IE65905B1 - New organic aicd esters with alcohol derivatives of 19-nor steroids and their salts their preparation process and the intermediates of this process their use as medicaments and the compostions containing them - Google Patents

Abstract

Products of general formula (I): in which R1 denotes an aliphatic hydrocarbon radical, R2 and R3, which are identical or different, denote a hydrogen atom or an alkyl radical, G denotes a hydrocarbon group containing from one to eighteen carbon atoms and optionally one or a number of identical or different heteroatoms, which is linked to the steroid nucleus by a carbon atom, and either X denotes XA, XA being a hydrogen atom, an alkyl radical, an arylalkyl radical or an acyl radical, and in this case Y denotes YA, YA being a group -B-O-CO-A-Z in which B denotes a saturated or unsaturated, linear or branched, divalent aliphatic radical, A denotes either a saturated or unsaturated, linear or branched, divalent aliphatic radical optionally interrupted or terminated by a divalent aromatic radical, or A denotes a divalent aromatic radical and Z denotes one of the functional groups -COOH or -SO3H, it being possible for these functional groups to be optionally converted into salt form or X denotes XB, XB being a group -CO-A-Z in which A and Z are as defined above and Y then denotes YB, YB being one of the groups chosen from -C IDENTICAL C-R4, -CH=CH-R4 or -CH2-CH2-R4, in which R4 denotes a hydrogen atom, a halogen atom, a trialkylsilyl radical, an alkyl radical or a phenyl radical, the said alkyl and phenyl radicals being optionally substituted.

Description

The present invention relates to new organic acid esters with alcohol derivatives of 19-nor steroid and their salts, their preparation process and the intermediates of this process, their use as medicaments and the compositions containing them.

A subject of the invention is the products of general formula (I): in which R-j represents an aliphatic hydrocarbon radical containing 1 to 8 carbon atoms, R2 and R3, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, G represents a hydrocarbon group containing 1 to 18 carbon atoms and optionally one or more identical or different heteroatoms, linked to the steroid nucleus by a carbon atom and either X represents X^, X& being a hydrogen atom, an alkyl radical containing 1 to 8 carbon atoms, an arylalkyl radical containing 7 to 15 carbon atoms or an acyl radical containing 1 to 8 carbon atoms and in this case Y represents Ya, Ya being a -B-O-CO-A-Z group in which B represents a saturated or unsaturated, linear or branched bivalent aliphatic radical, containing 1 to 8 carbon atoms, A represents either a saturated or - 2 65905 unsaturated, linear or branched bivalent aliphatic radical containing 1 to 6 carbon atoms and optionally interrupted or terminated by a bivalent aromatic radical, or A represents a bivalent aromatic radical, and Z represents one of the -COOH or -SO3H functions, these functions being able to be optionally salified in the form of an alkali metal or alkaline-earth salt, an ammonium salt or an amine salt, or X represents Xg, Xg being a -CO-A-Z group in which A and Z are as defined previously and Y then represents Yg, Yg being one of the groups chosen from —C=C—R4, —CH=CH—R4 or -CH2-CH2-R4 in which R4 represents a hydrogen atom, a halogen atom, a trialkylsilyl radical containing 3 to 12 carbon atoms, a linear or branched alkyl radical containing 1 to 6 carbon atoms or a phenyl radical, the said alkyl and phenyl radicals being optionally substituted, the wavy line in position 13 means that the Rq radical can be found in alpha or beta position.

R-| preferably represents a linear or branched alkyl radical containing 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl or butyl radical.

The products in which R-, is in the beta position are preferred.

When R2 or R3 represents an alkyl radical, it is preferably the methyl radical but R2 or R3 can also represent an ethyl, propyl, isopropyl or butyl radical.

G represents in particular: either an aryl radical containing 6 to 14 carbon atoms and optionally substituted by one or more radicals chosen from: — halogen atoms, — the carbamoyl radical, — saturated or unsaturated, linear or branched aliphatic radicals containing 1 to 6 carbon atoms and optionally substituted by one or more halogen atoms or by one of the following groups: carbamoyl, amino, alkylamino containing 1 to 4 carbon atoms, dialkylamino containing 2 to 8 carbon atoms or by a heterocyclic radical with 3 to 8 members having at least one nitrogen atom and optionally one or two heteroatoms chosen from oxygen or sulphur atoms, — linear or branched acyl radicals containing 1 to 6 carbon atoms, — the phenoxy radical optionally substituted by an amino group, an alkylamino group containing 1 to 4 carbon atoms, a dialkylamino group containing 2 to 8 carbon atoms or by a heterocyclic radical with 3 to 8 members having at least one nitrogen atom and optionally one or two heteroatoms chosen from oxygen or sulphur atoms, — the phenyl radical optionally substituted by an amino group, an alkylamino group containing 1 to 4 carbon atoms, a dialkylamino group containing 2 to 8 carbon atoms or by a heterocyclic radical with 3 to 8 members having at least one nitrogen atom and optionally one or two heteroatoms chosen from oxygen or sulphur atoms, — heterocyclic radicals with 3 to 8 members containing at least one nitrogen atom and optionally one or two heteroatoms chosen from sulphur or oxygen atoms and themselves being able to be substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, — alk-,alk2N(0)m-, alk3S(O)p- or alk4<)- radicals in which alk-|, alk2, alk3 and alk4, identical or different, represent independently of each other a hydrogen atom, a linear or branched alkyl radical containing 1 to 12 carbon atoms optionally substituted by an amino group, an alkylamino group containing 1 to 11 carbon atoms, a dialkylamino group containing 2 to 11 carbon atoms, a trialkylsilyl group containing 3 to 11 carbon atoms or by a heterocyclic radical with 3 to 8 members containing at least one nitrogen atom and optionally one or two heteroatoms chosen from sulphur or oxygen atoms and itself being able to be substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, m is equal to 0 or 1, and p is equal to 0, 1 or 2, — the trialkylsilyl groups containing 3 to 12 carbon atoms, or a saturated or unsaturated linear or branched aliphatic radical containing 1 to 18 carbon atoms and optionally substituted by one or more radicals chosen from: - halogen atoms, - the optionally substituted phenyl radical, - alkqalk2N(O)m-, alk3S(O)p- or alk4O- radicals in which alk·,, alk2, alk3, alk4, m and p are as defined previously, - heterocyclic radicals with 3 to 8 members containing at least one nitrogen atom and optionally one or two heteroatoms chosen from sulphur or oxygen atoms and itself being able to be substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, - from the trialkylsilyl groups containing 3 to 12 carbon atoms, or a heterocyclic radical optionally substituted by one or more radicals chosen from: - halogen atoms, - linear or branched alkyl radicals containing 1 to 6 carbon atoms and optionally substituted by a carbamoyl group, an amino group, an alkylamino group containing 1 to 4 carbon atoms, a dialkylamino group containing 2 to 8 carbon atoms or by a heterocyclic radical with 3 to 8 members having at least one nitrogen atom and optionally one or two heteroatoms chosen from oxygen or sulphur atoms, - alk-jalk2N(O)m-, alk3S(O)p- or alk4O- radicals in which alk·], alk2, alk3, alk4, m and p are as defined previously, - the trialkylsilyl groups containing 3 to 12 carbon atoms, or a condensed bicyclic system containing 1 to 3 nitrogen atoms and one of which is optionally oxidized, optionally substituted by one or more radicals chosen from halogen atoms or alkyl radicals containing 1 to 4 carbon atoms, or a cycloalkyl radical with 3 to 8 members and optionally substituted by one or more radicals chosen from: - halogen atoms, - the phenyl radical, - linear or branched alkyl radicals containing 1 to 6 carbon atoms and optionally substituted by a carbamoyl group, an amino group, an alkylamino group containing 1 to 4 carbon atoms, a dialkylamino group containing 2 to 8 carbon atoms or by a heterocyclic radical with 3 to 8 members having at least one nitrogen atom and optionally one or two heteroatoms chosen from oxygen or sulphur atoms, - alkTalk2N(O)m-, alk3S(O)p— or alk4O- radicals in which alk-j, alk2, alk3, alk4, m and p are as defined previously, - the trialkylsilyl groups containing 3 to 12 carbon atoms.

