WO1993014105A1

WO1993014105A1 - Difluoromethylenandrostenone derivatives and process for their preparation

Info

Publication number: WO1993014105A1
Application number: PCT/EP1993/000105
Authority: WO
Inventors: Franco Buzzetti; Antonio Longo; Angelo Crugnola; Enrico Di Salle
Original assignee: Farmitalia Carlo Erba S.R.L.
Priority date: 1992-01-21
Filing date: 1993-01-18
Publication date: 1993-07-22
Also published as: AU3351593A; HUT64968A; CA2106457A1; MX9300244A; ZA9335B; FI934093A; FI934093A0; JPH06507181A; IL104204A0; HU9302649D0; GB9201224D0

Abstract

The invention relates to new 6-difluoromethylenandrostenones having formula (I) wherein the symbol -^_-^_-^_ represents a double or single bond; R is hydrogen or C1-C4 alkyl; and A is a =C=O, =CH$(1,3)$OH or =CH$(1,3)$OR1 group, in which R1 is an acyl group, which are useful as steroidal aromatase inhibitors.

Description

DIFLUOROMETHYLENANDROSTENONE DERIVATIVES AND PROCESS FOR THEIR PREPARATION The present invention relates to new 6-difluoromethylen- androstenones, to a process for their preparation, to pharmaceutical compositions containing them, and to their use as therapeutic agents, in particular in the treatment of hormone-dependent diseases 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 hormone-dependent 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-dipendent tumours.

Known steroidal substances which have been reported to be endowed with an aromatase-inhibiting action are, for example, Δ¹-testololactone (U.S. Pat. 2,744,120), 4-hydroxy- androst-4-ene-3, 17-dione and esters thereof (see, for example, U.S.Pat. 4,235,893), 10-(1,2-propadienyl)-estr-4-ene-3, 17- dione (U.S.Pat.4,289,762), 10-(2-propynyl)-estr-4-ene-3,17-dione (J. Amer.Chem.Soc., 103, 3221 (1981) and U.S.Pat.4,322,416), 19-thioan- drostene derivatives ( Europ. Pat . Appl. 100, 566), androsta-4,6-diene-3, 17-dione, androsta-1,4,6-triene-3,17-dione (G.B. Pat. Appl.2,100,601A), androsta-1,4-diene-3,17-dione (Cancer Res. (Suppl.) 42,

3327 (1982)), 6-alkenylen-androsta-1,4-diene-3,17-diones (U.S. Pat. 4,808,816 and U.S. Pat. 4,904,650) and 6-alkenyl- en-androsta-1,4-dien-17-ol-3-one derivatives (U.S. Pat.

4,873,233).

The present invention provides new compounds having the following general formula (I)

(I)

wherein

the symbol --- represents a double or single bond; R is hydrogen or C₁-C₄ alkyl; and

A is a

C=O, CH OH or CH OR

₁ group, in which R₁ is

an acyl group.

Compounds falling within the scope of formula (I) above are all the possible isomers, stereoisomers and their mixtures, and the metabolites and the metabolic precursors or bio- precursors of the compound of formula (I). In the formulae of this specification the heavy solid lines indicate

that a substituent is in the β-configuration, i.e. above the plane of the ring, whereas a dotted line (,,,,,,) indicates that a substituent is in the α-configuration, and a wavy line indicates that a substituent may be either in the

α-configuration, i.e. below the plane of the ring, or in the β-configuration or in both, i.e. a mixture thereof.

In particular when in the compounds of formula (I) A is

OH or

OR the OH or OR substituent may be either in the α- or in the β-configuration or in both, i.e. a mixture thereof. Analogously, when the symbol ----- is a single bond, the R substituent may be either in the α- or β-configuration or in both, i.e. a mixture thereof.

The present invention includes all

the possible isomers, e.g. the single 1α, 17α; 1α, 17β;

1β,17α and 1β, 17β epimers, as well as all possible mixtures thereof, e.g. 1(α, β), 17α; 1(α, β), 17β; 1α, 17(α, β); 1 β , 17 (α , β ) and 1(α , β), 17(α, β)-isomers of the compounds of formula (I). Hence a compound of the invention herein specifically mentioned, without any indication of its stereochemistry, represents all the possible single isomers or mixtures thereof.

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 radical.

