GB2185258A

GB2185258A - 10 beta -Halo-alkynyl estrene derivatives and process for their preparation

Info

Publication number: GB2185258A
Application number: GB08630781A
Authority: GB
Inventors: Franco Faustini; Salle Enrico Di; Achille Panzeri; Paolo Lombardi
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1985-12-24
Filing date: 1986-12-23
Publication date: 1987-07-15
Also published as: IT8622840A0; DE3644301A1; GB2185258B; GB8531743D0; IT1213435B; GB8630781D0; JPS62190196A

Abstract

10 beta -Halo-alkynyl estrene derivatives of formula (I): <IMAGE> wherein X is halogen; n is zero, 1 or 2; Y is an oxo group or a methylene group; one of R1 and R2 is hydrogen and the other is hydrogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, and the symbol @ indicates that each of (a) and (b), independently is a single bond or a double bond; are aromatase inhibitors and therefore useful to treat, for example, advanced hormone-dependent tumors. <IMAGE>

Description

SPECIFICATION 10ss-halo-alkynyl estrene derivatives and process for their preparation The present invention relates to new 1 10ss-halo-alkynyl estrene derivatives, to a process for their preparation and to pharmaceutical compositions containing them.

The invention provides compounds of the following formula (I)

wherein X is halogen; n is zero, 1 or 2; Y is an oxo group or a methylene group; one of R1 and R2 is hydrogen and the other is hydrogen, C-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, and the symbol -- indicates that each of (a) and (b), independently, is a single bond or a double bond.

In the above formula (I) and subsequent formulae a dotted line (Inn ) indicates a substituent in the a-configuration, i.e. below the plane of the ring; a wedged line () indicates a substituent in the fl-configuration, i.e. above the plane of the ring; and a wavy line (~) indicates that a substituent may be in the a-configuration or in the ss-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 fl-configuration, or the formula may represent a mixture of both compounds having the substituent in the tx-configuration and compounds having the substituent in the fl-configuration.

It is intended that the present invention includes all the possible isomers of formula (I), both separately and in mixture.

In this specification the alkyl, alkenyl and alkynyl groups may be branched or straight chain.

A C1-C6 alkyl group is, preferably, methyl, ethyl, n-propyl or tert.butyl.

A C2-C6 alkenyl group is, preferably, a C2-C4 alkenyl, in particular, e.g., vinyl(CH2=CH-), allyl(CH2=CH-CH2-), 1-propenyl(CH3-CH=CH-), 1 -butenyl(CH3-CH2-CH = CH-) or 2-butenyl(CH3-CH =CH-CH2-).

A C2-C6 alkynyl group is, preferably, C2-C4 alkynyl, in particular, e.g., ethynyl(CH=-C-) or 2 propynyl(CH = C-CH2-). The halogen atom X is iodine, bromine, chlorine or fluorine, particularly preferred values being iodine and bromine. Particularly preferred C1-C6 alkyl groups for one of R and R2 are methyl and ethyl, most particularly methyl; a preferred C2-C6 alkenyl group is vinyl, and a preferred C2-C6 alkynyl group is ethynyl.

Most preferably in the above formula (I) R1 and R2 are both hydrogen; preferably Y is an oxo group; preferably (a) represents a double bond.

A preferred class of compounds under this invention are the compounds of formula (I) wherein X is halogen; n is zero, 1 or 2; Y is an oxo group; each of (a) and (b) is, independently, a single or a double bond; and R, and R2 are both hydrogen.

In the above preferred class the halogen X may be either iodine or bromine or chlorine or fluorine, iodine being a particularly preferred value; a particularly preferred n value is 1; preferably (a) is double bond and (b) is single bond.

Examples of specific compounds under this invention are: 1 Oss-(3-iodo-2-propynyl)estr-4-ene-3, 1 7-dione; 1 Oss-(3-bromo-2-propynyl)estr-4-ene-3, 1 7-dione; 1 Oss-(3-chloro-2-propynyl)estr-4-ene-3, 1 7-dione; 1 Oss-(3-fluoro-2-propynyl)estr-4-ene-3, 1 7-dione; 1 Oss-(3-iodo-2-propynyl)estra- 1 ,4-diene-3, 1 7-dione; 1 Oss-(3-bromo-2-propynyl)estra- 1 ,4-diene-3, 1 7-dione; 1 Oss-(3-chloro-2-propynyl)estra- 1 ,4-diene-3, 1 7-dione; 1 OP-(3-fluoro-2-propynyl)estra- ,4-diene-3, 1 7-dione; 1 Oss-(3-iodo-2-propynyl)estra- 1 ,4,6-triene-3, 1 7-dione; 1 Oss-(3-bromo-2-propynyi)estra- 1 ,4,6-triene-3, 1 7-dione; 1 OB-(3-chloro-2-propynyl)estra- ,4,6-triene-3,17-dione; 1 OP-(3-fluoro-2-propynyl)estra- 1 ,4,6-triene-3, 1 7-dione.

