IL95272A

IL95272A - Esters of organic acids with alcohol derivatives of 19-nor steroids and their salts process of preparation and pharmaceutical compositions containing them

Info

Publication number: IL95272A
Application number: IL9527290A
Authority: IL
Original assignee: Roussel Uclaf
Priority date: 1989-08-08
Filing date: 1990-08-02
Publication date: 1996-01-31
Also published as: RU2056431C1; PT94935B; EP0412907A3; FR2650748B1; MA21925A1; AU6020890A; NZ234824A; IE65905B1; YU151390A; HU904921D0; DE69014012D1; HUT55031A; IE902839A1; FI903905A0; TW201313B; ZA905812B; DE69014012T2; MX21771A; ES2063940T3; KR910004648A

Abstract

Products of general formula (I): <IMAGE> 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

225VIL ESTERS -OF ORGANIC ACIDS WITH ALCOHOL DERIVATIVES OF 19-NOR STEROIDS AND THEIR SALTS, PROCESS O PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM ' Tjj-19 i?a ni»t>n-3 nn in ay nmvn imam ¾».Ό.ηι>β ninp »i>enrn οη: ηί> ηυ»ΰ ,αη>ηίηη o-nwiDO Esters of organic acids with alcohol derivatives of 19-noJ steroids and their salts, process of preparation and pharmaceutical compositions containing them.

The present invention relates to new esters of organic acids 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 compositions containing them.

A subject of the invention is the products of general formula ( I ) : in which Rl represents an aliphatic hydrocarbonated radical containing one to eight carbon atoms, R2 and R3, different or identical, represent a hydrogen atom or an alkyl radical containing one to four carbon atoms, G represents a hydrocarbonated group containing one to eighteen carbon atoms and optionally one or more different or identical heteroatoms , linked to the steroid nucleus by a carbon atom and either X represents X^, X^ being a hydrogen atom, an alkyl radical containing one to eight carbon atoms, an arylalkyl radical containing seven to fifteen carbon atoms or an acyl radical containing one to eight carbon atoms and in this case -Y represents Y¾, Y¾ being a group ,· -B-O-CO-A-Z in which B represents a saturated or unsaturated linear or branched bivalent aliphatic radical, containing one to eight carbon atoms, A represents either a saturated or unsaturated, linear or branched, bivalent aliphatic radical containing one to six carbon atoms and optionally interrupted or completed by a bivalent aromatic radical, or A represents a bivalent aromatic radical, and Z represents one of the -COOH or -S03H 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 group - CO-A-Z in which A and Z are as defined previously and Y then represents Yg, Yg being one of the groups chosen from -G=C-R , - CH=CH-R4 or -CH2-CH2- 4 in which R4 represents a hydrogen atom, a halogen atom, a trialkylsilyl radical containing three to twelve carbon atoms, a linear or branched alkyl radical containing one to six carbon atoms, or a phenyl radical, said alkyl and phenyl radicals being optionally substituted, the wavy line in position 13 signifies that the radical Ri can be found in alpha or beta position .

Rl preferably represents a linear or branched alkyl radical, containing one to four carbon atoms such as the methyl, ethyl, propyl, isopropyl or butyl radicals.

The products in which R^ is found in beta position are preferred.

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

G notably represents: either an aryl radical containing six to fourteen carbon atoms and optionally substituted by one or more radicals chosen from: - halogen atoms, - the carbamoyl radical, - saturated or unsaturated, branched or linear aliphatic radicals, containing one to six carbon atoms and optionally substituted by one or more halogen atoms or by one of the following groups, carbamoyl, amino, alkylamino containing one to four carbon atoms, dialkylamino containing two to eight carbon atoms or by a heterocyclic radical with three to eight links having at least one nitrogen atom and optionally one or two heteroatoms chosen from oxygen or sulphur atoms, - linear or branched acyl radicals containing one to six carbon atoms, - the phenoxy radical optionally substituted by an amino group, alkylamino group containing one to four carbon atoms, dialkylamino group containing two to eight carbon atoms or by a heterocyclic radical with three to eight links 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, alkylamino group containing one to four carbon atoms, dialkylamino group containing two to eight carbon atoms of by a heterocyclic radical with three to eight links having at least a nitrogen atom and optionally one or two heteroatoms chosen from oxygen or sulphur atoms, - heterocyclic radicals with three to eight links containing at least one nitrogen atom and optionally one or two heteroatoms chosen from sulphur or oxygen atoms and being able themselves to be substituted by one or more alkyl radicals containing one to four carbon atoms, - alk^alk^N (0)m alk3$ (0)p - or alk40 - in which alki, alk2, alk3 and alk4, identical or different, represent independently of each other a hydrogen atom, a linear or branched alkyl radical containing one to twelve carbon atoms optionally substituted by an amino group, alkylamino group containing one to eleven carbon atoms, dialkylamino group containing two to eleven carbon atoms, trialkylsilyl group containing three to eleven carbon atoms or by a heterocyclic radical with three to eight links containing at least a nitrogen atom and optionally one or two heteroatoms chosen from sulphur or oxygen atoms and being able itself to be substituted by one or more alkyl . radicals containing one to four carbon atoms, m is equal to zero or one, and p is equal to zero, one or two, - trialkylsilyl groups containing three to twelve carbon atoms ; or a saturated or unsaturated, branched or linear aliphatic radical containing one to eighteen carbon atoms and optionally substituted by one or more radicals chosen from: - halogen atoms, - the optionally substituted phenyl radical, - alkialk2 (0)m -, alk3S(0)p - or alk40 - radicals in which alki, alk2, alk3, alk_i, m and p are as defined previously - heterocyclic radicals with three to eight links containing at least one nitrogen atom and optionally one or two heteroatoms chosen from sulphur or oxygen atoms and being able itself to be substituted by one or more alkyl radicals containing one to four carbon atoms, - trialkylsilyl groups containing three to twelve carbon atoms, or a heterocyclic radical optionally substituted by one or more radicals chosen from: - halogen atoms, - linear or branched alkyl radicals containing one to six carbon atoms and optionally substituted by a carbamoyl group, amino group, alkylamino group containing one to four carbon atoms, dialkylamino group containing two to eight carbon atoms or by a heterocyclic radical with three to eight links having at least one nitrogen atom and optionally one or two heteroatoms chosen from oxygen or sulphur atoms, - alkialk2N(0)m -, alk3S(0)p - or alk^^O - radicals in which alki, alk2, alk3, alk_j, m and p are as defined previously, - trialkylsilyl groups containing three to twelve carbon atoms, or a condensed bicyclic system containing one to three nitrogen atoms and of which one is optionally oxidized, optionally substituted by one or more radicals chosen from halogen atoms or alkyl radicals containing one to four carbon atoms, or a cycloalkyl radical with three to eight links and optionally substituted by one or more radicals chosen from: - halogen atoms, - the phenyl radical, - linear or branched alkyl radicals containing one to six carbon atoms and optionally substituted by a carbamoyl group, amino group, alkylamino group containing one to four carbon atoms, dialkylamino group containing two to eight carbon atoms or by a heterocyclic radical with three to eight links having at least one nitrogen atom and optionally one or two heteroatoms chosen from oxygen or sulphur atoms , - the alkialk2 (0)m -, alk3S(0)p - or alk40 - radicals in which alk^, alk2, alk3, alk4, m and p are as defined previously, - trialkylsilyl groups containing three to twelve carbon atoms .

