GB2166742A - Novel 4-thioandrostene derivatives useful as aromatase inhibitors - Google Patents

Abstract

4-Thioandrostene derivatives represented by formula (I): <IMAGE> wherein R1 is hydrogen; C1-C6 alkyl; a C1-C10 aryl or C7-C10 aralkyl group (either unsubstituted or ring substituted by C1-C6 alkyl, halogen, nitro, amino or hydroxy); or C2-C22 carboxylic acyl; R2 is hydrogen; C1-C6 alkyl; a C6-C10 aryl or C7-C10 aralkyl group (either unsubstituted or ring substituted by C1-C6 alkyl, halogen, nitro, amino or hydroxy); halogen; or a group -OR3 wherein R3 is hydrogen, C1-C6 alkyl or C2-C22 carboxylic acyl; or a dimer thereof in which there is no radical R1 as defined above but instead the sulphur atoms attached at the respective 4-positions of two compounds of formula (I) are joined together to form a disulphide linkage; and pharmaceutically acceptable salts of a compound of formula (I), or a said dimer, containing a salifiable group; are aromatase inhibitors useful in the treatment of estrogen-dependent tumors and prostatic hyperplasia.

Description

SPECIFICATION Novel 4-thioandrostene derivatives and process for their preparation The present invention relates to novel 4-thioandrostene derivatives, to a process for their preparation, to pharmaceutical compositions containing them, and to the use of said compounds as inhibitors of the biosynthesis of estrogens, i.e. as aromatase-inhibitors.

Basic and clinical data indicate that some human cancers, e.g. breast cancer, can be divided into hormone-independent and hormone-dependent subtypes.

Estrogens are the hormones involved in these pathogenic cellular changes and, although they are not themselves carcinogenic, they are the major hormonal stimulus for growth of hormone-dependent subtypes of, e.g., breast, endometrial and ovarian carcinoma. 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 aromatisation of the steroidic ring A, which is performed by the enzyme aromatase.

Therefore, this enzyme plays a key role both in the pathogenesis of estrogen-dependent tumors and in theirtreatment. As aromatisation 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 tumors.

Known substances which have been reported to be endowed with an aromatase-inhibiting action are, for example, testolactone (U.S. Patent 2,44,120), 4-hydroxy-A4-androstene-3,17-dione and esters thereof (see, for example, U.S. Patent 4,235,893), 1 0-(1 ,2-propadienyl)-A4-oestrene-3,1 7-dione (U.S. Patent 4,289,762), 1 0-(2-propynyl )-A4-oestrene-3,1 7-dione (J.A.C.S.1 981, 103,3221 and U.S. Patent 4,322,416), and 1 0-thio androstene derivatives (European patent application 100566).

A new group of 4-thioandrostene derivatives having aromatase-inhibiting properties have now been found, i.e. novel 4-thioandrost-4-ene-3,17-dione derivatives having the general formula (I)

wherein R1 is (a) hydrogen; (b) C1-Csalkyl; (c) a C6-C,0 aryl or C7-C10 aralkyl group, either unsubstituted or ring substituted by one or more substituents chosen from C1-C6 alkyl, halogen, nitro, amino and hydroxy; or (d) C2-C22 carboxylic acyl; R2 is (a') hydrogen; (b') C1-C6 alkyl; (c') a C6-CaO aryl or C7-C10 aralkyl group, either unsubstituted or ring substituted by one or more substituents chosen from C1 -C6 alkyl, halogen, nitro, amino and hydroxy; (d') halogen; or (e') a group -OR3 wherein R3 is hydrogen, C1 -C6 alkyl or C2-C22 carboxylic acyl.

The invention includes also dimers thereof in which there are no radicals R1 as defined above but instead the sulphur atoms attached at the respective 4-positions of two compounds of formula (I) are joined together to form a disulphide linkage; and pharmaceutically acceptable salts of a compound of formula (I), or a said dimer, containing a salifiable group; as well as all the possible isomers and their mixtures.

In this specification the alkyl groups, including the aliphatic moieties of the aralkyl groups and the aliphatic moieties possibly present in the carboxylic acyl groups, may be branched or straight chain.

