JPH0212480B2 - - Google Patents

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides a novel steroid compound having the basic structure of 20-spirooxane, namely, the general formula (): [In the formula, R represents a lower alkanoyl group, -A-
A- represents ethylene group or cyclopropylene group] 7α-acylthio-9α, 11α-epoxy-20
-Relating to spirooxy-4-ene-3,21-dione type lactone. The invention further relates to processes for the preparation of said compounds, pharmaceutical compositions containing said compounds and processes for their preparation, and therapeutic uses of said compounds and compositions in warm-blooded animals, especially humans.

The compounds according to the invention are distinguished by favorable biological properties. They exhibit potent aldosterone-antagonistic effects, particularly by reducing excess sodium retention and potassium excretion caused by aldosterone. Therefore, these compounds are useful as potassium-sparing diuretics in the treatment of diseases caused by electrolyte imbalance, such as heart failure, arrhythmia caused by potassium deficiency, cor pulmonale, liver cirrhosis, prevention of ascites, diabetes, and hypertension. It has important therapeutic uses.

[Prior art]

As steroids having an aldosterone antagonistic effect, in particular 20-spirooxane derivatives [for example, Fieser and Fieser: Steroids; p. 708 {Reinhold Publishing Corporation (Reinhold Publishing Corporation)
Publ. Corp., New York, 1959} and British Patent No. 1041534], in particular spironolactone (7α-acetylthio-20-spirooxy-4-ene-3,21-dione), which was commonly used in the treatment. Merck index, No.
10th edition, 8610; 1254 pages; Merck and Co., Rahway, New Jersey, USA.
Co.); 1983] is useful. However, all conventionally used therapeutic agents of this type have a significant drawback in that they always have sex-specific effects that sooner or later become a hindrance in normal long-term treatment. In this case, disorders due to the antiandrogenic effects of known antialdosterone preparations are particularly undesirable.

[Structure and effects of the invention]

As a result of biological testing in the dosage range of approximately 5 to 50 mg/Kg, spironolactone contains 9α and 11α in the molecule.
- It has been found that by introducing an epoxy group, a compound of the general formula () can be obtained which surprisingly has a complete aldosterone antagonistic effect of the basic compound and has no undesirable side effects on sex hormone balance. For example, 7α-acetylthio-9α,11α-epoxy-20-spirooxet-4-ene-3,21-dione has a strong aldosterone antagonistic effect similar to spironolactone (in the Kagawa test using adrenally removed male rats). (oral administration), but no anti-androgen effects were observed in any of the test procedures, even at significantly higher doses.

In the symbol R in the above general formula (), the lower alkanoyl group is derived from a particularly straight-chain C1-C4 alkanoic acid commonly used in steroid chemistry, especially acetic acid.

A cyclopropylene group with the symbol -AA- is preferably in the β-configuration, ie forms a 15β,16β-methylene group.

The term "lower" used in connection with the definition of a compound or substituent, unless otherwise specified, relates to a compound or substituent containing four or fewer carbon atoms.

Preferred compounds of general formula () are, for example, 7α
-Acetylthio-9α,11α-epoxy-20-spirooxe-4-ene-3,21-dione and bisono
It is a 15β, 16β-methylene analog.

The compounds of general formula () mentioned at the beginning can be produced by analogous methods known per se, for example as follows: a General formula (): General formula (): R-SH () [ In the formula, R represents the above-mentioned lower alkanethioic acid], or b General formula (): The 9(11)-double bond of the corresponding 9(11)-unsaturated compound of [in the formula, R and -A-A- represent the above] is epoxidized.

The addition reaction according to method a is carried out in a manner known per se. For example, a 6,7-dehydro compound of the general formula () in a small excess of the general formula () in a solvent, especially a lower alkanol, preferably methanol.
thiocarboxylic acids (lower alkanethioic acids), optionally with UV irradiation and/or using acid catalysts (e.g. organic sulfonic acids, e.g. p
- in the presence of an aromatic sulfonic acid of the toluenesulfonic acid or benzenesulfonic acid type). The reaction proceeds at room temperature or slightly above, with temperatures of about 50<0>C to about 80<0>C being preferred. Therefore, in the case of low-boiling solvents, such as especially methanol, it is advantageous to carry out the reaction at boiling temperature. The reaction temperature should not exceed about 90-100°C. The required reaction time may extend to several hours, but should be kept to a minimum for optimal results. It is particularly preferred to carry out the reaction under an inert gas, such as nitrogen or argon. Typical methods include cooling, optionally adding water beforehand and/or
Alternatively, the product formed is crystallized directly from the reaction mixture after evaporation of excess solvent. However, the product can optionally also be isolated or purified in conventional manner, for example by chromatography. The addition reaction under these conditions primarily yields the desired 7α-isomer.

The achievement of the process and the particularly favorable results are quite surprising since the unstable epoxy ring is expected to be affected by the acidity of the thiocarboxylic acid used as reagent.

9α, 11α-epoxy used as starting material
20-Spiroxa-4,6-diene-3,21-dione is known (J. Med. Chem. 6, pp. 732-735 (1963)
(2003)], and similar starting materials having methylene groups at the 15- and 16-positions can be obtained by similar methods known per se. Is the starting material of general formula () also known?
Or obtained by a known method.

The compounds of the general formula () according to the invention are the corresponding 9(11)-unsaturated compounds, i.e. the above-mentioned general formula ()
7α-acylthio-20-spirooxer-4,9
It can also be obtained by method b by epoxidizing the 9(11)-double bond in the (11)-diene-3,21-dione.