The compounds of the invention may be prepared by a process comprising: 1) oxidizing a compound of formula (II)

wherein R1, R2, X and n are as defined above; one of R3 and R4 is hydrogen and the other is hydroxy, thus obtaining a compound of formula (I) wherein (a) and (b) are both single bonds and Y is an oxo group, that is a compound of formula (la)

wherein R1, R2 X and n are as defined above; or 2) dehydrogenating a compound of formula (la) thus obtaining a compound of formula (I) wherein R1, R2, X and n are as defined above and Y is an oxo group, and wherein, according to the reaction conditions used, either (a) is double bond and (b) is single bond, or (a) is single bond and (b) is double bond; or 3) dehydrogenating a compound of formula (I) wherein R1, R2, X and n are as defined above, Y is an oxo group, (a) is single bond and (b) is double bond, thus obtaining a corresponding compound of formula (i) wherein (a) and (b) are both double bonds; or 4) converting a compound of formula (I) wherein Y is an oxo group, R1, R2 X and n are as defined above, and each of (a) and (b) is, independently, a single bond or a double bond, into a corresponding compound of formula (I) wherein Y is a methylene group; and, if desired, separating a mixture of isomers of formula (I) possibly obtained in any of the above reactions, into the single isomers.

The oxidation of a compound of formula (I) to give a compound of formula (la) may be carried out by the use of known oxidizing agents, e.g. with dicyclohexylcarbodiimide, pyridine and trifluoroacetic acid (the Moffatt's reagent) or with the Jones' or the Sarett's reagent.

The dehydrogenation of a compound of formula (la) to give a compound of formula (I) wherein R1, R2, X and n are as defined above, Y is an oxo group, (a) is a double bond and (b) is a single bond, may be carried out with a suitable dehydrogenating agent, e.g. with 2,3-dichloro-5,6dicyanobenzoquinone (DDQ) in an inert solvent, such as, e.g., dioxane, benzene, toluene or dichloromethane, at a temperature ranging, e.g., from 40"C to about 100"C and for reaction times ranging, e.g., from about 12 hours to about 72 hours.The dehydrogenation of a compound of formula (la) to give a compound of formula (I) wherein R1, R2, X and n are as defined above, Y is an oxo group, (a) is a single bond, (b) is a double bond, may be carried out with a suitable dehydrogenating agent such as, e.g., chloranil, i.e. 2,3,5,6-tetrachloro-1,4-benzoquinone, in an inert solvent such as, e.g., methanol, ethanol, tert, butanol or higher aliphatic alcohols at a temperature ranging, e.g., from about 40"C to about 120"C and for reaction times ranging, e.g., from about 12 hours to about 72 hours. The dehydrogenation of a compound of formula (I) wherein R1, R2, X and n are as defined above, Y is an oxo group, (a) is single bond and (b) is double bond, to obtain a corresponding compound of formula (I) wherein (a) and (b) are both double bonds, may be, e.g., carried out in analogous fashion as the dehydrogenation of a compound of formula (la) to give a compound of formula (I) wherein (a) is double bond and (b) is single bond.

The conversion of a compound of formula (I) wherein Y is an oxo group, R1, R2, X and n are as defined above, each of (a) and (b) is, independently, a single bond or a double bond into the corresponding compound of formula (I) wherein Y is a group methylene, may be, e.g., carried out by treatment with a Wittig reagent of formula (0)3P±CH3.Hal(- > wherein 4 is a phenyl or C1-C6 alkyl group and Hal is bromine or iodine, following conventional procedures.For example the reaction may be carried out using an equimolar amount of the Wittig reagent, operating in an inert organic solvent, such as, for instance, diethylether, tetrahydrofuran, N-hexane, dimethylsulfoxide, dimethylformamide or hexamethylphosphoramide, and in the presence of a base which may be, for example, sodium hydride or potassium tert-butoxide, at a temperature between about 0 C and the reflux temperature of the used solvent, preferably at room temperature.

Using in the above reaction an equimolar amount of the Wittig reagent, the 3-oxo group is made to react selectively with respect to the 1 7-oxo group; alternatively the latter group may be selectively protected in a conventional manner, before the Wittig reaction.