Preferably G can represent an aryl radical. This aromatic radical can be substituted in ortho, meta or para position by one or more alkyl radicals containing preferably 1 to 4 carbon atoms; by one or more alkyloxy 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 sulphoxide or sulphone such as methylthio, ethylthio; amino radicals, alkylamino radicals having one to four carbon atoms such as methylamino, ethylamino, dialkylamino radicals having two to eight carbon atoms optionally oxidized in the form of N-oxide such as the dimethylamino radical, diethylamino radical or (N-methylethylamino) radical, by an acyl radical such as formyl, acetyl, propionyl, butyryl or benzoyl, preferably acetyl; it being understood that the radicals susbstituting 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-4-dimethyLaminophenyl); G can also represent a heterocyclic radical optionally substituted by the different radicals envisaged above.

The following radicals can be cited: thienyl, furyl, isothienyl, isofuryl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridyl, piperidinyl or pyrrolidinyl or piperazinyl and heterocycles known to a man of the art; G can also represent a condensed bicyclic radical comprising a phenyl nucleus and a heterocyclic nucleus containing at least one nitrogen atom optionally substituted by the radicals envisaged previously; there can be cited the N-methyl-2-3-dihydro-indol-5-yl radical; G can also represent a cycloalkyl radical such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, cycloalkenyl such as cyclobutenyl or cyclopropenyl; G can also represent a radical comprising 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 morpholino, piperidinyl, pyrrolidinyl or 4-methyl piperazinyl radicals.

The aryl nucleus is then preferably the phenyl nucleus. As substituent on the aryl nucleus, an amino (substituted) alkyl radical can also be envisaged, such as the dimethylamino methyl radical, dimethylamino ethyl radical; an amino (substituted.) alkyloxy radical such as the dimetfhylamino ethyloxy radical-.

Radicals comprising a silicon atom can also be cited such as the trimethylsilyl phenyl radical or the [N-methyl-( 1-trimethylsilyl ) -methylamino ] -phenyl radical .

The radicals quoted previously comprising 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 .

: Therefore the following radicals may be cited: methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl , 2,2-dimethylpentyl, 3,3- dimethyl pentyl, 3-ethylpentyl, n-octyl, 2,2-dimethyl-hexyl, 3, 3-dimethylhexyl, 3-methyl-3-ethylpentyl, nonyl, 2,4-dimethyl heptyl, or n-decyl. There can also be cited the vinyl, isopropenyl, allyl, 2-methylallyl or isobutenyl radicals.

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

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

When X represents X¾, being an alkyl radical, it is preferably the methyl, ethyl or propyl radical.

When X represents X¾, X^ being an arylalkyl radical, it is preferably the benzyl or phenethyl radical.

When X represents X¾, ^ 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, butenylene, ethynylene, propynylene or butynylene radical .

A preferably represents the methylene, ethylene, trimethylene or tetramethylene radical; when it is interrupted by an aromatic ring, A therefore preferably represents the radical: when it is completed by an aromatic ring, it is preferably the radical: When A represents a bivalent aromatic radical, it is preferabl the ortho-phenylene, metaphenylene or para-phenylene or also the radical When Z represents a salified carboxy or sulpho group, it is preferably the salt of sodium, potassium, calcium, magnesium, ammonium, or an amine salt used in the manufacture 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 .

Notably a subject of the invention is the products of general formula (I) as defined previously and corresponding to the formula ( 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 C≡C-CH2", A' represents one of the bivalent -(CH2)n- radicals in which n can take one of the values from 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'Q, X'B being a group: -C0-(CH2)n-Z' in which n and Z' are as defined previously and Y' then represents Y'B being one of the groups -C≡C-R'4 or - CH=CH-R'4 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 one to four carbon atoms, dialkylamino group containing two to eight carbon atoms or trialkylsilyl group* containing three to twelve carbon atoms . n preferably takes one of the values from two to four; when R' 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 , dimethylaminomethyl , hydroxymethyl , methoxymethyl , or methylthio ethyl .

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

More precisely G represents an aryl radical substituted by a halogen atom, an aryl radical, an acyl radical containing one to eight 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 one 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 to which they are linked, a heterocyclic radical optionally substituted 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 one 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.

Particularly a subject of the invention is the products of formula (I) and (Ι') 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 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-l-piperazinyl ) ; formyl, acetyl, methoxy, phenoxy, [2-( dimethylamino) ethoxy], [ 2- ( 1-pyrrolidinyl ) -ethoxy ] , [2-(4-morpholinyl ) -ethoxy] , methylthio, ethylthio, isopentylthio, [ 2- (dimethylamino) ethylthio], [2-(l-pyrrolidinyl) ethylthio], [2-(4-morpholinyl) ethylthio], trimethylsilyl, methyl, isopropyl, [(dimethylamino) methyl], or by one of the fluorine, chlorine or bromine atoms .