A C1-C6 alkyl group is, preferably, C1C4 alkyl, in particular methyl or ethyl.

A C6-CaO aryl group is, preferably, phenyl, lx-naphthyl or t3-naphthyl, most preferably phenyl.

A C7-C10 aralkyl group is, preferably benzyl.

A C2-C22 carboxyl acyl is, preferably, an acyl group derived either from an optionally halo substituted aliphatic carboxylic acid, e.g. acetic or halo-acetic acid; or from an aromatic carboxylic acid, such as, e.g., benzoic acid, optionally ring substituted by C1 -C6 alkyl, halogen, nitro, amino or hydroxy; or from a fatty carboxylic acid such as, for instance, heptanoic, octanoic, dodecanoic, myristic, palmitic or stearic acid.

A halogen atom is, preferably, chlorine or bromine. When R1 is a C1-C6 alkyl group, this is, preferably methyl or ethyl.

When R1 is a C6-C10 aryl or C7-C10 aralkyl group optionally substituted or reported above, it is, preferably, phenyl or, respectively, benzyl, each unsubstituted or substituted by methyl, chlorine, bromine, nitro, amino or hydroxy.

The same applies to the substituent R2 when it is C1-C5- alkyl or, respectively, a C5-C10 aryl or C7-C70 aralkyl group, optionally substituted as reported above.

When R1 is a C2-C22 carboxylic acyl group as defined above, it is, preferably, a C2-C12 carboxylic acyl, in particular the acyl group deriving from acetic-, a-bromo-acetic, propionic, benzoic, heptanoic or dodecanoic acid.

When R2 is a group -OR3 wherein R3 is C1-Cs alkyl, it is, preferably, methoxy or ethoxy.

When R2 is a group -OR3 wherein R3 is a C2-C22 carboxylic acyl, the acyl group is, preferably, a C2-C12 carboxyli acyl, for example one of those specified hereabove as preferred for the substituent R1, when carboxylic acyl. The dimeric disulphide forms of the compounds of formula (I) wherein R1 is hydrogen are the compounds of formula (la)

wherein R2 is as defined above.

Pharmaceutically acceptable salts of the invention are the salts of the compounds of formula (I) or (la) containing a salifiable group, namely an amino group, at the R1 and/or R2 substituents; they are therefore the salts with pharmaceutically acceptable acids, either inorganic acids such as, e.g., hydrochloric, hydrobromic, nitric, sulfuric or phosphoric, or organic acids such as e.g., acetic, formic, propionic, benzoic, maleic, malic, fumaric, succinic, tartaric, citric, oxalic, methanesulphonic or ethanesulphonic.

In the above formula (I) and subsequent formulae a wedged line () indicates a substituent in the (3-configuration, i.e. above the plane of the ring ; a wavy line (-) indicates that a substituent may be in the a-configuration (i.e. below the plane of the ring:dotted line ) or in the -configuration or both.

Consequently, where a formula has a substituent with a wavy line bond, the formula may represent a compound having the substituent solely in the a-configuration or solely in the (3-configuration, or the formula may represent a mixture of both compounds having the substituent in the a-configuration and compounds having the substituent in the p-configuration.

A preferred class of compounds of the invention are th compounds of formula (I) and their salts wherein R1 is hydrogen;C1-C4 alkyl; a phenyl or benzyl group optionally ring substituted by nitro; or a C2-C12 aliphatic carboxylic acyl group. Another preferred class of compounds of the invention are those wherein R2 is hydrogen; halogen; C1-C4 alkyl; or a phenyl or benzyl group optionally ring substituted by nitro.

In the above preferred class, when R1 is C1-C4 alkyl, methyl and ethyl are preferred; when R1 is C2-C12 aliphatic carboxylic acyl, acetyl, propionyl, heptanoyl and dodecanoyl are preferred.

When R2 is halogen, this is, preferably chlorine, bromine or fluorine; when R2 is C1 -C4 alkyl, methyl and ethyl are preferred.