The compounds of formula (li) can be prepared by a series of reactions illustrated in the following scheme:

wherein R1, R2, R3, R4, n and X are as defined above, Z is a protected oxo group, preferably an ethylenedioxy group, and one of R'3 and R'4 is hydrogen and the other is hydroxy or protected hydroxy. The protected hydroxy group may be, e.g., a hydroxy group esterified with a carboxylic acid, either a C2-C7 aliphatic carboxylic acid such as e.g. acetic acid, or an aromatic carboxylic acid such as e.g., benzoic acid.

The compounds of formula (III) are known in the chemistry literature (see, e.g., H.J. Ringold, J.Am.Chem.Soc. 78, 2477, 1956) or can be prepared from known compounds following known methods as those reported, for instance, in: Fieser et al, "Steroids", Reinhold, New York, 1959; Djerassi, Ed., "Steroid Reactions", Holden Day, San Francisco, 1963; and J. Fried, J.A. Edwards "Organic Reactions in Steroid Chemistry", Van Nostrand Reinhold Company, N.Y., 1972). According to the above reaction sequence a compound of formula (III) is first epoxidized to give a compound of formula (IV).

The epoxidation may be performed according to known methods, for example by treatment with a N-halo-succinimide or N-halo-acetamide (e.g. N-bromosuccinimide or N-chloroacetamide) in a solvent such as, e.g., diemethylformamide or dimethylsulfoxide, to obtain the corresponding halohydrine, and sequential dehydrohalogenation in alkaline medium (e.g. with a sodium alkoxide, e.g. methoxide) to obtain a sterically pure 5 a, 10a-epoxide (Lucien Nedelec, Bull. Soc. Chim.

France 7, 2548, 1970).

A compound of formula (IV) so obtained is reacted with a metallorganic compound carrying a H-CC-(CH2)n-moiety, wherein n is as defined above, to give a compound of formula (V). The organometallic compound may be, for example, a Grignard compound H-C=C-(CH2)nMgHal wherein Hal is a halogen atom, preferably chlorine, bromine or iodine, prepared according to known methods: L. Brandsma and H.D. Werkruijsse, Synth. Acetylenes, Allenes and Cumulenes, 1981, 16.

The reaction of the compound (IV) with the organometallic compound may be, e.g., carried out in a solvent chosen from tetrahydrofurane, tetrahydropyrane, y-dihydropyrane, diethylether, anisole, and furane, e.g. at a temperature from about -30"C to the room temperature, preferably between -50C and + 100C.

For the conversion (halogenation) of a compound of formula (V) into a compound of formula (Vl), wherein X is halogen, conventional halogenation procedures may be followed, for example the compound of formula (V) may be transformed into a compound of formula (Vl) wherein X is bromine or iodine, by reaction with, e.g., an equimolar amount of N-bromo- or N- iodo-succinimide in the presence of catalytic amounts of silver nitrate.

The halogenation reaction is generally performed in acetone, but other solvents such as, e.g., tetrahydrofurane, ethanol or 1-methyl-2-pyrrolidone can be used: R. Wiechert et al, Angew.

Chem. Int. Ed. 23 (1984)9, 727-728.

A compound of formula (V) may be transformed into a compound of formula (VI) wherein X is chlorine or fluorine, for instance by treating it first with a strong base, e.g. sodium hydride, potassium hydride, methyllithium, butyllithium, potassium tert-butoxide, or with a Grignard reagent, e.g. methylmagnesium bromide, ethylmagnesium bromide, and then with a source of positive chlorine or fluorine, e.g., respectively, with N-chloro succinimide or a N-fluoro-N-alkylsulfonamide or perchloryl fluoride, according to, e.g., the methods described by W. Verboom et al., [Synthesis 296-297 (1979)] and by W.E. Barnette [J.A.C.S. 106, 452-454 (1984)].

The compound of formula (VI) is then dehydrated and deprotected to give a compound of formula (II). This step may be carried out with a suitable dehydrating agent which may be, for example, a mineral, preferably concentrated, acid such as, for instance, hydrochloric or sulfuric acid, or with a sulfonic resin as well. The reaction may be performed in an inert, organic, preferably anhydrous, solvent, such as, for instance, methanol, ethanol, benzene, toluene, nhexane or cyclohexane, at a temperature varying approximately between about 0 C and about 50"C, preferably at room temperature. Oxo protecting groups are removed during the dehydration process; hydroxy protecting groups possibly present, e.g. ester groups as defined above, may be removed by conventional saponification procedures.