R₁ as an acyl group may be residue of any physiologically tolerable acid. Preferred examples of said acids are

C₁-C₄alkanoic acids, in particular acetic, propionic and butyric acids.

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 of formula (I).

Preferred compounds of the invention are the compounds of formula (I) wherein

A is a -C=O or -CH OH group;

R is hydrogen; and

the symbol represents a single or double bond.

Examples of specific compounds of the invention are the following compounds which, when appropriate, may be either α- or β-epimers or α, β-mixtures of said epimers:

6-difluoromethylenandrost-4-ene-3,17-dione;

6-difluoromethylenandrost-4-en-17α-ol-3-one;

6-difluoromethylenandrost-4-en-17β-ol-3-one;

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

6-difluoromethylenandrosta-1,4-dien-17α(-ol-3-one; and

6-difluoromethylenandrosta-1,4-dien-17B-ol-3-one.

The compounds of the invention can be obtained by a process comprising:

a) dehydrofluorinating a compound of formula (II) I)

wherein

R is as defined above, thus obtaining a compound of formula (I) wherein the symbol --- is a single bond and

A is a

CO group; or

b) dehydrogenating a compound of formula (III)

wherein

R is as defined above , thus obtaini ng a compound of formula ( I ) wherein the symbol --- is a double bond and

A is a

CO group; or

c) reducing selectively a compound of formula (IV)

wherein

R and the symbol --- are as defined above, thus obtaining a compound of formula (I) wherein R and the symbol --- are as defined above and A is a H OH group; or

d) acylating a compound of formula (V)

wherein

R and the symbol --- are as defined above, thus obtaining a compound of formula (I) wherein R and the symbol --- are as defined above and A is a CH OR group in

which R₁ is an acyl group; 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 compounds of formula (I) into the single isomers.

The dehydrofluorination of a compound of formula (II) can be carried out by using basic dehydrohalogenation agents such as pyridine or a LiBr-Li₂CO₃-DMF mixture. Preferably the dehydrofluorination is carried out by chromatographing the raw steroid on neutral or basic alumina and using as eluant an inert solvent such as benzene, dichloromethane or ethyl acetate.

The dehydrogenation of a compound of formula (III) may be performed according to known methods, e.g. by treatment with DDQ, according to D. Walker and J.D. Hiebert: Chem. Rev. 67, 156 (1967), or by treatment with selenium dioxide, chloranil or benzeneseleninic acid. Preferably the reaction is performed by treatment with benzeneseleninic anhydride in an inert organic solvent, such as chlorobenzene or carbon tetrachloride, at a temperature ranging from about 60°C to about 120°C and reaction times varying from about 2 to about 48 hours.

The selective reduction of a compound of formula (IV) may be carried out by a well known method, for example as des cribed by C. Djerassi in Steroid Reactions (1963) or by J. Fried in Organic Reactions in Steroid Chemistry Vol. I (1972). Preferably the reduction is carried out with a complexed metal hydride, in particular with sodium borohydride in an inert organic solvent, in particular in methanol solution at temperatures ranging from about 0 to about

50°C.

The acylation of a compound of formula (V) can be performed by reaction with a reactive derivative of a suitable carboxylic acid, such as an anhydride or halide, in the presence of a basic agent, at temperatures ranging from about 0 to about 50°C. Preferably the acylation is carried out by reaction with the respective anhydride in the presence of an organic base, such as pyridine.

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 out according to known methods. For example a 17β-hydroxy derivative of a compound of formula (I) may be converted into the respective 17α-hydroxy derivative by basic catalysis, e.g. with 0.1N sodium hydroxide in an aliphatic alcohol, e.g. ethanol.

Similarly, processes b), c) and d) can be regarded as optional conversions of a compound of formula (I) into an- other compound of formula (I). In fact, a compound of for mula (III) is a compound of formula (I) wherein the symbol --- is a single bond, A is CO and R is as herein defined.

A compound of formula (IV) is a compound of formula (I) wherein A is CO and the symbol --- and R are as herein

defined; and a compound of formula (V) is a compound of formula (I) wherein A is CH OH and the symbol --- and

R are as herein defined.

A compound of formula (II) can be obtained by oxidizing a compound of formula (VI)

wherein R is as defined above.

