SI8611201A8 - Process for obtaining substituted androsta-1,4-dien-3,17-diones - Google Patents

Description

PROCEDURE FOR BEATING SUBSTITUTIONAL ANDROST-1,4-DIEN-3,17-DION

FIELD OF THE INVENTION

The invention is in the field of chemistry, closer to pharmaceutics and specifically to the field of hormone production.

Technical problem

The technical problem is how to get new 6-alkali 1idenandrosta-1,4diene-3,17-dianes, which will have good metabolic stability.

The state of the art

Endogenous estrogens are necessarily formed from either androstendione or testosterone as immediate precursors. The central reaction is the aromatic protection of steroid A, which is carried out by the aromatase enzyme. Aromatization is a unique reaction, and at least in a series of phases in estrogen trisynthesis, it is contemplated that effective inhibition of aromatase, derived from compounds that can interact with aromatization stages, may be useful for controlling the amount of circulating estrogens, reproduction processes that depend on: estrogen and estrogen dependent tumors.

Known published steroidal substances that have aronnrtase inhibitory action are, for example, delta ^ -testololactone / US Pat. 2,744,12-0 /, 4-hydroxy-androst-4-en-3,1-dione and its esters / see, e.g., U.S. Pat. ^; No. 4,235,893 /, 10- (l _T 2 «Hh;

failed 1) -estr-4-en-3,17-dione /U.S. Pat. No. 4,289,762 /, 10 (2-propyl) -estr-4-en-3,17-dione / J. Αιη.Cheni.Soc. , 103, 3221 (19B1) and U.S. Pat. Pat. 4,322,416 /, 19-thioandrosene derivatives (European Patent Application 100566), androsta-4,6-diene-3,17dione, androsta-1,4,6-triene-3,17-dione / G.Bb Pat. Appl.

2.100.601A / i androsta-1,4-diene-3,17-dione / Cancer Res. (Suppl.) 42, 3327 (1982) /.

Description of a solution to a technical problem with examples of execution

L;

The present invention relates to a process for making new ones

6-alkylidenandrosta-1,4-diene-3,17-dione. Basic and clinical data indicate that aromatized · androgen metabolites, i.e., estrogens, are hormones involved in pathological cellular changes that accompany the growth of some hormone-dependent cancers, such as breast cancers, endometrium, and. karci nomij: ja j ni ka.

New compounds of the present invention, in addition to expression •. -φίί'ί '. ·· powerful ¹ in vi three aromatase inhibition, are enriched with. - 'S and ^r '.

superior in vivo strength, based on their better metabolic stability when compared with compounds of the prior art ·.

The present invention provides compounds' having the following general formula:?

wherein each of R 1 and, independently, is hydrogen or C 1 -C 4 -alkyl and is hydrogen or C 1 -C 8 alkyl.

The forrail mentioned above for the compounds of the invention includes all possible isomers, especially the Z and E isomers, 1 especially and as a mixture, the compounds of formula (I) in the fat is R ₂ C ₁ * C ₆ a1ki1.

In the formulas in this application, broken lines {'*' ') indicate that the substituents are in alpha configuration, i.e., below the plane of the ring, while heavy solid lines (indicating that the substituents are in beta configuration, i.e., above the plane of the ring; wavy lines indicate groups can be 1 in alphaconflguradj1 111 in beta-konf1gurac1j1.

The C 1 -C 8 alkyl group is preferably a C 1 -C 6 alkyl group, in particular methyl, ethyl, propyl 111 butyl, preferably methyl 111 ethyl.

From these examples it is clear v1d1 that the alkyl radical can be a group, a straight 111 branched chain.

Preferred compounds of the invention are compounds of formula (I), in which:

R is hydrogen 111 C 1 -C 6 alkyl

R 1 is hydrogen, 111 C 1 -C 4 alkyl 1

R ₂ is hydrogen 111 C 1 -C 4 alkyl.

