GB2185257A - 10 beta (-Alkynyl-4,9(11)-estradiene derivatives and process for their preparation - Google Patents

Abstract

10 beta -Alkynyl-4,9(11)-estradiene derivatives of formula (I): <IMAGE> wherein R is hydrogen, C1-C4 alkyl or halogen; n is zero, 1 or 2; R1 and R2 are both hydrogen, or R1 and R2, taken together, form an oxo group or a methylene group; the symbol @ indicates that each (a) and (b), independently, is a single bond or a double bond; and one of R3 and R4 is hydrogen and the other is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or halogen or also, when (b) represents a single bond, one of R3 and R4 is divalent and is a C1-C6 alkylidene group and the other is hydrogen; are aromatose inhibitors and therefore useful to treat, for example, advanced hormone-dependent tumors.

Description

SPECIFICATION 10ss-alkynyl-4,9(1 1)-estradiene derivatives and process for their preparation The present invention relates to new 10ss-alkynyl-4,9(1 1)-estradiene derivatives, to a process for their preparation and to pharmaceutical compositions containing them.

The invention provides compounds of the following formula (I)

wherein R is hydrogen, C,-C4 alkyl or halogen; n is zero, 1 or 2; R, and R2 are both hydrogen, or R, and R2, taken together, form an oxo group or a methylene group; the symbol -- indicates that each of (a) and (b), independently, is a single bond or a double bond; and one of R3 and R4 is hydrogen and the other is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl or halogen or also, when (b) represents a single bond, one of R3 and R4 is divalent and is a C,-C6 alkylidene group and the other is hydrogen.

In the above formula (I) and subsequent formulae a dotted line ( ) 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 xx-configuration and compounds having the substituent in the ssconfiguration.

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, alkynyl and alkylidene groups may be branched or straight chain. A C,-C4 or C,-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-), al lyl(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 2propynyl (CH = C-CH2-).

A C,-C6 alkylidene group is, preferably, C,-C4 alkylidene, in particular, e.g., methylene (CH2=), ethylidene (CH3-CH=) or n-propylidene (CH3-CH2-CH=), most preferably methylene.

A halogen atom is, preferably, chlorine, bromine or fluorine.

When R is C,-C4 alkyl, methyl and ethyl are preferred, particularly methyl; when R is halogen, bromine and fluorine are preferred.

When one of R3 and R4 is C,-C6 alkyl, methyl and ethyl are preferred, in particular methyl.

When one of R3 and R4 is C2-C6 alkenyl or C2-C6 alkylyl, vinyl and, respectively, ethynyl are preferred.

When one of R3 and R4 is C,-C6 alkylidene, (b) being single bond, it is, preferably, methylene.

When one of R3 and R4 is halogen, this is, preferably fluorine.

Preferably in the above formula (I) R is hydrogen or halogen, in particular bromine or fluorine; preferably one of R3 and R4 is hydrogen and the other is hydrogen, C,-C4 alkyl in particular methyl, or halogen, in particular fluorine, or, when (b) is single bond, methylene.

A preferred class of compounds under this invention are the compounds of formula (I) wherein R is hydrogen or halogen; n is 1; R, and R2 are both hydrogen or, taken together, form an oxo or methylene group; (a) is single or double bond; and either (b) is single bond, one of R3 and R4 is hydrogen and the other is hydrogen, C,-C4 alkyl or C,-C4 alkylidene, or (b) is double bond, one of R3 and R4 is hydrogen and the other is hydrogen, C,-C4 alkyl or halogen.

In the above preferred class, when R is halogen, bromine and fluorine are preferred; when one of R3 and R4 is Ct-C4 alkyl, methyl is preferred; when one of R3 and R4 is alkylidene, methylene is preferred; and when one of R3 and R4 is halogen, fluorine is preferred.

Examples of specific compounds under this invention are: 10ss-(2-propynyl) estra-4,9( 1 1 )-diene-3, 1 7-dione; 1 Ofl-(2-propynyl) estra-4,9( 11 )-diene- 7-one; 3-methylene-10ss-(2-propynyl) estra-4,9(11)-diene-17-one; 6-methylene-10ss-(2-propynyl) estra-4,9(1 1 )-diene-3, 1 7-dione; 6a-methyl- 1 Ofl-(2-propynyl) estra-4,9( 11 )-diene-3, 1 7-dione; 7ss-methyl-1 Ofl-(2-propynyl) estra-4,9( 11 )-diene-3, 1 7-dione; 10ss-(2-propynyl) estra- 1,4,9(11 )-triene-3, 1 7-dione; 6-fluoro-10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione; 10ss-(2-propynyl) estra-1,4,6,9(11)-tetraene-3,17-dione; 6-methyl- 1 Ofl-(2-propynyl) estra- 1,4,6,9(11 )-tetraene-3, 1 7-dione; 6-methylene- 1 0ss-(2-propynyl) estra-4,9( 11 )-diene- 7-one; 6a-methyl- 1 0ss-(2-propynyl) estra-4,9( 11 )-diene- 7-one; 7ss-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-17-one; 6-methyl- 1 0ss-(2-propynyl) estra- 1,4,6,9(11 )-tetraene- 17-one; 10ss-(3-bromo-2-propynyl) estra-4,9(11)-diene-3,17-dione; 1 Oss-(3-fluoro-2-propynyl) estra-4,9( 11 )-diene-3, 1 7-dione; and 6-methyl-10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione.

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

wherein R1, R2, n, R3 and R4 are as defined above; R' is hydrogen or C,-C4 alkyl; one of R5 and R6 is hydrogen and the other is hydroxy, so obtaining a compound of formula (I) wherein R is hydrogen or C-C4 alkyl and (a) and (b) are both single bonds, or 2) dehydrating a compound of formula (III)

wherein R', n, R3 and R4 are as defined above;; R', and R'2 are both hydrogen or, taken together, form a free or protected oxo group, or methylene, and Z is a free or protected oxo group, so obtaining a compound of formula (I) wherein R is hydrogen or C,-C4 alkyl and (a) and (b) are both single bond, and, if desired, in any order, transforming a compound of formula (I) wherein (a) and (b) are both single bonds into a corresponding compound of formula (I) wherein one or both of (a) and (b) are double bonds and/or, if desired, converting a compound of formula (I) wherein R is hydrogen into a corresponding compound of formula (I) wherein R is a halogen and/or, if desired, converting a compound of formula (I) wherein R is a halogen into a corresponding compound of formula (I) wherein R is a different halogen, and/or, if desired, converting a compound of formula (I) wherein R, and R2, taken together, form the oxo group, into a corresponding compound of formula (I) wherein R, and R2 taken together form the group methylene and/or, if desired, separating a mixture of isomers of formula (I) into the single isomers.

A protected oxo group in the above formula (III) and subsequent formulae may be, e.g., an oxo group protected as acetal or thioacetal, e.g. dimethoxyacetal, diethoxyacetal, dimethylthioacetal or diethylthioacetal, or as ketal or thioketal, e.g. ethylenedioxy-ketal or ethylenedithio-ketal.