In accordance with the above the invention provides also, as further objects, the compounds of formula (II) and a process for the preparation of a compounds of formula (II), the said process comprising (a) epoxidizing a compound of formula (lil)

wherein Z is a protected oxo group and R1, R2, R'3 and R'4 are as defined above, so obtaining a compound of formula (IV)

wherein Z, R1, R2, R'3 and R'4 are as defined above; (b) reacting a compound of formula (IV) with a metallorganic compound carrying a H-C C-(CH2)-moiety, wherein n is as defined above, so obtaining a compound of formula (V)

wherein Z, n, R1, R2, R'3 and R'4 are as defined above;; (c) halogenating a compound of formula (V) so obtaining a compound of formula (VI)

wherein Z, X, n, F1, F2, R'3 and R'4 are as defined above; and (d) dehydrating/deprotecting a compound of formula (VI).

The compounds of this invention possess a very high aromatase inhibiting activity.

Aromatase (estrogen synthetase) is the enzyme responsible for the final step in biosynthesis of estrogens; as is known, the conversion of androgens to estrogens (e.g. of androstendione and testosterone to estrone and estradiol) is mediated by aromatase, a microsomal P450 enzyme that acts on the androgenic substrate.

The compounds of the invention, being aromatase inhibitors, can find therefore use as an alternative to endocrine ablation, e.g. oophorectomy, hypophysectomy or adrenalectomy in the treatment of advanced hormone-dependent tumors, in particular breast, ovarian and uterine cancers.

Furthermore, the compounds of the invention can find application in the treatment of prostatic hyperplasia, which involves a benignic enlargement of the prostatic gland due pedominantly to a disorder of the fibro muscolar stromal tissue stimulated by estrogens.

A further field of application of the aromatase inhibitors of formula (I) is in the management and control of reproduction, in particular, for instance, in the treatment of male fertility disturbances: Drugs 28:263, 1984.

The 1 10ss-halo-alkynyl derivatives of the invention show particularly enhanced in vivo activity, when compared with unsubstituted derivatives.

Further advantages of the compounds of the invention are the low toxicity and absent or reduced side effects. 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 solution 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 10 to about 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 pyrrolidine; 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 carrier 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 solution for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The following examples illustrate but do not limit the invention.

Example 1 To a suspension of 8.5 g of 17ss-acetoxy-3,3-ethylenedioxy-estr-5(10)-ene in 130 ml of dimethylformamide and 40 ml of water, 2.35 g of powdered CaCO3 and 8.39 g of N-bromosuccinimide are added at room temperature.

After stirring for 4 hours at room temperature, the yellow suspension is poured into ice-water and the precipitate filtered on buckner; the precipitate is dissolved in methylene chloride and the insoluble residue is filtered off; the filtrate is washed with water and dried over anhydrous sodium sulphate. Evaporation of the solvent yields 10.7 g of 17ss-acetoxy-3,3-ethylenedioxy-5a- hydroxy-10ss-bromoestrane as a white solid material, m.p. 140"C, dec.; I.R. (nujol): cm-' 3600-3100, 1735, 1375; N.M.R. (DMSO-d6) d: 0.66 (3H,s); 3.55 (1H, m); 3.90 (2H, m); 4.41 (1H, d); 4.48 (1H, s).

Into a two necked flask, kept under a nitrogen atmosphere, 10.7 g of 5a-hydroxy-17ss- acetoxy-10fl-bromo-3,3-ethylene-dioxyestrane are suspended in 108 ml of anhydrous methanol and treated with 4.173 g of sodium methoxide for 20 hours at room temperature.

The solution is then diluted with methylene chloride (1 I) and washed with water, brine, water and finally anhydrified over sodium sulphate.

Evaporation of the solvent leaves 9.5 g of white solid material, which is purified by flash chromatography on silica gel. Eluting with n-hexane:ethyl acetate:triethylamine (50:50:0.1) gives 6.57 g of 5, lOa-epoxy - 1 7ft-hydroxy-3,3-ethylendioxy-estrane, m.p. 96-98"C (diethyl ether); I.R. (nujol): cm-l 3500; N.M.R. (CDCI3) b: 0.77 (3H, s); 3.68 (1H, m); 3.90 (4H, m).