G can preferably represent an aryl radical. This aromatic radical can be substituted in the ortho, meta or para position by one or more alkyl radicals preferably containing 1 to 4 carbon atoms; by one or more alky loxy radicals preferably having 1 to 4 carbon atoms such as the following radicals: methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy; alkenyloxy such as vinyloxy or 2—propenyloxy; by one or more halogen atoms, preferably chlorine or fluorine; by one or more radicals chosen from the following radicals: hydroxyl, (2-amino 2-oxo ethyl), trifluoromethyl, alkylthio having 1 to 4 carbon atoms optionally oxidized in the form of the sulphoxide or the sulphone such as methylthio, ethylthio; amino, alkylamino having 1 to 4 carbon atoms such as methylamino, ethylamino, dialkylamino having 2 to 8 carbon atoms optionally oxidized in the form of the N-oxide such as the dimethylamino diethylamino or (N-methyl ethylamino) radical, by an acyl radical such as formyl, acetyl, propionyl, butyryl or benzoyl, preferably acetyl; of course the radicals substituting the aryl radical can also be optionally substituted as described previously; similarly the aryl radical can be substituted by a combination of these different radicals such as for example (3-fluoro 4dimethylamino phenyl); G can also represent a heterocyclic radical optionally substituted by the different radicals envisaged above. The following radicals can be mentioned: thienyl, furyl, isothienyl, isofuryl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridyl, piperidinyl or pyrrolidinyl or piperazinyl, as well as the heterocycles known to a man skilled in the art; G can also represent a condensed bicyclic radical containing a phenyl nucleus and a heterocyclic nucleus containing at least one nitrogen atom optionally substituted by the radicals envisaged previously; the N-methyl 2,3dihydro indol-5-yl radical can be mentioned; G can also represent a cycloalkyl radical such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, a cycloalkenyl radical such as cyclobutenyl or cyclopropenyl; G can also represent a radical containing an aryl nucleus substituted either by an amine function optionally substituted by one or two alkyl radicals having 1 to 8 carbon atoms, or by an amino radical incorporated in a heterocycle optionally containing another heteroatom chosen from the group formed by oxygen, nitrogen and sulphur, such as the morpholino, piperidinyl, pyrrolidinyl or 4-methyl piperazinyl radicals.

The aryl nucleus is then preferably the phenyl nucleus.

As substituent on the aryl nucleus there can also be envisaged an amino (substituted) alkyl radical, such as the dimethylamino methyl, dimethylamino ethyl radical; an amino (substituted) alkyloxy radical such as the dimethylamino ethyloxy radical.

There can also be mentioned the radicals containing a silicon atom such as the trimethylsilyl phenyl radical or the [N-methyl (1-trimethylsilyl) methylamino] phenyl radical.

The previously mentioned radicals containing a nitrogen atom can be oxidized.

G can also represent a saturated or unsaturated, linear or branched alkyl radical having 1 to 18 carbon atoms.

It is then preferably one of the following radicals: methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tertbutyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2, 2-dimethylpentyl, 3,3dimethyl pentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl, nonyl, 2,4dimethyl heptyl, or n-decyl. It can also be the vinyl, isopropenyl, allyl, 2-methylallyl or isobutenyl radicals.

The above-mentioned radicals can be substituted. Among the possible substituents the thioalkyl radicals can be mentioned such as thiomethyl or thioethyl; G can also be substituted by one or more halogen atoms such as fluorine, chlorine, bromine, iodine, or by substituted amino radicals such as dimethylamino.

In a general manner, the products are preferred in which substituent G contains a heteroatom, preferably nitrogen, oxygen or sulphur.

When X represents Xa, Xa being an alkyl radical, it is preferably the methyl, ethyl or propyl radical.

When X represents Xa, Xa being an arylalkyl radical, it is preferably the benzyl or phenethyl radical.

When X represents Xa, Xa being an acyl radical, it is preferably the formyl, acetyl, propionyl, butyryl or benzoyl radical.

B preferably represents either a saturated bivalent radical such as the methylene, ethylene, trimethylene or tetramethylene radical, or an unsaturated bivalent radical such as the vinylene, propenylene, bytenylene, ethynylene, propynylene or butynylene radical.

A preferably represents the methylene, ethylene, trimethylene or tetramethylene radical; when it is interrupted by an aromatic ring, A then preferably represents the radical: CH2—CH2or -CH2-CH2 ch2-ch2 when it is terminated by an aromatic ring, it is preferably the radical: CH2-CH2or CH2-CH2-CH2— When A represents a bivalent aromatic radical, it is preferably the ortho-phenylene, meta—phenylene or paraphenylene radical or also the radical or When Z represents a salified carboxy or sulpho group, it is preferably the sodium, potassium, calcium, magnesium, ammonium salt, or an amine salt used ih the production of medicaments, such as the salts of lysine, arginine, cysteine, betaine, carnitine, meglumine, quinine, sarcosine, procaine, histidine or N-methyl glucamine.

When R4 represents an alkyl radical, it is preferably a methyl, ethyl, propyl, butyl, isopropyl or isobutyl radical.

A particular subject of the invention is the products of general formula (I) as defined previously and corresponding to formula (I'): R1 OX· ||Y* R2 R3 O (I*) in which either X' represents a hydrogen atom and in this case Y' represents Y'a, Y'a being a group: -B'-O-CO-A'-Z' in which B' represents one of the bivalent -CH=CH—CH2- or -C^C-CH2— radicals, A' represents one of the bivalent -2)n- radicals in which n can take one of the values two to six or an ortho-, meta- or para—phenylene radical and Z' represents the carboxy or sulpho functions or their sodium salt, or X' represents X'g, X'b being a group: -CO-(CH2)n-Z' in which n and Z' are as defined previously and Y' then represents Υ'β, Y#b being one of the — C^c-R'4 or -CH=CH-R'4 groups in which R'4 represents a hydrogen atom, a halogen atom, a trimethylsilyl radical, or a methyl radical optionally substituted by one or more halogen atoms, a hydroxy radical or by an alkyloxy, alkylthio or alkylamino group containing 1 to 4 carbon atoms, a dialkylamino group containing 2 to 8 carbon atoms or a trialkylsilyl group containing 3 to 12 carbon atoms. n preferably takes one of the values 2 to 4; when R'4 represents a trialkylsilyl radical, it is preferably the trimethylsilyl radical.

When R'4 represents the optionally substituted methyl radical, it is preferably one of the following radicals: methyl, (fluoromethyl), (trifluoromethyl), (chloromethyl), (bromomethyl), (dimethylamino methyl), (hydroxymethyl), (methoxymethyl), or (methylthiomethy1).

When R'4 represents a halogen atom it is preferably a chlorine, bromine or iodine atom.

More particularly G represents an aryl radical substituted by a halogen atom, an aryl radical, an acyl radical containing 1 to 8 carbon atoms or by one of the -NH2, -NHR' or -NR'R functions, in which R' and R, identical or different, represent a phenyl radical, or a primary, secondary or tertiary alkyl radical containing 1 to 8 carbon atoms, optionally containing one or more heteroatoms, chosen from oxygen, nitrogen and sulphur atoms, or optionally substituted by a heterocycle, or R' and R represent with the nitrogen atom to which they are linked, an optionally substituted heterocyclic radical and optionally containing another heteroatom chosen from nitrogen, oxygen and sulphur atoms, or by one of the -OR"' or -SR' functions in which R' represents a phenyl radical or a primary, secondary or tertiary alkyl radical containing 1 to 8 carbon atoms, optionally containing one or more heteroatoms, chosen from oxygen, nitrogen, sulphur atoms or optionally substituted by a heterocycle, or G represents a 2, 3 or 4-pyridyl radical.