The oxidation of a compound of formula (II) 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 dehydration of a compound of formula (III) 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, n-hexane or cyclohexane, at a temperature varying approximately between about 0 C and about 50"C, preferably at room temperature. When the reaction is carried out on a compound of formula (III), wherein protected oxo groups are present, deprotection of the same proceed at the same time with dehydration.

The optional transformation of a compound of formula (I) wherein (a) and (b) are both single bonds into a corresponding compound of formula (I) wherein one or both of (a) and (b) are double bonds may be carried out with a suitable oxidizing agent. For example, using 2,3dichloro-5,6-dicyano-benzoquinone (DDQ) in an anhydrous inert solvent such as, e.g., benzene at reflux temperature, or using selenium dioxide according to conventional procedures, a compound of formula (I) wherein (a) and (b) are both single bonds and R, and R2, taken together, form an oxo group, may be transformed into the corresponding one wherein (a) is double bond and (b) is single bond.

If desired, an obtained compound of formula (I) wherein (a) is double bond and (b) is single bond and R, and R2, taken together, form an oxo group, may be further oxidized to the corresponding compound wherein (a) and (b) are both double bonds by treatment with, e.g., 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil): in this case an aliphatic alcohol such as, e.g., tert.butyl alcohol or a carboxylic acid, e.g. acetic acid, or an ester thereof e.g. ethyl or n-amyl acetate, or a mixture of two or more of these, may be used as solvent, preferably operating at the reflux temperature.

Chloranil and similar reaction conditions as those indicated hereabove, may also be used for converting a compound of formula (I) wherein (a) and (b) are both single bonds and R, and R2, taken together, form an oxo group, into the corresponding compound wherein (a) is single bond and (b) is double bond.

The optional conversion of a compound of formula (I) wherein R is hydrogen into a corresponding compound of formula (I) wherein R is halogen may be performed according to known methods. For example a compound of formula (I) wherein R is hydrogen may be transformed into a corresponding one wherein R 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., tetrahydrofuran, ethanol or 1-methyl-2-pyrrolidone can be used: R. Wiechert et al, Angew. Chem.

Int. Ed. 23 (1984)9, 727-728. If desired, an obtained compound of formula (I) wherein R is bromine or iodine may be in its turn converted into a corresponding one wherein R is fluorine through exchange reaction with, e.g., potassium fluoride in a solvent such as, for instance, dimethylformamide, according to known procedures.

The optional conversion of a compound of formula (I) wherein R, and R2, taken together, form an oxo group, into the corresponding compound of formula (I) wherein R, and R2, taken together, form the group methylene, may be, e.g., carried out by treatment with a Wittig reagent of formula (3P±CH3.Hal(- wherein Ib is a phenyl or C,-C6 alkyl group and Hal is bromine or chlorine, 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, nhexane, 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 equimolecolar amount of the Wittig reagent, the 3-oxo group is made to react selectively with respect to the 17-oxo group; alternatively the latter group may be selectively protected in a conventional manner, before the Wittig reaction. The optional separation of a mixture of isomers of formula (I) into the single isomers may be carried out according to conventional methods, e.g. fractional crystallization or chromatography.

A compound of formula (II) may be prepared dehydrating a compound of formula (IV)

wherein R', n, R', and R'2 are as defined above, and one of R'5 and R'6 is hydrogen and the other is a free or protected hydroxy, and removing the protecting groups possibly still present.

When in the compound of formula (IV) one of R'5 and R'6 is a protected hydroxy group, it is 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.

Dehydration may be, e.g., carried out following analogous procedure as that reported above for the dehydration of a compound of formula (III).

Oxo protecting groups possibly present are removed during the dehydration process; hydroxy protecting groups, i.e. ester groups as defined above, may be removed by conventional saponification procedures. If desired, an obtained compound of formula (II) wherein R, and R2, taken together, form an oxo group may be converted into a corresponding compound of formula (II) wherein R, and 112, taken together, form the methylene group, by reaction with a Wittig reagent of formula ()3P±CH3.Hal- wherein pl and Hal are as defined above, proceding in analogous fashion as reported before for the same conversion on a compound of formula (I).

Again, if desired, a compound of formula (II) wherein R, and R2, taken together, form an oxo group, may be converted into a corresponding compound of formula (II) wherein R1 and R2 are both hydrogen by preliminar thioketalization of the 3-oxo group, e.g. to form the 3,3-ethylenedithioketal, and subsequent reduction with, e.g., sodium in liquid ammonia or Raney nickel, following conventional procedures.

For the above optional conversions carried out on a compound of formula (II), the hydroxy group represented by one of R5 and R6 may be previously protected, e.g., as acetate or benzoate ester, and then deprotected, at the end of the reaction, if necessary.

A compound of formula (III) may be obtained reacting a compound of formula (V)

wherein R3 and R4 are as defined above, R", and R"2 are both hydrogen or, taken together, form a protected oxo group or methylene, and Z' represents a protected oxo group, with a metallorganic compound carrying a R'-C=C-(CH2)n- moiety wherein R' and n are as defined above, and, if desired, removing any oxo protecting group possibly present.

The organometallic compound carrying a R'-C=C-(CH2)n- moiety may be, for example, R'- C=C-(CH2)n-MgX, wherein X is a halogen atom, preferably chlorine, bromine or iodine, prepared according to known methods: L Brandsma and H.D. Verkruijsse, Synth. Acetylenes, Allenes and Cumulenes, 1981, 16. The reaction may be, e.g., carried out in a solvent chosen from tetrahydrofurane, tetrahydropyrane, y-dihydropyrane, diethylether and furane, e.g. at a temperature from about -30 C to the room temperature, preferably between -5"C and +10"C.

The subsequent removal of possibly present oxo protecting groups may be, e.g., carried out by mild hydrolysis, e.g. mild acid hydrolysis, for instance with a diluted mineral, e.g. hydrochloric or sulfuric acid, or with a sulphonic resin, in a solvent which may be, for instance, acetone, an aliphatic, e.g. methyl or ethyl, alcohol, or an aromatic hydrocarbon, e.g. benzene or toluene.

A compound of formula (IV) may be prepared reacting a compound of formula (VI)

wherein 11 , 11 2' R3, R4, R'5 and R'6 are as defined above, with a metallorganic compound carrying a R'-C=C-(CH2)n- moiety, wherein R' and n are as defined above, and, if desired, removing the protecting group possibly present.

The metallorganic compound carrying the R'-C=C-(CH2)n- moiety is like that previously indicated for the reaction with a compound of formula (V), and its reaction on the compound (VI) may be carried out in the same manner as on the compound (V).

Oxo protecting groups can be then removed, if desired, as previously reported in this specification; hydroxy protecting groups, i.e. ester groups as defined above, can be removed following conventional saponification procedures.