Example 2 Into a solution of 1.5 g of 5,1 Oa-epoxy -1 7fl-hydroxy-3,3-ethylenedioxy estrane in 40 ml of dry diethylether, cooled to 0 C with an external ice-cooling bath, 28 ml of a 1.6M solution of propargylmagnesium bromide (prepared according to the method reported in "Synthesis of Acetylenes, Allenes and Cumulenes", L. Brandsma and H.D. Verkruysse, page 16, Elsevier Scientific Publishing Company-Amsterdam, Oxford, New York 1981) are added in one portion, operating under nitrogen atmosphere.The mixture is stirred at 0 C for 18 hours, then 10 ml of saturated ammonium chloride aqueous solution are added dropwise, while cooling at 0 C; after 10 minutes of additional stirring at 0 C the solution is warmed to room temperature, diluted with 50 ml of saturated aqueous ammonium chloride solution and extracted with ethyl acetate; the organic phase is washed with water and dried over anhydrous sodium sulphate.The solvent is evaporated under vacuum and the residue (1.98 g) is purified by flash chromatography on silica gel, eluting with ethyl acetate: n-hexane:triethylamine 40:60:0.1, thus obtaining 1.119 g of pure Sa, 1 7fi-dihydroxy- 10ft-(2-prnpynyi)-3,3-ethyieneoioxy-estrnne as a colourless oil which is crystallized from ethyl acetate/n-hexane to give 1.119 g of crystalline compound, m.p. 120-121"C; [a]D+10.6 (c=1, CHCI3); I.R. (nujol): cam~' 3550, 3510, 3425, 3310, 3290, 2110, 840; N.M.R. (CDCl3) d: 0.76 (3H, s); 2.39 (2H, m); 3.74 (1H, m); 3.95 (4H, bs); 4.15 (1H, s).

Example 3 A solution of 374 mg of 5at-17ss-dihydroxy-10ss-(2-propynyl)-3,3-ethylenedioxyestrane in 15 ml of acetone is treated at room temperature with 316 mg of N-bromo succinimide and 34 mg of silver nitrate. After 4 hours the reaction mixture is poured, under stirring, into 150 ml of icewater and the precipitate that is formed is filtered off and dissolved in ethyl-acetate.

The resulting solution is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness in vacuo. The solid residue is purified by flash chromatography on silica gel eluting with ethylacetate:n-hexane: triethylamine (40:60:0.1), thus obtaining 264 mg of Sa, 1 7,b-dihydroxy- 10ft-(3-bromo-2-propynyl)-3,3-ethylenedioxyestrane. m.p. 134-1 36 C; [a]D+19.0 (c=1, CHCl3); I.R. (nujol) cm-1: 3520, 3470, 3400, 3290, 860; N.M.R. (CDCl3) J: 0.76 (3H, s), 2.39 (2H, m), 3.74 (1H, m), 3.95 (4H, bs), 4.15 (1H, s).

Example 4 A solution of 145 mg of Sa, 1 7fl-dihydroxy- 1 Ofl,(2-propynyl)-3,3-ethylenedioxyestrane in 7 ml of acetone is treated at room temperature with 174 mg of N-iodo-succinimide and 15 mg of silver nitrate. After 4 hours the reaction mixture is poured into 70 ml of ice-water and the precipitate that is formed is filtered off and dissolved in ethyl acetate. The resulting solution is washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. The solid residue is purified by flash chromatography on silica gel eluting with n-hexane:ethyl acetate:triethylamine 60:40:0.1 to give 90 mg of 5A, 1 7-dihydroxy- 70P-(3-iodo-2-propynyl)-3,3-ethylene- dioxy estrane, m.p. 105-107"C.

N.M.R. (CDCI,)G: 0.80 (3H, s); 2.88 (2H, m); 3.63 (1H, t); 3.98 (4H, bs); 4.19 (1H, s).

Example 5 To a solution of 374.5 mg of 5eY,17ss-dihydroxy-10ss-(2-propynyl)-3,3-ethylenedioxyestrane in 3.0 ml of anhydrous tetrahydrofurane, a solution of salt-free methyllithium (1.1 mmol) in diethyl ether (1.5 ml) is added under dry nitrogen atomosphere at -500C.

Subsequently, hexamethylphosphoric acid triamide (1 ml) is added, keeping the temperature below -500C. Stirring is continued for 15 minutes at --50"C, whereupon N-chloro-succinimide (201 mg) is added in small portions. During the addition the reaction temperature of the mixture is allowed to rise to --15"C. After stirring at room temperature for 1.5 hour, the dark reaction mixture is poured into ice-water and the formed precipitate is filtered off and dissolved in ethyl acetate.

The resulting solution is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The solid residue is purified by flash chromatography on silica gel eluting with ethyl acetate:n-hexane: triethylamine 40:60:0.1 to give 246 mg of Su-17P-dihydroxy-lOP-(3- chloro-2-propynyl)-3, 3-ethylenedioxyestrane.

N.M.R. (CDCl3)J: 0.79 (3H, s); 2.35 (2H, m); 3.63 (1H, t); 3.98 (4H, bs); 4.23 (1H, s).

