AU644671B2 - New 19-NOR steroids having a carbonated chain containing an amide function in position 11beta, their preparation, their use as medicaments and the pharmaceutical compositions containing them - Google Patents

Abstract

The invention relates to the compounds: <IMAGE> either n = 1, K = oxygen, R17 = hydroxyl, <IMAGE> R'17 = hydrogen, ethynyl, RA = methyl, RA' = isopropyl, butyl, heptafluorobutyl, X = methylene, phenylene or phenyloxy, Y = -(CH2)7; -(CH2)8-; -(CH2)5-C IDENTICAL C-; -(CH2)q-O-CH2-, q = 5 to 7, and -(CH2)5-S-CH2-, or n = 1 or 2, K = oxygen or sulphur, R17 and R'17 = ketone or R17 = hydroxyl or acyloxy and R'17 = hydrogen, alkyl, alkenyl, alkynyl, X = methylene, arylene, CH2-O, arylenoxy or arylenethio, Y = a bond or aliphatic chain optionally interrupted by arylene, oxygen or sulphur, optionally oxidised, and optionally ending with arylene, Z = bond and if Y and Z = bond, X NOTEQUAL CH2 or CH2-O, RA or RA' = hydrogen, alkyl, heterocycle (5 or 6 members) optionally substituted with RA or RA' NOTEQUAL hydrogen, - or n = 2, or K = sulphur, or X = arylenethio, or RA and RA' = heterocycle substituted by aryl or aralkyl, their preparation, their application as medicinal products and pharmaceutical compositions containing them.

Description

P/00/01 1 Regutation 3.2 644671

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

9 0 TO BE COMPLETED) BY APPLICANT ;.qame of Applicant: ROUSSEL-UCLAF Aciual Inventor(s): Andre Claussner, Francois Niqu Jean-Georges Teutsch and Patrick Van de Velde Adctess for Service: CALLINAN LAWRIE, 278 High Street, Kew, 3101, Victoria, Australia Invention Title: "NEW 19-NOR STEROIDS HAVING A CARBONATED CHAIN CONTAINING AN AMIDE FUNCUOGN IN POSITION ilBETA, THEIR.

PREPARATION, THEIR USE AS MEDICAMENTS AND THE PHARMACEUTCAL COMPOSMTONS CONTAINING THEM" The follow-ig statement is a full description of this invention, includin g the best method of performing it known to me:- New 19-Nor steroids having a carbonated chain containing an amide function in position 11beta, their preparation, their use as medicaments and the pharmaceutical compositions containing them The present invention relates to new 19-Nor steroids having a carbonated chain containing an amide or thioamide function in position 11beta, their preparation process and the intermediates of this process, their use as medicaments and the new pharmaceutical compositions containing them.

A subject of the invention is the compounds of formula R K

N-C

R Z 1 R

(I)

C17

H

in which: either n 1, K represents an oxygen atom,

R

17 represents a hydroxyl radical or a radical of formula

-O-C-(CH

2 2 optionally salified,

R'

17 represents a hydrogen atom or an ethynyl radical, RA represents a methyl radical, RB represents an isopropyl or linear butyl or heptafluorobutyl radical, X represents a methylene, phenylene or phenyloxy radical linked to the steroid by a carbon atom, Y represents one of the radicals chosen from the group constituted by -(CH 2 7

-(CH

2 8

-(CH

2 5

-(CH

2 )q-O-CH 2 with q 5 to 7 and -(CH 2 5

-S-CH

2 in which the sulphur atom is optionally oxidized in the form of the sulphoxide or sulphone, 2 Z represents a single bond, or n 1 or 2 K represents an oxygen or sulphur atom, R 17 and R' 17 are such that: either R 17 and R' 17 together form a ketone function, or R 17 is a hydroxyl radical or an acyloxy radical and

R'

17 represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical having at most 8 carbon atoms, X, Y and Z are such that: X represents a methylene radical, an arylene group, a CH 2 -O radical, arylenoxy or arylenethio radical linked to the steroid by a carbon atom, Y represents a single bond or a saturated or unsaturated, linear or branched aliphatic chain, containing 1 to 18 carbon atoms, optionally interrupted by one or more radicals chosen f from arylene, oxygen or sulphur radicals optionally oxidized in the form of the sulphoxide or sulphone and optionally terminated by an arylene radical, Z represents a single bond it being understood that when Y and Z are a single bond, X cannot be a methylene or CH 2 -0 radical, RA or Rg identical or different, represent a hydrogen atom, a linear or branched alkyl radical containing 1 to 8 carbon atoms, optionally substituted by an aryl, alkyl or dialkylamino, hydroxy or halogen radical, an esterified carboxyl radical or RA and RB form together with the nitrogen atom to which they are linked a heterocycle with or 6 links, saturated or not, optionally containing one or more heteroatoms chosen form the group constituted by oxygen, nitrogen and sulphur atoms and optionally substituted by an alkyl radical having 1 to 4 carbon atoms, an aryl or aralkyl radical having 6 to 10 carbon atoms, it being understood that at least one of the RA or RB radicals cannot be a hydrogen atom and that at least one of the following conditions is fulfilled: either n 2, -3-3.

or K is a sulphur atom, or X is an arylenethia radical linked Co the steroid by a carbon atom, or RA and RB form together with the carbon atom to which they are linked a heterocycle with 5 or 6 links substituted by an aryl or aralkyl radical.

Among the compounds of the invention, there can be mentioned in particular the products of formula the preparation of which is given further on in the experimental part and notably those whose names follow: llbeta-(4-( (7-(butylmethylamino)-carbonyl)heptyl)-oxy)phenyl)-3-hydroxy-estra-1 ,3,5(10)-trien-17beta-yl see monobutanedioate, llbeta-(4-((7-((butylmethylamino)-carbonyl)-heptyl)-oxy)phenyl)-3-hydroxy-estra-1,3,5(10)-trien-17beta-yl and sodium butanedioate, N-butyl-2-(6-(4-(3,17beta-dihydroxy--estra-1 0 00 trien-1 lbeta-yl)-phenoxy)-hexyloxy-N-methyl acetamide, N-butyl-8-(4-(3,17b,.ta-dihydroxy-estra-1,3,5(10)trien-1lbeta-yl)-phenoxy)-N-methyl-2-octynamide, N-butyl-2-((5-(4-(3,17beta-dihydroxy-estra-1,3,5(10)trien-1lbeta-yl)-phenyl)-pentyl)-thio)-N-methyl acetamide, N-butyl-4-(3,17beta-dihydroxy-estra-1,3,5(10)-trien- 1lbeta-yl)-N-methyl benzenenonamide, 6 N-butyl-2-((5- (4-(3,17beta-dlhydroxy-estra-1,3,5(10)trien-1 lbeta-yl)-phenyl)-pentyl)-oxy)-N-methyl acetamide, i.

2-((8-(3,17beta-dihydroxy-19-nor-17alpha-pregna-1,3,5(10)- (trien-20-yn-llbeta-yl)-octyl)-oxy)-N-methyl-N-(1methylethyl) acetamide.

Among the compounds of the invention, there can be particularly mentioned products corresponding to formula as defined above in which: n 1 or 2, K represents an oxygen or sulphur atom, R 1 7 and R' 17 are such that: either R 17 and R' 17 together form a ketone function, or R 17 is a hydroxyl or acyloxy radical and R' 17 represents an hydrogen atom, an optionally substituted alkyl, alkenyl or 4 alkynyl radical having at most 8 carbon atoms, X, Y and Z are such that: X represents a methylene radical, an arylene group, a

CH

2 arylenoxy or arylenethio radical linked to the steroid by a carbon atom, Y represents a single bond or a saturate or unsaturated, linear or branched aliphatic chain containing 1 to 18 carbon atoms, optionally interrupted by one or more radicals chosen from arylene or oxygen radicals or sulphur radicals optionally oxidized in the form of the sulphoxide or sulphone and optionally terminated by an arylene radical, Z represents a single bond, it being understood that when Y and Z are a single bond, X cannot be a methylene or CH 2

-O

radical, RA or RB identical or different represent a hydrogen atom, a linear or branched alkyl radical containing 1 to 8 carbon atoms, optionally substituted by an aryl, alkyl or dialkylamino, hydroxy, halogen radical or an esterified carboxyl radical or RA and RB form with the nitrogen atom to which they are linked a heterocycle with 5 or 6 links, saturated or not, optionally containing one or more heteroatoms chosen from the group constituted by oxygen, nitrogen and sulphur atoms and optionally substituted by an. alkyl radical having 1 to 4 carbon atoms, an aryl or aralkyl radical having 6 to 10 carbon atoms, it being understood that at le-st one of the RA or RB radicals is not a hydrogen atom and that at least any one of the following conditions is fulfilled: either n 2, or K is a sulphur atom, or X is an arylenethio radical linked to the steroid by a carbon atom, or RA and RB form with the carbon atom to which they are linked a heterocycle with 5 or 6 links substituted by an aryl or aralkyl radical.

When R 17 is an acyloxy radical it is notably the derivative of a saturated or unsaturated aliphatic or cycloaliphatic acid and notably an alkanoic acid such as for 5 example acetic, propionic, butyric or isobutyric, valerique or undecylic acid, an hydroxyalkanoic acid such as for example, hydroxyacetic acid; a cycloalkylcarboxylic or (cycloalkyl) alkanoic acid such as for example cyclopropyl, cyclopentyl or cyclohexylcarboxylic, cyclopentyl or cyclohexyl acetic or propionic acid, a benzoic acid, a salicylic acid or phenylalkanoic acid such as phenyl acetic or phenyl propionic acid, an amino acid such as diethylamino acetic or aspartic acid or formic acid. It is preferably the derivative of acetic, propionic, butyric or butanedioic acid.

When R' 1 7 represents an alkyl radical, it can be one of the following radicals. methyl, ethyl, propyl, isopropyl, em..

butyl, isobutyl, n-pentyl, n-hexyl, 2-methylpentyl, 2,3dimethylbutyl, n-heptyl, 2-methylexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,2- dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl.

It is preferably the methyl radical. e.

When R' 1 7 represents an alkenyl radical, it can be a vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl radical. It is preferably the vinyl or propenyl radical.

When R' 1 7 represents an alkynyl radical, it can be an m* ethynyl, propynyl, propargyl, butynyl or isobutynyl radical. It is preferabl" the ethynyl or propynyl radical.

The expression optionally substituted applied to the alkyl, alkenyl or alkynyl radical means one or more identical or different radicals chosen preferably from the following radicals: halogen such as fluorine, chlorine, bromine, iodine, alkoxy such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, amino, alkylamino such as methylamino or ethylamino, dialkylamino such as dimethylamino, diethylamino or methyl ethylamino, each of the dialkylamino radicals being optionally in the oxidized form, amino alkyl such as aminomethyl or aminoethyl, 6 dialkylaminoalkyl such as dimethylamino methyl or ethyl, dialkylaminoalkyloxy such as dimethylamino ethyloxy, optionally acylated hydroxyl, for example acetoxy or a radical of formula-O-C(CH2)nCO 2 H in which n 2 to

O

notably, acyl such as acetyl, propionyl, butyryl, benzoyl, -free or esterified carboxy such as alkoxy carbonyl for example methoxy carbonyl or ethoxy carbonyl, cyano, trifluoromethyl, aryl such as phenyl, furyl, thienyl or aralkyl such as benzyl, these radicals being themselves optionally goe substituted by alkyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or by the alkoxy, alkylthio, alkylamino or di-alkylamino radicals indicated above. e g.

When X represents an arylene group, it is preferably the phenylene radical.

When X represents an arylenoxy group, it is preferably the phenylenoxy radical.

When X represents an arylenethio radical, it is preferably nri phenylenethio radical.

9 U When Y represents a saturated or unsaturated, linear or branched aliphatic chain, it can be one of the following radicals: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, or tert-butylene, n-pentylene, n- *hexylene, 2-methyl pentylene, 2,3-iiethyl butylene, nhexpylene, 2-methyl pentylene, 2,-dimethylpe butylene, 3,3nheptylene, 2-methylhexylene, 2, 2-dimethylpentylene, 3,3dimethylpentylene, 3-ethyl-pentylene, n-octylene, 2,2dimethylhexylene, 3,3-dimethyl-hexylene, 3-methyl-3ethylpentylene, nonylene, 2,4-dimethyl heptylene, n-decylene, n-undecylene, n-dodecylene, n-tridecylene, n-tetradecylene, n-pentadecylene, n-hexadecylene, nheptadecylene or n-octadecylene, preferably n-nonylene or ndecylene. It can also be one of the following radicals: vinylene, isopropenylene, allylene, 2-methylallylene or isobutenylene, and when the chain is interrupted or 7 terminated by one or more arylene radicals, it is preferably the phenylene radical, it being understood that terminated relates to any one of the two ends of Y.

When RA or RB represents an alkyl radical, it can be one of the following radicals: 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, noctyl, 2,2-dimethylhexyle, 3,3-dimethylhexyl, 3-methyl 3ethylpentyl.

The aforementioned radicals can be substituted by one or more aryl radicals such as phenyl, furyl, thienyl, preferably a phenyl radical, by one or more alkylamino or dialkylamino radicals such as dimethylamino or by one or more esterified carboxyl radicals for example by a methoxycarbonyl or an ethoxycarbonyl, by one or more halogen atoms for example fluorine, chlorine or bromine. The 2,2,3,3,4,4,4 heptafluorobutyl radical can notably be mentioned.

When RA and Rg form with the nitrogen atom to which they are linked a heterocycle with 5 or 6 links, it is a saturated heterocycle, preferably a pyrrolidine or a piperidine optionally substituted by an alkyl radical such as methyl, ethyl, propyl or isopropyl, preferably methyl or ethyl, by an aryl radical such as phenyl or tolyl or by an alkylaryl radical such as benzyl or phenylethyl, preferably benzyl or an unsaturated heterocycle, preferably a pyrrole or a pyridine optionally substituted by an alkyl radical such as methyl, optionally containing another heteroatom, preferably a morpholine, piperazine or pyrimidine, optionally substituted by an alkyl radical, preferably methyl or ethyl.

More particularly the present Application relates to the products of formula in which n is equal to 1.

Among the preferred compounds of the invention there can be especially mentioned the products of formula in which K is a sulphur atom, X is an arylenoxy radical and Y represents a saturated linear chain containing 5 to 10 carbon atoms, optionally interrupted by an oxygen atom, those in -8 which X is an arylenethio radical and Y represents a saturated linear chain containing 5 to 10 carbon atoms and those in which X is an axylene radical, Y represents an unsaturated linear chain containing 5 to 10 carbon atoms, RA and RB torm with the atom to which they are linked a piperidine N-substituted by an aralkyl radical.

Among the preferred compounds of the invention there can therefore naturally be mentioned the products of formula (I) the preparation of which is given further on in the experimental part and more particularly: N-butyl-5-(4-(3,17beta-dihydroxy-estra-1 ,3,5(10)-trien- 1 lbeta-yl)-phenoxy)-pentyloxy)-N-methyl-ethanethioamide, of N-butyl-8-(4-(3,17beta-dihydroxy-estra-1 ,3,5(10)-trien- 00 11 beta-yl) -phenoxy) -N-methyl--octanethioamide, as well as llbeta-(4-( (7-(butylmethylamino)-carbonyl)-heptyl)-oxy)- phenyl)-3-hydroxy-estra-1 ,3,5(10)-Lrien-l7beta-yl monobutanedicate,* 1 lbeta-(4-( (butylmethylamino)-carbonyl)-heptyl)--oxy)phenyl)-3--hydroxy-estra-1 5(10)-trien-1 7beta-yl and sodium butanedioate, N-butyl-2-(6-(4-(3,17beta-dihydroxy-estra-1 ,3,5(10)-trien- 11 beta-yl) -phenoxy) -hexyloxy-N-methyl-acetamide, N-butyl-8-(4-(3,17beta-dihydroxy-estra-1 ,3,5(10)-trien- 1 lbeta-yl)-phenoxy)--N-methyl-2-octynamide, N-butyl--2-((5-(4-(3,l7beta-dihydroxy-estra--1,3,5(10)--0 trien-1 lbeta-yl)-phenyl)-pentyl)-thio)-N-methyl-acetamide,:0 N-butyl-4--(3,l7beta-dihydroxy-estra-1 5(10) -trien-ll1betayl )-N-methyl-benzenenonamide, N-butyl-2-((5-(4-(3,l7beta-dihydroxy-estra-1,3,5(10)trien-1 lbeta-yl)-phenyl)-pentyl)-oxy)-N-methyl-acetamide, (8-(3,17beta-dihydroxy-19-nor-17alpha-pregna-1 ,3,5(10)trien-20-yn-1 lbeta-yl)-octyl)-oxy)-N-methyl-N-(1-methylethyl) acetamide.

Also a subject of the present Application is a preparation process for the products of formula as defined above, characterized in that a compound of formula

(II):

9 R'17

(II)

CH 2 in which X, Y, n, R 17 and R' 17 have the same meaning as previously, it being understood that when R 17 represents a hydroxyl radical, this radical is protected, is subjected to the action of an oxidation agent in order to obtain the product of formula (III):

COOH

1 2 R17 (cH a' 7 (III) 0 which is subjected to the action of an agent which a'lows the carboxylic function to be activated, then to the action of a compound of formula RA H-N. (IV)

B

in which RA and RB have the same meaning as previously, in order to obtain the product of formula 10 R -A-C A \z R B Y R7

(V)

C R' 1 7 (CH 2 in which Z is a single bond, which products if necessary, are subjected to a deprotection reaction of the hydroxy function and, if desired, to a reducing agent when R 1 7 and R'1 7 together form a ketone function, then if appropriate, the hydroxylated derivative in position 17 thus obtained is subjected to an acylation agent, -or to saponification agent when R 17 represents an acyloxy function, which compound of formula is subjected to an aromatization agent of the A ring, then to a saponification agent used sparingly so as to obtain the products of formula which, if desired, are subjected to one or more of the following reactions: either, when R 17 and R' 17 together form a ketone function, it is subjected to a reducing agent or to a metal complex of formula M-R'17 (VI) in which M represents a metal atom and R' 17 has the same meaning as previously, with the exception of hydrogen, or when R 17 is a hydroxyl radical, it is subjected to a selective acylation agent in position 17, or, when RA or RB is a hydrogen atom, it is subjected to an appropriate alkylation agent, or, when Y represents an unsaturated aliphatic chain, it is subjected to a hydrogenation agent, 11 in order to obtain the products of formula in which K is an oxygen atom which, if desired, is subjected to a sulphuration agent in order to obtain the products of formula in which K is a sulphur atom.

