GB2191777A - Methylene derivatives of androst-4-ene-3,17-diones and process for their preparation - Google Patents

Description

SPECIFICATION Methylene derivatives of androst-4-ene-3,17-diones and process for their preparation

process for their preparation, to pharmaceutical compositions containing them, and to the use of said compounds for the treatment of hormone-dependent cancers in mammals. Basic and clinical data indicate that aromatized metabolites of androgens, i.e. the estrogens, are the hormones involved in the pathogenic cellular changes associated with the growth of some hormonedependent cancers, such as breast, endometrial and ovarian carcinomas. Estrogens are also involved in the pathogenesis of benign prostatic hyperplasia. Endogenous estrogens are ultimately formed from either androstenedione or testosterone as immediate precursors. The reaction of central importance is the aromatization of the steroidic ring A, which is performed by the enzyme aromatase. As aromatization is a unique reaction and the last in the series of steps in the biosynthesis of estrogens, it has been envisaged that an effective inhibition of the aromatase, resulting from compounds able to interact with the aromatizing steps, may have useful application for controlling the amount of circulating estrogens, estrogen-dependent processes in reproduction, and estrogen-dependent tumours. Known steroidal substances which have been reported to be endowed with an aromatase-inhibiting action are, for example, -testotoactone [U.S. Pat. 2,744,120], 4-hydroxy-androst-4-ene-3,17-dione and esters

762],10-(2-propynyl)-estr-4-ene-3,17-dione [J. Am. Chem. Soc., 103,3221 (1981) and U.S. Pat. 4,322,416], 19-thioandrostene derivatives (Europ. Pat. Appl. 100566), androsta-4,6-diene-3,17-dione, androsta-1,4,6triene-3,17-dione [G.B. Pat. Appl. 2,100,601A] and androsta-1,4-diene-3,17-dione [Cancer Res. (Suppl.) 42, 3327(1982)]. The present invention provides compounds having the following general formula (I)

wherein R is hydrogen orfluorine; one of R1 and R2 is =CH2 and the other is hydrogen or C1 C4 alkyl, and, when R2 is =CH2, at least one of R and R, is other than hydrogen. The invention also includes within its scope all the possible isomers, stereoisomers and their mixtures and the metabolites and the metabolic precursors or bio-precursors of the compounds of formula (I). In the formulae of the specification the broken lines (----) indicate that the substituents are in the a-configuration, i.e. below the plane of the ring, while the heavy solid lines ( ) indicate that the substituents are in the p-configuration, i.e. above the plane of the rings; a wavy bond ( ) indicates that a substituent may be either in the a- or in the (3-configuration or both. When in the compounds of formula (I) R1 is =CH2, the R2 substituent may be either in the a- or (3-configuration. Analogously when R2 is =CH2 then the R1 substituent may be either in the a or (3-configuration. A C1-C4 alkyl group is preferably a methyl or ethyl group, more preferably a methyl group. The alkyl radical may be a branched or straight chain group. As stated above the present invention also includes within its scope pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different formula to formula (I) above but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound offormula (I). Preferred compounds of the invention are the compounds offormula (I) wherein R is hydrogen of fluorine; one of R, and R2 is =CH2 and the other is C1-C4 alkyl. Examples of specific compounds of the invention are:

7p-ethyl-6-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione; 16-fluoro-6-methylene-1,2(3-cyclopropanoandrost-4-ene-3,17-dione;

16-fluoro-7p-methyl-6-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione; 16-fluoro-7a-ethyl-6-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione; 16-fluoro-7p-ethyl-6-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione; 7-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione;

6a-ethyl-7-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione; 6p-ethyl-7-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione; 16-fluoro-7-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione;

