DE3622841A1 - New 6-alkylidene-androstadiene-di:one derivs. - Google Patents

Abstract

6-Alhylidene-androsta-1,4 -diene-3,17-dione derivs. of formula (I) are new. R and R2 are H or 1-6C alkyl; R1 is H, halogen or 1-6C alkyl. Pref. cpds. (I) are e.g. 6-methylene-androsta-1,4- diene-3, 17-dione (Ia); the 1-methyl and 1-ethyl derivs. of (Ia); 6-ethylidene-androsta-1,4- diene-3,17-dione (Ib); and the 1-methyl and 4-fluoro derivs. of (Ib).

Description

The present invention relates to new ones 6-alkylidene androsta-1,4-diene-3,17-dione derivatives Process for their preparation on these compounds containing pharmaceutical preparations and for use of these compounds for the treatment of hormone-dependent Cancer in humans and mammals. Basic and clinical data indicate that flavored Metabolites of androgens, that is, the estrogens, those are the hormones involved in pathogenic cell changes play a role with the growth of certain hormone-dependent cancer, such as B. breast, endometrial and ovarian carcinomas.

Estrogens also play a role in Pathogenesis of benign prostatic hyperplasia.

Endogenous estrogens eventually become either Androstenedione or testosterone as immediate precursors educated. The response is central the aromatization of the steroid ring A by the enzyme Aromatase is effected. Because the flavoring is unique Represents reaction and the last reaction in one Series of stages in the biosynthesis of estrogens is it has been imagined that effective inhibition of the Aromatase, which is caused by compounds that to interact with the flavoring levels fortune might have a useful application to the crowd  of circulating estrogens, estrogen-dependent processes affecting reproduction and estrogen-dependent tumors.

Known steroid substances which have an aromatase inhibitory activity are, for example, Δ ¹ -testololactone (US Pat. No. 2,744,120), 4-hydroxy-androst-4-en-3,17-dione and esters thereof [see, for example, B. US Patent No. 42 35 893], 10- (1,2-propadienyl) -estr-4-en-3,17-dione [US Patent No. 42 89 762], 10- (2-propynyl ) -estr-4-en-3,17-dione [J. At the. Chem. Soc. 103, 3221 (1981) and U.S. Patent No. 43,222,416], 19-thioandrostene derivatives (European Published Patent Application No. 01 00 566), Androsta-4,6-diene-3,17-dione, Androsta -1,4,6-triene-3,17-dione (British published patent application No. 21 00 601A) and Androsta-1,4-diene-3,17-dione [Cancer Res. (Suppl.) 42, 3327 (1982 )].

It has now been found that the new connections not only a strong one according to the present invention have in vitro inhibition of aromatase, but also because their better metabolic stability compared to the Prior art compounds a superior in have a vivo effect.

The present invention relates to compounds of the following general formula: wherein each of the symbols R and R ₂ independently of the other represent a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms and R _{1 represents} a hydrogen atom, a halogen atom or an alkyl radical having 1 to 6 carbon atoms.

The formula shown above for the compounds according to the invention comprises all possible isomers, in particular the Z and E isomers, both separately and in the form of a mixture, of the compounds of the formula I in which R _{2 is} an alkyl radical having 1 to 6 carbon atoms . In the formulas presented in the present description, the broken lines () mean that the substituents are in the α configuration, i.e. below the plane of the ring, while the wedge-shaped lines () indicate that the substituents are in the β configuration , that is, above the level of the ring. The wavy lines () mean that the groups can exist both in the α configuration and in the β configuration.

As preferred alkyl groups with 1 to 6 carbon atoms come alkyl residues with 1 to 4 carbon atoms, especially the methyl, ethyl, propyl or tert. Butyl group, and more preferably the methyl or ethyl group in Question. From these examples it is clear that that the alkyl radicals are both branched and unbranched Can be groups.

Examples of halogen atoms are chlorine, fluorine, Bromine, especially chlorine and fluorine, and more preferred Fluorine.

Preferred compounds according to the invention are compounds of the general formula I in which R is a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, R _{1 is} a hydrogen atom, a fluorine atom, a chlorine atom or an alkyl radical with 1 to 4 carbon atoms and R _{2 is} a hydrogen atom or an alkyl radical 1 to 4 carbon atoms.

More preferred compounds according to the invention are the compounds of the formula I in which R is a hydrogen atom, a methyl radical or an ethyl radical R _{1 is} a hydrogen atom, a fluorine atom or a chlorine atom and R _{2 is} a hydrogen atom.

Examples of specific compounds according to the invention are the following:
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-3,17-dione;
4-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-ethyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-fluoro-6-methylenandrosta-1,4-diene-3,17-dione;
4-chloro-6-methylenandrosta-1,4-diene-3,17-dione;
6-ethylidene androsta-1,4-diene-3,17-dione;
6-propylidene androsta-1,4-diene-3,17-dione;
4-fluoro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-chloro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
1-methyl-6-ethylidenandrosta-1,4-diene-3,17-dione; and
4-fluoro-6-ethylidenandrosta-1,4-diene-3,17-dione.