A particular subject of the invention is the products of formulae (I) and (I') as defined previously and in which G represents a phenyl radical substituted in position 4 by one of the following radicals: amino, (methylamino), (dimethylamino) or its N-oxide, (diethylamino), (dipropylamino), (N— methyl ethylamino) (N-methyl isobutylamino), (N-methyl isopropylamino), (N-methyl isobutylamino), (N-methyl isopentylamino), 1-pyrrolidinyl, [2-(dimethylamino) N-methyl ethylamino], [N-methyl 2-(1-pyrrolidinyl) ethylamino], [Nmethyl 2-(4-morpholinyl) ethylamino], (4-methyl 1piperazinyl), formyl, acetyl, methoxy, phenoxy, [2(dimethylamino) ethoxy], [2-(1-pyrrolidinyl) ethoxy], [2-(4morpholinyl) ethoxy], (methylthio), (ethylthio), (isopentylthio), [2-(dimethylamino) ethylthio], [2-(1pyrrolidinyl) ethylthio] [2-(4-morpholinyl) ethylthio], (trimethylsilyl), methyl, isopropyl, [(dimethylamino) methyl], or by one of the fluorine, chlorine or bromine atoms.

A particular subject of the invention is the products of formula (I) as defined previously, in which R-j represents a methyl radical in position 13beta and R2 and R3 each represent a hydrogen atom, and quite particularly those whose names follow: — sodium and 21-chloro 11 beta-[4—(dimethylamino) phenyl] 3oxo 19-nor 17alpha-pregna-4,9-dien-20-yn-17beta-yl succinate, - sodium and 11beta-[4-(methylthio) phenyl] 3-oxo 17alpha-(1propynyl) estra-4,9-dien-17beta-yl succinate.

Also a subject of the invention is a preparation process for products of formula (I) as defined previously and characterized in that: A — the products of formula (lift) or of formula (ΙΙβ): ·"* Β—OH ο °XA (Ha) R1 OH RR Ο Lui C=C-R4a (ΙΙβ) in which R-j, R2, R3 and G have the meaning indicated above and R4a has the values indicated above for R4 as well as those values in which the reactive; functions are protected, are subjected, in a neutral solvent and in the presence of a base, a) to the action of a product of formula (III-j): 0=C C=0 (III! ) in order to obtain, after if necessary deprotection of the protected reactive functions and if desired salification of the carboxy function, the products of general formula (I) corresponding to formulae (Iai) and (Ibi) respectively: R Γ,ιιΙ B-O—CO-A-Zl (Iai) r3 O 2 (VD) which products are if desired subjected to a agent of the double bonds in order to obtain formulae (Ibs), (Ib6) an<^ (VIp) respectively hydrogenation the products of (IBS) (*B6> Rl O-CO-A-COOR5 CH2~CH2"R4 r2, R3 »*»»* (VID) or to a direct hydrogenation agent of the triple bonds into single bonds in order to obtain the products of formulae (IB5), (Ig6) and (VId) respectively; b) the products of formulae (Vp) and (VIp) are either hydrolyzed, or saponified in order to obtain the products of formulae (133) and (Ιβδ) respectively.

In a preferred implementation of the process described above, the action of (IIIi) on (lift) and (llg) is carried out in the presence of a base and in a neutral solvent, the hydroxy function optionally contained in R4 is protected in the form of a (2-tetrahydropyranyloxy) group by the action of 2,3—dihydropyrane.

The subsequent deprotection of this function takes place by passing it over a commercially-available sulphonie resin (acid form) or by acid treatment. The neutral solvent serving as reaction medium can be chloroform, methylene chloride, acetonitrile or ethyl ether; the base used is preferably a nitrogenous base such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine or N-methyl morpholine.

The oxidation of the mercapto group into the sulpho group is carried out using nitric acid, barium nitrate or by auto-oxidation in a basic medium.

The hydrogenation agent of the triple bonds into a double bond is hydrogen in the presence of a catalyst such as palladium on barium sulphate. The hydrogenation agent of the double or triple bonds into a single bond is hydrogen in the presence of a catalyst such as palladium on activated charcoal or chloro tris(triphenylphosphine) rhodium.

By functional derivatives of acids of formula (III2) or (III3) is meant the anhydrides obtained in situ by the action of an alkyl chloroformate such as isobutyl chloroformate, or a dicycloalkylcarbodiimide such as dicyclohexylcarbodiimide.

The hydrolysis and the saponification of the -COOR5 function, as well as the salification of the carboxy or sulpho functions, are carried out in the usual way.

In a preferred implementation of the process described previously for the preparation of products of formula (I'), - a) the product of formula (II*a) or (II'B): in which R*|, R2, R3 and G have the values indicated above and R*4a has the values indicated above for R'4 as well as those values in which the hydroxylated functions are protected, in a neutral solvent and in the presence of a base, is subjected to the action of a product of formula (III*η ): in which n takes one of the values from 2 to 6, in order to obtain, after if necessary deprotection of the protected hydroxy function contained in R*4 and if desired, salification of the free carboxy function by the action of a sodium bicarbonate solution, the product of formula (I*ai) or (I' B1) respectively: in which Z'-j represents a free carboxy group or its sodium salt; b) or the product of formula (II'a) as defined above is subjected, in the presence of a nitrogenous base, to the action of a product of formula (111*3): SO2C1 in order to obtain, if necessary and if desired, after salification by a sodium bicarbonate solution, a product of formula (I'a2): in which Z* 2 represents a sulpho group or its sodium salt; which products of formula (I*bi) are subjected, if desired, to the action of hydrogen in the presence of a catalyst in The products of formulae (Ha) ant^ (11b) used for the implementation of the preparation process for products of formula (1) are known in a general manner and their preparations are described in French Patent Nos 2377418, 2497807, 2522328, 2528434 and European Patent Nos 057115 and 190759.

Some of the products of formulae (111^), (III2) and (III3) are commercially-available products; others can be prepared by methods known to a man skilled in the art: - ETAIX, annales de Chimie (7) i p. 371 - LOVEN, j. Prakt. Chemie (2) 29 p. 376 - UHLENBROEK, Recueil des Travaux Chimiques des Pays-Bas (1957) 76 p. 129, 142.

The products of general formula (I) possess useful pharmacological properties.

The study of the products on the hormonal receptors enabled the progestomimetic or anti-progestomimetic, androgenic or anti-androgenic activities to be revealed.

The products of the present Patent Application may also have anti-glucocorticoid and/or glucocorticoid, antiproliferative, anti-estrogen and/or estrogen properties.

These products can therefore be used as medicaments mainly for combating the side effects of glucocorticoids; they also allow the combating of disorders due to a hypersecretion of glucocorticoids and in particular ageing in general and more particularly hypertension, glaucoma, atherosclerosis, osteoporosis, diabetes, obesity, as well as the depression of immunity and insomnia.

The products which possess anti-progestomimetic properties can be used to prepare original contraceptives or as agents for interrupting pregnancy.

The products which are a subject of the present Patent Application can also be used as menstruation inducers in women and more generally in warm-blooded female animals.

These products are then administered during periods when progesterone plays an essential physiological role, that is to say notably during the luteal phase of the cycle, at the moment of nidation (or implantation of the embryo) and during pregnancy. A contraception method according to the invention consists of administering at least one of the products of formula (I) to the woman for 1 to 5 days which are preferably at the end of the cycle. These products are then administered preferably by oral route or in vagino but they can also be used by parenteral route.

The products which are a subject of the present Patent Application can also be used by endonasal route.

Those products possessing anti-progestomimetic properties can also be used to combat hormonal disturbances and, furthermore, they may have a use in the treatment of hormone-dependent tumours.

Their actions on the hypophyseal secretions make the products of use in the menopause.

These products can also be used in the synchronization of oestrus in farm animals, in particular cattle and sheep.

