FR2600254A1 - METHYLENE DERIVATIVES OF ANDROSTEN-4 DIONES-3, 17, PROCESS FOR THEIR PREPARATION, AND THEIR USE AS MEDICAMENTS - Google Patents

Abstract

THE PRESENT INVENTION RELATES TO NEW METHYLENE-6 OR -7 CYCLOPROPRANO-1,2B ANDROSTENE-4 DIONES-3, 17, REPRESENTED BY THE FOLLOWING FORMULA: (CF DRAWING IN BOPI) FORMULA IN WHICH: R REPRESENTS HYDROGEN OR FLUORINE; ONE OF R AND R REPRESENTS CH AND THE OTHER REPRESENTS HYDROGEN OR ALKYL IN CC, AND WHEN R REPRESENTS CH, AT LEAST ONE OF R AND R IS OTHER THAN HYDROGEN, WHICH ARE USEFUL THERAPEUTICALLY, IN SPECIAL, AS ANTI-CANCER AGENTS.

Description

METHYLENE DERIVATIVES OF ANDROSTENE-4 DIONES-3,17, THEIR

  PREPARATION METHOD, AND THEIR APPLICATION COIME MEDICAXENTS.

  The present invention relates to novel 6-methylene or 7-cyclopropano-3-androstene-3-dione-3,17, to a process for their preparation, to pharmaceutical compositions containing them, and to the use of these compounds. for the treatment of cancers

  hormone-dependent in mammals.

  Basic and clinical data indicate that androgen-flavored metabolites, ie estrogens, are the hormones involved in pathogenic cellular changes associated with the evolution of certain hormone-dependent cancers, such as carcinoma of the carcinoma. breast, endometrium and ovary. Estrogens are also involved in the

  pathogenesis of benign prostatic hyperplasia.

  Endogenous estrogens are ultimately formed either from androstenedione or from testosterone as immediate precursors. The centrally important reaction is the aromatization of the steroidal ring A, which is carried out by the aromatase enzyme. Since aromatization is a unique reaction and the last of the series of steps in estrogen biosynthesis, it has been contemplated that effective aromatase inhibition, resulting from compounds capable of interacting with the steps of flavoring, could be applied

  usefully to control the amount of circulating estrogen, estrogen-dependent reproductive processes, and estrogen-dependent tumors.

  Known steroidal substances, which have been described in the literature as possessing an aromatase inhibiting action, are, for example: A1-testololactone [U.S. Patent No. 2,744,120; 2,744,120] 4-hydroxy-4-androstene-3-dione, 17 and its esters are referred to, for example, U.S. Patent No. 4,235,893]; 1,2-propadenyl-10-estrene-3-dione [U.S. Patent No. 4,289,762]; 4-(4-propynyl) -10-estrene-3,17-dione (J. Am.Chem.Soc., 103L, 3221 (1981) and US Patent No. 4,322,416); thio-19 androstene (European Patent Application No. 100,566); androstadiene-4,6-dione-3,17; androstatriene-1,4,6-dione-3,17 [British Patent Application No. 2 100 601 A] and,

  1,4-androsta-1,4-diene-3,17-dione [Cancer Res. <Suppl.) 142, 3327 (1982).

  The present invention provides compounds represented by the following general formula (I) CH 0 <R (I '

R2

  formula in which: R represents hydrogen or fluorine; one of R and represents = CH and the other 1 R2 2 and the other represents hydrogen or C1-C4 alkyl, and when R2 represents = CH2, at least one of R and R1 is

other than hydrogen.

  Also within the scope of the present invention are all possible isomers and stereoisomers and mixtures thereof, as well as

  metabolites and metabolic precursors or bioprecursors of compounds of formula (I).

  In the formulas in this specification descr-iptif, the dashes (t <iNl) indicate that the substituents are in configuration a, that is, below the plane of the cycle, whereas the solid lines in bold (<) indicate that the substituents are in the $ configuration, i.e., above the plane of the cycle; a wavy link (/) indicates that a substituent can be in either the a,

  either in the $ configuration, or in both.

  When in the compounds of the formula (I), R 1 is = CH 2, the substituent R 2 can be either in

  the configuration has either in the $ configuration.

  Similarly, when R2 is = CH2, then the substituent R1 may be in the

  configuration a, either in the $ configuration.

  The C1-C4 alkyl group is preferably a methyl or ethyl group, more preferably a methyl group. The alkyl radical can be a group

branch or straight chain.

  As indicated above, are also included within the scope of the present invention, the pharmaceutically acceptable bioprecursors (otherwise known as "pro-drugs") compounds of formula (I), ie to say compounds that

  have a formula different from the formula (I) above, but which, when administered to a human being, are converted directly or indirectly in vivo to a compound of formula (I).