In the hereabove list of specific compounds of the invention and in the subsequent examples and claims the wording "16-fluoro" is intended to include both a 16alpha - or 16alpha - or 160-isomer and a mixture thereof. The compounds of the invention can be prepared by a process comprising; a) methylenation of a compound of formula (II)

wherein R is as defined above and R1 is hydrogen or C1-C4 alkyl, at least one of R and R, being other than hydrogen, so as to obtain a compound of formula (I), wherein R2 is =CH2 and R and R, are defined above; or b) providing by means of a Grignard reaction a C1-C4 alkyl group at the 6-position of a compound of formula (III)

wherein R is as defined above, followed by hydrolysis and dehydration so as to obtain a compound offormula (I), wherein R1 is =CH2 and R2 is C1-C4 alkyl; or c) reduction of a compound of formula (III), as defined above, followed by hydrolysis and dehydration, so as to obtain a compound of formula (I) wherein R, is =CH2 and R2 is hydrogen;and, if desired, the conversion of a compound of formula (I) into another compound of formula (I), and/or, if desired the separation of a mixture of isomers of compounds of formula (I) into the single isomers. Methylenation, i.e. 6-methylenation, of a compound offormula (II) may be carried out according to known methods, e.g. according to K. Annen et al., Synthesis 1982, 34. Preferably a compound of formula (II) is reacted with formaldehyde diethyl acetal in a suitable organic solvent, e.g. chloroform, at reflux temperature, in the presence of a condensing agent, e.g. phosphoryl chloride and sodium acetate. Alternatively the same reaction may be carried out in other inert organic solvents, e.g. 1,2-dichloroethane, diethyl ether or dioxane and in the presence of other suitable condensing agents, e.g. phosphorous pentoxide or p-toluenesulfonic acid. The Grignard reaction on a compound of formula (III) may be carried out according to reaction conditions well known in organic chemistry, e.g. as described in "Grignard reactions of nonmetallic substances" by M.S. Kharasch and O. Reinmuch. Preferably the Grignard reagent is prepared in diethyl ether solution by reaction of a suitable C1-C4 alkyl iodide with magnesium. Then a compound of formula (III), dissolved in suitable solvent e.g. benzene ortetrahydrofuran, is added and the mixture heated to reflux. Alternatively the Grignard reagent may be prepared from a suitable C1-C4 alkyl bromide or chloride and using a suitable di (C1-C4 alkyl) ether. The subsequent hydrolysis of the ketal groups may be performed e.g. in acidic conditions at a temperature ranging from about 0[deg]C to boiling temperature. Preferably the acidic hydrolysis is carried out by treatment with a 2:1 mixture of glacial acetic acid and water at a temperature ranging from about 20[deg]C to about 60[deg]C. The final dehydration generally occurs during the hydrolysis step. Alternatively it may be performed in pyridine solution with thionyl chloride at temperatures ranging from about 0[deg]C to about 30[deg]C. The reduction of a compound of formula (III) may be carried out for example by treatment with a suitable hydride according to known methods, e.g. as described in "Complex Hydrides" by Andor Hajos (Elsevier Ed. 1979). Preferably the reduction is performed in ethyl ether solution with litium aluminium hydride at temperatures ranging from about 0[deg]C to reflux temperature. Alternatively other complex metal hydrides, e.g. lithium trisec-butylborohydride, and other suitable solvents, e.g. tetrahydrofuran, may be used. The following hydrolysis of the ketal groups and the dehydration of the resulting beta -hydroxy ketone are performed as described above. The separation of a mixture of isomers into the single isomers as well as the conversion of a compound of formula (I) into another compound of formula (I) may be carried according to known methods. For example a 6beta - or 7(3-methyl derivative of a compound of formula (I) may be converted into the respective 6a- or 7a-methyl derivative by heating to reflux in a lower alcohol, e.g. ethanol, with a basic agent, e.g. 0.1 N sodium hydroxide. The compound of formula (II) may be synthesized according to the following reaction scheme by using methods known per se:

R',=C,-C4alkyl. For example, ketalization of a compound of formula (IV) to obtain compound of formula (V) may be performed in dichloromethane solution at reflux temperature by reaction with ethylene glycol in the presence of triethyl orthoformate and p-toluene sulfonic acid. A compound of formula (VI) is obtained by brominating a compound of formula (V) according to known procedures. Preferably the bromination is carried out by treatment with anhydrous copper (II) bromide in boiling methanol according to E. R. Glazier, 1962, J.Org.Chem. 27, 4397. The conversion of a compound offormula (VI) into a compound offormula (VII) may be performed according to known methods e.g. J. Mann et al., J.Chem.Soc.PerkinTrans. 1, 2681 (1983). Thus the bromo-compound is reacted with pyridinium poly (hydrogen fluoride) in the presence of mercury (II) oxide at temperatures ranging from about 0[deg]C to about 80[deg]C. The deketalization of compound (VII) to obtain compound (VIII) may be performed as described above. The dehydrogenation of compound (VIII) to give compound (IX) may be carried out by known methods e.g. by treatment with chloranil in boiling tert-butanol. Alternatively the 6 double bond may be introduced by bromination with N-bromosuccinimide in boiling carbon tetrachloride to give the 6-bromo compound which in turn is dehydrobrominated with collidine at reflux temperature or with lithium carbonate and lithium chloride in dimethylformamide at temperature from 90.Cto120[deg]C. The 7-alkylation of compound (IX) to obtain a compound of formula (X), which is a compound of formula (II) wherein R is fluorine and R1 is C1-C4 alkyl, may be carried out by known methods. For example alkyl lithium is reacted with copper (I) iodide in ethyl ether solution at 0-10[deg]C to form the dialkyl copper lithium complex which is then added to a solution of compound (IX) in tetrahydrofurane at temperature ranging from 0[deg]C to 20.C. The compound offormula (VIII) is a compound offormula (II) where in R is fluorine and R1 is hydrogen. The compounds offormula (II) wherein R is hydrogen and R, C1-C4 alkyl may be obtained according to known methods starting from a compound of formula (IV). For example the compound of formula (IV) may be first submitted to dehydrogenation and then to 7-alkylation by following the same procedures described as to dehydrogenation of a compound offormula (VIII) to a compound of formula (IX) and 7-alkylation of a compound of formula (IX) to a compound of formula (X). Compound of formula (III) may be obtained according to known procedures; for example a compound of formula (III) wherein R is fluorine may be prepared according to the following reaction scheme:

The ketalization of compound (V) or (VII) to obtain a compound of formula (XI) may be carried out by known methods e.g. by reaction with ethylene glycol in the presence of p-toluenesulfonic acid in boiling benzene solution under continuous azeotropic water elimination. The oxygenation of compound (XI) to obtain compound (XII) may be carried out by known methods e.g. by oxidation with potassium permanganate in the presence of potassium carbonate in aqueous acetone solution at temperature ranging from 0[deg]to boiling temperature. Epoxidation of a compound of formula (XII) may be carried out by treatment with suitable oxidizing agents, preferably concentrated, e.g. 36%, H202 in alcoholic alkali metal hydroxide, preferably KOH or NaOH in methanol at temperatures ranging from 0[deg]C to 25[deg]C for about 2 hrs to several days. The Wittig reaction of compound (XIII) to obtain compound (III) may be carried out by known methods. For example the Wittig reagent is prepared by reacting methyl triphenyl phosphonium iodide with a strong base, e.g. potassium tert-butoxide in a suitable solvent like dimethyl sulfoxide at temperatures from 0[deg]C to 30[deg]C. Then compound (XII) is added and the reaction mixture heated to about 40[deg]C to 70[deg]C for 1 to 24 hrs. The starting compound offormula (IV) is known. For instance, it may be prepared by following the procedure described in example 24 of US patent 4,071,625. According to this procedure the starting material is 1,4-androstadiene-3,17-dione and the last reaction step

The compounds ofthe present invention are inhibitors ofthe biotransformation of androgens into estrogens, i.e., they are steroidal aromatase inhibitors. The aromatase inhibitory activity ofthese compounds was demonstrated by employing the in vitro test described by Thompson and Siiteri (E.A. Thompson and P.K. Siiteri, J.Biol.Chem. 249, 5364,1974) which utilizes the human placental microsomal fraction as enzyme source. In this test the aromatization rate of