These products can also be used to control the fertility of domestic animals such as dogs or cats.

The products which are a subject of the present Patent Application may also have progestomimetic properties and can thus be used in the treatment of amenorrhea, dysmenorrhea and luteal insufficiencies.

Those products which have anti-androgenic properties can be used in the treatment of hypertrophy and cancer of the prostate, virilism, anaemia, hirsutism and acne. They can also be used for male contraception.

Finally the products which are a subject of the present Patent Application and which have anti—proliferative, antiestrogen and/or estrogen properties can be used in the treatment of hormone-dependent carcinomas, such as for example mammary carcinomas and their metastases. These properties also make the products of use in the treatment of benign breast tumours.

The estrogen properties which the said products can also have also make them of use in the treatment of disorders linked to a hypofolliculinemia, for example amenorrhea, dysmenorrhea, repeated miscarriages, premenstrual disorders as well as in the treatment of the menopause.

Therefore a subject of the invention is, as medicaments, the products of formula (I) which are a subject of the present Patent Application and more particularly those of formula (I').

A quite particular subject of the invention is, as medicaments: - sodium and 21-chloro 11beta-[4-(dimethylamino) phenyl] 3oxo 19-nor 17alpha-pregna-4,9-dien-20-yn-17beta-y1 succinate. - sodium and 11beta-[4-(methylthio) phenyl] 3-oxo 17alpha-(1propynyl) estra 4,9-dien-17beta-yl succinate.

The useful dose varies as a function of the illness to be treated and the administration route; it can vary for example from 10 mg to 1 g per day in an adult by oral route.

The new products, which are a subject of the present Patent Application, as defined previously, can be used to prepare pharmaceutical compositions containing, as active ingredient, at least one of the said products.

These products are used by digestive, parenteral or local route. They can be prescribed in the form of plain or sugar-coated tablets, capsules, granules, suppositories, pessaries, injectable preparations, ointments, creams, gels, which are prepared according to the usual methods.

The active ingredient or ingredients can be incorporated with the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

Moreover, the products of general formula (I) in which Z represents a salified carboxy or salified sulpho group and quite particularly the products of formula (I') in which Z' represents -COONa or -S03Na, are very soluble in water; among these there can be mentioned in a non-limitative manner the solubility of the product of Example 18 which is greater than 25 g per 100 ml of water; this allows their use in the form of drinkable, nasal or auricular solutes, eye washes, aerosols, IM or IV injectable solutions or capsules.

Therefore a subject of the invention is the pharmaceutical compositions containing as active ingredient at least one product which is a subject of the present Patent Application.

Also a subject of the invention is, as new industrial products, the products of formulae (IVc), (IVj)), (IVe), (IVp), (VD) and (VIj)), as defined previously.

The following examples and the pharmacological study illustrate the invention without however limiting it.

EXAMPLE 1: (Z)—3—[ 11beta—[4—(dimethylamino) phenyl] 17beta— hydroxy 3—oxo estra—4,9-dien-17alpha—yl ] 2—propenyl acid succinate In a flask fitted with magnetic agitation, 900 mg of 11 beta—[4—(dimethylamino) phenyl] 17beta-hydroxy 17alphat(Z)-3-hydroxy 1-propenyl] estra-4,9-dien-3-one is dissolved in 9 ml of chloroform then 304 mg of succinic anhydride and 1.45 ml of triethylamine are added. The mixture thus formed is agitated for 15 hours at ambient temperature then evaporated to dryness, the 1.443 g of residue obtained is purified by chromatography on a silica column (eluant: (ethyl acetate 90—cyclohexane 10) - acetic acid 3%). After recrystallization from a methanol - water mixture (60-40), 695 mg of the desired product is obtained in the form of yellow crystals. M.P. = approx. 145°C.

Thin layer chromatography: Rf = 0.60. (support: KC 18 Whatman eluant: methanol - 0.05 molar aqueous solution of ammonium acetate (80-20)).

EXAMPLE 2: sodium and (Z)—3—[ 11beta—[4—(dimethylamino) phenyl] 17beta—hydroxy 3—oxo estra—4,9—dien—17alpha—yl] 2— propenyl succinate In a flask fitted with magnetic agitation, 93 mg of sodium bicarbonate is dissolved in 20 ml of water, a solution of 639 mg of the product obtained in Example 1 in 20 ml of ethanol is then added dropwise. The ethanol is driven off by azeotropic distillation and the agueous solution thus obtained is filtered on a millipore R membrane (0.45 microns) then lyophilized. 654 mg of desired product is collected in the form of a cream-coloured powder [alpha]p = +101° + 2° (c= 1% in water). Thin layer chromatography: Rf = 0.62. (support: KC 18 Whatman(r) eluant: methanol - 0.05 molar aqueous solution of ammonium acetate (80-20)).

EXAMPLE 3: 3—[11 beta—[4—(dimethylamino) phenyl] 17beta— hydroxy 3-oxo estra-4,9-dien-17alpha-yl] 2-propynyl acid succinate In a flask fitted with magnetic agitation, 900 mg of 11beta-[4—(dimethylamino) phenyl] 17beta-hydroxy 17alpha-(3hydroxy 1-propynyl) estra-4,9-dien-3-one is dissolved in 9 ml of chloroform, 303 mg of succinic anhydride and 1.4 ml of triethylamine are then added and the mixture thus formed is agitated for 17 hours at ambient temperature. After evaporation to dryness, 1.685 g of crude product is purified by chromatography on a Bondapack Cl8 ©column (eluting with a mixture of methanol and a 0.05 molar agueous solution of ammonium acetate (60-40)). In this way 1.104 g of the desired product is obtained.

Rf = 0.63 (thin layer chromatography, support: KC 18 Whatman®, eluant: methanol - 0.05 molar aqueous solution of ammonium acetate (80-20)).

EXAMPLE 4: sodium and 3— [1 Ibeta—[4— (dimethylamino) phenyl] 17beta—hydroxy 3-oxo estra—4,9-dien—17alpha-yl] 2-propynyl succinate The operation is carried out in the same manner as in Example 2 with 141 mg of sodium bicarbonate in 29 ml of water and 964 mg of the product prepared in Example 3 in 29 ml of ethanol, and 935 mg of the desired, product is then obtained, [alpha]]) = +55° ± 1.5° (c = 1% in water).

Rf = 0.63 (thin layer chromatography, support: KC 18 Whatman eluant: methanol - 0.05 molar aqueous solution of ammonium acetate (80-20)).

EXAMPLE 5: 11beta—[4-(dimethylamino) phenyl] 3—oxo 17alpha— (1—propynyl) estra-4,9-dien-17beta—yl acid succinate The reaction medium is prepared by adding 2.15 g of succinic anhydride, 2.2 ml of triethylamine and 215 mg of 4(dimethylamino) pyridine to a solution of 2.15 g of llbeta[4-(dimethylamino) phenyl] 17beta-hydroxy 17alpha-(1propynyl) estra-4,9-dien-3-one, in 22 ml of chloroform, then heating the whole under reflux for 42 hours, and 430 mg of 4(dimethylamino) pyridine and 4.4 ml of triethylamine are added. Heating under reflux is continued for 26 hours and the solution is then poured into a water-ice mixture. After the organic phase has been decanted, it is washed with water then dried and the chloroform is distilled off to give a brown-coloured dry extract. The aqueous phase is acidified with 0.5 N hydrochloric acid then neutralized by the addition of sodium acetate. Extraction is carried out again with ethyl acetate and the new organic phase is washed with water, dried, and after distillation of the solvent gives a residue which is united with the previous one. The product is purified on a silica column eluting with an ether - ethyl acetate mixture (9-1) with 3% of acetic acid and recrystallized twice from an ether - methylene chloride mixture. 1.435 g of the desired product is obtained.

M.p. = approx. 165°. [alpha]D = +97° (c = 0.8% in CHCI3).