  The preferred compounds of the present invention are the compounds of formula (I), wherein: R represents hydrogen or fluorine;

  one of R1 and R2 is = CH2 and the other is C1-C4 alkyl.

  Examples of specific compounds of the present invention are: * 7-methyl-6-methylene-1,3-cyclopropano-4-androstenedione-3,17-dione; 7-methyl-1,2-methylene-1,2-cyclopropano-4-androstene-4-dione; 3.17; 7α-ethyl-6-methylene-1-cyclopropano-2-androstene-3-ene-3,17-dione; * ethyl-7? 6-Methylene-1,2-cyclopropano-androstene-4-dione-3,17; fluoro-16-dione-3,17; * 16-fluoro-androstene-4 * 16-fluoro-androstene-4 * 16-fluoro-androstene-4 * 16-fluoro-4-androstene-6-methylene-1,2-cyclopropano-androstene-4-methyl-7α-methylene-6-cyclopropano -1, 23 dione-3.17; methyl-7? 6-Methylene-1,2-cyclopropanediol-3,17-dione; ethyl-7a-methylene-6-cyclopropano-1,2-dione-3,17; 7-ethyl-6-methylene-1,2-cyclopropano-3-dione; methylene? cyclopropano1,2 P androstene-4-dione-3,17; 6-methyl-7-methylene-1,2-cyclopropano-androstene-4-ene-3-dione; 6-methyl-7-methylene-1,2-cyclopropano-androstene-4-dione-3,17; 6α-ethyl-7-methylene-1,2-cyclopropanedrost-4-ene-3,17-dione; * Ethyl-6P methylene- 1,2-cyclopropanoandrost-4-ene-3,1-dione; 16-fluoro-7-methylene-1,3-cyclopropano-androstene-4-ene-3,1-dione; 16-fluoro methyl-6a methylene- 1,2-cyclopropanoandrostene-4-dione-3,17; 16-Fluoro-6-methyl-7-methylene-1,1-cyclopropano-androstene-4-dione-3,1-dione; 16-Fluoro-6α-ethyl-7-methylene-cyclopropano-1,2-p-androstene-4-dione-3,17; and, fluoro-16-ethyl-6-methylene- cyclopropano-l, 2B

androstene-4-dione-3,17.

  In the above list of specific compounds according to the present invention and in the following examples, the term "fluoro-16" should be understood to encompass both the fluoro-16a isomer or the isomer

  fluoro-16P and a mixture of these isomers.

  The compounds according to the present invention may be prepared by a process consisting of: a) performing the methylenation of a compound of formula <II>:

3 R

  Wherein R 1 is as defined above; and - R1 represents hydrogen or C1-C4 alkyl, at least one of R and R1 being other than hydrogen, so as to obtain a compound of formula (I), in which R2 represents = CH2 and R and R 1 are as defined above, or b) by means of a Grignard reaction, a C 1 -C 4 alkyl group at the 6-position of a

formula (III):

  Wherein R is as defined above, followed by hydrolysis and dehydration, to give a compound of formula (I), wherein R1 represents = CH and R2 represents C1-C4 alkyl; or c) reducing a compound of formula <III>, as defined above, followed by hydrolysis and dehydration, to give a compound of formula (I), wherein R1 is = CH2 and R2 is hydrogen; and, if desired, converting a compound of formula (I) into another compound of formula (I), and / or, if desired, separating a mixture of isomers from the compounds of formula (I) into

isolated isomers.

  Methylenation, i.e., the attachment of a methylene group at the 6-position, of a compound of formula (II) can be carried out according to known methods, for example, 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, for example, chloroform, at reflux temperature, in the presence of a condensing agent, for example, phosphoryl chloride and sodium acetate. Alternatively, the same reaction may be carried out in other inert organic solvents, for example 1,2-dichloroethane, diethyl ether or dioxane, and in the presence of other suitable condensation agents, for example

  for example, phosphorous pentoxide or p-toluenesulfonic acid.

  The Grignard reaction on a compound of formula (III) can be carried out in accordance with well known reaction conditions in organic chemistry, for example, as described in "Grignard reactions of nonmetallic substances" <Grignard reactions of substances

  non-metallic> by M.S. Kharasch and O. Reinmuth.

  Preferably, the Grignard reagent is prepared, in a solution of diethyl ether, by reaction of a

  C1-C4 alkyl iodide suitable with magnesium.

  Then, a compound of formula aII), dissolved in a suitable solvent, for example, benzene or tetrahydrofuran, is added, and the mixture is refluxed. Alternatively, the Grignard reagent may be prepared from a suitable C1-C4 alkyl bromide or chloride and with a suitable C1-C4 alkyl diol. Subsequent hydrolysis of the ketal groups can be carried out, for example, under acidic conditions, at a temperature in the range of about 0 ° C to the boiling point. Preferably, the acid hydrolysis is carried out by treatment with a 2: 1 mixture of glacial acetic acid and water, at a temperature of

  in the range of about 20 ° C to about 60 ° C.