The compounds according to the invention can be by making

a) a compound of the following general formula: wherein R _{a represents} a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms and R and R _{2 have} the same meanings as above, dehydrogenated to give a compound of formula I, wherein R _{1 represents} a hydrogen atom or an alkyl radical having 1 to 6 Is carbon atoms and R and R _{2 have} the same meanings as in claim 1; or but

b) a compound of the following general formula: wherein R and R _{2 have} the same meanings as above, are reacted with a hydrohalogenating agent to thereby obtain a compound of the formula I in which R _{1 represents} a halogen atom and R and R _{2 have} the same meanings as above, whereupon if desired, a mixture of isomers of compounds of the formula I obtained in this way is separated into the individual isomers.

Dethydration of a compound of the formula II can by treatment with a suitable dehydrating agent, such as B. dichlorodicyanobenzoquinone (DDQ), selenium dioxide or chloranil. Preferably one takes place such implementation by treating with DDQ in an inert Solvents such as B. dioxane, benzene, toluene or Dichloromethane at a temperature in the range from about 40 ° C to about 120 ° C, the reaction time between about 12 hours and about 72 Hours.

As a hydrohalogenating agent, which with a compound of formula III reacts, for example a hydrohalic acid or a trihaloborane called. The reaction of a compound of the formula III with a hydrohalic acid or a trihaloborane can by known methods, for example according to Camerino et al, 1956, I1 Farmaco 11, 586 and A. Bowers et al, 1958, Tetrahedron 3, 14.

Is used as hydrohalic acid hydrochloric acid or hydrobromic acid the reaction preferably in acetic acid or ethanol at a temperature in the range of about 0 ° C to about 100 ° C.

If a trihaloborane is used, for example Boron trifluoride, the reaction is preferably carried out in an inert solvent, such as. B. diethyl ether, Benzene or dichloromethane, at one temperature in the range of about -30 ° C to about 50 ° C.

Separating a mixture of isomers one Compound of formula I can be prepared by conventional means  known methods happen.

For example, you can separate one Mixture of geometric isomers by fractional Crystallization or by separation using column chromatography carry out.

The compounds of formula II, in which R _{a is} a hydrogen atom and R is an alkyl radical having 1 to 6 carbon atoms and R _{2 has} the meaning given above, can be synthesized according to the following reaction scheme using methods known per se. wherein R _{b is} an alkyl radical having 1 to 6 carbon atoms and and R _{a is} a hydrogen atom and R _{2 has} the meaning given above.

For example, the dehydrogenation of a compound of the Formula IV for the preparation of a compound of formula V. for example according to H.J. Ringold et al, 1962, Chemistry and Industry, 211. It is preferred by treatment with DDQ in boiling dioxane.

A compound of formula VI is obtained by alkylating a compound of formula V, for example according to one of the known methods. The alkylation is preferably carried out by adding a compound of Formula V, dissolved in an inert solvent a solution of dialkyllithium copper in the same or in another inert solvent. Suitable inert Examples of solvents are methylene chloride, Tetrahydrofuran, benzene or diethyl ether, where one preferred the diethyl ether. The implementation preferably takes place at a temperature between approximately -75 ° C and about 20 ° C, preferably one a temperature range from about -5 ° C to about 0 ° C will apply. The ratio of the reactants is not important, but at least you will Use 2 moles of dialkyllithium copper. Remarkably, that the addition occurs selectively on the β side. Consequently there will be an axial hydrogen atom in the 1 position that is suitable for elimination. links of formula VII can start from a compound of the formula VI by known methods, such as e.g. B. M. Mori, 1962, Chem. Pharm. Bull. (Tokyo). 10, 386. Therefore you can connect of formula VI by treatment with 1 to 1.2 Equivalents of bromine in acetic acid or in another suitable solvent at a temperature in the range of about 0 ° C to about 50 ° C, preferably  at room temperature, brominate, taking one a 4-bromo derivative is obtained, which is subsequently used without further Purification in a dimethylformamide solution in Presence of lithium chloride at about 140 to 150 ° C dehydrobrominated. A compound of formula II can be based on a compound of formula VII known methods can be obtained, for example using the method of K. Annen, 1982, Synthesis, 34. A compound of the formula VII with unsubstituted or in a suitable manner Alkyl with 1 to 6 carbon atoms substituted Formaldehyde diethylacetal under reflux in chloroform and in the presence of phosphoryl chloride and sodium acetate implemented. On the other hand, you can also the same implementation in another inert Solvents such as B. 1,2-dichloroethane, diethyl ether or dioxane, and in the presence of another suitable one Condensing agents such as B. phosphorus pentoxide or p-Toluenesulfonic acid.

Compounds of formula II, wherein both R _a and R _{b represent} a hydrogen atom and R _{2 has} the above meaning, can be obtained from commercially available androst-4-en-3,17-dione using the above for the preparation of a compound of formula II, starting from a compound of formula VII, described procedures.