Rf = approx. 0.40 (thin layer chromatography, support: SiO2, eluant: ether 9 - ethyl acetate 1 — acetic acid 3%).

EXAMPLE 6: sodium and 11 beta-[4-(dimethylamino) phenyl] 3-oxo 17alpha—(1 -propynyl) estra-4,9-dien-i7beta—yl succinate g of the product prepared in Example 5 and 94 ml of ethanol are introduced into a flask fitted with magnetic agitation and then a solution of 433 mg of sodium bicarbonate in 94 ml of water is poured in. After 30 minutes of agitation at ambient temperature, the ethanol is driven off by azeotropic distillation and the solution remaining is filtered on a millipore ® membrane (0.45 microns) and lyophilized. 2.88 g of the desired product is obtained, [alpha]]) = +48.5° + 1.5° (c = 1% in water).

Rf = 0.54 (thin layer chromatography, support: KC 18 Whatman®, eluant: methanol - 0.05 molar aqueous solution of ammonium acetate (80-20)).

EXAMPLE 7: 11 beta-[4-(dime thy lamino) phenyl] 3-oxo 17alpha[(Z)-l-propenyl] estra-4,9-dien-17beta-yl acid succinate 2.462 g of the product prepared in Example 5 is put in a flask fitted with magnetic agitation and 150 ml of ethyl acetate with 2% of pyridine, 15 ml of water and 50 mg of palladium hydroxide at 10% on barium sulphate are added.

After hydrogenation under agitation for 5 hours and 30 minutes, the reaction medium is filtered, the pyridine is driven off and the solution remaining is evaporated to dryness. The residue thus obtained is purified by two successive chromatographies on a Bondapack C 18 column eluting with a mixture of methanol and a 0.05 molar aqueous solution of ammonium acetate (65-35), and 576 mg of the desired product is obtained Rf - 0.50 (thin layer chromatography; support: KC 18 Whatman®, eluant: methanol 0.05 molar aqueous solution of ammonium acetate (80-20)). EXAMPLE 8: sodium and 11 beta—[4—(dimethylamino) phenyl] 3-oxo 17 alpha—[ (Z)—1-propenyl] estra—4,9-dien—17beta—yl succinate By operating in the same manner as in Example 2 with a solution of 100 mg of sodium bicarbonate in 21 ml of water and 665 mg of the product prepared in Example 7 in 21 ml of ethanol, 583 mg of the desired product is obtained. [alpha]D = +56.5° + 1.5° (c = 1% in water).

Rf = 0.50 (thin layer chromatography, support KC 18 Whatman®, eluant: methanol — 0.05 molar aqueous solution of ammonium acetate (80-20)).

EXAMPLE 9: 21-chloro 11 beta-[4-(dime thy lamino) phenyl] 3-oxo 19—nor 17alpha-pregna-4,9—dien—20—yn—17beta-yl acid succinate In a flask fitted with magnetic agitation, 1 .854 g of 21-chloro 11 beta-[4-(dimethylamino) phenyl] 17beta-hydroxy 17alpha-pregna-4,9-dien-20-yn-3-one is dissolved in 18.5 ml of chloroform then 2.497 g of succinic anhydride, 7 ml of triethylamine and 0.936 g of 4-(dimethylamino) pyridine are added. The mixture thus formed is heated under reflux for 42 hours. Then the reaction medium is poured into 31 ml of a 2N hydrochloric acid solution then the pH is adjusted to 6—7 by the addition of sodium acetate. The chloroform phase is separated off then extraction is carried out again twice with chloroform. The extracts collected are united, washed with water, dried over sodium sulphate then concentrated under reduced pressure, and 3.85 g of a brown residue is obtained which is purified by chromatography on a Kieselgel column, eluting first with ethyl ether then with a mixture of ethyl ether with 3% acetic acid. 1.8 g of crude product is obtained which is recrystallized from a methylene chloride ethyl ether mixture then from a methylene chloride — ethyl ether mixture. 1.21 g of expected product is obtained, M.p. = approx. 165°C. [alphaId = +63° ± 1.5° (c = 0.90 in CHCI3).

Thin layer chromatography: Rf = 0.53. (support: KCl8 Whatman R; eluant: methanol - 0.05 molar aqueous solution of ammonium acetate (80-20)).

EXAMPLE 10: sodium and 21—chloro 11 beta—[4—(dimethylamino) phenyl] 3-oxo 19-nor 17alpha—pregna—4,9—dien—20—yn-17beta—yl succinate 817 mg of the product prepared in Example 9 and 25 ml of ethanol are mixed together in a flask fitted with magnetic agitation; a solution of 113 mg of sodium bicarbonate in 25 ml of water is then poured in dropwise and the reaction medium is agitated for 30 minutes at ambient temperature.

The ethanol is then driven of by azeotropic distillation, the solution remaining is filtered on a millipore® membrane (0.45 microns) then lyophilized. 813 mg of lyophilizate is obtained which corresponds to the desired product. [alpha]D = +16.5° + 1° (c = 1% in H2O).

Rf = 0.54 (thin layer chromatography; support: KC 18 Whatman®, eluant: methanol - 0.05 molar aqueous solution of ammonium acetate (80-20)).

EXAMPLE 11: 11beta-[4-(methylthio) phenyl] 3-oxo 17alpha-(1propynyl) estra—4,9—dien—17beta—yl acid succinate 1.5 g of 17beta-hydroxy 11 beta-[4-(me thyl thio) phenyl] 17alpha—(1—propynyl) estra—4,9-dien—3—one, 15.3 ml of chloroform are mixed together in a flask fitted with magnetic agitation then 1.86 g of succinic anhydride, 6 ml of triethylamine and 794 mg of 4-(dimethylamino) pyridine are added and the whole is heated under reflux for 94 hours, poured into IN hydrochloric acid and extracted with chloroform. The chloroform phase is washed in water, dried over sodium sulphate and the solvent is eliminated under reduced pressure at 40°C. 2.26 g of crude product is obtained which is chromatographed on a Kieselgel 60H ® silica column (eluant: (methylene chloride 97.5 - methanol 2.5) acetic acid 1%). After recrystallization from a methylene chloride - isopropyl ether mixture, 826 mg of crystals of the desired product are formed. M.p. - 158°C.

Rf = 0.61 (thin layer chromatography, support KC<18 Whatman®, eluant: mixture of ethanol and a 0.05 molar aqueous solution of ammonium acetate (70-30)).

EXAMPLE 12: sodium and 11 beta— [4— (me thyl thio) phenyl] 3-oxo 17alpha— (1 —propynyl) estra—4,9-dien—17beta-yl succinate By operating in the same manner as in Example 2 with 108 mg of sodium bicarbonate in 21.5 ml of water and 719 mg of the product prepared in Example 11 in 21.5 ml of ethanol, 720 mg of a lyophilizate is obtained corresponding to the desired product. [alphalg = +74.5° ± 1.5° (c = 1% in water).

Rf = 0.61 (thin layer chromatography, support KC 18 Whatman®, eluant: ethanol — 0.05 molar aqueous solution of ammonium acetate (70-30)).

EXAMPLE 13: 3— [3—[1 Ibeta— [4— (dimethylamino) phenyl] 17betahydroxy 3-oxo estra—4,9-dien—17alpha—yl] 2—propynyloxycarbonyl] benzenesulphonic acid g of 11beta-[4-(dimethylamino) phenyl] 17beta-hydroxy 17alpha-(3-hydroxy 1—propynyl) estra—4,9—dien—3-one is dissolved in 10 ml of chloroform, 1.5 g of a pyridine3—(chlorosulphonyl) benzoic acid complex then 1.25 ml of triethylamine are added, the whole is taken to reflux for 45 minutes, a further 0.5 g of the preceding complex is added and heating under reflux is continued for 30 minutes. After cooling down and evaporation of the solvent, the residue is dissolved in water, then the solution is distilled in the presence of toluene. The dry extract obtained is dissolved in chloroform and filtered on a silica column, eluting with chloroform with 5% ethanol then with chloroform with 10% ethanol. An acid fraction is obtained from which 1.7 g of desired product is obtained in the form of a pale yellow resin.