Example 6 A solution of 202 mg of 5a, 1 7fl-dihydroxy-10fl-(2-propynyl)-3,3-ethylenedioxyestrane in 5 ml of anhydrous tetrahydrofurane is cooled to -78"C and 1.08 ml of 1.5 M n-butyl.lithium in nhexane is added dropwise. After the reaction has proceeded for 30 minutes at -78"C, the solution is diluted with 10 ml of anhydrous toluene and then added dropwise to a solution of Nfluoro-N-methyl-p-tolyl-sulfonamide (164 mg) in 5 ml of anhydrous toluene, kept at -780C with an external dry-ice/acetone cooling bath.The reaction mixture is then allowed to rise to room temperature, and saturated aqueous ammonium chloride solution is added; extraction with ethyl acetate affords, after evaporation of the solvent, 250 mg of dark oil, which is purified by flash chromatography on silica gel to give 105 mg of pure 5a; 17P-dihydroxy- 70P-(3-fluoro-2-propynyl)- 3,3-ethylenedioxyestrane.

N.M.R. (CDCI3)a: 0.78 (3H, s), 2.3 (2H, m), 3.63 (1H, t), 3.98 (4H, bs), 4.20 (1H, s).

Example 7 To a stirred solution of 453 mg of 5al,17ss-dihydroxy-10ss-(3-bromo-2-propnyl)-3,3-ethylene- dioxyestrane in 10 ml of methanol, 3.3 ml of 5N hydrochloric acid aqueous solution are added and the mixture is stirred for 20 hours at room temperature. Then the mixture is poured into 100 ml of ice-water and extracted with ethyl acetate, the organic extracts are washed with brine, water and anhydrified over sodium sulphate.

Evaporation of the solvent under vacuo affords 0.43 g of yellow oil, which is purified by flash chromatography on silica gel to give 304 mg of pure 17P-hydroxy- 10P-(3-bromo-2-propynyl) estr-4-en-3-one.

I.R. (nujol)cm-': 1660, 1620; N.M.R. (CDCi3)sS: 0.92 (3H, s); 3.63 (1H, t); 5.90 (1H, bs).

By proceeding analogously, the following compounds are prepared: 1 7fl-hydroxy- 1 Oss-(3-iodo-2-propynyl)-estr-4-en-3-one; 1 7fl-hydroxy- 1 Oss-(3-chloro-2-propynyl)-estr-4-en-3-one; 17ss-hydroxy- 1 Oss-(3-fluoro-2-propynyl)-estr-4-en-3-one.

Example 8 To a solution of 1.173 g of 17ss-hydroxy-1ss-(3-bromo-2-propynyl) estr-4-en-3-one in 30 ml of acetone, cooled to --25 C with an external cooling bath (acetone and dry-ice), 1.6 ml of 2.5 M Jones reagent are added, dropwise, with stirring. After an additional stirring of 10 minutes, the excess of oxidant is destroyed by addition of 0.5 ml of isopropyl alcohol. The solution is diluted with 200 ml of benzene and left to rise to room temperature. The organic layer is separated and washed with saturated ammonium sulphate aqueous solution, with water and then dried over anhydrous sodium sulphate.Evaporation of the solvent under vacuo affords 1.30 g of solid material, which is purified by flash-chromatography on silica gel, eluting with n-hexane:diethylether 20:80, to give 1.13 g of 10fi-(3-bromo-2-propynyl) estr-4-ene-3, 1 7-dione as a crystalline product, m.p. 180-182 C, dec.; [a]D+216 (c=1, CHCI3); I.R. (nujol) cm-': 1730, 1680, 1630; N.M.R. (CDCI3)J: 0.92 (3H, s), 5.90 (1H, bs).

By proceeding analogously, the following compounds are prepared: 10ss-(3-iodo-2-propynyl)estr-4-ene-3,17-dione, m.p. 157-159"C, dec.; 1 OP-(3-chloro-2-propynyl)estr-4-ene-3, 17-dione; 1 OP-(3-fluor-2-propynyl)estr-4-ene-3, 17-dione.

Example 9 A mixture of 188 mg of 10ss(3-bromo-2-propynyl) estr-4-ene-3, 1 7-dione and 376 mg of dichlorodicyanoquinone in 12.5 ml of dioxane is refluxed for 20 hours. The mixture is cooled and diluted with diethyl ester, then washed with aqueous sodium carbonate solution and dried.

The solvent is evaporated and the residue is purified by flash chromatography on silica gel eluting with ethyl acetate:n-hexane 30:70 to give 10P-(3-bromo-2-propynyl) estra-1,4-diene-3,17- dione, m.p. 202-204 C, dec.; U.V.:A mta xH 241 nm (10,435); max N.M.R. (CDCI3)o4: 0.94 (3H, s); 2.75 (2H, m), 6.17 (1H, s), 6.38 (1H, d); 7.31 (1H, d).