Compounds of the formula II in which R _{a is} an alkyl radical having 1 to 6 carbon atoms and the symbols R and R _{2 have} the above meanings can also be prepared by known methods. This can be done, for example, according to the following reaction scheme:

The alkylation of a compound of the formula VIII, that is Androst-4-en-3,17-dione and his 1-alkyl derivatives, using the Atwaters Working method [N.W.Atwater, JACS 79, 5315 (1957)] by slowly adding an alkyl chloride under reflux to a solution of the ketone in tert-butanol containing only a small excess of potassium tert-butoxide, provides a compound of the formula IX, that is a 4-alkylandrost-4-en-3,17-dione or its 1-alkyl derivatives.

The androst-4-en-3,17-dione and its 1-alkyl derivatives can, on the other hand, in the 4-position with formaldehyde  and a thiol under alkaline conditions in be selectively thiomethylated. For this purpose the thiol benzyl mercaptan is preferred.

The desulfurization of the as intermediates resulting 4-thioether leads to 4-methyllandrost-4-en- 3,17-dione or its 1-alkyl analogs.

The introduction of an alkylidene group in the 6-position in the compounds of formula IX can be according to the method described above (K. Annen et al., Synthesis 1982, 34).

The compounds of formula III can be prepared by processes known per se, for. B. according to the following reaction scheme:

The epoxidation of a compound of formula II to prepare a compound of formula X can be carried out by treatment with a suitable, preferably concentrated, oxidizing agent, e.g. B. 36% H ₂ O ₂ , in an alcoholic alkali hydroxide solution, preferably potassium hydroxide or sodium hydroxide in methanol, at a temperature in the range from 0 to 25 ° C for about 2 hours to several days.

The dehydrogenation of a compound of formula X for the preparation of a compound of formula III can by Treatment with a suitable dehydrating agent, e.g. B. Dichlorodicyanobenzoquinone, in a refluxing Solvents happen in the manner described above.

The compounds of formula IV and those of the formula VIII, in which R represents hydrogen, are known Links.

The compounds of formula VIII, wherein R represents an alkyl radical having 1 to 6 carbon atoms, are compounds of formula VII, which are in the above can be obtained as described.

The compounds according to the invention are inhibitors for the biotransformation of endogenous androgens, that is, they are steroid aromatase inhibitors.

Leave the compounds of the invention is therefore an alternative to ablation of the endocrine Glands, e.g. B. oophorectomy, hypophysectomy or adrenalectomy, in the treatment of advanced, hormone-dependent Breast cancer, pancreatic cancer, endometrial cancer and Ovarian cancer.  

Leave the aromatase inhibitors of formula I. also use it to control reproduction. A decrease in estrogen levels in vivo results in Acted to inhibit the sex glands and insufficient uterine development. The aromatase Inhibitors can also act as nidation inhibitors be used.

Another application of the invention Compounds is the treatment of prostate hypertrophy or hyperplasia, which in turn is related to excessive estrogen production and a shift of the estrogen-androgen ratio against higher values. The aromatase inhibition with the help of the Connections have been made e.g. B. in vitro (Human placenta aromatase) and in vivo (ovarian aromatase activity) determined in rats.

For example, the effect of 6-methylenandrosta-1,4-diene-3,17-dione (internal code FCE 24304) was compared to that of well-known aromatase inhibitors: 4-hydroxy-androst-4-en-3,17- dione (4OH-A), Δ ¹ -testololactone and androsta-1,4-diene-3,17-dione [AMH Brodie, Cancer Research (Suppl.) 42, 3312 s, (1982); DF Covey and WF Hood, Cancer Research (Suppl. 42, 3327s, 1982)] and 6-methylenandrost-4-en-3,17-dione, which is described in British Patent No. 9 29 985 as a suitable intermediate for the Production of therapeutically valuable 6α-methyl steroid hormones is described. A therapeutic use of this compound is not, however, ascribed to said patent.

a) Aromatase inhibition in vitro

The enzyme system was isolated from the microsome fraction of human placenta tissue by the usual method. The experiment according to Thompson and Siiteri [EA Thompson and PK Siiteri, J. Biol. Chem. 249, 5364 (1974)], which determines the rate of aromatization caused by the release of ³ H ₂ O from 4- [1β, 2β - ³ H] -androstene-3,17-dione is used. All incubations were carried out in a water bath with shaking at 37 ° C. in air in a 10 millimolar potassium phosphate buffer with a pH of 7.5, which contained 100 mmol KCI, 1 mmol EDA and 1 mmol dithiothreitol per liter. The experiments were carried out in a 1 ml incubation volume containing 50 nmol of 4- [ ³ H] -androstenedione, various concentrations of the inhibitors, 100 μmol of NADPH and 0.05 mg of microsome proteins per liter. After an incubation time of 15 minutes, the reaction was interrupted by adding 5 ml of chloroform. After centrifuging at 1500 x g for 5 minutes, 0.5 ml aliquots were removed from the aqueous phase to determine the ³ H ₂ O formed.