EXAMPLE 14: sodium 3—[3— [1 Ibeta— [4— (dimethylamino) phenyl] 17beta—hydroxy 3-oxo estra—4,9-dien— 17alpha—yl] 2—propynyl— oxycarbony 1 ] benzenesulphonate ml of an ethanolic solution of sodium acetate (0.24 mmole/ml) is added to the acid fraction obtained in the preceding example and the solution thus obtained is evaporated to dryness. The dry extract is taken up in methanol with 33% water and chromatographed on a LICHROSORB KC 18 ©column (eluants: methanol — water (3-6), methanol — water (1-1) then methanol - water (6-3)). The eluates are regrouped, refiltered, evaporated to dryness and the powder obtained is dried to give 1.35 g of the desired product, [alpha]}) = +107° (c = 0.2% in ethanol).

Microanalysis Calculated: C% 66.34 H% 5.87 N% 2.25 S% 4.92 Found: 66.6 6.30 2.50 4.7 EXAMPLE 15: 11beta-(4-acetyl phenyl) 3-oxo 17alpha-(1propynyl) estra—4,9—dien—17beta-yl acid succinate 1.8 g of 1Ibeta-(4-acetyl phenyl) 17beta-hydroxy 17alpha-(1—propynyl) estra-4,9-dien—3—one is dissolved in 18 ml of chloroform then 2.54 g of succinic anhydride, 7 ml of triethylamine and 0.95 g of 4-dimethylamino pyridine are added; the solution is taken to reflux and left at this temperature for 70 hours. After cooling down to ambient temperature, the reaction medium is poured into 2N hydrochloric acid, extracted with chloroform, the organic phase is washed with water, dried over sodium sulphate and evaporated to dryness under vacuum; the crude product thus obtained is chromatographed on a Kieselgel 60 © silica column, eluting firstly with ethyl ether then with ethyl ether with 3% acetic acid. 1.37 g of crude product is obtained which is purified by crystallization from a mixture of methylene chloride and ethyl ether then recrystallization from an identical mixture. 1.027 g of the desired product is then collected. M.p. = approx. 168°C.

Rf = 0.32 (thin layer chromatography; support: SiO2F254 Merck 60^ eluant: mixture of ethyl ether and ethyl acetate with 3% acetic acid (90-10)).

EXAMPLE 16: sodium and 11 beta— (4—acetyl phenyl) 3—oxo 17alpha— (1 —propynyl) estra—4,9-dien—17beta-y 1 succinate 0.874 g of the product prepared in Example 15 is dissolved in 30 ml of ethanol; this solution is added dropwise to a solution of 0.132 g of sodium bicarbonate in 30 ml of water; the ethanol is then driven off by azeotropic distillation, the aqueous solution obtained is filtered on a millipore ® membrane (0.45 microns) then lyophilized. In this way 0.908 g of the desired sodium salt is obtained, [alpha]}) = +67° + 1.5° (c = 1% in water).

Rf = 0.73 (thin layer chromatography; support: KCl8 Whatman®; eluant: mixture of methanol and a 0.05 molar aqueous solution of ammonium acetate (80-20)).

EXAMPLE 17: 11 beta—[4-( N—methyl isopropy lamino) phenyl] 3—oxo 17alpha—(1-propynyl) estra-4,9-dien— 17beta—yl acid succinate A solution containing 2.159 g of 11 beta-[4-(N-methyl isopropylamino) phenyl] 17beta-hydroxy 17alpha-(1-propynyl) estra-4,9-dien-3-one, 22 ml of triethylamine, 2,52 g of succinic anhydride, 8.1 ml of triethylamine and 1.07 g of 4dimethylamino pyridine is taken to reflux and left at this temperature for 24 hours. 0.339 g of succinic anhydride is added and heating under reflux is continued for 74 hours. After cooling down, the reaction medium is poured into 36 ml of 2N hydrochloric acid and the pH is adjusted to 6 by the addition of sodium acetate; after decantation of the organic phase, the aqueous phase is reextracted with chloroform. The united chloroform phases are washed with water, dried over sodium sulphate and evaporated to dryness under vacuum. The residue obtained is chromatographed on a 300 g Kieselgel 60 ® silica column eluting firstly with ethyl ether then with ethyl ether with 3% acetic acid. 1.493 g of crude product is obtained which is recrystallized from a methylene chloride — ethyl ether mixture. 1 .082 g of the desired acid succinate is thus obtained. M.p. = approx. 155°C.

Rf = 0.47 (thin layer chromatography; support: KC18 Whatman®; eluant: mixture of methanol and a 0.05 molar aqueous solution of ammonium acetate (80—20)).

EXAMPLE 18: sodium and 11beta—[4-( N—methyl isopropy lamino) phenyl] 3-oxo 17alpha-(1 -propynyl) estra—4,9-dien—17beta-yl succinate The operation is carried out in the same manner as in Example 16 with 0.128 g of sodium bicarbonate in 30 ml of water and 0.933 g of the product prepared in Example 17 in 30 ml of ethanol; 0.915 g of the desired sodium salt is thus obtained: [alpha]Q = +40.5° ± 1.5° (c = 1% in water).

Rf = 0.47 (thin layer chromatography, support KC18 Whatman ®; eluant: mixture of methanol and a 0.05 molar aqueous solution of ammonium acetate (80-20)).

EXAMPLE 19: Pharmaceutical compositions.

Tablets were prepared corresponding to the following formula: Product of Example 10 .............................. 50 mg Excipient (talc, starch, magnesium stearate) s.q. for a tablet made up to ........................120 mg EXAMPLE 20: An eye-wash was prepared corresponding to the following formula: Product of Example 10 .............................. 2 g Excipient (distilled water, sodium chloride, methyl cellulose, sodium borate) .......................... 100 ml PHARMACOLOGICAL STUDY ) Measurement of the relative bond affinity for the receptors of the steroid hormones: Glucocorticoid receptor of rat thymus: Male rats weighing 160 to 200 g are suprarenalectomized. to 8 days after this ablation, the animals are sacrificed, and the thymuses are removed and homogenized at 0°C using a Potter teflon-glass in a (TSD) buffer, 10 mM Tris, 0.25 M saccharose, 2 mM dithiothreitol, HCl pH 7.4 (1 g of tissue per 10 ml of TSD). The homogenate is then ultra-centrifuged (105,000 g x 90 min) at 0°C. Aliquots of the supernatant thus obtained, cytosol, are incubated at 0°C for 4 hours and 24 hours with a constant concentration (T = 2.5 nM) of tritiated dexamethasone in the presence of increasing concentrations (0 - 2,500 nM) of unlabelled dexamethasone or unlabelled product to be tested. The concentration of bound tritiated dexamethasone (B) is then measured in each incubate by the technique of adsorption with carbon dextran. Progesterone receptor of rabbit uterus: Impuberal rabbits weighing about 1 kg receive a cutaneous application of 25 jig of estradiol. Five days after this treatment, the animals are sacrificed, the uteruses are removed, weighed and homogenized at 0°C using a Potter teflon-glass in a (TS) buffer, 10 mM Tris, 0.25 M saccharose, HCl pH 7.4 (1 g of tissue per 50 ml of TS). The homogenate is then ultra-centrifuged (105,000 g x 90 min) at 0°C. The aliquots of the supernatant thus obtained, cytosol, are incubated at 0°C for 2 hours and 24 hours with a constant concentration (T = 5 nm) of tritiated R 5020 (17,21-dimethyl19-nor-4,9-pregnadien-3,20-dione), which is a powerful progestomimetic with a great affinity for the progesterone receptor, in the presence of increasing concentrations (0 - 2500 nM) of unlabelled progesterone, or the product to be tested.

