FR2665901A2 - New 19-nor steroids possessing in position 11-beta a carbon chain comprising an amide function, their preparation, and their application as medicaments - Google Patents

Abstract

The present application of the first certificate of addition has the particular objective of illustrating, by means of new examples, the general formula (I) of the main application. The present application relates, for example, to the following product: 2-((8-(3,17-beta-dihydroxy-19-nor-17-alpha-pregna-1,3,5(10)-trien-20-y n-11-beta-yl)octyl)oxy)-N-methyl-N(1-methylethyl)acetamide, and to its application as a medicament.

Description

In the main patent application filed on 24
February 1989 under the number 89 02384 the Applicant has described new 19-Nor steroids having in position 11 beta a carbon chain comprising an amide or carbamate function, their preparation process and the intermediates of this process, their application as drugs and compositions pharmaceutical products containing them.

dans laquelle les cycles A et B ont l'une des structures suivantes a) soit A et B représentent le groupement

dans lequel R2 et R'2 identiques ou différents représentent un atome d'hydrogène ou un radical alkyle ayant de 1 à 4 atomes de carbone b) soit A et B représentent le groupement

The main application thus relates to compounds of general formula (I)

in which cycles A and B have one of the following structures: a) A and B represent the grouping

in which R 2 and R '2, which are identical or different, represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms b), ie A and B represent the grouping

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 CH2 -O or arylenoxy radical bound to the steroid by a carbon atom, - Y represents a single bond or a linear or branched aliphatic chain, saturated or unsaturated, containing from 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 radical CH2 -O linked to the radical Y by the carbon atom, it being understood that when Y and Z are a single bond, X can not be a methylene or CH2-O radical,
RA and RA ', which may be identical or different, represent a hydrogen atom, a linear or branched alkyl radical containing from 1 to 8 carbon atoms, optionally substituted with an aryl, alkyl or dialkylamino, hydroxy or esterified carboxyl radical, or RA and RA 'form, with the nitrogen atom to which they are bonded, a 5- or 6-membered heterocycle, saturated or unsaturated, optionally containing one or more other heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and optionally substituted with an alkyl radical having 1 to 4 carbon atoms, it being understood that at least one of the substituents RA or RA 'is not a hydrogen atom.

dans laquelle X, Y, R17 et R'17 ont la même signification que précédemment, étant entendu que R17 ne peut représenter un radical hydroxyle, - soit à l'action d'un agent d'oxydation pour obtenir le produit de formule (III)

que l'on soumet à l'action d'un agent permettant d'activer la fonction carboxylique, puis à l'action d'un composé de formule (IV) ::

dans laquelle RA et RA' ont la même signification que précédemment, pour obtenir le produit de formule (Ia) correspondant au composé de formule (I) dans laquelle Z est une simple liaison et les cycles A et B représentent le groupement

dans lequel R2 et R'2 sont un atome d'hydrogène, - soit à une réaction d'introduction du radical

pour obtenir le produit de formule (I'a) correspondant au composé de formule (I) dans laquelle Z est un radical méthylénoxy et les cycles A et B ont la même signification que dans les produits de formule (Ia), produits (Ia) et (I'a) que, si désiré - soit l'on soumet à un agent de réduction lorsque R17 et R'17 forment ensemble une fonction cétone, - soit l'on soumet à un agent d'acylation lorsque R17 représente une fonction hydroxy, - soit l'on soumet à un agent de saponification lorsque R17 représente une fonction acyloxy, - soit l'on soumet à une alkylation en position 2, lorsque l'un au moins des radicaux R2 et R'2 représente un atome d'hydrogène, - soit l'on soumet à un agent d'aromatisation du cycle A, puis à un agent de saponification ménagée pour obtenir les produits de formule (Ib) correspondant aux produits de formule (Ia) et les produits de formule (I'b) correspondant aux produits de formule (I'a) et dans lesquelles les cycles A et B représentent le groupement

The main application also relates to a process for the preparation of the compounds of formula (I), characterized in that a compound of formula (II) is subjected

in which X, Y, R 17 and R '17 have the same meaning as above, it being understood that R 17 can not represent a hydroxyl radical, or to the action of an oxidation agent to obtain the product of formula (III )

that is subjected to the action of an agent for activating the carboxylic function, then to the action of a compound of formula (IV) ::

in which RA and RA 'have the same meaning as above, to obtain the product of formula (Ia) corresponding to the compound of formula (I) in which Z is a single bond and rings A and B represent the grouping

in which R2 and R'2 are a hydrogen atom, or to an introduction reaction of the radical

to obtain the product of formula (I'a) corresponding to the compound of formula (I) in which Z is a methylenoxy radical and the rings A and B have the same meaning as in the products of formula (Ia), products (Ia) and (1'a) that, if desired - either it is subjected to a reducing agent when R17 and R'17 together form a ketone function, - or it is subjected to an acylating agent when R17 represents a function hydroxy, - either it is subjected to a saponification agent when R17 represents an acyloxy function, or it is subjected to an alkylation in position 2, when at least one of the radicals R2 and R'2 represents a hydrogen atom. hydrogen, or it is subjected to an aromatizing agent of the ring A, then to a saponification agent to obtain the products of formula (Ib) corresponding to the products of formula (Ia) and the products of formula (I b) corresponding to the products of formula (I'a) and in which rings A and B represent the group is lying

Products of formula (Ib) and (I'b) that if desired, - either, when R17 and R'17 together form a ketone function, it is subjected to a reducing agent or subjected to a metal complex of formula (V) M-R'17 (V) in which M represents a metal atom and R'17 has the same meaning as above, it being understood that it is not a hydrogen atom, - either when R 17 is a hydroxyl radical, it is subjected to a selective acylating agent at position 17, or when RA or RA 'is a hydrogen atom, it is subjected to an alkylating agent.

 The present application for the first certificate of addition is intended to illustrate, by new examples, the general formula (I).

 The present application also aims to describe products (IA) related to said general formula (I) of the main patent.

 The present application relates to the following products the products corresponding to the general formula (I) of the main patent application whose preparation is given later in the experimental part and more particularly those whose names follow - the monobutanedioate of llbéta- (4). (- ((7- (butylmethylamino) carbonyl) heptyl) oxy) phenyl) -3-hydroxy-estra-1,3,5 (10) trien-17beta-yl, butanebiodate (4 - ((7- ((Butylmethylamino) carbonyl) heptyl) oxy) phenyl) -3-hydroxy-estra-1,3,5 (10) trien-17beta-yl and sodium, - N-butyl-2- (6- (4- (3,17beta-dihydroxy-estra-1,3,5 (10) trien-11beta-yl) phenoxy) hexyloxy-N-methyl-acetamide, N-butyl-8- (4- (3,17beta-dihydroxy) Estra-1,3,5 (10) -trien-11beta-yl) -phenoxy) -N-methyl-2-octynamide, N-butyl-4- (3,17-beta-dihydroxy-1,3-estra, 5 (10) -trien-11beta-yl) -N-methyl-benzenenonamide, N-butyl-2 - ((5- (4- (3,17beta-dihydroxy-estra-1,3,5 (10)) trien-11beta-yl) phenyl) pentyl) oxy) -N-methylacetamide 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.

dans laquelle n = 1 ou 2, les cycles A et B représentent le groupement

This application also relates to related products of formula (IA):

in which n = 1 or 2, the rings A and B represent the grouping

K represents an oxygen atom or a sulfur atom, R17 and
R'17 are such that - either R17 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 radical CH2-O, arylenoxy or aryienethio bonded to the steroid by a carbon atom, - Y represents a single bond or a linear or branched aliphatic chain saturated or unsaturated, containing from 1 to 18 carbon atoms, optionally interrupted by one or more radicals chosen from arylene, oxygen or sulfur radicals optionally oxidized in the form of sulphoxide or sulphone and optionally terminated by an arylene radical, - Z represents a simple bond being understood that when Y and Z are a single bond, X may not be a methylene radical or CH2-O,
RA or RAi, which may be identical or different, represent a hydrogen atom, a linear or branched alkyl radical containing from 1 to 8 carbon atoms, optionally substituted by an aryl, alkyl or dialkylamino, hydroxy, halogen or esterified carboxyl radical or RA and RA, form, with the nitrogen atom to which they are bonded, a saturated or unsaturated 5- or 6-membered heterocycle, optionally containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms and optionally substituted by an alkyl radical having from 1 to 4 carbon atoms, an aryl or aralkyl radical having from 6 to 10 carbon atoms, it being understood that at least one of the radicals RA or RA is not an atom hydrogen and at least one of the following conditions is met - either n = 2, - or K is a sulfur atom, - or X is an arylenethio radical bonded to the steroid by a carbon atom, - or Y is an aliphatic chain e interrupted by an optionally oxidized sulfur atom, - or RA or RA, is an alkyl radical substituted with one or more halogen atoms, - or RA and RA, form with the carbon atom to which they are bound a heterocycle to 5 or 6 links substituted by an aryl or aralkyl radical.

When R17 is an acyloxy radical it may be in particular the derivative of a saturated or unsaturated aliphatic or cycloaliphatic acid and in particular an alkanoic acid such as, for example, acetic acid, propionic acid, butyric acid or isobutyric acid, valeric acid or undecyl acid, a hydroxyalkanic acid such as, for example, hydroxyacetic acid; a cycloalkylcarboxylic or (cycloalkyl) alkanoic acid such as, for example, cyclopropyl, cyclopentyl or cyclohexylcarboxylic acid, cyclopentyl or cyclohexyl acetic acid or propionic acid, a benzoic acid, a salicylic acid or a phenylalkanoic acid such as phenyl acetic acid or phenyl propionic acid, an amino acid such as diethylamino acetic acid or aspartic acid or formic acid.

 It is preferably the derivative of acetic acid, propionic, butyric or butanedioic.

When R '17 represents an alkyl radical, it may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-pentyl, n-hexyl, 2-methylpentyl, 2,3-dimethylbutyl, n heptyl, 2-methyllexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl.

It is preferably methyl.

When R'17 represents an alkenyl radical, it may be a vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl radical. It is preferably vinyl or propenyl radical.

When R '17 represents an alkynyl radical, it may be the ethynyl, propynyl, propargyl, butynyl or isobutynyl radical. It is preferably ethynyl or propynyl.

CO2H dans lequel n = 2 à 5 notamment, - acyle tel que acétyle, propionyle, butyryle, benzoyle, - carboxy libre, estérifié tel que alkoxy carbonyle par exemple méthoxy carbonyle ou éthoxy carbonyle, - cyano, - trifluorométhyle, - aryle tel que phényle, furyle, thiényle ou aralkyle tel que benzyle, ces radicaux étant eux-mêmes éventuellement substitués par des radicaux alkyle, tel que méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tert-butyle ou par des radicaux, alkoxy, alkylthio, amino alkyl ou di-alkylamino indiqués ci-dessus.The optionally substituted expression applied to the alkyl, alkenyl or alkynyl radicals comprises one or more identical or different radicals chosen preferably from the radicals - halogen: 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 dimethylamino, diethylamino, methylethylamino, each of the dialkylamino radicals being optionally in oxidized form, amino alkyl such that aminomethyl or aminoethyl, dialkylaminoalkyl such as dimethylamino methyl or ethyl, dialkylaminoalkyloxy such as dimethylamino ethyloxy, hydroxyl optionally acylated, for example acetoxy or a radical of formula

CO2H in which n = 2 to 5 in particular, - acyl such as acetyl, propionyl, butyryl, benzoyl, - free carboxy, esterified 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 themselves being optionally substituted by alkyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or radicals, alkoxy, alkylthio, amino alkyl or di-alkylamino indicated above.

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

 When X is an arylenoxy group, it is preferably phenylenoxy.

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

 When Y represents a linear or branched, saturated or unsaturated aliphatic chain, it may be the methylene, ethylene, propylene, isopropylene, butylene, isobutylene or tert-butylene, n-pentylene, n-hexylene or 2-methylpentylene radical. 2,3-Dimethylbutylene, n-heptylene, 2-methylhexylene, 2,2-dimethylpentylene, 3,3-dimethylpentylene, 3-ethylpentylene, n-octylene, 2,2-dimethylhexylene, 3,3-dimethyl- hexylene, 3-methyl-3-ethylpentylene, nonylene, 2,4-dimethylheptylene, n-decylene, n-undecylene, n-dodecylene, n-tridecylene, n-tetradecylene, n-penta decylene, n-hexadecylene, nheptadecylene or n octadecylene, preferably n-nonylene or n-decylene. It can also be vinylene, isopropenylene, allylene, 2-methylallylene or isobutenylene radicals, and when the chain is interrupted or terminated by one or more arylene radicals, it is preferably a phenylene radical, it being understood that any one of the two ends of Y.

When RA or RA 'represents an alkyl radical, it may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, noctyle, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl.

The radicals mentioned above may be substituted with one or more aryl radicals such as phenyl, furyl, thienyl, preferably a phenyl radical, with one or more alkylamino or dialkylamino radicals such as dimethylamino or with one or more carboxyls esterified for example with a methoxycarbonyl or an ethoxycarbonyl, with one or more halogen atoms, for example fluorine, chlorine or bromine.

 There may be mentioned in particular the radical 2,2,3,3,4,4,4 heptafluorobutyl.

 When RA and RA 'form with the nitrogen atom to which they are bonded a 5- or 6-membered heterocycle, it is a saturated heterocycle, preferably a pyrrolidine or a piperidine optionally substituted by an alkyl radical such that methyl, ethyl, propyl or isopropyl, preferably methyl or ethyl, with an aryl radical such as phenyl or tolyl or with 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, a piperazine or a pyrimidine, optionally substituted by an alkyl radical, preferably methyl or ethyl.

 The present application relates more particularly to the products of formula (IA) for which n is equal to 1.