A compound with formula (V) or (Vl) may be prepared epoxidizing a compound of formula (VII)

wherein R",, R"2, R3 and R4 are as defined above, and either R"5 and R"6, taken together, form a protected oxo group (to prepare a compound with formula V), or one of R"5 and R"6 is hydrogen and the other is free or protected hydroxy (to prepare a compound with formula VI).

The epoxidation reaction may be performed according to known methods, for example as described by L. Nedelec in Bull. Soc. Chim. France 7, 2548, 1970.

A compound of formula (VII) may be obtained, in its turn, by a multistep process involving: 1) bromination and dehydrobromination on a compound of formula (VIII)

wherein R3, R4, R'5 and R'6 are as defined above, so obtaining a compound of formula (IX)

wherein R3, R4, R'5 and R'6 are as defined above;; 2) protection of the free carbonyl group in a compound of formula (IX), so obtaining a compound of formula (VII) wherein one of R"5 and R"6 is hydrogen and the other is a free or protected (esterified) hydroxy, and R", and R"2, taken together, form a protected oxo group, and 3) optional conversion of an obtained compound of formula (Vil) into another compound of formula (VII). The bromination and dehydrobromination on a compound of formula (VIII) may be carried out by known methods, for example by reaction with bromine, pyridine hydrobromide perbromide or pyrrolidine hydrobromide perbromide in pyridine, and subsequent treatment with an appropriate base.

The protection of the free carbonyl group in a compound of formula (IX) may be carried out according to known procedures; preferably protection by ketalization is carried out and conventional conditions are followed such as, for example, reaction with ethylene glycol, in the presence of catalytic amounts of ptoluenesulfonic acid and, optionally, of ethyl orthoformate.

The optional conversion of a compound of formula (VII) into another compound of formula (Vll) includes, e.g., the following transformations which may be carried out in any preferred order: a) saponification of a compound of formula (VII) wherein one of R"5 and R"6 is hydrogen and the other is an esterified hydroxy to obtain a compound of formula (VII) wherein one of R"5 and R"6 is hydrogen and the other is free hydroxy, and R", and R"2, taken together, form a protected oxo group;; b) oxidation of the hydroxy group represented by one of R"5 and R"6 and subsequent protection of the newly formed oxo group to obtain a compound of formula (VII) wherein R"5 and R"6, taken together, form a protected oxo group; c) reduction at the protected oxo group represented by R''1 and R"2 to obtain a compound of formula (VII) wherein R", and R"2 are both hydrogen; or d) deprotection of the oxo group represented by R"1 and R"2 and Wittig reaction with a compound of formula (3P(+)-CH3.HaI(-), wherein 6 and Hal are as defined above, to obtain a compound of formula (VII) wherein R", and R"2, taken together, form the group methylene.

The transformations indicated above may be performed according to known methods following conventional procedures; for example conditions similar to those previously described in this specification for analogous reactions may be followed.

The compounds of formula (VIII) may be obtained through protection, e.g., by ketalization as reported above, of a compound of formula (X)

wherein R3, R4, R'5 and R'6 are as defined above.

A mixture of A5(10) and A5(6) isomers of formula (Xl) and, respectively, (XII)

wherein R3, R4, R'5, R'6 and Z' are as defined above, is obtained.

The A5(10) isomer is separated from the mixture, e.g. by fractional crystallization or chromatography, and then deprotected at the oxo group in a conventional way.

In alternative, the compounds of formula (VIII) may also be obtained by dehydrating a compound of formula (XIII)

wherein R3, R4, R'5, R'6 and Z' are as defined above, and then removing the protecting group of the oxo function.

Dehydration may be, e.g., carried out with a dehydrating agent chosen from SOCI2, P205 and dicyclohexylcarbodiimide operating in an inert anhydrous solvent such as, for instance, pyridine, tetrahydrofuran, methylenechloride or benzene.

The removal of the protecting group of the oxo function may be performed conventionally, preferably under mild conditions, e.g. with acetic or formic or oxalic acid in aqueous acetone.

The compounds of formula (X) are known [R. Villotti, J. Am. Chem. Soc. 81, 4566 and J. F.

Grunwell, Steroids 27, 6, 759] or may be prepared by known methods.

Also the compounds of formula (XIII) are known compounds or may be prepared following known procedures.

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.

A mechanism-based enzyme inhibitor is a relatively unreactive compound that bears a structural similarity to the substrate or product of the target enzyme which, via its normal mechanism of action, converts the inhibitor into another molecule that binds to the target enzyme without prior release, and prevents enzyme catalysis from occurring.

The essential feature is that this type of inhibitor, unlike all of the others, requires the target enzyme to transform it into the active inhibitor species. With regard to drug design, a mechanism-based inhibitor has several advantages over conventional inhibitors, avoiding the problems related to the non-covalent reversible inhibitors (compounds which reversibly block the active site of the enzyme) and affinity labeling agents (compounds containing a reactive functional group which form a non-specific covalent bond with other biomolecules producing toxic side effects).

The compounds of the invention, in that mechanism-based inhibitors, are unreactive and activated only by the target enzyme; no non-specific reactions occur and this results in lower toxicity of the drug.

10ss-propynyl steroids were shown to inactivate aromatase: D. F. Covey J. Bio. Chem. 256, 1076, 1980 and B.W. Metcalf J. Am. Chem. Soc. 103, 3221, 1981.

The 10fl-alkynyl-4,9(1 1)-estradiene derivatives subject of this invention show higher affinity for the enzyme, that appears to be correlated to a flat 4,9-diene-structure and to a complementary fit between amino acids of the enzymatic site and the structural steroidic ring A, characteristic of these compounds. The compounds of this invention show enhanced in vitro and in vivo activity when compared with 9,11-saturated compounds, due to their structural features, and a longerlasting aromatase inhibiting activity when administered parenterally or orally. Moreover the compounds of the invention show lower toxicity and absent or reduced side effects in that these steroidal analogues are devoid of significant hormonal effects by themselves or through their metabolites.

The aromatase-inhibitors of formula (I) can find use as an alternative to endocrine ablation, e.g.

oophorectomy, hypophysectomy or adrenalectomy in the treatment of advanced hormone-dependent tumors, in particular breast cancer.

Furthermore the compounds of the invention can find application in the treatment of prostatic hyperplasia, which involves a benignic enlargment of the prostatic gland.

Clinical investigations carried out on dogs show that estrogen treatment leads to a stimulation of the interstice whereas androgens stimulate the glandular epithelium. It has also been shown that fibroblast cultures from human prostatic hyperplasic tissue aromatise testosterone to form estrogen more strongly then fibroblast cultures originating from healthy prostate tissue: H.U.

Schweikert 1979, Horm. Met. Res. 11, 635-40.

There are evidences that estrogens have a dominant role in the interstice (stromal) tissue proliferation; it follows that prostatic hyperplasia is predominantly a disorder of the fibro muscular stromal tissue, stimulated by estrogens: Junda Lin and al. J.Clin.End.and Met.1984,59(4)710.