The oxidation of a compound of formula (VI) can be performed according to known methods, e.g. by treatment with the Jones reagent as described by Fieser and Fieser in Reagents for Organic Synthesis 1, 142 (Wiley 1967). Jones reagent is a solution of chromic acid and sulfuric acid in water. The oxidation may be carried out by titrating a stirred solution of the alcoholic compound in acetone at temperatures ranging from about -20°C to about 30°C with the Jones reagent. A compound of formula (VI) wherein R is as defined above may be obtained by saponification of a compound of formula (VII)

wherein R is as defined above and R₁, being as herein defined, is preferably a lower alkanoyl group, in particular acetyl.

The saponification may be performed by a conventional method, e.g. by treatment with an alkali metal hydroxide in alcoholic solution, preferably with potassium hydroxide in methanol or ethanol at temperatures ranging from about 20°C to reflux temperature.

A compound of formula (VII), wherein R and R₁ are as defined above, may be obtained from a compound of formula (VIII)

wherein R and R₁ are as defined above by applying e.g. the method described in U.S. Pat. 3,504,002. Accordingly, the 6-ketosteroid of formula (VII) is treated with at least equimolar amounts of tributylphosphine and sodium chloro- difluoroacetate, at a temperature in the range of 150 - 200°C, using as solvent disubstituted hydrocarbon amide. It is viewed as involving the in situ production of tri- butylphosphinedifluoromethylene, which reacts with the 6-keto group. Alternatively, the method mentioned in U.S. Pat. 4,567,000 can be used. Accordingly, a solution of the protected 6-ketosteroid in an inert solvent such as THF, dioxane or diglyme is added to a cold solution of (di- ethylphosphinyl )difluoromethyllithium at about -60°C to about -80°C. This reagent may be prepared by treatment of diethyl difluoromethylphosphonate with 1.1 equivalent of lithium diisopropylamide in THF at -78ºC.

A compound of formula (VIII) wherein R and R₁ are as defined above may be obtained by oxidation of a compound of formula (IX)

in which R and R₁ are as defined above. This conversion may be performed according to a well known oxidation method in steroid chemistry, e.g. according to the method described above.

A compound of formula (IX) wherein R and R₁ are as defined above may be obtained by cleavage of the 5β, 6β-epoxide ring in a compound of formula (X)

wherein R and R₁ are as defined above.

The cleavage may be carried out, e.g., accordingly to

H.B. Henbest et al. (J. Chem. Soc. 1957, 4765) by reaction with the boron trifluoride-ether complex in an inert organic solvent such as benzene or ethyl ether at temperatures ranging from about 0 to 50°C. In the case of 5,6β- epoxide, the cleavage affords the diaxial 5α, 6β-fluoro- hydrin as desired.

A compound of formula (X), wherein R and R₁ are as defined above, may be obtained from a compound of formula (XI)

(XI)

wherein R and R₁ are as defined above;

by dehydrobromination, e.g. according to J.F. Templeton et al. in J. Chem. Soc. Perkin Trans. I, 1361 (1987). Thus a solution of the 5α, 6β-bromohydrin in an inert organic solvent, such as dichloromethane or THF, is stirred with basic alumina at room temperature. Alternatively, the 5α, 6β-bromohydrin can be treated with a weak base such as sodium acetate in alcoholic solution, e.g. in methanol, at temperatures ranging from about 20°C to reflux temperature, e.g. as described in Belg. Pat. 625,669.

A compound of formula (XI), wherein R and R₁ are as defined above, may be obtained from a compound of formula (XII)

(XII)

wherein R and R₁ are as defined above;

by treatment with a N-bromoamide such as N-bromoacetamide or N-bromosuccinimide in the presence or not of perchloric acid in an aqueous solvent mixture such as aqueous dioxan or aqueous 1,2-dimethoxyethane at temperatures ranging from about 0°C to room temperature, e.g. as described in J. Chem. Soc. 1959, 4108.

The compounds of formula (XII) are known compounds or may be obtained by known methods from known compounds. When in the new compounds of the present invention and in the intermediate products thereof groups are present which need to be protected before submitting them to the here- above illustrated reactions, they may be protected before the reactions take place and then deprotected at the end of the reaction, according to well known methods in organic chemistry.