  Final dehydration generally occurs during the hydrolysis step. Alternatively, it can be carried out in a solution of pyridine with thionyl chloride, at temperatures ranging from about 0 ° C to

about 30 ° C.

  The reduction of a compound of formula (III) can be carried out, for example, by treatment with a suitable hydride, in accordance with known methods, for example as described in: "Hydride Complex"

  complexes) by Andor Hajos (Elsevier Ed. 1979).

  Preferably, the reduction is carried out in a solution of ethyl ether with lithium aluminum hydride at temperatures in the range of about 0 ° C to reflux temperature. Alternatively, other complex metal hydrides, for example, the. lithium tributylborohydride, and

  other suitable solvents, for example, tetrahydrofuran, may be used.

  The following hydrolysis of the ketal groups and the dehydration of the resulting hydroxy-ketone are

  performed as described above.

  The separation of a mixture of isomers into the isolated isomers, as well as the conversion of a compound of formula (I) into another compound of formula (I), can be carried out according to known methods. For example, a methylated derivative in the 6e or 7e position of a compound of formula (I) can be converted to the methylated derivative at the 6a or 7a position, respectively, by refluxing in a lower alcohol, for example , Ethanol, with a basic agent, for example, 0.1 N sodium hydroxide. The compound of formula (II) can be synthesized in accordance with the following reaction scheme, using methods known per se: s H "H, HH

(IV) (V)

0 "I H F r

(VII) (VI)

H

HIti H StA

(VIII) (IX)

o O H Hil

 '

(X)

R'1 = C1-C4 alkyl.

  For example, the ketalization of a compound of formula (IV) in order to obtain a compound of formula (V) may be carried out in a solution of dichloromethane, at the reflux temperature, by reaction with ethylene glycol,

  5. in the presence of triethyl orthoformate and ptoluenesulphonic acid.

  A compound of formula (VI) is obtained by bromination of a compound of formula CV> 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 of formula (VI) into a compound of formula (VII) may be carried out according to known methods, for example according to J. Mann et al.

  J.Chem.SocPerkin-Trans. I, 2681 (1983).

  Thus, the bromo compound is reacted with poly

  (Pyridinium hydrogen fluoride) in the presence of mercuric oxide II at temperatures in the range of about 0 ° C to about 80 ° C.

  The decetalisation of the compound (VII) in order to obtain the compound (VIII) can be carried out as

described above.

  The dehydrogenation of the compound (VIII) to give the compound (IX) can be carried out by known methods, for example by treatment with chloranil in

boiling tert.-butanol.

  Alternatively, the a6 double bond can be introduced by bromination with N-bromosuccinimide into boiling carbon tetrachloride to give a brominated compound at the 6-position which, in turn, is dehydrobrominated by collidine at room temperature. refluxing, or lithium carbonate and lithium chloride in dimethylformamide, at a temperature ranging from 90.degree. C. to 120.degree. C. The alkylation at position 7 of the compound (IX) to obtain a compound of Formula (X), which is a compound of formula (II), wherein R is fluorine and R is C 1 -C 4 alkyl, can be carried out by known methods. For example, an alkyl lithium is reacted with copper I-iodide in a solution of ethyl ether at 0-10 C to form the dialkyl copper lithium complex, which is then added to a solution of the compound ( IX) in tetrahydrofuran, at a temperature of

  in the range from 0OC to 20 ° C.

  The compound of formula (VIII) is a compound of

  formula (II) wherein R is fluorine and R1 is hydrogen.

  Compounds of formula (II) in which R is hydrogen and R 1, C 1 -C 4 alkyl can be obtained according to known methods, starting from a compound of formula (IV). For example, the compound Of formula (IV) first to dehydrogenation and then

  at an alkylation at position 7, following the same procedures as those described for the dehydrogenation of a compound of formula (VIII) to a compound of formula (IX), and for the alkylation in position 7 of a compound of formula (IX) to a compound of formula (X).

  A compound of formula (III) can 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: Compound (V) (R = H> I Compound (VII) <R = F>) Hm RRH vt (XII) 25 R

(XIII)

  R (III) The ketalization of the compound <V> or (VII> in order to obtain a compound of formula (XI) may be carried out by known methods, for example by reaction with ethylene glycol, in the presence of Ptoluenesulphonic acid in a boiling benzene solution with elimination

azeotropic continuous water.

  Oxygenation of the compound (XI) in order to obtain the compound (XII) can be carried out by known methods, for example, by oxidation with potassium permanganate, in the presence of potassium carbonate, in an aqueous solution of acetone, at a temperature in the

  range from 0OC to boiling point.