The concentration (IC ₅₀ ) of each compound required to reduce the control aromatase by 50% was determined by plotting the percentage inhibition against the logarithm of the inhibitor concentration. The relative activity of each compound against 4OH-A was calculated according to the following equation:

b) in vivo aromatase inhibition in rats

Adult female rats were treated with 100 I.U. Serum gonadotropin from pregnant mares (PMSG) twice Treated subcutaneously at 4 day intervals to control the Ovarian aromatase effect according to the Brodie method [A.M.H. Brodie et al., Steroids 38, 693, (1981)] increase. 3 days after the second PMSG treatment Groups of 6 animals each orally with the carrier (0.5% methocel) or the inhibitor at 30 mg / kg. After 24 hours the animals were killed, the microsomes isolated from the ovaries and their Aromatase effect using a similar method determines how this has been described in paragraph a) is.

The incubations were carried out for 30 minutes in a 1 ml incubation volume containing 0.1 mg microsome proteins, 100 nmol / liter 4- [ ³ H] -androstenedione and 100 µmol / liter NADPH. The inhibition of the control aromatase activity in% was calculated.

table

Inhibition of human placenta aromatase in vitro and of rat ovarian aromatase in vivo

The above results show that it is it is very clear that the new connection, namely 6-methylene androsta-1,4-diene-3,17-dione (FCE 24304) both an extraordinarily strong one in vitro as well as in vivo Is aromatase inhibitor.

In vitro, the new compound FCE 24304 is approximately three times more effective than the related androsta-1,4-diene-3,17-dione and 200 times more effective than the Δ ¹ -testololactone. Although its in vitro activity is only slightly higher than that of 4-OH-A, the new compound is extremely effective when administered orally in vivo, which is a consequence of the unusual resistance to hepatic metabolism, whereas 4-OH- A is ineffective.

One must note that the main disadvantage of 4-OH-A as an anti-tumor agent in therapeutic use in women it can be seen that this connection must be administered parenterally because of the compound is highly conjugated after oral administration [R.C. Coombes et al, Lancet II, 1237 (1984)].

In view of their high therapeutic indices, the compounds according to the invention can be used safely in medicine. For example, it has been found that the approximate acute toxicity (LD ₅₀ ) of the compounds according to the invention in mice, determined by single administration of increasing doses and measured on the 7th day after the treatment, is practically negligible.

The compounds according to the invention can be apply in different dosage forms, e.g. B. orally in Form of tablets, capsules, with sugar or with films  coated tablets, liquid in the form of solutions or Suspensions, rectally in the form of suppositories, parenterally, for example intramuscularly, or by intravenous injection or infusion.

The dosage depends on the age, weight, condition of the patient and the mode of administration. For example the dosage when given orally to adults People for the compound FCE 24304 in the invention Ranges from about 10 to about 150 to 200 mg each Dose once to five times a day.

The invention also includes pharmaceutical Preparations which are one of the compounds according to the invention in connection with a pharmaceutically harmless Excipiens, which is a carrier or a diluent can be included.

Those containing the compounds according to the invention pharmaceutical preparations can be in Generally and can produce according to usual methods administered in a pharmaceutically suitable form will.

For example, the solid oral forms can coexist the active substance diluent, e.g. B. lactose, dextrose, Sucrose, cellulose, corn starch or potato starch, Lubricants, e.g. B. silicon dioxide, talc, stearic acid, Magnesium or calcium stearate and / or polyethylene glycols, Binders, e.g. B. starches, gum arabic, gelatin, Methyl cellulose, carboxymethyl cellulose or polyvinyl pyrrolidone, Disintegrants such as B. a strength Alginic acid, alginates or "sodium starch glycolate",  foaming mixtures, colorants, sweeteners, wetting agents, such as B. lecithin, polysorbates, lauryl sulfates, and in general non-toxic and pharmacologically inactive substances, as used in pharmaceutical formulations contain. Such pharmaceutical preparations can be in produce in a known manner, for example by Mixing, granulating, tableting, coating with sugar or coating with films.

The liquid dispersions for oral administration can e.g. B. in the form of syrups, emulsions and suspensions are available.

The syrups can be used as carriers, for example sucrose or sucrose with glycerin and / or mannitol and / or Contain sorbitol.

The suspensions and emulsions can be used as Carrier, for example, a natural rubber, Agar, sodium alginate, pectin, methyl cellulose, carboxy contain methyl cellulose or polyvinyl alcohol.

The suspensions and solutions for intramuscular In addition to the active substance, injections can be pharmaceutical harmless carrier, e.g. B. sterile water, Olive oil, ethyl oleate, glycols, such as. B. propylene glycol, and, if desired, an appropriate amount of lidocaine contain hydrochloride. The solutions for intravenous Injections or infusions can be used as carriers e.g. B. contain sterile water, or they can preferably in the form of sterile, aqueous, isotonic Saline solutions are available.

