HU199157B - Process for producing 17-substituted androsta-1,4-dien-3-one derivatives and pharmaceutical compositions comprising same as active ingredient - Google Patents

Abstract

17-Substd. androsta-1,4-dien-3-one derivs. of formula (I) and their pharmaceutically acceptable salts are new. R, R3 = H or 1-6C alkyl; R1 = H, halogen or 1-6C alkyl; R2 = H or 1-6C alkyl; R4 = H or F; R5 = H, 1-6C alkyl, phenyl (opt. substd. by one or two 1-6C alkyl, halogen or NH2), acyl or a hydroxy protecting gp. Also claimed is a process for prepg. (I), a pharmaceutical compsn. contg. cpd. (I), use of the compsn. for treating hormone dependent diseases and for treating breast, pancreatic, endometrial or ovarian cancers. - Pref, R, R3 = H or 1-4C alkyl; R1 = H, F, Cl or 1-4C alkyl; R2 = H or 1-4C alkyl; R5 = H, 1-4C alkyl, or an acyl gp. derived form an acid selected from acetic, propionic, valeric, undecylic, phenylacetic, cyclopentylpropionic, oleic, aminoacetic, succinic, sulphuric and phosphoric acid.

Description

The present invention relates to novel 17-substituted androsta-1,4-diene derivatives of formula (I) and to pharmaceutical compositions containing them as active ingredients.

Results from basic and clinical studies show that aromatic androgen metabolites (metabolites), or estrogens, are hormones that play a role in certain hormone-dependent cancers, such as breast, endometrial and ovarian carcinomas. the development.

Estrogen hormones also influence the pathogenesis of benign prostatic hyperptasia.

Endogenous estrogens are eventually formed either from androstenedione or from testosterone as a direct precursor. The most important reaction is the aromatization of the steroid A ring, which is carried out using the enzyme aromatase. Because aromatization is a special reaction and the final step in the biosynthesis of estrogens, it is readily apparent that, when the aromatase enzyme is effectively inhibited by compounds capable of interfering with the aromatization steps, this can control the amount of estrogen-dependent tumors.

Known steroid substances mentioned in the literature as having aromatase inhibitory activity are, for example, A'-testolokone (U.S. Pat. No. 2,774,120), 4-hydroxyandrost-4-ene-3,17-dione and esters (see, for example, U.S. Patent No. 4,235,893); 10- (1,2-propadienyl) estr-4-en-3,17-dione (U.S. Patent No. 4,289,762). ), 10- (2-propynyl) -estr-4-ene-3,17-dione (J. Am. Chem. Soc., 1981, 103, 3221 (1981)) and U.S. Patent No. 4,322,416. Hungarian Patent No. 187,149 for androst-4,6-diene-3, 17-dione and androst-1,4,6-triene-3,17-dione (U.S. Patent No. 2,100,601). and U.S. Patent Nos. 4,3327 (1982) and Androst-1,4-diene-3,17-dione (Cancer Res. (Suppl.) 42: 327-82).

The novel compounds of the present invention effectively inhibit estrogen biosynthesis by inhibiting the aromatization reaction during which the adrogens are converted to estrogens.

In addition, the novel compounds have an androgenic effect that may enhance inhibition of estrogen synthesis by reducing gonadotropin secretion.

In the pre-menopausal state, aromatase synthesis is essentially regulated by gonadotropins, so that the novel compounds of the present invention can reduce estrogen levels in two ways: inhibiting aromatase activity (inhibiting aromatase activity) and inhibiting aromatase synthesis (gonadotropin). .

The present invention relates to compounds of the formula I wherein

R 1 is hydrogen or halogen, R ₅ is hydrogen, C 1 -C 5 alkanoyl or -SO ₃ H, and their salts with bases.

When R _{s is} an acyl group, the acid residue is preferably an acid residue or an -SO ₃ H group of an acid such as acetic acid, propionic acid, valeric acid.

As stated above, the invention also relates to the preparation of salts of the compound of formula I with pharmaceutically acceptable bases. Preferred are the compounds of formula (I), its salts in which R ₅ a polybasic - acid acid residue of a pharmaceutically acceptable base - preferably dibasic.