  The epoxidation of a compound of formula (XII) can be carried out by treatment with suitable oxidizing agents, preferably concentrated, for example 36% H 2 O 2 in an alcoholic alkali metal hydroxide, preferably KOH or NaOH in methanol, at temperatures in the range of 0 ° C to 25 ° C, for approximately

hours to several days.

  The Wittig reaction of the compound (XIII) to obtain the compound (III) can be carried out by known methods. For example, the Wittig reagent is prepared by reacting methyl triphenyl phosphonium iodide with a strong base, for example potassium tert.25 butoxide, in a suitable solvent, such as

  dimethyl sulfoxide, at temperatures ranging from 0 ° C to 30 ° C.

  Then, the compound (XII) is added, and the reaction mixture is heated to about 40 ° C at 70 ° C, while

1 to 24 hours.

  The starting compound of formula (IV) is known.

  For example, it can be prepared by following the procedure described in Example 24 of the US Patent.

of America No. 4,071,625.

  According to this procedure, the starting material is androstadiene-1,4-dione-3,17 and the last reaction step involves the oxidation of methylene-1,20

  androstene-5-diol-3S, 17 by Jones's reagent.

  The compounds of the present invention are inhibitors of the metabolism of androgens to estrogens, that is, they are steroidal inhibitors

aromatase.

  The aromatase inhibitory activity of these compounds has been demonstrated by employing the in vitro assay described by Thompson and Siiteri <E.A. Thompson and P.K. Siiteri, J.Biol.Chem. 249, 5364, 1974>, which uses the microsomal fraction of the human placenta as an enzyme source. In this test, the rate of aromatization of androstenedione to estrone was evaluated by incubating [13,3B-3H] androstenedione (50 nX) in the presence of NADPH with the enzyme preparation, and measuring the amount of

  of 3H20 formed during a 20 min incubation at 37C.

  The new compounds, incubated at various concentrations, showed inhibitory activity.

  the aromatase that was significant.

  By virtue of their ability to inhibit aromatase and thus reduce estrogen levels, the novel compounds are useful in the treatment and prevention of various estrogen-dependent diseases, i.e. breast, endometrial, ovarian or 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 treatment

  and / or prophylactic prostatic hyperplasia, an estrogen-dependent stroma tissue disease.

  The new compounds can also find use for the treatment of male infertility associated with oligospermia and for the control of

  female fertility, by virtue of their ability to inhibit ovulation and implantation of the egg.

  Given their high therapeutic index, the compounds of the present invention can be safely used in medicine. For example, the approximate acute toxicity (LD50) of the compounds according to the present invention in mice, determined by the single administration of increasing doses, and measured on the seventh day

  after treatment, was found to be negligible.

  The compounds according to the present invention can be administered in various dosage forms, for example, orally, in the form of tablets, capsules, sugar coated tablets or film, liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, for example, intramuscularly, or by injection or

intravenous infusion.

  The dosage depends on the age, weight, condition of the patient and the route of administration; for example, the

  The dosage adopted for oral administration to adult humans may be in the range of about 10 to about 150-200 mg per dose, 1 to 5 times daily.

  The present invention encompasses pharmaceutical compositions comprising a compound of the present invention in combination with a pharmaceutically acceptable excipient (which may be a carrier or diluent). The pharmaceutical compositions containing the compounds of the present invention are usually prepared according to conventional methods and are

  administered in a pharmaceutically acceptable form.

  For example, the solid oral forms may contain, together with the active compound, diluents, for example, lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example, silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; liaison agents, for example,

  starches, gum arabic, gelatin, methyl-

  cellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrants, for example, starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; coloring matters; sweeteners; wetting agents, such as lecithin, polysorbates, lauryl sulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. The aforesaid pharmaceutical preparations can be manufactured in a known manner, for example by means of mixing, granulation,

  tablets, coating with sugar or coating with a film.

  Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions. The syrups may contain, as carriers, for example, sucrose or sucrose with glycerin and / or mannitol and / or sorbitol; in particular, a syrup which can be administered to diabetic patients may contain, as supports, only products which are not metabolizable in glucose, or which can be metabolized to glucose in a very small amount,

for example, sorbitol.

  The suspensions and emulsions may contain, as a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, for example sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol and, if desired, a

  appropriate amount of lidocaine hydrochloride.

  Solutions for intravenous injections or infusions may contain, for example, sterile water or, preferably,

  in the form of isotonic saline solutions, aqueous, sterile.

  The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant, or lecithin.

  The following examples illustrate this

  invention without limiting its scope.