The compounds of the present invention are inhibitors of the biotransformation of androgens into estrogens, i.e., they are steroidal aromatase inhibitors. The aromatase inhibitory activity of these 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 androstenedione into estrone was evaluated by incubating (1β-³H)androstenedione (50 nM) in the presence of NADPH with the enzyme preparation and by measuring the amount of ³H₂O formed during 20 min incubation at 37°C.

The 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 compounds of the invention are useful in mammals, including humans, 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 compounds of the invention 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 low toxicity 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 adminis tration 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 or film 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 of the patient and admininistration 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 of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent).

The pharmaceutical compositions containing the compounds of the 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 carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, 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 of lidocaine 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 present invention also provides a compound of formula (I) for use in a method of treatment of the human or animal body by therapy, especially for use as an aromatase

inhibitor.

The present invention additionally provides the use of a compound of formula (I) in the manufacture of a medicament for use as an aromatase inhibitor.

The present invention further provides a method of

inhibiting aromatase in mammals, including humans, which comprises applying thereto an effective amount of a compound of formula (I).

The present invention still further provides an aromatase inhibiting agent comprising a compound of formula (I).

The following examples further illustrate the invention:

Example 1 (I, A=

C=O, R=H, --- single bond)

First Jones reagent is prepared by dissolving 2.672 g of chromic trioxide in 2.3 ml of cone. sulfuric acid and diluting with water to a volume of 10 ml. Then to a stirred solution of 6-difluoromethylene-5α(-fluoroandrostan-3,17- diol (358 mg, 1 mmol) in acetone (30 ml) is added portionwise under cooling 2 ml Jones reagent. After stirring for ½ h at 10-15°C and another½ h at 20-25°C, methanol ( 1 ml ) is added to destroy excess reagent. The resultant green solution is filtered to remove the chromium salts and then carefully diluted with water in order to precipitate raw 6-difluoromethylene-5α-fluoroandrostan-3,17-dione. The precipitate is filtered off, desiccated, dissolved in

benzene (10 ml) and adsorbed onto a basic alumina column (20 g). Finally elution with benzene-ether affords pure 6-difluoromethylene-androst-4-ene-3,17-dione (167 mg, 50% yield).

C₂₀H₂₄F₂O₂ calcd: C 71.83 H 7.23 F 11.36

found: C 71.71 H 7.11 F 11.42

IR cm^-1: 1740 (17-CO), 1725 (C=CF₂), 1670 (3-CO), 1620

MS (m/z): 334

Example 2 (I, A=

C=O, R=H, --- double bond)

A solution of 6-difluoromethylenandrost-4-ene-3,17-dione (334 mg, 1 mmol) and benzene selenic anhydride (360 mmol) in chlorobenzene (30 mol) is heated for 4 h at 90-100°C. Then the solvent is removed in vacuum and the residue

chromatographed on silica gel with benzene-ether mixture as eluant thus giving pure 6-difluoromethylenandrosta-1,4- diene-3,17-dione (266 mg, 80% yield).

C₂₀H₂₂F₂O₂ calcd: C 72.27 H 6.67 F 11.43

found: C 72.15 H 6.55 F 11.35

IR cm^-1: 1735 (17-CO), 1720 (C=CF₂), 1650 (3-CO), 1610 (Δ⁴) MS (m/z): 332. Example 3 (I, A= CH-OH, R=H, --- single or double bond)

To a stirred solution of 6-difluoromethylenandrost-4-ene- 3,17-dione (334 mg, 1 mmol) in methanol (20 ml) is added sodium borohydride (57 mg, 1.5 mmol) over a period of 10 min at 0°C and stirring is continued for 1 h at 0°C. After addition of few drops of acetic acid, the mixture is concentrated under vacuum, diluted with water and then extracted with ethyl acetate. The combined organic phases are washed with saline solution, dried over sodium sulfate and then evaporated in vacuum. The residue is submitted to column chromatography on silica gel. Gradient elution with benzene-ether mixtures affords pure 6-difluoromethylen- androst-4-en-17β-ol-3-one (202 mg, 60 % yield).

C₂₀H₂₆F₂O₂ calcd: C 71.40 H 7.79 F 11.30

found: C 71.31 H 7.68 F 11.15

IR cm^-1: 3410 (OH), 1720 (C=CF₂), 1675 (3-CO), 1625 (Δ⁴) MS (m/z): 336.