In this light the administration of the aromatase-inhibitor compounds of the invention may prevent the formation of biologically active estrogens; in prostatic hyperplasic patients the stimulation of the fibromuscular tissue is thereby prevented and regression results accompanied by a decrease in size of prostatic gland and reduction in the clinical symptoms and discomfort of the patients. A further application of hormone therapy is for the treatment of male fertility disturbances by use of inhibitors of testosterone aromatisation (Drugs 28:263, 1984); this bases on the postulate that estradiol may play a role in regulating spermatogenesis.

Estradiol may also indirectly inhibit spermatogenesis by preventing the Leidig cells from maximally producing testosterone in response to LH.

Therefore decreased estradiol formation, as can be obtained through administration of the compounds of the invention, leads to an improvement of both sperm count and fertility, in patients with infertility due to oligozoospermia.

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

In view of their high therapeutic index, the compounds of the invention can be used safely in medicine.

For example, the approximate acute toxicity (LDso) of the compounds of the invention in the mouse, determined by single administration of increasing doses and measured on the seventh day after the treatment was found to be negligible.

The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar 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 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, diluent, 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; 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 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.

In this specification the abbreviations THF, DMS0 and DMF stand, respectively, for tetrahydrofuran, dimethylsulphoxide and dimethylformamide.

The following examples illustrate but do not limit the invention.

Example 1 A slurry of 1 9-nor-5a-hydrnxy-6fl-methyl-3-oxo- 1 7fl-hydroxy androstane-3,3-ethylenedioxy- 17- acetate (12.69 g) in 190 ml of pyridine is cooled with external bath and then, under stirring, 12.7 ml of SOCI2 are dropped into the vessel and the temperature is maintained below 5"C.

When the addition is completed, the mixture is stirred for 10 minutes then water (200 ml) is added and the aqueous layer is extracted some times with ethylacetate.

The organic phase is washed with water, dried over Na2S04 and the solvent is removed to yield 14.2 g of crude 6ss-methyl-17ss-hydroxy-5,10-estren-3-one-3,3-ethylenedioxy-17-acetate [NMR (CDCI3Zd: 0.81 (3H,s); 1.05 (3H,d); 2.03 (3H,s); 3.98 (4H,s); 4.66 (1H,dd)].

The crude product is dissolved in 50 ml of diethylether and the solution is treated with 250 ml of 65% aqueous acetic acid and stirred 24 hours at room temperature (20"C). The reaction mixture is diluted with 800 ml of water and extracted several times with ethylacetate.

The organic phase is dried, the solvent removed in vacuum and the acetic acid is distilled in azeotropic mixture with cyclohexane. The crude is purified on silica gel using diethylether:nhexane 1:1 as eluant to give 7.85 g of pure oily 6fl-methyl-17fl-hydroxy-5,10-estren-3-one-17- acetate, NMR (CDCI3)a:0.84 (3H,s,C,8); 1.04 (3H,d,C6); 2.04 (3H,s); 2.63 (1H,d,C4); 2,98 (1H,d,C4); 4.65 (1 H,dd,C17).

Using the same method the following compounds are prepared: 6ss-ethyl- 1 7fl-hydroxy-5, 1 0-estren-3-one- 17-acetate; 6ss-n-propyl- 1 7ss-hydroxy-5,1 0-estren-3-one- 7acetate; 6fl-isopropyl- 1 7ss-hydroxy-5, 1 0-estren-3-one- 7acetate.

When 6fl-methyl- 1 7fl-hydroxy-5, 1 0-estren-3-one- 17-acetate (7.15 g) is dissolved into 500 ml of dry benzene and 50 g of basic Al303 are added, the mixture is warmed to reflux for 1 hour, the Al2O3 is filtered and the solvent removed, then crude 6&alpha;-methyl-17ss-hydroxy-5,10-estren-3- one-17-acetate (7.1 g) is obtained; chromatographic purification on silica gel using ethyl acetate:n-hexane 1:1 yields 4 g of pure 6a-methyl-1 7fl-hydroxy-5,10-estren-3-one-17-acetate (oil).

Example 2 To a solution of 6fl-methyl-17fl-hydroxy-5,10-estren-3-one-17-acetate (7.85 g) in 190 ml of dry pyridine, operating in atmosphere of dry nitrogen and cooling with external bath, 9.14 g of pyridinium hydrobromide perbromide is added portionwise. The mixture is stirred for 15 minutes then warmed at 50"C and stirred 1 hour.

The reaction mixture is quenched in 500 ml of water, acidified to pH 2 with 98% H2SO4 and extracted with ethylacetate. The organic phase is dried then the solvent is removed in vacuum and the crude 6ss-methyl-17ss-hydroxy-4,5-9,10-estradien-3-one-17-acetate is chromatographed on silica gel using diethyl ether:n-hexane 6:4 thus obtaining 6.12 g of pure 6ss-methyl-17ss- hydroxy-4,5-9,10-estradien-3-one-17-acetate as white crystals, m.p. 97-99 C, UV (EtOH)Amax=304, e= 19,429; [&alpha;]D=-215 (C= 1 ,CHCl3); NMR (CDCl3)J:0.92 (3H,s); 1.04 (3H,d); 2.02 (3H,s); 4.64 (1H,dd); 5.70 (1H,s).

Following analogous procedure the following extradien derivatives are prepared: 6ss-ethyl- 1 7fl-hydroxy-4,5-9, 1 0-estradien-3-one- 17-acetate; 6a-methyl- 1 7ss-hydroxy-4,5-9, 1 0-estradien-3-one- 17-acetate; 7a-methyl- 1 7fl-hydroxy-4,5-9, 1 0-estradien-3-one- 17-acetate; 7a-ethyl- 1 7fl-hydroxy-4,5-9, 1 0-estradien-3-one- 17-acetate.

Example 3 To a solution of 6ss-methyl-17ss-hydroxy-4,5-9,10-estradien-3-one-17-acetate (9.2 g) in 100 ml of dry CH2CI2, 6.3 ml of ethylene glycol, 7.5 ml of ethyl orthoformate and 0.24 g of ptoluenesulphonic acid are added, then the mixture is warmed at 40 C and stirred for 1.5 hours.

The reaction mixture is neutralized with triethylamine, diluted with 100 ml of ethyl acetate, washed with saturated potassium carbonate solution and dried; the solvent is then removed to yield 10 g of crude 6ss-methyl-17ss-hydroxy-5,10-9,11-estradien-3-one-3,3-ethylenedioxy-17-acetate. The crude product is dissolved in 150 ml of methanol and treated with 6 g of lithium hydroxide and 50 ml of water. The solution is stirred 1.5 hours at room temperature then neutralized with 2N HCI; the methanol is distilled off and the residue extracted with ethylacetate.