More preferred compounds of the invention are compounds of formula (I) wherein

R is hydrogen, methyl or ethyl;

Rj is hydrogen, i

R ₂ is hydrogen.

r ·> | Ι.Μ

Examples of specific compounds of the invention are:

6-methylenandrosta-1,4-diene-3,17-dione;

1-methyl-6-methylenandrosta-1,4-diene-3,17 ~ dione;

1-ethyl-6-methylenandrosta-1,4-diene-p, 17-dione; methyl-6-methylenandrosta-1,4-diene-5β17-dione;

4-ethyl-6-methylenandrosta-1,4-diene-3,17-dione;

6-ethylidenandrosta-1 _T 4-diene — 5,17-dione;

6- Propylidenandrosta.-1,4-dien- ^, 17-dione; i

1-me tyl-6-ethylidenandrosta-1,4 _; _dien-$ 5.17-share

The compounds of the invention may be prepared by a process comprising:

. dehydrogenation of compounds of formula (II):

in which:

R, R and R ₂ as defined above; and if necessary, a mixture of isomers of the compounds of formula (I) is separated into the individual isomers.

The dehydrogenation of a compound of formula (II) may be effected by treatment with a suitable dehydrogenating agent, e.g., dichlorodicyanobenzoquinone (DDQ), selenium dioxide or chloroanil. Preferably, the reaction is performed by treatment with DDQ, in an inert solvent, such as dioxane, toluene or dichloroethane, at a temperature ranging from about 40 ° C to about 1 20 ⁰ C and the reaction times vary from about 12 hours to about 72 hours .

. '- · Λ ι · 1.1'

Separation of the mixture of Isomers of the compounds of formula (I) can be carried out according to conventional methods known per se.

J

For example, separation of a mixture of geometric isomers can be accomplished by fractional crystallization or by column chromatography.

Compounds of formula (II) in which hydrogen, R is C 1 -C 8 alkyl 1 R ₂ is as defined above, can be synthesized according to the following reaction scheme using methods known per se:

where R 1 is C 1 -C 8 alkyl, R is hydrogen and R 4 is as defined above.

For example, the dehydrogenation of a compound of formula (IV) to obtain a compound of formula (V) may be carried out, e.g., according to H.J.

Ringold et al. 1962, Chera1stry and Industry, 211. Preferably by treatment with DDQ in boiling dloxane.

The compound of formula (VI) is obtained by alclating the compound of formula (V), e.g., according to known methods. Preferably, the alkylation is carried out by adding a compound of formula (V) dissolved in an Inert solvent to a solution of dlalkyllithium-copper in the same 111 different Inert solvent. Suitable Inert solvents are, for example, methylene chloride, tetrahydrofiated, benzene lylether, the latter being preferred. The reaction is preferably carried out at temperatures ranging from about -75 ° C to about 25 ° C, with a temperature interval of about -5 ° C to about 0 ° C which is preferred. The ratio of reagents is not critical, but at least 2 moles of dulcid Hume copper are present. It is emphasized that ad1c1ja occurs selectively at beta-surfaceS1n1; therefore, there is an axial hydrogen atom in the 1-position that is suitable for ellmlnactia. The compound of formula (VII) can be obtained starting from the compound of formula (VI) according to known methods, e.g., M. Mori, 1962, (Chem. Pharm. Bul), (Tokyo), 10, 386. Therefore, the compound of formula (VI) can be brominated by treatment with 1-1.2 equivalents of bromafii to acetic kselin, 111. . _; r '·; : · Other suitable solvents, at a temperature ranging from about 0 ° C to about 50 ° C, preferably at room temperature, to give 4-bromo-der 1vat which is then dehydrated, without purification, in dimethyl fluororoamide solution in the presence of Uti yum -chloride at about 140-150 ° C. The compound of formula (II) can be prepared starting from the compound of formula (VII) according to known methods, e.g., according to method 1z K, Annen, 1982, Synthesis, 34. A preferred compound of formula (VII) is reacted with unsubstituted formula 111 of the corresponding Cj -εθ alkyl substituted with 1 ra formyl deh1d-diethylacetal in refluxing chloroform, in the presence of phosphoryl chloride and sodium acetate. Alternatively, the same reaction may be carried out in other inert solvents, e.g., 1,2-dichloroethane, diethyl ether 111 dloxane, 6 in the presence of other suitable condensaclonal agents, e.g., phosphorus pentoxide or p-toluenesulfonic acid.