By proceeding analogously, the following compounds are prepared: 10ss-(3-iodo-2-propynyl)estra-1,4-diene-3,1 7-dione, m.p. 180-182"C, dec; 1 Oss-(3-chloro-2-propynyl)estra- 1,4-diene-3,17-dione; 1 OP-(3-fluoro-2-propynyl)estra- 1,4-diene-3,17-dione.

Example 10 A mixture of 313 mg of 1 10ss-(3-bromo-2-propynyl) estr-4-ene-3, 1 7-dione and 575 mg of chloranil in 21 ml of tert-butyl alcohol is heated at reflux for 2 hours. The mixture is diluted with ethyl acetate and filtered and the filtrate is washed with aqueous 1N sodium hydroxide, with brine and dried over sodium sulphate.

The solvent is then evaporated and the residue chromatographed on silica gel using ethyl acetate/n-hexane to give 140 mg of 10P-(3-bromo-2-propynyl) estra-4,6-diene-3, 1 7-dione, U.V.:# EtOH 287 nm (18,035); max N.M.R. (CDCI,)G: 0.92 (3H, s); 2.75 (2H, m), 2.99 (1H, m), 5.78 (1H, bs); 7.23 (2H, m).

By proceeding analogously, the following compounds are prepared: 1 Oss(3-iodo-2-propynyl)estra-4,6-diene-3,17-dione; 1 Oss3-chloro-2-propynyl)estra-4,6-diene-3,17-dione; 1 Oss-(3-fluoro-2-propynyl)estra-4,6-diene-3,17-dione.

Example 11 A mixture of 500 mg of 10ss(3-bromo-2-propynyl)estra-4,6-diene-3,17-dione and 1.60 g of 2,3-dichloro-5,6-dicyanobenzoquinone in 20 ml of dioxane is refluxed for 3 hours. The mixture is diluted with ethyl acetate and filtered, and the filtrate is washed with aqueous 1N sodium hydroxide, with brine and dried over sodium sulphate. The solvent is then evaporated and the residue chromatographed on silica gel using ethyl acetate/n-hexane to give 100 mg of 10ft-(3- bromo-2-propynyl) estra- 1,4,6-triene-3, 1 7-dione, EtOH mta xH 225 nm (10,580), 254 nm (10,000), 298 nm (10,230); max N.M.R. (CDCI3)#: 0.92 (3H, s); 6.12 (1H, dd), 6.50 (1H, dd), 6.35 (1H, d); 7.15 (1H, d).

By proceeding analogously the following compounds are prepared: 1 Ofl-(3-iodo-2-propynyl)estra- 1,4,6-triene-3,1 7-dione; 1 Oss-3-chloro-2-propynyl)estra- 1 ,4,6-triene-3, 1 7-dione; 1 Ofl-(3-fluoro-2-propynyl)estra- 1,4,6-triene-3,1 7-dione.

Example 12 To a solution of 389 mg of 1 10ss(3-bromo-2-propynyl)estra-4-ene-3,17-dione in 2 ml of anhydrous dimethylsulfoxide, 3.75 ml of a 4N solution of methylene-triphenylphosphonium ylide (obtained by portionwise addition of 1.96 g of methyl-triphenyl-phosphonium iodide to a solution of 449 mg of potassium tert. butoxide in 10 ml of anhydrous dimethyl-sulfoxide, while cooling to about 18"C) are added dropwise at room temperature in 5 hours.

The mixture is poured into water and extracted with ethyl acetate, the organic extracts are washed with water, dried over Na2SO4 and the solvent removed under vacuum.

The crude is chromatographed on silica gel eluting with n-hexane:diethylether 40:60 to give 190 mg of 3merhylene- I0P-(3-bromo-2-propynyl)esrr-4-ene-3, 17-dione, I.R. (nujol) cm-: 1730, 1600-1635 N.M.R. (CDCI3)a: 0.92 (3H, s); 4.7 (2H, m); 5.7(1H, m).

Example 13 Tables each weighing 0.150 g and containing 25 mg of the active substance, were manufactured as follows: Composition (for 10,000 tablets) 1 Oss(3-bromo-2-propynyl)estr-4-ene-3,17-dione 250 g Lactose 800 g Corn starch 415 g Talc powder 30 g Magnesium stearate 5g The 10ss-(3-bromo-2-propnyl)estr-4-ene-3,17-dione, the lactose and half the corn starch were mixed; the mixture was then forced throught 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 14 Capsules, each dosed at 0.200 g and containing 20 mg of the active substance were prepared.

Composition for 500 capsules: 1 Oss-(3-bromo-2-propynyl)estr-4-ene-3,17-dione 10 g Lactose 80 g Corn starch 5g Magnesium stearate 5g This formulation was encapsulated in two-piece hard gelatin capsules and dosed at 0.200 g for each capsule.