Epoxidation of the 9(11)-double bond is carried out in a manner known per se by reacting a starting material of the general formula () with a peroxide-based oxidizing agent, for example hydrogen peroxide, preferably in the presence of a nitrile, for example trichloroacetonitrile. or by treatment with a peroxyacid, preferably an organic peroxyacid, for example an aliphatic peroxyacid, such as especially performic acid or peracetic acid, or preferably an aromatic peroxyacid. Among the aromatic peroxyacids, preference is given to using perbenzoic acid or substituted perbenzoic acids, such as m-chloroperbenzoic acid, p-nitrobenzoic acid or monoperoxyphthalic acid (perphthalic acid). The reaction is preferably carried out in inert organic solvents, such as alkanes, such as pentane, hexane or heptane, halogenated lower alkanes, such as especially methylene chloride, chloroform or 1,2-dichloroethane, or open-chain or cyclic ethers, such as especially diethyl ether, dioxane or tetrahydrofuran. or in a suitable mixture thereof. The reaction temperature should generally not exceed the temperature at which spontaneous decomposition of the reaction reagents proceeds faster than the epoxidation reaction, in particular room temperature or preferably from about -20°C to room temperature, especially from -10°C to +10°C.
Operate at °C.

If the starting material of general formula () is not known,
Similar methods known per se, e.g. 20-spirooxer
Similarly to the above addition of a lower alkanethioic acid to 4,6,9(11)-triene-3,21-dione [known per se, see J. Med. Chem. 6 Ring, pp. 732-735 (1963)]. In the case of a 15,16-methylene compound, it can be obtained by a method known per se.

Pharmaceutical formulations of the invention containing compounds of general formula () can be used in particular for the treatment of various types of hyperaldosteronism. These contain an effective amount of the active ingredient alone or in admixture with pharmaceutically acceptable inorganic or organic solid or liquid excipients and optionally other pharmaceutically or therapeutically useful substances, in particular Suitable for intraintestinal administration, eg oral or rectal administration, or parenteral administration.

Unless otherwise specified, the concept of "active ingredient" as used in the following description shall mean a compound of the general formula () as defined at the beginning.

The present invention particularly provides the use of at least one compound of the present invention of the general formula () as an active ingredient in a sterilized and/or
or in the form of an isotonic aqueous solution or as a mixture with at least one solid or semi-solid excipient.

The present invention further provides for the use of medicaments, particularly at least one compound of the present invention, alone or in one or more excipients.
In particular, it relates to a medicament in the form of a dosage unit containing admixtures with excipients in solid form.

The invention particularly relates to tablets (including troches, granules and soft lozenges), sugar-coated tablets, capsules,
It relates to a medicament containing the active ingredient alone or in admixture with one or more excipients, in the form of pills, ampoules, dry vials or suppositories.

A special form of the pharmaceutical compositions and medicaments of the present invention includes, in addition to the aldosterone-antagonist compounds of the general formula () according to the present invention (designated component A in this connection), in addition to Examples include those containing diuretic component B.

Such diuretic components B, which are non-specific with respect to the excretion of electrolytes, include conventional "classical" diuretics or mixtures thereof, which improve diuresis by renal and extrarenal effects on tissues, especially in the renal tubules. Suitable substances include substances that have an inhibitory effect on reabsorption in the body, such as salt diuretics or ethacrynic acid and its analogues. A detailed review of suitable diuretics of this type can be found at
For example, it is described in US Pat. No. 4,261,985. Particularly suitable as electrolyte non-specific component B are benzothiadiazine derivatives, such as thiazides and hydrothiazides, as well as benzenesulfonic acid amide, phenoxyacetic acid, benzofuran-2
-carboxylic acid and 2,3-dihydrobenzofuran-2-carboxylic acid. Electrolyte non-specific component B
may consist of only one active ingredient or of an advantageous combination of several active ingredients, in which case the active ingredient may be one or more of the aforementioned groups of substances. As component B, the following conventional diuretics are particularly relevant: 1-oxo-3-(3-sulfamyl-4-
chlorophenyl)-3-hydroxyisoindoline, 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1
-Dioxide, 3-cyclopentylmethyl-6-
Chloro-7-sulfamyl-3,4-dihydro-
1,2,4-Benzothiadiazine 1,1-dioxide, 4-(2-methylenebutyryl)-2,3-
Dichlorophenoxyacetic acid, 4-thenoyl-2,3
-dichlorophenoxyacetic acid, (1-oxo-2-
Methyl-2-phenyl-6,7-dichloro-5-
indanyloxy)-acetic acid, 2-chloro-4-furfurylamino-5-carboxybenzenesulfonamide, 2-phenoxy-3-butylamino-
5-carboxybenzenesulfonamide and 2-
Phenoxy-3-[3-(1-pyrrolyl)-propyl]-5-carboxybenzenesulfonamide.

In such pharmaceutical compositions and medicaments according to the invention, the ratio of component A:component B for the respective average effective dose is from about 4:1 to about 1:4, preferably from about 3:2 to about 2: It is 3. Since the average effective dosage of a particular ingredient is known or can be easily ascertained by known pharmacological testing methods, appropriate proportions of both ingredients within the above ranges may be administered to each patient for that particular purpose. It is readily possible for those skilled in the art to prescribe according to the symptoms, general state of health, individual responsiveness and age as well as their gender.

For example, this type of complex preparation may contain, per dosage unit,
15 to 150 mg of the compound of general formula () as component A,
Especially 20-100 mg and 2-chloro-5 as component B.
-[3-hydroxy-1-oxo-isoindol-3-yl]-benzenesulfonamide or 4-(2-methylenebutyryl)-2,3-dichlorophenoxyacetic acid 10 to 100 mg, especially 25 to 50 mg,
6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide or 2-chloro-4-furfurylamino-5-carboxybenzenesulfonamide 5
~50mg, especially 12-25mg, 2-phenoxy-3-
[3-(1-pyrrolyl)-propyl]-5-carboxybenzenesulfonamide 2 to 20 mg, especially 5
~10mg, 3-cyclopentylmethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,
2,4-Benzothiadiazine 1,1-dioxide or 2-phenoxy-3-butylamino-5
-Carboxybenzenesulfonamide 0.1-1.0
mg, especially 0.25-0.5 mg, 4-thenoyl-2,3-
Dichlorophenoxyacetic acid 100-400mg, especially 200mg,
and racemic (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid from 5 to 25 mg, especially 10 mg, or half the amount of the levorotatory form of this acid.

To treat edema in cases of moderate severity, dosage units containing the active ingredient in weights falling within the upper limits of the preferred dosages mentioned above are administered, for example, from 1 to 3 times a day. Moderate cases of essential hypertension are treated, for example, with 1 to 3 dosage units whose active ingredient content is within the lower limits of the amounts mentioned as particularly preferred.