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

Also a subject of the invention is a preparation process for the products of formula (I) as defined previously and characterized in that: A - the products of formula (H ) or formula (ΙΙβ) in which X^, R , R2, R3 and G have the meanings indicated above and RA3 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 (ΙΙΙχ): to obtain after, if necessary, deprotection of the protected reactive functions and, if desired, salification of the carboxy function, the products of general formulae (I) corresponding respectively to formula (IAI) and (Ιβΐ): in which Z\ represents an optionally salified carboxy radical , b) to the action of a product of formula (III2): HOOC-A-U (IH2) or also a functional derivative of this acid in which U represents one of the groups - COOH, - COOR5 in which R5 represents an alkyl radical containing one to six carbon atoms or an arylalkyl radical containing seven to twelve carbon atoms, or -SH, so as to obtain after, if necessary deprotection of the protected reactive functions, products of formulae (IVA) and (IVB) respectively: which products of formulae (IVA) and (IVB): - when U represents the free carboxy group, correspond, after optional salification, to products of formulae ( IAI ) and (IBI), - when U represents the -COOR5 group, correspond to the products of formulae (IVQ) and (IVD): 1 O-CO-A-COOR5 which presets of formulae (IVQ) and (IVp) are hydrolyzed or saponified to obtain the products of formulae (I¾i) and (IBI) respectively, - when U represents the -SH group, correspond to products of formulae (IVg) and (IVp): which products of formulae (IVg) and (IVp) are oxidized and if desired salified to obtain the products of general formula ( I ) corresponding to formulae ( 1^2 ) an<^ (Ig2) respectively: dA2) in which Z2 represents an optionally salified sulpho group, c) or to the action of a product of formula (III3): H00C-A-S02C1 (IH3) or also a functional derivative of this acid, so as to obtain if necessary after deprotection of reactive functions contained in R^a and if desired after salification, products of formula (I 2) anc* (Ιβ2) respectively; and in that: B - the products of formula (Ιβΐ)/ (1β2) and (ivD) ARE subjected if desired: a) either to a hydrogenation agent of the triple bonds so as to obtain the products of formulae (Ιβ3)/ (!β4) and (VQ) respectively: products which are, if desired, subjected to a hydrogenati agent of the double bonds so as to obtain products of formulae (Ιβ5)/ (Ιββ) and (VID) respectively: or toi an agent for direct hydrogenation of the triple bonds into single bonds so as to obtain the products of formulae (IB5), (IB6) AND (VID) respectively. b) the products of formulae (Vp) and (VIp) are either hydrolyzed, or saponified to obtain the products of formulae (Ig3) and (Ifi5) respectively.

In a preferred embodiment of the above-described process the action of (III^) on (11^) and (ΙΙβ) is effected 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-tetrahydropyrannyloxy) group by the action of 2,3-dihydropyran .

The subsequent deprotection of this function takes place by passage over commercial sulphonic resin (acid form) or by acidic treatment. The neutral solvent serving as reaction medium can be the 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 effected with nitric acid, barium nitrate or by auto-oxidation in a basic medium.

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

By functional derivatives of acids of formula (III2) or (III3), is meant the anhydrides obtained "in situ" by action of an alkyl chloroformate such as isobutyl chloroformate, or a dicycloalkylcarbodiimide such as dicyclohexylcarbodiimide . The hydrolysis and saponification of the -COOR5 function, as well as the salification of the carboxy or sulpho functions, is carried out in the usual way.

In a preferred embodiment of the process described previously for the preparation of products of formula (Ι'), - a) /either the product of formula (II Ά) or (Il'g): in which R]_, R2, R3 and G have the values indicated above and R'4a has 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 on a base, is subjected to the action of a product of formula (ΙΙΙ'χ): in which n takes one of the values from two to six so as obtain, if necessary after deprotection of the protected hydroxy function contained in R'4 and if desired, after salification of the free carboxy function by the action solution of sodium bicarbonate, the product of formula (!'Al) or (i'Bl) respectively: in which Z ' i represents a free carboxy group or its sodium salt, b) or the product of formula (II 'Α) as defined above is subjected, in the presence of a nitrogenous base, to the action of a product of formula (III13): so as to obtain, if necessary and if desired, after salification by a solution of sodium bicarbonate, a product of formula (I'A2): in which Z ' 2 represents a sulpho group or its sodium salt which products of formula (I'ui)/ if desired, are subjected to the action of hydrogen in the presence of a catalyst so as to obtain the products of formula (1*53): The products of formulae (IIA) anc* (ϋβ) used for the implementation of the preparation process for products of formula (I) are generally known 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 (ΙΙΙ^), (III2) and (III3) are commercially available products; the others can be prepared by methods known to a man of the art: - ETAIX, annales de Chemie (7) 9 p. 371 - LOVEN, J. Prakt. Chemie (2) 29 p. 376 - UHLENBROEK, Recueil des Travau Chimiques des Pays-Bas (1957) 76 p. 129, 142.

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

The study of the products on hormonal receptors has allowed the highlighting of progestomimetic or anti- progestomimetic, androgen or anti-androgen activities.

The products of the present Patent Application can also show antiglucocorticoid and/or glucocorticoid, antiproliferative, anti-estrogen and/or estrogen properties .

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

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

The products which are subjects of the present Patent Application can also be used as inducers of womens ' periods and more generally for warm-blooded female animals.

These products are, then, administered during periods where 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 method of contraception according to the invention consists of administering to the woman at least one of products of formula (I) during 1 to 5 days preferably situated at the end of the cycle. These products are then preferably administered by oral route or in vagino but they can also be used by parenteral route.

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

Those products possessing antiprogestomimetic properties can also be used against hormonal disturbances and, furthermore, they can be useful in the treatment of hormono-dependent tumours .

Their action on hypophysial secretions render the products usable for the menopause.

These products can egually be used in the synchronization of estrus in farm animals, especially cattle and sheep.

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

The product which are subjects of the present Patent Application can also present progestomimetic properties and can' thus be used in the treatment of amenorrheas, dysmenorrheas and luteal insufficiencies .

Those products that present anti-androgen properties can be used in the treatment of hypertrophia and cancer of the prostate, virilism, anaemia, hirsutism and acne.

They can also be used for male contraception.

Finally the products which are subjects of the present Patent Application that present anti-proliferative, anti-estrogen and/or estrogen properties can be used in the treatment of hormono-dependent carcinomas, such as for example mammary carcinomas and their metastases. These properties also render the products usable in the treatment of benign breast tumours .