Suppositories can be in addition to the active substance a pharmaceutically acceptable carrier, e.g. B. cocoa butter,  Polyethylene glycol, a surfactant Polyoxyethylene sorbitan fatty acid ester or lecithin contain.

The following examples are intended to illustrate the present Illustrate the invention without, however, restricting it.

example 1

0.50 g of 6-methylenandrost-4-en-3,17-dione and 0.57 g of dichlorodicyanobenzoquinone are refluxed in 20 ml of anhydrous dioxane for about 15 hours. To remove the DDQ, the suspension is filtered through aluminum oxide. After evaporation of the solvent, the residue is dissolved in ethyl acetate, the organic layer washed with water, dried over sodium sulfate and the solvent removed in vacuo. The crude product is chromatographed on silica gel using a mixture of hexane and ethyl acetate (40%), whereby 0.25 g of pure 6-methylene-androsta-1,4-diene-3,17-dione, melting point 188 to 191 ° C., λ _max 247 mµ (ε 13,750) is obtained.
Found: C 81.01; H 8.05. C ₂₀ H ₂₄ O ₂ requires: C 81.04; H 8.16.

The following compounds are prepared according to the procedure described above:
1-methyl-6-methylenandrosta-1,4-diene-3,17-dione,
Found: C 81.18; H 8.37. C ₂₁ H ₂₆ O ₂ requires: C 81.25; H 8.44.
1-ethyl-6-methylenandrosta-1,4-diene-3,17-dione,
Found: C 81.32; H 8.62. C ₂₂ H ₂₈ O ₂ requires: C 81.44; H 8.70.
4-methyl-6-methylenandrosta-1,4-diene-3,17-dione,
Found: C 81.15; H 8.32. C ₂₁ H ₂₆ O ₂ requires: C 81.25; H 8.44.
4-ethyl-6-methylenandrosta-1,4-diene-3,17-dione;
6-ethylidene androsta-1,4-diene-3,17-dione;
6-propylidene androsta-1,4-diene-3,17-dione; and
1-methyl-6-ethylidenandrosta-1,4-diene-3,17-dione.

Example 2

A mixture of 6-methylenandrost-4-en-3.17- dione (0.50 g), selenium dioxide (0.50 g) and tert-butyl alcohol (200 ml) is kept under nitrogen for about Heated to boiling under reflux for 30 hours. The cooled solution is then filtered and then on evaporated to dryness under reduced pressure. The Residue is taken up in 100 ml of ethyl acetate with Coal treated and successively with water, ammonium sulfide solution, cold 17% ammonium hydroxide, cold diluted hydrochloric acid and water, then washed with Dried sodium sulfate and finally to dryness evaporated. The raw product is made in the same way chromatographed as in Example 1, giving 0.20 g pure 6-methylenandrosta-1,4-diene-3,17-dione, melting point 188 to 191 ° C.

The following compounds are obtained in an analogous manner:
1-methyl-6-methylenandrosta-1,4-diene-3,17-dione,
Found: C 81.18; H 8.37. C ₂₁ H ₂₆ O ₂ requires: C 81.25; H 8.44.
1-ethyl-6-methylenandrosta-1,4-diene-3,17-dione,
Found: C 81.32; H 8.62. C ₂₂ H ₂₈ O ₂ requires: C 81.44; H 8.70.
4-methyl-6-methylenandrosta-1,4-diene-3,17-dione,
Found: C 81.15; H 8.32. C ₂₁ H ₂₆ O ₂ requires: C 81.25; H 8.44.
4-ethyl-6-methylenandrosta-1,4-diene-3,17-dione;
6-ethylidene androsta-1,4-diene-3,17-dione;
6-propylidenandrosta-1,4-diene-3,17-dione; and
1-methyl-6-ethylidenandrosta-1,4-diene-3,17-dione.

Example 3

A solution of 1.0 g of 4,5-epoxy-6-methylene androst-1-en-3,17-dione in 10 ml of glacial acetic acid is treated with gaseous hydrogen chloride for 30 minutes at room temperature. The resulting precipitate is filtered off, washed with diethyl ether, dried and chromatographed on silica gel, using a mixture of hexane and ethyl acetate. In this way, 0.8 g of pure 4-chloro-6-methylenandrosta-1,4-diene-3,17-dione is obtained.
Found: C 72.40; H 6.91; Cl 10.53; C ₂₀ H ₂₃ ClO ₂ requires:
C 72.61; H 7.01; Cl 10.72.
NMR, δ, ppm: 0.84 (3H, s); 1.24 (3H, s); 5.13 (1H s);
5.43 (1H, s); 6.37 (1H, d); 7.08 (1H, d).
MS (m / z): 330.