 Among the preferred compounds of the invention, mention may especially be made of the products of formula (IA) for which K is a sulfur atom, X is an aryleneoxy radical and Y represents a saturated linear chain containing from 5 to 10 carbon atoms, optionally interrupted by an oxygen atom, those for which X is an arylenethio radical and Y represents a saturated linear chain containing from 5 to 10 carbon atoms, those for which X is an arylene or arylenoxy radical and Y is a linear saturated chain containing from 5 to 10 carbon atoms and interrupted by an optionally oxidized sulfur atom, those for which X is an arylene or arylenoxy radical, Y is a saturated or unsaturated aliphatic chain and RA or RA, is an alkyl radical substituted by one or more halogen atoms and those for which X is an arylene radical, Y represents an unsaturated linear chain containing from 5 to 10 carbon atoms, RA and RA, formen with the atom to which they are attached an N-substituted piperidine with an alkyl radical.

 Among the preferred compounds of the invention, the products of formula (IA) whose preparation is given later in the experimental part and more particularly - N-butyl-5- (4- (3,17beta) dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) phenoxy) pentyloxy) -N-methyl-ethanethioamide; N-butyl-8- (4- (3,17beta-dihydroxy estra) 1,3,5 (10) -trien IIbeta-yl) phenoxy) -N-methyl-octanethioamide, N-butyl-2 - ((5- (4- (3,17beta-dihydroxy-1,3-estra) 5 (10) trien-11beta-yl) phenyl) pentyl) thio) -N-methyl-acetamide.

dans laquelle X, Y, n, R17 et R'17 ont la même signification que précédemment, étant entendu que lorsque R17 représente un radical hydroxyle ce radical est protégé, à l'action d'un agent d'oxydation pour obtenir le produit de formule (IIIA)

que l'on soumet à l'action d'un agent permettant d'activer la fonction carboxylique, puis à l'action d'un composé de formule (IVA)

dans laquelle RA et RA' ont la même signification que précé demment, pour obtenir le produit de formule (VA)

dans laquelle Z est une simple liaison, produits (VA) que, si nécessaire, l'on soumet à une réaction de déprotection de la fonction hydroxy et que, si désiré, - soit l'on soumet à un agent de réduction lorsque R17 et R'17 forment ensemble une fonction cétone, - soit l'on soumet à un agent d'acylation lorsque R17 représente une fonction hydroxy, - soit l'on soumet à un agent de saponification lorsque R17 représente une fonction acyloxy, puis que l'on soumet à un agent d'aromatisation du cycle A, puis à un agent de saponification ménagée pour obtenir les produits de formule (IA) que si désiré, - soit, lorsque R17 et R'17 forment ensemble une fonction cétone, l'on soumet à un agent de réduction ou que l'on soumet à un complexe métallique de formule (VIA)
M-R' (VIA) dans laquelle M représente un atome métallique et R'17 a la même signification que précédemment, étant entendu qu'il ne s'agit pas d'un atome d'hydrogène, - soit, lorsque R17 est un radical hydroxyle, l'on soumet à un agent d'acylation sélective en position 17, - soit, lorsque RA ou RA' est un atome d'hydrogène, on soumet à un agent d'alkylation, - soit, lorsque Y représente une chaine aliphatique insaturée, l'on soumet à un agent d'hydrogénation, pour obtenir les produits de formule (IA) dans laquelle K est un atome d'oxygène que, si désiré, l'on soumet à un agent de sulfuration pour obtenir les produits de formule (IA) dans laquelle K est un atome de soufre.The present application also relates to a process for preparing the products of formula (IA) as defined above, characterized in that a compound of formula (IIA) is subjected

in which X, Y, n, R 17 and R 17 have the same meaning as above, it being understood that when R 17 represents a hydroxyl radical, this radical is protected by the action of an oxidation agent to obtain the product of formula (IIIA)

that is subjected to the action of an agent for activating the carboxylic function, then to the action of a compound of formula (IVA)

in which RA and RA 'have the same meaning as above, to obtain the product of formula (VA)

wherein Z is a single bond, produced (VA) that, if necessary, is subjected to a deprotection reaction of the hydroxy function and that, if desired, or is subjected to a reducing agent when R17 and R'17 together form a ketone function, - either it is subjected to an acylating agent when R17 represents a hydroxy function, - or it is subjected to a saponification agent when R17 represents an acyloxy function, then that the subjected to an aromatizing agent of the ring A, then to a saponification agent to obtain the products of formula (IA) that if desired, - or, when R17 and R'17 together form a ketone function, one subjected to a reducing agent or subjected to a metal complex of formula (VIA)
MR '(VIA) in which M represents a metal atom and R'17 has the same meaning as above, it being understood that it is not a hydrogen atom, - or, when R17 is a hydroxyl radical it is subjected to a selective acylating agent at position 17, either when RA or RA 'is a hydrogen atom, it is subjected to an alkylating agent, or when Y represents an unsaturated aliphatic chain. it is subjected to a hydrogenation agent, to obtain the products of formula (IA) in which K is an oxygen atom which, if desired, is subjected to a sulphurizing agent to obtain the products of formula (IA) wherein K is a sulfur atom.

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

 The product of formula (IIIA) is obtained using an oxidizing agent such as, for example, the CrO.sub.3 sulfuric acid mixture in a neutral solvent such as, for example, acetone.

In a preferred embodiment of the invention, the compounds of formula (IIA) comprise an IIbeta chain terminated by an alcohol function chosen from the following table.
XY
≈- (CH2) 7 - CH2OH
i - (CH2) 5-S-CH2-CH2OH
m Crn-C- (CH 2) 5 -CH 2 OH
O - (CH2) 7 - CH2OH
i (CH2) 5-O-CH2-CH2OH
- (CH2) 5-SO-CH2-CH2OH
As illustrated in the examples below, the compounds of formula (IIIA) comprise a chain terminated in beta, terminated by a carboxylic function, corresponding to the oxidation product of a chain selected from the chains in IIbeta terminated by one of the alcohol functions cited above, the compound of formula (IVA) is chosen from amines butylamine, methyl butylamine, methylisopropylamine or benzylpiperidine which are known products, or methyl heptafluorobutylamine whose preparation is given below.

 When (VA) has a ketone at 17, the corresponding 17beta hydroxylated steroid is obtained by the action of a reducing agent such as sodium borohydride in a neutral solvent such as methanol or triterbutoxylithium aluminum hydride in the tetrahydrofuran.

 When (VA) has a hydroxyl function at 17, the corresponding acyloxylated steroid 17beta is obtained by the action of an acylating agent, for example acetylation such as acetic anhydride in pyridine, optionally in the presence of 4 -diméthylaminopyridine.

 When (VA) has an acyloxy function at 17, the corresponding 17beta hydroxyl steroid is obtained by the action of a saponification agent such as potassium hydroxide in an alcoholic medium.

 The compounds of formula (IA) which are steroids derived from estradiol having an IIbeta chain having a substituted amide function are obtained from the compounds of formula (VA) by the action of an aromatizing agent such as palladium hydroxide on magnesia in methanol or the acetyl bromide-acetic anhydride mixture, at a temperature not exceeding ambient temperature, followed by a controlled saponification reaction with, for example, potassium hydroxide in methanol, sodium bicarbonate or methanol in the presence of hydrochloric acid.

 When (IA) has a ketone function at 17, the corresponding hydroxylated 17beta steroid is obtained, under the conditions described above, for (VA) for example by the action of a reducing agent such as sodium borohydride in a neutral solvent such as methanol, the corresponding compound of formula (IA) having an R '17 radical which represents an optionally substituted alkyl, alkenyl or alkynyl radical, using as complex, for example, a lithium complex, according to US Pat. process described in patent application EP 57115.

 When (IA) has a 17-hydroxy function, the corresponding acyloxylated 17beta steroid is obtained by the action of a selective acylating agent, for example acetic anhydride in pyridine.

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

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

 When Y is an unsaturated aliphatic chain, the product (IA) for reducing the corresponding triple bond is obtained either with 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, either with palladium hydroxide alone or with chlorotris (triphenylphosphine) rhodium in the case of a total reduction.

 The products of formula (IA) in which Y represents a branched aliphatic chain can be prepared by alkylation of the products of formula (IA) in which Y represents a linear aliphatic chain after having, if necessary, blocked the reactive functions in 3 and in 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 (IA) in which K is a sulfur atom is obtained by the action of a sulfurization agent, for example (2,4-bis (4-methoxyphenyl) - 1,3-dithia-2,4-diphosphenate-2,4-disulfide] (Lawesson reagent), after possible blocking of the reactive functions at 3 and 17.

dans laquelle W représente soit un radical -OH, soit un radical mercapto éventuellement protégé, soit un radical -C -CH, n ayant la même signification que celle indiquée précédemment, Ra17 et Ra'17 ayant les mêmes significations que celle indiquée précédemment pour R17 et R'17, les cycles A' et B' sont - soit

- soit

où R3 représente un atome d'hydrogène ou un radical alkyle renfermant de 1 à 4 atomes de carbone ou un radical acyle, et dans laquelle les fonctions réactives en 3 et 17 sont éventuellement protégées, ou bien, dans le cas où W représente un radical C --CH à l'action d'un dérivé halogéné de formule (XIA)

dans laquelle Hal est un atome d'halogène, Z, RA et RA' ont la même signification que celle indiquée précédemment et Y' représente la chaine aliphatique Y ci-dessus comportant 2 atomes de carbone en moins, en présence d'une base forte et soumet le cas échéant à l'action d'un agent de déprotection, pour obtenir le produit de formule (XIIA)al : :

produit que, si désiré, l'on soumet à un agent de réduction partielle ou totale de la triple liaison pour obtenir le produit de formule (XII > )a2 :

ou bien, soit dans le cas où W représente un radical -OH, soit dans le cas où W représente un radical mercapto ou un dérivé éventuellement activé du radical mercapto, à l'action d'un dérivé halogéné de formule (XIIIA)

dans laquelle Hal, Y, Z, RA et R' ont la même signification que celle indiquée précédemment, en présence d'un agent alcalin, puis le cas échéant, à l'action d'un agent de déprotection pour obtenir un produit de formule (XIIA)a3

dans laquelle K' représente soit un atome d'oxygène, soit un atome de soufre, produits (XIIA)al, (XIIA)a2 et (XIIA)a3 que si désiré l'on soumet à l'une quelconque des réactions indiquées précédemment pour (VA), puis l'on soumet les produits (XII)aî, (XIIA)a2 et (XIIA)a3 dans lesquels les cycles A' et
B' sont

à un agent d'aromatisation du cycle, puis à un agent de saponification ménagée pour obtenir les produits de formule (ira') que, si désiré, l'on soumet à l'une quelconque des réactions indiquées précédemment pour (IA). The invention also relates to a process for preparing the products of formula (IA ') corresponding to products of formula (IA) 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 comprising at least 3 carbon atoms or bonded to the arylene group by an oxygen atom or a sulfur atom, characterized in that one submits a compound of formula (XA)

in which W represents either an -OH radical, an optionally protected mercapto radical, or a -C-CH radical, n having the same meaning as that indicated above, Ra17 and Ra'17 having the same meanings as that indicated previously for R17 and R'17, the cycles A 'and B' are - either

- is

where R3 represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms or an acyl radical, and in which the reactive functions at 3 and 17 are optionally protected, or else, in the case where W represents a radical C --CH with the action of a halogenated derivative of formula (XIA)

in which Hal is a halogen atom, Z, RA and RA 'have the same meaning as previously indicated and Y' represents the aliphatic chain Y above having 2 less carbon atoms, in the presence of a strong base and if appropriate subject to the action of a deprotection agent, to obtain the product of formula (XIIA):

product that, if desired, is subjected to a partial or total reduction agent of the triple bond to obtain the product of formula (XII>) a2:

or else, in the case where W represents an -OH radical, or in the case where W represents a mercapto radical or an optionally activated derivative of the mercapto radical, to the action of a halogenated derivative of formula (XIIIA)

in which Hal, Y, Z, RA and R 'have the same meaning as that indicated above, in the presence of an alkaline agent, then, if appropriate, by the action of a deprotection agent to obtain a product of formula (XIIA) a3

in which K 'represents either an oxygen atom or a sulfur atom, produced (XIIA) a1, (XIIA) a2 and (XIIA) a3, if desired, are subjected to any of the reactions indicated above for (VA), then the products (XII), (XIIA) a2 and (XIIA) a3 are subjected in which the cycles A 'and
B 'are

to an aromatizing agent of the cycle, then to a mild saponification agent to obtain the products of formula (ira ') that, if desired, any of the reactions indicated above for (IA) are subjected to.

 When W represents a derivative of the mercapto radical, it may be a thioether such as an alkylthio derivative, for example tert-butylthio, triphenyl-methylthio, isobutyloxy methylthio or a derivative of a 5 or 6-membered ring. linkages optionally containing a heteroatom belonging to the group of nitrogen, oxygen or sulfur, preferably oxygen, for example tetrahydropyranylthio.

 When W represents an activated derivative of the mercapto radical, it may be a metal thiolate, for example silver.

 According to a preferred embodiment of the process of the invention described above - the possible protective groups of the hydroxyl functions at 3 and at 17 are chosen from the usual groups such as tetrahydropyranyl and tert-butyl, - the halogen atom which Hal represents, for example, a bromine, chlorine or iodine atom, - the strong base used is, for example, butyllithium or sodium hydride, - the possible reduction of the triple bond is carried out either with the aid of hydrogen in the presence of palladium on activated charcoal, barium sulfate and optionally a base such as pyridine or quinoline, in the case of a partial reduction, either using palladium hydroxide alone or chlorotris (triphenylphosphine) ) rhodium in the case of a total reduction, - the possible activation of the mercapto radical is carried out by action of a metal salt, for example silver nitrate, on the mercapto protected by a group such as t trahydropyranyl, - the alkaline agent used is an alkaline hydroxide, for example sodium hydroxide, - the unblocking of the protected functions is carried out using a usual hydrolysis agent such as hydrochloric acid, - in the compounds of formula (XA) used initially, the radical W is in para position.

 The compounds of formula (I) and formula (IA) have interesting pharmacological properties. The study of the products on the hormonal receptors made it possible to demonstrate that they possess in particular a remarkable anti-estrogenic activity and anti-proliferative properties, as the results of the tests given below show.