The estrogen properties which can also be presented by the said products make them usable in the treatment of disorders linked to a hypofolliculinemia, for example amenorrheas, dysmenorrheas, repeated abortions, premenstrual disorders as well as treatment for the menopause.

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

More particularly a subject of the invention is, as medicaments : - Sodium and 21-chloro-llbeta-[4-(dimethyl-amino)-phenyl]-3-oxo-19-nor-17alpha-pregna-4, 9-dien-20-yn-17beta-yl succinate .

- Sodium and llbeta- [ 4- (methylthio ) -phenyl ] -3-oxo-17alpha-( 1-propynyl ) -estra-4 , 9-dien-17beta-yl succinate .

The useful dosage varies according to the affection to be treated and the administration route; it can vary for example from 10 mg to 1 g per day for an adult by oral route .

The new products which are subjects 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 simple or sugar-coated tablets, capsules, granules, suppositories, vaginal suppositories, 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 group or salified sulpho group and quite particularly the products of formula ( I ' ) in which Z' represents -COONa or -SC>3Na, are very soluble in water; among the latter there can be cited in a non-limiting manner the solubility of the product of Example 18 which is greater than 25g for 100 ml of water; this allows" their use in the form of drinkable, nasal or auricular solutes, collyria, aerosols, IM or IV injectable solutions or capsules.

Also 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 .

Therefore a subject of the invention is, as new industrial products, the products of formulae (IV ), (IVQ), (IVE), (IVp), (Vp) and (VIp) as defined previously.

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

EXAMPLE 1: ( Z ) -3- Γ 1lbeta-Γ 4- (dimethylamino ) -phenyl T-17beta-hydroxy-3-oxo-estra-4 , 9-dien-17alpha-yl 1 -2-propenyl acid succinate . 900 mg of 1 lbeta- [4- (dimethylamino) -phenyl ]-17beta-hydroxy- 17alpha- [ ( Z ) -3-hydroxy-1-propenyl ] -estra-4 , 9-dien-3-one is dissolved in 9 ml of chloroform in a flask provided with magnetic agitation, 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, 1.443 g of residue obtained is purified by chromatographed on a column of silica (eluant: (ethyl acetate 90-cyclohexane 10) -acetic acid 3%). After recristallization 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 R; eluant: methanol-aqueous 0.05 molar ammonium acetate solution (80 - 20)).

EXAMPLE 2 :Sodium and (Z)-3-rilbeta-r4-(dimethylamino)-phenyl Ί -17beta-hydroxy-3-oxo-estra-4 , 9-dien-17alpha-yl ~ -2-propenyl succinate . 93 mg of sodium bicarbonate is dissolved in 20 ml of water, in a flask provided with magnetic agitation, a solution of 639 mg of product obtained in Example 1 in 20 ml of ethanol is then added drop by drop. The ethanol is eliminated by azeotropy and the aqueous solution thus obtained is filtered on Millipore ©membrane (0.45 micron) 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 ^ eluant: methanol - aqueous 0.05 jnolar solution of ammonium acetate (80 -20)).

EXAMPLE 3: 3- f 1lbeta- Γ 4- (dimethylamino ) -phenyl 1 - 17beta-hydroxy-3-oxo-estra-4 , 9-dien-17alpha-yl 1 -2-propynyl acid succinate 900 mg of llbeta-[4-(dimethylamino)-phenyl]-17beta- hydroxy-17alpha- ( 3-hydroxy-1-propyny1 ) -estra-4 , 9-dien-3-one is dissolved in 9 ml of chloroform in a flask provided with magnetic agitation, 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 C18 ©column (eluting with a mixture of methanol and aqueous 0.05 molar solution of ammonium acetate (60-40)). 1.104 g of sought product is obtained.

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

EXAMPLE 4: sodium and 3-Γ llbeta- Γ 4- (dimethyl-amino)-phenyn-17beta-hydroxy-3-oxo-estra-4/ 9-dien-17alpha-y1 ] -2-propyny1 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, 935 mg of the sought product is then obtained. [alphaJo = +55° + 1.5° (c = 1% in water).

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

EXAMPLE 5: 1lbeta- Γ 4- (dimethylamino ) -phenyl 1 -3-oxo 17alpha-( 1-propynyl ) -estra- , 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- ( l-propynyl) -estra-4, 9-dien-3-one, in 22 ml of chloroform, then heated under reflux for 42 hours and 430 mg of 4-( dimethylamino) -pyridine and 4.4 ml of triethylamine are added* Reflux is continued for 26 hours and the solution is then poured into a water - ice mixture. After decantation of the organic phase, it is washed in water then dried and the chloroform is distilled off to give a dry brown-coloured extract. The aqueous phase is acidified with 0.5N hydrochloric acid then neutralised 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 a residue results that 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% acetic acid and is recrystallized twice from an ether - methylene chloride mixture. 1.435 g of the sought product is obtained. M.p. = approx. 165°. [alpha]D = +97° (c = 0.8% in CHCI3 ) .

Rf = approx. 0.40 (thin layer chromatography, support: SiC>2, eluant: ether - ethyl acetate (9- 1) - 3% acetic acid ). EXAMPLE 6; Sodium and llbeta-r4-(dimethyl-amino)-phenyl1-3-oxo-17alpha- ( 1-propynyl ) -estra-4 , 9-dien-17beta-yl succinate 3 g of the product prepared in Example 5 and 94 ml of ethanol are introduced into a flask provided with magnetic agitation and a solution of 433 mg of sodium bicarbonate in 94 ml of water is then poured in. After 30 minutes of agitation at ambient temperature, the ethanol is eliminated by azeptropy and the remaining solution is filtered on MilliporeJL mbrane (0.45 microns) and lyophilized 2.88 g of sought product is obtained. [alpha]o = +48.5o + 1.5o (c = 1% in water).

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

EXAMPLE 7: llbeta- Γ 4- (dimethylamino ) -phenyl 1 -3-oxo-17alpha-Γ ( Z ) -1-propenyl Ί -estra-4 , 9-dien-17beta-yl acid succinate 2.462 g of the product prepared in Example 5 is put into a flask provided with magnetic agitation and 150 ml of ethyl acetate with 2% pyridine, 15 ml of water and 50 mg of 10% palladium hydroxide on barium sulphate are added. After hydroigenation with agitation for five and a half hours, the reaction medium is filtered, the pyridine is eliminated and the remaining solution is evaporated to dryness. The residue thus obtained is purified twice in succession by chromatography on a Bondapack C 18 column eluting with a mixture of methanol - aqueous 0.05 molar solution of ammomium acetate (65-35), 576 mg of the sought product is layer chromatography; support: KC methanol - aqueous 0.05 molar solution of ammonium acetate (80 - 20)).