The compounds of formula are obtained by reacting a compound of formula (III) activated for example in the form of the mixed anhydride by the action of an agent such as a chloroformate, for example isobutyl chloroformate, in the presence of a base such as a tertiary amine, for example Nmethylmorpholine, in an anhydrous solvent such as a chlorinated solvent, for example methylene chloride, with the amine of formula (IV).

The product of formula (III) is obtained using an oxidation agent such as, for example, the mixture Cr0 3 sulphuric acid in a neutral solvent such as for e;-imple, acetone.

In a preferred method of implementing the invention, the compouris of formula (II) contain a chain in the 11beta position terminated by an alcohol function chosen from the following table: X Y

S-(CH

2 7

-CH

2 0H

-(CH

2 5

-S-CH

2

-CH

2 0H H -CEC-(CH 2 5 -CH20H o (CH 2 7

-CH

2 0H 0 (CH 2 5 -0-CH 2

-CH

2 0H S- (CH 2 5

-SO-CH

2

-CH

2 0H As illustrated in the examples hereafter, the compounds of formula (III) contain a chain in position 11beta, terminated by a carboxylic function, corresponding to the oxidation product of a chain chosen from the chains in position 11beta terminated by one of the alcohol function mentioned above, the compound of formula (IV) is chosen from the amines such as for example bucylamine, methylbutylamine, methylisopropylamine or benzylpiperidine which are known products, or methyl heptafluorobutylamine, the preparation of which is given further on.

When the compound of formula has a ketone function 12 in position 17, the corresponding steroid hydroxylated in position 17beta is obtained, by the action of a reducing agent such as sodium borohydride in a neutral solvent such as methanol or triterbutoxylithium aluminium hydride in tetrahydrofuran.

When the compound of formula has a hydroxy function in position 17, the corresponding steroid acyloxylated in position 17beta is obtained, by the action of an acylation agent, for example an acetylation agent such as acetic anhydride in pyridine, optionally in the presence of 4dimethylaminopyridine.

When the compound of formula has an acyioxy function **ee* in position 17, the corresponding steroid hydroxylated in position 17beta is obtained, by the action of a saponification agent, such as potash in an alcoholic medium.

The compounds of formula which are steroid derivatives of oestradiol having a chain in position 11beta comprising a substituted amide function are obtained starting from compounds of formula by the action of an o aromatization agent such as palladium hydroxide on magnesia in methanol or the mixture acetyl bromide acetic anhydride, at a temperature not exceeding ambient temperature, followed by a careful saponification reaction with for example potash in methanol, sodium bicarbonate or methanol in the presence of hydrochloric acid. When the compound of formula has a ketone function in position 17, the following are obtained: the corresponding hydroxylated 17beta steroid, in the conditions described above, for the compound of formula (V) for example by the action of a reducing agent such as sodium borohydride in a neutral solvent such as methanol, the corresponding compound of f la comprising an

R'

1 7 radical which represents an opcionally substituted alkyl, alkenyl or alkynyl radical, using as the complex, for example, a lithium complex, according to the process described in the Patent Application EP 57115.

When the compound of formula has a hydroxy function in position 17, the corresponding acyloxylated 17beta steroid 13 is obtained, by the action of a selective acylation agent, for example acetic anhydride in pyridine.

When RA or Rg is a hydrogen atom, the corresponding alkylated product is obtained, by the action of an alkyl halide, for example methyl or ethyl iodide, methyl or ethyl bromide in a solvent such as tetrahydrofuran.

It is of course understood that if R' 17 contains an alkyl, alkenyl or alkynyl radical substituted by a reactive function, this can be provisionally protected by the usual methods.

When Y is an unsaturated aliphatic chain the corresponding triple bond reduction product of formula is obtained either using hydrogen in the presence of palladium on activated charcoal, barium sulphate and optionally a base such as pyridine or quinoline, in the case of a partial reduction, or using palladium hydroxide alone or tris- (triphenylphosphine)chlororhodium in the case of a total reduction. The products of formula in which Y represents a branched aliphatic chain can be prepared by the alkylation of the products of formula in which Y represents a linear aliphatic chain after having, if appropriate, blocked the reactive functions in positions 3 and 17. The alkylation is carried out for example using an alkyl halide such as methyl.

iodide, in the presence of lithium diisopropylamide.* When K is an oxygen atom, the corresponding product of formula is obtained in which K is a sulphur atom, by the I action of a sulphuration agent, for example [2,4-bis *0 methyoxyphenyl)-1,3-dithia-2,4-diphosphenate-2,4-disulphide] (Lawesson reagent), after optionally blocking the reactive functions in positions 3 and 17.

The invention also relates to a preparation process for the products of formula corresponding to the products of formula in which X represents an arylene radical and Y represents an aliphatic chain optionally linked to the arylene group by a double or a triple bond and containing at least 3 carbon atoms or linked to the arylene group by an oxygen or sulphur atom, characterized in thac a compound of 14 formula (VII): L7 L7

(VII)

in which W represents either an -OH radical, or an optionally activated mercapto radical, or a -C=CH radical, n, R 17 and R' having the same meaning as indicated previously, it being understood that when R 17 represents an -OH radical, it is optionally protected, the A' and B' rings are: either A B 0; ew 9 r 9@49 .c S *9 9 4 9..

or where R 3 represents a hydrogen atom or a protector group of the hydroxyl function, is subjected either, in the case where W represents a C=CH radical to the action of a halogenated derivative of formula (VIII): o 9.

°o g go

RA

Hal-Y'-Z-CO-N

RB

(VIII)

in which Hal is a halogen atom, Z, RA and Rg have the same meaning as indicated previously and Y' represents the above aliphatic chain Y comprising at least 2 carbon atoms, in the presence of a strong base and if appropriate, is subjected to the action of a deprotection agent in position 3 and/or 15 position 17, in order to obtain the product of formula (IXA): A

R

17 N-CO-Z-Y'-C-C 0 R 1 7 A(IXA) A'C 3 BA B which product, if desired, is subjected to an agent giving partial or complete reduction of the triple bond in order to obtain the product of formula (IXB): A 17 R 17 (IXB) A' B' or, in the case where W represents an -OH radical, a mercapto radical or an activated mercapto radical, to the action of a halogenated derivative of formula s o

RA

Hal-Y-Z-CO-N (X)

RB

in which Hal, Y, Z, RA and Rg have the same meaning as indicated previously, in the presence of an alkaline agent, then if appropriate, to the action of a deprotection agent in order to obtain a product of formula (IXc): 16 A R17 -CO-Z-Y-K' 0 7

S(IXC)

RB "'17 in which K' represents either an oxygen atom, or a sulphur atom, which products of formula (IXA), (IXB) or (IXC) are, if appropriate, treated as indicated previously for the products of formula in order to obtain the products of formula which, if appropriate, are treated as indicated previously for the products of formula When W represents an activated derivative of the mercapto radical, it is a metal thiolate, for example, silver. According to a preferred method of the process of invention described above: the optional protection groups of the hydroxyl functions in o" positions 3 and 17 are chosen from the usual groups such as tetrahydropyrannyl and tert-butyl, the halogen atom which is represented by Hal is for *0 example a bromine, chlorine or iodine atom, the strong base used is for example butyllithium or sodium hydride, the optional reduction of the triple bond is carried out 04 either using hydrogen in the presence of palladium on activated charcoal, barium sulphate and optionally a base such as pyridine or quinoline, in the case of a partial reduction, or using palladium hydroxide alone or tris- (triphenylphosphine)chlororhodium in the case of total reduction, the optional activation of the mercapto radical is carried out by the action of a metal salt, for example the silver nitrate, on a protected mercapto which can be for example a thioether such as an a:'-ylthio derivative, for example tertbutylthio, triphenyl-methylthio, isobutyloxymethylthio or a 17 derivative of a ring with 5 or 6 links optionally containing a heteroatom belonging to the group of nitrogen, oxygen or sulphur, preferably oxygen. As an example of a protected mercapto radical, there can be notably mentioned the tetrahydropyranylthio radical, the alkaline agent used is an alkaline hydroxide for example sodium hydroxide, the deblocking of the protected functions is carried out using a standard hydrolysis agent such as hydrochloric acid, in the compounds )f formula (VII) used at the start, the W radical is in para position.

The compounds of formula have useful pharmacological properties. The study of the products on hormonal receptors has proven that they possess in particular a remarkable antioestrogen activity and anti-proliferative properties, as is shown in the results of the tests given further on.

These properties make the compounds of formula (I) usable in the treatment of hormone-dependent carcinomas, such as for example mammary carcinomas and their metastases and in the treatment of benign tumors of the breast.

Therefore a subject of the invention is the products of formula as medicaments.

Among the medicaments of the invention there can be particularly mentioned the compounds described in the experimental part and quite particularly the products of Examples 1, 2, 3, 4, 6, 7, 9, 10, 11 and 14. The useful dose varies according to the affection to be treated and the administration route; it can vary for example from 1 to 100 mg per day for an adult by oral route.

The invention extends to pharmaceutical compositions containing at least one of the medicaments defined above as active ingredient.

The compounds of formula are used by digestive, parenteral or local route, for example by percutaneous route.

They can be prescribed in the form of plain or sugar-coated tablets, capsules, granules, suppositories, pessaries, injectable preparations, ointments; cream, gels, microspheres, implants, patches, which are prepared according 18 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.

Some of the intermediates of formula (II) or (III) are new products and therefore a subject of the invention is also the products of formula (II) and (III) as defined previously, in which: either n 2, The new compounds of formula (II) as defined previously are prepared according to an operating method an example of which is given further on. In a general manner, the compounds of formula (II) can be prepared according to the following process: The magnesium-compound derivative of a halogenated alcohol of formula

(XI)

in which X and Y have meaning given previously, Hal is a halogen atom, preferably a chlorine or bromine atom a and R is either a hydrogen atom or a protector group **a of the alcohol function, for example a group: <H3 -Si-C-(CH 3 3

CH

3 is reacted in the presence of a copper salt on a compound of formula (XII): 19 0

(XII)

n .o

K

3 in which n has the meaning given previously, K 3 is a protector group of the ketone function in position 3 such as a cyclic ketal, in order to obtain the product of formula

(XIII):

CH 2R x which, if desired, is subjected, either to a lithium-compound derivative of the product of formula (XIV): H-R'17 (XIV) in which R' 1 7 has the meaning given previously, it being understood that it is not a hydrogen atom, or to a reducing agent, then optionally to an acylation agent, and that it is subjected to a dehydration and hydrolysis agent which can free the 3-keto delta-4 function and the alcohol function in order to obtain the compound of formula (II).

The products of formula (XII) necessary for the implementation of the process are known products. Their preparation is described for example in the Patent EP 0057115 when n 1 and in the European Application EP 0116974 when n 2.

20 The products of formula (VII) necessary for the implementation of the process, in which n 1 and W is different to a mercapto radical, are described notably in the European Patent Application EP 0245170. The products in which n 2 and W is different to a mercapto radical are obtained by the same process starting with product (XII) in which n 2.

The products of formula (VII) in which W is an optionally activated mercapto radical, are new products and therefore a subject of the invention is also the products of formula (VII) as defined previously, in which W represents an optionally activated mercapto radical, as new intermediate products. The new products (VII) defined above can be prepared by the action of a magnesium-compound containing a mercapto group on a product of formula (XII). Specific preparation examples of such new products (VII) are described hereafter in the examples. The European Patent Application EP 0384842 (our/case 2235) filed 22nd February 1990 has described new 19-Nor steroids see having a carbonated chain in position 11beta comprising an amide or carbamate function, corresponding to the general formula: 0 0 R -N-C A I Aj N Y R Bs:o B X ,R 1 7 S' R'17

R

A B in which rings A and B have one of following structures: a) either A and B represent the group: 21 0 in which R 2 and R' 2 identical or different, represent a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms; b) or A and B represent the group: A B

HO

in which R 3 represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or an acyl radical, I.o*.

R

17 and R' 17 are such that: either R 17 and R' 17 together form a ketone function, or R17 is a hydroxyl radical or an acyloxy radical and R' 17 represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical having at most 8 carbon atoms, X, Y and Z are such that: X represents a methylene radical, an arylene group, a CH 2 -0 or arylenoxy radical linked to the steroid by a carbon atom, Y represents a single bond or a saturated or unsaturated, linear or branched aliphatic chain, containing 1 to 18 carbon atoms, optionally interrupted by one or more radicals chosen from arylene or oxygen radicals and optionally terminated by an arylene radical, Z represents a single bond or a CH 2 -O radical linked to the Y radical by a carbon atom, it being understood that when Y and Z are a single bond, X 36 cannot be a methylene or CH 2 -0 radical, RA and Rg identical or different, represent a hydrogen atom, a linear or branched alkyl radical containing 1 to 8 carbon atoms, optionally substituted by an aryl, alkyl or dialkylamino, hydroxy or esterified carboxyl radical, or RA and RB form with the nitrogen atom to which they are linked a heterocycle with 5 or 6 links, saturated or not, optionally containing one or more other heteroatoms chosen from the group constituted by oxygen, nitrogen and sulphur atoms and 22 optionally substituted by an alkyl radical having 1 to 4 carbon atoms, it being understood that at least one of the substituents RA or RB is not a hydrogen atom.

Some of the compounds of formula of the present Application constitute, compounds corresponding to the above general formula but not described by name in this application and some constitute related compounds.

Examples of the preparation of products (VIII) and (X) are shown hereafter in the experimental part.

4 *0

S

S SS 0@ S Preparation 1: N-hepta-fluorobutyl N-methylamine hydrochloride.

100 cm 3 of anhydrous ether and 100 cm 3 of anhydrous tetrahydrofuran are cooled down to 0 0 C, then methylamine is bubbled through for 10 minutes. 44.98 g of heptafluorobutyric anhydride is introduced over half an hour, while maintaining a weak bubbling through of methylamine. Agitation takes place whilst allowing the temperature to return to ambient The medium is distilled to a small volume under reduced pressure, taken up in 200 cm 3 of anhydrous tetrahydrofuran and 30 cm 3 of diborane-dimethyl sulphide complex is introduced slowly. The mixture is refluxed for 16 0 hours, cooled down to ambient temperature then 200 cm 3 of methanol is introduced slowly. Then gaseous hydrochloric acid is bubbled through for 15 minutes. The reaction medium is taken to reflux for one hour, then the solvents are distilled off under reduced pressure. The residue is taken up in 200 cm 3 of methanol. Gaseous hydrochloric acid is again bubbled through for 10 minutes, followed by refluxing for 2 hours. The solvent is distilled off and the residue is agitated for 10 minutes in 100 cm 3 of ice-cooled 6N hydrochloric acid. After separating, washing with 2N hydrochloric acid and drying, 22.699 g of expected product is obtained. The hydrochloride obtained above is purified by crystallization from 140 cm 3 of eth nol. Then 140 cm 3 of ether is added, agitation is carried out for half an hour, followed by separating, washing with ether and drying under reduced pressure. 21.7 g of desired product is obtained *0 (subliming at about 200°C). 0*e Analysis: C 5

H

6

F

7 N, HC1: 249.56 Calculated: C% 24.06 H% 2.83 Cl% 14.20 F% 53.29 N% 5.61 Found 24.0 2.8 14.4 52.3-52.1 5.6 Preparation 2: [(5-chloro pentyl)-oxy]-dimethyl (1,1dimethyl)-silane.

13.8 cm 3 of triethylamine then 200 mg of 4-dimethyl aminopyridine are added under a nitrogen atmosphere to a solution of 10.2 g of 5-chloropentanol in 80 cm 3 of methylene chloride, the mixture is cooled down to -10 0 C and 13.75 g of C terbutyl chloro dimethyl-silane is added. The mixture is agitated for 15 minutes at -10 0 C, left to reheat to ambient temperature and diluted with a saturated solution of sodium bicarbonate. The oily crude derivative is separated out and chromatographed on silica (eluant: cyclohexane ethyl acetate 95-5) and 18 g of expected product is obtained.

IR Spectrum: (CHCl 3 OH absence O-Si+ presence Preparation 3: [(3-bromopropyloxy)]-dimethyl-(1,1-dimethylethyl)-silane. Stage A: 3-[[dimethyl-(1,1-dimethylethyl)-silyl]-oxy]propanol. 9.46 g of sodium hydride at 50% in oil is introduced into a spherical flask placed under an argon atmosphere, the oil is eliminated by washing with hexane, 380 ml of tetrahydrofuran and 15 g of 1,3-propanediol are added and agitation is carried out for one hour at ambient temperature. After cooling down the mixture to +5 0 C, 29.7 g of terbutylchlorodimethyl silane is added, agitation is carried out for one hour at ambient temperature and the mixture is poured into 3.5 litres of ethyl ether. It is washed with 1 litre of a 10% aqueous solution of potassium carbonate, then with 1

C

litre of a saturated aqueous solution of sodium chloride, then dried over sodium sulphate and evaporated to dryness under reduced pressure. The residue (35.5 g) is chromatographed on silica (eluant: ethyl acetate cyclohexane 30.6 g of expected product is obtained.

IR Spectrum: (CHC1 3 OH 3625, 3500 cm- 1 -O-Si+ 1258, 838 cm- 1 Stage B: [(3-bromopropyl)-oxy]-dimethyl-(1,1-dimethyl-ethyl)silane.

5.44 g of tetrabromomethane ar.d 4.30 g of triphenylphosphine are added to a solution of 2.5 g of product obtained in Stage A above in 27 ml of methylene chloride cooled down to -25 0 C. The reaction solution is agitated for one hour 30 minutes at 0 C then it is chromatographed on eisilica (eluant: ethyl acetate cyclohexane 2.885 g of expected product is isolated.

Analysis: C 9

H

21 BrOSi Calculated: C% 42.68 H% 8,35 Br% 31.55 Found 40.0 7.9 36.6 IR Spectrum: (CHC1 3 -O-Si+ 1258, 837 cm- 1 Preparation 4: 4-trimethylsilylethynyl-bromobenzene.

150 g of 97% bromo iodo benzene, 500 cm 3 of anhydrous dimethylformamide, 100 cm 3 of triethylamine, 50 g of trimethylsilyl acetylene, 2.1 g of copper iodide and 2.22 g of bis-(triphenylphosphine)-palladium (II) dichloride are mixed together, the whole is agitated for 2 hours then 500 cm 3 of ice-cooled water is added and extraction is carried out 3 times with 500 cm 3 of ethyl acetate. The organic phase is washed with salt water then dried over sodium sulphate. The solvents are evaporated under reduced pressure. 136.54 g of a brown oil is obtained. Purification is carried out by distillation under reduced pressure and 106.97 g of expected product is obtained. B.p. 75-82 0

C

under 0.2 mbar. M.p. 62 0

C.