Compounds of formula (II) wherein R1 is hydrogen, is hydrogen, 1 Rg is as defined above, "This may be obtained from commercially available androst-4-en-3,17-d1one use" of the same procedures as described above to obtain the compound of formula (II) starting from the compound of formula (Vil).

Compounds of formula (II) in which R 1 is C 1 -C 8 alkyl 1 R 1 Rg are as defined above "can be prepared according to known methods, for example, as shown in the following reaction scheme:

d

Alkylation of the compound of formula (VIII), i.e. "andrnst-4-erl · 3,17-dione and its 1-alkyl derivatives, using the" Atwater method / NJI. Atwater, JACS 79 »5315 (1957) 7 The light addition of alkyl chloride into the luf enhances the ketone solution in t-biitanoi. Which contains only the eraTi multifunctionality of t-thu-tutoxide produces the -forTsule {ΤΧ) compound. 4-en-3.17-dione, or alkyl derivatives thereof.

Alternatively, with the "1-bis-4-en-3,1-dione" its 1-alkyl derivatives can selectively thiomethyl in position 4 with forma dehydro and thio fracture under the base axes. Ben zi 1 mer kap ta n wished jan thiol.

Desulfurization of the intermediate 4-thioether leads to 4-methylthioandrost-4-ene-3,17-dione, or to its 1-alkyl analogs.

The introduction of an alkylidene group at position 6 in the compounds of formula (IX) can be achieved by the method described previously (K. Annen et al., Syntbesis 1982 »34).

lo

Compounds of Formula (IV) 1 Those of Formula (VIII) in which R is hydrogen are known compounds.

The compounds of formula (VIII) wherein the R c ^ -C _g alkyl su compounds of formula (VII) may be prepared Koja are obtainable such as a mountain described.

The compounds of the present invention are inhlbtors of blotransformation of endogenous androgens, i.e., they are inhlbitorl steroidal aromatases.

Therefore, the compounds of the 1z of the invention may be useful as an alternative to endocrine ablation, e.g., oforectemia. Hypophysectomy 111 Adrenalectomy, in the treatment of advanced cancers, dependent on hormones, breast, pancreas, endometrial 1 cancer of the ovaries.

Inhlbitorl aromatases of formula (I) are also used in the control of reproduction: in fact, reducing estrogen levels 1n in vivo leads to activity to inhibit gonad 1 to insufficient uterine development; inhlbitorl aromatases can be Simultaneously implantable implantation.

Another use of compound 1z of the invention is in the treatment of hypertrophy of 111m hyperplasia of the prostate, in connection with the overproduction of estrogen 1 by shifting the estrogen / androgen ratio to a lower value. Aromatase inhibition by the compound of the present invention has been determined. e.g., and in vitro (human placental aromatase) 1 in vivo (ovarian aromatase activity) in rats.

As one example, the activity of 6-methylenandrosta-1,4-diene-5,17 dione / internal at FOE 24Jo4 / has been compared with that of well-known aromatase inhibitors:. 4-hydroxy-androst-4-en3 _f 17-dione (4oII-A), delta-testololactone and androsta-1,4diene-3,1711 dione / AMH Bredle, Cancer Research (SupplJ 42, 3312 s, (1982) ;

D.F. Covev and W.F. Hood, Cancer Research (Suppl.) 42, 3327 s (1982) / and 6-methylandrost-4-ene-3,17-dione, which is described in British Pat. 929,985 as a suitable Intermediate for the production of the therapeutically valuable 6a1α-methyl steroid hormones; however, no therapeutic utility has been attributed to said compound in the above British Patent.

a) Inhibition of aromatase in vitro

Enzymatic system 1z of the microsomal fraction of human placental tissue was isolated according to standard procedure. Thorapson and S1iter1 /E.A assay was used. Thompson and P. K. Sllterl, J.