Examples of preferred specific compounds under this invention are: 4-mercaptoandrost-4-ene-3,1 7-dione; bis(androst-4-ene-3,17-dione-4-yl)disulphide; 4-ethylthioandrost-4-ene-3,17-dione; 4-acetylthioandrost-4-ene-3,1 7-dione; 6ss-methyl-4-mercaptoandrost-4-ene-3,17-dione.

The compounds of the invention may be prepared by a process comprising reacting a compound of formula (II)

wherein R2 is as defined above, with a compound of formula (III) R'1- SH (III) wherein R'1 is hydrogen, a C-C6 alkyl group, or a C6-Cs0-aryl or C7-C10 aralkyl group, either unsubstituted or ring substituted by one or more substituents chosen from C1-C5-alkyl, halogen, nitro, amino and hydroxy, so obtaining a compound of formula (I) wherein R1 has the meanings reported above for R'1 or a dimer of formula (la);; and, if desired, acylating a compound of formula (I) wherein R1 is hydrogen with a C2-C22 carboxylic acid or a reactive derivative thereof, so obtaining a compound of formula (I) wherein R1 is a C2-C22 carboxylic acyl; and/or, if desired, converting a compound of formula (I) or a said dimer into a pharmaceutically acceptable salt thereof and/or, if desired, separating a mixture of isomers of formula (I) or (la) into the single isomers.

The reaction between a compound of formula (II) and a compound of formula (III) wherein R'1 is hydrogen (i.e. hydrogen sulphide) leading, by oxirane ring cleavage, to a compound of formula (I) wherein R1 is hydrogen, is carried out in presence of a base, either organic such as, for instance, pyridine or a tri-C1-C6-alkylamine, e.g. triethylamine, or inorganic such as, e.g. sodium or potassium hydroxide, operating in an inert solvent, such as, for example, methanol, ethanol, water, dioxane or dimethoxyethane, and under inert atmosphere.

When the reaction is carried out under air or oxygen atmosphere, a dimer of formula (la) is obtained, the interconversion between a thiol and its dimeric disulphide according to the reaction oxidation la I (Ra = H) reduction being an easy known process.

The reaction between compound of formula (II) and a compound of formula (III) wherein R'1 is a C1-C6 alkyl group or a C6-Cr0 aryl or C7-C10 aralkyl group optionally substituted as reported above, leading by oxirane ring cleavage, to a compound of formula (I) wherein R1 has the meaning reported above under (b) and (c), is carried out in the presence of an acid such as, for example, polyphosphoric acid, operating in an inert solvent which may be, for instance, dioxane, dimethoxyethane, water, methanol or ethanol.

The reaction between a compound of formula (II) and a compound of formula (III) may be performed at a temperature between about 0 C and about 50"C, the room temperature being generally preferred.

The optional acylation of a compound of formula (I) wherein R1 is hydrogen, in order to obtain a compound of formula (I) wherein R1 is a carboxylic acyl as previously defined, may be carried out by reaction with the desired C2-C22 carboxylic acid or most preferably, with a reactive derivative thereof. The latter may be, for example, the corresponding acyl halide, preferably the chloride, or the corresponding anhydride or a mixed anhydride.

The acylation reaction is preferably carried out, e.g. at room temperature, in an inert solvent which may be, for instance, dioxane, dimethoxyethane, dimethylformamide, water or a halogenated hydrocarbon such as, e.g., chloroform or methylene chloride.

When the carboxylic acid is used as such the presence of a coupling agent such as, e.g., dicylohexylcarbodiimide is usually required; when a carboxylic acid halide or anhydride is used for acylation, the reaction is preferably carried out in presence of a base either an organic base, for instance pyridine or a tri-C1-C5-alkylamine such as, e.g., triethylamine, or an inorganic base, for example sodium or potassium hydroxide.

The optional conversion of a compound of formula (I) or (la) into a pharmaceutically acceptable salt thereof may be carried out according to the known and usual salification procedures. Conventional methods may also be followed for the optional separation of a mixture of isomers of formula (I) or (la) into single isomers; typical techniques may be, for instance, fractional crystallization and chromatography.

The compounds of formula (II) may be prepared by epoxidation of a compound of formula (IV)

wherein R2 is as defined above.