  Example 1 A mixture of sodium acetate (0.985 g; 12 mmol), absolute chloroform (30 ml), crude formaldehyde diethyl acetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml), 0.04 mole), and 7α-methyl-1,2-cyclopropano-4-androstene-3-dione (0.835 g, 2.7 mmol) is stirred under reflux for about 5 hours, i.e. until the starting material has disappeared, the suspension is allowed to cool and, with vigorous stirring, a saturated solution of sodium carbonate is added dropwise until the pH of the aqueous layer becomes alkaline (approximately

1 hour).

  The organic layer is separated, neutralized with water, and dried over sodium sulfate. After concentration under reduced pressure, the oily residue is purified by chromatography on silica gel with hexane / ethyl acetate as eluent. There is thus obtained 7-methyl-6-methyl-1,2-cyclopropano-4-androstene-3-dione-3-dione, with a yield of%.

Found: C 81.32, H 8.50.

  C 22H 2802 requires: C 81.44, H 8.70.

  By following the procedure described above and starting from the appropriate derivative, the following compounds can be prepared in the form of the pure isomer of these compounds or a mixture of isomers: ethyl-7a 6-Methylene-1,2-cyclopropano-androstene-4-dione-3,17; 16-fluoro-6-methylene-1,2-cyclopropanandrost-4-ene-3,17-dione; 16-fluoro-7-methyl-6-methylene-1,2-cyclopropano-4-androstene-3,17-dione; 16-Fluoro-7-ethyl-6-methylene-cyclopropano-1,2-p-androstene-4-dione-3,17; 7-ethyl-6-methylene-1,2-cyclopropano-androstene-4-dione-3,17; * methyl-7? 6-Methylene-1,2-cyclopropano-androstene-4-dione-3,17; 16-fluoro-7-methyl-6-methylene-1,1-cyclopropanoandrost-4-ene-3,17-dione; and,

  16-Fluoro-7-ethyl-6-methylene-1,2-cyclopropanoandrostene-4-dione3,17.

Example 2

  4.146 g (10 mmol of bis (ethylenedioxy) -3,17-epoxy-5,6a-methylen-7-cyclopropan-1,2-androstane in 700 ml of benzene are added to a mixture of Grignard prepared from magnesium (0.94 g). g, 40 mmol and methyl iodide (1.42 g, 50 mmol) in 150 ml of diethyl ether The solvent is removed until the boiling point reaches 78 ° C. The heating is then For 3 hours more ice and saturated ammonium chloride solution were added, the product was extracted with ethyl acetate, and the organic layer was evaporated in vacuo after washing and The oily residue is chromatographed on silica gel with hexane / ethyl acetate as eluent, yielding 3.3 g of bis (ethylenedioxy) -3,17-hydroxy-5-methyl-6-yl. Methylene- 1,2-cyclopropan

pure androstane.

  The compound obtained above is dissolved in a 2: 1 acetic acid-water mixture (66 ml) and the solution is heated for 6 hours at 40 ° -50 ° C. Water is then

  added, and the product is extracted with ethyl acetate.

  The organic layer is washed with sodium bicarbonate solution, dried, and evaporated in vacuo. The residue is purified by chromatography on silica gel, thus giving 2.5 g of methyl-6B methylene-7

  1,2-cyclopropano-androstene-4-dione-3,17 pure.

Found: C, 81.33, H, 8.65.

  C22H2802 requires: C 81.44, H 8.70. 22 28 2 methyl-6α methylene-? cyclopropano-1,2P androst-4-ene-3,1-dione? can be obtained from isomer 63 by refluxing an ethanolic solution of the latter with 0.1 N sodium hydroxide, while

1/2 hour.

  By proceeding in an analogous manner, the following compounds can be obtained in the form of their pure isomers a or B, or a mixture of these isomers: 6-ethyl-7-methylene-1,2-cyclopropanoandrostene -4-dione-3.17; 6-ethyl-7-methylene-1,2-cyclopropanedrostene-4-dione-3,17-dione; 16-fluoro-6-methyl-methylene- 1,2-cyclopropanoandrostene-4-dione-3,17; 16-Fluoro-6-methyl-7-methyl-1,2-cyclopropanedrost-4-ene-3-dione; 16-Fluoro-6α-ethyl-7-methylene-cyclopropanol1,23 androstene-4-dione-3,17; and, fluoro-16-ethyl-6-methylene- cyclopropano-1,2P

androstene-4-dione-3.1 ?.

  EXAMPLE 3 To a solution of lithium aluminum hydride (0.38 g) in diethyl ether (30 ml), a solution of bis (ethylenedioxy) -3,1? epoxy-5,6a methylene- 1,2-cyclopropanoanidrostane (4.146 g, 10 mmol) in tetrahydrofuran (100 ml). The resulting mixture is stirred at 20 ° C for about 18 hours. Then, an aqueous solution of

  sodium and potassium tartrate. The mixture is filtered and concentrated to low volume under reduced pressure.