Biol. Chera. 249, 5364, (1974) / which determines the rate of aromatl3 3 healed as measured by the release of H ^ O 1z; 4- / 1 beta, 2beta-H / -androst3,17-d1one. All incubations were returned to a water bath at 37 ° C in air in 10mM potassium phosphate buffer, pH 7.5, which contained 100 mM KC1, 1 mM EDA and 1 mM dithiothreitol. The experiments were performed in a 1 ml incubation volume containing 50 nM 4- / H / androstendylone, various concentrations of 1nh1b1tor, 100 NADPH 1 0.05 mg ralcrosomain protein.

After 15 minutes of incubation, the reaction was stopped by the addition of chloroform (5 ml). After centrifugation at 1500 xg for minutes, allquotil (0.5 ml) was separated from the aqueous phase to determine the H ₂ O formed.

The concentration of each compound required to reduce the aromatase control by 50% (IC ^ g) was determined by graphlcklr by applying S Inhibition versus the log concentration of 1nh1bitor. The relative strength of each compound versus 4 OH-A was calculated by ligation:

IC ₅₀ 4 0H-A

Relative power = -ICj-o testlran ^ compound

b) Inhibition of aromatase i n vivo in rats

Adult female rats were treated subcutaneously twice with 100 I.U. gonadotrophic serum of pregnant donkeys (PMSG) at 4-day intervals to increase aromatase activity; '$ 3 ovaries, according to Brodie's procedure /A.M.H. Brodle et al.,

2

Steroids 38, 693 (1981). Three days after the second PMSG treatment, groups of 6 animals were given an oral vehicle (0.52 metocele) or an inhibitor at 30 mg / kg. The molluscs are killed 24 hours later, the microsomes are isolated from the ovary 1 and their aromatase activity is determined by a similar procedure to that described in a).

Incubations were performed for 30 minutes in a volume for Roll Incubation containing 0.1 mg of ricrosomal proteins, 100 nH 4- / H / androstendlone 1 100 ^ uM NADPH. 2 inhibitions of control of aroraatlase activity were calculated.

Tablet. Inhibition of human placental aromatase in vitro and rat ovarian aromatase 1 n vivo

IN VITRO IN VIVO The compound nM ^0U (Relative power) 2 Aromatase inhibition at 3 ^ mg / kg p.o. 4-hydroxy-androst-4- en-3,17-d1on 44 (1.00 by definition) Inactive delta-tetestololactone (testolatton) 8240 (0.005) Inaktlvan 6-methyleneandrost-4- en-3.17-dion 74 (0.59) inactive androsta-1,4-diene3,17-dione 11 2 (0. ³ 9) 37 ' 6-methylenandrosta-1,4diene-3,17-dione (FCE 24304) 39 (1.13 81

From the results in the table, it is evident that the new compound 6-methylenandrosta-1,4-diene-3,17-dione (FCE 24304) is a very potent aromatase inhibitor 1 “1n vitro” 1 in vivo ¹¹ .

In vitro, the new compound FCE 24304 is about 3 times more potent than the related androst-1,4-diene-3,17-dione and two hundred times more potent than delta ^ -testollactone. Although the in vitro potency is only slightly higher than 4-OH-A, the new compound is very effective when administered orally, as a result of unusual resistance to meta bo 1ization in the liver, while 4-OH-A is ineffective.