The organic phase is dried and evaporated in vacuum to yield 9.7 g of 6fl-methyl-17fl-hydroxy- 5,10-9,11 -estradien-3-one-3,3-ethylenedioxy, m.p. 131-132 C; NMR (CDCl30.85 (3H,s,C16), 1.09 (3H,d,C6), 3.98 (4H,s,ethylenedioxy), 5.56 (1H,m,C").

Following analogous procedure the below listed compounds are prepared: 1 7fl-hydroxy-5, 10-9,11 -estradien-3,3-ethylenedioxy-3-one; 6fl-ethyl- 1 7fl-hydroxy-5, 10-9,11 -estradien-3,3-ethylenedioxy-3-one; 6&alpha;-methyl-17ss-hydroxy-5,10-9,11-estradien-3,3-ethylenedioxy-3-one; 6a-ethyl- 1 7fl-hydroxy-5, 10-9,11 -estradien-3,3-ethylenedioxy-3-one; 6-methylene- 1 7ss-hydroxy-5,10-9,11 -estradien-3,3-ethylenedioxy-3-one; 7a-methyl- 1 7fl-hydroxy-5,10-9,11 -estradien-3,3-ethylenedioxy-3-one; 7ss-methyl-17ss-hydroxy-5,10-9,11-estradien-3,3-ethylenedioxy-3-one.

Example 4 A solution of 6ss-methyl-17ss-hydroxy-3,3-ethylenedioxy-5,10-9,1 1-estradien-3-one (3.60 g) in 100 ml of CH2CI2, cooled to -5 to -10 C, is treated portionwise with 2.40 g of m-chloroperbenzoic acid, and stirred for 15 minutes; then, under stirring, 2.30 g of K2CO3 are added and the slurry is left to rise to room temperature in 30 minutes. The solid is filtered and the organic phase washed with 5% NaHCO3 aqueous solution, dried, then the solvent is removed.

The crude product is chromatographed on silica gel using n-hexane:ethyl acetate: triethylamine 70:30:0.2 as eluant to yield 1.85 g of 6ss-methyl-5,10-a-epoxide-17ss-hydroxy-3,3-ethylenedioxy- 9,11-estren-3-one, NMR (CDCI3)a: 0.83 (3H,s); 1.14 (3H,d); 3.92 (4H,m); 6.04 (1H,m).

Using analogous procedure, the 5,10-a-epoxide derivatives of the compounds listed below are prepared: 5,10-&alpha;-epoxide-17ss-hydroxy-3,3-ethylenedioxy-9,11-estren-3-one; 6ss-ethyl-5, 1 O-a-epoxide- 1 7ss-hydroxy-3,3-ethylenedioxy-9, 11 -estren-3-one; 6a-methyl-5, 1 O-a-epoxide- 1 7ss-hydroxy-3 ,3-ethylenedioxy-9, 11 1 -estren-3-one; 7a-methyl-5, 1 O-a-epoxide- 1 7P-hyd roxy3 ,3-ethylenedioxy-9, 11 -estren-3-one; 7fl-methyl-5, 1 O-a-epoxide- 1 7P-hydroxy-3 ,3-ethylenedioxy-9, 11 -estren-3-one.

Example 5 Into a solution of 1.5 g of 5,10-&alpha;-epoxide-17ss-hydroxy-3,3-ethylenedioxy-9,11-estren-3-one in 40 ml of dry diethylether, cooled to 0 C with external cooling-bath, and operating under nitrogen atmosphere, 33 ml of 0.5 molar propargyl magnesium bromide (prepared according to the method reported in "Synthesis of Acetylenes, Allenes and Cumulenes", L. Brandsma and H.D.

Verkruijsse, page 16, Elsevier Scientific Publishing Company-Amsterdam-Oxford-New York 1981) are dropped.

The mixture is stirred for 90 minutes and the temperature is maintained at 0 C.

Once the reaction is completed, 10 ml of saturated ammonium chloride aqueous solution are added dropwise and stirring is continued at 0 C for 10 minutes; then the temperature is left to rise to room temperature.

The solution is diluted with 50 ml of saturated aqueous ammonium chloride solution, then extracted with ethylacetate and the organic phase is washed with water and dried. The solvent is removed in vacuum and the crude is chromatographed on silica gel using ethylacetate:n hexane:triethylamine 50:50:0.1 as eluant, thus obtaining 1.51 g of pure 5&alpha;, 17ss-dihydroxy-10ss- (2-propynyl)-3,3-ethylenedioxy-9(11)-estren-3-one, m.p.=169-170 C; I.R. (nujol) cm-1: 3,500; 3,300; 2,110.

Following the same method the below listed compounds are prepared: 6&alpha;l-methyl-5&alpha;,17ss-dihydroxy-10ss-(2-propynyl)-3,3-ethylenedioxy-9(11)-estren-3-one; 7ss-methyl-5&alpha;,17ss-dihydroxy-10ss-(2-propynyl)-3,3-ethylenedioxy-9(11)-estren-3-one; 6&alpha;-chloro-5&alpha;,17ss-dihydroxy-10ss-(2-propynyl)-3,3-ethylenedioxy-9(11)-estren-3-one; 6&alpha;-fluoro-5&alpha;,17ss-dihydroxy-10ss-(2-propynyl)-3,3-ethylenedioxy-9(11)-estren-3-one; 5&alpha;,17ss-dihydroxy-10ss-(3-butynyl)-3,3-ethylenedioxy-9(11)-estren-3-one; 5&alpha;,17ss-dihydroxy-10ss-ethynyl-3,3-ethylenedioxy-9(11)-estren-3-one.

Example 6 Into a solution of 1.60 g of 5&alpha;,17ss-dihydroxy-10ss-(2-propynyl)-3,3-ethylenedioxy-9(11)-estren- 3-one in 20 ml of methanol, 4 ml of 5N HCI are added and the mixture is stirred for 10 hours at room temperature.

The mixture is quenched with 250 ml of ice-water, neutralized with 25 ml of 1N NaOH, then extracted with ethylacetate.

The organic phase is separated and washed with brine and water, then it is dried and the solvent removed to yield 1.21 g of yellow oil. The crude is chromatographed on silica gel to collect 1.03 g of pure 10ss-(2-propynyl)-17ss-hydroxy-estra-4,9(11)-diene-3-one, NMR (CDCl3)#: 0.79 (3H,s,C18), 2.60 (2H,m,C19), 3.73 (1H,m,C17), 5.63 (1H,m,C11), 5.82 (1 H,bs,C4).

Following analogous procedure the below listed compounds are obtained: 6a-methyl- 1 OP-(2-propynyl)-l 7P-hydroxy-estra-4,9( ll)-diene3-one; 7fl-methyl- 1 OP-(2-propynyl)-l 7P-hydroxy-estra-4,9( ll)-diene3-one; 7a-methyl- 1 OP-(2-propynyl)-l 7P-hydroxy-estra-4;9( ll)-diene3-one; 6-methylene- 1 OP-(2-propynyl)-l 7P-hydroxy-estra-4,9( ll)-diene-3-one; 6a-ethyl- 1 OP-(2-propynyl)-l 7P-hydroxy-estra-4,9( ll)-diene3-one; 7fl-ethyl- 1 OP-(2-propynyl)-l 7P-hydroxy-estra-4,9( ll)-diene3-one; 7&alpha;-ethyl-10ss-(2-propynyl)-17ss-hydroxy-estra-4,9(11)-diene-3-one.

