylformamide, mixed with 3.89 g of lithium carbonate and 3.89 g of lithium bromide and stirred for 3 hours at 1Ö0 ° C. The cooled mixture is poured with stirring into 750 ml of ice water, and the precipitate is filtered off with suction and washed with water. The filter cake is dissolved in chloroform, dried with sodium sulfate and evaporated to dryness in a water-jet vacuum. The solution of the resulting residue in methylene chloride is filtered through a column of neutral alumina (Activity II) and eluted with further portions of the same solvent. The eluates are concentrated and the desired 15β, 16β-methylene-20-spiroxa-4,6,9 (11) -triene-3,21-dione is precipitated in amorphous form by the addition of ether. The product is uniform according to thin-layer chromatography and suitable for further processing.

Ao) A solution of 100 mg, 15β, 16β-methylene-20-spiroxa-4,6,9 (11) -triene-3,21-dione in 2 ml of methylene chloride is treated with 75 mg of 90% m-chloroperbenzoic acid and 18 Hours at about 4 ° C and then left for 3 hours at room temperature. After dilution with methylene chloride, the mixture is washed successively with 10% potassium iodide solution, 10% Natritimthiosalfattösurtg7e chalter saturated sodium bicarbonate solution and water, dried and evaporated in a water-jet vacuum. The amorphous crude product is chromatographed on a silica gel column. Elution with a mixture of hexane-ethyl acetate (3: 2) gives the desired 9a, 11a-epoxy-15β, 16β-methylene-20-spiroxa-4,6-diene-3,21-dione, mp 258 ° C (sintering) -276 ° C (decomposition).

Variant B

Bn) To a solution of 415 mg of 15β, 16β-methylene-20-spiroxa-4 _/ 9 (11) -diene-3,21-dione in 8 ml of methylene chloride is added 400 mg of m-chloroperbenzoic acid and stirred at room temperature for 80 minutes. The reaction mixture is worked up analogously to process stage Ao and the crude product is chromatographed on a silica gel column. By elution with hexane-ethyl acetate (1: 1, V / V) gives the chromatographically uniform 9a, 11a-epoxy-15ß, 16ß-methylene-20-spirox-4-en-3,21-dione, which after crystallization from Methylene chloride diisopropyl ether at 264 ° C-266 ° C melts.

Bo) A solution of 310 mg of the latter compound in 0.2 ml of methylene chloride and 2.1 ml of a 0.2N solution of dry hydrogen chloride gas in dioxane is added with 230 mg of 2,3-dichloro-5,6-dicyanobenzoquinone and 45 Stirred minutes at room temperature. The reaction mixture is filtered through neutral alumina and the adsorbent washed with methylene chloride. After distilling off the solvent results in the desired 9a, 11a-epoxy-15ß, 16ßmethylen-20-spiroxa-4,6-diene-3,21-dione, which is identical to the product of variant A and after redissolving from methylene chloride diisopropyl ether at 254 ⁰ C (sintering) -275 ° C (decomposition) melts.

Example 3: A solution of 414 mg of 7a-acetylthio-20-spiroxa-4,9 (11) -diene-3,21-dione and 320 mg of m-chloroperbenzoic acid in 10 ml of dichloromethane is allowed to stand for 16 hours at 5 ° C. After dilution with a mixture of dichloromethane-ether (1: 3), the reaction solution is washed successively with water, a dilute aqueous potassium iodide solution, a dilute aqueous sodium thiosulfate solution, and again with water, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (60 g). After a forerun, containing the unreacted starting material, followed by hexane-ethyl acetate (2: 1) fractions whose usual work-up (see Example 1) the desired Ta-acetylthio-SaJia-epoxy ^ O-spirox ^ -en-S ^ I-dione, identical to the product of Example 1, gives.

Example 4: Tablets containing about 50mg of active ingredient, e.g. 7a-acetylthio-9a, 11a-epoxy-20-spirox-4-ene-3,21-dione, are prepared as follows:

Composition for 1000 tablets

Active ingredient, finely ground 50.0 g

Powdered sugar (sucrose) 79.0 g

Arabian gum 4.75 g

Sorbitol 3.75 g

Taik 2,5g

Magnesium stearate 4.9 g

Mineral oil 0.1 g

Carboxymethylcellulose (Na salt) 5.0 g

150.0g production

The active ingredient is mixed with the powdered sugar and the arabic gum, sieved and granulated by means of an approximately 35% aqueous sorbitol solution. The granules are driven through a sieve, dried, sieved again and intimately mixed with the other excipients (talc, magnesium stearate, mineral oil and carboxymethylcellulose sodium salt). The mixture is compressed in the usual way to tablets of 150 mg.