IR Spectrum: (CHC1 3 absence of C=CH C=C 2160 cm- 1 Preparation 5: [(8-bromo-octyl)-oxy]-dimethyl-(1,1-dimethylethyl)-silane.

1.55 g of imidazole is added to a solution of 3.97 g of 8-bromo octanol in 19 cm 3 of dimethylformamide, and over minutes 3.32 g of terbutyl chloro dimethyl silane in solution in 4.7 cm 3 of tetrahydrofuran is added. The mixture is agitated for one hour at ambient temperature, the inscluble part is filtered off and evaporated to dryness under reduced pressure. The residue is chromatographed on silica (eluant: cyclohexane toluene 8-2) and 5.4 g of expected product is obtained.

Preparation A of Example 1: 11beta-(4-hydroxyphenyl)-estra- 4,9-dien-3,17-dione.

Stage A: cyclic 3-(1,2-ethanediyl) acetal of 11beta-(4- 6hydroxyphenyl)-5-alpha-hydroxy-estra-9-en-3,7-dione.

a) Preparation of the magnesium compound g of trimethylsilyloxy 4-bromo benzene in 100 cm 3 of tetrahydrofuran is added drop by drop under reflux to a suspension of 7.'i g of magnesium turnings in 14.5 cm 3 of tetrahydrofuran. After agitation for 30 minutes under reflux a solution of about 0.95 M of magnesium compound is obtained.

b) Condensation g of cyclic 3-(1,2-ethanediyl) acetal of 10Oalpha-epoxy-estr-9,11-en-3,17-dione obtained according to EP 0057115 (Example 7) in solution in 200 cm 3 of tetrahydrofuran and 0.45 g of copper chloride is agitated for minutes at ambient temperature. 110 cm 3 of the magnesium compound solution obtained above is added over 20 minutes, without exceeding 27°C. After one hour 30 minutes of agitation, the mixture is poured into 1300 cm 3 of a saturated ice-cooled solution of ammonium chloride. The aqueous phase is extracted 3 times with ethyl acetate, washed with a saturated solution of dehydrated sodium chloride and evaporated to dryness under reduced pressure. 34.9 g of crude product is obtained.

C) Desilylation 4.

The crude product obtained above is dissolved in 150 cm 3 of tetrahydrofuran and 130 cm 3 of a 1M solution of tetrabutylammonium fluoride is added. The mixture is agitated for 15 minutes at ambient temperature, poured into water, extracted with ethyl acetate, the extracts are washed with water, dried and evaporated to dryness under reduced pressure. 26.9 g of crude product is obtained which is made into a paste at 40°C over 30 minutes in 100 cm 3 of an ethyl acetate methylene chloride mixture The insoluble part is filtered off and 5.77 g of desired product is obtained. The mother liquors are chromatographed on silica (eluant: ethyl acetate methylene chloride 1-1) and an additional 5.7 g of desired product is collected. The two batches of product obtained are united (11.47 g) and recrystallized from ethanol. 8 g of expected product is obtained. M.p. 255°C.

IR Spectrum: (CHC1 3 OH region 3464, 3280 cm- 1 C=O 1720 cm- 1 aromatic 1613, 1592, 1511 cm- 1 Stage B: 11beta-(4-hydroxyphenyl)-estra-4,9-dien-3,17-dione.

g of the product obtained in Stage A, 110 cm 3 of ethanol and 28 cm 3 of 2N hydrochloric acid are agitated for one hour 30 minutes. The mixture is alkalized to a pH of about 9 with concentrated liquid ammonia. It is evaporated to dryness and the residue is taken up in ethyl acetate, washed with water and with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue (4.8 g) is chromatographed on silica (eluant: methylene chloride ethyl acetate 3.97 g of desired product is obtained. IR Spectrum: (CHC1 3 OH 3596 cm- 1 C=O 1735 cm- 1 C=0 1657 cm- 1 aromatic 1612, 1593, 1511 cm- 1 Preparation B of Example 1: methyl acetamide.

Stage A: bromo N-butyl N-methyl acetamide.

26 g of butylmethylamine in solution in 120 cm 3 of ether is added to a solution, cooled down to -20 0 C, of 11.9 cm 3 of bromoacetyl bromide in 180 cm 3 of ether. The temperature is returned to 20 0 C, the mixture is agitated for 30 minutes, diluted with water and extracted with ether. The extracts are evaporated to dryness under reduced pressure. The residue (27.4 g) is distilled under reduced pressure (0.05 mbar) at 79/83 0 C. 19.36 g of desired product is obtained.

Analysis: C 7

H

14 BrNO 208.105 Calculated: C% 40.40 H% 6.78 N% 6.73 Br% 38.39 Found 40.3 7.0 6.7 38.2 Stage B: 5-[[(dimethyl-(1,1-dimethylethyl)-silyl]-oxy]pentanol.

19.14 g of tertbutylchlorodimethylsilane is added, while 1I cooling, to a solution composed of 10 g of 4-pentanol, 200 cm 3 of methylene chloride, 19.5 cm 3 of triethylamine and 566 mg of 4-dimethylaminopyridine. The mixture is agitated for one hour at ambient temperature, diluted with water, the organic phase is decanted, washed, dried and evaporated to dryness under vacuum. The residue (42 g) is chromatographed on silica (eluant: essence G ethyl acetate 95-5). 23.3 g of silyloxy pentene is obtained which is dissolved in 250 cm 3 of tetrahydrofuran. 6 cm 3 of borane-methylsulphide complex is added at 20 0 C. Agitation is carried out for 30 minutes at 20/25 0 C, then for 30 minutes at 35 0 C. 18 cm 3 of caustic soda 3 lye, then 18 cm 3 of hydrogen peroxide are added at +10 0

C,

and agitation is continued for 30 minutes. The reaction medium is diluted with water, extracted with ethyl acetate, the extracts are washed with a 10% solution of sodium thiosulphate, dried and concentrated to dryness under reduced pressure. The residue (25.85 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 22.7 g of product is collected which is distilled under reduced pressure (0.06 mbar) and 18.7 g of desired compound is obtained.

B.p. 73-75 0 C/0.06 mbar.

Stage C: N-butyl-[(5-hydroxypentyl)-oxy]-N-methyl acetamide.

2.16 g of sodium hydride at 50% in oil is added to a solution of 8 g of the alcohol obtained in Stage B above in i*.

40 cm 3 of tetrahydrofuran, the mixture is agitated for 30 minutes at ambient temperature, a solution of 9.5 g of the brominated product obtained in Stage A above in 13 cm 3 of tetrahydrofuran is added drop by drop over 15 minutes. After agitation for 16 hours at ambient temperature, a saturated aqueous solution of ammonium chloride is added, extraction is carried out with ethyl acetate, the extracts are washed, dried and evaporated to dryness under vacuum. 14.8 g of intermediate N-butyl-[[5-[[dimethyl-(1,1-dimethylethyl)silyl]-oxy]-pentyl]-oxy]-N-methyl acetamide is obtained which is dissolved in 83 cm 3 of tetrahydrofuran and 46 cm 3 of a 1M solution of tetrabutylammonium fluoride. Agitation is carried out for 2 hours at ambient temperature, the mixture is poured into water, extracted with ethyl acetate, evaporated to dryness under reduced pressure. The residue (13.6 g) is chromatographed on silica (eluant: methylene chloride isopropanol 94-6) and 7.28 g of the desired compound is obtained.

IR Spectrum: (CHC1 3 -OH 3628 cm- 1 C=O 1645 cm- 1 Stage D: [(5-bromopentyl)-cxy]-N-butyl-N-methyl acetamide.

13 g of tetrabromomethane and 10.3 g of triphenylphosphine is added at -10 0 C to a solution of 7.2 g of the product obtained in Stage C above in 73 cm 3 of methylene chloride. The reaction medium is agitated for one hour at 0°C and chromatographed on silica (eluant: ethyl acetate cyclohexane 7.49 g of the desired compound is obtained.

CR Spectrum: (CHC1 3 C=O 1644 cm- Analysis C 12

H

2 4 BrN0 2 294.24 Calculated: C% 48.98 H% 8.22 N% 4.76 Br% 27.15 Found 48.6 8.2 4.6 26.3 Example 1: N-butyl-5-(3,17beta-dihydroxy-estra-1,3,5(10)trien-11beta-yl)-phenoxy)-pentyloxy)-N-methyl-ethanethioamide.

Stage A: N-butyl-[5-[4-(3,17-dioxo-estra-4,9-dien-11beta-yl)phenoxy]-pentyloxy]-N-methyl acetamide.

3.75 g of [(5-bromopentyl)-oxy]-N-butyl-N-methyl acetamide obtained above in solution in 6 cm 3 of acetone is added to a solution of 2.5 g of product obtained in Stage B of Preparation A of Example 1 in 26 cm 3 of acetone and 6.4 cm 3 of 2N soda. The mixture is agitated for 5 hours at 50 0

C,

cooled, poured into water, acidified with 2N hydrochloric acid, extracted with ethyl acetate, the extracts are washed, dried and evaporated to dryness under reduced pressure. The residue (6.8 g) is chromatographed on silica (eluant: ethyl acetate) and 2.63 g of the desired product is obtained.

IR Spectrum: (CHC1 3 C=O r1735 cm- 1 (17-keto) 1657 cm- 1 C=C aromatic 1609, 1580, 1509 cm- 1 Stage B: N-butyl-[5-[4-(3-hydroxy-17-oxo-estra-1,3,5(10)trien-11beta-yl)-phenoxy]-pentyloxy]-N-methyl acetamide.

2.61 g of palladium hydroxide at 20% on magnesium oxide is added to a solution of 2.61 g of product obtained in Stage A above in 50 cm 3 of methanol. The mixture is heated under reflux for 30 minutes. The catalyst is filtered off, washed with methanol, the filtrate is evaporated to dryness under reduced pressure and the residue (2.5 g) is taken up in cm 3 of methanol. 2.45 g of potash in pellet form is added and agitation is carried out for 45 minutes at ambient temperature. 130 g of ice and 50 cm 3 of 2N hydrochloric acid are added, extraction is carried out with methylene chloride and the extracts are evaporated to dryness under reduced pressure. The residue (2.75 g) is chromatographed on silica (eluant: ethyl acetate essence G 9-1) and 1.83 g of the desired product is obtained.

IR Spectrum: (CHC1 3 0 OH 3598 cm- 1 C=O 1732 cm- 1 1634 cm aromatic 1611, 1581, 1511 cm- 1 Stage C: N-butyl-[5-[4-(3,17beta-dihydroxy-estra-1,3,5(10)trien-11beta-yl)-phenoxy]-pentyloxy]-N-methyl acetamide.

66 mg of boron and sodium hydride is introduced over minutes into a solution of 500 mg of product obtained in Stage B above in 8 cm 3 of methanol. The mixture is agitated for 2 hours and poured into 40 cm 3 of water, then extracted with methylene chloride. The extracts are evaporated to dryness under reduced pressure. The residue (514 mg) is chromatographed on silica (eluant: ethyl acetate) then a second time with the same eluant. 343 mg of desired product is obtained.

[alpha] D -31.10 (c 1% chloroform).

IR Spectrum: -HC1 3 OH 3603 cm- 1 C=O 1634 cm- 1 (amide III) aromatic 1611, 1581, 1511 cm- 1 Analysis: C 36

H

51 N0 5 577.81 Calculated: C% 74.83 H% 8.89 N% 2.42 Found 74.8 9.0 2.3 Stage D: N-butyl-[5-[4-(3,17beta-diacetoxy-estra-1,3,5(10)trien-11beta-yl)-phenoxy]-pentyloxy]-N-methyl-acetamide.

0.9 cm 3 of 98% acetic anhydride and 23 mg of 4dimethylaminopyridine are added to a solution of 450 mg of product obtained in Stage C above in 2.3 cm 3 of pyridine.

The mixture is agitated for one hour and 5 cm 3 of water and 5 cm 3 of methanol are added. Agitation is carried out for 10 minutes followed by extraction with ethyl acetate.

The extracts are washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue (580 mg) is chromatographed on silica (eluant: ethyl acetate) and the desired product is obtained. IR Spectrum: (CHC13) diacetate 1730, 1760 cm- 1 (shoulder) amide 1640, 1660 cm- I *1 Stage E: N-butyl-[5-[4-(3,17beta-diacetoxy-estra-1,3,5(10)trien-11beta-yl)-phenoxy]-pentoxy]-N-methyl-ethanethioamide. 400 mg of Lawesson reagent is added to a solution of 480 mg of product obtained in Stage D above in 10 cm 3 of toluene.

The mixture is agitated for one hour at 500C. After it has cooled down to ambient temperature, it is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue (840 mg) is chromatographed on silica (eluant; essence G ethyl acetate 1-1) and 450 mg of desired product is obtained. IR Spectrum: (CHC13) diacetate 1730, 1760 cm- 1 (shoulder) aromatic 1600 cm- 1 Stage F: N-butyl-[5-[4-(3,17beta-dihydroxy-estra-1,3,5(10)trien-11beta-yl)-phenoxy]-pentyloxy]-N-methyl-ethanethioamide.

2.8 cm 3 of 2N soda is added to a solution of 480 mg of product obtained in Stage E above in 10 cm 3 of methanol. The mixture is agitated for 4 hours at ambient temperature, then neutralized with 2N hydrochloric acid. Extraction is carried out with ethyl acetate, the extracts are washed with a saturated solution of sodium chloride, dried then evaporated to dryness under reduced pressure. The residue (428 mg) is chromatographed on silica (eluant: essence G ethyl acetate 365 mg of expected product is obtained.

[alpha]D -22.50 1.50 (c 1% CHC1 3 Analysis: for C 36

H

51 N04S 593.88 Calculated: C% 72.81 H% 8.65 N% 2.36 S% 5.40 Found 71.9 8.8 2.3 5.6 IR Spectrum: (CHC1 3 C=O absence OH 3603 cm- 1 associated aromatic 1630, 1581, 1512 cm-1 Preparation of Example 2: 8-bromo-N-butyl-N-methyl octanamide. 9.1 cm 3 of N-methylmorpholine then 10.4 cm 3 of isobutyl chloroformate are added drop by drop at -100/-150C to a solution of 5 g of 8-bromo octanoic acid in 200 cm 3 of methylene chloride. The mixture is agitated for 30 minutes at -100/-150C, then at this temperature 13 cm 3 of N- methylbutylamine is added. The mixture is left to reheat to ambient temperature and left at rest for 40 minutes, then 150 cm 3 of a saturated solution of sodium bicarbonate is added.

Agitation is carried out for 10 minutes. After decanting, extraction is done with methylene chloride, the extracts are washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue is chromatographed on silica (eluant: methylene

CC

chloride acetone 95-5) and 6.14 g of the expected product is obtained.

IR Spectrum: (CHC1 3 C=O 1627 cm- 1 (amide III) Example 2: N-butyl-8-(4-(3,17beta-dihydroxy-estra-1,3,5(10)trien-11beta-yl)-phenoxy)-N-methyl-octanethioamide.

Stage A: 8-[4-(3,17beta-dioxoestra-4,9-dien-11beta-yl)phenoxy]-N-butyl-N-methyl octanamide.

The operation is carried out as in Stage A of Example 1 starting with 725 mg of product obtained in Stage B of Preparation A of Example 1 using 0.2 cm 3 of 8-bromo-N-butyl- N-methyl octanamide obtained in the above preparation. After 0 chromatography on silica (eluant: essence G ethyl acetate 540 mg of the expected product is obtained.

IR Spectrum: (CHC1 3 17-keto 1735 cm- 1 3-keto 1657 cm- 1 amide III 1628 cm- 1 aromatic bands 1580, 1509 cm- 1 of the -0-C 6

H

5 type Stage B: 8-[4-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien- 11beta-yl)-phenoxy]-N-butyl-N-methyl octanamide.

The operation is carried out as in Stage B of Example 1 starting with 470 mg of the product obtained in Stage A above using 260 mg of palladium hydroxide on magnesium oxide.

After chromatography on silica (eluant: ethyl acetate essence G 360 mg of the desired compound is obtained.

IR Spectrum: (CHC1 3 OH 3596 cm-l C=O 1732 cm- 1 amide III 1623 cm- 1 aromatic bands 1581, 1511 cm- 1

I"'

Stage C: N-butyl-8-[4-(3,17beta-dihydroxy-estra-1,3,5(10)trien-11beta-yl)-phenoxy]-N-methyl octanamide.

The operation is carried out as in Stage C of Example 1 starting with 360 mg of the product obtained in Stage B above using 72 mg of boron and sodium hydride. 460 mg of expected product is obtained.

IR Spectrum: (CHC1 3 *6 OH 3602 cm- 1 C=O 1623 cm- 1 (amide III) aromatic bands 1581, 1511 cm- 1 Stage D: N-butyl-8-[4-(3,17beta-diacetoxy-estra-1,3,5(10)trien-11beta-yl)-phenoxy]-N-methyl octanamide.

The operation is carried out as in Stage D of Example 1 starting with 460 mg of product obtained in Stage C above using 0.9 cm 3 of acetic anhydride and 24 mg of 4-dimethyl amino pyridine.

The residue (510 mg) is chromatographed on silica (eluant: essence G ethyl acetate 1-1) and the desired product is obtained.

H IR Spectrum: (CHCl 3 diacetate 1730 cm- 1 1720 cm-1 (shoulder) amide 1630 cm 1 Stage E: N-butyl-8-[4-3,17beta-acetoxy-estra-1,3,5(10)-trien- 11beta-yl)-phenoxy]-N-methyl octane thioamide.

The operation is carried out as in Stage E of Example 1 starting with 510 mg of product obtained in Stage D above using 1.54 g of Lawesson reagent. Heating is carried out at for 3 hours 15 minutes. 1.18 g of residue is obtained which is chromatographed on silica (eluant: essence G ethyl acetate 7-3) and 430 mg of desired product is obtained.

IR Spectrum: (CHCl 3 diacetate 1730 cm 1 1750 cm 1 (shoulder) C=S 1500 cm- 1 Stage F: N-butyl-8-[4-[3,17beta-dihydroxy-estra-1,3,5(10)trien-11beta-yll-phenoxy]-N-methyl-octane thioamide. *1.

The operation is carried out as in Stage F of Example 1 starting with 408 mg of product obtained in Stage E above.

Agitation is carried out at ambient temperature for one hour.