Epoxidation may be carried out according to known methods, for example by treatment with hydrogen peroxide and sodium hydroxide in a protic solvent following, e.g., the procedure described in J.Cheam.Soc.Perkin I, 1973, 1830.

The compound of formula (IV) wherein R2 is hydrogen is the known androst4-ene3,1 7-dione of natural configuration [The Merck Index 9th Ed.page 669].

A compound of formula (IV) wherein R2 is other than hydrogen may be obtained by known methods from known compounds.

In particular, for example, a compound offormula (IV) wherein R2 is C1-C6 alkyl or a C6-C10 aryl or C7-C10 aralkyl group as defined above may be obtained from the compound of formula (IV) wherein R2 is hydrogen, i.e. the known androst-4-ene-3,17-dione, by the following procedure.

The androst -4-ene-3,17-dione is firstly converted, according to known procedures, into the compound of formula (V)

and the compound of formula (V) is then reacted with a suitable metallorganic compound carrying a R'2 moiety, wherein R'2 is C1-C6 alkyl or a C6-C10 aryl or C7-C10aralkyl group as defined hereabove for R2, for example with a Grignard reagent of formula R'2MgX, wherein R'2 is as defined above and Xis a halogen atom, preferably, bromine, chlorine or iodine: according to established sequences [J. Am. Chem. Soc. 80, 4717, 1958] a compound of formula (11) is so obtained with a R2 substituent either in the a- or in the (3-configuration, the R2 substituent having the meanings reported above for R'2.

As already said, the compounds of the invention are endowed with aromatase inhibiting activity.

Thus, for example, the inhibitory effect of the compound of the invention 4-mercapto-androst-4-ene-3,17 dione on aromatase was determined in vivo, according to the procedure reported below, in comparison with the well known aromatase inhibitor 4-hydroxy-androst-4-ene-3,1 7 dione [A.M.H.BRODIE, at al, Steroids 38, 693, 1981] taken as the reference compound.

Aromatase inhibition in vivo in rats: adult female rats were subcutaneously treated with 100 I.U. pregnant mares' serum gonadotropin (PMSG) on alternate days for six times in order to increase ovarian aromatase activity, according to Brodie procedure [A.M.H. BRODIE, et al, Steroids 38,693, 1981]. On the last day of PMSG treatment, groups of 3 animals each were given subcutaneous injections of vehicle or the inhibitors at 3 and 30 mg/kg. Animals were killed 24 hr later, microsomes were prepared from ovaries and their aromatase activity was determined.The assay of Thompson and Siiteri [E.A.THOMPSON and P.K.SIITERI, J.Biol. Chem. 249, 5364,1947] which determines the rate of aromatization as measured by the liberation of 3H2O from 4 [1P, 2p- 3H] androstene-3,17 dione was used. All incubations were carried out in a shaking water bath at 37"C in air in 10m M potassium phosphate buffer,pH 7.5, which contained 100 mM KCI, 1 mM EDTA and 1 mM dithiothreitol.

The experiments were carried out for 20 min in 2 ml incubation volume containing 0.15 mg of microsomal proteins, 100 nM 4-[3H]androstenedione and 100 FM NADPH.

After 20 minutes of incubation the reaction was stopped by the addition of chloroform (5 ml). After centrifugation at 1500xg for 5 min aliquots (0.5 ml) were removed from the water phase for determination of 3H2O formed.

The results are referred to as % of inhibition of control samples, and appear summarized in the following table 1.

TABLE 1. INHIBITION OF RAT OVARIAN AROMATASE IN VIVO Dose Estrogen formed Aromatase mg/kg (pmoles/mg/20 min) inhibition Compound s.c.

Vehicle - 456 + 39 0 372 + 58 4-hydroxy-androst-4-ene- 3 18 3,17 dione 59 5** 30 87 280 + 22* 4-mercapto-androst-4-ene- 3 39 3,17 dione 47t t 30 90 *P < 0.05; **P < 0.01 versus vehicle treated group.

The tabulated data show that 24 hours after in vivo treatment in rats, both components at 30 mg/kg determine a maximal inhibition of ovarian aromatase, but at 3 mg/kg only 4-mercapto-andrnst-4-ene-3,1 7 dione significantly reduces aromatase activity.