The term "drug" is used to refer to aliquoted portions of a homogeneous composition suitable for drug administration.
The term "medicament in the form of a dosage unit" is used herein to mean a medicament suitable for pharmaceutical administration, each containing a specified amount of the active ingredient according to the invention (from about 0.05 to about 2, preferably from about 0.1 to about 1. used to refer to aliquoted portions of a homogeneous composition containing (equivalent to a daily dose).

Excipients used in pharmaceutical compositions (e.g. granules) for the production of tablets, dragees, capsules and pills are, for example: a diluents, e.g. starch, sugars (e.g. lactose, glucose and sucrose); ), mannite, sorbitol and silica, b binders such as carboxymethyl cellulose and other cellulose derivatives, alginic acid and its salts (e.g. sodium alginate), gelatin and polyvinylpyrrolidone, c wetting agents such as glycerin, d disintegrants such as agar, calcium carbonate and sodium bicarbonate; e. a retardant to slow the absorption of the active ingredient;
f absorption enhancers, such as quaternary ammonium compounds, g surfactants, such as cetyl alcohol and glycerin monostearate, h adsorbents, such as kaolin and bentonite, i flow regulators and lubricants, such as talc, Calcium stearate, magnesium stearate and solid polyethylene glycol.

These and similar excipients or auxiliaries can also be used for several of the purposes mentioned above.

The tablets, dragees, capsules and pills containing the above-mentioned pharmaceutical compositions according to the invention can be provided with customary coatings and coating materials and optionally dyes or pigments, for example for identification or identification purposes. Can be added. This coating may have a composition that makes it possible to delay the release of the active ingredient. For this purpose, for example, waxes and cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate are suitable.

The composition can also be administered in the form of microcapsules.

Pharmaceutical compositions according to the invention preferably contain from about 0.1 to about 99.5% by weight, especially from about 1 to about 90% by weight of the active ingredient.
include.

The recommended daily dose of the active ingredient of the general formula () for a warm-blooded animal weighing 75 kg is approximately 30-300
mg, preferably 50-150 mg. However, this may be significantly above or below this range depending on the species, age and individual responsiveness.

The above-mentioned pharmaceutical compositions, formulations, medicaments and medicaments in the form of dosage units according to the invention can be prepared by conventional manufacturing methods known per se in the pharmaceutical industry, such as conventional mixing, granulation, tabletting, dragee-coating, dissolving and freezing. They are produced by drying methods, optionally operating under aseptic conditions or sterilizing the intermediate or finished product.

The invention further provides the use of compounds of general formula () for the treatment of various types of hyperaldosteronism in humans and other warm-blooded animals and the use of an effective amount of at least one active ingredient alone or in combination. The present invention relates to a therapeutic method characterized in that it is administered together with more than one excipient or in the form of a drug. In this case, the active ingredient according to the invention is administered either enterally, for example rectally or especially orally, or parenterally, for example intravenously. A special implementation of the method of treatment according to the invention is that aldosterone antagonist steroids -
It is contemplated that the compound of the general formula () according to the invention as component A and the diuretic component non-specific with respect to electrolyte excretion (component B) may be administered separately simultaneously or in admixture, in particular in the form of a corresponding pharmaceutical composition or medicament. Features.

Next, the present invention will be explained in detail based on examples.
The present invention is not limited to this. Temperatures are given in degrees Celsius. Melting points are not corrected.

(Example) Example 1 9α in 275 ml of methanol and 11 ml of thioacetic acid,
A solution of 6.5 g of 11α-epoxy-20-spirooxer-4,6-diene-3,21-dione was boiled under reflux for 3.5 hours under argon gas, and the solvent was evaporated at atmospheric pressure to give a solution of about 1/2. Concentrate to 3 and cool. The reaction product which has 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) yields a more homogeneous desired product. The obtained 7α-acetylthio-9α,11α-epoxy-20-spiroox-4-ene-3,21-dione was mixed with methylene chloride/
Crystallize from methanol. Melting point 224℃ (sintered)
~242℃ (decomposition).

Alternative methods of isolating the substance of interest can also be carried out as described below. The fully reacted reaction mixture obtained in the above manner is diluted while still hot with 10 ml of water and concentrated under argon at atmospheric pressure until a distillate of 190 ml is obtained. The product which crystallizes out after cooling is treated in the manner described above.

In a similar manner, replacing thioacetic acid with thiopropionic acid or thiobutyric acid, the following compounds can be obtained: a 7α-propionylthio-9α,11α-epoxy-20-spiroox-4-ene-3,21-dione (amorphous) or b 7α-butyrylthio-9α,11α-epoxy-20
- Spirooxe-4-ene-3,21-dione (amorphous).

Example 2 In the same manner as described in Example 1, 9α, 11α-
Epoxy-15β,16β-methylene-20-spirooxa-4,6-diene-3,21-diene was reacted with thioacetic acid in methanol and further treated according to method b, melting point 268°C (sintered) to 292°C. (disassembly)
7α-acetylthio-9α, 11α-epoxy-15β,
16β-methylene-20-spirooxe-4-ene-
3,21-dione is obtained.

9α, 11α-epoxy used as starting material
15β, 16β-methylene-20-spirooxer-4,
6-Diene-3,21-diene can be prepared by the following method: a. in 150 ml of pyridine and 150 g of acetic anhydride.
A solution of 20 g of 17α,20;20,21-bismethylenedioxypregn-5-ene-3β,11β-diol is heated under reflux for 1 hour. Pour the cooled reaction solution onto 3000 g of ice cubes while stirring, and stir further until the ice melts. Aspirate the precipitate and dry with air. Crude 3β,11β-diacetoxy-
The 17α,20;20,21-bis-methylenedioxypregn-5-ene is further processed without purification.

b. 20.3 g of air-dried 3,11-diacetate was added in small portions with stirring while externally cooling with ice water to 100 ml of isopropyl alcohol, 48 g of urea and water.
71 ml of a solution previously prepared by introducing 141 g of gaseous hydrogen fluoride into a solution consisting of 9.6 ml at approximately 0°C are added.