  The concentrate is taken up in ether and washed thoroughly with water. The ether solution is dried over magnesium sulphate, filtered, and the ether is removed in vacuo to give a residue which is chromatographed on silica gel, eluting with a mixture of hexane / ethyl acetate, give pure bis (ethylenedioxy) -3,17-hydroxy-5-methylene-7-cyclopropano-1,2-androstane (0.30 g). The compound obtained above is dissolved in a 2: 1 mixture of acetic acid and water <60 ml), and the

  The solution is heated for about 6 hours at 40-50 ° C.

  Water is then 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 the

  methylene? 1,2-cyclopropan-1-β-androstene-3-dione pure (<0.25 g).

Found: C 81.19, H 8.36.

  C21H2602 requires: C 81.25, H 8.44.

  By proceeding in an analogous manner, the following compound can be prepared in the form of a pure C or B isomer, or a mixture of these isomers: 16-fluoro-7-methylene-1,2-cyclopropanandrostene- 4-dione-3, 17. EXAMPLE 4 A mixture of 1,2-cyclopropanedrosten-4-dione-3,17, ethylene glycol, triethyl orthoformate and p-tolenesulfonic acid in dichloromethane is heated at reflux, while 3 hours. Then the mixture is cooled, neutralized with triethylamine, the organic layer is washed with sodium bicarbonate solution, dried and evaporated in vacuo. The residue is crystallized from an acetone-hexane mixture, to provide

  3-ethylenedioxy-1,2-cyclopropanoandrost-5-en-1-one.

  A solution of 3-ethylenedioxy-1,2-cyclopropano-androstene-5-one-1-one and cupric bromide in methanol is refluxed for 20 hours. The light yellow solution is poured into water, and the resulting mixture is extracted with chloroform. The organic extracts are dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue is chromatographed on silica gel, and after gradient elution it gives a

  benzene / ethyl ether mixture, the bromo-16a-3-ethylenedioxy-1,2-cyclopropano-androstene-5-one-17.

  The compound obtained above is added to a vigorously stirred suspension of yellow mercury-II oxide in pyridinium poly (hydrofluoric acid), at

ambient temperature.

  After 3 hours, the mixture is poured onto crushed ice and extracted with dichloromethane. The combined extracts are washed with water, dried, and evaporated in vacuo. The residue is chromatographed twice on silica gel, with a mixture of

  benzene / ethyl ether, to give fluoro-16a ethylene-.

  3-dioxy-1,2-cyclopropanandrosten-5-one-17.

  A solution of 4-fluoro-3-ethylenedioxy-1,2-cyclopropano-5-androstene-5-one 17-one in an acidic mixture

  Acetic acid-water (2: 1) is kept for 6 hours at 40 C.

  Then, the reaction mixture is extracted with ethyl acetate, the organic layer is separated, washed with saturated sodium bicarbonate solution, dried, and finally evaporated in vacuo to dryness. Column chromatography of the crude product, on silica gel, with hexane / ethyl acetate as eluent, provides 16α-fluoro-1,2-cyclopropanoate.

androstene-4-dione-3,17 pure.

  A mixture of 16-fluoro-1,2-cyclopropano-4-androstene-3-dione, Nbromo succinimide and benzoyl peroxide in carbon tetrachloride is

  refluxed for 4 hours.

  After cooling, the precipitate is removed by filtration, the residue washed with carbon tetrachloride, and the combined filtrates are evaporated in vacuo. The resulting crude bromo-6β-fluoro-16α-cyclopropano-1,2,3-androstene-4-dione-3,17 is dissolved in dimethylformamide and lithium carbonate and lithium chloride are added. The mixture is heated for 2 hours at 90 ° C. Then the mixture is filtered, diluted with water and extracted with benzene. The organic layer is washed with water, dried, and evaporated in vacuo. The residue is chromatographed on silica gel and provides, after gradient elution by the

  benzene / ethyl ether mixture, 16α-fluoro-1,3-cyclopropano-androsta-4,6-diene pure-3,17-dione.

  Lithium dimethyl copper solution is prepared by the addition of 1.6 M methyl lithium in ether (15 ml) to a slurry in cuprous iodide ether (760 mg) at 0 ° C under nitrogen. The solution is stirred at 0 ° C. for 1/2 hour and then a solution of 16α-fluoro-cyclopropan-1,2-androsta-4,6-diene-3,17-dione (314 mg) in anhydrous tetrahydrofuran (10 ml. added over 20 minutes, and stirred for an additional 30 minutes, the mixture is poured onto ice-cold dilute hydrochloric acid, benzene is added, and the resulting mixture is filtered through ice-cold water. 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, eluent a benzene / ethyl ether mixture, to give the two separate isomers, namely fluoro-16 "mithyl-7a cyc 1,2-1,2-propano-androstene 4-dione-3,17 and 16-fluoro-16α-methyl-7-one. cyclopropano-1,2-androstene-4-dione-3,17

(230 mg>.