These results indicate that the compounds of the invention, in particular the 4-mercapto-androst-4-ene-3, 17 dione, are more potent than 4-hydroxy-androst-4-ene-3,17 dione in inhibiting aromatase activity in vivo.

In view of the above indicated activity the compounds of the invention are therapeutically useful in the situations in which a decrease in estrogen biosynthesis is desirable, such as, e.g., pre- and post- menopausal breast tumors, ovarian tumors, endometrial tumors and prostatic hyperplasia.

Accordingly, object of the invention is also method producing inhibition of the enzyme aromatase and, consequently, because of inhibition of estrogen biosynthesis, a method of treating estrogen-dependent tumors, such as, e.g., breast tumors, ovarian tumors and uterine tumors, and also prostatic hyperplasia, in a patient in need of it, which method comprises administering to the patient an effective amount of a compound of the invention or a pharmaceutical composition containing it.

The toxicity of the compounds of the invention is quite negligible so that they can be safely used in therapy. 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 administration route; for example the dosage adopted for oral administration to adult humans may range from about 20 to about 400 mg pro dose, from 1 to 5 times daily.

As already said 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, gelatine, 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; 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, 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 infusion 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 4-mercaptoandrost-4-ene-3, 17 dione (I, RI=R2=HI To a stirred solution of 4,5-epoxyandrostane-3,17-dione (II,R2=H; 1.208 g; 4 mmol) in dioxane (25my) and ethanol (25 ml) was added a solution of technical sodium hydrosulphide (1.6 g) in ethanol (50 ml) dropwise under nitrogen at 10 C.

The resulting mixture was stirred at room temperature for 1 hour, neutralized with glacial acetic acid (2 ml) and extracted with chloroform (100 ml). The organic extract was washed with water, a sodium bicarbonate saturated aqueous solution, water, and then dried over sodium sulfate.

The solvent was evaporated in vacuo and the crude product was column chromatographed over silica gel eluting with benzene. The combined fractions were evaporated and the residue crystallized from methanol.

There were obtained 550 mg of the title product (43% yield), m.p. 190-1 92'C; Elemental analysis: calculated % (found %): C71.65 (71.20) H 8.23 ( 8.30) S 10.07 ( 9.85) I.R. (KBr,cm-1):2560, 1730, 1660, 1560; U.V. (EtOH, nm, E1 ) 300 ):300(225); NMR (CDCI3,8): 0.93 (3H,s) 1.22 (3H,s) 4.77 (1H,s).

EXAMPLE 2 Bis handrost-4-ene-3, 17-dione-4-yl)disulphide (is, R2=H).

To a stirred solution of 4,5-epoxy-androstane-3,17-dione (il, R2=H; 1.208 g, 4 mmol) in dioxane (25 ml) and ethanol (25 ml) was added a solution of technical sodium hydrosulphide (1.6 g) in ethanol (50 ml) dropwise at 10 C under ambient atmosphere.

The resulting mixture was stirred at room temperature for 1 hour while kept basic by addition of few drops of 1 N sodium hydroxide aqueous solution at intervals. After a work up and a purification similar two those described in the Example 1, there were obtained 530 mg of the title product (21% yield), m.p. 270-273"C; Elemental analysis: calculated % (found %): C 71.88 (71.08) H 7.94( 7.84) 510.10( 9.69) I.R. (KBr,cmx 1735,1675,1550; NMR (CDCI3,8):0.91 (3H,s) 1.28 (3H,s) 3.65 (1 H,m) mle: 634,318,128,55.

EXAMPLE 3 4Ethylthioandrost-4-ene-3, 17-dione (I, R=Et, R H).

To a stirred solution of 4,5-epoxyandrostane-3,17-dione (II,R2=H; 1.5 g, 497 mmol) in dioxane (57 ml) was added ethylthiol (3 ml) and polyphosphoric acid (3 g) at room temperature under nitrogen. The reaction mixture was stirred for 6 hours and allowed to stand for a further 40 hours, then it was poured into a mixture of water and crushed icei neutralized with sodium bicarbonate (5 g) and extracted with ethyl acetate. The organic extracts were washed with brine and dried over sodium sulfate.