EXAMPLE 8: Sodium and 1lbeta-Γ -(dimethyl-amino) -phenyl 1-3-oxo-17alpha- Γ ( Z ) -1-propenyl 1 -estra-4 , 9-dien-17beta-yl succinate The operation is carried out 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 sought product is obtained. [alpha]D = +56.5° + 1.5° (c = 1% in water).

Rf = 0, (thin layer chromatography, support KC 18 Whatman eluant: methanol - aqueous 0.05 molar solution of ammonium acetate (80 -20)).

EXAMPLE 9: 21-chloro-llbeta- f 4- (dimethylamino ) -phenyl 1-3-oxo-19-nor-17alpha-preqna-4 , 9-dien-20-yn-17beta-yl acid succinate 1.854 g of 21-chloro-llbeta-[4-(dimethylamino)-phenyl]- 17beta-hydroxy-17alpha-pregna-4 , 9-dien-20-yn-3-one is dissolved in 18.5 ml of chloroform in a flask provided with magnetic agitation, 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. The reaction medium is then 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, then extracted twice with chloroform. The collected extracts are united, washed with water, dried on sodium sulphate then concentrated under reduced pressure, 3.85 g of a brown residue is obtained which is purified by chromatography on a column of Kieselgel eluting first with ethyl/ether then with an ethyl ether and 3% acetic acid mixture. 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. [alpha]D = +63° + 1.5° (c = 0.90 in CHC13).

Thin layer chromatography: Rf = 0.53. (support: KC18 Whatman ©; eluant: methanol - aqueous 0.05 molar solution of ammonium acetate (80-20)).

EXAMPLE 10: Sodium and 21-chloro-llbeta-r4-(dimethylamino)-pheny11 -3-oxo-19-nor-17alpha-preqna- , 9-dien-20-yn-17beta-y1 succinate 817 mg of the product prepared in Example 9 and 25 ml of ethanol are mixed together in a flask provided with magnetic agitation, a solution of 113 mg of sodium bicarbonate in 25 ml of water is then poured in drop by drop and the reaction medium is agitated for 30 minutes at ambient temperature. The ethanol is then eliminated by azeotropy, the remaining solution is filtered on Millipore(* membrane (0.45 microns) then lyophilized. 813 mg of lyophilizate is obtained, which corresponds to the sought product. [alpha]D = +16.5° + 1° (c = 1% in H2O).

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

EXAMPLE 11: llbeta- Γ 4-(methylthio)-phenyl T-3-oxo-17alpha-( 1-propynyl )-estra-4 , 9-dien-17beta-yl acid succinate 1.5 g of 17beta-hydroxy-llbeta-[4-(methylthio)-phenyl]- 17alpha-(l-propynyl)-estra-4,9-dien-3-one, 15.3 ml of chloroform are mixed together in a flask provided with magnetic agitation and a cooling agent, and 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 with water, dried on 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 60H Kieselqel ®silica column (eluant: (methylene chloride 97.5-methanol 2.5 - acetic acid 1%). After recristallization from a methylene chloride - isopropyl ether mixture, 826 mg of crystals of the sought product are formed. M.p. = 158°C. Rf = 0.61 (thin layer chromatography, support KC 18 Whatman() eluant: mixture of ethanol and aqueous 0.05 molar solution of ammonium acetate (70 - 30)).

EXAMPLE 12: Sodium and 1lbeta-Γ 4- (methylthio) -phenyl 1-3-oxo-17alpha-(l-propynyl ) -estra-4 , 9-dien-17beta-yl succinate By operating in the same way 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 sought product. [ alpha ]D = +74.5° + 1.5° (c = 1% in water).

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

EXAMPLE 13: 3- Γ 3- Γ 1lbeta- Γ 4- (dimethylamino) -phenyl Ί -17beta-hydroxy-3-oxo-estra-4 , 9-dien-17alpha-yl 1 -2-propynyloxy-carbonyl 1 -benzenesulphonic acid 1 g of llbeta-[4-(dimethylamino)-phenyl]-17beta-hydroxy- 17alpha- ( 3-hydroxy-1-propyny1 )-estra-4,9-dien-3-one is dissolved in 10 ml of chloroform, 1.5 g of the pyridine-3- (chlorosulphonyl) -benzoic acid complex then 1.25 ml of triethylamine are added, the whole is taken to reflux for 45 minutes, another 0.5 g of the previous complex is added and heating is continued under reflux for 30 minutes. After cooling, the solvent is evaporated off, the residue is dissolved in water, and then the solution is distilled in the presence of toluene. The dry extract obtained is dissolved in chloroform and filtered on a column of silica, eluting with chloroform with 5% ethanol, then with chloroform with 10% ethanol. An acid fraction is collected, from which 1.7 g of sought product is isolated in the form of a pale yellow resin.

EXAMPLE 14:Sodium 3- Γ 3- Γ 1lbeta- Γ 4- (dimethylamino) -phenyl 1 -17beta-hydroxy-3-oxo-estra-4 , 9-dien-17alpha-yl } -2-propyny1-oxycarbonyl 1 -benzenesulphonate 25 ml of an ethanol solution of sodium acetate (0.24 mmole/ml ) is added to the acid fraction obtained in the previous 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 eluants are regrouped, refiltered, evaporated to dryness and the powder obtained is dried to give 1.35 g of sought product. [alpha]D = +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 15:1lbeta- (4-acetyl-phenyl ) -3-oxo-17alpha-( 1-propynyl)-estra-4#9-dien-17beta-yl acid succinate 1.8 g of llbeta- ( 4-acetyl-phenyl ) -17beta-hydroxy-17alpha-( 1-propynyl ) -estra- , 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 to ambient temperature, the reaction medium is poured into 2N hydrochloric acid, extracted with chloroform, the organic phase is washed with water, dried on sodium sulphate and evaporated to dryness under vacuum; the crude product thus obtained is chromatographed on a Kieselgel 60 ica column, eluting first 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 recristal-lization from an identical mixture. 1.027 g of sought product is then collected.