Example 7 A solution of 0.77 g of 10ss-(2-propynyl)-17ss-hydroxy-estra-4,9(11)-diene-3-one in 5 ml of dry pyridine and 0.15 ml of acetic anhydride is stirred at 25 C for 12 hours. The reaction mixture-is quenched with 50 ml of ice-water under stirring. The mixture is extracted with ethyl acetate and the organic phase is washed with saturated ammonium sulphate aqueous solution and water.

The organic phase is dried and the solvent distilled at reduced pressure to yield 10ss-(2- propynyl)-17ss-acetoxy-estra-4,9(11)-diene-3-one (0.81 g).

Using analogous procedure the 17-acyloxy-derivatives of the compounds reported in the previous example 6 and following example 9 are prepared, in particular the following 17-acetoxy compounds: 6a-methyl- 1 OP-(2-propynyl)-l 7P-acetoxy-estra-4,9( ll)-diene3-one; 7fl-methyl- 1 OP-(2-propynyl)-l 7P-acetoxy-estra-4,9( ll)-diene-3-one; 6&alpha;-ethyl-10ss-(2-propynyl)-17ss-acetoxy-estra-4,9(11)-diene-3-one; 7ss-ethyl-10ss-(2-propynyl)-17ss-acetoxy-estra-4,9(11)-diene-3-one; 7&alpha;-ethyl-10ss-(2-propynyl)-17ss-acetoxy-estra-4,9(11)-diene-3-one; 6-methylene-10ss-(2-propynyl)-17ss-acetoxy-estra-4,9(11)-diene-3-one.

Example 8 To a solution of 1.05 g of 10ss-(2-propynyl)-17ss-acetoxy-estra-4,9(11)-diene-3-one in 20 ml of glacial acetic acid, 0.5 ml of 1,2-ethanedithiol and 1 ml of BF3 etherate are added cooling the flask with ice-water.

The slurry is stirred for 30 minutes and the 10P-(2-propynyl)-l 7P-acetoxy-estra-4,9(1 l)-diene- 3-ethylenedithioketal (1.16 g) is collected. The product is dissolved in 35 ml of dry THF, added to a mixture of Raney nickel (4 g) in 10 ml of ethanol and stirred for 20 minutes.

The slurry is filtered and the organic phase evaporated in vacuo to yield 0.65 g of 10ss-2- propynyl)-17ss-acetoxy-estra-4,9(11)-diene.

Following analogous procedure the below listed compounds are prepared: 6&alpha;-methyl-10ss-(2-propynyl)-17ss-acetoxy-estra-4,9(11)-diene; 7ss-methyl-10ss-(2-propynyl)-17ss-acetoxy-estra-4,9(11)-diene; 6-methylene-10ss-(2-propynyl)-17ss-acetoxy-estra-4,9(11)-diene.

Example 9 To a solution of 1OP-(2-propynyl)-17P-acetoxy-estra-4,9(1 l)-diene3-one (0.6 g) in 30 ml of methanol, cooled with ice-water, 5 ml of 20% NaOH aqueous solution are dropped under stirring and stirring is continued for 30 minutes.

The reaction mixture is diluted with water and the product is extracted with ethylacetate; the organic phase is washed with water, dried and the solvent removed.

The crude is purified on silica gel using ethyl acetate: n-hexane 80:20 as eluant so obtaining 0.42 g of pure 10ss-(2-propynyl)-17ss-hydroxy-estra-4,9(11)-diene-3-one.

Following the same procedure the below listed compounds are prepared: 6a-methyl- 1 OP-(2-propynyl)-l 7P-hydroxy-estra-4,9( ll)-diene; 7ss-methyl-10ss-(2-propynyl)-17ss-hydroxy-estra-4,9(11)-diene; 6-methylene- 1 OP-(2-propynyl)-l 7P-hydroxy-estra-4,9( ll)-diene.

Example 10 Under atmosphere of dry nitrogen, 1.92 g of triphenylmethyl-phosphonium iodide are added portionwise to a solution of 0.440 g of potassium-tert-butoxide in 6 ml of dry DMSO stirring and cooling with external water bath. The yellow-orange ylide solution (5 ml) is added to 1.20 g of 10P-(2-propynyl)-l 7P-hydroxy-estra-4,9(1 l)-diene3-one, dissolved in 5 ml of dry DMSO.

The reaction mixture is stirred for 6 hours then quenched with 150 ml of ice-water and extracted with ethyl acetate. The organic phase is washed with water, dried and the solvent removed in vacuo to give an oily crude that is chromatographed on silica gel using n-hexane:diethyl ether 20:80 as eluant, to give 1.23 g of pure 3-methylene-10ss-(2-propynyl)-17ss-hydroxy- estra-4,9(11)-diene.

Using analogous procedure, starting from the compounds prepared according to the example 6, the corresponding 3-methylene derivatives are prepared.

Example 11 To a solution of 1OP-(2-propynyl)-17P-hydroxy-estra-4,9(1 l)-diene3-one (0.620 g) in 15 ml of acetone cooled to -10 C with external cooling bath, 1.00 ml of 2.5 molar Jones reagent are dropped under stirring.

The solution is stirred 5 minutes then the excess of reagent is destroyed by adding 0.5 ml of isopropyl alcohol. The temperature is left to rise to 100C and 90 ml of benzene are added. The solution is washed with saturated aqueous ammonium sulphate solution and water, then the organic layer is dried and the solvent removed in vacuo.

The crude residue is purified on silica gel flash chromatography using a gradient eluant phase from ethyl acetate: n-hexane 30:70 to ethyl acetate:n-hexane 50:50, so obtaining 0.580 g of pure 10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione, m.p.=133-134.5 C (uncorrected); [a]D= + 138.9 (CHCl3); NMR (CDCI3)a: 0.82 (3H,s,C18), 5.66 (1H,m,C1l), 5.83 (1H,bs,C4); IR (nujol) cm-1: 3,240; 1,735; 1,660; 1,610.