The solution was evaporated in vacuo and the resulting residue was column chromatographed over silica gel.

Elution with benzene afforded 3,4-bis(ethylthio)androst-3-ene-17-one (850 mg). Further elution with benzene:ethyl acetate 90:10 afforded the title compound (380 mg).

The former product, dissolved in chloroform (60 ml), was treated with gaseous hydrochloric acid during 3 hours with cooling to give, after evaporation of the solvent, more title product (400 mg). The two aliquots were combined and crystallized from methanol to yield the title compound (750 mg, 44% yield), m.p.

133-135"C; Elemental analysis: calculated % (found %): C 72.78 (71.41) H 8.73 ( 8.68) S 9.25 ( 9.04) I.R. (KBr,cm~1): 1740,1680,1555; NMR (CDCI3,8); 0.93 (3H,s) 1.13 (3H,t) 1.26 (3H,s) 2.68 (2H,q) 3.82 (1 H,m).

In analogous fashion the following compounds were prepared: 4-methylthio androst-4-ene-3,1 7-dione; 4-tert.butylthio androst-4-ene-3,1 7-dione; 4-phenylthio androst-4-ene-3,1 7-dione, and 4-(p-nitro-benzylthio) androst-4-ene-3,1 7-dione.

EXAMPLE 4 4-Acetylthioandrost-4-ene-3, 1 7-dione (I, R=CH3CO,R2=H).

To 4-mercaptoandrost-4-ene-3,1 7-dione (420 mg, 1.32 mmol), prepared as described in the Example 1, dissolved in dry pyridine (3 ml) was added acetic anhydride (3 ml).

The reaction mixture was stirred for 1 hour at ambient temperature under nitrogen, then it was poured into water (50 ml) and the resulting precipitate was filtered, washed with water, dried and crystallized from methanol.There were obtained 320 mg of the title compound (67% yield), m.p. 200-202 C; Elemental analysis: calculated % (found %): C 69.96 (69.80) H 7.83 ( 7.86) s 8.89 ( 8.83) I.R. (KBr, cm-): 1740, 1700, 1680, 1560; NMR (CDC13,8): 0.94 (3H,s) 1.33 (3H,s) 2.39 (3H,s) 3.15 (1H,m).

By analogous procedure the following compounds were prepared: 4-propionylthio androst-4-ene-3,17-dione; 4-heptanoylthio androst-4-ene-3,17-dione; and 4-dodecanoylthio androst-4-ene-3,17-dione.

EXAMPLE 5 6ss-Methyl-4-mercaptoandrost-4-ene-3, 1 7-dione (/,R'=H,R2=CH3) To a stirred solution of 4a,5-epoxy-6ss-methylandrostane-3,17-dione (II, R2=CH3, 780 mg, 2.47 mmol) in dioxane (10.4 ml) and ethanol (10.4 ml) was added a solution of technical sodium hydrosulphide (1.1 g) in ethanol (35 ml) dropwise under nitrogen at 10"C.

The resulting mixture was treated and worked up as reported in the Example 1. The crude product was column chromatographed over silica gel, eluting with benzene, and crystallized from methanol. There were obtained 250 mg of the title compound (30% yield), I.R. (KBr), cm-): 2520, 1735, 1675; NMR (CDCI3,8): 0.94 (3H,s) 1.25 (3H,d,J=6.0) 1.27 (3H,s) 3.12 (1H,m,J=15,6.0,7.3) 4.87 (1H,s).

In analogous fashion the following compounds were prepared: 6c-methyl-4-mercaptoandrost-4-ene-3,17-dione; 6(3-ethyl-4-mercaptoandrost-4ene-3,1 7-dione; 6a-ethyl-4-mercarptoandrost-4-ene-3,1 7-dione; 6(3-(p-nitro-phenyl)-4-mercaptoandrost-4-ene-3,1 7-dione; 6&alpha;-(p-nitro-phenyl)-4-mercaptoandrost-4-ene-3,17-dione: 6ss-(p-nitro-benzyl)-4-mercaptoandrost-4-ene-3,17-dione, and 6a-(p-nitro-benzyl)-4-mercaptoandrost-4-ene-3,1 7-dione.