The reaction mixture is stirred for 1 hour while cooling with ice water, poured carefully 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, washed successively with saturated sodium chloride solution, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again dilute sodium chloride solution, dried and concentrated by evaporation under a water jet vacuum. The residue is chromatographed on 100 times the weight of silica gel. Elution with a methylene chloride-acetone (95:5) mixture gives a homogeneous fraction which, once dissolved and recrystallized from methylene chloride/methanol/ether, has a melting point of 231-233°C. 3β, 11β―
Diacetoxy-17α,21-dihydroxypregn-5-en-20-one is obtained.

c The compound just mentioned in 207 ml of dioxane
Finely powdered manganese dioxide69 in 13.8g solution
g and boil under reflux for 3 hours. After cooling to room temperature, remove solids by suction filtration and wash thoroughly with chloroform. Concentrate the liquid by evaporation,
Dissolve in methylene chloride and filter through 10 times the weight of neutral aluminum oxide. When the solvent evaporates,
Crystal 3β,11β-diacetoxyandrost-5
-en-17-one is obtained, which melts at 177-179°C after one recrystallization from methylene chloride/petroleum ether.

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

e To a stirred suspension of 2.35 g of lithium aluminum hydride in 95 ml of tetrahydrofuran, add 5 to 10
3β in 140 ml of tetrahydrofuran at an internal temperature of °C,
A solution of 4.7 g of 11β-diacetoxy-17,17-ethylenedioxyandrost-5-ene is added dropwise, washed with 9 ml of tetrahydrofuran and the mixture is boiled under reflux for 12 hours. The reaction mixture is decomposed at an internal temperature of up to 5° C. by carefully dropwise addition of a mixture of 9 ml of tetrahydrofuran and 14 ml of ethyl acetate and subsequently of a mixture of 9 ml of tetrahydrofuran and 14 ml of water, and after addition of 70 g of anhydrous sodium sulfate. , the mixture is stirred for an additional 30 minutes without cooling. The solids are removed by suction filtration over diatomaceous earth (washing with tetrahydrofuran) and the liquid is concentrated under a water jet vacuum. The amorphous residue is chromatographed on 50 times its weight of silica gel. A homogeneous 17,17-ethylenedioxyandrost-5-ene-3β,11β was obtained by elution with a mixture of methylene chloride/acetone (93:7) and evaporation of the solvent.
-diol is obtained which, after one dissolution and recrystallization from methylene chloride/ether, is 123
Melts at ~125°C.

f 17,17-ethylenedioxy-androst-5-ene-3β in 102 ml of tetrahydrofuran,
36.3 g of pyridine hydropromide perbromide are added to a solution of 16.8 g of 11β-diol and the whole is stirred at room temperature for 11/2 hours. Add 26.9 g of sodium iodide to the mixture and stir for an additional 30 minutes. water 50.4
A solution of 36.3 g of sodium thiosulfate in ml and 100 ml of pyridine are successively added to the mixture and stirred for a further 2 hours at room temperature. The reaction mixture is diluted with 100 ml of water and concentrated under water pump vacuum at about 45°C.
The residue is taken up in ethyl acetate and washed successively with saturated sodium chloride solution, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again saturated sodium chloride solution and dried over sodium sulfate. By distilling off the solvent in the vacuum of a water jet pump, crude
An amorphous residue of 16α-bromo-17,17-ethylenedioxyandrost-5-ene-3β,11β-diol is formed. The crude product obtained.

(13 g) was dissolved in 143 ml of dimethyl sulfoxide, and while stirring at 45°C for 30 minutes, potassium tert-
Add a mixture of 7 g of butoxide and add 50℃ (bath temperature).
Stir for 20 hours. The mixture is cooled to room temperature, diluted with approximately 1300 ml of saturated ammonium chloride solution and taken up in ethyl acetate. The organic phase is washed three times with saturated sodium chloride solution and dried over sodium sulfate. When the solvent is distilled off under the vacuum of a water jet pump,
Amorphous 17, 17 of a purity suitable for further processing.
Ethylenedioxyandroster-5,15-diene-3β,11β-diol is obtained.

g To a solution of 800 mg of 17,17-ethylenedioxyandroster-5,15-diene-3β,11β-diol in 40 ml of acetone was added 4 ml of a solution of 100 mg of p-toluenesulfonic acid in 10 ml of water, and the whole was stirred at room temperature. Stir for 6 hours. After dilution with 40 ml of water, the acetone is distilled off under a water jet vacuum, the oily residue is taken up in chloroform and washed with ice-cold saturated sodium bicarbonate solution. Evaporation of the organic solvent yields amorphous 3β,11β-dihydroxy-androster-5,15-dien-17-one,
This can be used in the next step without further purification.

h To dimethyl sulfoxide (64 ml) under a nitrogen atmosphere was added 1.52 g of 55-60% sodium hydride (as a suspension in mineral oil) and 7.57 g of trimethyl sulfoxonium iodide, and the whole was first incubated at room temperature for 30 min.
minutes, then stir for a further 30 minutes at an external temperature of 34-40°C. The mixture was cooled to room temperature and 3β,11β-dihydroxyandroster-5,15-diene-17
- Add 8g of dimethyl sulfoxide and 26g of dimethyl sulfoxide.
Wash with ml. The reaction mixture was stirred at room temperature for 3 hours, poured onto ice-cold saturated sodium chloride solution, washed with a small amount of methyl alcohol and water,
Acidify with dilute hydrochloric acid and stir for 30 minutes. The oil that precipitates out is taken up in ethyl acetate and the organic phase is washed successively with saturated sodium chloride solution, ice-cold dilute sodium hydroxide solution and again with saturated sodium chloride solution. After drying, the solvent is evaporated under the vacuum of a water jet pump,
The resulting amorphous 3β,11β-dihydroxy-15β,
16β-methylene androst-5-ene-17-
Continue acetylation without purification.