The bases may be inorganic, for example hydroxides of alkali metals such as sodium or potassium or alkaline earth metals such as calcium or magnesium, or organic bases such as alkylamines such as methylamine or triethylamine, aralkylamines such as benzylamine, dibenzylamine, or β-phenylethylamine, or heterocyclic amines such as piperidine, 1-methylpiperidine, piperazine or morpholine.

In the formulas in this description, the dashed lines (»» ·) indicate that the substituent is in the β configuration, that is, above the plane of the ring, while the wavy lines (^ indicate that the moiety is both α- and β-). configuration.

Preferred compounds of the present invention are those of formula (I) wherein:

R 1 is hydrogen, fluoro or chloro, R ₅ is hydrogen or an acyl group derived from acetic acid, propionic acid, valeric acid, or

-SO ₃ H - and their pharmaceutically acceptable basic salts.

The process of the invention comprises the following steps:

a) dehydrogenating a compound of formula II wherein R 1 and R ₅ are as defined above, or

b) for the preparation of a compound of formula I wherein R 1 is halogen and R ₅ is as defined above, a compound of formula III wherein R 1 and R ₅ are as defined above is reacted with a hydrohalogenating agent; or

c) a compound of formula IV, wherein R 1 and R ₅ are as defined above, with a source of formaldehyde, preferably paraformaldehyde, or a R ₂ CHO

-3199157, wherein R ' ₂ is a C 1-6 alkyl group, and an amine of formula VI wherein the two R' groups may be the same or different and independently of one another a C 1-4 alkyl group, and case

(i) converting a resulting compound of formula (I) wherein R ₅ is hydrogen into a compound of formula (I) wherein R ₅ is C 1 -C 5 alkanoyl, or (ii) the resulting compound of formula (I) wherein R ₅ represents a hydrogen atom, is converted into a (1) a compound of formula wherein R ₅ is -SO ₃ H group, and iii) obtained as described above in any of (I), a free compound of formula into a pharmaceutically acceptable salt formed with a base.

The dehydrogenation of the compound of formula (II) may be carried out with a suitable dehydrogenating agent such as dichlorodicyanobenzoquinone (DDQ), selenium dioxide or chloranil. The treatment is preferably carried out with DDQ in an inert solvent such as dioxane, benzene, toluene or dichloromethane for approx. 40 and approx. 120 ° C, approx. 12 and approx. The reaction is performed for 72 hours.

The hydrogen halogenation of compound (III) may be carried out using a hydrogen halide or trihaloborane. The reaction between the compound of formula (III) and the hydrogen halide or trihaloborane can be carried out by known methods, for example, Camerio et al. (1956, II Farmaco, 11, 586) and A. Bowers et al. (1958, Tetrahedron 3). , 14). When hydrochloric acid or hydrobromic acid is used as the hydrogen halide, the reaction is preferably carried out in acetic acid or ethanol for approx. 0 ° to approx. 100 ° C.

When a trihaloborane such as boron trifluoride is used, the reaction is preferably carried out in an inert solvent such as diethyl ether, benzene or dichloromethane for about 10 minutes. —30 to approx. 50 ° C.

The compound (VI), R _p lower alkyl group may be, for example C1-4 alkyl, preferably methyl or ethyl, preferably methyl. The salt of the compound of formula (VI) may be, for example, a salt with an inorganic acid, preferably a hydrogen halide acid, more preferably hydrochloric acid.

The reaction of a compound of formula (IV) with a source of formaldehyde or an aldehyde of formula R'CHO and a salt of a compound of formula (VI) is preferably carried out in a high-boiling alcohol such as isopentanol for approx. At or above 130 ° C for about 3 hours. This is carried out over a period of 1 day. In a preferred embodiment, the formaldehyde source, i.e., the aldehyde of formula R ' ₂ CHO, is first reacted with a salt of a compound of formula VI, followed by the addition of a compound of formula IV to the Mannich salt thus obtained.

It has been found that many compounds of formula I can be converted to another compound of formula I by known methods.