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

 The subject of the invention is therefore the products of formula (I) and the products of formula (IA) as medicaments.

 Among the medicaments of the invention, mention may be made especially of the compounds described in the experimental part and most particularly the products of Examples 1, 2, 3, 4, 6, 7, 9, 10, 11 and 14.

 The dosage varies with the condition being treated and the route of administration; it may vary for example from 1 to 100 mg per day in the adult orally.

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

 The compounds of formula (I) and formula (IA) are used digestive, parenteral or local, for example percutaneously. They may be prescribed in the form of single or coated tablets, capsules, granules, suppositories, ova, injectables, ointments, creams, gels, microspheres, implants, patches, which are prepared according to the usual methods.

 The active ingredient (s) can be incorporated into 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, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 Some of the intermediates of formula (IIA) or (IIIA) are novel products and the invention therefore also relates to the products of formula (IIA) and (IIIA) as defined above, it being understood that at least one the following 2 conditions are fulfilled - either n = 2, - or Y is an aliphatic chain interrupted by an optionally oxidized sulfur atom, as new intermediate products.

sur un composé de formule (XXIA)

dans laquelle n a la signification donnée précédemment, K3 est un groupement protecteur de la fonction cétone en 3 tel qu'un cétal cyclique, pour obtenir le produit de formule (XXII) :

que l'on soumet, si désiré, - soit au dérivé lithien du produit de formule (XXIIIA)
H-R'17 (XXIIIA) dans laquelle R'17 a la signification donnée précédemment, étant entendu qu'il ne s'agit pas d'un atome d'hydrogène - soit à un agent de réduction, puis éventuellement à un agent d'acylation, et que l'on soumet à un agent de déshydratation et d'hydrolyse susceptible de libérer la fonction 3-céto delta-4 et la fonction alcool pour obtenir le composé de formule (lIA)
Les produits de formule (XXIA) nécessaires à la mise en oeuvre du procédé sont des produits connus.Leur préparation est décrite par exemple dans le brevet EP 0057115 lorsque n = 1 et dans la demande européen EP 0116974 lorsque n = 2.The novel compounds of formula (IIA) as defined above are prepared according to a procedure, an example of which is given below. In general, the compounds of formula (IIA) can be prepared according to the following process
In the presence of a copper salt, the magnesium derivative of a halogenated alcohol of formula (XXA) is reacted
in which X and Y have the meanings given above, hal is a halogen atom, preferably a chlorine or bromine atom and R is either a hydrogen atom or a protective group of H 2 -XY-CH 2 OR (XXA); the alcohol function for example a grouping

on a compound of formula (XXIA)

wherein n has the meaning given above, K3 is a protecting group of the 3-ketone function such as a cyclic ketal, to obtain the product of formula (XXII):

which, if desired, is subjected either to the lithian derivative of the product of formula (XXIIIA)
H-R'17 (XXIIIA) in which R'17 has the meaning given above, it being understood that it is not a hydrogen atom - either to a reducing agent, then possibly to an agent of acylation, and subjected to a dehydration and hydrolysis agent capable of releasing the 3-keto delta-4 function and the alcohol function to obtain the compound of formula (IIA)
The products of formula (XXIA) necessary for carrying out the process are known products. Their preparation is described, for example, in EP 0057115 when n = 1 and in European application EP 0116974 when n = 2.

 Products of formula (XA) necessary for carrying out the process, in which n = 1 and W is different from a mercapto radical, are described in particular in European patent application EP 0245170. The products in which n = 2 and W is different from a mercapto radical are obtained by the same method starting from the product (XXIA) in which n = 2.

 The products of formula (XA) in which W is a mercapto radical, optionally protected, are novel products and the invention therefore also relates to the products of formula (XA) as defined above, in which W represents a mercapto radical. possibly protected as new intermediate products. The novel products (XA) defined above can be prepared by the action of a magnesium containing a mercapto group on a product of formula (XXIA). Specific examples of preparations of such novel products (XA) are described below in the examples.

 Examples of product preparation (XIA) and (XIIIA) are given below in the experimental section.

Preparation 1: N-hepta-fluorobutyl N-methylamine hydrochloride.

 100 cm3 of anhydrous ether, 100 cm3 of anhydrous tetrahydrofuran (100 cc) are then cooled down to 0.degree. C. and methylamine is then bubbled in for 10 minutes. Half a hour is introduced 44.98 g of heptafluorobutyric anhydride maintaining a low bubbling of methylamine. Stirred for 2 hours, allowing to return to room temperature. It is distilled at low volume under reduced pressure, taken up in 200 cm3 of anhydrous tetrahydrofuran and slowly introduced 30 cm3 of diborane-dimethyl sulfide complex. Refluxed for 16 hours. Cooled to room temperature and then slowly introduced 200 cm of methanol. Gaseous hydrochloric acid is then bubbled for 15 minutes. Refluxed for 1 hour and then distilled the solvents under reduced pressure. The residue is taken up in 200 cm3 of methanol. The gaseous hydrochloric acid is bubbled again for 10 minutes and then refluxed for 2 hours. The solvent is distilled and the mixture is stirred for 10 minutes in ice-cold 6N hydrochloric acid (100 cc). The mixture is filtered off with suction, washed with 2N hydrochloric acid and dried to obtain 22.699 g of expected product. The hydrochloride obtained above is purified by crystallization in 140 cm3 of ethanol. 140 cm3 of ether are then added, the mixture is stirred for half an hour, drained, washed with ether and dried under reduced pressure. 21.7 g of desired product are obtained (sublime at about 200 ° C.).

Analvse: C5H6F7N, HC1: 249.56
Calculated: C% 24.06 H% 2.83 C1 14.20 F% 53.29 N% 5.61
Found: 24.0 2.8 14.4 52.3-52.1 5.6 Prenaration 2: E (5-chloro-pentyl) -dienethyl ether (1,1-dimethyl-silane.

 To a solution of 10.2 g of 5-chloropentanol in 80 cm 3 of methylene chloride, 13.8 cm 3 of triethylamine and then 200 mg of 4-dimethylaminopyridine are added under a nitrogen atmosphere, cooled to -10 ° C. and added. 13.75 g of terbutyl chlorodimethylsilane. Stirred for 15 minutes at -10 C and allowed to warm to room temperature and diluted with saturated sodium bicarbonate solution. The oily crude derivative is separated off and chromatographed on silica (eluent cyclohexane-ethyl acetate 95-5) and 18 g of expected product are obtained.

IR spectrum: (CHC13)
OH absence
O-Si + presence
Preparation 3: t (3-bromopropyloxy)] - dimethyl- (1,1-dimethylethyl) -silane.

Step A: 3- (Edimethyl (1,1-dimethylethyl) silyl) oxy) propanol.

 9.46 g of 50% sodium hydride in oil are introduced into a flask placed under an argon atmosphere and washed off with hexane, 380 ml of tetrahydrofuran, 15 g of 1,3-propanediol and stirred for 1 hour at room temperature. It is cooled to +5 ° C., 29.7 g of tert-butylchlorodimethylsilane are added, the mixture is stirred for 1 hour at room temperature and then poured into 3.5 liters of ethyl ether.

Wash with 1 liter of 10% aqueous potassium carbonate solution and then with 1 liter of saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness under reduced pressure. The residue (35.5 g) is chromatographed on silica (eluent: ethylcyclohexane acetate 4-6). 30.6 g of expected product are obtained.

IR spectrum: (CHC13)
OH 3625, 3500 cm 1 1258, 1258, 838 cm -1
Step B: ((3-Bromopropyl) oxy] dimethyl (1,1-dimethylethyl) silane.

 To a solution of 2.5 g of the product obtained in Stage A above in 27 ml of methylene chloride cooled to -25 ° C. are added 5.44 g of tetrabromomethane and 4.30 g of triphenylphosphine. The mixture is stirred for 1 h at 0 ° C. and the reaction solution is chromatographed on silica (eluent: ethyl acetate cyclohexane 1-9). 2.885 g of expected product are isolated.

Analvse: C9H21BrOSi
% C% H% Br
Calculated: 42.68 8.35 31.55
Found: 40.0 7.9 36.6
IR spectrum: (CHCl 3) -1 -O-1 + 1258.837 cm
Preparation 4: 4-trimethylsilylethynyl-bromobenzene

 150 g of 97% bromo iodo benzene, 500 cm3 of anhydrous dimethylformamide, 100 cm3 of triethylamine, 50 g of trimethylsilyl acetylene, 2.1 g of copper iodide and 2.22 g of bis (triphenylphosphine) palladium are introduced ( II) dichloride. Stirred for 2 hours then added 500 cm3 of ice water and extracted 3 times with 500 cm3 of ethyl acetate. The organic phase is washed with salt water and then dried over sodium sulphate. The solvents are evaporated under reduced pressure. 136.54 g of brown oil are obtained. It is purified by distillation under reduced pressure and 106.97 g of expected product is obtained.

Eb: 75-82 ° C at 0.2 mbar, mp = 62 ° C.

IR spectrum: (CHCl3) absence of C = CH
C = C 2160 cm -1 Prenaration 5: [(8-bromooctyl) oxy) dimethyl (1,1-dimethylethyl) silane.

 To a solution of 3.97 g of 8-bromo octanol in 19 cm3 of dimethylformamide is added 1.55 g of imidazole, and in 10 minutes, 3.32 g of terbutyl chlorodimethyl silane in solution in 4.7 cm3. of tetrahydrofuran. It is stirred for 1 hour at ambient temperature, the insoluble material is filtered and the mixture is evaporated to dryness under reduced pressure. Chromatography on silica (eluent cyclohexane-toluene 8-2) and 5.4 g of expected product.

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

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

a) Preparation of the magnesian
To a suspension of 7.1 g of magnesium in turnings in 14.5 cm3 of tetrahydrofuran is added dropwise under reflux 50 g of trimethylsilyloxy 4-bromo benzene in 100 cm3 of tetrahydrofuran. It is stirred for 30 minutes under reflux and gives a solution of approximately 0.95 M magnesium.

b) Condensation
10 g of Salpha 3- (1,2-ethanediyl) acetalcyclic acid, 10alpha-epoxy estr-9,11-en-3,17-dione obtained according to EP 0057 115 (Example 7) are stirred for 10 minutes at room temperature. in solution in 200 cm3 of tetrahydrofuran and 0.45 g of copper chloride. 110 cm 3 of the magnesium solution obtained above is added over 20 minutes, without exceeding 27 ° C.

After stirring for 1 h, it is poured into 1300 cm3 of saturated ice-cold solution of ammonium chloride. The aqueous phase is extracted 3 times with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure to obtain 34.9 g of crude product.

(c) Disilvlation
The crude product obtained above is dissolved in 150 cm3 of tetrahydrofuran, 130 cm3 of a 1M solution of tetrabutylammonium fluoride are added. It is stirred for 15 minutes at room temperature, poured into water, extracted with ethyl acetate, washed with water, dried and evaporated to dryness under reduced pressure. 26.9 g of crude product are obtained which is impasted at 400 ° C. for 30 minutes in 100 cm 3 of a mixture of ethyl acetate and methylene chloride (1-1). The insoluble material is filtered off and 5.77 g of desired product is obtained. By chromatography on silica of the mother liquors (eluent: ethyl acetate-methylene chloride 1-1), an additional 5.7 g of the desired product is collected. The two batches of products obtained (11.47 g) are collected together It is recrystallized from ethanol. 8 g of the expected product are obtained. Mp = 255 ° C.

IR spectrum: (CHC13)
Region OH 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.

The mixture is stirred for 1 h 30.5 g of the product obtained at the stage.
A, 110 cm3 of ethanol and 28 cm3 of 2N hydrochloric acid. Basified to pH about 9 with concentrated ammonia. Evaporated to dryness and taken up with ethyl acetate, washed with water, with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue is chromatographed (4.8 g) on silica (eluent: methylene chloride ethyl acetate 7-3). 3.97 g of desired product are obtained.

IR spectrum: (CHC13)
OH 3596 cm -1
C = O 1735 cm -1
C = O 1657 cm aromatic 1612, 1593, 1511 cm -1
Preparation B of Example 1: 1 (5-bromopentyl) N-butyl oxide
N-methyl acetamide

Stage A: N-butyl bromo N-methylacetamide.

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

Analvse: C7H14BrNO = 208.105
Calculated: C% 40.40 H% 6.78 N% 6.73 Br% 38.39
Found: 40.3 7.0 6.7 38.2
Step B: 5 - [[(dimethyl (1,1-dimethylethyl) silyl] oxy] pentanol.

 To a solution consisting of 10 g of 4-pentanol, 200 cm 3 of methylene chloride, 19.5 cm 3 of triethylamine and 566 mg of 4-dimethylaminopyridine, 19.14 g of tert-butylchlorodimethylsilane are added with cooling. It is stirred for 1 hour at room temperature, diluted with water, decanted the organic phase, washed, dried and evaporated to dryness in vacuo. The residue is chromatographed (42 g) on silica (eluent: G-ethyl acetate 95-5). 23.3 g of silyloxy pentene are obtained and dissolved in 250 cm3 of tetrahydrofuran. 6 cm3 of borane-methylsulfide complex are added at 200 ° C. The mixture is stirred for 30 minutes at 20/25 ° C. and then for 30 minutes at 35 ° C. 18 cm3 of sodium hydroxide solution and then 18 cm3 of hydrogen peroxide are added at + 10 ° C., the mixture is stirred for 30 minutes, diluted with water, extracted with ethyl acetate and washed with a solution of thiosulphate. 10% sodium, dried and concentrated to dryness under reduced pressure, the residue (25.85 g) is chromatographed on silica (eluent: cyclohexane-ethyl acetate 82), and 22.7 g of product are recovered. it is distilled under reduced pressure (0.06 mbar) and 18.7 g of the desired compound are obtained.

Eb = 73-75 ° C / 0.06 mbar.

Stage C: N-butyl [(5-hydroxypentyl) oxy) N-methylacetamide.