M.p. approx. 168°C.

Rf = 0.32 (thin layer chromatography; support: S1O2F25 Merck 60 eluant: mixture of ethyl ether -ethyL acetate with 3% acetic acid (90-10)).

EXAMPLE 16; Sodium and llbeta- ( -acetyl-phenyl )-3-oxo-17alpha- ( 1-propynyl ) -estra-4 , 9-dien-17beta-yl succinate 0.874 g of the product prepared in Example 15 is dissolved in 30 ml of ethanol; this solution is added drop by drop to a solution of 0.132 g of sodium bicarbonate in 30 ml of water; the ethanol is then eliminated by azeotropy, 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]D = +67° + 1.5° (c = 1% in water).

Rf = 0.73 (thin layer chromatography; support: KC18 Whatman eluant: mixture of methanol and aqueous 0.05 molar solution of ammonium acetate (80 - 20)).

EXAMPLE 17 : llbeta-Γ 4-(N-methyl-isopropylamino)-phenyl 1 -3-oxo-17alpha-( 1-propynyl ) -estra-4, 9-dien-17beta-yl acid succinate A solution containing 2.159 g of llbeta- [ 4- (N-methyl-isopropylamino ) -phenyl ] -17beta-hydroxy-17alpha- ( 1-propyny1 ) -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 4-dimethylamino pyridine is taken to reflux and left at this, temperature for 24 hours. Another 0.339 g of succinic anhydride is added and reflux is continued for 74 hours.

After cooling, the reaction medium is poured into 36 ml of 2N hydrochloric acid and the pH is adjusted to 6 by addition of sodium acetate; after decantation of the organic phase, the aqueous phase is reextracted with chloroform. The reunited chloroform phases are washed with water, dried on sodium sulphate and evaporated to dryness under vacuum. The residue obtained is chromatographed on a column of 300 g of Kieselgel 60()silica, eluting first with ethyl ether and 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 sought acid succinate is thus obtained. M.p. approx. 155°C. Rf = 0.47 (thin layer chromatography; support: KC18 Whatman(E) eluant: mixture of methanol and aqueous 0.05 molarj solution of ammonium acetate (80 - 20)).

EXAMPLE 18; Sodium and llbeta-Γ - (N-methyl-isopropylamino)-phenyl 1-3-oxo-17alpha-( 1-propynyl ) -estra-4 , 9-dien-17beta-yl succinate The operation is carried out in the same way 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 sought sodium salt are thus obtained: [alpha]D = +40.5° + 1.5° (c = 1% in water).

Rf = 0.47 (thin layer chromatography, support KC18 Whatman s); eluant: mixture of methanol and aqueous 0.05 molar 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) q.s. for a tablet completed at 120 mg EXAMPLE 20: The collyrium 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 1) Measurement of the relative bond affinity for the receptors of steroid hormones: Glucocorticoid receptor of rat's thymus: Male rats weighing 160 to 200 g are supra-renalectomized. 4 to 8 days after this removal, the animals are killed, and the thymuses are removed and homogenized at 0°C using a a Potter teflon-flask in a (TSD) 10 mM Tris, 0.25 M saccharose, 2 mM dithiothreitol, HC1 pH 7.4 buffer (1 g of tissue per 10 ml of TSD). The homogenate is then ultracentrifuged (105,000 g x 90 mn) at 0°C. Aliquots of thje 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 cold dexamethasone or of the cold product under test. The concentration of the bonded tritiated dexamethasone (B) is then measured in each incubate by the technique of adsorption with carbon-dextran .

Progesterone receptor of rabbit's uterus; : Impuberal female rabbits weighing about 1 kg receive a cutaneous application of 25 ug of estradiol. Five days after this treatment, the animals are killed, the uteruses are removed, weighed and homogenized at 0°C using a Potter teflon-flask in a (TS) 10 m Tris, 0.25 M saccharose, HCl pH 7.4 buffer ( 1 g of tissue per 50 ml of TS). The homogenate is then ultra-centrifuged (105,000 g x 90 inn) at 0°C. 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-dimethyl-19-nor-4, 9-pregnadien-3 , 20-dione) , strongly progestomimetic having a great affinity for the progesterone receptor, in the presence of increasing concentrations (0 -2500 nM) of cold progesterone, or of the product under test. The concentration of bonded tritiated R 5020 (B) is then measured in each incubate by the technique of adsorption with carbon-dextran.

Androgen receptor of rat ' s prostate Male rats weighing 160 to 200 g are castrated. 24 hours after the castration, the animals are killed, the prostates are removed, weighed and homogenized at 0°C, using a Potter teflon-flask in a (TSDPM) 10 mM Tris, 0.25 M saccharose, 0.1 nM phenylmethanesulphonylfluoride, 20 mM molybdate, 2 mM dithiothreitol, HCl pH 7.4 buffer ( 1 g of tissue per 5 ml of TSDPM) . The homogenate is then ultracentrifuged (105,000 g x 60 mn) at 0°C. Aliquots of the supernatant thus obtained," cytosol", are incubated at 0°C with a constant concentration (0 - 1000 nM) of cold testosterone or of the product under test. After half an hour and 24 hours of incubation, the concentration of bonded tritiated testosterone (B) is measured in each incubate by the technique of adsorption with carbon-dextran.

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

The following two curves are drawn: the percentage of bonded tritiated hormone B as a function of the logarithm of T the concentration of the cold reference hormone and B as a function of the logarithm of the concentration of the T cold product under test.

The straight line of the equation: I50 = (1 max + min)/2 T T is determined.

B max = Percentage of bonded tritiated hormone for an T incubation of this tritiated hormone at the concentration (T) . B min = Percentage of bonded tritiated hormone for an T incubation of this tritiated hormone at the concentration (T) in the presence of a great excess of cold hormone (2500 x 10~9M) .

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

The relative bond affinity (RBA) of the product under test is determined by the equation RBA = 100 (CH) (CX) The results obtained are the following: Progesterone Glucocorticoid Androgen.

The products of Examples 12 and 10 show a good anti-progesterone activity. 2) Anti-glucocorticdid activity vis-a-vis dexamethasone Study in vitro Incorporation of uridin in rat thymocytes Glucocorticoids cause an inhibition of the incorporation of nucleosides in lymphoid tissue. The measurement of the incorporation of radio-active uridin in the thymocytes in the presence of a product under test allows its glucocorticoid activity to be evaluated.