Esterification of a free hydroxy group gives a compound of formula (I) wherein R ₅ is acyl. This operation may also be carried out by one of the known methods, for example with a suitable acylating agent, for example a reactive derivative of a suitable acid, for example anhydride or a halide, preferably chloride, in the presence of a basic reagent, preferably an organic base such as pyridine. The reaction was carried out at room temperature and ca. It can be carried out at a temperature of 100 ° C.

If desired, the reactive functional groups may be protected with suitable protecting reagents, which may be removed after the reaction by methods known in the chemical literature.

Known and obvious methods for converting a compound of formula I into a salt may also be used.

A compound of formula (II) may be prepared from a compound of formula (VII) by known methods, such as those described by K. Annen (1982) Synthesis, 34. Preferably, the compound of formula (VII) is reacted with unsubstituted or C 1-6 -alkyl-formaldehyde diethyl acetal in chloroform under reflux in the presence of phosphoryl chloride and sodium acetate. The same reaction may also be carried out in the presence of other inert solvents such as 1,2-dichloroethane, diethyl ether or dioxane and other suitable condensing agents such as phosphorus pentoxide or p-toluenesulfonic acid.

The compounds of formula (III) may be prepared in a known manner, for example as shown in Scheme 1.

To prepare a compound of formula VIII, epoxidation of a compound of formula II is accomplished by treating the compound with a solution of an alkali metal hydroxide of methanol, preferably potassium or sodium hydroxide, in a solution of ca. 0 ° C and approx. At 25 ° C, approx. 2 hours approx. for a few days with a suitable oxidizing agent, preferably concentrated hydrogen peroxide, for example 36%. The dehydrogenation of the compound of formula (VIII) is carried out by preparing H.J. According to the method described by Ringold et al., 4199157 (Chemistry and Industry 211, 1962), a suitable dehydrogenating agent, such as dichlorodicyanobenzoquinone, is treated in a solvent at reflux temperature. Compounds of formula (IV) are prepared starting from compounds of formula (VII). At position 1, the brush comb is formed by the method described above (H. J. Ringold et al., 1962, Chem. And Ind. 211).

The compounds of the present invention are inhibitors of the biological conversion of androgens to oestrogens, i.e. steroid aromatase inhibitors.

The aromatase inhibitory activity of the compounds was demonstrated using, for example, in vivo in vivo rat assays described in Prodie (A.M.H. Brodie et al., Steroids, 38, 693, 1981).

Adult female rats were treated with 4 times 100 IU serum gonadotropin (PMSG) from pregnant mares at 4 day intervals to enhance ovarian aromatase activity. Three days after the second dose of PMSG, groups of 6 animals were administered orally and / or subcutaneously with a hundred new aromatase inhibitors. After 24 hours, the animals were sacrificed and the aromatase activity was determined in the microsomes isolated from the ovaries by Thompson and Siiteri (J. Biol. Chem. 249, 5364, 1974). This method determines the rate of aromatization to measure the ³ H ₂ O has the release of [1β, 2β- ³ Η] androsten-dione. Incubation was carried out for 30 minutes with 1 ml of incubation solution containing 0.1 mg microsomal protein, 100 nM pH] -androstone ^: dione and 100 μΜ NADPH.

The androgenic properties of the compounds of the present invention have been demonstrated, inter alia, by their affinity for binding to androgen receptors.

Binding affinity for cytoplasmic androgen receptors (rat prostate) was determined by the standard dextran-coated activated carbon adsorption procedure (Raynaud J.P. et al., J. Steroid. Biochem. 6, 615-622, 1975). Prostate tissue was obtained from Sprague-Dawley rats, in which both the adrenal gland and testis were removed. Tissue was homogenized in a motor-driven mixer in Tris-hydrochloric acid (pH 10.4, 10 nM, 1.5 nM EDTA and 1 nM dithiothreitol, 1:10). The homogenate was centrifuged at 105,000 g for 1 hour at 0 ° C. Aliquots (0.2 ml) were withdrawn from the cytosol, and duplicate concentrations of the test v20 as well as a defined amount of pH] -5α-dihydrotestosterone (DHT, final concentration of 1 nM in 0.4 ml incubation volume) were added in duplicate. . The free radioactive materials were then adsorbed on a 0.2 to 25 ml suspension of dextran-coated activated carbon, followed by

After centrifugation at 1.5 g for 10 minutes, bound radioactivity was determined by liquid scintillation measurement with Rialumin in the mother liquor.