The concentration of bound tritiated R 5020 (B) is then measured in each incubate by the technique of adsorption with carbon dextran.

Androgenic receptor of rat prostate Male rats weighing 160 to 200 g are castrated. 24 hours after the castration, the animals are sacrificed, the prostates are removed, weighed and homogenized at 0°C, using a Potter teflon-glass in a (TSDPM) buffer, 10 mM Tris, 0.25 M saccharose, 0.1 nM pheny lmethanesulphonylfluoride, 20 mM molybdate, 2 mM dithiothreitol, HCl pH 7.4 (1 g of tissue per 5 ml of TSDPM). The homogenate is then ultra—centrifuged (105,000 g x 60 min) at 0°C. Aliquots of the supernatant thus obtained, cytosol, are incubated at 0°C with a constant concentration (0 - 1000 nM) of unlabelled, testosterone or the product to be tested. After half an hour and 24 hours of incubation, the concentration of bound tritiated testosterone (B) is measured in each incubate by the technique of absorption with carbon dextran.

Calculation of the relative bond affinity: The calculation of the relative bond affinity (RBA) is identical for all the receptors.

The following 2 curves are drawn: the percentage of bound tritiated hormone B as a function of the logarithm of T the concentration of the unlabelled reference hormone and B as a function of the logarithm of the concentration of the T unlabelled tested product.

The straight line of the equation: I50 max + £ min)/2 is determined.

T T B max = Percentage of bound tritiated hormone for an T incubation of this tritiated hormone at the concentration (T).

B min = Percentage of bound tritiated hormone for an T incubation of this tritiated hormone at the concentration (T) in the presence of a large excess of unlabelled hormone (2500x10"9M).

The intersections of the straight line I50 and the curves allow the evaluation of the concentrations of unlabelled reference hormone (CH) and unlabelled tested product (CX) which inhibit by 50% the binding of the tritiated hormone on the receptor.

The relative bond affinity (RBA) of the tested product is determined by the equation RBA = 100 (CH) (CX) The following results were obtained: Ί ' Progesterone 1 1 1 Glucocorticoid I 1 | I I . Androgenic ι 1 1 | Examples 1 1 , 2 H j 24H 1 ' 1 4H 24H 11 i ! 1 1 1 | 0.5H 1 5H i 1 1 1 EX. 5 i 2 8 | 28 1 77 1 °·6 * 1 EX. 12 • 1.2 3.6 | 9.5 I 24 1 °-8 * * * * * 1 0.3 EX. 4 1 14 * * 26 1 31.5 J 27 ι 5.1 | 2.8 EX. 2 I 21 881 62 1 48 , 12 I 39 EX. 10 1 3 * * 1337 | 77 I 1.9 1 8.6 EX. 6 1 1 2 6 , 26 I 54 ι 2.2 4.1 The products of Examples 12 and 10 have a good antiprogesterone activity. 2) Anti—glucocorticoid activity vis—a—vis dexamethasone Study in vitro Incorporation of uridine in rat thymocytes The glucocorticoids cause an inhibition of the incorporation of the nucleosides at the level of the lymphoid tissue. Measurement of the incorporation of radioactive uridine in the thymocytes in the presence of a product to be tested allows the evaluation of its glucocorticoid activity.

Method It is inspired by the technique described by Dausse et al. (3). The thymus of a suprarenalectomized rat (160 to 180 g) is removed, shredded and homogenized slowly using a teflon-glass homogenizer in a Hanks solution. The cellular suspension obtained is filtered on gauze, then centrifuged at 800 g x 10 min. Another centrifugation is then carried out, 800 g χ 10 min. The pellet thus obtained is suspended in a nutritive medium (M.E.M. Gibco) and the cellular concentration is adjusted to approximately 20x10θ cells per ml. Aliquots of 250 μΐ are then incubated under carbogen for 3 hours at 37°C with 5x10"®M of dexamethasone in the presence or not of increasing concentrations of product (10-®M to 10"8M). 0.1 pCi of tritiated uridine is then added to each incubate and the incubation is continued for one hour. The incubates are then cooled down and 1 ml of an unlabelled solution of trichloracetic acid (TCA) at 5% weight/volume is added to them. The precipitates are collected on Whatman GF/C filters and are washed with 4 x 2 ml of 5% ice-cooled TCA. The radioactivity retained on the filters (representing the tritiated uridine incorporated in the thymocytes) is measured using a liquid scintillation spectrometer.

Thymocytes % of inhibition of the incorporation of uridine Molar concentration of the product to be tested Product of Example - p ! 10~6M I ι ι ' I I -r 10_7M ! I I 10_8M I I I 5 . 135 1 I I 100 1 28 1 8 1 8 1 ° 1 ° 1 12 104 |62 4 22 I 2.5 1 2 , ee . 1 1 * 1 10 ' 78 , 19 1 ° 1 0 1 6 ! 78 ι 27 1 1 1 ι 1 1 The products of Examples 5 and 12 have a good antiglucocorticoid activity.

Claims (14)

1. ) The products of general formula (I): Rl OX R 3 r 2 (I) in which R-| represents an aliphatic hydrocarbon radical containing 1 to 8 carbon atoms, R2 and R3, identical or different, represent a hydrogen atom or an alkyl radical 15 containing 1 to 4 carbon atoms, G represents a hydrocarbon group containing 1 to 18 carbon atoms and optionally one or more identical or different heteroatoms, linked to the steroid nucleus by a carbon atom and either X represents X&, Xa being a hydrogen atom, an alkyl 20 radical containing 1 to 8 carbon atoms, an arylalkyl radical containing 7 to 15 carbon atoms or an acyl radical containing 1 to 8 carbon atoms and in this case Y represents Ya, Ya being a 25 -B-O-CO-A-Z group in which B represents a saturated or unsaturated, linear or branched bivalent aliphatic radical, containing 1 to 8 carbon atoms, A represents either a saturated or 30 unsaturated, linear or branched bivalent aliphatic radical containing 1 to 6 carbon atoms and optionally interrupted or terminated by a bivalent aromatic radical, or A represents a bivalent aromatic radical, and Z represents one of the -COOH or — SO3H functions, these functions being able to be 35 optionally salified in the form of an alkali metal or alkaline-earth salt, an ammonium salt or an amine salt, or X represents Xg, Xq being a -CO-A-Z group in which A and Z are as defined previously and Y then represents Yg, Yg being one of the groups chosen from —C=C—R4, —CH=CH-R4 or -CH2-CH2—R4 in which R4 represents a hydrogen atom, a halogen atom, a trialkylsilyl radical containing 3 to 12 carbon atoms, a linear or branched alkyl radical containing 1 to 6 carbon atoms or a phenyl radical, the said alkyl and phenyl radicals being optionally substituted, the wavy line in position 13 means that the Rq radical can be found in alpha or beta position.

2. , 3 or 4-pyridyl radical. 2) The products of general formula (I) as defined in claim 1, corresponding to formula (I ·): Rl ox* (I*) in which either X' represents a hydrogen atom and in this case Y' represents Y'a, Y'a being a group: -B'-O-CO-A'-Z' in which B' represents one of the bivalent radicals -CH=CH-CH2- or CSC-CH2-, A' represents one of the bivalent radicals -(CH2) n - in which n can take one of the values 2 to 6 or an ortho-, meta- or para-phenylene radical and Z' represents the carboxy or sulpho functions or their sodium salt, or X' represents X'g, X'g being a group: -CO-(CH 2 ) n -Z' in which n and Z' are as defined previously and Y' then represents Y'g, Y'g being one of the -C=C-R'4 or -CH=CH-R'4 groups in which R'4 represents a hydrogen atom, a halogen atom, a trimethylsilyl radical, or a methyl radical optionally substituted by one or more halogen atoms, a hydroxy radical or by an alklyloxy, alkylthio or alkylamino group containing 1 to 4 carbon atoms, a dialkylamino group containing 2 to 8 carbon atoms or a trialkylsilyl group containing 3 to 12 carbon atoms.