i in 39.5 ml of pyridine and 39.5 ml of acetic anhydride.
A solution of 7.9 g of 3β,11β-dihydroxy-15β,16β-methyleneandrost-5-en-17-one was left at room temperature for 5 hours, diluted with 800 ml of ice water,
After standing for 1 hour, extract with ethyl acetate. The organic phase is washed successively with saturated sodium chloride solution, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again saturated sodium chloride solution, dried and concentrated under a water jet vacuum. The crude product was chromatographed on 30 times the weight of silica gel and eluted with a mixture of methylene chloride/acetone (98:2) to give 3β-acetoxy-11β-hydroxy-15β,16β-methylene androst.
5-en-17-one is obtained, which melts at 209 DEG -211 DEG C. after one dissolution and recrystallization from methylene chloride/ether/petroleum ether.

j 3β-acetoxy-11β-hydroxy-15β,16β-methylene-androst-5- in 10.5 ml of dimethylformamide and 3.5 ml of γ-collidine.
A solution of 5% by weight sulfur dioxide in methanesulfonic acid chloride to a solution of 1.75 g of en-17-one 2.6
ml and stirred the whole thing for 20 minutes, at which time the internal temperature
Raise to 45°C. Pour the mixture along with the resulting precipitate onto 17.5 ml of ice water with stirring and add 10
Continue stirring for 1 minute. The precipitated oil is taken up in ethyl acetate and washed successively with saturated sodium chloride solution, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again with saturated sodium chloride solution. After evaporation of the solvent, a homogeneous 3β-
Acetoxy-15β,16β-methyleneandroster-5,9(11)-dien-17-one is formed, which is processed further without purification.

k 3β-acetoxy-15β,16β-methyleneandroster-5 in 127.5 ml of tetrahydrofuran,
Add a lithium wire (a small piece about 5 mm long) to a solution of 5.2 g of 9(11)-diene-17-one while cooling with ice water.
Add 1.78 g of cyclic ethylene acetal of β-chloropropionaldehyde [2-(3-chloropropyl)] in 12.75 ml of tetrahydrofuran.
-1,3-dioxolane] 12.75ml solution
Add dropwise over minutes and then stir the whole thing for 1 hour while cooling with ice and 16 hours at room temperature. Add 330 ml of ethyl acetate to the reaction mixture, stir for 45 minutes, dilute with ethyl acetate, wash successively with saturated sodium chloride solution, ice-cooled dilute hydrochloric acid, ice-cooled dilute sodium hydroxide solution, and again with saturated sodium chloride solution, and dry. , concentrate under water pump vacuum.
The oily crude product is dissolved in a mixture of toluene/ethyl acetate (90:10) and filtered through 10 times the weight of silica gel. After evaporation of the solvent from the liquid, 4.84 g of amorphous material is obtained. Dissolve this in 363ml of chloroform and add acidic aluminum oxide.

(Activation stage 1) Add 242g, 21/2 at reflux temperature
Stir for an hour, dilute with 363 ml of chloroform, stir for an additional 5 minutes, and cool. The mixture is filtered with suction over diatomaceous earth, the filter cake is washed with chloroform, and the liquid is concentrated under a water jet vacuum. The obtained crude 21-carbaldehyde (4 g) was mixed with 20 ml of methylene chloride and 80 ml of acetone.
8N chromium () dissolved in 5 minutes at 5℃
- Add 8 ml of sulfuric acid solution and stir for 45 minutes while cooling with ice. 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 under a water jet vacuum, a crystalline crude product is obtained, which is filtered as a solution in methylene chloride over 5 times the weight of neutral aluminum oxide. After dissolving and recrystallizing the crystals obtained by distilling off the solvent from the main fraction once from methylene chloride/ether, the melting point was 241.
3β-acetoxy-15β,16β-methylene-20-spirooxer-5,9(11)-diene-21 at ~243℃
- On occurs.

l Chloroform 26.6ml and methyl alcohol
3β-acetoxy-15β,16β-methylene-20-spirooxer-5,9(11)-diene-21 in 190ml
- Add 19 ml of 1N sodium hydroxide solution to a suspension of 1.9 g of . The mixture is stirred at room temperature for 1 hour, diluted with 190 ml of water and extracted once each with chloroform and a (90:10) mixture of chloroform and methanol. After drying, the combined organic phases are concentrated under a water jet vacuum and the crystalline crude product is recrystallized once from methylene chloride/ether/petroleum ether. The obtained 3β-hydroxy-15β,16β-methylene-20-spirooxa-5,9(11)-dien-21-one is 244-
Melts at 246°C.

m in 20 ml toluene and 3 ml cyclohexanone
3β-hydroxy-15β, 16β-methylene-20-
Spirooxer-5,9(11)-diene-21-one
From 400 mg of suspension, 4 ml of solvent is distilled off at normal pressure.
Cool to an internal temperature of about 80° C., add 480 mg of aluminum isopropoxide, and stir the whole under reflux for 2 hours. Cool the solution to room temperature and add toluene 0.8
A solution of 0.4 ml of acetic acid in ml is added and the whole is evaporated to dryness under a water pump vacuum four times with 5 ml of water each time. Take up the oily residue in chloroform and
Washed successively with ice-cold dilute hydrochloric acid, water, ice-cold sodium hydroxide solution and again with water, the organic phase is dried and evaporated under a water jet vacuum. The amorphous crude product is applied to 50 times the weight of silica gel and chromatographed with a mixture of methylene chloride/acetone (98:2). After one dissolution and recrystallization from methylene chloride/ether/petroleum ether, the resulting 15β,16β-methylene-20-spirooxer-4,9(11)-diene-3,21-dione was heated at 172-174°C. melt.