presence of NADPH with the enzyme preparation and by measuring the amount of H2O formed during 20 min incubation at 37[deg]C. The new compounds, incubated at various concentrations, showed a relevant aromatase inhibitory activity. By virtue of their ability to inhibit aromatase and, consequently, to reduce estrogen levels, the new compounds are useful in the treatment and prevention of various estrogen dependent diseases, i.e., breast, endometrial, ovarian and pancreatic cancers, gynecomastia, benign breast disease, endometriosis, polycystic ovarian disease and precocious puberty. Another application of the compounds of the invention is in the therapeutic and/or prophylactic treatment of prostatic hyperplasia, a disease of the estrogen dependent stromal tissue. The new compounds can find also use for the treatment of male infertility associated with oligospermia and for female fertility control, by virtue of their ability to inhibit ovulation and egg nidation. In view of their high therapeutic index, the compounds of the invention can be used safely in medicine. For example, the approximate acute toxicity (LD50) of the compounds of the invention in the mouse, determined by single administration of increasing doses and measured on the seventh day after the treatment was found to be negligible. The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar orfilm coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous injection or infusion. The dosage depends on the age, weight, conditions ofthe patient and administration route; for example the dosage adopted for oral administration to adult humans may range from about 10 to about 150-200 mg pro dose, from 1 to 5 times daily. The invention includes pharmaceutical compositions comprising a compound ofthe invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent). The pharmaceutical compositions containing the compounds ofthe invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. For example, the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. The syrups may contain as carriers for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol; in particular a syrup to be administered to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amount to glucose, for example sorbitol. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethyl-cellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount oflidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The following examples illustrate but do not limit the invention.

Example 1 A mixture of sodium acetate (0.985 g; 12 mmol), absolute chloroform (30 ml), formaldehyde diethyl acetal

3,17-dione (0.835 g, 2.7 mol) is stirred at reflux for about 5 hours, i.e. until the starting material has disappeared. The suspension is allowed to cool and under vigorous stirring a saturated sodium carbonate solution is added dropwise until the pH of the aqueous layer becomes alkaline (about 1 hour). The organic layer is separated, neutralized with water, and dried with sodium sulfate. After concentration under reduced pressure the oily residue is purified by chromatography on silica gel using hexane/ethyl

obtained in 60% yield. Found: C 81.32, H 8.50. C22H28O2 requires: C 81.44, H 8.70. Following the above described procedure and starting from the appropriate derivative the following compounds can be prepared as a pure a- or (3-isomer or a mixture thereof:

16-fluoro-6-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione; 16-fl u oro-7a-methyl-6-methylene-1,2p-cyclop ropa noa ndrost-4-ene-3,17-d ion e;

methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione.

Example 2

700 ml of benzene are added to a Grignard mixture prepared from magnesium (0.94 g, 40 mmol) and methyl iodide (1.42 g, 50 mmol) in 150 ml of diethyl ether. Solvent is removed until the boiling point reaches 78[deg]C. Heating is then continued for a further 3 hrs. Ice and saturated ammonium chloride solution are added, the product extracted with ethyl acetate and the organic layer is evaporated in vacuo after having washed and dried it. The residual oil is chromatographed on silica

methyl-7-methylene-1,2p-cyclopropanoandrostane. The above obtained compound is dissolved in an acetic acid-water 2:1 mixture (66 ml) and the solution heated for 6 hrs at 45[deg]-50[deg]C. Then water is added and the product extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate solution, dried and evaporated in vacuo. The residue is purified by

ene-3,17-dione. Found: C 81.33, H 8.65. C22H28O2 requires: C 81.44, H 8.70. The 6a-methyl-7-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione can be obtained from the 6beta isomer by heating its ethanol solution with 0.1 N sodium hydroxide for 1/2 hr at reflux. By proceeding analogously the following compounds can be obtained as a pure a- or p- isomer or a mixture thereof:

and 16-fluoro-6p-ethyl-7-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione.

Example 3 To a solution of lithium aluminium hydride (0.38 g) in diethyl ether (30 ml) is added gradually a solution of

rahydrofuran (100 ml). The resulting mixture is stirred at 20[deg]C for about 18 hours. Then an aqueous solution of sodium potassium tartrate is added. The mixture is filtered and concentrated to a small volume under reduced pressure. The concentrate is taken up in ether and washed well with water. The ether solution is dried over magnesium sulfate, filtered and the ether removed under vacuum to yield a residue which is chromatographed on silica gel using n-hexane/ethylacetate as eluant to yield pure 3,17-bis (ethylenedioxy)-5a-hydroxy7-methylene-1,2p-cyclopropanoandrostane (0.30 g). The above obtained compound is dissolved in a 2:1 mixture of acetic acid and water (60 ml) and the solution heated for about 6 hrs at 40-50[deg]C. Then water is added and the product extracted with ethyl acetate. The organic layer is separated, washed with sodium bicarbonate solution, dried and evaporated in vacuo. The residue is purified by column chromatography on silica gel to give pure 7-methylene-1,2pcyclopropanoandrost-4-ene-3,17-dione (0.25 g). Found: C 81.19, H, 8.36. C21H26O2 requires: C 81.25, H 8.44. By proceeding analogously the following compound can be prepared as a pure a- or 0-isomer or a mixture thereof:

Example 4

A mixture of 1,2p-cyclopropanoandrost-4-ene-3,17-dione, ethylene glycol, triethyl orthoformate and ptoluene-sulfonic acid in dichloromethane is heated for 3 hrs at reflux. Then the mixture is cooled, neutralized with triethylamine, the organic layer washed with sodium bicarbonate solution, dried and evaporated under vacuum. The residue is crystallized from acetone-hexane to yield 3-ethylenedioxy-1,2p-cyclopropanoandrost5-en-17-one. A solution of 3-ethylenedioxy-1,2p-cyclopropanoandrost-5-en-7-one and cupric bromide in methanol is refluxed for 20 hrs. The light yellow solution is poured into water and the resulting mixture extracted with chloroform. The organic extracts are dried over magnesium sulfate, filtered, and evaporated under vacuum. The residue is chromatographed on silica gel and affords after gradient elution with benzene/ethyl ether the

The above obtained compound is added to vigorously stirred suspension of yellow mercury (II) oxide in pyridinium poly (hydrogen fluoride) at room temperature. After 3 hrs the mixture is poured onto crushed ice and extracted with dichloromethane. The combined extracts are washed with water, dried and evaporated under vacuum. The residue is chromatographed twice on silica gel using benzene/ethyl ether as eluantto yield pure 16a-fluoro-3-ethylenedioxy-1,2(3cyclopropanoandrost-5-en-17-one. A solution of 16a-fluoro-ethylenedioxy-1,2(3-cyclopropanoandrost-5-en-17-one in acetic acid-water (2: 1) is kept for 6 hrs at 40[deg]C. Then the reaction mixture is extracted with ethyl acetate, the organic layer separated, washed with saturated sodium bicarbonate solution, dried and finally evaporated under vacuum to dryness. Column chromatography of the crude product over silica gel using hexane/ethyl acetate as eluant affords pure

peroxide in carbon tetrachloride is heated to reflux for 4 hrs. After cooling the precipitate is filtered off, the residue washed with carbon tetrachloride and the combined filtrates evaporated under vacuum. The resulting

and lithium carbonate and lithium chloride is added. The mixture is heated for 2 hrs at 90[deg]C. Then the mixture is filtered, diluted with water and extracted with benzene.The organic layer is washed with water, dried and evaporated under vacuum. The residue is chromatographed on silica gel and affords, after gradient elution

A solution of lithium dimethylcopper is prepared by the addition of 1.6 M ethereal methyllithium (15 ml) to an ether slurry of cuprous iodide (760 mg) at 0[deg]C under nitrogen. The solution is stirred at 0[deg]C for 1/2 hr and

drofuran (10 ml) is added over a 20 minute period and stirred for an additional 30 minutes. The mixtures is poured onto ice cold diluted hydrochloric acid; benzene is added and the resulting mixture filtered through diatomaceous earth. The organic layer is washed with aqueous ammonium chloride, water, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel using

dione (230 mg). Found: C 76.21; H 8.15; F 5.62. C21H27O2F requires: C 76.33; H 8.24; F 5.75. Following the above reported procedure but using lithium diethyl copper as reagent the following compounds can be obtained:

about 20 hrs in the presence of p-toluenesulfonic acid under simulataneous azeotropic water removal. Then the reaction mixture is cooled, the organic layer washed with ice cold sodium bicarbonate solution and water, dried and finally evaporated under vacuum. The residue is chromatographed on silica gel to give pure 3,17-bis

made alkaline by potassium carbonate addition, concentrated aqueous potassium permanganate is added portionwise until the solution remains coloured. Then the acetone is removed by evaporation under vacuum and the crude product isolated by filtration. Column chromatography on silica gel furnishes the pure