According to the procedure described above and starting from a suitable 4,5-epoxy derivative, the following compounds are prepared using a suitable gaseous hydrohalic acid:
4-bromo-6-methylenandrosta-1,4-diene-3,17-dione,
Found: C 63.90: H 6.03: Br 21.15. C ₂₀ H ₂₃ BrO ₂ requires:
C 64.00; H 6.18; Br 21.29;
4-fluoro-6-methylenandrosta-1,4-diene-3,17-dione,
Found: C 76.35; H 7.34; F 6.01. C ₂₀ H ₂₃ FO ₂ requires:
C 76.41; H 7.37; F 6.04.
4-chloro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-bromo-1-methyl-6-methylene androsta-1,4-diene-3,17-dione;
4-fluoro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione,
Found: C 76.75; H 7.62; F 5.71. C ₂₁ H ₂₅ FO ₂ requires:
C 76.80; H 7.67; F 5.79.
4-chloro-6-ethylidenandrosta-1,4-diene-3,17-dione;
4-bromo-6-ethylidenandrosta-1,4-diene-3,17-dione; and
4-fluoro-6-ethylidenandrosta-1,4-diene-3,17-dione.

Example 4

A solution of 1.0 g of 4.5 epoxy-6-methylene androst-1-en-3,17-dione in 100 ml of diethyl ether is treated with 1.4 ml of boron trifluoride etherate for 3 hours at room temperature. The solution is then washed with 5% sodium carbonate solution and water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue obtained is dissolved in 20 ml of pyridine and 0.4 ml of thionyl chloride is added to this solution at 0 ° C. After 5 minutes, water is added and the product is isolated with ether. The ether extracts are washed with 2N hydrochloric acid and water, dried over sodium sulfate and evaporated. The crude product so obtained is chromatographed on silica gel using a mixture of hexane and ethyl acetate as the eluent to give 0.6 g of pure 4-fluoro-6-methylene-androsta-1,4-diene-3,17-dione.
Found: C 76.30; H 7.35; F 5.91; C ₂₀ H ₂₃ FO ₂ requires:
C 76.40; H 7.37; F 6.04.

The following compounds are obtained when working according to the above method:
4-fluoro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-fluoro-6-ethylidenandrosta-1,4-diene-3,17-dione.

Example 5

5 g of 6-methylenandrost-4-en-3,17-dione are dissolved in 200 ml of methanol and this solution is cooled to 0 ° C. Then 17 ml of ice-cold 36% hydrogen peroxide and 9 ml of a 2% sodium hydroxide solution are added. The mixture is then stirred for 1 hour, left to stand at 5 ° C. for 20 hours and then poured into 1400 ml of ice water with vigorous stirring, whereupon the product is filtered off, washed with water and dried, 4.2 g (80% ) 4,5-epoxy-6-methylenandrosta-3,17-dione [α / β-epoxy mixture) is obtained.
NMR, δ, ppm: 0.90 (3H, s); 0.97 (3H, s); 3.52 (1H, s);
4.92 (1H, broad); 5.06 (1H, broad).

3 g of 4,5-epoxy-6-methylenandrosta-3,17-dione and 1.7 g of dichlorodicyanobenzoquinone, dissolved in 60 ml of anhydrous dioxane, are refluxed for about 15 hours. The cooled solution is filtered through aluminum oxide and the solvent evaporated in vacuo. The residue is taken up in ethyl acetate, the organic layer is washed with water, dried and the solvent is removed in vacuo. The crude product is chromatographed on silica gel using a mixture of hexane and ethyl acetate (10 to 40%) to give 1.5 g of pure 4,5-epoxy-6-methylenandrost-1-en-3,17-dione.
NMR, δ, ppm: 0.93 (3H, s); 1.13 (3H, s); 3.71 (1H, d);
5.03 (2H, m); 5.86 (1H; d); 6.78 (1H, d).

Following the procedure described above, the following compounds are prepared using a suitable 6-alkylidene-androst-4-en-3,17-dione:
1-methyl-4,5-epoxy-6-methylene-androst-1-ene-3,17-dione;
1-ethyl-4,5-epoxy-6-methylene-androst-1-ene-3,17-dione;
4,5-epoxy-6-ethylidene androst-1-ene-3,17-dione;
1-methyl-4,5-epoxy-6-ethylidene-androst-1-en-3,17-dione; and
1-ethyl-4,5-epoxy-6-ethylidene androst-1-en-3,17-dione.

Example 6

A solution of lithium dimethyl copper is prepared by adding 1.6 molar ethereal methyl lithium under nitrogen to a slurry of cuproiodide in anhydrous ether at 0 ° C. The solution thus obtained is stirred at 0 ° C. for 20 minutes and then within 20 minutes 5α-androst-1-en-3,17-dione in anhydrous tetrahydrofuran was added and the mixture was stirred for a further 30 minutes. The mixture is then poured onto a saturated aqueous ammonium chloride solution, then benzene is added and the mixture obtained is finally rapidly filtered through diatomaceous earth. The organic layer is washed with aqueous ammonium chloride and then with water, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel using a mixture of hexane and ethyl acetate (10 to 20%) to give 1β-methyl-5α-androsta-3,17-dione.
IR (KBr): 1710 cm ^-1 (3-oxo), 1740 cm ^-1 (17-oxo).