Example 5: Dragees containing approximately 50 mg of active ingredient (eg 7a-acetylthio-9a, 11a-epoxy-15β, 16β-methylene-20-spirox-4-ene-3,21-dione from Example 2) are prepared as follows: Composition a dragee core

Active ingredient, micronized 50.0 mg corn starch 90.0 mg Tricalcium phosphate 100.0 mg Polyvinylpyrrolidone K25 15.0 mg magnesium stearate 2.0 mg sodium 33.0 mg

290.0 mg Preparation of 50000 coated cores The mixture of 2.5 kg of active ingredient, micronized, 4.5 kg of corn starch and 5 kg of tricalcium phosphate is granulated in a fluidized bed solution containing 0.75 kg of polyvinylpyrrolidone K25 in 5 kg of distilled water. The dried at 45 ° C and pressed through a sieve of 1 mm mesh size granules 0.1 kg of magnesium stearate and 1.65 kg Natriumcarboxymethylstärke be mixed and pressed into curved tablets ä 290 mg.

Production of 6.6 kg sugar dragees

6kg of the dragee kernels are weighed into a 45 cm diameter coating pan with a sugar syrup (2 parts sugar and 1 part by weight distilled water) in which 1.5% polyvinylpyrrolidone K25 and 1% polyethylene glycol 6000 are dissolved and 20% talc suspended of 360 mg portionwise coated, in between is dried with hot air of about 60 ⁰ C. Then sugar syrup (2 parts sugar and 1 part water) is applied in portions up to the final weight of 400 mg. The dragees are finally shined with a solution of 2% carnauba wax in trichlorethylene.

Example 6: Soft gelatin capsules containing 50 mg of active ingredient (see Example 4 or 5) are obtained as follows: Composition of a soft gelatin capsule

Active substance, micronized 50.0 mg

-Sojateeithin 1> 5mg

Beeswax 2.5 mg

Vegetable oil 110.0 mg

Plants oil, partially hydrogenated 54.0 mg

218.0 mg

Preparation of 100,000 soft gelatine capsules

5.0 kg of active ingredient, micronized, are suspended in a melt-made mixture of 0.15 kg of soybean lecithin, 0.25 kg of beeswax, 5.4 kg of partially hydrogenated vegetable oil and 11 kg of vegetable oil and brought into gelatin capsules after the punching process. The gelatin shell consists of approx. 71% gelatin, approx. 28% glycerol (85%) and approx. 1% titanium dioxide, as well as 0.3% p-hydroxybenzoic acid propyl ester. The capsule size is 4 minims (shape oblong).

Example 7: Filmdragees containing 100 mg of active ingredient (see Example 4 or 5) are prepared as follows: Composition of a film-seed core Drug micronized 100.0 mg

Polyethylene glycol 6000 52.0 mg

Colloidal silica 5.0 mg

Stearic acid 3.0 mg

160.0 mg

Production of 10000 cores

1.0 kg of active ingredient, micronized, is mixed with a melt of 0.52 kg of polyethylene glycol (prepared with the addition of 0.05 kg of colloidal silica [specific surface 200rrr / g]) and, after cooling, forced through a sieve of 1 mm mesh width , The granules 0.03kg powdered, in advance sieved stearic acid are added and pressed into weakly curved tablets 160mg

Production of 30,000 film dragees

4.8 kg kernels are in a coating pan of 45cm diameter with a solution of hydroxypropylmethylcellulose (viscosity 6cP, 2% solution in water) in distilled water suspended in eggs 2% talc continuously sprayed at warm air supply of 35 ⁰ C to each Core 5 mg varnish is present. '

Step Example! 8: Tablets containing about 50% component A and about 25% component B are prepared as follows:

Composition of a tablet

Component A, micronized 50.0 mg

Component B, micronized 25.0 mg

Cornstarch 50.0 mg

Silica, colloidal 5.0 mg

Gelatin 5.0 mg

Cellulose microcrystalline 75.0 mg

Sodium carboxymethyl starch 20.0 mg

Magnesium stearate 1.5 mg

231.5 mg production of 100000 tablets

5kg component A, micronized 2.5kg component B, micronized, and 5.0 kg of corn starch are Mito, mixed 5kg colloidal silica and a solution of 0.5 kg of gelatin in 5.0 kg of distilled water (3O ⁰ C) processed a moist mass. This is driven through a sieve of 3 mm mesh size and dried at 45 ⁰ C (fluidized bed dryer). The dry granules are forced through a 0.8mm mesh screen, mixed with a pre-screened mixture of 7.5kg microcrystalline cellulose and 2.0kg sodium carboxymethyl starch and 0.15kg magnesium stearate, and compressed into tablets weighing 231.5mg.

As component A, e.g. 7a-acetylthio-9a, 11a-epoxy-20-spirox-4-ene-3,21-dione, as component B 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1 , 1-dioxide used.

In an analogous manner, the following active compounds can also be used as component B in the corresponding quantities: 2-chloro-5- (3-hydroxy-1-oxo-isoindolyl-3) -benzenesulfonamide or 4- (2-methylenebutyryl) -2,3 dichlorophenoxyacetic acid (50 mg each), e-chloro-3-sulfamyl-S 1 -dihydro-1-benzo-benzothiadiazine-1-dioxide (25 mg), 2-phenoxy-3-butylamino-5-carboxybenzenesulfonamide (0, 5 mg), (1-oxo-2-methyl-2-phenyl-6,7-dichloro-indanyl-5-oxy) -acetic acid (as racemate 20 mg, as the laevo form 10 mg) or S-cyclopentylmethyl-e-chloro ^ -sulfamyl-S ^ -dihydro-i ^^ - benzothiadiazine-iji-dioxide (0.5 mg).

Example 9: Soft gelatin capsules containing 50 mg of Component A and 12.5 mg of Component B are obtained as follows:

Composition of a soft gelatin capsule

Component A, micronized 50.0 mg

Component B, micronized 12.5 mg

Soy lecithin 1.5 mg

Beeswax 2.5 mg

Vegetable oil 100.0 mg

Vegetable oil, partially hydrogenated 54.0 mg

220.5 mg - -

Preparation of 100,000 soft gelatine capsules

6.25 kg of a uniform mixture of components A and B in the weight ratio 4: 1, micronized, are processed in the manner described in Example 5 with the same amounts of the support materials.

As component A, the steroid active ingredient indicated in Example 8 is used as component B e-chloro-sulfamyl-SA-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

In an analogous manner, it is also possible to use the following active ingredients as components in the appropriate quantities:

S-cyclopentylmethyl-e-chloro -sulfamyl-S-dihydro-i ^^ benzothiadiazine-ii-dioxide (0.25 mg), 4-thienyl-2,3-dichlorophenoxyacetic acid (125 mg), 2-chloro-5- (3-hydroxy-1-oxo-isoindolyl-3) -benzenesulfonamide (25 mg) or 2-chloro-4-furfurylamino-5-carboxybenzenesulfonamide (15 mg).

Example 10: Film dragees containing 100 mg of component A and 10 mg of component B are prepared as follows: Composition of a film-seed core

Component A, micronized 100.0 mg

Component B, micronized 10.0 mg

Polyethylene glycol 6000 52.0 mg

Colloidal silica 5.0 mg

Stearic acid 3.0 mg

170.0 mg Production of 10000 cores

1.1 kg of a uniform mixture of components A and B in a weight ratio of 10: 1, micronized, with a melt of 0.52 kg of polyethylene glycol (prepared with the addition of 0.05 kg of colloidal silica [specific surface area 200 m ² / g] ) and pressed after cooling through a sieve of 1 mm iVlaschenbreite. The granules 0.03 kg of powdered, previously sieved stearic acid are added and compressed to slightly curved tablets ä 170 mg.

Production of 30,000 film dragees 5.1 kg of cores are continuously poured in a coiler of 45 cm diameter with a solution of hydroxypropylmethylcellulose (viscosity 5 cP, 2% solution in water) in distilled water in which 2% talc suspended under hot air of 35 ⁰ C sprayed until there is 5rng of paint on each core.