370 mg of residue is isolated. After chromatography, 261 mg of expected product is isolated.

[alpha]D -31.50 1.3° (C 1% CHCl 3 Analysis: C 37

H

5 3NO3S 591.90 Calculated: C% 75.08 H% 9.02 N% 2.37 S% 5.42 Found 75.3 9.2 2.3 5.52 IR Spectrum: (CHC1 3 OH 3601 cm- 1 aromatic 1610 1580 1511 cm- 1 Example 3: 11beta-(4-((7-((butylmethylamino)-carbonyl)heptyl)-oxy)-,henyl)-3-hydroxy-estra-1,3,5(10)-trien-17betayl monobutanedioate.

210 mg of succinic anhydride is added to a solution of 200 mg of product obtained in Stage C of Example 2 in 2 cm 3 of pyridine. The mixture is heated for 5 hours in a bath at 1150C. 2 cm 3 of water, 350 mg of potassium carbonate and 2 cm 3 of methanol are added. Agitation is carried out for 4 hours at ambient temperature, followed by acidification with 6N hydrochloric acid. Extraction is carried out with ethyl acetate, the extracts are washed with a saturated solution of sodium chloride, dried then evaporated to dryness under reduced pressure. The residue (300 mg) is chromatographed on silica (eluant: essence G acetone 6-4, acetic acid and 176 mg of expected product is obtained.

[alpha] D -750 (C 1% CHC1 3 Analysis: C 4 1

H

5 7

NO

7 675.91 Calculated: C% 72.86 H% 8.50 N% 2.07 Found 72.9 8.7 2.1 IR Spectrum: (CHC1 3 OH 3600 cm- 1 C=O complex 1730 cm 1 (shoulder) 1717 cm- 1 C=O amide III 1622 cm- 1 aromatic 1611, 1583, 1511 cm 1 b Example 4: 11beta- ((butylmethylamino)-carbonyl)heptyl)-oxy)-phenyl)-3-hydroxy-estra-1 ,3,5(10 )-trien-17beta- e yl and sodium butanedioate.

A solution of 160 mg of the product obtained in Example 3 in 6 cm 3 of ethanol is added to a solution of 18 mg of sodium bicarbonate in 3 cm 3 of water. The mixture is agitated for 30 minutes, the ethanol is distilled off under 0 reduced pressure and filtration is carried out. After lyophilization, 145 mg of expected product is obtained.

Analysis: C 4 1

H

5 6 N NaO 7 697.90 Calculated: C% 70.56 H% 8.09 N% 2.01 Found 69.9 8.1 Preparation of Example 5: 8-[4-(3,17-dioxo-estra-4,9-dien- 11beta-yl)-phenoxy]-octanoic acid.

335 mg of 8-bromo octanoic acid is added to a solution of 181 mg of product obtained in Stage B of Preparation A of Example 1 in 4 cm 3 of acetone and 1.5 cm 3 of 2N soda. The mixture is maintained under reflux for 5 hours, cooled down to ambient temperature then acidified with 2N hydrochloric acid. Extraction is carried out with ethyl acetate, the extracts are washed with a saturated solution of sodium chloride, dried then evaporated to dryness under reduced -fc pressure. 600 mg of product is obtained which is used as it is.

Example 5: 8-(4-(3,17beta-dihydroxy-estra-1,3,5(10)-trien- 11beta-vl)-phenoxy)-N-(2,2,3,3.4.4,4-heptafluorobutyl)-Nmethyl-octanamide.

Stage A: 8-[4-(3,17-dioxo-estra-4,9-dien-11beta-yl)-phenoxy]- N-(2,2,3,3,4,4,4-heptafluoro butyl)-N-methyloctanamide.

1.29 g of crude product obtained according to the above preparation, 13 cm 3 of methylene chloride and 0.65 cm 3 of methylmorpholine are introduced successively into a spherical flask under nitrogen atmosphere. The mixture is cooled down to -10 0 C and 0.39 cm 3 of isobutyl chloroformate is added drop by drop. Agitation is carried out for 30 minutes at -10 0

C.

1.78 mg of N-heptafluoro butyl N-methylamine hydrochloride obtained in Preparation 1 is introduced into the solution obtained and maintained at -10 0 C. The resultant medium is left to reheat to ambient temperature over 30 minutes, agitated for 30 minutes, washed with a saturated solution of sodium chloride and evaporated to dryness under reduced pressure. The residue (1.88 g) is chromatographed on silica (eluant: essence G ethyl acetate 1-1) and 990 mg of expected product is obtained.

IR Spectrum: (CHCl 3 C=O p1735 cm- 1 (17-keto) 1659 cm- 1 (dienone amidp III) C=C aromatic 1609, 1578, 1509 cm- 1 Stage B: 8-[4-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien-11beta- yl)-phenoxy]-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl octanamide.

980 mg of the product obtained in Stage A above and cm 3 of methylene chloride are introduced into a spherical flask under a nitrogen atmosphere. The mixture is cooled down to 0 C and 1 cm 3 of 98% acetic anhydride and 0.5 cm 3 of acetyl bromide are added over 5 minutes. Agitation is carried out for 45 minutes at ambient temperature then the medium is alkalized with sodium bicarbonate. After agitation for 45 minutes, the organic phase is collected, washed with a saturated solution of sodium chloride, dried then evaporated S-4 to dryness under reduced pressure. The residue obtained (1.02 g) is dissolved under an argon atmosphere in 10 cm 3 of methanol, then 1.4 cm 3 of 2N soda is added. Agitation is carried out for one hour at ambient temperature, followed by neutralizing with 1.4 cm 3 of 2N hydrochloric acid. After extraction with methylene chloride, the extracts are washed with water, dried, then evaporated to dryness under reduced pressure. The residue (1 g) is chromatographed on silica (eluant: essence G ethyl acetate 6-4) and 630 mg of expected product is obtained.

IR Spectrum: (CHC1 3 OH 3600 cm- 1 C=O 1732 cm-' (17-keto) 1658 cm- 1 (amide III) aromatic 1610, 1576, 1511 cm 1 Stage C: 8-[4-(3,17beta-dihydroxy-estra-1,3,5(10)-trien- 11beta-yl)-phenoxy]-N-(2,2,3,3,4,4,4-heptafluorobutyl)-Nmethyl-octanamide.

18 mg of boron and sodium hydride is added to a solution of 310 mg of product obtained in Stage B above in 4 cm 3 of methanol, which is cooled down to 0°C. The mixture is agitated for 45 minutes at 0 0 C, extracted with methylene chloride, the extracts are dried then evaporated to dryness under vacuum. The residue (315 mg) is chromatographed on silica (eluant: essence G ethyl acetate 1-1) and 280 mg of expected product is obtained. Analysis: C 37

H

46

F

7 N0 4 701.77 Calculated: C% 63.33 H% 6.60 F% 18.95 N% 1.99 Found 63.3 6.6 19.3 IR Spectrum: (CHC1 3 OH 3603 cm- 1 C=O 1658 cm- 1 aromatic 1610, 1576, 1511 cm- 1 Preparation of Example 6: 2-[(6-bromcnexyl)-oxy]-N-butyl-Nmethylacetamide.

Stage A: 6-[[dimethyl-(1,1-dimethylethyl)-silyl]-oxy]hexanol.

The operation is carried out as in Stage A of Preparation 3 starting with 8.12 g of sodium hydride at in oil, 20 g of 1,6-hexane diol and 25.5 g of terbutyl dimethyl chloro silane. After chromatography, 20.7 g of expected product is obtained.

IR Spectrum: (CHC1 3 OH 3625 cm- 1 O-Si+ 1257, 837 cm- 1 Stage B: N-butyl-[(6-hydroxyhexyl)-oxy]-N-methyl acetamide.

1.78 g of sodium hydride at 50% in oil is added to a solution of 7 g of product obtained in Stage A above in cm 3 of tetrahycrofuran, agitation is carried out for 40 minutes at ambient temperature, and a solution of 7.8 g of bromo N-butyl N-methylacetamide obtained in Stage A of Preparation B of Example 1 in 10 cm 3 of tetrahydrofuran is added drop by drop over 10 minutes. Agitation is continued for 16 hours at ambient temperature, a saturated aqueous solution of ammonium chloride is added, extraction is carried out with ethyl acetate, the extracts are washed, dried and evaporated to dryness under reduced pressure. The residue (13.4 g) is dissolved in 69 cm 3 of tetrahydrofuran and 48 cm 3 of a 1M solution of tetrabutylammonium fluoride is added.

Agitation is carried out for 3 hours at ambient temperature,, the mixture is poured into water, extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried and then evaporated under reduced pressure. The residue (10.8 g) is chromatographed on silica (eluant: I 6* methylene chloride isopropanol 94-6) and 5.56 g of expected product is obtained.

IR Spectrum: (CHC1 3 OH 3624 cm- 1 C=O 1636 cm- 1 complex Stage C: 2-[(6-bromohexyl)-oxy]-N-butyl-N-methylacetamide.

9.3 g of tetrabromomethane and 7.4 g of triphenyl phosphine are added at -15 0 C to a solution of 5.52 g of product obtained in Stage B above in 55 cm 3 of methylene chloride. The reaction mixture is agitated for one hour at 0°C then chromatographed on silica (eluant: ethyl acetate cyclohexane 7-3) and 6.22 g of expected product is obtained.

3 Analysis: C 1 3

H

2 6 BrNO 2 308.26 Calculated: C% 50.65 H% 8.50 N% 4.54 Br% 25.92 Found 50.4 8.8 4.6 25.5 IR Spectrum: (CHC1 3 C=O 1640 cm-1 Example 6: N-butyl-2-(6-(3,17beta-dihydroxy-estra-1,3,5(10)trien-11beta-vl)-phenoxy)-hexyloxy)-N-methyl- acetamide.

Stage A: N-butyl-2-[6-[4-(3,17-dioxo-estra-4,9-dien-llbetayl)-phenoxy]-hexyloxy]-N-methyl acetamide.

The operation is carried out as in Stage A of Example 1 starting with 2 g of product obtained in Stage B of :,.Ze Preparation A of Example 1 using 3.14 g of 2-[(6-bromohexyl)oxy]-N-butyl-N- methyl acetamide obtained above. The residue (5.7 g) is chromatographed on silica (eluant: ethyl acetate) and 2.68 g of the expected product is obtained.

IR Spectrum: (CHC1 3 C=O 1735 cm-1 (17-keto) 1656 cm- 1 (dienone amide III) a aromatic 1609, 1580, 1509 cm- 1 Stage B: N-butyl-2-[6-[4-(3-hydroxy-17-oxo-estra-1,3,5(10)trien-11beta-yl)-phenoxy]-hexyloxyI-N-methylacetamide.

The operation is carried out as in Stage B of Example 1 o. 0 starting with 2.63 g of product obtained in Stage A above :0 using 2.63 g of palladium hydroxide on magnesium oxide. The residue (2.165 g) is chromatographed on silica (eluant: methylene chloride isopropanol 94-6) and 1.62 g of expected product is obtained.

S

IR Spectrum: (CHC1 3 OH 3599 cm- 1 C=O 1732 cm-1 (17-keto) 1635 cm- 1 (amide III) Stage C: N-butyl-2-[6-4-(3,17beta-dihydroxy-estra-1,3,5(10)trien-llbeta-yl)-phenoxy-N-methylacetamide.

The operation is carried out as n Stage C of Example 1 starting with 450 mg of product obtained in Stage B above using 58 mg of boron and sodium hydride. The residue (461 mg) is chromatographed on silica (eluant: methylene chloride isopropanol 94-6) then a second time (eluant: -z ethyl acetate). 274 mg of expected product is obtained.

[alpha]D -32.50 (C 1% ethanol) Analysis: C 37

H

53

NO

5 591.84 Calculated: C% 75.09 H% 9.03 N% 2.37 Found 75.4 9.1 2.4 IR Spectrum: (CHC1 3 OH 3603 cm- 1 C=O 1635 cm- 1 aromatic 1611, 1581, 1511 cm- 1 Preparation of Example 7: 8-bromo-N-butyl-N-methyl-2octynamide.

Stage A: dimethyl-(1,1-dimethyl-ethyl)-[(5-heptyn-l-yl)oxy]-silane. 1.63 g of lithium acetylide, ethylene diamine complex and 15 cm 3 of dimethyl sulphoxide are introduced into a spherical flask under a nitrogen atmosphere. The mixture is agitated for 30 minutes at ambient temperature, then 3.64 g of the product obtained in Preparation 2 is added over 45 minutes. Agitation is carried out for 4 hours, the mixture is poured into an ice-cooled saturated solution of ammonium chloride, washed with hexane, then with water, dried and evaporated to dryness under reduced pressure. 3.08 g of crude product is obtained. Stage B: 8-[(dimethyl-(1,1-dimethyl-ethyl)]-silyloxy]-2- octynoic acid. 2.4 cm 3 of a solution of butyl lithium at 15% in hexane is added at -60 0 /-70 0 C under a nitrogen atmosphere to a solution of 630 mg of the crude product obtained in Stage A above in 4 cm 3 of tetrahydrofuran. The mixture is agitated for 15 minutes at -60 0 C, then placed under a CO 2 atmosphere.

It is left under CO 2 for 15 minutes at -60 0 C, then left to return to ambient temperature. It is diluted with water and ethyl acetate while emulsifying. The aqueous phase is separated out then the organic phase is extracted with an aqueous solution of sodium bicarbonate. The alkaline aqueous phase is acidified by the addition of monosodium phosphate, then extracted with ethyl acetate. The organic phase is evaporated to dryness under reduced pressure and 540 mg of LA the expected product is obtained.

Stage C: N-butyl-8-[[dimethyl-(1,1-dimethyl-ethyl)]silyloxy]-N-methyl-2-octynamide.

2.8 cm 3 of methyl morpholine is added to a solution of 4.55 g obtained according to the process of Stage B above in cm 3 of methylene chloride, the mixture is cooled down to 0 C under a nitrogen atmosphere then 3.3 cm 3 of isobutyl chloroformate in solution in 10 ml of methylene chloride is added slowly. After agitation at -5 0 C for 35 minutes, 4 cm 3 of methyl butylamine is added at 0 C over 5 minutes. The reaction medium is left to return to ambient temperature and poured into an aqueous solution of sodium bicarbonate.

Extraction is carried out with methylene chloride, the extracts are dried and evaporated to dryness under reduced pressure. The residue (6.9 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 7-3) and 2 g of expected product is obtained.

IR Spectrum: (CHC1 3 C=-C 2234 cm- 1 C=O 1616 cm" 1 (conjugated) C-O-Si+ 1257, 1094, 836 cm- 1 Stage D: N-butyl-8-hydroxy-N-methyl-2-octynamide.

1 cm 3 of 2N hydrochloric acid is added to a solution of 1.9 g of product obtained in Stage C above. The mixture is maintained for one hour at ambient temperature, extracted with ethyl acetate, the extracts are washed with water, dried 6 and evaporated to dryness under reduced pressure. The residue (1.79 g) is chroma.ographed on silica (eluant: ethyl acetate). 870 mg of expected product is obtained.

IR Spectrum: (CHC1 3 OH 3625 cm- 1 C=C 2285 cm- 1 C=O 1616 cm 1 (amide) Stage E: 8-bromo-N-butyl-N-methyl-2-octynamide.

1.205 g of triphenylphosphine is added to a solution of 855 mg of product obtained in Stage D above in 4 cm 3 of methylene chloride. The mixture is cooled down to -10 0 C and 1.522 g of tetrabromomethane is added. After agitation for one hour at -5 0 C the reaction mixture is chromatographed on silica (eluant: cyclohexane ethyl acetate 35-65). 0.98 g of expected product is obtained.

Example 7: N-butyl-8-(4-(3,17beta-dihydroxy-estra-1,3,5(10)trien-11beta-yl)-phenoxy)-N-methyl-2-octynamide.

Stage A: N-butyl-8-[4-(3,17-dioxo-estra-4,9-dien-11beta-yl)phenoxy]-N-methyl-2-octynamide.

A solution of 970 mg of product obtained in Stage E above in 6 cm 3 of acetone is introduced over 40 minutes into a solution of 1.09 g of the product obtained in Stage B of Preparation A of Example 1 in 20 cm 3 of acetone and 1.5 cm 3 of 2N soda which is taken to reflux under a nitrogen atmosphere. The mixture is maintained under reflux for 6 hours, cooled down and diluted with an ammonium chloride solution. Extraction is carried out with methylene chloride, the extracts are washed, dried and evaporated to dryness under reduced pressure. The residue (2.13 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 4-6) and 1.21 g of expected product is obtained. IR Spectrum: (CHC1 3 C C 2235 cm- 1 C=O 1735 cm-1 (17-keto) 1658 cm- 1 (dienone) 1614 cm- 1 (amide) aromatic 1580, 1509 cm- 1 Stage B: N-butyl-8-(4-(3,17beta-dihydroxy-estra-1,3,5(10)- 00 trien-11beta-yl)-phenoxy)-N-methyl-2-octynamide.

0.8 cm 3 of acetic anhydride and 0.4 cm 3 of acetyl bromide are added to the solution of 830 mg of product obtained in Stage A above in 8 cm 3 of methylene chloride cooled down to 00/+5 0 C and under a nitrogen atmosphere. The mixture is maintained at this temperature for 10 minutes, then at ambient temperature for one hour. A saturated solution of sodium bicarbonate is added, an emulsion is made, 3.5 ml of methanol is added then extraction is carried out with methylene chloride. The organic phase is collected, washed with the above bicarbonate solution, dried and evaporated to dryness under reduced pressure. 950 mg of 43 product is obtained which is used as it is in solution in cm 3 of methanol and which is cooled down to 00 5 0 C. 0.2 g of boron and sodium hydride is added. Agitation is carried out for 45 minutes, 2 cm 3 of water and 1 ml of 2N soda are added. The reaction medium is maintained for one hour at ambient temperature, diluted with a saturated solution of ammonium chloride, extracted with methylene chloride. The organic phase is collected, washed with water, dried and evaporated to dryness under reduced pressure. The residue (850 mg) is chromatographed on silica (eluant: cyclohexane ethyl acetate 4-6) and 438 mg of expected product is obtained.

Analysis: C 37

H

49 N04 571.81 Calculated: C% 77.72 H% 8.63 N% 2.44 Found 77.7 8.9 2.3 IR Spectrum: (CHCl 3 OH 3603 cm- 1 C ~C 2235 cm- 1 C=O 1612 cm- 1 (conjugated amide) aromatic 1581, 1511 cm- 1 Preparation of Example 8: methyl acetamide.