To a solution of 3.025 g (10 mmol) of 1β-methyl 5α-androsta-3,17-dione in 100 ml glacial acetic acid is added to 20 to 25 ° C dropwise a solution with vigorous stirring of bromine (1.60 g, 10 mmol) in glacial acetic acid (30 ml) containing a drop of 47% hydrobromic acid. The Bromine is used up after 20 minutes.  

The solution is poured into water and the resulting precipitate is collected, washed thoroughly with water and dried in vacuo, giving 3.82 g (100%) of crude 4-bromo-1β-methyl-5α-androsta-3.17- dion receives.
IR (KBr): 1740 cm ^-1 (3-oxo, 17-oxo).

A solution of the crude bromine compound thus obtained in 100 ml of dimethylformamide is stirred at 140 to 150 ° C. with 7 g of dried lithium chloride. After cooling the solution, it is poured into water and the resulting oily product is extracted with ether. The organic layer is washed with 10% hydrochloric acid and then with water, dried and then evaporated to dryness in vacuo. The residue is chromatographed on silica gel using a mixture of hexane and ethyl acetate (10 to 30%) to give 2.4 g (80%) of 1β-methyl-androst-4-ene-3,17-dione.
IR (KBr): 1620 (Δ ⁴ ), 1660 (3-oxo), 1735 cm ^-1 (17-oxo).

A mixture of 1 g sodium acetate, 30 ml absolute chloroform, 30 ml (0.24 mol) formaldehyde diethyl acetal, 3.8 ml (0.04 mol) phosphoryl chloride and 0.811 g (2.7 mmol) 1β-methyllandrost 4-en-3,17-dione is heated to boiling under reflux for about 7 hours, that is, until the starting material has disappeared. The suspension is then allowed to cool and saturated sodium carbonate solution is added dropwise with vigorous stirring until the pH of the aqueous layer has become alkaline (after approximately 1 hour). The organic layer is separated, washed neutral with water and dried with sodium sulfate. After concentration under reduced pressure, the oily residue is purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as the eluent. In this way, 0.195 g of pure 1β-methyl-6-methylenandrost-4-ene-3,17-dione is obtained in a yield of 60%.
IR (KBr): 3100 (6 = CH ₂ ), 1735 (17-oxo), 1680 (3-oxo),
1630, 1660 cm ^-1 (Δ ⁴ and 6 = CH ₂ ).

The following connections are made in an analogous manner:
1β-ethyl-6-methylenandrost-4-en-3,17-dione;
1β-methyl-6-ethylidene-androst-4-en-3,17-dione; and
1β-ethyl-6-ethylidene-androst-4-en-3,17-dione.

Example 7

A solution of androst-4-en-3,17-dione in tert-butanol is heated to boiling and then added to a likewise boiling solution of potassium tert-butoxide in tert-butanol. Methyl chloride in tert-butanol is slowly added. The solution is cooled, acidified with concentrated hydrochloric acid and diluted with water. The excess tert. Butanol is removed in vacuo and the aqueous layer extracted with ethyl acetate. The combined extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel and eluted with a mixture of hexane and ethyl acetate. The eluent is evaporated and the residue is crystallized from ether to give 4-methylandrost-4-en-3,17-dione.
IR (KBr): 1735 (17-oxo), 1660 (3-oxo), 1620 cm ^-1 (Δ ⁴ ).

Alternatively, a mixture of androst-4-en-3,17- dione, thiophenol, 40% aqueous formaldehyde, triethylamine  and ethanol for a period of approximately 48 Heated to reflux for hours. The chilled Solution is poured into an aqueous sodium hydroxide solution and the product isolated by extraction with ether. The ether extracts are washed with water and over Magnesium sulfate dried. The resulting residue is triturated with hexane to remove all of the thiophenol and the condensation by-products derived from formaldehyde to remove. The 4-phenylthiomethylandrost 4-en-3,17-dione is added by dissolving in acetone and adding a suspension of Raney nickel in refluxing Desulphurized acetone. The mixture becomes approximate with stirring Heated to reflux for 5 hours. The hot solution is filtered and the catalyst boiling Washed ethanol and water. The combined filtrates are concentrated under vacuum, whereupon the product separates out as a solid mass. The recrystallization from a mixture of acetone and hexane gives 4-methylane drost-4-en-3,17-dione.

A mixture of sodium acetate (1 g) absolute Chloroform (30 ml), formaldehyde diethylacetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol) and 4-Methyllandrost-4-en-3,17-dione (0.18 g, 2.7 mmol) for about 7 hours, that is, until that Starting material has disappeared, refluxing to boiling heated. Then the suspension is allowed to cool and with vigorous stirring dropwise with a saturated Sodium carbonate solution is added until the pH of the aqueous layer (after about 1 hour) become alkaline is. The organic layer is separated off with water washed neutral and over sodium sulfate the oily Residue by chromatography on silica gel using  a mixture of hexane and ethyl acetate as Eluent purified by chromatography.