As component A is a steroid active ingredient according to Example 8, used as component B 2-phenoxy-3- [3- (1-pyrroly!) - propyl] -5-carboxybenzolsulfonamid.

In an analogous manner, it is also possible to use the following active compounds as component B in the corresponding quantities:

e-Chloro-sulfamyl-S-dihydro-i-benzothiadiazine-i-dioxide (25 mg), 2-chloro-5- (3-hydroxy-1-oxo-isoindolyl-3 -) - benzenesulfonamide (50 mg ), 4- (2-methylbutyryl) -2,3-dichlorophenoxyacetic acid (50mg), 2-chloro-4-furfurylamino-5-carboxybenzenesulfonamide (20mg), 2-phenoxy-4-butylamino-5-carboxy-benzenesulfonamide (0, 5mg) or 3-cyclopentylmethyl-6-chloro -sulfamyl-S ^ -dihydro-i ^^ - benzothiadiazine-i ^ -dioxide (0.5mg).

Example 11: dragees containing 40 mg 7a-acetylthio-9a, 11a-epoxy-20-spirox-4-ene-3,21-dione as component A and 10 mg e-chloro-J-suifamyl-S-dihydro-1H Abenzothiadiazine IJ dioxide as component B.

Composition of a dragee

Component A 40 mg

Lactose 160 mg

Stearyl alcohol 77 mg

Polyvinylpyrrolidone 20 mg

Magnesium stearate 3 mg

300 mg protective lacquer Case:

6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-10 mg

benzothiadiazine 1,1-dioxide

Sugar, talc, dye, 190 mg

Binder q. s. ad

500 mg production

The steroid component and milk sugar are granulated with the stearyl alcohol melt and a concentrated polyvinylpyrrolidone solution and dried. The mass obtained is sieved and pressed into compacts of 300 mg weight. These are coated with a protective lacquer layer and then coated with colored sugar syrup in which the diuretic component B is dissolved, to a final weight of about 500 mg.

Example 12: Gelatin capsules containing about 50 mg of 7a-acetylthio-9a, 11a-epoxy-20-spirox-4-ene-3,21-dione as component A and 125 mg of 4-thenoxy-2,3-dichlorophenoxyacetic acid as component B. prepared as follows:

Composition of a dry capsule

Component A 50.0 mg

4-thenoyl-2,3-dichlorophenoxyacetic acid 125.0 mg

Lactose 124.0 mg

Magnesium stearate 1.0 mg

"350, umg" ~ ~ ~ ~

Production of 10 000 dry capsules

0.50 kg of 7α-acetylthio-9α, 11α-epoxy-20-spirox-4-ene-3,21-dione, finely ground, is intimately mixed with 1.25 kg of 4-thenoyl-2,3-dichlorophenoxyacetic acid and after Need still grated; To this mixture is added 1.24 kg micronized lactose and 0.01 kg magnesium stearate through a sieve, and homogenized. The powder is sieved and bottled dry in portions of 350 mg each in gelatine capsules.

Claims (4)

Invention claim: wherein R is a lower alkanoyl and -A-A- is the ethylene or cyclopropylene group and optionally its pharmaceutical composition, characterized in that a) in a corresponding 6,7-unsaturated 9a, 11a-epoxy compound of the formula (H) wherein -A-A- has the abovementioned meaning, to the 6,7-double bond, a lower alkanethioic acid R-SH (HI), wherein R has the meaning given above, attached, or b) a corresponding 9 (11) -unsaturated compound of the formula CiL Civ) S-R in which R and -AA- have the abovementioned meaning, the 9 (11 (double bond epoxidized and optionally the compounds prepared by this process and, if desired, additionally a non-specific for electrolysis diuretic component B with at least one pharmaceutically acceptable carrier material by a non-chemical means processed into a pharmaceutical composition. 2. The method according to item 1, characterized in that one prepares a compound of formula I, wherein R is acetyl. "3." Process according to item T, characterized in that 7a-acetylthio-9a, 11 a-epoxy-20-spirox-4-ene-3,21-dione are prepared. 4. The method according to item 1, characterized in that one prepares 7a-acetylthio-9a, 11a-epoxy-15ß, 16ß-methylene-20-spirox-4-en-3,21-dione.