Stage A: cm 3 of 5-chloropentanol is added to a suspension of potassium thioacetate in 100 cm 3 of ethanol. Under a nitrogen atmosphere, the mixture is maintained under reflux for one hour. After cooling, 100 cm 3 of ethyl ether is added, followed by filtering and evaporating the filtrate to dryness. 100 cm 3 of ethyl ether is added to the oily residue obtained. The precipitate formed is filtered and the organic solution is evaporated to dryness. 12.5 g of oily residue is obtained which is put in solution in 50 cm 3 of methanol. cm 3 of 10N soda is added and the solution is maintained for one hour at ambient temperature. A saturated solution of ammonium chloride is added, extraction is carried out with ethyl acetate then with methylene chloride. The organic phases are dried and evaporated to dryness under reduced pressure. 9.3 g of oily residue is obtained which is put in 4 1 solution in 50 cm 3 of methanol with 10% water, and nitrogen is bubbled through for 15 minutes. 5 cm 3 of n-tributylphosphine is added slowly over 2 minutes and the whole is maintained for 2 hours 30 minutes at ambient temperature.

Extraction is carried out with ethyl acetate, the extracts are dried and evaporated to dryness under reduced pressure.

The residue (13.6 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 1-1) and 6.55 g of expected product is obtained.

IR Spectrum: (CHC1 3 on product purified by distillation 90/95 0 C under 10 mm Hg)..

OH 3624 cm- 1 SH 2570 cm- 1 Stage B: acetamide.

1.4 g of sodium hydride at 50% in oil and 6 g of bromo N-butyl-N-methyl acetamide obtained in Stage A of Preparation B of Example 1 are added to a solution of 3.36 g of product obtained in Stage A above in 45 cm 3 of tetrahydrofuran under a nitrogen atmosphere. The mixture is agitated for 2 hours at ambient temperature, poured into an ammonium chloride solution, extracted with ethyl acetate, the extracts are washed and evaporated to dryness under reduced pressure. The residue (10 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 2-8) and 5.27 g of expected product is obtained.

IR Spectrum: (CHC1 3 OH 3623 cm- 1 C=O 1632 cm- 1 (amide III) Stage C: 2-[(5-bromopentyl)-thio]-N-butyl-N-methyl acetamide.

6.88 g of triphenylphosphine is added to a solution of 5.27 g of product obtained in Stage B above in 52 cm 3 of methylene chloride. The mixture is cooled down to 0 0 /+5 0

C

under a nitrogen atmosphere, 8.68 g of tetrabromo methane is added, with agitation for one hour at 0°C, the reaction mixture is chromatographed on silica (eluant: cyclohexane ethyl acetate 2-1) and 6.2 g of expected product is obtained.

IR Spectrum: (CHC1 3 C=O 1638 cm- 1 (amide III) Example 8: N-butyl-2-((5-(4-(3,17beta-dihydroxy-estra- 1,3,5(10)-trien-11beta-yl)-phenoxy)-pentyl)-sulphinyl)-Nmethyl-acetamide.

Stage A: N-butyl-2-[5-[4-(3,17-dioxo-estra-4,9-dien-11betayl)-phenoxy]-pentylthio]-N-methylacetamide.

5.1 cm 3 of 2N soda is added to a solution of 3.09 g of product obtained in Stage B of Preparation A of Example 1 in cm 3 of acetone, the mixture is heated under reflux under a nitrogen atmosphere and 6.2 g of product obtained in Stage D above is added in 4 fractions over 2 hours. The mixture is maintained under reflux for one hour 20 minutes, cooled down, and diluted with a saturated solution of ammonium chloride. Extraction is carried out with ethyl acetate, the extracts are washed, dried, and evaporated to dryness under reduced pressure. The residue (10 g) is chromatographed on silica (eluant: essence G ethyl acetate 4-6) and 3.4 g of expected product is obtained. IR Spectrum: (CHC1 3 i" C=O (1735 cm- 1 (17-keto) 1656 cm 1 (dienone) 1640 cm- 1 (amide III) C=C 1610, 1580, 1509 cm- 1 aromatic Stage B: N-butyl-[5-[4-(3-hydroxy-17-oxo-estra-1,3,5(10)- trien-11beta-yl)-phenoxy]-pentylthio]-N-methylacetamide. The operation is carried out as in Stage B of Example starting with 2.6 g of product obtained in Stage A above in 26 cm 3 of methylene chloride under a nitrogen atmosphere and by adding 2.6 cm 3 of acetic anhydride and 1.3 cm 3 of acetyl bromide. After chromatography on silica 1.6 g of expected product is obtained.

IR Spectrum: (CHCl 3 OH 3598 cm- 1 C=O 1732 cm- 1 (17-keto) 1627 cm- 1 (amide III) aromatic 1581, 1511 cm- 1 Stage C: N-butyl-[5-[4-(3,17beta-dihydroxy estra-1,3,5(10)- Z, C, trien-1 lbeta-yl) -phenoxy] -pentylthiol-N-methylacetamide.

The operation is carried out as in Stage C of Example starting with 600 mg of product obtained in Stage B above and mg of boron and sodium hydride. The expected product is obtained.

IR Spectrum: (CHCl 3 OH 3603 cm- 1 associated) C=O 1627 cm- 1 aromatic 1581, 1511 cm- 1 [aiphalD -32.50 (C CHCl 3 Stage D: N-butyl-2-f [5-I l7beta-*dihydroxy-estra- 1 ,3,5(1o)-trien-llbeta-yl)-phenoxyl-pentyl-sulphinyl]-Nmethylacetamide.

4 cm 3 of a 0.1M solution of sodium periodate is added to a solution of 147 mg of product obtained in Stage C above in cm 3 of methanol. The mixture is heated under reflux for minutes, cooled down, diluted with water, extracted with chloroform and the extracts are evaporated to dryness under reduced pressure. The residue (180 mg) is chromatographed on silica (eluant: ethyl acetate acetone 1-1) and 150 mg of expected product is obtained.

Analysis: C 36

HE;

1 N0 5 S =609.88 Calculated: C% 70.90 H% 8.42 N% 2.29 S% 5.27 Found 71.0 8.6 2.3 5.1 IR Spectrum: (CHCl 3 OH 3604 cm- 1 associated) C=O 1637 cm- 1 aromatic 1611, 1581, 1511 cm* 1 Preparation A of Example 9: 3,l7beta-bis-[tetrahydro-2H-2pyrannyl)-oxy] (4-ethynyl-phenyl)-estra-1,3,5(1 0)-trien- 1 lbeta-yl.

Stage A: (5aipha, ilbeta) 3-(cyclic 1,2--ethanediyl acetal) 5-hydroxy-11-I[4-(1 ,1-dimethylethyl)-dimethylsilyl]-ethynYlphenyl I-estr-9-en-3, 17-dione.

The operation is carried out as in Stage A of Preparation A of Example 1 starting with 30 g of 3-(cyclic 1,2-ethanediyl acetal of Salpha, l0alpha-epoxy estr-9,11-ene- 3,7-dione obtained according to EP 0 057 115 (Example 7) a a. a a S.

S.

a a a Sa a a. *aaa a. a a a *5 S a. a S a

S.

a..

a a.aS a. a a a a.

a. S a a a.

1i4 using for the preparation of the magnesium compound 81.254 g of bromine derivative, 4 -trimethylsilylethynyl-bromobenzene obtained in Preparation 4 and 7.96 g of magnesium, then for the condensation, 1.4 g of copper chloride. The crude product obtained, to which is added the product from an operation carried out in an identical way starting with 16.52 g of epoxide, is chromatographed on silica (eluant: methylene chloride acetone 98-2). 50.8 g of pure product A and 6 g of slightly less pure product B are obtained, which are used as they are for the following stage.

IR Spectrum: (CHC1 3 OH 3508 cm- 1 C=C 2156 cm- 1 1602 cm- 1 aromatics 1555 cm- 1 1502 cm- 1 Stage B: 11beta-(4-ethynylphenyl)-estra-4,9-dien-3,17-dione.

A suspension of 46.8 g of the product obtained in Stage A, 200 cm 3 of ethanol and 8.1 cm 3 of caustic soda lye is agitated for 30 minutes. Next 16.7 cm 3 of concentrated hydrochloric acid is added, agitation is carried out at ambient temperature then the mixture is concentrated to half its volume, extracted with methylene chloride, the extracts are dried and evaporated under reduced pressure. The residue (38.23 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 1-1) and 31.06 g of desired product is obtained. M.p. 184 0

C.

IR Spectrum: (CHCl 3 C CH 3302 cm- 1 C=O 1736 cm- 1 (17-keto) 1659 cm- 1 1640 cm- 1 dienone aromatic 1556, 1506 cm- 1 Stage C: 3beta-hydroxy-estra-1,3,5(10)-trien-11beta-yl-(4ethynylphenyl)-17-one.

47.1 cm 3 of acetic anhydride and 23.8 cm 3 of acetyl bromide are added at 0 0 /-5 0 C to a solution of 31 g of product obtained in Stage B in solution in 340 ml of methylene 4 chloride. The mixture is agitated for one hour 30 minutes at ambient temperature then poured into a mixture of 2 litres of a saturated solution of sodium bicarbonate and 700 g of ice.

Agitation is carried out for 15 minutes followed by extraction with methylene chloride, and the extracts are evaporated to dryness under nitrogen at reduced pressure.

The residue is chromatographed on silica (eluant: methylene chloride acetone 31.2 g of is obtained with the acetate at position 3, which is agitated for one hour in 930 cm 3 of methanol and 20.96 g of potash. After cooling down to 0°C, and neutralizing with 2N hydrochloric acid, extraction is carried out with methylene chloride and the extracts are evaporated to dryness under reduced pressure. After..

chromatography on silica (eluant: cyclohexane ethyl acetake 27.03 g of crude product is obtained which is made into a paste in ether in order to collect 22.85 g of the desired product. M.p. 163 0

C.

IR Spectrum: (CHC1 3 OH 3597 cm-1 C.=CH 3303 cm- 1 C=O 1733 cm- 1 aromatic 1606, 1582, 1556, 1503 cm- 1 Stage D: 3,17beta-bis-[(tetrahydro-2H-2-pyrannyl)-oxy]-(4ethynylphenyl)-estra-1,3,5(10)-trien-11beta-yl. a) Reduction of the ketone in position 17. i g of boron and sodium hydride is added at 0 0 /+5 0 C to a solution of 14 g of product obtained in Stage C in 120 cm 3 of methanol, and the resultant mixture is agitated for 3 hours at ambient temperature. 380 g of a water ice (1-1) mixture is added then the pH is adjusted to between 4 and with 2N hydrochloric acid, sodium chloride is added until saturation is reached and extraction is carried out with ethyl acetate. The residue is evaporated to dryness. 17.3 g of crude product is isolated.

b) Dihydropyranylation 17.3 g of the 17-hydroxy intermediate obtained above is agitated for 2 hours 30 minutes in the presence of 700 cm 3 of ether, 34.4 cm 3 of dihydropyran and 0.3 g of paratoluene I sulphonic acid. 35 cm 3 of triethylamine is added, the medium is poured into a mixture of ice and a saturated solution of sodium bicarbonate. Extraction is carried out with ether, followed by filtering and evaporating to dryness under nitrogen at reduced pressure. The residue is chromatographed on silica (eluant: cyclohexane ethyl acetate 13.6 g of crude product is obtained which is taken up in isopropyl ether in order to collect 10.23 g of desired product. M.p. 213-215 0

C.

IR Spectrum: (CHC13) C SCH 3302 cm- 1 aromatic 1607, 1570, 1556, 1498 cm- 1 Preparation B of Example 9: 5-[4-[3,17beta-bis-[(tetrahydro- 2H-2-pyrannyl)-oxy]-estra-1,3,5(10)-trien-11beta-yl]-phenyl]- 4-pentyl-l-ol.

Stage A: 3,17beta-bis-[(tetrahydro-2H-2-pyrannyl)-oxy]- 11beta-[4-5-[[dimethyl-(11-dimethyl-ethyl)-silyll-oxy]-1- pentynyl]-phenyl]-estra-1,3,5(10)-triene. 3 5.9 cm 3 of hexamethylphosphorotriamide is added to a solution of 714 mg of product obtained in Stage D of Preparation A above in 5.9 cm 3 of tetrahydrofuran. 1.5 cm 3 of 1.32M solution of butyl lithium in hexane and then 669 mg of brominated product obtained in Stage B of Preparation 3 are added over 5 minutes at -35 0 C. Agitation is carried out s over one hour at ambient temperature, then the mixture is poured into a saturated aqueous solution of sodium chloride. Extraction is carried out with ethyl acetate, the extracts 0e are washed with a saturated solution of sodium chloride, dried then evaporated to dryness under reduced pressure. The residue obtained is dissolved in water then extracted with ethyl ether, the extracts are washed with water, dried and evaporated to dryness under reduced pressure. The residue obtained (1.198 g) is chromatographed on silica (eluant: ethyl acetate cyclohexane 1-9 with 0.1% triethylamine) and 941 mg of expected intermediate product is obtained.

Stage B: 5-(4-[3,17beta-bis-[(tetrahydro-2H-2-pyrannyl)-oxy)estra-1,3,5(10)-trien-11beta-yl]-phenyl]-4-pentyn-1-ol.

1.4 cm 3 of a 1M solution of tetrabutylammonium fluoride o is added to a solution of 931 mg of product obtained in Stage A above in solution in 10 cm 3 of tetrahydrofuran. The mixture is agitated for one hour 45 minutes at ambient temperature then poured into water, extracted with ethyl acetate, the extracts are washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue (755 mg) is chromatographed on silica (eluant: ethyl acetate cyclohexane 4-6 with 0.1% triethylamine). 408 mg of expected product is obtained.

IR Spectrum: (CHC1 3 OH 3640 cm- 1 aromatic 1500, 1610 cm 1 0 Preparation C of Example 9: N-methyl-N-butyl-mercapto- acetamide.

Stage A: 2-(acetylthio)-N-butyl-N-methylacetamide. 4.16 g of bromo-N-butyl-N-methylacetamide obtained in Preparation B of Example 1 Stage A in 1.5 cm 3 of methanol is added to a suspension of 2.28 g of potassium thioacetate in cm 3 of methanol, the mixture is heated for one hour at 40 0 C under an argon atmosphere. After evaporation to dryness under reduced pressure, the residue is dissolved with ethyl ether, the insoluble part is filtered off and the solution is evaporated to dryness. 4.06 g of oily productis obtained. IR Spectrum: (CHC1 3 C=O 1644 cm- 1 (amide) acetate 1700 cm- 1 Stage B: N-methyl-N-butyl mercaptoacetamide. 1 cm 3 of hydrazine hydrate is added to a solution of 3.99 g of product obtained in Stage A above in 10 cm 3 of tetrahydrofuran, agitation is carried out for 16 hours at ambient temperature, 0.5 cm 3 of hydrazine hydrate is added, agitation is continued for 16 hours at ambient temperature and the medium is poured into a mixture of 40 cm 3 of 2N hydrochloric acid and 40 g of ice. Extraction is carried out with ethyl acetate, the extracts are washed with a saturated solution of sodium chloride, dried, and evaporated to dryness under reduced pressure. The residue (3.13 g) is chromatographed on silica (eluant: ethyl acetate ethyl ether 7-3) and 79.5 mg of expected product is obtained.

Example 9: N-butyl-2-((5-(4-(3,17beta-dihydroxy-estra- 1,3.5(10)-trien-11beta-vl)-phenyl)-pentyl)-thio)-N-methylacetamide.

Stage A: 2-[[5-[4-[3,17beta-bis[(tetrahydro-2H-2-pyrannyl)oxy-estra-1,3,5(10)-trien-11beta-yl]-phenyl]-4-pentynyl]thio]-N-butyl-N-methyl acetamida.

cm 3 of pyridine and 259 mg of tosyl chloride are added to a solution of 408 mg of product obtained in Stage B of Preparation B above. The mixture is agitated for 4 hours at ambient temperature then poured into a saturated aqueous solution of potassium bicarbonate, extracted with ethyl acetate, the extracts are washed with a satur-ted solution of sodium chloride, dried and evaporated to dryness under reduced pressure. rhe tosylated crude product obtained (512 mg) is dissolved in 4.5 ml of methanol and 165 mg of N- mechyl-N-butyl mercaptoacetamide obtained in Preparation C above and 0.94 cm 3 of a solution of sodium methylate at 58.4 mg/cm 3 in methanol are added. Reflux is maintained until total reaction is achieved, and the methanol is evaporated under reduced pressure. Water is added, extraction is carried out with ethyl acetate, the extracts are washed with a saturated aqueous solution of sodium chloride, dried then evaporated to dryness under reduced pressure. The residue (677 mg) is chromatographed on silica (eluant: ethyl acetate- cyclohexane 4-6 with 0.1% triethylamine) and 315 mg of expected product is obtained. 64 IR Spectrum: (CHC1 3 C=O 1640 cm- 1 (amide III) aromatic 1500, 1580 cm- 1 Stage B: N-butyl-2-[[5-[4-[3,17beta-dihydroxy-estra- 1,3,5(10)-trien-11beta-yl]-phenyl]-4-pentynyl]-thioj-Nmethyl-acetamide.

16 cm 3 of methancl, then 3.2 cm 3 of 2N hydrochloric acid are added to a solution of 315 g of product obtained in Stage A above. The mixture is agitated for one hour at ambient temperature, then poured into a saturated aqueous solution of sodium chloride. Extraction is carried out with methylene chloride, the extracts are washed, dried then evaporated to dryness under reduced pressure. 225 mg of expected product is obtained.

IR Spectrum: (CHCl 3 OH 3610 cm- 1 C=O 1640 cm- 1 (amide III) aromatic 1500, 1590 cm- 1 Stage C: N-butyl-2-((5-(4-(3,17beta-dihydroxy-estra- 1,3,5(10)-trien-11beta-yl)-phenyl)-pentyl)-thio)-Nmethylacetamide.

mg of tris(triphenylphosphine)chlororhodium is added to a solution of 222 mg of product obtained in Stage B above in 2.2 cm 3 of methanol and 2.2 cm 3 of toluene. Hydrogenation is carried out under 1885 mbars for 18 hours. A further 22.5 mg of tris(triphenylphosphine)chlororhodium, 0.7 cm 3 of ethanol and 0.7 cm 3 of toluene are added. Hydrogenation is carried out until saturation is obtained. Evaporation to dryness is carried out under reduced pressure. The residue (333 mg) is chromatographed on silica (eluant: ethyl acetate cyclohexane 7-3) and 103 mg of expected product is .,.tained.