According to the above described procedure and starting from the appropriate compound of formula (IV)

respectively one can prepare the following products as single isomers, as well as their 17α, 17β-mixtures:

6-difluoromethylenandrost-4-en-17α-ol-3-one;

6-difluoromethylenandrosta-1,4-dien-17α-ol-3-one; and 6-difluoromethylenandrosta-1,4-dien-17β-ol-3-one. Example 4

A solution of 3β,17β-diacetoxy-6-difluoromethylene-5α- fluoroandrostane (442 mg, 1 mmol) in methanol (15 ml) containing potassium hydroxide (336 mg, 6 mmol) is refluxed for 4 h. The reaction mixture Is concentrated under vacuum, diluted with water and extracted with ethyl acetate. The combined organic layers are washed with saline solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is crystallized from acetone-hexane giving pure 6-difluoromethylene-5α-fluoroandrostane-3,17- diol (323 mg, 90 % yield).

C₂₀H₂₉F₃O₂ calcd: C 67.02 H 8.15 F 15.90

found: C 67.10 H 8.05 F 15.81 MS (m/z): 358.

IR cm^-1: 3350 (OH), 1720 (C=CF₂)

Example 5

A solution of 3β,17β-diacetoxy-5α-fluoroandrostan-6-one (408 g, 1 mmol) and tributylphosphine (344 mg, 1.7 mmol) in N-methyl-2-pyrrolidone ( 2 ml ) is heated to 180°C. To this solution is added dropwise during 40 min a solution of sodium chlorodifluoroacetate (401 mg, 3.3 mmol) in N-methyl-2-pyrrolidone (6 ml). The reaction mixture is dissolved in benzene after cooling and the solution submitted to column chromatography. Gradient elution with benzene-ether mixture affords besides starting material the desired 3β,17β-diacetoxy-6-difluoromethylene-5α-fluoroandrostane (133 mg, 30 % yield).

C₂₄H₃₃F₃O₄ calcd: C 65.14 H 7.52 F 12.88

found: C 65.05 H 7.44 F 12.75

MS (m/z): 442.

IR cm^-1: 1740 (-OCOCH₃), 1725 (C=CF₂).

Example 6

To a solution of 3β,17β-diacetoxy-5α-fluoroandrostan-6β- ol (408 mg, 1 mmol) in acetone (20 ml) is added portionwise Jones reagent (1 ml) under cooling at 10-15°C. The stirring is continued for ½ h at 10-15°C and another ½ h at 20-25°C. After addition of methanol (1 ml), the green mixture is filtered and the filtrate carefully diluted with water In order to precipitate the raw product. This is filtered off and chromatographed on silica gel using gradient elution with benzene-ether mixtures. Thus pure 3β,17β-diacetoxy-5α-fluoroandrostan-3-one is obtained (327 mg, 80 % yield).

C₂₃H₃₃FO₅ calcd: C 67.62 H 8.14 F 4.65

found: C 67.45 H 8.05 F 4.57 MS (m/z): 408.

IR cm^-1 : 1735 (acetate), 1705 (6-ketone).

Example 7

A solution of 3β,17β-diacetoxy-5, 6β-epoxyandrostane (389 mg, 1 mmol) in benzene (20 ml) is treated with boron trifluoride etherate (227 mg, 1.6 mmol) at 20-25°C for % h. The solution is washed with water, dried over potassium carbonate and the solvent evaporated under vacuum. The residue is chromatographed as usually to give pure 3β,17β- diacetoxy-5α-fluoro-androstan-6β-ol (308 mg, 75 % yield). C₂₃H₃₅FO₅ calcd: C 67.29 H 8.59 F 4.63

found: C 67.15 H 8.46 F 4.55

MS (m/z): 408

IR cm^-1: 3350 (hydroxy), 1735 (acetate)

Example 8

A solution of 5α-bromo-3β,17β-diacetoxyandrostan-6β-ol (471 mg, 1 mmol) in dichloromethane (25 ml) containing basic alumina (3 g) is stirred for 2 h at 20-25°C. The alumina is filtered off, the residue washed with dichloromethane and the combined filtrate evaporated under vacuum. The residue is crystallized from dichloromethane-acetone to afford pure 3β,17β-diacetoxy-5,6β-epoxyandrostane

(233 mg, 60 % yield).