Method A: An 15β,16β-methylene-20 in 16.35 ml dioxane and 6.54 ml orthoformic acid trimethyl ester.
-Spiroxer-4,9(11)-Diene-3,21-
A solution of 3.27 g of dione in 10 ml of dioxane and 2 ml of ethyl alcohol was added to p-toluenesulfonic acid.
Mix with 0.654 ml of 900 mg solution and let the whole thing stand at room temperature for 4 hours.
Stir for an hour and ice-cold 0.2N sodium hydroxide solution.
Pour into 430ml with stirring and stir vigorously for 15 minutes. The precipitate is filtered off with suction, washed with water and dried on a suction rack. The resulting crude 3-ethoxy-15β,16β-methylene-20-spirooxa-3,5,9(11)-trien-21-one was dissolved in 105 ml of acetone and dissolved in sodium acetate (trihydrate) in 8.84 ml of water. ) 1.13 g of solution and treated sequentially with 1.55 g of N-bromoacetamide and 1.13 ml of acetic acid while cooling to -5°C. The mixture was stirred for 30 minutes at an internal temperature of about -3° C., then for a further 15 minutes without cooling, and 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 was prepared. are added successively and the mixture is stirred for a further 5 minutes and then 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. The amorphous residue obtained by drying and concentrating the organic phase was dissolved in 78 ml of dimethylformamide and 3.89 g of lithium carbonate was added.
Add 3.89g of lithium bromide and heat the whole to 100℃.
Stir for 3 hours. The mixture was cooled, poured onto 750 ml of ice water with stirring, and the precipitate was filtered off with suction.
Wash with water. The filter cake is dissolved in chloroform, dried over sodium sulfate and evaporated to dryness under a water jet vacuum. The resulting residue is dissolved in methylene chloride and passed through a column of neutral aluminum oxide (active), eluting with the same solvent. Concentration of the eluent and addition of ether yields the desired 15β,16β-methylene-20-spirooxer-4,6,9(11)-triene-3,21
-Zion precipitates in an amorphous form. The product is homogeneous by thin layer chromatography and suitable for further processing.

Ao 75 mg of 90% m-chloroperbenzoic acid in 2 ml of methylene chloride 15β,16β-methylene-20-spirooxer-4,6,9(11)-triene-3,21-
Add to a solution of 100 mg of dione and keep the whole at about 4°C.
Leave for 18 hours and then 3 hours at room temperature. After dilution with methylene chloride, the mixture is washed successively with 10% potassium iodide solution, 10% sodium thiosulfate solution, ice-cold saturated sodium bicarbonate solution and water, dried and concentrated by evaporation under a water pump vacuum. The crude amorphous product is chromatographed on a column of silica gel. When eluted with a mixture of hexane/ethyl acetate (3:2), mp 258
Desired 9α, 11α from ℃ (sintering) to 276℃ (decomposition)
-Epoxy-15β,16β-methylene-20-spirooxer-4,6-diene-3,21-dione is obtained.

Method B Bn 400 mg of m-chloroperbenzoic acid was dissolved in 15β,16β-methylene-20-spirooxa-4,6,(11)-diene-3,21-dione in 8 ml of methylene chloride.
415 mg of the solution is added and the whole is stirred at room temperature for 80 minutes. The reaction mixture is worked up analogously to step Ao and the crude product is chromatographed on a column of silica gel. When eluted with hexane/ethyl acetate (1:1, v/v), chromatographically homogeneous 9α,11α-epoxy-15β,16β-methylene-20-spirooxer
A 4-diene-3,21-dione is formed which, after crystallization from methylene chloride/diisopropyl ether, melts at 264-266°C.

Bo 230 mg of 2,3-dichloro-5,6-dicyanobenzoquinone are added to a solution of 310 mg of the last named compound in 0.2 ml of methylene chloride and 2.1 ml of a 0.2N solution of dry hydrogen chloride gas in dioxane,
The whole is stirred at room temperature for 45 minutes. The reaction mixture is filtered through neutral aluminum oxide and the adsorbent is washed with methylene chloride. After distilling off the solvent, the desired 9α,11α-epoxy-15β,16β-methylene-
20-spirooxer-4,6-diene-3,21-
The dione is obtained, which is identical to the product of method A, after dissolution and recrystallization from methylene chloride/diisopropyl ether at 254 °C (sintered).
Melts at ~275°C (decomposition).

Example 3 7α-acetylthio in 10 ml of dichloromethane
20-Spiroxer-4,9(11)-Diene-3,21-
A solution of 414 mg of dione and 320 mg of m-chloroperbenzoic acid is left at 5° C. for 16 hours. After dilution with a mixture of dichloromethane/ether (1:3), the reaction solution is washed successively with water, dilute aqueous potassium iodide, dilute aqueous sodium thiosulfate and again water, dried over sodium sulfate and concentrated in vacuo. do. The residue is chromatographed on silica gel (60 g). Using hexane/ethyl acetate (2:1),
The fraction effluent following the first distillation containing unreacted starting materials is, after conventional work-up (see Example 1),
Desired 7α-acetylthio-9α,11α-epoxy-
20-spiroox-4-ene-3,21-dione (identical to the product of Example 1) is produced.

Example 4 Approximately 50 mg of active ingredient, e.g. 7α-acetylthio-9α, 11α-epoxy-20-spirooxy-4-
Tablets containing ene-3,21-dione are manufactured as follows: Composition for 1000 tablets: Very finely ground active ingredient 50.0 g Powdered sugar (sucrose) 79.0 g Gum arabic 4.75 g Sorbit 3.75 g Talc 2.5g Magnesium stearate 4.9g Mineral oil 0.1g Carboxymethylcellulose (Na salt) 5.0g 150.0g Production: The active ingredient is mixed with powdered sugar and gum arabic, sieved and granulated using an approximately 35% aqueous sorbit solution. do. The granules are passed through a sieve, dried, sieved again and mixed intimately with the remaining auxiliaries (talc, magnesium stearate, mineral oil and sodium salt of carboxymethyl cellulose). The mixture is conventionally compressed to form 150 mg tablets.

Example 5 Approximately 50 mg of active ingredient (e.g. 7α-acetylthio-9α, 11α-epoxy-15β, 16β-methylene-20-spirooxy-4-ene-3,21- from Example 2)
Dragee-coated tablets containing diones are manufactured as follows: Composition of dragee core: Ultrafine active ingredient 50.0mg Corn starch 90.0mg Tricalcium phosphate 100.0mg Polyvinylpyrrolidone K25 15.0mg Magnesium stearate 2.0mg Sodium carboxymethylcellulose 33.0mg 290.0 Manufacture of 50,000 mg dragee cores Ultrafine powder active ingredient 2.5Kg, corn starch 4.5Kg
and 5 kg of tricalcium phosphate is granulated in a fluidized bed method using a solution of 0.75 kg of polyvinylpyrrolidone K25 in 5 kg of distilled water. Dry at 45℃,
0.1 Kg of magnesium stearate and 1.65 Kg of sodium carboxymethyl starch are added to the granules compressed through a 1 mm mesh width sieve and the mixture is compressed to form medium-height tablets of 290 mg.