Claims

1. A compound of formula (I)

wherein X is halogen n is zero, 1 or 2; Y is an oxo group or a methylene group; one of R1 and R2 is hydrogen and the other is hydrogen, C,-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, and the symbol = indicates that each of (a) and (b), independently is a single bond or a double bond.

2. A compound of formula (I) according to claim 1 wherein X is halogen; n is zero, 1 or 2; Y is an oxo group; each of (a) and (b) is, independently, a single or a double bond; and R, and R2 are both hydrogen.

3. A compound selected from the group consisting of: 1 Oss(3-iodo-2-propynyl)estr-4-ene-3,17-dione; 1 0ss-(3-bromo-2-propynyl)estr-4-ene-3,17-dione; 1 0ss-(3-chloro-2-propynyl)estr-4-ene-3, 1 7-dione; 1 Oss-(3-fluoro-2-propynyl)estr-4-ene-3,17-dione; 1 Ofl-(3-iodo-2-propynyl)estra- 1,4-diene-3,1 7-dione; 1 Ofl-(3-bromo-2-propynyl)estra- 1,4-diene-3,1 7-dione; 1 Ofl-(3-chloro-2-propynyl)estra- 1 ,4-diene-3, 1 7-dione; 1 Oss-(3-fluoro-2-propynyl)estra- 1,4-diene-3,1 7-dione; 1 Oss-(3-iodo-2-propynyl)estra- 1,4,6-triene-3,17-dione; 1 Ofl-(3-bromo-2-propynyl)estra- 1 ,4,6-triene-3,17-dione; 1 Ofl-(3-chloro-2-propynyl)estra- 1,4,6-triene-3,17-dione; 1 Oss-(3-fluoro-2-propynyl)estra- 1,4,6-triene-3,17-dione.

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

wherein R1, R2, X and n are as defined in claim 1; one of R3 and R4 is hydrogen and the other is hydroxy thus obtaining a compound of formula (I) wherein (a) and (b) are both single bonds and Y is an oxo group, that is a compound of formula (la)

wherein R1, R2, X and n are as defined in claim 1; or 2) dehydrogenating a compound of formula (la) thus obtaining a compound of formula (I) wherein R1, R2, X and n are as defined in claim 1 and Y is an oxo group, and wherein, according to the reaction conditions used, either (a) is double bond and (b) is single bond, or (a) is single bond and (b) is double bond; or 3) dehydrogenating a compound of formula (I) wherein R1, R2, X and n are as defined in claim 1, Y is an oxo group, (a) is single bond and (b) is double bond, thus obtaining a corresponding compound of formula (I) wherein (a) and (b) are both double bonds; or 4) converting a compound of formula (I) wherein Y is an oxo group, R1, R2 X and n are as defined in claim 1, and each of (a) and (b) is, independently, a single bond or a double bond, into a corresponding compound of formula (I) wherein Y is a methylene group; and, if desired, separating a mixture of isomers of formula (I) possibly obtained in any of the above reactions, into the single isomers.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and, as the active substance, a compound according to anyone of claims 1 to 3.

6. A compound of formula (II) as defined in claim 4.

7. A process for the preparation of a compound of formula (II) as reported in claim 4, the process comprising: (a) epoxidizing a compound of formula (III)

wherein Z is a protected oxo group, R, and R2 are as defined in claim 1 and one of R'3 and R'4 is hydrogen and the other is hydroxy or protected hydroxy so obtaining a compound of formula (lav)

wherein Z, R1, R2, R'3 and R'4 are as defined above; (b) reacting a compound of formula (IV) with a metallorganic compound carrying a H-C= C-(CH2)n-moiety, wherein n is as defined in claim 1 so obtaining a compound of formula (V)

wherein Z, X, n, R1, R2, R'3, and R'4 are as defined above; and (d) dehydrating/deprotecting a compound of formula (VI).

8. A compound of formula (I), as defined in claim 1, for use in a method of treatment of the human or animal body surgery or therapy or of diagnosis practised on the human or animal body.

9. A compound according to claim 8 for use as an aromatase-inhibitor.

10. A compound according to claim 8 for use in the treatment of advanced hormonedependent tumors.

11. A compound according to claim 10 for use in the treatment of breast, ovarian or uterine cancer.

12. A compound according to claim 8 for use in the treatment of prostatic hyperplasia.

13. A compound according to claim 8 for use in the treatment of male fertility disturbances.

14. A process for the preparation of a compound of formula (I) as defined in claim 1, said process being substantially as hereinbefore described in any one of Examples 8 to 12.

15. A pharmaceutical composition substantially as hereinbefore described in Example 13 or 14.