 To a solution of 8 g of the alcohol obtained in Stage B above, in 40 cm3 of tetrahydrofuran, 2.16 g of 50% sodium hydride in oil, stirred for 30 minutes at room temperature, added drop. dropwise in 15 minutes a solution of 9.5 g of the brominated product obtained in Step A above in 13 cm3 of tetrahydrofuran. It is stirred for 16 hours at room temperature, saturated aqueous ammonium chloride solution is added, the mixture is extracted with ethyl acetate, washed, dried and evaporated to dryness in vacuo. 14.8 g of intermediate N-butyl ((5- ((dimethyl (1,1-dimethylethyl) silyl) oxy] pentyl] oxy) N -methylacetamide are obtained which are dissolved in 83 cm 3 of tetrahydrofuran and 46 cm 3 of 1M solution of tetrabutylammonium fluoride.Stirred for 2 hours at room temperature, poured into water, extracted with ethyl acetate, evaporated to dryness under reduced pressure, the residue (13.6 g) is chromatographed on silica. (eluent: methylene chloride-isopropanol 94-6) and gives 7.28 g of the title compound.

IR spectrum: (CHCl3) -OH 3628 cm
C = O 1645 cml
Stage D: [(5-bromopentyl) oxy] N-butyl N-methylacetamide.

 To a solution of 7.2 g of the product obtained in Step C above in 73 cm 3 of methylene chloride, 13 g of tetrabromomethane and 10.3 g of triphenylphosphine are added at -10 ° C. The mixture is stirred for 1 hour at 0 ° C. and the reaction medium is chromatographed on silica (eluent: ethyl acetate-cyclohexane 7-3). 7.49 g of the desired compound are obtained.

IR spectrum: (CHC13)
C = O 1644 cm -1
Analvse: C12H24BrNO2 = 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- (3beta-dihydroxo-estra-1,3,5 (10) -trien-11beta-1-yl) phenoxy) pentyloxy) -N-methyl-ethanethioamide.

Step A: N-butyl (5- [4- (3,17-dioxo-estra-4,9-di-11beta-yl) phenoxy] pentyloxy] -N-methylacetamide.

 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 sodium hydroxide, 3.75 g of ((5-bromopentyl are added. ) oxy] N-butyl N-methylacetamide obtained above in solution in 6 cm3 of acetone, the mixture is stirred for 5 hours at 50 ° C., cooled, poured into water, acidified with 2N hydrochloric acid, extracted with The ethyl acetate is washed, dried and evaporated to dryness under reduced pressure and the residue (6.8 g) is chromatographed on silica (eluent: ethyl acetate) to give 2.63 g of the desired product.

IR spectrum: (CHC13)

<tb> C = O <SEP> 1735 <SEP>cm'l<SEP> (17-keto) <SEP>
<tb><SEP> 1657 <SEP>cm'l<SEP>
<Tb>
C = C + aromatic 1609, 1580, 1509 cm -1
Step B: N-butyl [5- (4- (3-hydroxy-17-oxo-estra-1,3,5 (10) trien-11beta-yl) phenoxy] pentyloxy] -N-methylacetamide.

 To a solution of 2.61 g of the product obtained in Stage A above in 50 cm3 of methanol is added 2.61 g of 20% palladium hydroxide on magnesium oxide. Refluxed for 30 minutes. The catalyst is filtered, washed with methanol, the filtrate is evaporated to dryness under reduced pressure and the residue (2.5 g) is taken up with 75 cm3 of methanol. To the solution obtained, 2.45 g of potash in pellet are added and the mixture is stirred for 45 minutes at room temperature. 130 g of ice and 50 cm 3 of 2N hydrochloric acid are added, the mixture is extracted with methylene chloride and the mixture is evaporated to dryness under reduced pressure. The residue is chromatographed (2.75 g) on silica (eluent: ethyl acetate-gasoline G 9-1) and 1.83 g of the desired product are obtained.

IR spectrum: (CHC13)
OH 3598 cm 1

<tb> C = O <SEP> 1732 <SEP>cm'l<SEP>
<tb><SEP> 11634 <SEP>cm'l<SEP>
<tb> aromatic 1611, 1581, 1511 cm'l
Stage C: N-butyl CS-E4- (3,17beta-dihydroxy-estra-1,3,5 (10) trien-11beta-yl) phenoxy] pentyloxy] N-methylacetamide.

 To a solution of 500 mg of the product obtained in Stage B above in 8 cm3 of methanol is introduced in 15 minutes 66 mg of boron hydride and sodium. Stirred for 2 hours and poured into 40 cm3 of water, extracted with methyl chloride. It is evaporated to dryness under reduced pressure. The residue (514 mg) is chromatographed on silica (eluent: ethyl acetate) and then a second time with the same eluent. 343 mg of desired product is obtained.

 [α1pHA = = -31.1 ° (c = 1% chloroform).

IR spectrum: (CHC13)
OH 3603 cm 1
C = O 1634 cm 1 (aromatic amide III) 1611, 1581, 1511 cm -1
Analysis: C36H51NO5 = 577.81
Calculated: C% 74.83H% 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.

 To a solution of 450 mg of the product obtained in Step C above in 2.3 cm3 of pyridine was added 0.9 cm3 of 98% acetic anhydride and 23 mg of 4-dimethylaminopyridine.

 Stir for 1 hour and add 5 cm3 of water and 5 cm3 of methanol. It is stirred for 10 minutes and then extracted with ethyl acetate. Wash with saturated sodium chloride solution, dry and evaporate to dryness under reduced pressure. The residue (580 mg) is chromatographed on silica (eluent: ethyl acetate) and the desired product is obtained.

IR spectrum: (CHCl 3) diacetate 1730, 1760 cm -1 (shoulder) amide 1640, 1660 cm -1
Step E: N-butyl- [5- [4- (3,17beta-diacetoxy-estra-1,3,5 (10) -trien-11beta-yl) phenoxy] pentoxy) -N-methyl-ethanethioamide.

To a solution of 480 mg of product obtained in Step D above in 10 cm3 of toluene is added 400 mg of reagent of
Lawesson. The mixture is stirred for 1 hour at 50 ° C. After cooling to room temperature, it is filtered and then evaporated to dryness under reduced pressure The residue (840 mg) is chromatographed on silica (eluent: gasoline G-ethyl acetate 1-1) and obtains 450 mg of desired product.

IR spectrum: (CHCl 3) 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.

 To a solution of 480 mg of product obtained in Stage E above in 10 cm3 of methanol is added 2.8 cm3 of 2N sodium hydroxide.

It is stirred for 4 hours at room temperature. It is neutralized with 2N hydrochloric acid. Extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue (428 mg) is chromatographed on silica (eluent gasoline G-ethyl acetate 1-1). 365 mg of expected product is obtained.

[alpha] D -22 "5 + 1" 5 (c = 1% CHCl 3)
Analvse: for C36H51NO4S = 593.88 8%
Calculated 72.81 8.65 2.36 5.40
Found 71.9 8.8 2.3 5.6
IR spectrum: (CHCl3)
C = O absence
OH 3603 cm 1 + aromatic partner 1630, 1581, 1512 cm -1
Preparation of Example 2: 8-bromo-N-butyl N-methyl octanamide

 To a solution of 5 g of 8-bromo octanoic acid in 200 cm3 of methylene chloride is added dropwise at 10 "/ -15" C, 9.1 cm3 of N-methylmorpholine and 10.4 cm3 of chloroformate d. isobutyl. Stirred for 30 minutes at 10 / -15 C, then added at this temperature 13 cm3 of N-methylbutylamine. Allowed to warm to room temperature and stand 40 minutes, then 150 cm3 of a saturated solution of sodium bicarbonate. Stirred for 10 minutes.

Decanted, extracted with methylene chloride, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue is chromatographed on silica (eluent: 95-5 methylene chloride-acetone) and 6.14 g of the expected product is obtained.

IR spectrum: (CHCl 3) C = O 1627 cm -1 (amide III)
Example 2: N-Butol-8- (4- (3.17beta-dihydroxy-estra-1.3.5 (10) -trien-11beta-yl) phenoxy) -N-methyl-octanethioamide.

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

 The procedure is as in Stage A of Example 1 starting from 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 from the preparation above. After chromatography on silica (eluent: gasoline G-ethyl acetate 4-6), we obtain 540 mg of the expected product.

IR spectrum: (CHCl3) 17-keto 1735 cm 3-keto 1657 cm-1 amide III 1628 cm-1 aromatic bands 1580, 1509 cm-1 of the type -O-C6H5
Step B: 8- [4- (3-Hydroxy-17-oxo-estra-1,3,5 (10) -trien-11-betanyl) phenoxy] -N-butyl-N-methyl-octanamide.

 The procedure is as in Step B of Example 1 from 470 mg of the product obtained in Step A above using 260 mg of palladium hydroxide on magnesium oxide. After chromatography on silica (eluent: ethyl acetate-gasoline G 11), 360 mg of the desired compound is obtained.

IR spectrum: (CHC13)
OH 3596 cm -1
C = O 1732 cm amide III 1623 cm-1 aromatic bands 1581, 1511 cml
Stage C: N-Butyl-8- [4- (3,17beta-dihydroxy-estra-1,3,5 (10) trien-11beta-yl) phenoxy] -N-methyl-octanamide.

 The procedure is as in Step C of Example 1 from 360 mg of the product obtained in Step B above using 72 mg of boron hydride and sodium. 460 mg of expected product is obtained.

IR spectrum: (CHC13)
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 procedure is as in Step D of Example 1 from 460 mg of the product obtained in Step C above using 0.9 cm3 of acetic anhydride and 24 mg of 4-dimethylamino pyridine.

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

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 procedure is as in Step E of Example 1 from 510 mg of product obtained in Step D above using 1.54 g of Lawesson's reagent. The heating at 50 ° C. is carried out for 3 h 15. 1.18 g of residue is obtained, which is chromatographed on silica (eluent: gasoline G-ethyl acetate 7-3) and gives 430 mg of desired product.

IR spectrum: (CHCl 3) -1-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-yl] phenoxy] -N-methyl-octane thioamide.

 The procedure is as in Stage F of Example 1 from 408 mg of product obtained in Step E above. Stirring at room temperature is carried out for 1 hour. 370 mg of residue are isolated. After chromatography, 261 mg of expected product are isolated.

[alpha] D = -31 5 + 1 (C = 1% CHCl 3)
Analvse: C37H53NO3S = 591.90
C% H% N% S%
Calculated 75.08 9.02 2.37 5.42
Found 75.3 9.2 2.3 5.52
IR spectrum: (CHCl3)
OH 3601 cm-1 aromatic 1610 - 1580 - 1511 callus
Example 3: Tetra (4 - ((7 - ((butylmethylamino) carbonyl) heptyl) oxymethylene (3-hydroxy-estra-1,3,5 (10) -trien-17beta-ole monobutanedioate.

 To a solution of 200 mg of product obtained in Step C of Example 2 in 2 cm3 of pyridine is added 210 mg of succinic anhydride. The mixture is heated for 5 hours in a bath at 15 ° C. 2 cm 3 of water, 350 mg of potassium carbonate and 2 cm 3 of methanol are added and the mixture is stirred for 4 hours at room temperature and then acidified with hydrochloric acid. 6N, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and then evaporated to dryness under reduced pressure The residue (300 mg) is chromatographed on silica (eluent: gasoline G-acetone 6 -4, 1% acetic acid) and obtains 176 mg of expected product.

[alpha] D = -75 (C = 1% CHCl 3)
Analvse: C41H57N7 = 675.91
C% H% N%
Calculated 72.86 8.50 2.07
Found 72.9 8.7 2.1
IR spectrum: (CHC13)
OH 3600 cm 1
C = O complex 1730 cm -1 (shoulder)
1717 cml
C = O amide III 1622 cm -1 aromatic 1611, 1583, 1511 cm -1 Example 4: Butyl beta (4 - ((7-X (butylmethylamino) carbonyl) heptol) oxy) phenyl) -3-hydroxy-estra butanedioate -1.3.5 (10) - trien-17beta-vle and sodium.

 To a solution of 18 mg of sodium bicarbonate in 3 cm3 of water is added a solution of 160 mg of the product obtained in Example 3 in 6 cm3 of ethanol. Stirred for 30 minutes, distilled ethanol under reduced pressure and filtered. After lyophilization, 145 mg of expected product is obtained.

Analysis: C41H56N NaO7 = 697.90
Calculated 70.56 8.09 2.01
Found 69.9 8.1 2.0
Preparation of Example 5 8- (4- (3,17-dioxo-estra 4,9-dien-11beta-yl) phenoxy] octanoic acid.

 To a solution of 181 mg of product obtained in Stage B of Preparation A of Example 1 in 4 cm3 of acetone and 1.5 cm3 of 2N sodium hydroxide are added 335 mg of 8-bromo octanoic acid.

The mixture is refluxed for 5 hours, cooled to ambient temperature and then acidified with 2N hydrochloric acid.

Extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. 600 mg of product is obtained which is used as.

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

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

 In a flask under a nitrogen atmosphere, 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. It is cooled to -10 ° C. and 0.39 cm 3 of isobutyl chloroformate is introduced dropwise. Stirring is carried out for 30 minutes at -10 ° C. 1.78 mg of N-heptafluoro-butyl-N-methylamine hydrochloride obtained in Preparation 1 are introduced into the solution obtained and maintained at -10 ° C. The mixture is allowed to warm to room temperature. 30 minutes, stirred for 30 minutes, washed with saturated sodium chloride solution and evaporated to dryness under reduced pressure. The residue (1.88 g) is chromatographed on silica (eluent: ethyl acetate-1-1 gasoline) and 990 mg of expected product is obtained.