The concentration of test compounds that reduced the specific ³ H-DHT binding by 50% was determined from a graph plotting the bound radio35 activity versus the logarithm of the concentration of the compound in question.

The following table shows one of the representative compounds of the compounds of the invention, 6-methylene-androst-1,4-diene-176-ol-3-one and U.S. Pat. United Kingdom Patent 6,6-methylene-androst-1,4-diene-3,17-dione.

Androgen Receptor Binding Affinity Compound Ι0 ₅ θ (ηΜ) ^χ

6-methylene-androst-1,4-diene-17S-ol-3-one 6 10 + 82

Mean deviation of standard deviation for 6-methylene-androst-1,4-diene-3, 17-dione 8 + 2 measurement

-5199157

The table shows that the 6-methylene-androst-1,4-diene-4-ol-3-one produced by the process of the present invention has a very high affinity for the androgen receptor: the effect of the above-mentioned corresponding 17-keto derivative. 76 times.

From inhibit aromatase and their effect, are capable of reducing ősztrogénszint whereby, the new compounds are useful for various hormone dependent diseases - such as · ^breast, méhbelhártya-, ovarian and pancreatic cancer, ginekomastia, benign breast tumors, endometriosis, polycystic treatment and prevention of ovarian inflammation and premature puberty.

Due to their inhibitory effect on ovulation and oviposition, the new compounds can also be used as contraceptives and for the treatment of male infertility associated with oligospermia.

Due to their high therapeutic index, the compounds of the present invention are safe to use in medicine. For example, when measuring the acute toxicity (LD ₅₀ ) of these compounds in mice by simply recording the increasing doses and measuring the toxicity on the seventh day after treatment, it is found that the value obtained is negligible. Compositions containing the compounds as active ingredients may be administered in a variety of dosage forms, for example, orally in the form of tablets, capsules, sugar or film coated dragees, liquid solutions or suspensions; rectally in the form of suppositories; and parenterally, for example, intramuscularly, or intravenously or by infusion.

The dose to be used will depend on the age, weight, condition and route of administration of the patient, e.g. 10 mg to ca. It can range from 200 to 400 mg.

It is a further object of the present invention to provide a pharmaceutical composition comprising a compound of the present invention in association with a pharmaceutically acceptable carrier or diluent.

Pharmaceutical compositions containing the compounds of the present invention are generally prepared by conventional methods and are administered to the patient in a pharmaceutically acceptable form.

Solid form preparations for oral administration may contain, in addition to the active ingredient, diluents such as lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants (lubricants) such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; binders, such as starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures, dyes, sweeteners, wetting agents such as lecithin, polysorbates, lauryl sulfates, and generally non-toxic, pharmaceutically inactive substances. These compositions may be prepared by known methods, such as mixing, granulating, tabletting, sugar or film coating.

Liquid dispersions for oral administration may be, for example, syrups, emulsions or suspensions.

Syrups may contain as carrier, for example, sucrose or sucrose mixed with glycerol and / or mannitol and / or sorbitol.

Suspensions or solutions for intramuscular injection may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol and, if desired, an appropriate amount of lidocaine hydrochloride. Solutions for intravenous injection or infusion may contain as carrier, for example, sterile water or, preferably, sterile, aqueous, isotonic saline.

Suppositories may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier, such as cocoa butter, polyethylene glycol, polyoxyethylene, surfactant sorbitol fatty acid esters or lecithin.

The following examples are intended to illustrate the invention but are not intended to limit its scope.