Found: C, 76.21; H, 8.15; F, 5.62.

  C21H2 O2F requires: C, 76.33; H, 8.24; F 5.75.

3521 27 2

  Following the procedure described above, but using lithium diethyl copper as a reagent, the following compounds can be obtained: 16-fluoro-7α-ethylcyclopropano-1,1,5-androstene-3,17-dione; and 16-fluoro-7α-ethyl-1,2-cyclopropanedrost-4-ene-3-dione, 17. Exempe A solution of 3-ethylenedioxy-16α-fluoro-1,2-cyclopropano-5-androstene-5-one-1-one in the The benzene is refluxed for about 20 hours in the presence of p-toluenesulphonic acid with simultaneous azeotropic removal of the water, the reaction mixture is then cooled, the organic layer is washed with sodium bicarbonate solution. cooled with ice and with water, dried, and finally evaporated in vacuo The residue is chromatographed on silica gel, for

  give bis (ethylenedioxy) -3,17-fluoro-16a-cyclopropanol-1, 2-androstene-5 pure.

  To a solution of bis (ethylenedioxy) -3,17-fluoro-16a-cyclopropano-1, 2-androstene-5 in aqueous acetone, made alkaline by the addition of potassium carbonate, is added, in portions, concentrated aqueous potassium permanganate , until the solution remains colored. Then, the acetone is removed by evaporation under vacuum, and the crude product is isolated by filtration. Column chromatography on silica gel provides the

  bis (α-ethylenedioxy) -3,17-fluoro-16α-cyclopropano-1,2-androsten-5-one-pure.

  To a solution cooled with ice of bis (éth-ethylenedioxy) -3,17-fluoro-16α-1,2-cyclopropano-5-androstene-5-one in methanol, hydrogen peroxide was gradually added to 36% and 2% sodium hydroxide. The mixture is allowed to stand at 0-5 ° C. for hours. Then, ice water is added, and the precipitated crude product is collected by filtration. Crystallization from acetonehexane gives bis (ethylenediaxy) -3,17 epoxy-5,6a fluoro-16a cyclopropano-1,2P

androstanone-7 pure.

  To a solution of potassium tert-butoxide (<449 mg) in dimethyl sulfoxide (20 ml) was added, in portions, methyl triphenyl phosphonium iodide (1616 mg) at 20-25 ° C. nitrogen, and the mixture is kept for another 30 minutes at this temperature. Then, a solution of dimethylsulfoxide (10 ml) of bis (ethylenedioxy) -3,17 epoxy-5,6a-fluoro-16c-1,2-cyclopropanoandrostanone-7 (435 mg) was added and the mixture was heated. gradually up to 40 ° C for a period of 4 hours. The reaction mixture is poured onto ice, the product is extracted with ethyl acetate, the organic layer is washed with water, dried, and evaporated in vacuo. The residue is chromatographed on silica gel and eluted with hexane / ethyl acetate to give pure bis (ethylenedioxy) -3,17 epoxy-5,6a-fluoro-16a-methylene-7-cyclopropano1,2P androstane.

(340 mg).

Found: C, 69.35; H, 7.65; F, 4.33.

  C25H3305F requires: C, 69.42; H, 7.69; F, 4.39.

  By proceeding in a similar manner, but using 3-ethylenedioxy-cyclopropano-1,2-p-androstene-5-one-17 as a starting material, the following compound can be prepared: bis (ethylenedioxy) -3,17 epoxy- 5,6a-7-Methylene-1,2-cyclopropanoandrostane. Example 6 Tablets each weighing 0.150 g and containing mg of the active substance can be manufactured as follows: Composition (per 10,000 tablets) 16α-fluoro-7α-methyl-6-methylcyclopropane-1,23-androstene-3-ene-3 , 17 ... 250 g 5 Lactose ..................................... 800 g Starch but.......

  ..................... 415 g Talcum powder ........................ 30 ..... DTD:. Magnesium stearate ......................... 5 g Fluoro-16α-methyl-7α-methylene-6-cyclohepropano-1,23-androstene-4-ene 3.17, lactose and half of the corn starch are mixed; the mixture is forced through a sieve with a mesh size of 0.5 mm. Corn starch (10 g) is suspended (DTD: in hot water <90 ml) and the resulting paste is used to granulate the powder.

  The granulate is dried, reduced to small pieces on a sieve of 1.4 mm mesh size; then the remaining amount of starch, talc and stearate

  magnesium are added, thoroughly mixed and tableted.

Example 7

  Capsules, each dosed at 0.200 g and

  containing 20 mg of the active substance, can be prepared.