IR spectrum: (CHCl3)

<tb> C = O <SEP> 1735 <SEP>cm'l<SEP> (17-keto) <SEP>
<tb><SEP> 1659 <SEP> cm <SEP> 1 <SEP> (Dienone <SEP> + <SEP> Amide <SEP> III)
<Tb>
C = C + aromatic 1609, 1578, 1509 cm -1
Step 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 10 cm 3 of methylene chloride are introduced into a flask under a nitrogen atmosphere. Cooled to 00C and added in 5 minutes 1 cm3 of 98% acetic anhydride and 0.5 cm3 of acetyl bromide. It is stirred for 45 minutes at room temperature and then basified with sodium bicarbonate. Stirred for 45 minutes, the organic phase is collected, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue obtained (1.02 g) is dissolved under an argon atmosphere in 10 cm3 of methanol, then 1.4 cm3 of 2N sodium hydroxide solution is added. Stirred for 1 hour at room temperature, neutralized with 1.4 cm3 of 2N hydrochloric acid. It is extracted with methylene chloride, washed with water, dried and then evaporated to dryness under reduced pressure. The residue (1 g) is chromatographed on silica (eluent: gasoline G-ethyl acetate 6-4) and obtains 630 mg of expected product.

IR spectrum: (CHC13)
OH 3600 cm-1

<tb> C = O <SEP> 1732 <SEP>cm'l<SEP> (17-keto)
<tb><SEP> 1658 <SEP> cm-1 <SEP> (amide <SEP> III)
<tb> aromatic 1610, 1576, 1511 cm'l
Step C: 8- [4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) phenoxy] -N- (2,2,3,3,4,4, 4-heptafluorobutyl) -N-methyl-octanamide.

 To a solution of 310 mg of product obtained in Stage B above in 4 cm3 of methanol which is cooled to 0 ° C., 18 mg of boron hydride and sodium are added. It is stirred for 45 minutes at 0 ° C., extracted with methylene chloride, dried and then evaporated to dryness under vacuum. The residue is chromatographed (315 mg) on silica (eluent: gasoline G-ethyl acetate 1-1) and 280 mg of expected product is obtained.

Analysis: C37H46F7NO4 = 701.77
C% H% F% N%
Calculated 63.33 6.60 18.95 1.99
Found 63.3 6.6 19.3 2.0
IR spectrum: (CHC13)
OH 3603 cm-1
C = O 1658 cm -1 aromatic 1610, 1576, 1511 cml
Preparation of Example 6: 2 - [(6-Bromohexyl) oxy] -N-butyl
N-methyl acetamide

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

 The procedure is as in Stage A of Preparation 3 starting from 8.12 g of 50% sodium hydride 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 are obtained.

IR spectrum: (CHC13)
OH 3625 cm 1
I. 1257.837 cm
O-Sl + 1257, -1
Stage B: N-butyl ((6-hydroxyhexyl) oxy) -N-methylacetamide.

 To a solution of 7 g of the product obtained in Stage A above in 35 cm 3 of tetrahydrofuran is added 1.78 g of 50% sodium hydride in the oil, stirred for 40 minutes at room temperature, added dropwise in vacuo. 10 minutes a solution of 7.8 g of bromo N-butyl N-methylacetamide obtained in Step A of Preparation B of Example 1 in 10 cm3 of tetrahydrofuran. It is stirred for 16 hours at room temperature, saturated aqueous ammonium chloride solution is added, the mixture is extracted with ethyl acetate, 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 1 M tetrabutylammonium fluoride solution are added. The mixture is stirred for 3 hours at room temperature, poured into water and extracted with acetate. of ethyl, washed with a saturated solution of sodium chloride, dried and evaporated under reduced pressure. The residue (10.8 g) is chromatographed on silica (eluent: methylene chloride-isopropanol 94-6) and 5.56 g of expected product is obtained.

IR spectrum: (CHC13)
OH 3624 cm 1
C = O 1636 cm'l complex
Stage C: 2 - [(6-bromohexyl) oxy] -N-butyl-N-methylacetamide.

 To a solution of 5.52 g of product obtained in Stage B above in 55 cm3 of methylene chloride is added at -15 C 9.3 g of tetrabromomethane and 7.4 g of triphenyl phosphine.

The mixture is stirred for 1 hour at 0 ° C. The reaction mixture is chromatographed on silica (eluent: ethyl acetate-cyclohexane 7-3) and 6.22 g of expected product is obtained.

Analvse: C13H26BrN2 = 308.26C% H% N% Br%
Calculated 50.65 8.50 4.54 25.92
Found 50.4 8.8 4.6 25.5
IR spectrum: (CHCl 3)
C = O 1640 cm -1
Example 6 N-Butyl-2-X6- (3,17beta-dihydroxo-estra-1,3,5 (10) -trien-11beta-vinyl) phenoxy) hexyloxy) -N-methyl-acetamide.

Step A: N-Butyl-2- [6- [4- [3,17-dioxo-estra-4,9-dien-11beta-yl) phenoxy] hexyloxy] -N-methylacetamide.

 The procedure is as in Stage A of Example 1 starting from 2 g of product obtained in Stage B of 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 (eluent: ethyl acetate) and 2.68 g of the expected product are obtained.

IR spectrum: (CHC13)

<tb> C = O <SEP> 1735 <SEP> cm-1 <SEP> (17-keto) <SEP>
<tb><SEP> 1656 <SEP> cm <SEP> 1 <SEP> (dienone <SEP> + <SEP> amide <SEP> III)
<tb> aromatic 1609, 1580, 1509 cm-1
Step B: N-Butyl-2- [6- [4- (3-hydroxy-17-oxo-estra-1,3,5 (10) -trien-11beta-yl) phenoxy] hexyloxy] -N-methylacetamide.

 The procedure is as in Step B of Example 1 from 2.63 g of the product obtained in Step A above using 2.63 g of palladium hydroxide on magnesium oxide. The residue (2.165 g) is chromatographed on silica (eluent: methylene chloride-isopropanol 94-6) and 1.62 g of expected product is obtained.

IR spectrum: (CHC13)
OH 3599 cm-1

<tb> C = O <SEP> 1732 <SEP> cm-1 <SEP> (17-keto)
<tb><SEP> 1635 <SEP> cm-1 <SEP> (amide <SEP> III)
<Tb>
Stage C: N-Butyl-2- [6-4 (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) phenoxy] -N-methylacetamide.

 The procedure is as in Step C of Example 1 from 450 mg of the product obtained in Step B above using 58 mg of boron hydride and sodium. The residue is chromatographed (461 mg) on silica (eluent: methylene chloride isopropanol 94-6) and then a second time (eluent: ethyl acetate). 274 mg of expected product is obtained.

(alpha) = -32 5 (C = 1% ethanol)
Analysis: C37H53NO5 = 591.84
Calculated 75.09 9.03 2.37
Found 75.4 9.1 2.4
IR spectrum: (CHC13) -1
OH 3603 cm
C = 0 1635 cm -1 aromatic 1611, 1581, 1511 cm -1 Prenaration of Example 7 8-bron-N-butyl-N-methyl-2-octylgene.

Step A: dimethyl- (1,1-methylethyl) (β-heptyn-1-yl) oxy] silane.

 1.63 g of lithium acetylide complex, ethylene diamine and 15 cm3 of dimethyl sulfoxide are introduced into a flask under a nitrogen atmosphere. It is stirred for 30 minutes at room temperature, then 3.64 g of the product obtained in Preparation 2 are added over 45 minutes. The mixture is stirred for 4 hours, poured into an ice-cold solution of saturated ammonium chloride, washed with hexane, then with water, dry and evaporate to dryness under reduced pressure. 3.08 g of crude product is obtained.

Step B: 8 - [(dimethyl- (1,1-dimethylethyl)] silyloxy] 2-octynoic acid.

To a solution of 630 mg of the crude product obtained at
To above in 4 cm3 of tetrahydrofuran is added at -60 / -70 C, under a nitrogen atmosphere, 2.4 cm3 of butyl lithium solution 15% in hexane. It is stirred for 15 minutes at -60 ° C. and then placed under a CO2 atmosphere. The mixture is left under CO2 for 15 minutes at -60 ° C. and then allowed to return to ambient temperature. It is diluted with water and ethyl acetate by emulsification. The aqueous phase is separated and the organic phase is extracted with an aqueous solution of sodium bicarbonate. The aqueous alkaline phase is acidified by adding monosodium phosphate and then extracted with ethyl acetate. The organic phase is evaporated to dryness under reduced pressure to give 540 mg of the expected product.

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

To a solution of 4.55 g obtained according to the stadium process
B above in 20 cm3 of chloride, methylene is added 2.8 cm3 of methyl morpholine, cooled to -30 C under nitrogen and then slowly added 3.3 cm3 of isobutyl chloroformate dissolved in 10 ml methylene chloride.

Stirred at -5 C for 35 minutes and then added, at 0 C in 5 minutes, 4 cm3 of methyl butylamine. Allowed to warm to room temperature and poured into an aqueous solution of sodium bicarbonate. It is extracted with methylene chloride, dried and evaporated to dryness under reduced pressure. The residue is chromatographed (6.9 g) on silica (eluent cyclohexane-ethyl acetate 7-3) and 2 g of expected product are obtained.

2234 cal
C=O 1616 cm'l (conjugué)
C-O-Si+ 1257, 1094, 836 cal
Stade D : N-butyl-8-hydroxy-N-méthyl 2-octynamide.IR spectrum: (CHC13)

2234 cal
C = 1616 cm -1 (conjugated)
CO-Si + 1257, 1094, 836 cal
Stage D: N-Butyl-8-hydroxy-N-methyl 2-octynamide.

 To a solution of 1.9 g of the product obtained in Step C above, 1 cm3 of 2N hydrochloric acid is added. It is maintained at ambient temperature for 1 hour, extracted with ethyl acetate, washed with water, dried and evaporated to dryness under reduced pressure. The residue (1.79 g) is chromatographed on silica (eluent: ethyl acetate). 870 mg of expected product is obtained.

2285 cm'l
C=O 1616 cm 1 (amide)
Stade E : 8-bromo N-butyl-N-méthyl 2-octynamide.IR spectrum: (CHC13)
OH 3625 cm 1

2285 cm'l
C = O 1616 cm 1 (amide)
Stage E: 8-bromo N-butyl-N-methyl 2-octynamide.

 To a solution of 855 mg of the product obtained in Stage D above in 4 cm3 of methylene chloride is added 1.205 g of triphenylphosphine. Cooled to -10 C and added 1.522 g of tetrabromomethane. The mixture is stirred for 1 hour at -5 ° C. and the reaction mixture is chromatographed on silica (eluent: cyclohexane-ethyl acetate 35-65). 0.98 g of expected product is obtained.

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

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

 To a solution of 1.09 g of the product obtained in Stage B of Preparation A of Example 1 in 20 cm3 of acetone and 1.5 cm3 of 2N sodium hydroxide which is heated under reflux under a nitrogen atmosphere. a solution of 970 mg of product obtained in stage E above in 6 cm3 of acetone is introduced over 40 minutes. Refluxed for 6 hours, cooled and diluted with ammonium chloride solution. It is extracted with methylene chloride, washed, dried and evaporated to dryness under reduced pressure. The residue (2.13 g) is chromatographed on silica (eluent: cyclohexane-ethyl acetate 4-6) to give 1.21 g of expected product.

2235 cml

IR spectrum: (CHC13)

2235 cml

<tb> C = O <SEP> 1735 <SEP> cm1 <SEP><17-keto)<SEP>
<tb><SEP> 1658 <SEP> cm-1 <SEP> (Dienone)
<tb><SEP> 1614 <SEP> cm <SEP> 1 <SEP> (amide)
<tb> aromatic 1580, 1509 cm -1
Step B: N-Butyl-8- (4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) phenoxy) -N-methyl-2-octynamide.

 To the solution of 830 mg of the product obtained in Stage A above in 8 cm3 of methylene chloride cooled to 0 / + 5 C and under a nitrogen atmosphere is added 0.8 cm3 of acetic anhydride and 0.4 cm3 of bromide. acetyl. This temperature is maintained at this temperature for 10 minutes and then at ambient temperature for 1 hour. A saturated solution of sodium bicarbonate is added, emulsified, 3.5 ml of methanol are added and the mixture is then extracted 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 product are obtained which is used as in solution in 10 cm3 of methanol and which is cooled to 0 + 5 C. 0.2 g of boron and sodium hydride are added. Stirred for 45 minutes, adding 2 cm3 of water and 1 ml of 2N sodium hydroxide. It is kept at room temperature for 1 hour, diluted with saturated ammonium chloride solution and extracted with methylene chloride.

The organic phase is collected, washed with water, dried and evaporated to dryness under reduced pressure. The residue is chromatographed (850 mg) on silica (eluent: cyclohexane-ethyl acetate 4/6) and 438 mg of expected product is obtained.

2235 cm'l
C=O 1612 cm 1 (amide conjugué) aromatique 1581, 1511 cm'l
Préparation de l'exemple 8 : 2-C(S-bromopentyl) thioj-N-butyî-
N-méthyl acétamide.Analvse: C37H49NO4 = 571.81
C% H% N%
Calculated 77.72 8.63 2.44
Found 77.7 8.9 2.3
IR spectrum: (CHCl3)
OH 3603 cm 1

2235 cm'l
C = O 1612 cm 1 (conjugated amide) aromatic 1581, 1511 cm -1
Preparation of Example 8: 2-C (5-bromopentyl) thio] -N-butyl
N-methyl acetamide

Stage A: 5-mercaptopentanol.

 To a suspension of potassium thioacetate in 100 cm3 of ethanol is added 10 cm3 of 5-chloropentanol. Under a nitrogen atmosphere, the mixture is refluxed for 1 hour. Cool, add 100 cm3 of ethyl ether, filter and evaporate to dryness. 100 cm3 of ethyl ether is added to the oily residue obtained. The precipitate formed is filtered off and the organic solution is evaporated to dryness. 12.5 g of oily residue are obtained, which is dissolved in 50 cm3 of methanol. 10 cm3 of 10N sodium hydroxide and maintained for 1 hour at room temperature. A saturated solution of ammonium chloride is added, extracted with ethyl acetate and then with methylene chloride. The organic phases are dried and evaporated to dryness under reduced pressure. 9.3 g of oily residue are obtained which is dissolved in 50 cm 3 of 10% methanol of water, while sparging with nitrogen for 15 minutes. 5 cm3 of n-tributylphosphine are added slowly over 2 minutes and the mixture is kept for 2 hours at room temperature. Extracted with ethyl acetate, dried and evaporated to dryness under reduced pressure. The residue is chromatographed (13.6 g) on silica (eluent: cyclohexane-ethyl acetate 1-1) and 6.55 g of expected product is obtained.