Example 1

A mixture of 0.50 g of 6-methylene-androst-4-en-17p-ol-3-one and 0.57 g of dichlorodicyanobenzoquinone in 20 ml of anhydrous dioxane was stirred at ca. Reflux for 15 hours. After removal of the dichlorodicyanobenzoquinone suspension, the mixture was filtered through alumina, and after evaporation of the solvent, the residue was dissolved in ethyl acetate, the organic layer was washed with water, dried over sodium sulfate and the solvent removed in vacuo.

The crude product was chromatographed on silica gel with a 20:80 mixture of n-hexane and diethyl ether to give 0.25 g of pure 6-methylene-androst-1,4-diene-1 H -ol-3-one, m.p. 136 ° C. λ / παχ - 247 sec (ε 13.750). Analysis for C ₂₀ H ₂₄ O ₂ Calcd: C: 80.49, H: 8.68%;

Found: C, 80.01; H, 8.95.

Example 2

Dissolve 1.0 g of 4,5-epoxy-6-methylene-androst-1-ene-17β-ο1-3-οηί in 10 ml of glacial acetic acid and treat with hydrogen chloride gas at room temperature for 30 minutes.

The precipitate was filtered off, the filtrate was washed with diethyl ether and then with hexane and ethyl acetate.

Chromatography on silica gel (6199157) gave 0.8 g of pure 4-chloro-6-methylene-androst-1,4-diene-176-ol-3-one.

Elemental analysis for C _2O H ₂₅ C1 ₂ O: Calculated: C, 72.18; H, 7.52; Cl, 10.68%; Found: C, 72.35; H, 7.35; Cl, 10.58.

MS (m / z): 332.

If the above procedure is repeated starting from the corresponding 4,5-epoxy derivative and using the appropriate gaseous hydrogen halide, the following compounds may be prepared:

4-bromo-6-methylene-androsta-l, 4-diene-173-ol-3-one;

4-fluoro-6-methylene-androsta-l, 4-diene-17-ol-3-one.

Example 3

5.31 g (0.177 mol) of paraformaldehyde and

A mixture of diethylamine hydrochloride (17.32 g, 0.212 mol) in isopentanol (200 ml) was heated to reflux (about 131 ° C) in a flask equipped with a Dean-Stark separator. In the separator, a mixture of water and isopentanol of approx. 60 ml are collected and discarded. The reaction temperature in the flask was then reduced to ca. After reduction to 10-15 ° C, boldenone (androsta-1,4-diene-176-ol-3-one) (4.55 g) is added and the mixture is heated to reflux again for 15 hours.

After cooling, the mixture was treated with 60 ml of 0.1 N sodium hydroxide solution and stirred for 30 minutes. The organic layer was separated, washed with water and evaporated in vacuo (external temperature: 80 ° C) until ca. 80 ml of suspension are obtained.

The mother liquor was separated, and the resulting precipitate was washed with hexane (2 x 10 mL) and recrystallized from ethanol / water (25 mL, 70:30). The filtered white precipitate was dried under vacuum at 40 ° C to give 1.55 g (0.0052 mole) of 6-methylene-androst-1,4-diene-17? -Ol-3-one, m.p. 135 -137 ° C.

Example 4 Sodium acetate, 30 ml absolute chloroform, 30 ml (0.24 mol) formaldehyde diacetal and 0.93 g (2.7 mol) ip-methyl-androst-4-en-17p-ol-3 -on-17-acetate mixture was heated at reflux for 7 hours or until starting material disappeared. The suspension is then allowed to cool and saturated sodium carbonate solution is added dropwise with vigorous stirring until the aqueous medium is made alkaline (about 1 hour). The organic layer was separated, washed with water to neutral pH and then dried over sodium sulfate. After evaporation under reduced pressure, the oily residue was purified by chromatography on silica gel eluting with a mixture of hexane and ethyl acetate to give 0.575 g of pure Ιβ-methyl-6-methylene-androsta-4-en-17p-ol-3-one-17-. acetate was obtained.

Results of infrared spectroscopy with potassium bromide:

3100 (6 = _CH2), 1725 (17-acetoxy) 1680 (3-oxo), 1630, 1660 ^cm-1 (Δ ⁴ and 6 = _CH2).