Analysis: C 36

H

51 N0 3 S 577.88 Calculated: C% 74.82 H% 8.89 S% 5.55 N% 2.42 0* Found 74.4 8.8 6.0 2.7 IR Spectrum: (CHC1 3 OH 3608 cm- 1 associate) C=O 1625 cm- 1 (amide III) aromatic 1583, 1499 cm- 1 Preparation of Example 10: 7-bromo-N-butyl-N-methylheptanamide.

The operation is carried out as in the preparation of Example 2 starting with 707 mg of 7-bromoheptanoic acid, obtained by agitation for 3 hours of 3 g of ethyl 7bromoheptanoate in 28 cm 3 of 2N soda and 10 cm 3 of ethanol then extraction at pH=1 with ethyl ether and evaporation to dryness under vacuum of 1.4 cm 3 of N- methylmorpholine, 1.69 cm 3 of isobutyl chloroformate, then 2.1 cm 3 of Nmethylbutylamine. 3.124 g of oily residue is isolated which i is distilled under reduced pressure and 676 mg of expected product is obtained in the form of an oil.

IR Spectrum: (CHC1 3 C=O 1630 cm- 1 (amide III) Example 10: N-butyl-4-(3.17beta-dihydroxy-estra-1,3.5(10)trien-11beta-yl)-N-methyl-benzenenonamide.

Stage A: 9-[4-[3,17beta-bis-[(tetrahydro-2H-2-pyrannyl)-oxy]estra-1,3,5(10)-trien-11beta-yl]-phenyl]-N-bucyl-N-methyl-8nonynamide.

5 cm 3 of hexamethylphosphorotriamide, then slowly 1.22 cm 3 of a 1.1M solution of butyl lithium in hexane are added at -30 0 C to a solution of 0.6 g of 3,17beta-bis-[(tetrahydro- 2H-2-pyrannyl)-oxy]-(4-ethynylphenyl)-estra-1 ,3,5(10)-trien- 11beta-yl obtained in Stage D of Preparation A of Example 9 in 5 cm 3 of tetrahydrofuran. The mixture is agitated at 0 C for 30 minutes then 0.401 g of brominated product obtained in the above preparation is added. Agitation is carried out for one hour 30 minutes at ambient temperature then the mixture is poured into 20 cm 3 of a saturated aqueous solution of monosodium phosphate. Extraction is carried out with methylene chloride, the extracts are dried, and evaporated to dryness under reduced pressure. The residue (5.4 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 1-1) and 0.67 g of expected product is obtained. IR Spectrum: (CHC1 3 C=O 1626 cm- 1 (amide III) aromatic 1580, 1550, 1497 cm- 1 Stage B: N-butyl-4-(3,17beta-dihydroxy-estra-1,3,5(10)-trien- 11beta-yl)-N-methyl-benzenenonamide.

cm 3 of 2N hydrochloric acid then 20 cm 3 of water are added to a solution of 0.640 g of product obtained in Stage A above in 20 cm 3 of ethanol. Extraction is carried out with methylene chloride, the extracts are dried and evaporated to dryness under reduced pressure and 0.494 mg of residue is isolated.

mg of palladium on charcoal is added to a solution of 0.26 g of the above crude product in 20 cm 3 of ethanol and hydrogenation is carried out under 1120 mbars for 20 minutes.

After filtration and washing in ethanol, the solution is evaporated to dryness under reduced pressure. The residue (0.272 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 1-1) and 0.198 mg of expected product is obtained.

Analysis: C 38

H

55

NO

3 573.87 Calculated: C% 79.53 H% 9.66 N% 2.44 Found 79.8 9.8 2.4 IR Spectrum: (CHCl 3 OH 3603 cm 1 associated C=O 1622 cn- 1 aromatic 1582, 1429 cm- 1 Preparation of Example 11: [(3-bromopropyl)-oxy]-N-butyl-Nmethylacetamide.

Stage A: N-butyl-[(3-hydroxypropyl)-oxy]-N-methylacetamide. The operation is carried out as in Stage B of the preparation of Example 6 starting with 2.5 g of 3- [[(dimethyl-(1,1-dimethylethyl)-silyl]-oxy]-propanol obtained in Stage A of Preparation 3, 775 mg of sodium hydride at in oil and 3.42 g of bromo-N-butyl-N-methylacetamide. 4.92 g of residue is obtained which is treated with 16.4 cm 3 of a tetrabutyl ammonium fluoride solution. After chromatography 1.61 g of expected product is obtained. Analysis: C 10

H

21 0 3 N 202.283 Calculated: C% 59.08 H% 10.41 N% 6.89

VS

Found 58.5 10.6 6.4 IR Spectrum: (CHC13) OH 3620 cm 1 associated) C=O 1645 cm- 1 (amide III) Stage B: [(3-bromopropyl)-oxy]-N-butyl-N-methylacetamide.

The operation is carried out as in Stage C of the preparation of Example 6 starting with 1.56 g of product obtained in Stage A above, 3.18 g of tetrabromomethane and 2.51 g of triphenylphosphine. After chromatography, 1.356 g of expected product is obtained.

Analysis: C 10

H

20 BrNO 2 266.18 Calculated: C% 45.12 H% 7.57 N% 5.26 Br% 30.2 Zound 45.2 7.8 5.1 29.4 IR Spectrum: (CHC1 3 C=O 1646 cm- 1 (amide III) Example 11: N-butyl-2-((5-(4-(3,17beta-dihvdroxy-estra- 1.3.5(10)-trien-11beta-yl)-phenyl)-pentyl)-oxy)-N-methylacetamide.

Stage A: N-butyl-N-methyl-2-[[5-[4-[3,17beta-bis- [(tetrahydro-2H-2-pyrannyl)-oxy]-estra-1,3,5(10)-trien- 11beta-yl]-phenyl]-4-pentynyl]-oxy]-acetamide.

The operation is carried out as in Stage A of Example 9 starting with 800 mg of product obtained in Stage D of Preparation A of Example 9, 6.5 cm 3 of hexamethyl phosphorotriamide and 1.9 cm 3 of 1M butyl lithium solution then 517 mg of product obtained in Stage B of the above preparation. Extraction is carried out with methylene chloride and 5.858 g of intermediate residue is obtained.

The residue (1.42 g) is chromatographed on silica (eluant: ethyl acetate cyclohexane 1-1 with 0.1% triethylamine) and 478 mg of expected prodv is obtained.

IR Spectrum: (CHC1 3 C=O 1645 cm- 1 (amide III) aromatic 1583, 1500 cm- 1 Stage B: N-butyl-2-[[5-[4-(3,17beta-dihydroxy-estra- 1,3,5(10)-trien-11beta-yl)-phenyl]-pentyl]-oxy]-N-methyl- acetamide. The operation is carried out as in Stage B of Example 10 starting with 478 mg of product obtained in Stage A above in e.

solution in methanol then the intermediate residue (356 mg) is hydrogenated in the presence 178 mg of palladium on charcoal. After chromatography of the residue (317 mg) (eluant: ethyl acetate cyclohexane 199 mg of expected product is obtained.

Analysis: C 36

H

51 N04 561.81 Calculated: C% 76.96 H% 9.15 N% 2.49 Found 77.0 9.3 2.6 IR Spectrum: (CHC1 3 OH 3604 cm- 1 associate) C=O 1633 cm- 1 (amide III) aromatic 1583, 1500 cm-1 Preparation of Example 12: sodium 6-bromo hexanoate.

cm 3 of N soda is added to a solution of 14.60 g of 6bromohexanoic acid in 20 cm 3 of methylene chloride, then distillation is carried out at 60 0 C. The residue is washed with toluene and the product obtained is used as it is.

Example 12: 8-(4-(3,17beta-dihdroxv-estra-1,3,5(10)-trien- 1lbeta-vl)-phenyl)-N-(2,2,3,3,44,4-heptafluorobutyl)-Nmethvl-7-octynamide.

Stage A: 8-[4-13,1 7beta-bis-[(tetrahydro-2H-2-pyrannyl)-oxylestra-1,3,5(10)-trien- lbeta-yl]-phenyl]-7-octynoic acid.

cm 3 of hexamethylphosphorotriamide then 31.5 cm 3 of a 1M solution of butyl lithium in hexane are added at -30 0 C to a solution of 17 g of 3,17beta-bis-[(tetrahydro-2H-2pyrannyl)-oxy]-(4-ethynyl-phenyl)-estra-1,3,5(10)-trien- 11beta-yl obtained in Stage D of Preparation A of Example 9 in 60 cm 3 of tetrahydrofuran. The mixture is agitated for 30 minutes at -30 0 C then 15.7 g of sodium 6-bromohexanoate obtained according to the above preparation is added.

Agitation is carried out for 5 hours at ambient temperature, the mixture is poured into a solution of monosodium phosphate at OOC, and extracted with ethyl ether. The extracts are evaporated to dryness and the residue (41 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 1-1) and 10.163 g of expected product is obtained.

0.

IR Spectrum: (CHCl 3 C=O 1709 cm- 1 aromatic 1607, 1572, 1497 cm 1 Stage B: 8-[4-(3,17beta-dihydroxy estra-1,3,5(10)-trienllbeta-yl)-phenyl]-N-(2,2,3,3,4,4,4-heptafluorobutyl)-Nmethyl-octynamide.

0.31 cm 3 of N-methylmorpholine then 0.39 cm 3 of isobutyl chloroformate are added to a solution of 0.604 g of product obtained in Stage A above in 10 cm 3 of methylene chloride.

The mixture is agitated for 10 minutes then 0.826 g of Nheptafluorobutyl-N-methylamine hydrochloride obtained in Preparation 1 is added. Agitation is carried out for minutes at ambient temperature, 20 cm 3 of saturated sodium bicarbonate solution is added, extraction is carried out with methylene chloride, the extracts are dried and evaporated to dryness under reduced pressure. The residue (3.369 g) is chromatographed on silica (eluant: methylene chloride acetone 0.782 mg of intermediate product is obtained which is put in solution in 10 cm 3 of 2N hydrochloric acid in the presence of 10 cm 3 of ethanol and 2 cm 3 of methylene chloride. Concentration is carried out twice by distillation under reduced press-re, water is added, followed by extraction with methylene chloride; the extracts are dried and evaporated to dryness under reduced pressure. The residue (1.403 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 1-1) and 0.440 g of expected product is obtained in the form of an oil. [alpha] D 28.50 2.50 (C 0.45% ethanol) Analysis: C 37

H

42

F

7 N0 3 681.74 Calculated: C% 65.19 H% 6.21 F% 19.51 N% 2.05*** Found 65.0 6.3 19.1 IR Spectrum: (CHC1 3 absence of C C OH 3602 cm-1 associated) C=O 1656 cm- 1 aromatic 1584, 1505, 1483 cm- 1 Example 13: 1-(8-(4-(3,17beta-dihydroxy-estra-1,3,5(10)trien-11beta-yl)-phenyl)-1-oxo-7-octynyl)-4-(phenylmethyl)piperidine. The operation is carried out as in Stage B of Example 12 starting with 1 g of 8-[4-[3,17beta-bis-[(tetrahydro-2H-2pyrannyl)-oxyl-estra-1,3,5(10)-trien-11beta-yl]-phenyl]-7octynoic acid, 0.7 cm 3 of isobutyl chloroformate and 0.8 cm 3 of 4-benzyl-piperidine. The residue (2.4 g) is chromatographed on silica (eluant: methylene chloride acetone 95-5) and 1.01 g of intermediate product is obtained which is depyrannylated. After chromatography on silica (eluant: methylene chloride acetone 0.462 g of expected product is obtained.

[alpha]D -380 2.50 (C 0.5% ethanol) Analysis: C 44

H

53 N0 3 643.92 i Calculated: C% 82.07 H% 8.30 N% 2.18 Found 81.9 8.5 1.9 IR Spectrum: (CHC1 3 OH 3602 cm- 1 associated) C=O 1625 cm- 1 (amide III) aromatic 1585, 1555, 1504 cm- 1 Preparation A of Example 14: bromo-N-methyl-N-(1-methyl ethyl)-acetamide.

A solution of 26 cm 3 of methylisopropylamine in 100 cm 3 of ether is added to a solution of 10 cm 3 of bromo acetyl bromide in 150 cm 3 of ether cooled down to -20 0 C. The mixture is left to return to 20 0 C and agitated for 30 minutes at 0 C. It is diluted with water, decanted, extracted with ether, the extracts are dried and separated out by distil- lation. 13 g of expected product is obtained.

B.p. 71/72 0 C under 1 mmHg.

Preparation B of Example 14: 11beta-(8-hydroxy octyl)-estra- 4,9-dien-3,17-dione.

Stage A: cyclic 3-(1,2-ethanediyl) acetal of 11beta-[8dimethyl-(1,1-dimethylethyl)-silyloxy]-octyl-5alpha-hydroxyestr-9-en-3,17-dione...

The operation is carried out as in Stage A of Preparation A of Example 9 starting with 3.96 g of cyclic (1,2-ethanediyl acetal) of 5alpha, 10alpha-epoxy-estr-9,11o en-3,17-dione obtained according to EP 0057115 (Ex. 7) using for the preparation of the magnesium compound 5.4 g of bromo octyl)-oxy]-dimethyl-(1,1-dimethylethyl) silane obtained in Preparation 5 and 1 g of magnesium turnings, then for the condensation 0.4 g of copper chloride. After chromatography on Lichrosorb Rp18 (eluant: methanol water 3.85 g of the expected compound is obtained, used as it is for the following stage.

Stage B: 11beta-(8-hydroxy-octyl)-estra-4,9-dien-3,17-dione.

1.77 g of product obtained in Stage A above, 35 cm 3 of methanol and 8.85 cm 3 of 2N hydrochloric acid are agitated for one hour 15 minutes at ambient temperature. The mixture is alkalized to a pH of about 9 with concentrated liquid ammonia then evaporated to dryness under reduced pressure.

The residue is taken up in ethyl acetate, washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. After chromatography on silica (eluant: methylene chloride ethyl acetate 1.08 g of the desired compound is obtained.

IR Spectrum: (CHC1 3 OH 3624 cm- 1 C=O '1735 cm-1 (17-keto) 1656, 1602 cm- 1 (dienone) Example 14: 2-((8-(3,17beta-dihydroxy-19-nor-17alpha-pregna- 1,3,5(10)-trien-20-yn-l11beta-yl)-octyl)-oxy)-N-methyl-N-(1- methylethyl)-acetamide.

Stage A: [[8-(3,17-dioxo estra-4,9-dien-11beta-yl)-octyl]oxy]-N-methyl-N-(1-methylethyl) acetamide. 1.4 cm 3 of bromo-N-methyl-N-(1-methylethyl)-acetamide (obtained in Preparation A above) and 285 mg of sodium iodide then 140 mg of sodium hydride at 50% in oil are added to a solution of 570 mg of the compound obtained in the above preparation in 10 cm 3 of tetrahydrofuran. The mixture is agitated for one hour, poured into an N hydrochloric acid solution at 0°C and extracted with methylene chloride...

Evaporation to dryness is carried out and the residue (2 g) is chromatographed on silica (eluant: ethyl acetate ether 350 mg of the desired product is obtained. IR Spectrum: (CHC13) 17-keto 1736 cm- 1 3-keto 1655 cm- 1 amide III 1628 cm- 1 C=C 1603 cm- 1 Stage B: 2-[[8-(3-hydroxy-17-oxo-estra-1,3,5(10)-trien- 11beta-yl)-octyl]-oxy]-N-methyl-N-(1-methylethyl)-acetamide.

cm 3 of acetic anhydride and 5 cm 3 of acetyl bromide are added at OOC to a solution of 9.4 g of product obtained in Stage A above in 195 cm 3 of methylene chloride placed under a nitrogen atmosphere. The mixture is agitated for minutes at OOC then for 2 hours 30 minutes at ambient temperature. The mixture is cooled down to 00/+5 0 C, water then methanol are added slowly, agitation is continued for 63 minutes and 50 cm 3 of 2N soda is added. The organic phase is collected, extracted again with methylene chloride, the extracts are dried and evaporated to dryness under reduced pressure. 10 g of acetylated residue is obtained which is dissolved in 100 cm 3 of methanol under a nitrogen atmosphere.

cm 3 of 2N soda is added and the mixture is left to react for one hour at ambient temperature. Acidification is carried out with 2N hydrochloric acid, extraction is done with methylene chloride, the extracts are washed, dried and evaporated to dryness under reduced pressure. The residue (9 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 3-7) and 7.9 g of expected product is obtained.

Stage D: 2-[[8-(3,17beta-dihydroxy-19-nor-17alpha-pregna- 1,3,5(10)-trien-20-yn-11beta-yl)-octyl]-oxy]-N-methyl-N-(1- methylethyl)-acetamide.

A suspension of potassium acetylide is obtained by placing, to begin with, 3 cm 3 of a 0.88 M of potassium terbutylate in tetrahydrofuran in a spherical flask under a nitrogen atmosphere, to which 5 cm 3 of tetrahydrofuran is added then acetylene is bubbled through for 15 minutes. A solution of 520 mg of product obtained in Stage C above in 5 cm 3 of tetrahydrofuran is added. After reaction for 30 minutes at ambient tempera-ture, a saturated aqueous solution of ammonium chloride is added, extraction is carried out with ethyl acetate, the extracts are washed, dried and evaporated to dryness under reduced pressure. The residue (550 mg) is chromatographed on silica (eluant: methanol water 85-15) and 470 mg of expected product is obtained.

Analysis: C 34

H

51 N0 4 537.79 Calculated: C% 75.93 H% 9.55 N% 2.60 Found 75.8 9.7 2.30 IR Spectrum: (CHC1 3 OH 3600 cm- 1 C-CH 3305 cm- 1 C=O 1625 cm- 1 (amide III) aromatic 1583, 1499 cm- 1 Preparation A of Example 15: 2-[(4-bromophenyl)-thio]tetrahydro-2H-pyran.

6. 2.3 mg of paratoluene sulphonic acid is added to a solution of 1 g of 4-bromo thiophenol in 1 cm 3 of 3,4dihydro-[2H]-pyran and 1 cm 3 of tetrahydrofuran, then 'he mixture is agitated for 20 hours at ambient temperature.

0.1 cm 3 of triethylamine is added, the mixture is poured into a saturated solution of sodium bicarbonate, extracted with ethyl acetate, the extracts are washed with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue (1.603 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 97.5-2.5) and 1.246 g of expected product is obtained.