IR spectrum: (CHCl 3) on product purified by distillation (bp: 90/95 C at 10 mm Hg)
OH 3624 cm -1
SH 2570 cm-1
Stage B: N-butyl-2 - [(5-hydroxypentyl) thio] -N-methylacetamide.

 To a solution of 3.36 g of the product obtained in Stage A above in 45 cm3 of tetrahydrofuran under a nitrogen atmosphere, 1.4 g of 50% sodium hydride in oil and 6 g of bromo N are added. -butyl N-methylacetamide obtained in Stage A of Preparation B of Example 1. Stirred for 2 hours at room temperature, poured into an ammonium chloride solution, extracted with ethyl acetate, washing evaporate to dryness under reduced pressure. The residue is chromatographed (10 g) on silica (eluent: cyclohexane-ethyl acetate 2-8) and 5.27 g of expected product is obtained.

IR spectrum: (CHC13)
OH 3623 cml
C = 1632 cm-1 (amide III)
Stage C: 2 - [(5-bromopentyl) thio] -N-butyl-N-methylacetamide.

 To a solution of 5.27 g of product obtained in Stage B above in 52 cm3 of methylene chloride is added 6.88 g of triphenylphosphine. Under nitrogen atmosphere is cooled to 0 / + 5 C, added 8.68 g of tetrabromo methane, stirred for 1 hour at 0 C, chromatography reaction mixture on silica (eluent: cyclohexane-ethyl acetate 2-1) and obtains 6.2 g of expected product.

IR spectrum: (CHC13)
C = 1638 cml (amide III)
Example 8: N-Butyl-2 ((5- (4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) phenoxy) pentyl) sulfinyl) -N-methyl- acetamide.

Step A: N-Butyl-2- [5- [4 (3,17-dioxo-estra-4,9-dien-11beta-yl) phenoxy] pentylthio] -N-methylacetamide.

 To a solution of 3.09 g of the product obtained in Stage B of Preparation A of Example 1 in 45 cm3 of acetone is added 5.1 cm3 of 2N sodium hydroxide, heated under reflux under a nitrogen atmosphere and added in 4 fractions for 2 hours 6.2 g of the product obtained in Stage D above. It is refluxed for 1 h 20, cooled, diluted with saturated ammonium chloride solution. Extracted with ethyl acetate, washed, dried and evaporated to dryness under reduced pressure. The residue is chromatographed (10 g) on silica (eluent: gasoline ethyl acetate 4-6) and 3.4 g of expected product are obtained.

IR spectrum: (CHCl3)

<tb> C = O <SEP> 1735 <SEP> cm-1 <SEP> (17-keto)
<tb><SEP> 1656 <SEP> cm <SEP> 1 <SEP> (Dienone)
<tb><SEP> 1640 <SEP> cm <SEP> 1 <SEP> (amide <SEP> III)
<Tb>
C = C 1610, 1580, 1509 cm -1 aromatic
Step B: N-Butyl- [5- [4- (3-hydroxy-17-oxo-estra-1,3,5 (10) -trien-11beta-yl) phenoxy] pentylthio] -N-methylacetamide.

 The procedure is as in Step B of Example 5 starting from 2.6 g of the product obtained in Step A above in 26 cm3 of methylene chloride under a nitrogen atmosphere and adding 2.6 cm3 of acetic anhydride. and 1.3 cm3 of acetyl bromide.

After chromatography on silica, 1.6 g of expected product are obtained.

IR spectrum: (CHC13)
OH 3598 cm
C = O 1732 cm-1 (17-keto)
1627 cm 1 (amide III) aromatic 1581, 1511 callus
Stage C: N-butyl- [5- [4- (3,17beta-dihydroxy-1,3,8-tetra (10) trien-11beta-yl) phenoxy] pentylthio] N-methylacetamide.

 The procedure is as in Step C of Example 5 starting from 600 mg of the product obtained in Step B above and 60 mg of boron hydride and sodium. The expected product is obtained.

IR spectrum: (CHC13)
OH 3603 cm-1 (+ associate)
C = O 1627 cm -1 aromatic 1581, 1511 cm -1 [alpha] D = -32 5 (C = 0.1% CHCl 3)
Stage D: N-Butyl-2 [[5- [4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) phenoxy] pentyl) sulfinyl] -N-methylacetamide.

 To a solution of 147 mg of the product obtained in Step C above in 10 cm3 of methanol is added 4 cm 3 of a solution of 0.1 M sodium periodate. It is refluxed for 40 minutes, cooled, diluted with water, extracted with chloroform and evaporated to dryness under reduced pressure. The residue is chromatographed (180 mg) on silica (eluent: ethyl acetate-acetone 1-1) and 150 mg of expected product is obtained.

Analvse: C36H51NO5S = 609.88% C% Ht N% S%
Calculated 70.90 8.42 2.29 5.27
Found 71.0 8.6 2.3 5.1
IR spectrum: (CHC13)
OH 3604 cm 1 (+ associate)
C = O 1637 cm -1 aromatic 1611, 1581, 1511 cm -1
Preparation A of Example 9: 3,17beta-bis-tetrahydro-2H-2-pyranyl) oxyl (4-ethynylphenyl) estra-1,3,5 (10) -trien-11beta-yl.

Step A: (5alpha, 11beta) Cyclic 3- (1,2-ethanediyl acetal) 5-hydroxy 11 - [[4- (1,1-dimethylethyl) dimethylsilyl] ethynylphenyl] estr-9-en-3,17-dione .

 The reaction is carried out as in Stage A of Preparation A of Example 1 starting from 30 g of cyclic 3- (1,2-ethanediyl acetal of 5alpha, loalpha-epoxy estr-9,11-ene-3,7-dione obtained according to EP 0 057 115 (Example 7) using 81.254 g of the brominated derivative, 4 trimethylsilylethynylbromobenzene obtained in Preparation 4 and 7.96 g of magnesium for the preparation of the magnesium, and then, for the condensation, 1.4 g of Copper chloride The crude product obtained is chromatographed on silica, to which is added the product from an operation carried out identically from 16.52 g of epoxide (eluent: methylene chloride-acetone 98-2). 50.8 g of pure product A and 6 g of slightly less pure product B are obtained, which is used as it is for the next stage.

IR spectrum: (CHC13)
OH 3508 cm-1
C = C 2156 cm -1
1602 cm1 aromatic 1555 cml
1502 cm
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 cm3 of ethanol and 8.1 cm3 of sodium hydroxide solution is stirred for 30 minutes. 16.7 cm3 of concentrated hydrochloric acid are then added, the mixture is stirred at ambient temperature and then concentrated to half, extracted with methylene chloride, dried and evaporated under reduced pressure. The residue (38.23 g) is chromatographed on silica (eluent: cyclohexane-ethyl acetate 11) to give 31.06 g of desired product. M.p. 184 ° C.

IR spectrum: (CHC13)
C CH 3302 cm 1
C = O 1736 cm-1 (17-keto)
1659 callus
1640 cm 1 aromatic dienone 1556, 1506 cm'l
Stage C: 3 beta-hydroxy estra 1,3,5 (10) -trien-11-beta-yl (4-ethynylphenyl) -17-one.

 To a solution of 31 g of the product obtained in stage B in solution in 340 ml of methylene chloride, 47.1 cm3 of acetic anhydride and 23.8 cm3 of acetyl bromide are added at 0 / -5 C. It is stirred for 1 h 30 at room temperature poured onto a mixture of 2 liters of saturated sodium bicarbonate solution and 700 g of ice. Stir 15 minutes and then extracted with methylene chloride, evaporated to dryness under reduced nitrogen pressure. The residue is chromatographed on silica (eluent: methylene chloride-acetone 9-1). 31.2 g of acetate in 3 are obtained which is stirred for 1 hour in 930 cm3 of methanol and 20.96 g of potassium hydroxide. It is cooled to 0 ° C., neutralized with 2N hydrochloric acid, extracted with methylene chloride and evaporated to dryness under reduced pressure.

After chromatography on silica (eluent: cyclohexane-ethyl acetate 7-3), 27.03 g of crude product are obtained which is pasted in ether to collect 22.85 g of the desired product. M.p. 163 ° C.

3303 cm'l
C=O 1733 cm1 aromatique 1606, 1582, 1556, 1503 cm'l
Stade D : 3,17béta-bis(tétrahydro-2H-2-pyrannyl) oxy] (4éthynylphényl) estra-1,3,5(10)-trièn-llbéta-yl. IR spectrum: (CHC13)
OH 3597 cm 1

3303 cm -1
C = O 1733 cm1 aromatic 1606, 1582, 1556, 1503 cm -1
Stage D: 3,17beta-bis (tetrahydro-2H-2-pyranyl) oxy] (4-ethynylphenyl) estra-1,3,5 (10) -trien-11beta-yl.

a) Reduction of ketone in 17.

 To a solution of 14 g of product obtained in Stage C in 120 cm 3 of methanol, 10 g of boron and sodium hydride are added at 0 / + 5 C. and the mixture is stirred for 3 hours at room temperature. 380 g of water-ice mixture (1-1) are added and the pH is adjusted to between 4 and 5 with 2N hydrochloric acid, sodium chloride is added until saturation and extraction is carried out with ethyl acetate. The residue is evaporated to dryness. 17.3 g of crude product are isolated.

b) Dihydropyranylation
17.3 g of the 17-hydroxy-intermediate obtained above are stirred for 2 hours in the presence of 700 cm 3 of ether, 34.4 cm 3 of dihydropyran and 0.3 g of para-toluenesulphonic acid.

35 cm3 of triethylamine are added, poured into a mixture (1-1) of ice and saturated sodium bicarbonate solution. Extracted with ether, filtered and evaporated to dryness under reduced nitrogen pressure. The residue is chromatographed on silica (eluent: cyclohexane-ethyl acetate 1-1). 13.6 g of crude product are obtained which is taken up in isopropyl ether to obtain 10.23 g of desired product. M.p. 213-215 ° C.

3302 cm1 aromatique 1607, 1570, 1556, 1498 cm'l Prénaration B de l'exemple 9 : 5-[4-[3,17béta-bis ((tétrahydro-2H-2-pyrannyl) oxy-estra-1,3,5(10)-trièn-llbéta-yl phényl]-4-pentyl-1-ol. IR spectrum: (CHC1q)

3302 cm1 aromatic 1607, 1570, 1556, 1498 cm -1 Preparation B of Example 9: 5- [4- [3,17beta-bis ((tetrahydro-2H-2-pyranyl) oxy-estra-1,3, (10) -trien-11beta-ylphenyl] -4-pentyl-1-ol.

Step A: 3,17beta-bis [(tetrahydro-2H-2-pyranyl) oxy] -beta [4-5 [[dimethyl (11-dimethylethyl) silyl] oxy] -1-penynyl] phenyl] estra; 1,3,5 (10) -triene.

 To a solution of 714 mg of product obtained in Stage D of Preparation A above in 5.9 cm3 of tetrahydrofuran, 5.9 cm 3 of hexamethylphosphoric triamide is added. 1.5 cm 3 of 1.32 M butyl lithium solution in hexane and then 669 mg of brominated product obtained in Stage B of Preparation 3 are added over a period of 5 minutes at -35 C. The mixture is stirred for 1 hour at room temperature. then poured into a saturated aqueous solution of sodium chloride. Extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue obtained is dissolved in water and then extracted with ethyl ether, washed with water, dried and evaporated to dryness under reduced pressure. The residue obtained (1.198 g) is chromatographed on silica (eluent: sodium acetate). ethyl-cyclohexane 1-9 to 0.1% triethylamine) and obtains 941 mg of expected intermediate product.

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

 To a solution of 931 mg of the product obtained in Step A above dissolved in 10 cm3 of tetrahydrofuran is added 1.4 cm3 of 1M tetrabutylammonium fluoride solution. It is stirred for 1 h 45 at room temperature and then poured into water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue (755 mg) is chromatographed on silica (eluent: ethyl acetate-cyclohexane 4-6 with 0.1% triethylamine). 408 mg of expected product is obtained.

IR spectrum: (CHC13)
OH 3640 cm 1 aromatic 1500, 1610 cm -1 Preparation C of Example 9: N-methyl-N-butyl mercaptoacetamide.

Step A: 2- (Acetylthio) -N-butyl-N-methylacetamide.

To a suspension of 2.28 g of potassium thioacetate in 10 cm3 of methanol is added 4.16 g of bromo-N-butyl-N-methylacetamide obtained in Preparation B of Example 1 stage
A in 1.5 cm3 of methanol, heated for 1 hour at 40 ° C under an argon atmosphere, evaporated to dryness under reduced pressure, the residue dissolved with ethyl ether, insoluble filter and the solution evaporated to dryness. 4.06 g of oily product are obtained.

IR spectrum: (CHC13)
C = O 1644 cm 1 (amide) acetate 1700 cm -1
Stage B: N-methyl-N-butyl mercaptoacetamide.

 To a solution of 3.99 g of the product obtained in Stage A above in 10 cm3 of tetrahydrofuran is added 1 cm3 of hydrazine hydrate, stirred for 16 hours at room temperature, 0.5 cm3 of hydrate is added. hydrazine, stirred for 16 hours at room temperature and poured into a mixture of 40 cm3 of 2N hydrochloric acid and 40 g of ice. Extracted with ethyl acetate, washed with saturated sodium chloride solution, dried, evaporated to dryness under reduced pressure. The residue (3.13 g) is chromatographed on silica (eluent: 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-libeta-1-yl) phenyl) entyl) thio) -N-methylacetamide .