In fact, a major drawback for the therapeutic use of 4-OH-A as an antitumor agent in women in need of parenteral administration is that the compound is extensively conjugated after oral administration of /R.C. Coombes et al., Lancet 11, 1237 (19841

Due to their high therapeutic index, the compounds of the invention can be safely used in medicine. For example, the approximate acute toxicity, (LD _5q ) of the compounds of the invention in mice, determined by single administration of increasing doses and measured at day 7 after treatment, was found to be negligible.

The compounds of the invention may be administered in various dosage forms, e.g., orally, in the form of tablets, capsules, tablets coated with Sugar or film, liquid solutions or emulsions; rectally, in the form of suppositories; parenterally, e.g., intramuscularly, or by intravenous injection with 11i Infusion.

The dose depends on the age, weight, condition of the patient and the route of administration; for example, the dosage accepted for adults, e.g., for a representative compound of the invention FCE 24304, may vary from about 10 to about 150-200 mg per dose, from 1 to 5 times daily.

The invention includes pharmaceutical compositions comprising the compound of the invention together with a pharmaceutically acceptable ingredient (which may be a diluent carrier 111).

Pharmaceutical preparations containing the compounds of the invention are typically made by conventional methods and administered in a pharmaceutically acceptable form.

For example, solid oral forms may contain, in conjunction with the active compound, a solubilizer, e.g., lactose, dextrose, sucrose, cellulose, corn starch 111 potato starch; lubricants, for example, silica, talc, stearic acid, magnesium or calcium stearate and / 111 polyethylene glycol wheels; binders, e.g., starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose'411 polyvinylpyrrolidone;

-14 chopping agents, e.g., starch, alaic acid, a1 ginate or sodium sulphate and col at; mixtures for pen «.Dream; colors; sweeteners; wetting agents, such as lecithin, polysorbates, 1aurylsulfates; and, generally, non-toxic 1 pharmacologically inactive substances used in pharmacist formulations. The aforesaid pharmaceutical preparations may; be produced in a known manner, for example, by means of mixing, granulating, tabletting, sugar coating 111 film coating processes.

Liquid dispersions for oral administration may be, e.g., syrups, 1 suspension emulsions.

The syrups may contain as a carrier, for example, sucrose or sucrose with glycerin and / or mannitol and / or sorbitol.

Suspensions and emulsions may contain a kaon carrier, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxyethylcellulose or polyvinyl alcohol.

Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., sterile water, rawhide oil, ethylolate, glycols, e.g., propylene glycol, and, if necessary, an appropriate amount of 1docaine chloride.

Solutions for Intravenous Injections 111 may contain as a carrier, for example, sterile water, or preferably may be in the form of sterile, aqueous, isotonic saline solutions.

Suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., how-buter, polyethylene glycol, sorbitan fatty acid ester such as surfactant or lecithin. The following examples illustrate but do not limit the invention.

V; · 'ι; ·

Example 1 ο, 5ο g of 6-methylenandrost-4-en-3,17-dione and o, 57 g of dichlorodicyanobenzoquinone are refluxed in 2 ml of anhydrous dioxane for about 15 hours. To separate the DDQ, the suspension is filtered through alumina. 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 was removed in vacuo. The crude product was chromatographed on silica gel using hexane / ethyl acetate to give about 25 g of pure 6-methylenandrost -1,4-diene-3,17-dione, mp 188-191 ° C.

lambda _max 24-7 mu / epsilon 13.75o /

Found; G 81.ol ·, H 8.ο5 · ^G 2o ^H 24 ⁰ 2 ^for gaskets: G 81.o4, H 8.16.

The following compounds of 1-methyl-6-methylenandrosta-1,4-diene-3,17-chion, mp 178-18 ° C, were prepared according to the procedure described above. Found: C 81.18; H, 8.37. ^G 21 ^H 26 ° 2 ^requires: · ^G 81.25; H 8.4-4-; 1-ethyl-6-methylenedrosa-1,4-diene-3,17-dione,

Found: C 81.32; H 8.62 ^G 22 ^ 28 ^ 2 ^for ^ - ^ ^{eva: G} 81 * 4-4-; H, 8.7o;

4 ~ methyl-6-methylenandrosta-1,4-diene-3,17-chion,

Found: C 81.15; H, 8.32. ^G 21 ^H 26 ° 2 requires: G 81.25; H 8.4-4;

4-Ethyl 1-6-methylenandrosta-1,4-diene-3,17-dione;

6- ethylidenandrosta -1,4-diene-3,17-dione;

6-propylidenandrosta-1,4-diene-3,17-dione, and 1-methyl-6-ethylidenandrosa-1,4-diene-3,17-dione.