  Composition for 500 capsules: fluoro-16-methyl-7a-6-methyl-1,2-cyclopropano-androstene-4-dione-3; 17 ... 10 g Lactose ..............

  ..................... 80 g Corn starch ........................ ...... 5 g Magnesium stearate ....................... 5 g This formulation is encapsulated in two-part hard gelatin capsules , and dosed at 0.200 g for..DTD: each capsule.

Claims (6)

1 - Compound of formula (I): ## STR2 ## in which formula: R represents hydrogen or fluorine; one of R and R represents = CH and the other represents hydrogen or C 1 -C 4 alkyl, and when R 2 represents = CHz, at least one of R and R 1 is other than hydrogen.   2 - Compound of formula (I), according to claim 1, characterized in that: - R represents hydrogen or fluorine; one of R1 and R2 represents = CH2 and the other represents C1-C4 alkyl. A compound of formula (I) according to claim 1, characterized in that it is chosen from the group consisting of by: 7-methyl-6-methylene-1,2-cyclopropano-androstene-4-dione-3,17; 7-methyl-6-methyl-1,2-cyclopropano-4-androstene-3-dione; 7α-ethyl-6-methylene-1,2-cyclopropano-androstene-4-dione-3,17; * ethyl-7? 6-Methylene-1,2-cyclopropanoandrostane-4-dione-3,17; 16-fluoro-1,2-methylene-1,2-cyclopropanedrostene-4-dione-3,17-dione; 16-fluoro-7-methyl-6-methylen 1,2-cyclopropano-androstene-4-dione-3,17; 16-fluoro-7-methyl-6-methylene-cyclopropano-1,2-androstene-4-dione-3,17; 16-Fluoro-7-ethyl-6-methylene-cyclopropano-1,2-p-androstene-4-dione-3,17; 16-Fluoro-7-methyl-6-methyl-1,2-cyclopropano-androstene-4-dione, 17; methylene? 1,2-cyclopropano-androstene-4-dione, 17; * Methyl-6a methylene- 1,2-cyclopropano-androstene-4-dione-3.1; * methyl-6P methylene- 1,2-cyclopropano-androstene-4-dione-3,1; * 6-ethyl-methylene- 1,2-cyclopropanoandrostene-4-dione-3,17; * Ethyl-6P methylene- 1,2-cyclopropanoandrostene-4-dione-3,17; 16-fluoro-3,17-dione; 16-fluoro-androstene-4-fluoro-16-androstene-4-fluoro-16-androstene-4-fluoro-16-androstene-4-methylene- cyclopropano-1,23 androstene-4-methyl-6a methylene- cyclopropan-1,2-dione-3,1; 6-methyl-7-methylene-1,2-cyclopropanediol-3,17-dione; Ethyl-6a methylene- cyclopropan-1,2-dione-3,17; and,   6-ethyl-methylene- cyclopropano-1,2P-3,11-dione.   4 - Process for the preparation of a compound of formula (I), according to claim 1, characterized in that it consists in: a> performing the methylenation of a compound of formula (II): II) formula wherein: - R is as defined in claim 1; and - R1 represents hydrogen or C1-C4 alkyl, at least one of R and R1 being other than hydrogen, so as to obtain a compound of formula (I), in which R2 represents = CH2 and R and R1 are as defined in claim 1; or b) placing, by means of a Grignard reaction, a C 1 -C 4 alkyl group at the 6-position of a compound of formula (III): C : 3 (III) Hill X 0 CH2   formula in which R is as defined in claim 1, followed by hydrolysis and dehydration, to obtain a compound of formula (I), wherein R1 represents = CH and R 1 2 2 represents C1-alkyl C4; or c) reducing a compound of formula (III) as defined above, followed by hydrolysis and dehydration, to obtain a compound of formula (I), wherein R1 is = CH2 and R2 represents hydrogen; and, if desired, converting a compound of formula (I) into another compound of formula (I), and / or, if desired,   separating a mixture of isomers of compound of formula (I) into the isolated isomers.   - A pharmaceutical composition, characterized in that it contains a suitable carrier and / or diluent, and, as an active ingredient, a compound of   formula (I) as defined in claim 1.   6 - Compound of.formula (I), according to claim 1, intended to be used, in medicine, in the treatment of advanced cancer, hormonodependent, breast, pancreas, endometrial or ovarian.   7 - Compound of formula <(I), according to claim 1, for use in medicine in the treatment prostatic hyperplasia.   The use of a compound of the general formula (I) according to claim 1 in the preparation of a pharmaceutical composition for the treatment of advanced, hormone-dependent, breast, pancreatic, the endometrium or ovary.   9 - Use of a compound of general formula (I) according to claim 1 in the preparation of a pharmaceutical composition for the treatment of prostatic hyperplasia.