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

 To a solution of 408 mg of product obtained in Stage B of Preparation B above are added 1.5 cm3 of pyridine and 259 mg of tosyl chloride. It is stirred for 4 hours at room temperature and then poured into a saturated aqueous solution of potassium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The obtained tosyl crude product (512 mg) is dissolved in 4.5 ml of methanol and 165 mg of N-methyl-N-butyl mercaptoacetamide obtained in Preparation C above and 0.94 cm 3 of a methylate solution are added. Sodium at 58.4 mg / cm3 in methanol. It is refluxed until the reaction is complete, the methanol is evaporated off under reduced pressure. Water is added, the mixture is extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. Dry and evaporate to dryness under reduced pressure. The residue (677 mg) is chromatographed on silica (eluent: ethyl acetate-cyclohexane 4-6 with 0.1% triethylamine) and 315 mg of expected product is obtained.

IR spectrum: (CHC13)
C = O 1640 cm 1 (aromatic amide III) 1500, 1580 cm -1
Step B: N-Butyl-2- [E5- [4- [3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl] phenyl] -4-pentynyl] thio] -N methyl-acetamide.

 To a solution of 315 g of the product obtained in Step A above, 16 cm3 of methanol and then 3.2 cm3 of 2N hydrochloric acid are added. It is stirred for 1 hour at room temperature and then poured into a saturated aqueous solution of sodium chloride. It is extracted with methylene chloride, washed, dried and then evaporated to dryness under reduced pressure. 225 mg of expected product is obtained.

IR spectrum: (CHC13)
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) -N-methylacetamide.

 To a solution of 222 mg of the product obtained in Stage B above in 2.2 cm3 of methanol and 2.2 cm3 of toluene is added 90 mg of chloro (tris triphenylphosphine) rhodium. It is hydrogenated under 1885 mbar for 18 hours. 22.5 mg of chloro (tris triphenylphosphine) rhodium, 0.7 cm3 of ethanol and 0.7 cm3 of toluene are added again. It is hydrogenated until the plateau. It is evaporated to dryness under reduced pressure.

The residue (333 mg) is chromatographed on silica (eluent ethyl acetate-cyclohexane 7-3) and 103 mg of expected product is obtained.

Analvse: C36H51NO3S = 577.88
C% H% S% N%
Calculated 74.82 8.89 5.55 2.42
Found 74.4 8.8 6.0 2.7
IR spectrum: (CHC13)
OH 3608 cm 1 (+ associate)
C = O 1625 cm 1 (aromatic amide III) 1583, 1499 cm -1
Preparation of Example 10: 7-bromo-N-butyl N-methylheptanamide

 The procedure is as in the preparation of Example 2 starting from 707 mg of 7-bromoheptanoic acid, obtained by stirring for 3 hours of 3 g of ethyl 7-bromoheptanoate in 28 cm of 2N sodium hydroxide and 10 cm of ethanol and then extraction at pH = 1 with ethyl ether and evaporation to dryness under vacuum, 1.4 cm of N-methylmorpholine, 1.69 cm3 of isobutyl chloroformate, then 2.1 cm3 of N-methylbutylamine. 3.124 g of oily residue are isolated, which is distilled under reduced pressure and 676 mg of expected product is obtained in the form of an oil.

IR spectrum: (CHC13)
C = O 1630 cm 1 (amide III)
Example 10 N-Butyl-4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) -N-methylbenzenenonamid
Step A: 9- [4- [3,17beta-bis [(tetrahydro-2H-2-pyranyl) oxy] estra-1,3,5 (10) -trien-11beta-yl] phenyl] -N-butyl N-methyl-8-nonynamide.

To a solution of 0.6 g of 3,17beta-bis [(tetrahydro-2H-2-pyranyl) oxy] (4-ethynylphenyl) estra-1,3,5 (10) -trien-11betanyl obtained at the stage D of Preparation A of Example 9 in 5
3 cm 3 of tetrahydrofuran is added at -30 C 5 cm3 of hexamethylphosphorotriamide then slowly 1.22 cm3 of a solution of 1.1 M butyl lithium in hexane. The mixture is stirred at -30 ° C. for 30 minutes and then 0.401 g of brominated product obtained in the above preparation is added. It is stirred for 1 h 30 at room temperature and then poured into 20 cm3 of a saturated aqueous sodium phosphate solution. It is extracted with methylene chloride, dried and evaporated to dryness under reduced pressure. The residue (5.4 g) is chromatographed on silica (eluent: cyclohexane-ethyl acetate 1-1) and 0.67 g of expected product is obtained.

IR spectrum: (CHC13)
C = O 1626 cm 1 (aromatic amide III) 1580, 1550, 1497 cm -1
Step B: N-Butyl-4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) N-methylbenzenenonamide.

 To a solution of 0.640 g of the product obtained in Step A above in 20 cm3 of ethanol is added 10 cm3 of 2N hydrochloric acid and then 20 cm3 of water. It is extracted with methylene chloride. Dry and evaporate to dryness under reduced pressure and isolate 0.494 mg of residue.

 To a solution of 0.26 g of crude product above in 20 cm3 of ethanol is added 30 mg of palladium on carbon and hydrogen under 1120 mbar for 20 minutes. It is filtered, washed with ethanol and the solution evaporated to dryness under reduced pressure. The residue is chromatographed (0.272 g) on silica (eluent: cyclohexane-ethyl acetate 1-1) and 0.189 mg of expected product is obtained.

Analvse: C38H55NO3 = 573.87
C% H% N%
Calculated 79.53 9.66 2.44
Found 79.8 9.8 2.4
IR spectrum: (CHC13)
OH 3603 cml + associate
C = O 1622 cm -1 aromatic 1582, 1429 cm -1
Preparation of Example 11: C (3-bromopropyl) oxy] -N-butyl-N-methylacetamide.

Step A: N-butyl [(3-hydroxypropyl) oxy] -N-methylacetamide.

 The procedure is as in Step B of the preparation of Example 6 starting from 2.5 g of 3 - [[(dimethyl (1,1-dimethylethyl) silyl] oxy] propanol obtained in Step A of Preparation 3, 775 mg of 50% sodium hydride in oil and 3.42 g of bromo-N-butyl-N-methylacetamide give 4.92 g of residue which is treated with 16.4 cm3 of solution of tetrabutylammonium fluoride After chromatography, 1.61 g of expected product is obtained.

Analvse: C10H21 3N = 202.283
C% H% N%
Calculated 59.08 10.41 6.89
Found 58.5 10.6 6.4
IR spectrum: (CHC13)
OH 3620 cm 1 (+ associate)
C = O 1645 cm 1 (amide III)
Step B: [(3-Bromopropyl) oxy] -N-butyl-N-methylacetamide.

 The procedure is as in Step C of the preparation of Example 6 starting from 1.56 g of the product obtained in Step A above, 3.18 g tetrabromomethane and 2.51 g of triphenylphosphine.

After chromatography, 1.356 g of expected product are obtained.

Analvse: C10H20BrNO2 = 266.18% C% H% N% Br%
Calculated 45.12 7.57 5.26 30.2
Found 45.2 7.8 5.1 29.4
IR spectrum: (CHC13)
C = O 1646 cm 1 (amide III)
Example 11: N-Butyl-2 - ((5- (4- (3.17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) phenyl) pentyl) oxy) -N-methylacetamide.

Step A: N-Butyl-N-methyl-2-CCS-C4-C3,17beta-bis [(tetrahydro-2H-2-pyranyl) oxy] -estra-1,3,5 (10) -trien-11beta-yl ] phenyl] 4-pentynyl] oxy] acetamide.

 The procedure is as in Stage A of Example 9 starting from 800 mg of product obtained in Step D of Preparation A of Example 9, 6.5 cm 3 of hexamethyl phosphor triamide and 1.9 cm 3 of butyl lithium solution. 1M then 517 mg of product obtained in Stage B of the preparation above. It is extracted with methylene chloride and 5.888 g of intermediate residue is obtained. The residue (1.142 g) is chromatographed on silica (eluent ethyl acetate-cyclohexane -1-1 at 0.1% triethylamine) and 478 mg of expected product is obtained.

IR spectrum: (CHC13)
C = O 1645 cm 1 (amide III) aromatic 1583, 1500 cm -1
Step B: N-Butyl-2 - [[5- [4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) phenyl] pentyl] oxy] -N-methyl acetamide.

 The procedure is as in Step B of Example 10 starting from 478 mg of the product obtained in Step A above in solution in methanol and hydrogen the intermediate residue (356 mg) in the presence of 178 mg of palladium on charcoal. After chromatography of the residue (317 mg) (eluent: ethylcyclohexane acetate 8-2), 199 mg of expected product is obtained.

Analvse: C36H51NO4 = 561.81
C% H% N%
Calculated 76.96 9.15 2.49
Found 77.0 9.3 2.6
IR spectrum: (CHC13)
OH 3604 cm 1 (+ associate)
C = O 1633 cm 1 (aromatic amide III) 1583, 1500 cm -1 Prenaration of Example 12: sodium 6-bromo hexanoate.

 To a solution of 14.60 g of 6-bromohexanoic acid in 20 cm3 of methylene chloride is added 75 cm3 of N sodium hydroxide and then distilled at 60 C. The residue is washed with toluene and uses the product obtained as it is.

 Example 12 8 -f4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-vi) phenyl) -N- (2.2.3.3.4.4.4-heptafluorobutyl) -N-methyl- 7-octynamide.

Step A: 8- [4- [3,17beta-bis [(tetrahydro-2H-2-pyranyl) oxy] -estra-1,3,5 (10) -trien-11beta-yl] phenyl] -7- octynoique.

 To a solution of 17 g of 3,17beta-bis [(tetrahydro-2H-2-pyranyl) oxy] (4-ethynylphenyl) estra-1,3,5 (10) -trien IIbeta-yl obtained in stage D of Preparation A of Example 9 in 60 cm3 of tetrahydrofuran is added at -30 C 60 cm3 of hexamethylphosphorotriamide then 31.5 cm3 of butyl lithium solution 1M in hexane. Stirred for 30 minutes at -30 C and then added 15.7 g of sodium 6-bromohexanoate obtained according to the preparation above. It is stirred for 5 hours at room temperature, poured into a solution of mono-sodium phosphate at 0 ° C. and extracted with ethyl ether. The mixture is evaporated to dryness and the residue is chromatographed (41 g) on silica (eluent: cyclohexane-ethyl acetate 1-1) to give 10.163 g of the expected product.

IR spectrum: (CHC13)
C = O 1709 cm aromatic 1607, 1572, 1497 cm -1
Step B: 8-t4- (3,17beta-dihydroxy-1,3,5 (10) -trienllbeta-yl) phenyl] -N- (2,2,3,3,4,4,4-heptafluorobutyl) N-methyl octynamide.

 To a solution of 0.604 g of the product obtained in Stage A above in 10 cm3 of methylene chloride is added 0.31 cm3 of N-methylmorpholine and then 0.39 cm3 of isobutyl chloroformate. Stirring is carried out for 10 minutes and then 0.826 g of N-heptafluorobutyl-N-methylamine hydrochloride obtained in Preparation 1 is added. The mixture is stirred for 30 minutes at room temperature, 20 cm of saturated sodium bicarbonate solution are added, and the mixture is extracted with sodium chloride. methylene, dry and evaporate to dryness under reduced pressure. The residue (3.369 g) is chromatographed on silica (eluent: 9-1 methyleneacetone chloride). 0.782 mg of intermediate product is obtained which is dissolved in 10 cm 3 of 2N hydrochloric acid in the presence of 10 cm 3 of ethanol and 2 cm 3 of methylene chloride. Concentrated twice by distillation under reduced pressure, the water, extracted with methylene chloride, dried and evaporated to dryness under reduced pressure. The residue (1.403 g) is chromatographed on silica (eluent cyclohexane-ethyl acetate 1-1) and 0.440 g of expected product is obtained in the form of an oil.

[alpha] D = 28 5 + 2 (C = 0.45% ethanol)
Analysis: C37H42F7NO3 = 681.74
H% F% N%
Calculated 65.19 6.21 19.51 2.05
Found 65.0 6.3 19.1 2.0
IR spectrum: <CHCl3) absence of CC
OH 3602 cm-1 (+ associate)
C = O 1656 cm1 aromatic 1584, 1505, 1483 cm -1
Example 13 1- (8- (4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-1-yl) phenyl) -1-oxo-7-octynyl) -4- (phenylmethyl) - piDeridine.

 The procedure is as in Step B of Example 12 starting from 1 g of 8-t4- [3,17beta-bis (<tetrahydro-2H-2-pyranyl) oxy] -estra-1,3,5 acid ( 10) -trien-11beta-yl] phenyl] -7-octynoic, 0.7 cc of isobutyl chloroformate and 0.8 cc of 4-benzylpiperidine. The residue (2.4 g) is chromatographed on silica (eluent: 95-5 methylene chloride-acetone) and 1.01 g of intermediate product is obtained which is depyrannylated. After chromatography on silica (eluent: methyleneacetone chloride 9-1), 0.462 g of expected product is obtained.

talpha] D = -38 + 25 (C = 0.5% ethanol)
Analvse: C44H53NO3 = 643.92
C% H% N%
Calculated 82.07 8.30 2.18
Found 81.9 8.5 1.9
IR spectrum: (CHC13)
OH 3602 cm 1 (+ associate)
C = O 1625 cm 1 (aromatic amide III) 1585, 1555, 1504 cm -1
Preparation A of Example 14: Bromo-N-methyl N- (1-methylethyl) acetamide.

 To a solution of 10 cm3 of bromoacetyl bromide in 150 cm3 of ether cooled to -20 ° C., a solution of 26 cm3 of methylisopropylamine in 100 cm3 of ether is added. Allowed to return to 20 C and stirred for 30 minutes at 20 C. It is diluted with water, decanted, extracted with ether, dried and separated by distillation.

13 g of expected product are obtained. Eb: 71/72 C at 1 mmHg.

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

Step A: 11beta- [8-dimethyl (1,1-dimethylethyl) silyloxy] octyl salpha-hydroxy-estr-9-en-3,17-dione cyclic acetal 3- (1,2-ethanediyl) acetal.