Production of 6.6Kg of dragee-coated tablets In a coating container with a diameter of 45cm, 6Kg of dragee-coated tablet cores
1.5% polyvinylpyrrolidone K25 and 1
Dissolve % polyethylene glycol 6000, 20%
It is coated little by little with sugar syrup in which talc is suspended (2 parts by weight of sugar and 1 part by weight of distilled water) until it reaches a weight of 360 mg, during which time it is dried with warm air at about 60°C. Sugar syrup (2 parts sugar and 1 part water) 400
Apply in small portions until final weight of mg. lastly,
The dragees are given a glossy coating with a solution of 2% carnauba wax in trichlorethylene.

Example 6 Soft gelatin capsules containing 50 mg of active ingredient (see Examples 4 or 5) are obtained as follows: Composition of soft gelatin capsule: Micronized active ingredient 50.0 mg Soybean lecithin 1.5 mg Beeswax 2.5 mg Vegetable oil 110.0 mg Partially hydrogenated vegetable oil 54.0mg 218.0mg Production of 100,000 soft gelatin capsules 5.0Kg of ultra-fine active ingredient, 0.15Kg of soybean lecithin,
Beeswax 0.25Kg, partially hydrogenated vegetable oil
5.4 Kg and 11 Kg of vegetable oil are suspended in a mixture prepared by melting and introduced into gelatin capsules after punching operation. Gelatin coating is about 71% gelatin, about 28% glycerin (85%) and about 1
% titanium dioxide and 0.3% p-hydroxybenzoic acid propyl ester. The dimensions of the capsule are 4 minims (oval).

Example 7 Film-coated dragee tablets containing 100 mg of active ingredient (see Examples 4 or 5) are manufactured as follows: Composition of the film-coated dragee core: Micronized active ingredient 100.0 mg Polyethylene glycol 6000 52.0 mg Colloidal silica 5.0 mg stearic acid 3.0mg 160.0mg Production of 10,000 nuclei 1.0Kg of ultrafine active ingredient is mixed with 0.52Kg of polyethylene glycol (colloidal silica [specific surface area 200m ² /
g] (manufactured by adding 0.05 Kg), cooled, and compressed through a sieve with a mesh width of 1 mm. 0.03 Kg of pre-sieved powdered stearic acid is incorporated into the granules and the mixture is compressed to form slightly medium-height tablets of 160 mg.

Production of 30,000 film-coated dragee tablets In a coating container of diameter 45 cm, supplied with hot air at 35°C, 4.8 kg of kernels were prepared in a solution of hydroxypropyl methylcellulose in distilled water (viscosity 6 cP) in which 2% talc was suspended. , 2% aqueous solution) continuously until each core is coated with 5 mg of lacquer.

Example 8 A tablet containing about 50 mg of ingredient A and about 25 mg of ingredient B is prepared as follows: Tablet composition: Ultrafine ingredient A 50.0 mg Ultrafine ingredient B 25.0 mg Corn starch 50.0 mg Colloidal silica 5.0 mg Gelatin 5.0 mg Microcrystalline cellulose 75.0 mg Sodium carboxymethyl starch 20.0 mg Magnesium stearate 1.5 mg 231.5 mg Manufacturing of 100,000 tablets 5 kg of ultrafine powder component A, 2.5 kg of ultrafine powder component B, and 5.0 kg of corn starch are combined with 0.5 kg of colloidal silica. Mix and treat the mixture with a solution of 0.5 Kg gelatin in 5.0 Kg distilled water (30°C) to form a moist mass.
The mass is passed through a sieve with a mesh width of 3 mm and dried at 45°C (fluidized bed dryer). Dry granules mesh width 0.8
mm sieve and mixed with a mixture of 7.5 Kg of previously sieved microcrystalline cellulose and 2.0 Kg of sodium carboxymethyl starch and 0.15 Kg of magnesium stearate and compressed to form 231.5 mg tablets.

As component A, for example, 7α-acetylthio-
9α,11α-epoxy-20-spirooxa-4-ene-3,21-dione, component B is 6-chloro-7-sulfamyl-3,4-dihydro-1,
2,4-benzothiadiazine 1,1-dioxide is used.

In a similar manner, it is also possible to use corresponding amounts of the following active ingredients as component B: 2-chloro-5-(3-hydroxy-1-oxoisoindol-3-yl)-benzenesulfonamide or 4 -(2-methylenebutyryl)
-2,3-dichloro-phenoxyacetic acid (each
50mg), 6-chloro-7-sulfamyl-3,4
-Dihydro-1,2,4-benzothiadiazine 1,1-dioxide (25mg), 2-phenoxy-
3-Butylamino-5-carboxybenzenesulfonamide (0.5 mg), (1-oxo-2-methyl-2-phenyl-6,7-dichloro-indanyl-5-oxy)-acetic acid (20 mg as racemate)
mg, 10 mg as levorotatory form), or 3-cyclopentylmethyl-6-chloro-7-sulfamyl-
3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide (0.5 mg).

Example 9 A soft gelatin capsule containing 50 mg of component A and 12.5 mg of component B is obtained as follows: Composition of the soft gelatin capsule: Ultrafine powder component A 50.0 mg Ultrafine powder component B 12.5 mg Soybean lecithin 1.5 mg Beeswax 2.5 mg Vegetable oil 100.0 mg Partially Hydrogenated Vegetable Oil 54.0mg 220.5mg Production of 100000 Soft Gelatin Capsules Using 6.25Kg of a homogeneous mixture of components A and B (ultrafine powder) in a weight ratio of 4:1 and the same amount of excipients. and processed as described in Example 5.

As component A, the steroid active ingredient listed in Example 8 is used, and as component B, 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide is used.