- 1'6 Example 2

A mixture of 6-methylenandrost-4-ene-3,77-dione (0.10 g), ethylene dioxide (0.50 g) of 1 t-butyl alcohol (200 acre) was refluxed under nitrogen for about 30 hours. The cooled solution was filtered and then evaporated to dryness under reduced pressure. The residue was collected in ethyl acetate (100 acre), treated with charcoal and washed consecutively with water, with a solution of ammonium sulfide, with a cold 17% solution of ammonium hydroxide, with cold dilute hydrochloric acid, with water, dried over sodium sulfate 1 it finally evaporates to dryness. The crude product was chromatographed as described in the example to give 0.20 g of pure 6-methylenandrosta-1,4-diene-3,17-dione, m.p. 188-191 ° C.

The following compounds were obtained by analogous treatment:

1-methyl 1-6-methyl 1enandrosta-1,4-diene-3,17-dione,

Found: C 81.18; H, 8.37. θ £ 1 ^ 26 ° 2 ^for ^ ^teva: -25; H, 8.44;

1- [1-6-Methylenandrosta-1,4-diene-3,17-dione,

Found: C 81.32; H, 8.62. ^C 22 ^ 28 ° 2 ^{for Teva: c} -44; H 8.70;

4-methyl-1-6-methylenandrosta-1,4-diene-3,17-dione,

Found: 61.15; H, 8.32. ^C 21 ^H 26 ° 2 ^{seals: c} 81.25; H. 8.44;

4-ethyl 1-6-methylenandrosta-1,4-diene-3,17-dione;

6-Ethylindenone $ ta-1,4-diene-3,17-dione;

6-propyl 1-dendrosta-1,4-diene-3,17-dione, 1

1-methyl-6-ethylidenandrosta ^ 1,4-dene-3,17-dione.

Example 3

A solution of 1 mum-dimethyl-copper was made under nitrogen by adding 1.6 M ether methyl 1-1 thium to a suspension of cupro-iodide in anhydrous ether at 0 ° C. The solution was stirred at 0 ° C for 20 minutes and then 5alpha.-Androst-1-en3,17-dione in anhydrous tetra hydrofuran 1 was added over a period of 20 minutes and stirred for another 30 minutes. The mixture was poured onto saturated aqueous ammonium chloride, then benzene was added and the resulting mixture was quickly filtered through diatomaceous earth. The organic layer was washed with aqueous anions of jum-chlorine dom, water, dried over magnesium jum-siilfate 1 and evaporated to dryness. The residue was chromatographed on silica gel using hexane / ethyl acetate 10-2-0% to give 1betaethyl-5alpha-androsta-3,17-dione;

IR (KBr): 1710 cm ¹ (3-oxo), 1740 cm ¹ (17-oxo).

To a solution of 1beta-methyl-1-5alpha-androst-3,17-dione (3.025 g) (10 mmol) in glacial acetic acid (100 ml) was added dropwise at 20-25 ° C. with strong solution of bromine solution (1.60 g, 10 mmol) in glacial acetic acid (30 acre) containing one drop of 47% HBr. Bromine still consumes after 20 minutes. The solution was poured into water and the resulting precipitate collected, washed well with water and dried in vacuo to give 3.82 g (100%) of crude 4-bromo-1beta-methyl-5alpha-androsta-3,17-dione; IR (KBr): 1740 cm ^-1 (3-oxo, 17-oxo).