Following analogous procedure the below listed compounds are prepared: 6&alpha;-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 7ss-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 7&alpha;-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 6-methylene-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 6&alpha;-ethyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; -/P-ethyl-l OP-(2-propynyl) estra-4,9(1 1)-diene-3,1 7-dione; 7&alpha;-ethyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 10ss-(2-propynyl) estra-4,9(11)-diene-17-one; 3-methylene- 1 Oss-(2-propynyl) estra-4,9( 11 )-diene- 17-one; 3-methylene-6&alpha;-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-17-one; 3-methylene-7ss-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-17-one; 3-methylene-7&alpha;-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-17-one; 3-methylene-6-methylene- 1 Oss-(2-propynyl) estra-4,9( 11 )-diene- 17-one; 3-methylene-6&alpha;-ethyl-10ss-(2-propynyl) estra-4,9(11)-diene-17-one; 3-methylene-7ss-ethyl-10ss-(2-propynyl) estra-4,9(11)-diene-17-one; 3-methylene-7a-ethyl- 1 0ss-(2-propynyl) estra-4,9( 11 )-diene- 17-one; 6&alpha;-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-17-one; 7ss-methyl- 1 Oss-(2-propynyl) estra-4,9( 11 )-diene- 17-one; 6-methylene-10ss-(2-propynyl) estra-4,9(11)-diene-17-one.

Example 12 To a solution of 5&alpha;-hydroxy-10ss-(2-propynyl)-3,3-17,17-bis ethylenedioxy-9,11-estren-3,17-dione (1.1 g) in 15 ml of methanol are added with stirring 3 ml of 5N HCI. After being allowed to stand 48 hours at 25 C the mixture is poured into 200 ml of ice-water, neutralized with 1N NaOH and it is extracted with ethylacetate.

The organic extract is washed with brine, water, then dried and concentrated. Crystallization of the residual oil from ethylacetate n-hexane gives 0.650 g of pure 10ss-(2-propynyl) estra-4,9(11)- diene-3,17-dione, m.p. 133-134.5 C.

Following the same procedure the below listed compounds are prepared: 6&alpha;-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 6ss-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 7&alpha;-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 7ss-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 7&alpha;-ethyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 7ss-ethyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione.

Example 13 Selenium dioxide (0.26 g) is added to a solution of 0.382 g of 10ss-(2-propynyl) estra-4,9(11)- diene-3, 1 7-dione in tert-butyl alcohol (25 ml) containing pyridine (0.05 ml). The slurry is refluxed for a night under nitrogen atmosphere.

The precipitated selenium is filtered and the solution evaporated to dryness; the crude residue is purified on silica gel using ethylacetate:n-hexane 60:40 to yield 0.220 g of 10ss-(2-propynyl) estra-1,4,9(11)-triene-3,17-dione, U.V.(EtOH)#max=241 nm, #= 10,436; [&alpha;]D=-5.1 (c=1, CHCl3).

Using analogous procedure the following compounds are prepared: 6&alpha;-methyl-10ss-(2-propynyl) estra-1,4,9(11)-triene-3,17-dione; 6a-ethyl- 1 Ofl-(2-propynyl) estra- 1,4,9(11)-triene-3,17-dione; 7&alpha;-methyl-10ss-(2-propynyl) estra-1,4,9(11)-triene-3,17-dione; 7&alpha;-ethyl-10ss-(2-propynyl) estra-1,4,9(11)-triene-3,17-dione; 6&alpha;-fluoro-10ss-(2-propynyl) estra-1,4,9(11)-triene-3,17-dione; 6&alpha;-chloro-10ss-(2-propynyl) estra-1,4,9(11)-triene-3,17-dione; 6ss-methyl-10ss-(2-propynyl) estra-1,4,9(11)-triene-3,17-dione; 7ss-methyl-10ss-(2-propynyl) estra-1,4,9(11)-triene-3,17-dione.

Example 14 A stirred mixture of 3.39 g of 10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione and 17.1 g of chloranil in 350 ml of tert-butyl alcohol is heated at reflux temperature for 3 hours. The excess of chloranil is taken up with chloroform (300 ml) and the solution washed with 30 ml portion of water (3 times), 5% aqueous sodium hydroxide (4 times) and again with water (4 times).

Evaporation of the chloroform affords a crystalline residue which, when triturated, gives 2.18 g of 10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione, UV (EtOH): #max=287, #=18,035.

Following analogous procedure the below listed compounds are prepared: 6-methyl-10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione; 6-ethyl-10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione; 7-methyl-10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione; 7-ethyl-10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione; 6-fluoro-10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione; 6-chloro-10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione; 6-ethynyl-10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione; 7-ethynyl-10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione; 3-methylene-6-methyl- 1 0ss-(2-propynyl) estra-4,6, 9(11 )-triene- 17-one; 6-methyl- 1 Ofl-(2-propynyl) estra-4,6,9( 11 )-triene- 17-one; 1 0ss-(2-propynyl) estra-4,6,9( 11 )-triene- 17-one.

Example 15 Selenium dioxide (200 mg) is added to a solution of 0.350 g of 10ss-(2-propynyl) estra 1,6,9(1 1)-triene-3,17-dione in in 25 ml of tert-butyl alcohol containing 0.05 ml of pyridine, and the mixture is heated and refluxed under nitrogen atmosphere for 36 hours.

Ethyl acetate (50 ml) is added and the reaction mixture is filtered through a layer of CeliteR to remove the precipitated selenium.

The solvent is then removed in vacuo and the residue chromatographed on silica gel using ethylacetate:n-hexane 65:35 to afford 0.180 g of pure 10ss-(2-propynyl) estra-1,4,6,9(1 1)-tetra- ene-3,17-dione.

Following analogous procedure the below listed compounds are prepared: 6-methyl-10ss-(2-propynyl) estra-1,4,6,9(11)-tetraene-3,17-dione; 6-chloro-10ss-(2-propynyl) estra-1,4,6,9(11)-tetraene-3,17-dione; 6-fluoro-10ss-(2-propynyl) estra-1,4,6,9(11)-tetraene-3,17-dione; 7-methyl-10ss-(2-propynyl) estra-1,4,6,9(11)-tetraene-3,17-dione; 6-methyl- 1 0ss-(2-propynyl estra- 1,4,6,9(11 )-tetraene- 17-one.

Example 16 A suspension of 10ss-(2-propynyl) estra-4,9(1 1)-diene-3,17-dione (0.924 g) in 20 ml of acetone is treated at 25 C with 0.534 g of N-bromosuccinimide and 50 mg of silver nitrate. After 60 minutes the reaction mixture is poured into ice-water and stirred for 30 minutes.

The mixture is extracted with ethylacetate (50 ml) two times, and the organic phase is washed with water, dried and the solvent removed at reduced pressure. The crude is purified with chromatographic flash silica gel column using ethylacetate:n-hexane 40:60 to yield 0.860 g of pure 10ss-(3-bromo-2-propynyl) estra-4,9(11)-diene-3,17-dione, m.p. 155-157 C (dec); [a]D=+81.0 (CHCI3); Mass spectra: [M]+ 386(388), [M-CH3] 371(373), [M-Br] 307, [M-Br-CC-CH2] 269; IR (nujol) cm-': 1,730; 1,680; 1,635; 1,620.