In a similar manner, the following compounds may be prepared:

1β-εΗ1-6-πιβίΐ1έη-3η0Γθ5ζί-4-επ-17β-ο1-3-οη acetate, 4-methyl-6-ethylidene-androst-4-en-176-ol-3-one acetate, and

16-ethyl-6-ethylidene-androst-4-ene-17β'-ο1-3-οη acetate.

Example 5 6-Methylene-androst-4-en-176-ol-3-one (g) was dissolved in methanol (200 ml), cooled to 0 ° C and treated with 36% hydrogen peroxide (17 ml) and 2% ice-cold mixture of sodium hydroxide.

The reaction mixture was stirred for 1 hour, allowed to stand at 5 ° C for 20 hours, then poured into ice-water (1400 ml) with vigorous stirring. The resulting product was filtered, washed with water and dried to give 4.2 g of 4,5-β 6-ΓηείίΙέη-3ηΰΓθ5ζί3-17β-οΙ-3-οηί (a mixture of α- and β-epoxide, yield: 80%).

4.5 g of 4,5-epoxy-6-methylene-androst-4-ol-3-one and 1.7 g of dichlorodicyanobenzoquinone are dissolved in 60 ml of anhydrous dioxane and refluxed for 15 hours. The cooled solution was filtered through alumina and concentrated in vacuo. The residue was taken up in ethyl acetate and the organic layer was washed with water, dried and evaporated in vacuo. The crude product was chromatographed on silica gel with hexane / ethyl acetate to give 1.5 g of pure 4,5-epoxy-6-methylene-androst-1-en-176-ol-3-one.

Example 6

6-Methylene-androst-1,4-diene-17β-η -1 -3-one (1.0 g) was dissolved in pyridine (10 ml) and treated with propionyl chloride (1.08 ml) at 5 ° C. After stirring overnight at room temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate.

The organic extracts were washed with 2N hydrochloric acid, water, dried over sodium sulfate and evaporated.

The product was recrystallized from a mixture of n-hexane and ether to give 0.95 g of 6-methylene-androst-1,4-diene-17β-ο1-3-οη-17-propionate, mp 123-125 ° C.

NMR δ (ppm): 0.88 (3H, s), 1.17 (6H, s + t),

2.35 (2H, m), 4.66 (1H, m), 5.02 (2H, m),

6.25 (2H, m), 7.09 (1H, d).

By the above procedure, the following compounds can be prepared from the corresponding steroids:

6-methylene-androst-1,4-diene-17β-ο1-3-one-17-acetate,

6-methylene-androst-1,4-diene-17β-ο1-3 οη-17-valerate.

Example 7

1.2 g (4 mmol) of 6-methylene-androsta-1,4--π-17β-οΙ-3-οηί are dissolved in 40 ml of pyridine and a catalytic amount of 4-dimethylaminopyridine is added.

-7199157

The reaction mixture was cooled to -15 ° C and 1.33 mL (20 mmol) of chlorosulfonic acid was added with stirring, allowed to stand at room temperature for 4 hours, and then diluted with sodium hydroxide solution.

The aqueous solution was washed with ethyl ether, acidified with 2N hydrochloric acid and extracted with methylene chloride.

The organic extracts were dried over sodium sulfate and evaporated under reduced pressure to give 0.95 g of pure 6-methylene-androst-1,4-diene-17β-ol-3-one-7-sulfate. NMR δ (ppm): 0.75 (3H, s), 1.05 (3H, s), 4.05 (1H, m), 4.85 (2H, m), 5.9 (1H, d) , 3.97 (1H, dd), 6.82 (1H, d).

Example 8

1.89 g of 6-methylene-androsta-1,4-diene-17? -Ol-3-one-17-sulfate are dissolved in 10 ml of 0.5N ethanolic sodium hydroxide solution and diluted with acetone.

After 10 minutes, the resulting sodium salt was filtered off and washed with ethyl ether.

Analysis for C ₃₀ H ₂₅ NaO ₅ S: Calc: C, 60.00; H, 6.25; Na, 5.75;

S, 8.00%;

Found: C, 59.87; H, 6.31; Na, 5.7.

S, 94%.