In a similar manner, it is also possible to use corresponding amounts of the following active ingredients as component B: 3-Cyclopentylmethyl-6-chloro-7-
Sulfamyl-3,4-dihydro-1,2,4-
Benzothiadiazine 1,1-dioxide (0.25
mg), 4-thienyl-2,3-dichlorophenoxyacetic acid (125 mg), 2-chloro-5-(3-hydroxy-1-oxoisoindol-3-yl)-
Benzenesulfonamide (25mg) or 2-chloro-4-furfurylamino-5-carboxybenzenesulfonamide (15mg).

Example 10 A film-coated sugar-coated tablet containing 100 mg of ingredient A and 10 mg of ingredient B is manufactured as follows: Composition of the film-coated sugar-coated tablet core: Ultrafine active ingredient A 100.0 mg Ultrafine active ingredient B 10.0 mg Polyethylene glycol 6000 52.0 mg Colloidal silica 5.0mg stearic acid 3.0mg 170.0mg Production of 10,000 nuclei 1.1Kg of a homogeneous mixture of ultrafine active ingredients A and B in a weight ratio of 10:1 was added to polyethylene glycol.
0.52Kg (colloidal silica [specific surface area 200m ² /g]
0.05 Kg], and after cooling, it is compressed through a sieve with a mesh width of 1 mm. 0.03 Kg of pre-sieved powdered stearic acid is incorporated into the granules and the resulting mixture is compressed to form 170 mg slightly medium-height tablets.

Production of 30,000 film-coated dragee tablets In a coating container of diameter 45 cm, supplied with hot air at 35°C, 5.1 kg of kernels were prepared in a solution of hydroxypropyl methylcellulose in distilled water (viscosity 6 cP) in which 2% talc was suspended. , 2% aqueous solution) continuously until each core is coated with 5 mg of lacquer.

steroid active ingredient according to Example 8 as component A;
As component B, 2-phenoxy-3-[3-(1-
(pyrrolyl)-propyl]-5-carboxybenzenesulfonamide is used.

In a similar manner, it is also possible to use corresponding amounts of the following active ingredients as component B: 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1 ―
Dioxide (25 mg), 2-chloro-5-(3-hydroxy-1-oxoisoindol-3-yl)-benzenesulfonamide (50 mg), 4-
(2-methylenebutyryl)-2,3-dichlorophenoxyacetic acid (50mg), 2-chloro-4-furfurylamino-5-carboxybenzenesulfonamide (20mg), 2-phenoxy-4-butylamino- 5-Carboxybenzenesulfonamide (0.5 mg or 3-cyclopentylmethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,
2,4-benzothiadiazine 1,1-dioxide (0.5 mg).

Example 11 Component A is 7α-acetylthio-9α,11α-epoxy-20-spirooxy-4-ene-3,21-
Composition of dragee-coated tablet containing 40 mg of dione and 10 mg of 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide as component B: Core: 40 mg of component A, 160 mg of lactose Stearyl alcohol 77mg Polyvinylpyrrolidone 20mg Magnesium stearate 3mg 300mg Protective lacquer coating: 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1
-Dioxide 10mg Sugar, talc, coloring agent 190mg Binder appropriate amount 500mg Production Granulate the steroid component and lactose with stearyl alcohol melt and concentrated polyvinylpyrrolidone solution and dry. The resulting mass is sieved and compressed to form a compact weighing 300 mg. This is coated with a protective lacquer layer and then the diuretic component B is dissolved and coated with colored sugar syrup to a final weight of about 500 mg.

Example 12 Approximately 50 mg of 7α-acetylthio-9α as component A,
11α-epoxy-20-spirooxy-4-ene-
3,21-dione and 4-thenoyl as component B
Gelatin capsules containing 125 mg of 2,3-dichlorophenoxyacetic acid are prepared as follows.

Composition of dry capsules: Ingredient A 50.0mg 4-Thenoyl-2,3-dichloro-phenoxyacetic acid 125.0mg Lactose 124.0mg Magnesium stearate 1.0mg 300.0mg Production of 10,000 dry capsules Very finely ground 7α-acetylthio-9α,
11α-epoxy-20-spirooxy-4-ene-
0.50Kg of 3,21-dione to 4-thenoyl-2,3-
Mix evenly with 1.25Kg of dichlorophenoxyacetic acid,
Grind as necessary. 1.24 Kg of very finely ground lactose and 0.01 Kg of magnesium stearate are added to this mixture, which is then sieved and homogenized. The powder is sieved and 350 mg portions thereof are introduced dry into gelatin capsules.

Claims (1)

[Claims] 1 General formula (): [In the formula, R represents a lower alkanoyl group, -A-
A- represents an ethylene group or a cyclopropylene group] 9α,11α-epoxy steroid. 2. The compound according to claim 1, wherein R is an acetyl group. 3 7α-acetylthio-9α, 11α-epoxy-20
The compound according to claim 1, which is spirooxy-4-ene-3,21-dione. 4 7α-Acetylthio-9α,11α-Epoxy-
15β,16β-methylene-20-spirooxy-4-
Claim 1 which is en-3,21-dione
Compounds described in Section. 5. The compound according to any one of claims 1 to 4 for use as a diuretic. 6 General formula (): [In the formula, R represents a lower alkanoyl group, -A-
A- represents an ethylene group or a cyclopropylene group] In order to produce a 9α,11α-epoxy steroid, a general formula (): General formula (): R-SH () [ In the formula, R represents the above-mentioned lower alkanethioic acid], or b General formula (): It is characterized by epoxidizing the 9(11)-double bond of the corresponding 9(11)-unsaturated compound of [in the formula, R and -A-A- represent the above]
Method for producing 9α, 11α-epoxy steroids. 7. The method according to claim 6 for producing the compounds described in claims 2 to 4. 8 General formula (): [In the formula, R represents a lower alkanoyl group, -A-
An anti-androsterone preparation characterized by containing a 9α,11α-epoxy steroid of A- represents an ethylene group or a cyclopropylene group as an active ingredient. 9. The anti-androsterone preparation according to claim 8, further comprising a diuretic component that is non-specific for electrolytes.