Method It is in accordance with the technique described by Dausse and Coll (3). The thymus of a suprarenalectomized rat (160 to 180 g) is removed, shredded and homogenized slowly using a teflon-flask homogenizer in Hanks solution. The cellular suspension obtained is filtered on gauze, then centrifuged at 800 g x 10 mn. A new centrifugation is then carried out at 800 g x 10 mn. The deposit thus obtained is put in suspension in a nutritive medium (M.E.M. Gibco) and the cellular concentration is adjusted to approximately 20 x 106 cells per ml. Aliquots of 250 ul are then incubated under carbogen for 3 hours at 37°C with 5 x 10~8M of dexamethasone in the presence or not of increasing concentrations of product (10~½ to 10~6M) . 0.1 jiCi of tritiated uridin is then added to each incubate and the incubation is continued for one hour. The incubates are then cooled and 1 ml of a cold solution of trichloracetic acid (TCA) at 5% weight/volume is added. The precipitates are collected on Whatman GF/C filters and are washed with 4 x 2 ml of 5% iced TCA. The radioactivity retained on the filters (representing the tritiated uridin incorporated in the thymocytes) is measured using a liquid scintillation spectrometer.

Thymocytes % of inhibition of the incorporation of uridine Molar concentration of the product under test The products of Examples 5 and 12 show a good anti-glucocorticoid activity.

Claims

95272/3 CLAIMS:

1. A compound of the general formula wherein Q designates one of the following: PX OXA mi v ml B-O-CO-A-COOR O-CO-A-COOR5 Ϊ C=C-R4 0% £,,11 B-O-CO-A-SH in which Rj. represents an aliphatic hydrocarbon radical containing one to eight carbon atoms, R2 and R3/ identical or different, represent a hydrogen atom or an alkyl radical containing one to four carbon atoms, G represents a hydrocarbon group containing one to eighteen carbon atoms and optionally one or more identical or different heteroatoms selected from nitrogen, oxygen, sulfur and silicon linked to the steroid nucleus by a carbon atom and either X represents XA, XA being a hydrogen atom, an alkyl radical containing one to eight carbon atoms, a arylalkyl radical containing seven to fifteen carbon atoms -37a- 95272'2 or an acyl radical containing one to eight carbon atoms and in this case Y represents ΥΛ, YA being a group -B-0-CO-A-Z in which B represents a saturated or unsaturated, linear or branched bivalent aliphatic radical containing one to eight carbon atoms, A represents either a saturated or unsaturated, linear or branched, bivalent aliphatic radical containing one to six carbon atoms and optionally interrupted or completed by a bivalent aromatic radical, or A represents a bivalent aromatic radical, and Z represents one of the functions -C00H, -C00Rs in which Rs represents an alkyl radical containing one to twelve carbon atoms, SH or -S03H, the functions COOH or S03H being able to be optionally salified in the form of an alkali metal or alkaline-earth salt, of an ammonium salt or of an amine salt, or X represents XQ, Xa being a group -CO-A-Z in which A and Z are as defined previously and Y then represents YB, YB being one of the groups 1 chosen from -C≡C-R4, -CH=CH-R4 or -CH2-CH2- 4 in which R4 represents a hydrogen atom, a halogen atom, a trialkylsilyl radical containing three to twelve carbon atoms, a linear or branched alkyl radical containing one to six carbon atoms, or a phenyl radical, the said alkyl and phenyl radicals being optionally substituted, the wavy line in position 13 signifies that the radical R^ can be found in alpha or beta position .

2. ) The products of general formula (I.): in which Ra represents an aliphatic hydrocarbon radical containing one to eight carbon atoms, R2 and R3/ identical or different, represent a hydrogen atom or an -37b- 95272/2 alkyl radical containing one to four carbon atoms, G represents a hydrocarbon group containing one to eighteen carbon atoms and optionally one or more identical or different heteroatoms selected from nitrogen, oxygen, sulfur and silicon linked to the steroid nucleus by a carbon atom and either X represents ΧΛ, XA being a hydrogen atom, an alkyl radical containing one to eight carbon atoms, a arylalkyl radical containing seven to fifteen carbon atoms or an acyl radical containing one to eight carbon atoms and in this case Y represents YA, ΥΛ being a group -3-0-CO-A-Z in which B represents a saturated or unsaturated, linear or branched bivalent aliphatic radical containing one to eight carbon atoms, A represents either a saturated or unsaturated, linear or branched, bivalent aliphatic radical containing one to six carbon atoms and optionally interrupted or completed by a bivalent aromatic radical, or A represents a bivalent aromatic radical, and Z represents one of the functions -C00H, -C00 5 in whi li R5 jr-epresents an alkyl radical containing one to twolvo oarbon atomo, Oil or -S03H, the functions COOH or S03H being able to be optionally salified in the form of an alkali metal or alkaline-earth salt, of an ammonium salt or of an amine salt, or X represents ΧΘ, B being a group -CO-A-Z in which A and Z are as" defined previously and Y then represents YB, Ys being one of the groups chosen from 95272/2 - 38 - -C=C-R4, -CH=CH-R4 or -CH2-CH2-R4 in which R4 represents a hydrogen atom, a halogen atom, a trialkylsilyl radical containing three to twelve carbon atoms, a linear or branched alkyl radical containing one to six carbon atoms, or a phenyl radical, the said alkyl and phenyl radicals being optionally substituted, the wavy line in position 13 signifies that the radical R^ can be found in alpha or beta positio .

3. ) The products of general formula (I) as defined in claim 2, corresponding to the formula (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 -C=C-CH2-, A' represents one of the bivalent radicals -(CH2)N- i-n which n can take one of the values from 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'Q, X'B being a group: -CO-(CH2)n-Z ' in which n and Z' are as defined previously and Y' then represents Y'B/ Y'B being one of the groups -CsC-R'4 or -CH=CH-R'4 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 one to four carbon atoms, a dialkylamino group containing two to eight carbon atoms or a trialkyl- 95272/2 - 39 - silyl group containing three to twelve carbon atoms.