In this way, the pure 4-methyl-6-methylenandrost-4-en-3,17-dione is obtained in a yield of 60%.
IR (KBr): 3080 (6 = CH ₂ ), 1735 (17-oxo), 1665 (3-oxo),
1635, 1595 cm ^-1 (Δ ⁴ and 6 = CH ₂ ).

The following connections are made in an analogous manner:
1β, 4-dimethyl-6-methylenandrost-4-en-3,17-dione;
1β-ethyl-4-methyl-6-methylenandrost-4-en-3,17-dione;
1β, 4-diethyl-6-methylenandrost-4-en-3,17-dione;
4-methyl-6-ethylidene androst-4-en-3,17-dione; and
1β, 4-dimethyl-6-ethylidene androst-4-en-3,17-dione.

Example 8

Tablets, each weighing 0.150 g and 25 mg of active substance are manufactured in the following way:

Composition (for 10,000 tablets)

6-methylene androsta-1,4-diene-3,17-dione 250 g
Lactose 800 g
Corn starch 415 g
Talcum powder 30 g
Magnesium stearate 5 g

The 6-methylene androsta-1,4-diene-3,17-dione, the Lactose and half of the cornstarch are mixed together mixed. This mixture is then passed through a sieve pressed with a mesh size of 0.5 mm. On the other hand 10 g of corn starch are suspended in 90 ml of warm water,  and the resulting paste becomes granulating of the powder used.

The granules are dried on a sieve a mesh size of 1.4 mm crushed and this material then with the remaining amount of starch, the talc and the magnesium stearate, mixed thoroughly and processed into tablets.

Example 9

Capsules dosed with 0.200 g each and 20 mg Containing active substance are manufactured as follows:

Composition for 500 capsules:

6-methylene androsta-1,4-diene-3,17-dione 10 g
Lactose 80 g
Corn starch 5 g
Magnesium stearate 5 g

This formulation comes in two-part hard gelatin capsules packed and dosed with 0.200 g per capsule.

Claims (13)

1. Compounds of the following general formula: wherein each of the symbols R and R ₂ independently of the other represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms and R _{1 represents} a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms. 2. Compounds of formula I according to claim 1, wherein R is a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, R _{1 is} a hydrogen atom, a fluorine atom, a chlorine atom or an alkyl group having 1 to 4 carbon atoms and R _{2 is} a hydrogen atom or an alkyl group 1 to 4 carbon atoms. 3. Compounds of formula I according to claim 1, wherein R is a hydrogen atom, a methyl radical or an ethyl radical, R _{1 is} a hydrogen atom, a fluorine atom or a chlorine atom and R _{2 is} a hydrogen atom. 4. 6-methylenandrosta-1,4-diene-3,17-dione according to Claim 1. 5. As compounds according to claim 1:
1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
1-ethyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-ethyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-fluoro-6-methylenandrosta-1,4-diene-3,17-dione;
4-chloro-6-methylenandrosta-1,4-diene-3,17-dione;
6-ethylidene androsta-1,4-diene-3,17-dione;
6-propylidene androsta-1,4-diene-3,17-dione;
4-fluoro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-chloro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
1-methyl-6-ethylidenandrosta-1,4-diene-3,17-dione; and
4-fluoro-6-ethylidenandrosta-1,4-diene-3,17-dione. 6. Method of making connections of formula I according to any one of claims 1 to 5, characterized characterized that one a) a compound of the following general formula: wherein R _{a represents} a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms and R and R _{2 have} the same meanings as in claim 1, dehydrated to give a compound of formula I, wherein R _{1 represents} a hydrogen atom or an alkyl radical having 1 is up to 6 carbon atoms and R and R _{2 have} the same meanings as in claim 1; or but b) a compound of the following general formula: wherein R and R _{2 have} the same meanings as in claim 1, are reacted with a hydrohalogenating agent to thereby obtain a compound of the formula I in which R _{1 represents} a halogen atom and R and R _{2 have} the same meanings as in claim 1 have, whereupon, if desired, a mixture of isomers of compounds of the formula I obtained in this way is separated into the individual isomers. 7. Pharmaceutical preparation, characterized in that it is a suitable vehicle and / or Diluent and a compound as an active substance of formula I according to claim 1. 8. Compounds of formula I according to claim 1 for use in medicine for the treatment of advanced hormone-dependent breast cancer, pancreatic cancer, Endometrial cancer and ovarian cancer. 9. Compounds of formula I according to claim 1 for use in medicine for the treatment of prostate hypertrophy and prostate hyperplasia. 10. Use a general connection Formula I according to claim 1 for the production of  pharmaceutical preparations for the treatment of advanced hormone-dependent breast cancer, pancreatic cancer, Endometrial cancer and ovarian cancer. 11. Use a general connection Formula I according to claim 1 for the manufacture of a pharmaceutical preparation for the treatment of prostate hypertrophy and prostate hyperplasia.