Melting point:> 200 ° C (with decomposition).

Example 9

Tablets weighing 0.150 g each and containing 25 mg of active ingredient are prepared as follows:

Composition: (per 1000 tablets)

6-methylene-androst-1,4-diene-17β-ο1-3-οη 250 g lactose 800 g maize starch 415 g talcum powder 30 g magnesium stearate 5 g.

6-Methylene-androsta-1,4-diene-17? -O-3-one is mixed with lactose and one half of the corn starch and passed through a 0.5 mm mesh sieve. 10 g of corn starch are suspended in 90 ml of water and the resulting mass is used to granulate the powder.

The granulate is dried, sieved through a 1.4 mm mesh sieve, then the remaining starch, talc and magnesium stearate are added, mixed thoroughly and processed into tablets.

Example 10

Each weighs 0.200 g and contains 20 mg of active ingredient.

containing tablets was live as follows: Composition: (for 500 capsules) 6-methylene-androsta-1,4-diene - -17β-ο1-3-οη 10 S lactose 80 g cornstarch 5 g magnesium stearate 5 g ·

This mixture was filled into two-piece hard gelatin capsules weighing 0.200 g each.

Claims (7)

PATENT CLAIMS 1) Process for the preparation of compounds of formula I wherein: R 5 is hydrogen or halogen, R ₅ is hydrogen, C 1-5 alkanoyl, or -SO ₃ H, and pharmaceutically acceptable base salts thereof, characterized in that: 10 a) dehydrogenating a compound of formula II wherein R 1 and R ₅ are as defined above, or b) for the preparation of a compound of formula I wherein R 1 is halogen, R ₅ is a reaction of a compound of formula III, wherein R ₅ is as defined above, with a hydrohalogenating agent; or c) a compound of formula IV: 20 wherein R and R ₅ are as stated above - a _R'2 CHO aldehyde of formula - wherein R _'2 represents a hydrogen atom or a C1-6 alkyl group - and an amine or a salt of formula (VI) - wherein each R _p cso25 the powder represents the same or different C 1-4 alkyl groups and optionally i) a compound of formula (I) obtained wherein R ₅ is hydrogen is such Converting it to a compound of formula (I) wherein R ₅ is C 1-5 alkanoyl; or (ii) a resulting compound of formula (I) wherein R _s is hydrogen; Converted into 35 a compound of formula (I), wherein R ₅ is -SO ₃ H group, and iii) the processes a) to c) and i) to ii) obtained by any of (I) free compound of formula a pharmaceutically acceptable base, It is converted to 40 skilled salts. 2) The process of claim 1, wherein the compounds of formula I are wherein R 1 is hydrogen, fluoro or chloro, R ₅ is hydrogen, or an acyl group derived from acetic acid, propionic acid, valeric acid - or a -SO ₃ H group and pharmaceutically acceptable base salts thereof, characterized in that 50 appropriately substituted starting materials are used. 3) A process according to claim 1 for the preparation of 6-methylene-androst-1,4-diene-4-ol-3-one, characterized in that 6-Methylene-androst-4-en-17? -Ol-3-one was used as the material. 4) A process according to claim 1 for the preparation of 4-chloro-6-methylene-androsta-1,4-diene-17? -Pl-3-one, characterized in that the starting material is 4,5-epoxy-6-methylene. -androst-1-en-17p-ol is used. 5) Process according to claim 1 6-methylene-androsta-l, 4-diene-178-ol-3-one-17-propionate thereof, characterized in that starting from 6-methylene-androsta-4 ⁶⁵ - diene-17? -ol-3-one. -8199157 6) The process according to claim 1 for the preparation of 6-methylene-androst-1,4-diene-17? -Ol-3-one sulfate, characterized in that starting material is 6-methylene-androst-1,4-diene-17β. -ol-3-one is used. 7) A process for preparing a pharmaceutical composition, wherein the active compound prepared as in 1 igény14 process (I) in which R, and _R5 are as defined in claim 1, in the pharmaceutical industry commonly al ₅ kalmazott diluent and / or and mixed with additives to form a pharmaceutical composition.