Claims (13)

1. Acompound offormula (I)

wherein R1 is (a) hydrogen; (b) C1-C6aIkyl; (c) a C6-C10aryl or C7-C10 aralkyl group, either unsubstituted or ring substituted by one or more substituents chosen from C1 -C6 alkyl, halogen, nitro, amino and hydroxy; or (d) C2-C22 carboxylic acyl; R2 is (a') hydrogen; (b') C1-C6alkyl; (c') a C6-CsO aryl or C7-C10 aralkyl group, either unsubstituted or ring substituted by one or more substituents chosen from C1-C6 alkyl, halogen, nitro, amino and hydroxy: (d') halogen; or (e') a group - OR3 wherein R3 is hydrogen, C1-C6 alkyl or C2-C22 carboxylic acyl; or a dimerthereof in which there are no radicals R1 as defined above but instead the sulphur atoms attached at the respective 4-positions of two compounds of formula (I) are joined together to form a disulphide linkage; and pharmaceutically acceptable salts of a compound of formula (I), or a said dimer, containing a salifiable group.

2. A compound fo formula (I) or salt thereof according to claim 1 wherein R1 is hydrogen; C1-C4 alkyl; a phenyl or benzyl group optionally ring substituted by nitro; or a C2-C12 aliphatic carboxylic acyl group.

3. A compound according to claim 1 or 2 wherein R2 is hydrogen; halogen; C1 -C4 alkyl; or a phenyl or benzyl group optionally ring substituted by nitro.

4. A compound selected from the group consisting of: 4-mercaptoandrost-4-ene-3,17-dione; bis(androst-4-ene-3,17-dione-4-yl)disulphide; 4-ethylthioandrost-4-ene-3,17-dione; 4-acetylthioandrost-4-ene-3,17-dione; and 6ss-methyl-4-mercaptoandrost-4-ene-3,17-dione.

5. A process for the preparation of a compound as claimed in any one of the preceding claims, the process comprising reacting a compound of formula (II)

wherein R2 is as defined in claim 1, with a compound of formula (Ill) R',- SH (III) wherein R' is hydrogen, a C1-C6 alkyl group, or a C6-C10 aryl or C7-C10 aralkyl group, either unsubstituted or substituted by one or more substituents chosen from C1-C6-alkyl, halogen, nitro, amino and hydroxy, so obtaining a compound of formula (I) as shown in claim 1 wherein R1 has the meanings reported above for R'1 or a dimer as claimed in claim 1; and, if desired, acylating a compound of formula (I) wherein R1 is hydrogen with a C2-C22 carboxylic acid or a reactive derivative thereof, so obtaining a compound of formula (I) wherein R1 is a C2-C22 carboxylic acyl; and/or, if desired, converting a compound of formula (I) or a said dimer into a pharmaceutically acceptable salt thereof and/or, if desired, separating a mixture of isomers of formula (I) or of isomers of said dimers into the single isomers.

6. A pharmaceutical composition containing an inert carrier and/or diluent and, as the active principle, a compound as claimed in any one of claims 1 to 4.

7. Method of producing inhibition of the enzyme aromatase in a patient in need of it, which method comprises administering to the patient an effective amount of a compound according to any one of claims 1 to 4 or a composition according to claim 6.

8. Method of treating estrogen-dependent tumors or prostatic hyperplasia in a patient in need of it, which method comprises administering to the patient an effective amount of a compound according to any one of claims 1 to 4 or a composition according to claim 6.

9. Method according to claim 8 wherein the estrogen-dependent tumor is a breast tumor or an ovarian tumor or an endometrial tumor.

10. A compound as claimed in claim 1 hereinbefore specified but not claimed in claim 4.

11. A compound as claimed in claim 1 for use in a method of treatment of the human or animal body by therapy.

12. A compound according to claim 11 for use as an aromatase-inhibitor.

13. Process for the preparation of a compound as claimed in claim 1, said process being substantially as hereinbefore described in any one of Examples 1 to 5.