A solution of the crude bromo compound obtained as above in dimethylformamide (100 ml) was mixed with dried 1 thium chloride (7 g) at 140-150 C. After cooling, the solution was poured into water and the resulting oily product extracted with ether. The organic layer was washed with 10% hydrochloric acid and well, dried and then evaporated in vacuo. The residue was chromatographed on silica gel using hexane / ethyl acetate 10-30% to give 2.4 g (80%) of 1-beta-methyl-androst-4-ene ~ 3,17 ~ d1one; I.R.

(KBr): 1620 (delta ⁴ ), 1660 (3-oxo), < 1735 cm &lt; ¹ &gt; (17-oxo).

A mixture of sodium sulfate (1 g), absolute chloroform (30 ml), formaldehyde-diethyl acetate (30 ml. 0.24 mol), phosphoryl chloride (3.8 nil, 0.04 mol) and 1 beta-methyl 1 androst-4 en-3 .1 7-dione (0.811 g, 2.7 mmol) was stirred at reflux for about 7 hours, i.e., until the starting material was gone. The suspension was allowed to cool and, under vigorous stirring, a saturated solution of sodium carbonate was added dropwise until the pH of the aqueous layer became alkaline (about 1 hour). The organic layer was evaporated, neutralized with water and dried and

with sodium sulfate. After concentration under reduced pressure, the oily residue was purified by chromatography on silica gel using bexane / ethyl acetate as the eluent. This gave pure 1beta-methyl-6-methylenandrost-4-ene ~ 3,17-dione in 60% yield (0.193 g);

IR {KBr): 3100 (6 = CH ₂ ), 1735 (17-oxo), 1680 (3-oxo), 1639, 660 cm ^-1 (delta ⁴ and 6 = CH ₂ ).

The following compounds were prepared by analogous treatment:

beta-ethyl 1-6-methylenandrost-4-en-3,17-dione;

1beta-methyl-1-6-ethylidenandrost-4-ene-3,17-dione; i

1beta-ethyl-1-6-ethyl-1idenandrost-4-en-3,17-dione.

Example 4

A solution of androst-4-en-3,17-dione in t-butanol is heated to boiling point and added to the boiling solution of t-butoxide in t-butanol. Methyl chloride in t-butanol is added lightly. The solution was cooled, acidified with concentrated hydrochloric acid and diluted with water. The excess t-butanol was separated in vacuo 1 and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate 1 and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with hexane, ethyl acetate. The eluent was evaporated and the residue was crystallized from ether to give 4-methylandrost-4-ene-3,17-dione; IR (KBr): 1735 (17-oxo), 1660 (3-oxo), 1620 cm ^-1 (delta ⁴ ).

Alternatively, a mixture of androst-4-ene-3,17-dione, thiophenol,

40% of aqueous formaldehyde, triethylamine and ethanol were heated under reflux for about 48 hours. The cooled solution was poured into aqueous sodium hydroxide solution and the product was isolated by extraction with etrpm. The ether extracts were washed with water and dried over magnesium sulfate. The resulting residue was triturated with hexane to separate the porous condensation product derived from thiophenol and form! dehydration. The 4-phenylthiomethylandrost-4-ene-3,17-dione thus obtained is desulfurized by dissolving in acetone and adding to the suspension of Raney nickel in refluxed acetone.

The mixture was refluxed for about 5 hours with stirring. The hot solution was filtered and the catalyst was washed with boiling ethanol and water. The combined filtrates were concentrated in vacuo after which the product was separated - as a solid. Recrystallization from acetone / hexane afforded 4 ~ methylendrost-4-ene-3,17-dione.