Following analogous procedure the below listed compounds are prepared: 1 Oss-(3-bromo-2-propynyl) estra-4,9( 11 )-diene- 17-one; 3-methylene- 1 0ss-(3-bromo-2-propynyl) estra-4,9( 11 )-diene- 17-one; 6&alpha;-methyl-10ss-(3-bromo-2-propynyl) estra-4,9(11)-diene-3,17-dione; 7ss-methyl-10ss-(3-bromo-2-propynyl) estra-4,9(11)-diene-3,17-dione; 10P-(3-bromo-2-propynyl) estra-1,4,9(11)-triene-3,17-dione; and, using N-iodo succinimide, the 3iodo derivatives corresponding to the listed 3-bromo compounds are prepared too.

Example 17 To a suspension of 0.116 g of potassium fluoride [finely ground ( < 100 mesh) and dried in vacuo oven at 100 C for 8 hours prior to use] in dry dimethylformamide (20 ml), 0.387 g of 1 0fl-(3-bromo-2-propynyl) estra-4,9( 11 )-diene-3, 17 dione are added and the mixture is warmed at 1200C for 12 hours.

The cooled mixture is filtered and the separated inorganic salts washed with DMF. The organic phase is washed with water, dried and the solvent is removed in vacuo.

The residue is crystallized from ethylacetate/n-hexane to yield 0.125 g of pure 10ss(3-fluoro-2- propynyl) estra-4,9(11)-diene-3,17-dione.

According to the above reported procedure the following compounds are also prepared: 1 Oss-(3-fluoro-2-propynyl) estra-4,9( 11 )-diene- 17-one; 3-methylene- 1 0ss-(3-fluoro-2-propynyl) estra-4,9( 11 )-diene- 17-one; 6a-methyl- 1 Oss-(3-fluoro-2-propynyl) estra-4,9(11)-diene-3,17-dione; 7ss-methyl-10ss-(3-fluoro-2-propynyl) estra-4,9(11)-diene-3,17-dione; 10ss-(3-fluoro-2-propynyl) estra-1,4,9(11)-triene-3,17-dione.

Example 18 Tablets each weighing 0.150 g and containing 25 mg of the active substance, are manufactured as follows: Composition (for 10,000 tablets) 10ss-(2-propynyl) estra-4,9(1 1)-diene-3,17-dione 250 g Lactose 800 g Corn starch 415 g Talc powder 30 g Magnesium stearate 5 g.

The 10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione, the lactose and half the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm mesh size.

Corn starch (10 g) is suspended in warm water (90 mli and the resulting paste is used to granulate the powder.

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

Example 19 Capsules, each dosed at 0.200 g and containing 20 mg of the active substance are prepared.

Composition for 500 capsules: 10ss-(2-propynyl) estra-1,4,9(11)-triene-3,17-dione 10 g Lactose 80 g Corn starch 5 g Magnesium stearate 5 g.

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

Claims (13)

1. A compound having the following formula (I)

wherein R is hydrogen, C1-C4 alkyl or halogen; n is zero, 1 or 2; R, and R2 are both hydrogen, or R1 and R2, taken together, form an oxo group or a methylene group; the symbol = indicates that each of (a) and (b), independently, is a single bond or a double bond; and one of R3 and R4 is hydrogen and the other is hydrogen, C,-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or halogen or also, when (b) represents a single bond, one of R3 and R4 is divalent and is a C,-C6 alkylidene group and the other is hydrogen.

2. A compound of formula (I), according to claim 1, wherein R is hydrogen or halogen; n is 1; R1 and R2 are both hydrogen or, taken together, form an oxo or methylene group; (a) is single or double bond; and either (b) is single bond, one of R3 and R4 is hydrogen and the other is hydrogen, C1-C4 alkyl or C1-C4 alkylidene, or (b) is double bond, one of R3 and R4 is hydrogen and the other is hydrogen, C,-C4 alkyl or halogen.

3. A compound selected from the group consisting of: 10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 10ss-(2-propynyl) estra-4,9(11)-diene-17-one; 3-methylene-10ss-(2-propynyl) estra-4,9(11)-diene-17-one; 6-methylene-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 6&alpha;-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 7ss-methyl-10ss-(2-propynyl) estra-4,9(11)-diene-3,17-dione; 10ss-(2-propynyl) estra-1,4,9(11)-triene-3,17-dione; 6-fluoro-10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione; 10ss-(2-propynyl) estra-1,4,6,9(11)-tetraene-3,17-dione; 6-methyl-10ss-(2-propynyl) estra-1,4,6,9(11)-tetraene-3,17-dione; 6-methylene-10ss-(2-propynyl) estra-4,9(11)-diene-17-one; 6&alpha;-methyl-1 Ofl-(2-propynyl) estra-4,9( 11 )-diene- 17-one; 7ss-methyl-1 Ofl-(2-propynyl) estra-4,9( 11 )-diene- 17-one; 6-methyl-10ss-(2-propynyl) estra-1,4,6,9(11)-tetraene-17-one; 10ss-(3-bromo-2-propynyl) estra-4,9(11)-diene-3,17-dione; 10ss-(3-fluoro-2-propynyl) estra-4,9(11)-diene-3,17-dione; and 6-methyl-10ss-(2-propynyl) estra-4,6,9(11)-triene-3,17-dione.

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

wherein R1, R2, n, R3 and R4 are as defined in claim 1; R' is hydrogen or C1-C4 alkyl; one of R5 and R6 is hydrogen and the other is hydroxy, so obtaining a compound of formula (I) wherein R is hydrogen or Ca-C4 alkyl and (a) and (b) are both single bonds, or 2) dehydrating a compound of formula (III)

wherein R', n, R3 and R4 are as defined above;; R', and R'2 are both hydrogen or, taken together, form a free or protected oxo group, or methylene, and Z is a free or protected oxo group, so obtaining a compound of formula (I) wherein R is hydrogen or C1-C4 alkyl and (a) and (b) are both single bond, and, if desired, in any order, transforming a compound of formula (I) wherein (a) and (b) are both single bonds into a corresponding compound of formula (I) wherein one or both of (a) and (b) are double bonds and/or, if desired, converting a compound of formula (I) wherein R is hydrogen into a corresponding compound of formula (I) wherein R is a halogen and/or, if desired, converting a compound of formula (I) wherein R is a halogen into a corresponding compound of formula (I) wherein R is a different halogen, and/or, if desired, converting a compound of formula (I) wherein R1 and R2, taken together, form the oxo group, into a corresponding compound of formula (I) wherein R1 and R2 taken together form the group methylene and/or, if desired, separating a mixture of isomers of formula (I) into the single isomers.

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

6. A compound of formula (I), as defined in claim 1, hereinbefore specified but not claimed in claim 3.

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

8. A compound according to claim 7 for use as an aromatase-inhibitor.

9. A compound according to claim 7 for use in the treatment of breast cancer.

10. A compound according to claim 7 for use in the treatment of prostatic hyperplasia.

11. A compound according to claim 7 for use in the treatment of male fertility disturbances.

12. 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 11 to 17.

13. A pharmaceutical composition substantially as hereinbefore described in Example 18 or 19.