To an ice cold solution of3,17-bis (ethylenedioxy)-16a-fluoro-1,2(3-cyclopropanoandrost-4-en-7-one in methanol 36% hydrogen peroxide and 2% sodium hydroxide are added gradually.The mixture is allowed to stand at 0-5[deg]C for 20 hrs. Then ice water is added and the precipitated raw product filtered off. Crystallization

cyclopropanoandrostan-7-one. To a solution of potassium tert-butoxide (449 mg) in dimethyl sulfoxide (20 ml) methyltriphenyl phosphonium iodide (1616 mg) is added portion-wise at 20-25[deg]C under nitrogen and the mixture kept for another 30' at this temperature. Then a dimethyl sulfoxide solution (10 ml) of 3,17-bis (ethylenedioxy)-5,6a-epoxy-16afluoro-1,2(3-cyclopropanoandrostan-7-one (435 mg) is added and the mixture heated gradually to 40[deg]C during a period of 4 hrs. The reaction mixture is poured onto ice, the produce extracted with ethyl acetate, the organic layer washed with water, dried and evaporated under vacuum. The residue is chromatographed on silica gel and eluted with hexane/ethyl acetate to give pure 3,17-bis (ethylenedioxy)-5,6a-epoxy-16a-fluoro-7methylene-1,2p-cyclopropanoandrostane (340 mg). Found: C 69.35; H 7.65; F 4.33. C25H33O5F requires: C 69.42; F 4.39.

Example 6

Tablets each weighing 0.150 g and containing 25 mg of the active substance, can be manufactured as follows: Composition (for 10000 tablets)

corn starch are mixed; the mixture is then forced throught a sieve of 0.5 mm mesh size. Corn starch (10 g) is suspended in warm water (90 ml) and the resulting paste is used to granulate the powder. The granulate is dried, comminuted on a sieve of 1.4 mm mesh size, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets.

Example 7 Capsules, each dosed at 0.200 g and containing 20 mg of the active substance can be prepared. Composition for 500 capsules:

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

Claims (11)

1. A compound offormula (I)

wherein I R is hydrogen orfluorine; one of R1 and R2 is =CH2 and the other is hydrogen or Ci-C4 alkyl, and, when R2 is =CH2, at least one of R and R1 is other than hydrogen.

2. A compound offormula (I), according to claim 1, wherein R is hydrogen or fluorine; one of R1 and R2 is =CH2 and the other is C1-C4 alkyl.

3. A compound selected from the group consisting of:

16-fluoro-7p-ethyl-6-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione; 7-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione;

and 16-fluoro-6p-ethyl-7-methylene-1,2p-cyclopropanoandrost-4-ene-3,17-dione.

4. A process for the preparation of a compound of formula (II), according to claim 1, said process comprising: a) methylenation of a compound of formula (II)

wherein R is as defined in claim 1 and R1 is hydrogen or C1-C4 alkyl, at least one of Rand R, being other than hydrogen, so as to obtain a compound of formula (I), wherein R2 is =CH2 and Rand R, are defined in claim 1; or b) providing by means of a Grignard reaction a C1-C4 alkyl group at the 6-position of a compound of formula (III)

wherein R is as defined in claim 1, followed by hydrolysis and dehydration so as to obtain a compound of formula (I), wherein R, is =CH2 and R2 is C1-C4 alkyl; or c) reduction of a compound of formula (III), as defined above, followed by hydrolysis and dehydration, so as to obtain a compound of formula (I) wherein R1 is =CH2 and R2 is hydrogen; and, if desired, the conversion of a compound of formula (I) into another compound of formula (I), and/or, if desired the separation of a mixture of isomers of compounds of formula (I) into the single isomers.

5. A pharmaceutical composition containing a suitable carrier and/or diluent and, as an active principle, a compound offormula (I) according to claim 1.

6. A compound of formula (I), according to claim 1, for use in medicine in the treatment of an advanced hormone-dependent breast, pancreatic, endometrial or ovarian cancer.

7. A compound of formula([), according to claim 1, for use in medicine in the treatment of prostatic hyperplasia.

8. The use of a compound of general formula (I), according to claim 1, in the preparation of a pharmaceutical composition for the treatment of an advanced hormone-dependent breast, pancreatic, endometrial or ovarian cancer.

9. The use of a compound of general formula (1), according to claim 1, in the preparation of a pharmaceutical composition for the treatment of prostatic hyperplasia.

10. A process for the preparation of a compound of formula (I) as defined in claim 1, said process being substantially as hereinbefore described in any one of Examples 1 to 3.

11. A pharmaceutical composition substantially as hereinbefore described in Example 6 or 7.