A mixture of sodium sulfate (1 g), absolute chloroform (30 ml), forraaldehyde diethyl acetal (30 ml, 0.24 mol), phosphorous (3.8 ml, 0.03 mol) and 4-methylandrost-4-ene-3,1 7-dione (0.31 g,

2.7 mmol) was refluxed for about 7 hours, i.e., until the starting material disappeared. Allow the suspension to cool and vigorously stir with saturated sodium bicarbonate solution dropwise until the pH of the solution becomes alkaline (about 1 hour). The organic layer was separated, neutralized with water and dried over sodium sulfate. After concentration under reduced pressure, the oily residue was purified by chromatography on silica gel using hexane / ethyl acetate as the eluent. This is how it gets clean

4-methyl-6-methyleneandrost-4-en-3,17-dione in 6% yield;

IR (KBr): 3o8 (6 = CH ₂ ), 1735 (17-oxo), 1665 (3-oxo), 1635, 1595 cm ¹ (delta ⁴ and 6 = CH ₂ ).

The following compounds were made by analogous treatment:

beta, 4-dimethyl-6-methyleneandrost-4-ene-3,17-dione;

beta-ethyl-4-methyl-6-methyleneandrost-4-ene-3,17-dione;

beta, 4-diethyl-6-methylenandrost-4-ene-3,17 ~ dione;

4-methyl-6-ethylidenandrost ~ 4-en-3,17-dione; and 1 beta, 4-dimethyl-6-ethylidenandrost-4-en-3,17-dione.

2ο

Example 5

Tablets weighing 0.150 g and containing 25 mg of the active substance are manufactured as follows:

Composition (for 10,000 tablets)

6-methylenandrosta-1,4-diene-3,17-dione

Lactose

Corn starch

Talk powder

Magnesium stearate

250 g 800 g 415 q g 5 g

6-Methylenandrosta-1,4-diene-3,17-dione, 1actose and half of cornstarch are mixed; the mixture is then forced through a sieve of 0.5 ram raesh size. The corn starch (10 g) was suspended in warm water (90 ml) and the resulting paste was used for granulating the powder. The granulate is dried, ground to a 1.4 mm mesh size, then the remaining amount of starch, talcum 1 stearate, is added, mixed carefully and processed into tablets.

Example 6

Capsules are made, which are dosed at 0.200 g and contain 20 mg of the active substance.

Composition for 500 Caspulas:

6-raeti1enandrosta-1,4-diene-3,17-dione 10 g Lactose 20 a Cornstarch 5 g Magnesium stearate 5 g

This formulation is encapsulated in two-part hard gelatin capsules and dosed at 0.200 g for each capsule.

ippicnAR .: · ν'Γ <ΚΒ y ⁿ · E fc

-LINK OF THE BEST WAY TO ECONOMICLY USE THE APPLICATION FOUND

The invention is best applied as follows.

A mixture of 6-methylenandrosta-4-en-3,17-dione, 5o g / and dichlorodicyanobenzoquinone / 57 g was refluxed in 2o ml of anhydrous dioxane for about 15 hours. To separate the DDQ, the suspension is filtered through alumina. 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 was removed in vacuo. The crude product is chromatographed on silica gel using hexane / ethyl acetate to give o.25 g of pure 6-methylenedrosta-1,4-diene-3,17-dione.

Claims (2)

1. The process of a general dione for the production of substituted androst-1. 4-diene-3,17 formula (I) t o , υ n that in which R and Rj. _{t is,} independently of one another, hydrogen (R) and C 1 -C 6 alkyl ar ₂ is hydrogen, One hundred ee compound of formula (II) in which R, R, R ₂ as defined above mountain, at the reflux temperature of a "dehidrogenizuje in the presence of means for dehidrogenizaciju such as a dihlorodicijanobenzohinon, in the presence of orgsnskog solvent such as a dioxane, and axle if necessary, separate «mixtures of isomers of compounds of formula (I) into individual isomers. (Priorities 851736o-Vel.Brit., Dated o9.o7.1985). 2. The process of claim 1, wherein the dehydrogenation is carried out in the presence of selenium dioxide and a lower solvent is used as the organic solvent such as t-butyl alcohol. (Priority "from 08. © 7.1986, - Yugoslavia).