Analysis: C 11

H

13 BrOS 273.19 Calculated: C% 48.36 H% 4.79 Br% 29.24 S% 11.73 Found 47.9 4.6 28.8 11.6 IR Spectrum: (CHC1 3 aromatic 1477 cm 1 type -Br presence of 0S- Preparation B of Example 15: 11beta-[4-[(tetrahydro-2H-2pyrannyl)-thio]-phenyl]-estra-4,9-dien-3,17-dione. a) preparation of the magnesium compound 1.045 g of 2-[(4-bromo phenyl)-thio]-tetrahydro-2H-pyran obtained in Preparation A above in solution in 2.5 cm 3 of tetrahydrofuran is added over 15 minutes at 60 0 /65 0 C to a suspension of 139 mg of powdered magnesium in 0.65 cm 3 of tetrahydrofuran placed under an argon atmosphere, and agitation is carried out for 30 minutes.

b) condensation The suspension obtained above is cooled down to 0 0 /+5 0

C,

29 mg of copper chloride and 1 cm 3 of tetrahydrofuran are added and the whole is agitated for 15 minutes to 0°C. After cooling down to -20 0 C, 650 mg of cyclic 3-(1,2-ethanediyl) acetal of 5alpha, 10alpha-epoxy-estra-9,11-en-3,17-dione obtained according to EP 0057115 (Ex 7) in solution in 4 cm 3 of tetrahydrofuran is added. Agitation is carried out for minutes at -15 0 C then for one hour 30 minutes at 0°C. The mixture is poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, the extracts are dried and evaporated to dryness under reduced pressure.

1.409 g of crude product is obtained.

c) deketalization 6 cm 3 of 2N hydrochloric acid is added to a solution of 1.409 g of product obtained above in 30 cm 3 of methanol placed under an argon atmosphere. The mixture is agitated for one hour at ambient temperature and poured into a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, the extracts are washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue (1.27 g) is chromatographed on silica (eluant: ethyl acetate cyclohexane 1-1) and 647 mg of expected product is obtained which is crystallized from a mixture of methiylene chloride and isopropyl ether. 596 mg of crystals are obtained.

Analysis: C 29

H

34 0 3 S 462.65 i'" Calculated: C% 75.28 H% 7.40 S% 6.93 Found 75.0 7.5 6.8 IR Spectrum: (CHC1 3 C=O 1736 cm-1 (17-keto) 1656 cm 1 (dienone) 1603 cm- 1 aromatic 1493 cm 1 presence of 0 o Example 15: N-butyl-8-(4-(3,17beta-dihydroxy-estra-1,,3,5(10)trien-1lbeta-yl)-phenylthio)-N-methyl-octanamide.

Stage A: N-butyl-[8-[4-(3,17-dioxo-estra-4,9-dien-11beta-yl)phenylthio]-N-methyloctamide.

a) formation of the silver thiolate cm 3 of methanol, then 1 cm 3 of a 1M aqueous solution of silver nitrate are added to a solution of 368 mg of product obtained in Preparation B above in 3.7 cm 3 of chloroform at 40 0 C. Agitation is carried out for 10 minutes at 40 0 C, the mixture is cooled down to 0/+5 0 C and the precipitate is retained by decanting the supernatant.

1 b) S-alKylation A solution of 353 mg of 8-bromo-N-butyl-N-methyl octanamide obtained in the preparation of Example 2, in 7.4 cm 3 of acetone, then 103 mg of potassium bicarbonate and 2.95 cm 3 of hexamethyl phosphorotriamide are added to the precipitate obtained above in solution in 3.7 cm 3 of chloroform. The mixture is heated to 60 0 C for 70 hours, cooled down to ambient temperature and poured into a 1M hydrochloric acid solution. After extraction with ethyl acetate and filtering, the organic phara is washed with a saturated solution of sodium chloride, dried then evaporated to dryness under reduced pressure. 0.74 cm 3 of a 2N soda solution is added to the oily residue obtained (1.362 g) which has been put in solution with 3.7 cm 3 of acetone. The mixture is heated to 60 0 C for one hour then poured into e water, acidified with 2N hydrochloric acid, extracted with ethyl acetate, dried and evaporated to dryness under reduced pressure. The residue (914 mg) is chromatographed on silica (eluant: ethyl acetate methylene chloride 1-1) and 332 mg of expected product is obtained in the form of an oil.

IR Spectrum: (CHC1 3 C=O 1736 cm- 1 (17-keto) 1655 cm- 1 (dienone) 1628 cm- 1 (amide III) 0 aromatic 1580, 1492 cm- 1 Stage B: N-butyl-8-(4-(3,17beta-dihydroxy-estra-1,3,5(10)- trien-11beta-yl)-phenyl)-thio)-N-methyl-octanamide.

The operation is carried out as in Stage B of Example 7 starting with 333 mg of product obtained in Stage A above, 0.34 cm 3 of acetic anhydride and 0.17 cm 3 of acetyl bromide, then extraction is carried out with ethyl acetate. The residue (335 mg) is treated with 27.5 mg of boron and sodium hydride, then 0.7 ml of 2N soda. After extraction with ethyl acetate, the residue (303 mg) is chromatographed on Lichroprep Si 60 (eluant: acetone methylene chloride 1-9) then on Lichrosorb RP 18 (eluant: methanol water 9-1) and 134 mg of expected product is obtained.

[alpha]

D

-49.50 (C 1.1% CHC1 3 tI Analysis: C 37 1 53

NO

3 S 591.90 Calculated: C% 75.08 H% 9.02 S% 5.41 N% 2.36 Found 75.4 9.3 5.5 2.4 IR Spectrum: (CHC1 3 OH 3605 cm- 1 associated) C=O 1621 cm- 1 (amide III) aromatic 1582, 1558, 1498, 1492 cm- 1 Preparation of Example 16: 3,17abeta-bis-[(tetrahydro-2H-2pyrannyl)-oxy]-11beta-(4-ethynylphenyl)-D-homo-estra- 1,3,5(10)-triene. Stage A: 5alpha, 10alpha-epoxy-17alpha-[(tetrahydro-2H-2pyrannyl)-oxy]-D-homo-estr-9(11)-en-3one cyclic 1,2ethanediyl acetal. 0.6 cm 3 of pyridine, then at 0°C 1.7 cm 3 of hexafluoroacetone and over 5 minutes 3.4 cm 3 of 50% hydrogen peroxide are added to a solution of 6 g of 17abeta- [(tetrahydro-2H-2-pyrannyl)-oxy]-D-homo-estra-5(10), 9(11)dien-3-one cyclic 1,2-ethanediyl acetal which can be obtained according to the Patent FR 2594830 (Example 6 Stage A) in cm 3 of methylene chloride. The mixture is agitated for 6 hours 30 minutes at 0°C, poured into a saturated solution of sodium thiosulphate, and washed until the peroxide has gone.

Extraction is carried out with methylene chloride, the 4 extracts are washed with a saturated solution of sodium chloride, dried, and evaporated to dryness under reduced pressure. The residue (12 g) corresponding to 2 identical preparations is chromatographed on silica (eluant: cyclohexane ethyl acetate 9-1 with 0.5% triethylamine) and 7.1 g of expected alpha-epoxide is obtained.

Staqe B: 11beta-(4-ethynylphenyl)-17abeta-hydroxy-D-homoestra-4,9-dien-3-one.

a) condensation The operation is carried out as in Stage A of Preparation A of Example 1 starting with 5.7 g of the above epoxide in solution in 46 cm 3 of tetrahydrofuran, 232 mg of copper chloride and 60 cm 3 of magnesium compound prepared according to Stage A of Preparation A of Example 9 starting kSwith 4-trimethyl-ethynyl-bromobenzene described in Preparation 4, which is introduced slowly, under a nitrogen atmosphere at -5 0 C/0OC. The residue is chromatographed on silica (eluant: cyclohexane ethyl acetate 7-3 with triethylamine) and 6.3 g of product is obtained which is desilylated in solution in 100 cm 3 of methanol and 20 cm 3 of methylene chloride by the addition of 2.6 cm 3 of 10N soda.

The protected functions in positions 17 and 3 are then liberated by the addition of 7.2 cm 3 of concentrated hydrochloric acid at 0 0 C/+5 0 C, then after dilution with ice, by adjusting the pH to 8-9 with concentrated liquid ammonia. Extraction is carried out with methylene chloride, the extracts are washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue (4.3 g) is chromatographed on silica (eluant: methylene chloride acetone 96-4) and 3.36 g of expected product is obtained. TR Spectrum: (CHC1 3 OH 3612 cm- 1 =CH 3302 cm- 1 C=O 1656, 1604 cm- 1 (dienone) aromatic 1555, 1504 cm- 1 i Stage C: 11beta-[4-ethynyl-phenyl]-D-homo-estra-1,3,5(10)- trien-3,17abeta-diol 3,17abeta-diacetate. 0.09 cm 3 of acetyl bromide then 0.18 cm 3 of acetic anhydride are E.dded at 0/+5 0 C to a solution of 200 mg of a product obtained tage B above in 2 cm 3 of methylene chloride. The mixture is agitated for 3 hours at ambient temperature, poured into 20 g of a mixture of ice and saturated potassium bicarbonate solution, extracted with methylene chloride, the extracts are washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue (230 mg) is chromatographed on silica (eluant: cyclohexane ethyl acetate 9-1) and 147 mg of expected product is obtained.

IR Spectrum: (CHC1 3 ECH 3303 cm- 1 phenol acetate 1749 cm 1 k) acetate at 17 1727 cm 1 aromatic 1608, 1588, 1556, 1505, 1494 cm- 1 Stage D: 3,17abeta-bis-[(tetrahydro-2H-2-pyrannyl)-oxyl- 11beta-(4-ethynylphenyl)-D-homo-estra-1,3,5(10)-triene.

2.395 g of product obtained according to the process described in Stage C above in a 1M solution of potash in methanol is agitated under an argon atmosphere. The mixture is heated to 35 0 C for 30 minutes, poured into ice-cooled water, the pH is adjusted to 7 with 2N hydrochloric acid, extraction is carried out with methylene chloride, the extracts are washed with a saturated sodium chloride solution, dried and evaporate to dryness under reduced pressure. The residue (2.14 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 6-4) and 1.89 g of intermediate deacylated product is obtained. Starting with 1.8 g of the above product in solution in 60 cm 3 of ethyl ether, 3.2 cm 3 of dihydropyran and 50 mg of paratoluene sulphonic acid are added. The resultant mixture is agitated for 3 hours at ambient temperature. 30 cm 3 of saturated sodium bicarbonate solution is added, followed by extraction with ethyl acetate, the extracts are washed, dried and evaporate to dryness under reduced pressure. The residue (2.7 g) is chromatographed on silica (eluant: cyclohexane ethyl acetate 9-1 with 0.5% triethylamine) and 2.429 g of 0"

**S

expected product is obtained. IR Spectrum: (CHC1 3 ECH 3302 cm- 1 aromatic 1607, 1575, 1555, 1499 cm- 1 Example 16: N-butyl-8-(4-(3,17abeta-dihydroxy-D-homoestra- 1,3,5(10)-trien-11beta-yl)-phenyl)-N-methyl-7-octynamide.

The operation is carried out as in Stage A of Example starting with 0.8 g of product obtained in Stage D of the above Preparation, 6.5 cm 3 of hexamethylphosphorotriamide and 1.7 cm 3 of a 1.1M butyl lithium solution, then 530 mg of 6bromo-N-butyl-N-methyl hexanamide prepared as in the Preparation of Example 2 starting with 6-bromohexanoic acid i added. The mixture is poured into a saturated solution of sodium chloride, and extracted with ethyl acetate. After 6 't chromatographing the residue (3 844 mg of product is obtained from which the pyrannyl group in positions 3 and 17 is eliminated in solution in 40 ml of methanol to which 8 ml of 2N hydrochloric acid is added. The medium is poured into a water ice mixture, extracted with methylene chloride, the extracts are washed, dried and evaporated to dryness under reduced pressure. The residue (610 mg) is chromatographed on silica (eluant: methylene chloride acetone 8-2) and 536 mg of expected product is obtained.

Analysis: C 38

H

51 N0 3 =569.84 Calculated: C% 80.10 H% 9.02 N% 2.43 ago 0 0 Found 80.1 9.2 2.4 to IR Spectrum: (CHCl 3 OH 3603 cm- 1 C=O 1625 cm- 1 (amide III) g aromatic 1580, 1556, 1507 cm- 1 Example 17: N-butyl-4- (3.1 7beta-dihydroxv-D-homoestra- 1 ,3,5(10) -trien-1 1beta-vl )-f-methyl-benzeneoctanamide.

The operation is carried out as for the reduction in Stage B of Example 10 starting with 360 mg of product obtained in Example 16 and 180 mg of palladium on charcoal.

The residue (375 mg) is chromatographed on silica (eluant: methylene chloride acetone 9-1) and 336 mg of expected product is obtained.

(alphalD -26-50 10 (C 1% ethanol) Analysis.: C 38

H

55

NO

3 573.87 Calculated: C% 79.54 H% 9.66 N% 2.44 Found 1. 79.2 9.8 2.4 IR Spectrum: (CHCl 3 OH 3606 cm- 1 C=O 1622 cm- 1 (amide III) aromatic 1585, 1500 cm- 1 Example 18: I-butyl-2-( 3, l7beta-dihydroxy-estra- 1 ,3,5(10) -trien-1 1beta-vl )-phenoxy) -pentyl )-thio) -T-methylethanethioamide.- The operation is carried out as in Stages D, E and F of Example 1 starting with 570 g of N-butyl-[5-[4-(3,17-betadihydroxy-estra-1 ,3,5(10)-trien-llbeta-yl)-phenoxy]r pentylthio]-N-methyl-acetamide obtained in Stage C of Example 8: for Stage D, 0.57 cm 3 of acetic anhydride and 28 mg of 4-dimethyl-aminopyridine are used and 682 mg of crude residue of the expected 3,17-diacetoxy product is obtained.

IR Spectrum: (CHC1 3 absence of OH C=O (1720, 1760 cm- 1 (ester) 1640 cm- 1 (amide) aromatic 1605, 1580, 1500 cm-1 for Stage E, 680 mg of the above crude product and 250 mg of Lawesson reagent are used, agitation is carried out for 4 hours at 50 0 C and 560 mg of crude residue of the expected thioamide product is obtained.

IR Spectrum: (CHC1 3 acetate 1720 to 1760 cm- 1 C=0 (amide) absence C S 1605 cm-1 aromatic 1500, 1580 cm 1 for Stage F 560 mg of the preceding crude product and 4 cm 3 of 2N soda are used, 516 mg of crude residue is obtained and after chromatography (eluant: essence G ethyl acetate 6-4) 395 mg of expected product is isolated. [alpha]D -300 10 (C 0.45% CHC1 3 Analysis: C 3 6

H

5 1

NO

3

S

2 609.94 Calculated: C% 70.89 H% 8.43 N% 2.30 S% 10.51 Found 70.9 8.4 2.3 10.4 IR Spectrum: (CHC1 3 OH 3602 cm- 1 aromatic 1610, 1578, 1512 cm- 1 EXAMPLE 19 :llbeta-(4-(5-((2-(butl-methylamino)-2oxoethyl)-thio)-pentyloxy)-phenyl)-3-hydroxy-estra 1 .3,5(10)trien-1 7beta-vl monobutanedioate.

760 mg of N-butyl-(5-(4-(3, 17beta-dihydroxy-estra- 1,3, 5(10)-trien-1lbeta-yl)-phenoxy)-pentylthio)-N-methyl acetamide prepared as in Example 77 of the European Patent Application No. 90400493.4 and 760 mg of succinic anhydride with 80 mg of dimethylaminopyridine and 8 cm 3 of pyridine are heated under reflux for three hours thirty minutes. The solution containing the monoester and diester mixture is cooled down to ambient temperature, 8 cm 3 of methanol, 8 cm 3 of water and 1.3 g of potassium carbonate are added.

Agitation takes place for 6 hours at ambient temperature, followed by cooling to 4 0 C, the reaction medium is acidified with 2N hydrochloric acid, extracted with ethyl acetate, washed with 2N hydrochloric acid, then salt water, dried and the solvents are eliminated under reduced pressure. 1.2 g of the expected crude monoester is obtained which is chromatographed on silica (eluant: petroleum ether 40-700 acetone -ethyl acetate 60-40-1) and 650 mg of pure ester is obtained.

Rf 0.22.

IR Spectrum (CHC1 3 OH 3600 cm- 1 C=O 1717 cm- 1 (complex) and 1626 cma 1 0 0. S 3 5 aromatic :1611, 1581 and 1511 cm- 1 EXAMPLE 20: llbeta-(4--(5-( 12-(butyl-methylamino)-2-oxoethl)thio)-pentyloxy)-phenyl)-3-hvdroxy-estra 1 .3.5(10 )-trienl7beta-yl and sodium butanedioate.

Io 72 mg of sodium bicarbonate is dissolved in 7 cm 3 of water then 630 mg of the product obtained above in 8 cm 3 of ethanol is added. The solution obtained is agitated for minutes, the ethanol is eliminated under reduced pressure, followed by diluting with water, filtering and lyophilizing.

600 mg of expected product is obtained.

Analysis: C 40

H

54 NNaO 7

S

Calculated: C% 67.13 H% 7.60 N% 1.96 S% 4.48 Found 67.0 7.7 1.9 4.8 Pharmaceutical compositions: Tablets were prepared corresponding to the following formula: Product of Example 2 50 mg Excipient (talc, starch, magnesium stearate) sufficient quantity for a tablet completed at 120 mg S S

S

e *S e 9 55 Pharmacological study of the products of the invention 1 Study of the activity of the products of the invention on the oestrocen receptor of the uterus of a mouse: Impubic female mice 18 to 21 days old are killed, the uteri are removed then homogenized at 0°C using of a Potter teflon-glass in a TS buffer solution (Tris 10 mM, saccharose 0.25 M, HC1 pH 7.4 (1 g of tissue for 25 ml of TS). The homogenate is then ultracentrifuged (105,000 g x 90 min) at 0°C. The supernatant aliquots thus obtained are incubated at 0°C or at 25 0 C for a time with a constant concentration of tritiated estradiol in the presence of increasing concentrations (0 1000.10 9 M) either of cold estradiol, or of cold product tested. The concentration of bound tritiated estradiol is then measured in each incubate by the 5e technique of adsorption on carbon dextran. Calculation of the relative bond affinity: The calculation of the relative bond affinity (RBA) is identical for all 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 cold reference hormone and B

T

as a function of the logarithm of the concentration of the o.o cold product tested. The straight line of the equation 150 (B max B min)/2 is determined. T T B max Percentage of bound tritiated hormone for an

T

incubation of this tritiated hormone at a concentration B min Percentage of bound tritiated hormone for an

T

incubation of this tritiated hormone at a concentration in the presence of a large excess of cold hormone (2500.10-9M).