4. ) The products of general formula (I) as defined in claims 2 and 3 in which G represents an aryl radical substituted by a halogen atom, an aryl radical, an acyl 5 radical containing one to eight carbon atoms or by one of the functions -NH2, -NHR' or -NR'R", in which R' and R", identical or different, represent a phenyl radical, or a primary, secondary or tertiary alkyl radical containing one to eight carbon atoms, optionally containing one or more 10 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, a heterocyclic radical optionally substituted and optionally containing another heteroatom chosen from nitrogen, oxygen 15 and sulphur atoms, or by one of the functions -OR"' or -SR" ' in which R" ' represents a phenyl radical or a primary, secondary or tertiary alkyl radical containing one to eight carbon atoms, optionally containing one or more heteroatoms, chosen from oxygen, nitrogen, sulphur atoms or optionally 20 substituted by a heterocycle, or G represents a 2-, 3- or 4- pyridyl radical.

5. ) The products of general formula (I) as defined in claim 4 , in which G represents a phenyl radical substituted in position 4 by one or the following radicals: amino, 25 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- 30 morpholinyl ) -ethylamino] , ( 4-methyl-l-piperazinyl ) , formyl, acetyl, methoxy, phenoxy, [ 2- (dimethylamino ) -ethoxy ] , [2-(l- pyrrolidinyl ) -ethoxy] , [ 2- ( 4-morpholinyl ) -ethoxy] , methylthio, ethylthio, isopentylthio, [ 2- (dimethylamino) - ethylthio], [ 2- ( 1-pyrrolidinyl ) -ethylthio ] [2- (4- 35 morpholinyl ) -ethylthio ] , trimethylsilyl , methyl, isopropyl, [ (dimethylamino ) -methyl ] , or by one of the fluorine, chlorine or bromine atoms.

6. ) The products of general formula (I) as defined in 95272/2 - 40 - one of claims 2 to 5 in which represents a methyl radical in 13beta position and R2 and R3 each represent a hydrogen atom.

7. ) The products of general formula (I) as defined in claim 6 of which the names follow: - sodium and 21-chloro-llbeta-[4-(dimethylamino)-phenyl]-3-oxo-19-nor-17alpha-pregna-4, 9-dien-20-yn-17beta-yl succinate, - sodium and llbeta-[ 4- (methylthio) -phenyl ]-3-oxo-17alpha-( 1-propynyl ) -estra-4 , 9-dien-17beta-yl succinate .

8. ) Process for the preparation of products of general formula (I) as defined in claim2 , characterized in that A - the products of formula (HA) or or formula (ΙΙβ): in which R^, R2 , R3 and G have the meaning indicated in claim 1 and R A has the values indicated in claim 1 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 (ΙΙΙχ): o=c c=o •V (nil) - 41 - so as to obtain, if necessary after deprotection of the protected reactive functions and if desired after salification of the carboxy function, the products of general formula (I) corresponding respectively to the formula (IAI) and ( IB I ) : in which represents an optionally salified carboxy radical, b) to the action of a product of formula ( I I I 2 ) : HOOC-A-U ( I H 2 ) or also of a functional derivative of this acid in which U represents one of the groups -COOH, -COOR5 in which R5 represents an alkyl radical containing one to six carbon atoms or an arylakyl radical containing seven to twelve carbon atoms, or -SH, so as to obtain, if necessary after deprotection of the protected reactive functions, the products of formula (IV^) and (IVg) respectively: - 42 - which products of formulae (IVA) and (IVg): - when U represents the free carboxy group, correspond, after optional salification, to the products of formulae (IAl) and (IBl), - when U represents the group -COOR5, correspond to the products of formulae (IVQ) and (IVD): - 43 - which products of formulae (IVQ) and (IVp) are hydrolysed or saponified so as to obtain the products of formulae (I^i) and (Ιβΐ) respectively, - when U represents the group -SH, correspond to the products of formulae (IVg) and (IVp): which products of formulae (IVg) and (IVp) are oxidized and if desired salified, so as to obtain the products of general formula (I) corresponding to the formulae (I&2) and (Ιβ2) respectively: -0-CO-A-Z2 - 44 - in which Z2 represents an optionally salified sulpho group, c) or to the action of a product of formula (III3): HOOC-A-SO2CI (III3) or also of a functional derivative of this acid, so as to obtain, if necessary after deprotection of the reactive functions contained in R4A and if desired after salification, the products of formulae (Ij2) ANC* (*B2) respectively; and in that: B - the products of formulae (Ιβΐ (iB2) anc (iv'D) ARE subjected if desired: a) either to an agent for hydrogenation of the triple bonds so as to obtain the products of formulae (Ιβ3) (JB4) anc (VQ) respectively: dB4) - 45 - which products are, if desired, subjected to an agent for hydrogenation of the double bonds so as to obtain the products of formulae (IBS)/ (IB6) AND (VID) respectively: or to an agent for direct hydrogenation of the triple bonds into single bonds, so as to obtain the products of formulae (∑B5)/ (∑B6) AND (VID) respectively; 95272/2 - 46 - b) the products of formulae (VD) and (VIQ) are either hydrolyzed or saponified to obtain the products of formulae (lB3) .and (135) respectively.

9. ) Process according to claim 8 for the preparation of products of formula (I') as defined in claim 2, characterized in that: - a) either the product of formula (II'A) or (H'B): in which R]_, R2, R3 and G have the values indicated in claim 2 and '4a has the values indicated in claim 2 for R'4, as well as those values in which the hydroxyl 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'l): in which n takes one of the values from two to six, so as to obtain, if necessary after deprotection of the protected hydroxy function contained in R'4 and if desired after salification of the free carboxy function by the action of a - 47 - solution of sodium bicarbonate, the product of formula (ΙΆΐ) or (i'Bl) respectively: in which Z ' i represents a free carboxy group or its sodium salt; b) or the product of formula (ΙΙ'^) as defined above is subjected, in the presence of a nitrogenous base, to the action of a product of formula (III '3): so as to obtain, if necessary and if desired, after sali cation by a solution of sodium bicarbonate, a product of formula (I'A2) : - 48 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, so as to obtain the products of formula (Ι'Β3)·

10. A pharmaceutical composition containing as active ingredient efficient quantity of a compound claimed in Claim 2.

11. A pharmaceutical composition containing as active ingredient compound as claimed in any of Claims 3 to 7.