3. , in which G represents a phenyl radical substituted in position 4 by an one of the following radicals: amino, (methylamino), (dimethylamino) or its N-oxide, (diethylamino), (dipropylamino), (N-methyl ethylamino), (N-methyl isopropylamino), (N-methyl isobutylamino), (N-methyl isopentylamino), 1-pyrrolidinyl, [2-(dimethylamino) N-methyl ethylamino], [N-methyl 2-(1-pyrrolidinyl) ethylamino], [N— methyl 2-(4-morpholinyl) ethylamino], (4-methyl 1piperazinyl), formyl, acetyl, methoxy, phenoxy, [2(dimethylamino) ethoxy], [2-(1-pyrrolidinyl) ethoxy], [2-(4morpholinyl) ethoxy], (methylthio), (ethylthio), (isopentylthio), [2-(dimethylamino) ethylthio], [2-(1pyrroMdinyl) ethylthio] [2-(4-morpholinyl) ethylthio], (trimethylsilyl), methyl, isopropyl, [(dimethylamino) methyl], or by one of the fluorine, chlorine or bromine S atoms. 3) The products of general formula (I) as defined in claims 1 and 2 in which G represents an aryl radical substituted by a halogen atom, an aryl radical, an acyl radical containing 1 to 8 carbon atoms or by one of the -NH2, —NHR* or -NR*R” functions, in which R' and R, identical or different, represent a phenyl radical, or a primary, secondary or tertiary alkyl radical, containing 1 to 8 carbon atoms, optionally containing one or more heteroatoms, chosen from oxygen, nitrogen and sulphur atoms, or optionally substituted by a heterocycle, or R* and R represent with the nitrogen atom to which they are linked, an optionally substituted heterocyclic radical optionally containing another heteroatom chosen from nitrogen, oxygen and sulphur atoms, or by one of the —OR”* or —SR”* functions in which R”* represents a phenyl radical or a primary, secondary or tertiary alkyl radical containing 1 to 8 carbon atoms, optionally containing one pr more heteroatoms, chosen from oxygen, nitrogen, sulphur atoms or optionally substituted by a heterocycle, or G represents a

4. ) The products of general formula (I) as defined in claim

5. ) The products of general formula (I) as defined in one of claims 1 to 4 In which R-) represents a methyl radical In position 13beta and R2 and R3 each represent a hydrogen atom.

6. ) The products of general formula (I) as defined in claim

7. ) Preparation process for products of general formula (I) as defined in claim 1 characterized in that A - the products of formula (!!&) or formula (Ila): (II B ) in which R), Rj, R3 and G have the meaning indicated in claim 1 and R4a has the values indicated in claim 1 for R4 as well 35 as those values in which the reactive functions are protected, are subjected, in a neutral solvent and in the presence of a base, a) to the action of a product of formula (111-)): - 39 z A \ (nil) in order to obtain after if necessary deprotecfcion of the protected reactive functions and if desired salification of the carboxy function, the products of general fonnula (I) corresponding to formulae (I at) and (Xri) respectively: (lAI) (lB1) in which Z} represents an optionally salified carboxy radical, b) to the action of a product of formula (III2): HOOC A-U (Hl2> . or also a functional derivative of this acid in which U represents one of the -COOH, -COOR5 groups in which R s represents an alkyl radical containing 1 to 6 carbon atoms or an arylalkyl radical containing 7 to 12 carbon atoms, or -SH, in order to obtain, after if necessary deprotection of the protected reactive functions, the products of formulae (IV^) and (IV B ) respectively: (IV B ) which products of formulae (IVa) and (IVb): - in the ca&e where U represents the free carboxy group, correspond, after optional salification, to the products of formulae (Iai) and (Ιβί), - in the case where U represents the -COOR5 group, correspond to the products of formulae (IVq) and (IVp): (IV C ) (IV D ) which products of formulae (IVc) an< 3 (IVd) are hydrolyzed or saponified, in order to obtain the products of formulae (Iai) and (Ιβΐ) respectively, - 41 — in the case where U represents the -SH group, correspond to the products of formulae (IV E ) and (IVp): (IV E ) (IVp) which products of formulae (IV E ) and (IVp) are oxidized and if desired salified in order to obtain the products of 20 general formula (I) corresponding to formulae (Ia2) and (Ib2) respectively: (IA2) (IB 2 ) in which Z 2 represents an optionally salified sulpho group, c) or to the action of a product of formula (III3): HOOC-A-SO2CI (IH3) or also a functional derivative of this acid, in order to obtain if necessary after deprotection of the reactive functions contained in R4 a and if desired salification, the products of formulae (Xa2) and (Ιβ2) respectively; in that: B - the products of formulae (Igq), (Ιβ2) and (IV'g) are subjected if desired: a) either to a hydrogenation agent of the triple bonds in order to obtain the products of formulae (133), (134) and (Vg) respectively: dB3) (Ib4> (V D ) hydrogenation the products of which products are if desired subjected to a agent of the double bonds in order to obtain formulae (I B 5), (I B 6) an ^ (VI D ) respectively: ( Σ Β5) ( ς Β6) (VI D ) or to a direct hydrogenation agent of the triple bonds into single bonds in order to obtain the products of formulae (I B 5b ( T B6) and (VI D ) respectively; b) the products of formulae (Vp) and (VIp) are either hydrolyzed, or saponified, in order to obtain the products of formulae (Ιββ) and (1 B 5) respectively.

8. ) Process according to claim 7 for the preparation of the products of formula (I*) as defined in claim 2 characterized in that: - a) either the product of formula (II'a) or *1 OH furt B'-OH *2 O in which Rq , R2, R3 and G have the values indicated in claim 2 and R'4 a has the values indicated in claim 2 for R'4 as

9. ) As medicaments, the products of general formula (I) as defined in claim 1.

10. ) As medicaments, the products of general formula (I) as defined in* any one of claims 2 to 6. 10 well as those values in which the hydroxylated functions are protected, in a neutral solvent and in the presence of a base, is subjected to the action of a product of formula <111*1): (IH'1 ) in which n takes one of the values from 2 to 6, in order to 20 obtain, after if necessary deprotection of the protected hydroxy function contained in R'4 and if desired, salification of the free carboxy function by the action of a sodium bicarbonate solution, the product of formula (I'ai) or (I'Bi) respectively: Rl O-CO-(CH2)n z *1 (I'Bl) in which Z'i represents a free carboxy group or its sodium salt; b) or the product of formula (II* A ) as defined above is subjected, in the presence of a nitrogenous base, to the action of a product of formula (III*3): HOOC^^ J”~ ®°2^· (Π1' 3 ) in order to obtain, if necessary and if desired, after salification by a sodium bicarbonate solution, a product of formula (I'A2) : \==Ζ^Ζ·2 (I'A2> in which Z*2 represents a sulpho group or its sodium salt; which product of formula (I'bi) is subjected, if desired, to the action of hydrogen in the presence of a catalyst in order to obtain the products of formula (I' B3) : (I'B3) 10 5 the names of which follow: - sodium and 21-chloro 11 beta-[4-(dimethylamino) phenyl] 3oxo 19-nor l7alpha-pregna-4,9-dien-20-yn-17beta-yl succinate, - sodium and 11 beta-[4-(methylthio) phenyl] 3-oxo 17alpha (1propynyl) estra-4,9-dien-i7beta-yl succinate. 15

11. ) Pharmaceutical compositions containing as active ingredient, at least one of the medicaments defined according • * W to claim 9 or 10.

12. ) As new industrial products, the products of formulae (IV C ), (IV D ), (IV E ), (IV F ), (V D ) and (VI D ).

13. ) A process according to any one of claims 7 or 8, substantially as hereinbefore described by way of Example.

14. ) The products according to any one of claims 1 to 6 whenever prepared by a process as claimed in any of claims 7, 8 or 13.