The intersections of the straight line 150 and the curves allow the concentrations of cold reference hormone (CH) and of the cold product tested (CX) which inhibits by the bond of the tritiated hormone on the receptor, to be evaluated.

The relative bond affinity (RBA) of the tested product is determined by the equation RBA 100 (CH).

(CX)

The following results were obtained: Products of Oestrogen Receptors Examples Incubation time 2 Hrs 5 Hrs 1 20 2 16 0 23 6 3.3 29 9 11.7 14 2.8 47 18 16 a 0* a.

a

S

0 Sr 5 9 e g.

Conclusion: The products studied, in particular the product of Example 14, have a marked affinity for the oestrogen receptors over the second time period.

Furthermore, most of the products are deprived of uterotrophic activity.

2 Anti-proliferative activity of the products of invention on the growth of mammary tumour cells MCF-7 Description of the test: a) Cell culture: MCF-7 lines are maintained in culture in an FCS (1) medium at 37 0 C in a humid atmosphere containing 5% CO 2 The cells are collected at subconfluence by trypsination (trypsin 0.05%, EDTA 0.02%) then rinsed by gentle centrifugation. A sample of cells in suspension is counted on Malassez cells.

b) Study of the growth: The cells, resuspended in the FCS medium are seeded at a rate of 30,000 cells per well in multi-well plates (24 wells of 2.5 cm 2 Twenty four hours after seeding(DO), the product under test is added to the medium in an ethanolic solution (final concentration of ethanol: at a concentration of 10- 12 to 10-6M, the control wells receiving the same concentration of ethanol. The media are renewed every 48 hours. At the end of the experiment the medium is aspirated and the cells are immediately fixed with 150 microlitres of methanol in order to determine the DNA.

The anti-proliferative activity of the products is evaluated by their capacity to inhibit the increase of DNA. c) Determination of the DNA: The DNA is determined by a fluorimetric method using DABA (3,5-diaminobenzoic acid) 150 microlitres of DABA are added to each well; the plates are then incubated for minutes at 56 0 C, then 2 ml of 1N HC1 is added. The fluorescence is measured using a fluorimeter (excitation wavelength: 408 nm, transmitted wavelength: 510 nm).

9 The quantity of DNA per well is evaluated relative to a standard range obtained by treating a DNA standard from a calf's thymus under the same conditions. Results The concentration in nm which inhibits the growth of

MCF

7 cells by 50% (IC 50 was determined in the manner indicated above: Results: Product of Example 1: IC 50 0.03 nM Product of Example 2: IC 50 0.035 nM Product of Example 5: IC 50 0.02 nM Product of Example 6: IC 50 0.007 nM Product of Example 9: IC 50 0.009 nM Product of Example 14: IC 50 0.015 nM Furthermore, the maximum inhibiting effect of the products reached approximately IL( The culture medium of foetal calf serum (FCA) is prepared as follows: MEM Medium (minimal Essent.Lal Medium) to which are added: non-essential amino acids (GIBCO), peni-strepto (penicillin 100 U/ml, streptomycin 0.1 mglml), fungizone 0.1%, insulin (50 nglml), steroid-free foetal calf serum (10% final concentration).

Puzas and Goodman, Analytical Biochemistry, Vol. 86, pp. 50, 1978.

*Poo too 4,00

Claims (7)

1. (E Compounds of formula RA\ /K R K N-C R/ B (I) 17 n in which: either n 1, K represents an oxygen atom, R 1 7 represents a hydroxyl radical or a radical of formula -O-C-(CH 2 2 -COOH optionally salified, II O 0 R' 1 7 represents a hydrogen atom or an ethynyl radical, RA represents a methyl radical, RB represents an isopropyl or linear butyl or heptafluorobutyl radical, X represents a methylene, phenylene or phenyloxy radical linked to the steroid by a carbon atom, Y represents one of the radicals chosen from the group constituted by -(CH 2 7 -(CH 2 8 -(CH 2 5 -C -(CH2)q-O-CH 2 with q 5 to 7 and -(CH 2 5 -S-CH 2 in which the sulphur atom is optionally oxidized in the form of the sulphoxide or sulphone, Z represents a single bond, or n 1 or 2 K represents an oxygen or sulphur atom, R 17 and R' 1 7 are such that: either R 17 and R' 1 7 together form a ketone function, C c Y S S. S9 S. a a. S Sb S. S 5 Sb S

5.5 55 -It or R 17 is a hydroxyl radical or an acyloxy radical and R' 17 represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical having at most 8 carbon atoms, X, Y and Z are such that: X represents a methylene radical, an arylene group, a CH 2 -O radical, an arylenoxy or arylenethio radical linked to the steroid by a carbon atom, Y represents a single bond or a saturated or unsaturated, linear or branched aliphatic chain, containing 1 to 18 carbon atoms, optionally interrupted by one or more radicals chosen from arylene, oxygen or sulphur radicals optionally oxidized 046 in the form of the sulphoxide or sulphone and optionally terminated by an arylene radical, Z represents a single bond, it being understood that when Y and Z are a single bond, X cannot be a methylene or CH 2 -0 radical, RA or RB identical or different, represent a hydrogen atom, a linear or branched alkyl radical containing 1 to 8 carbon atoms, optionally substituted by an aryl, alkyl or dialkylamino, hydroxy or halogen radical, an esterified carboxyl radical or RA and RB form together with the nitrogen atom to which they are linked a heterocycle with 5 Eu or 6 links, saturated or not, optionally containing one or more heteroatoms chosen form the group constituted by oxygen, nitrogen and sulphur atoms and optionally substituted by an alkyl radical having 1 to 4 carbon atoms, an aryl or aralkyl radical having 6 to 10 carbon atoms, it being understood that at least one of the RA or Rg radicals is not a hydrogen atom and that at least any one of the following conditions is fulfilled: either n 2, or K is a sulphur atom, or X is an arylenethio radical linked to the steroid by a carbon atom, or RA and RB form together with the carbon atom to which they are linked a heterocycle with 5 or 6 links substituted by an aryl or aralkyl radical. if 2. Thejyrdcscropnigt oe~ formula as defined in claim 1, the names of which follow: llbeta-(4-((7-(butylmethylamino)-carbonyl)-heptyl)-oxy)- phenyl)-3--hydroxy-estra-1 ,3,5(1 0)-trien-1 7beta-yl monobutanedioate, 1llbeta-(4-( (7-i (butylmethylamino)-carbonyl)-heptyl)-oxy)- phenyl)-3-hydroxy-estra-1 ,3,5(1 0)-trien-l7beta-yl and sodium butanedioate, -N-butyl--2-(6-(4-(3,l7beta-dihydroxy-estra-1 ,3,5(10)- trien-1 1beta-yl)-phenoxy)-hexyloxy-N-methyl acetamide, N-butyl-8-(4-(3,l7beta-dihydroxy-estra-1 ,3,5(10)- trien-1 lbeta-yl)--phenoxy)--N-methyl-2-octyniamide, N-butyl-2-((5-(4-(3,17beta--dihydroxy-estra-1 ,3,5(10)- trien-1 lbeta-yl)-phenyl)-pentyl)-thio)-N-methyl acetamide, N-butyl-4-(3, l7beta-dihydroxy-estra-1 ,3,5(10)-trien- 11 beta-yl )-N-methyl benzenenonamide, N-butyl-2-((5-(4-(3,17beta-dihydroxy-estra-1,3,5(10)- %g trien-1 lbeta-yl)-phenyl)-pentyl)-oxy)-N-methyl acetamide, (8-(3,17beta-dihydroxy-19-nor-17alpha-pregna-1 ,3,5(10)- methylethyl) ace tamide, N-butyl-2-( (5-(4-(3,17beta-dihydroxy-estra-1 ,3,5(10)-trien- lbeta-yl)-phenyl)-pentyl)--thio) -N-methyl acetamide. Thqrdcscrr~od.ng~ formula as defined in claim 1 in which: n =1 or 2, K represento an oxygen or sulphur atom, R 17 and R' 17 are such go that: either R 17 and R' 17 together form a ketone function, or R 17 is a hydroxyl or acyloxy radical and R' 17 represents an hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical having at most 8 carbon atoms, X, Y and Z are such that: X represents *a methylene radical, an arylene group, a 0H 2 arylenoxy or arylenethio radical linked to the steroid by a carbon atom, Y represents a single bond or a saturated or unsaturated, linear or branched aliphatic chain containing 1 to 18 carbon k'b atoms, optionally interrupted by one or more radicals chosen from arylene or oxygen radicals or sulphur radicals optionally oxidized in the form of the sulphoxide or sulphone and optionally term: Ated by an arylene radical, Z represents a single bond, it being understood that when Y and Z are a single bond, X cannot be a methylene or CH 2 -O radical, RA or RB identical or different, represent a hydrogen atom, a linear or branched alkyl radical containing 1 to 8 carbon atoms, optionally substituted by an aryl, alkyl or dialkylamino, hydroxy, halogen radical or an esterified carboxyl radical or RA and RB form with the nitrogen atom to which they are linked a heterocycle with 5 or 6 links, saturated or not, optionally containing one o- more heteroatoms chosen from the group constituted by oxygen, nitrogen and sulphur atoms and optionally substituted by an alkyl radical having 1 to 4 carbon atoms, an aryl or aralkyl radical having 6 to 10 carbon atoms, it being understood that at least one of the RA or Rg radicals is not a hydrogen atom and that at least any one of the following conditions is fulfilled: either n 2, or K is a sulphur atom, or X is an arylenethio radical linked to the steroid by a carbon atom, or RA and RB form with the carbon atom to which they are 5* linked a heterocycle with 5 or 6 links substituted by an aryl I or aralkyl radical. o oos 4. The products-corresponding t formula as defined in claim 3 in which n is equal to 1. The .p-odut-s according to claim 4 in which K is a sulphur atom, X is an aryleneoxy radical and Y represents a saturated linear chain containing 5 to 10 carbon atoms, optionally interrupted by an oxygen atom.

6. The -prod according to cl im 4 in which X is an arylenethio radical and Y represeints a saturated linear chain containing 5 to 10 carbon atoms.

7. The c a-ccording to claim 4 in which X is an h 4 t G sacodn 11 arylene radical, Y represents an unsaturated linear chain containing 5 to 10 carbon atoms, RA and R B form with the atom to which they linked a piperidine N-substitated by an aralkyl radical.

8. The pv~u~s ?f formula according to claim 1 the names of which follow: N-butyl-5-(4--(3,17beta-dihydroxy-estra-1 ,3,5(10)-trien- 11 beta-yl) -phenoxy) -pentyloxy) -N-methyl-ethanethioamide, N-butyl-8--(4-(3,17beta-dihydroxy-estra-1 ,3,5(10)-trien- 11 beta-yl )-phenoxy )-N-methyl-octanethioamide, llbeta-(4-( (7-(butylmethylamino)-carbonyl)-heptyl)-oxy)- phenyl)-3--hydroxy-estra-1 ,3,5(10)-trien-17beta-yl monobutanedioate, -llbeta-(4-( (butylmethylamino)-carbonyl)-heptyl)-oxy)- phenyl)-3-hydroxy-estra-1 ,3,5(10)-trien-17beta-yl and sodium butanedioate,**S N-butyl--2-(6-(4-(3,17beta-dihydroxy-estra-1 ,3,5(10)-tri 11 beta-yl) -phenoxy) -hexyloxy-N--methyl-acetamide, N-butyl-8--(4-(3,l7beta-dihydroxy-estra-1 ,3,5(1Q)-trien- 11beta-yl) -phenoxy) -N-methyl--2-octynamide, N-butyl--2-((5-(4--(3,l7beta-dihydroxy-estra-1 B trien-1 1beta-yl) -phenyl) -pentyl) -thio) -N-methyl--acetamide, N-butyl-4-(3,l7beta-dihydroxy-estra-1 ,3,5(10)-trien-llbeta- not* yl )-N-methyl-benzenenonamide, N-butyl-2-((5-(4-(3,17beta-d.4hydroxy-estra-1,3,5,10)-: trien-1 lbeta-yl)-phenyl)-pentyl)--oxy)-N-methyl-acetamide, (8-(3,l7beta-dihydroxy-19-nor-l7alpha-pregna-1 ,3,5(10)- trien-20-yn-llbeta-yl)-octyl)-oxy)-N-methyl-N-(1-methylethyl) acetamide.

9. Preparation process for the pzoQ 4 4.G&Lof formula as defined in claim 1, characterized in that a compound of formula (II): Y- CnOH (II) R' 1 7 in which X, Y, n, R 17 and R' 17 have the same meaning as in claim 1, it being understood that when R 17 represents a hydroxyl radical, this radical is protected, is subjected to the action of an oxidation agent in order to obtain the product of formula (III): S COOH Y e.. S* S* S(CH1 (III) i l l O 4 ee which is subjected to the action of an agent which allows the e* carboxylic function to be activated, then to the action of a compound of formula RA H-N (IV) Rg in which RA and RB have the same meaning as in claim 1, in order to obtain the product of formula 0 R -N-C A RB Y R. (V) (CH 1 7 q2 n 0 in which Z is a single bond, which products if necessary, are subjected to a deprotection reaction of the hydroxy function and, if desired, to a reducing agent when R 17 and R' 17 together form a ketone function, then if appropriate, the hydroxylated derivative in position 17 thus obtained is subjected to an acylation agent, 0. -or to a saponification agent when R 17 represents an acyloxy function, which compound of formula is subjected to an aromatization agent of the A ring, then to a saponification agent used sparingly so as to obtain the products of formula which, if desired, are subjected to one or more of the following reactions: either, when R 17 and R' 17 together form a ketone function, they are subjected to a reducing agent or to a metal complex of formula S. M-R'17 (VI) in which M represents a metal atom and R' 17 has the same meaning as in claim 1, with the exception of hydrogen, or when R 17 is a hydroxyl radical, they are subjected to a selective acylation agent in position 17, or, when RA or RB is a hydrogen atom, they are subjected to an appropriate alkylation agent, or, when Y represents an unsaturated aliphatic chain, they are subjected to a hydrogenation agent, in order to obtain the products of formula in which K is an oxygen atom which, if desired, are subjected to a sulphuration agent in order to obtain the products of formula in which K is a sulphur atom. c Preparation process for -predttes/of formula compoonds corresponding to produtsof formula as defined in claim 1 in which X represents an arylene radical and Y represents an aliphatic chain optionally linked to the arylene group by a double or a triple bond and containing at least 3 carbon atoms or linked to the arylene group by an oxygen or sulphur atom, characterized in that a compound of formula (VII): W 17 R* 7 (VII) R' having the same meaning as indicated in claim 1, it being understood that when R 17 represents an -OH radical, it isall optionally protected, the A' and B' rings are: either A B 0- or A B RO where R 3 represents a hydrogen atom or a protector group of the hydroxyl function, is subjected either, in the case where W represents a CSCH radical, to the action of a halogenated derivative of formula (VIII): RA Hal-Y'-Z-CO-N (VIII) R in which Hal is a halogen atom, Z, R A and RB have the same meaning as indicated in claim 1 and Y' represents the above aliphatic chain Y comprising at least 2 carbon atoms, .n the presence of a strong base and if appropriate, is subjected to the action of a deprotection agent in position 3 and/or position 17, in order to obtain the product of formula (IXA): R 17 N-CO-Z-Y'-C=C B 17 I X A o B' which product, if desired, is subjected to an agent giving partial or complete reduction of the triple bond in order to obtain the product of formula (IXB): RA N-CO-Z-Y'-c-C 0 L7 R' 1 7 (IXB) A' B' or, in the case where W represents an -OH radical, a mercapto radical or an activated mercapto radical, to the action of a halogenated derivative of formula

84- a (X) in which Hal, Y, Z, RA and RB have the same meaning as indicated in claim 1, in the presence of an alkaline agent, then if appropriate, to the action of a deprotection agent in order to obtain a product of formula (DIX): LT RL7 IX c) F3 in which K' represents either an oxygen atom, or a sulphur atom, which products of formula (IXA), (DXB) or (DIX) are, if appropriate, treated as indicated in claim 1 for the products of formula in order to obtain the products of formula which, if appropriate, are treated as indicated in claim 9 for the products of formula 11. Compounds of formula as defined in claim 1, substantially as herein described with reference to any one of the Examples. S" 12. Pharmaceutical compositions containing as active ingredient at least one of the compounds of formula as defined in any one of claims 1 to 8 together with a pharmaceutically acceptable suitable carrier, adjuvant and/or excipient. 13. Preparation process according to claim 9 in which n 2 in the compounds of formula (II) and (II). 14. Preparation process according to claim 10 in which W represents an optionally activated mercapto radical in the compounds of formula (VII). Preparation process for the compounds of formula as defined in claim 1 which process is substantially as herein described with reference to any one i I 85 of Examples 1 to 16. The compounds of formula as defined in claim 1 whenever prepared by the process of any one of claims 9, 10 or 13 to 17. A method of treating hormone-dependent carcinomas and their metastases in a patient/mammal requiring such treatment whicl, method includes administering to said patient/mammal an effective amount of compounds of formula as defined in any one of claims 1 to 8 or 11 or a pharmaceutical composition as defined in claim 12. 18. The method of claim 17, wherein said hormone-dependent carcinomas are mammary carcinomas. 19. A method of treating benign tumours of the breast in a patient/mammal requiring such treatment which method comprises administering to said patient/mammal an effective amount of compounds of formula as defined in any one of claims 1 to 8 or 11 or a pharmaceutical composition as defined in claim 12. DATED this 14th day of August 1991. ROUSSEL-UCLAF Bytheir Patent Attorneys: "SO CALLINAN LAWRIE 4 C 1 1 -86- ABSTRACT 19-Nor steroids with llbeta amide or thioamide substituents are provided which are found to have anti-oestrogen activity and anti-proliferative properties. The invention also provides pharmaceutical preparations containing suci compounds and processes for preparing the compounds from a steroid having diene conjugation in the A and B rings which carries an 11 substituent having a terminal alcohol which is oxidised to a carboxylic acid. The acid is then reacted with an amine, followed by aromatization of the A ring and saponification to compounds of the invention. A process for preparing alternative compounds in which the 11beta substituent has an arylene radical and an aliphatic chain contained therein. oel