C₂₃H₃₄O₅ calcd: C 70.74 H 8.78

found: C 70.55 H 8.65

MS (m/z): 390

IR cm^-1: 1735 (acetate). Example 9

A solution of 3β,17β-diacetoxyandrost-5-ene (379 mg, 1 mmol) in dioxan (5 ml) is treated with N-bromoacetamide (193 mg, 1.4 mmol), perchloric acid 70 % (0.1 ml) and water (1 ml) for ½ h at 20-25°C. The mixture is diluted with water and then extracted with benzene. The organic layer is separated, washed with water, dried over sodium sulfate and evaporated in vacuum. The residue is crystallized from chloroform-hexane to give pure 5α-bromo-3β,17β- diacetoxy-androstan-6β-ol (306 mg, 65 % yield).

C₂₃H₃₅BrO₅ calcd: C 58.60 H 7.48 Br 16.95

found: C 58.30 H 7.35 Br 16.60

MS (m/z): 471

IR cm^-1: 3350 (OH), 1735 (acetate).

Example 10

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

Composition (for 10,000 tablets):

6-difluoromethylenandrost-4-ene-3,17-dione 250 g

Lactose 800 g

Corn starch 415 g

Talc powder 30 g

Magnesium stearate 5 g The 6-difluoromethylenandrost-4-ene-3,17-dione, the lactose and half the corn starch were mixed; the mixture was then forced through a sieve of 0.5 mm mesh size. Corn starch (10 g) was suspended in warm water (90 ml) and the resulting paste was used to granulate the powder.

The granulate was dried, comminuted on a sieve of 1.4 mm mesh size, then the remaining quantity of starch, talc and magnesium stearate was added, carefully mixed and processed into tablets.

Example 11

Capsules, each dosed at 0.200 g and containing 20 mg of the active substance were prepared.

Composition for 500 capsules:

6-difluoromethylenandrost-4-en-17β-ol-3-one 10 g

Lactose 80 g

Corn starch 5 g

Magnesium stearate 5 g

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

Claims

CLAIMS :

1. A compound having the following general formula (I)

wherein

the symbol --- represents a double or single bond;

R is hydrogen or C₁-C₄ alkyl; and

A is a C=O, OH or OR

₁ group, in which

R₁ is an acyl group.

2. A compound of formula (I), according to claim 1, wherein

A is a

C O or

OH group;

R is hydrogen; and

the symbol --- represents a single or double bond.

3. A compound selected from

6-difluoromethyleneandrost-4-ene-3,17-dione;

6-difluoromethylenandrost-4-en-17α-ol-3-one;

6-difluoromethylenandrost-4-en-17β-ol-3-one;

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

6-difluoromethylenandrosta-1,4-dien-17α-ol-3-one; and 6-difluoromethylenandrosta-1,4-dien-17β-ol-3-one; which, when appropriate, may be either α - or β-epimer or α,β-mixture of said epimers.

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

wherein

R is as defined in claim 1, thus obtaining a compound of formula (I) wherein the symbol --- is a single bond and A is a

CO group; or

b) dehydrogenating a compound of formula (III)

wherein

R is as defined in claim 1, thus obtaining a compound of formula (I) wherein the symbol --- is a double bond and A is a

CO group; or

c) reducing selectively a compound of formula (IV)

(IV)

wherein

R and the symbol --- are as defined in claim 1, thus obtaining a compound of formula (I) wherein the symbols --- and R are as defined in claim 1 and A is a

OH group; or

d) acylating a compound of formula (V)

(V)

wherein

R and the symbol --- are as defined in claim 1, thus obtaining a compound of formula (I) wherein R and the symbol --- are as defined in claim 1 and A is a

OR₁ group in which R₁ is an acyl group; 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 compounds of formula (I) into the single isomers.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and, as an active principle, a compound of formula (I) as claimed in claim 1.

6. A compound of formula (I), as defined in claim 1, for use in a method of treatment of the human or animal body by therapy.

7. A compound of formula (I), as defined in claim 1, for use as an aromatase inhibitor.

8. Use of a compound of formula (I), as defined in

claim 1, in the manufacture of a medicament for use as an aromatase inhibitor.

9. A method of inhibiting aromatase in mammals which

comprises applying thereto an effective amount of a compound of formula (I) according to claim 1.

10. An aromatase inhibiting agent comprising a compound of formula (I) according to claim 1.