 The reaction is carried out as in Stage A of Preparation A of Example 9 starting from 3.96 g of cyclic 3- (1,2-ethanediyl acetal) 5alpha, 10α-epoxy Estr-9,11-en-3, 17-dione obtained according to EP 0057115 (example 7) using for the preparation of magnesium 5.4 g of [(8-bromooctyl) oxy] dimethyl (1,1-dimethylethyl) silane obtained in preparation 5 and 1 g magnesium turnings, then for condensation 0.4 g of copper chloride. After chromatography on Lichrosorb Rpl8 (eluent: methanol-water 9-1), we obtain 3.85 g of the expected compound used as such for the next stage.

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

 1.77 g of the product obtained in Stage A above, 35 cm 3 of methanol and 8.85 cm 3 of 2N hydrochloric acid are stirred for 1 h at room temperature. The mixture is basified to pH 9 with concentrated ammonia and then evaporated to dryness under reduced pressure. The residue is taken up with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. After chromatography on silica (eluent: methylene chloride ethyl acetate 1-1), 1.08 g of the title compound is obtained.

IR spectrum: (CHC13)
OH 3624 cm-1

<tb> C = O <SEP> 1735 <SEP>cm'l<SEP> (17-keto)
<tb><SEP> 1656, <SEP> 1602 <SEP> cm-1 <SEP> (Dienone)
<Tb>
Example 14: 2 - ((8- (3,17beta-dihydroxy) -9-nor-17alpha-preqna-1,3,5 (10) -trien-20-yl) -beta-yl) octyl) oxy) -N-methyl N- (1-methylethyl) acetamide.

Step A: [8- (3,17-dioxo estra-4,9-dien-11-beta-yl) octyl] oxy] N-methyl N- (1-methylethyl) acetamide.

 To a solution of 570 mg of the compound obtained in the above preparation in 10 cm3 of tetrahydrofuran is added 1.4 cm 3 of bromo-N-methyl N- (1-methylethyl) acetamide (obtained in Preparation A above). 285 mg of sodium iodide and then 140 mg of 50% sodium hydride in the oil are stirred for 1 hour, poured into a solution of N hydrochloric acid at 0 ° C. and extracted with methylene chloride. The residue is evaporated to dryness and chromatographed (2 g) on silica (eluent: ethyl acetate-ether 8-2) to give 350 mg of the desired product.

IR spectrum: (CHCl 3) 17-keto 1736 cm-1 3-keto 1655 cm -1 amide III 1628 cm -1
C = C 1603 cm -1
Step B: 2 - [[8- (3-hydroxy-17-oxo-estra-1,3,5 (10) -trien-11beta-yl) octyl] oxy] -N-methyl-N- (1-methylethyl) ) acetamide.

 To a solution of 9.4 g of the product obtained in Stage A above in 195 cm3 of methylene chloride placed under a nitrogen atmosphere is added at 0 ° C. 10 cm3 of acetic anhydride and 5 cm3 of acetyl bromide. The mixture is stirred for 5 minutes at 0 ° C. and then for 2 hours at room temperature. Cooled to 0 / + 5 C, slowly added water and then methanol, stirred for 5 minutes and added 50 cm3 of 2N sodium hydroxide. The organic phase is collected, extracted again with methylene chloride, washed, dried and evaporated to dryness under reduced pressure. 10 g of acetylated residue are obtained which is dissolved in 100 cm3 of methanol under a nitrogen atmosphere. 2N sodium hydroxide (20 cc) is added and allowed to react for 1 hour at room temperature. It is acidified with 2N hydrochloric acid, extracted with methylene chloride, washed, dried and evaporated to dryness under reduced pressure. The residue is chromatographed (9 g) on silica (eluent: cyclohexane-ethyl acetate 3-7) and 7.9 g of expected product are 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- (lméthyléthyl) -acetamide.

 In a flask placed under a nitrogen atmosphere, a suspension of potassium acetylide is obtained starting from 3 cm 3 of 0.88 M solution of potassium tert-butrofuran in which tetrahydrofuran (5 cc) is added and then sparged with water. acetylene for 15 minutes. A solution of 520 mg of the product obtained in Step C above in 5 cm3 of tetrahydrofuran is added. After reaction for 30 minutes at room temperature, a saturated aqueous ammonium chloride solution is added, extracted with ethyl acetate, washed, dried and evaporated to dryness under reduced pressure. The residue is chromatographed (550 mg) on silica (eluent: methanol-water 85-15) and 470 mg of expected product is obtained.

3305 cm'l
C=O 1625 cm 1 (amide III) aromatique 1583, 1499 cm'l PréDaration A de l'exemple 15 : 2-t(4-bromophényl) thio] tétrahydro- 2 K-pyranne. Analvse: C34H51NO4 = 537.79
C% H% N%
Calculated 75.93 9.55 2.60
Found 75.8 9.7 2.30
IR spectrum: (CHC13)
OH 3600 cm 1

3305 cm -1
C = O 1625 cm 1 (aromatic amide III) 1583, 1499 cm -1 Preparation A of Example 15: 2-t (4-bromophenyl) thio] tetrahydro-2 K-pyran.

 To a solution of 1 g of 4-bromo thiophenol in 1 cm3 of 3,4-dihydro- (2H) -pyran and 1 cm3 of tetrahydrofuran is added 2.3 mg of para-toluenesulphonic acid and then stirred for 20 hours at room temperature. ambient temperature. Triethylamine (0.1 cc) is added, poured into saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue (1.603 g) is chromatographed on silica (eluent: cyclohexane-ethyl acetate 97.5-2.5) to give 1.246 g of expected product.

présence de

Analvse: C11H13BrOS = 273.19 Br% 5%
Calculated 48.36 4.79 29.24 11.73
Found 47.9 4.6 28.8 11.6
IR spectrum: (CHCl3) aromatic 1477 cm-1 type

presence of

Preparation B of Example 15 tibeta- (4 - ((tetrahydro-2H-2-pyranyl) thio] phenyl] estra-4,9-dien-3,17-dione.

a) Maasian preparation
To a suspension of 139 mg of powdered magnesium in 0.65 cm 3 of tetrahydrofuran placed under an argon atmosphere, is added over 15 minutes at 60 ° C / 65 ° C 1.045 g of 2 - [(4-bromo phenyl) thio] tetrahydro -2H-pyran obtained in Preparation A above in solution in 2.5 cm3 of tetrahydrofuran and stirred for 30 minutes.

b) condensation
the suspension obtained above is cooled to 0 / + 5 ° C., 29 mg of copper chloride, 1 cm3 of tetrahydrofuran are added and the mixture is stirred for 15 minutes at 0 ° C. It is cooled to -20 ° C. and 650 mg of 3- Cyclic acetal (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 cm3 of tetrahydrofuran, and stirred for 30 minutes at -15 C then for 1 h 30 at 0 C. It is poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, dried and evaporated to dryness under reduced pressure to give 1.409 g of product. gross.

(c) decetalisation
To a solution of 1.409 g of product obtained above in 30 cm3 of methanol placed under an argon atmosphere is added 6 cm3 of 2N hydrochloric acid. It is stirred for 1 hour at room temperature and poured into a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue is chromatographed (1.27 g) on silica (eluent: ethyl acetate-cyclohexane 1-1) and 647 mg of expected product is obtained, which is crystallized from a mixture of methylene chloride and isopropyl ether. 596 mg of crystals are obtained.

Analvse: C29H34 3S = 462.65
C% H% S%
Calculated 75.28 7.40 6.93
Found 75.0 7.5 6.8
IR spectrum: (CHC13)

<tb> C = O <SEP> 1736 <SEP> cal <SEP> (17-keto) <SEP>
<tb><SEP> 1656 <SEP> cm-1 <SEP> (Dienone)
<tb><SEP> 1603 <SEP>cm'l<SEP>
<tb> aromatic 1493 cm'l presence of

Example 15: N-Butyl-8- (4- (3.17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) phenylthio) -N-methyl-octanamide.

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

a) formation of the arpent thiolate
To a solution of 368 mg of the product obtained in Preparation B above in 3.7 cm 3 of chloroform at 40 ° C., 4.5 cm 3 of methanol and then 1 cm 3 of a 1 M aqueous solution of silver nitrate are added. It is stirred for 10 minutes at 40 ° C., cooled to 0 ° C. + 5 ° C. and the precipitate is retained by decantation of the supernatant.

(b) S-alkylation
To the precipitate obtained above in solution in 3.7 cm 3 of chloroform is added 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 cm3 of hexamethylphosphoric triamide. The mixture is heated at 60 ° C. for 70 hours, cooled to room temperature and poured into a 1M hydrochloric acid solution.

Extracted with ethyl acetate, filtered, the organic phase washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. To the oily residue obtained (1.362 g) dissolved in 3.7 cm3 of acetone is added 0.74 cm3 of 2N sodium hydroxide solution. The mixture is heated at 60 ° C. for 1 hour and then poured into water, acidified with 2N hydrochloric acid, extracted with ethyl acetate, dried and evaporated to dryness under reduced pressure. 914 mg) on silica (eluent: methylene chloride-methylene acetate 1-1) and obtains, in the form of an oil, 332 mg of expected product.

IR spectrum: (CHCl3>

<tb> C = O <SEP> 1736 <SEP>cm'l<SEP> (17-keto)
<tb><SEP> 1655 <SEP> cm <SEP> 1 <SEP> (Dienone)
<tb><SEP> 1628 <SEP> cm <SEP> 1 <SEP> (amide <SEP> III)
<tb> aromatic 1580, 1492 cm'l
Step B: N-Butyl-8- (4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) phenyl) thio) -N-methyl-octanamide.

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

[alpha] D = -49 5 (C = 1.1% CHCl3) Analysis: C37H53NO3S = 591.90
C% H% S% N%
Calculates 75.08 9.02 5.41 2.36
Found 75.4 9.3 5.5 2.4
IR spectrum: (CHC13)
OH 3605 cm 1 (+ assosed)
C = O 1621 cm-1 (amide III) aromatic 1582, 1558, 1498, 1492 cml Preparation of Example 16: 3, 17β-bis ((tetrahydro-2H-2-pyranyl) oxy] -11beta ( 4-ethynylphenyl) -D-homo-estra-1,3,5 (10) -triene.

Step A: 5alpha-1,2-ethanediyl acetalcyclic, 10alpha-epoxy 17alpha - [(tetrahydro-2H-2-pyranyl) oxy] -D-homo estr9 (11) en-3one.

To a solution of 6 g of cyclic 1,2-ethanediyl acetal of 17abeta- [(tetrahydro-2H-2-pyranyl) oxy] -D-homo estra5 (10), 9 (11) -dien-3one which is can get according to the patent
FR 2594830 (Example 6 - Stage A) in 60 cm 3 of methylene chloride, 0.6 cm 3 of pyridine is added and then at 0 C 1.7 cm 3 of hexafluoroacetone and in 5 minutes 3.4 cm 3 of oxygenated water at 50 ° C. %. It is stirred for 6 h at 0 ° C., poured into a saturated solution of sodium thiosulphate and washed to the end of the peroxide. Extracted with methylene chloride, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue (12 g) corresponding to 2 identical preparations is chromatographed on silica (eluent cyclohexane-ethyl acetate 9-1 to 0.5% triethylamine) and gives 7.1 g of expected alpha-epoxide.

Stage B: 11beta- (4-ethynylphenyl) -17abeta-hydroxy-D-homo estra-4,9-dien-3One.

a) condensation
The procedure is as in Step A of Preparation A of Example 1 starting from 5.7 g of epoxide above in solution in 46 cm3 of tetrahydrofuran, 232 mg of copper chloride and 60 cm3 of magnesium prepared according to Stage A of Preparation A of Example 9 from 4-trimethyl ethynyl bromobenzene described in Preparation 4, which is slowly introduced under a nitrogen atmosphere at -5 ° C./0 C. The residue is chromatographed on silica (eluent: cyclohexane-ethyl acetate 7-3 to 0.5% triethylamine) and obtained 6.3 g of product which is desilylated in solution in 100 cm3 of methanol and 20 cm3 of methylene chloride by addition 2.6 cm3 of 10N sodium hydroxide. The functions protected at 17 and 3 are then liberated by addition of concentrated hydrochloric acid (7.2 cc) at 0 C / + C, and then, after dilution with ice, by adjusting the pH to 8-9 with concentrated ammonia. It is extracted with methylene chloride, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue is chromatographed (4.3 g) on silica (eluent: methylene chloride-acetone 96-4) and 3.36 g of expected product are obtained.

3302 cm'l
C=O 1656, 1604 cm 1 (diénone) aromatique 1555, 1504 cm'l
Stade C : 3,l7abéta-diacétate de îîbéta-[4-éthynyl phenyl]-D- homo-estra-1,3,5(10) trien-3,17abéta-diol.IR spectrum: (CHC13)
OH 3612 cm 1

3302 cm'l
C = O 1656, 1604 cm 1 (aromatic dienone) 1555, 1504 cm -1
Step C: 3,17beta- [4-ethynyl phenyl] -D-homo-estra-1,3,5 (10) trien-3,17-abeta-diol beta- diacetate.

 To a solution of 200 mg of the product obtained in Stage B above in 2 cm3 of methylene chloride, 0.09 cm3 of acetyl bromide and then 0.18 cm3 of acetic anhydride are added at 0 / + 5 ° C. It is stirred for 3 hours at room temperature, poured into 20 g of ice-cold solution (1-1) and saturated solution of potassium bicarbonate, extracted with methylene chloride, washed with saturated sodium chloride solution, dried and dried. evaporated to dryness under reduced pressure. The residue is chromatographed (230 mg) on silica (eluent cyclohexane-ethyl acetate 9-1) and 147 mg of expected product is obtained.

IR spectrum: (CHCl 3) = CH 3 O 3 cm 1 phenolic acetate 1749 cm 1 acetate 17 1727 cm -1 aromatic 1608, 1588, 1556, 1505, 1494 cm -1
Stage D: 3,17beta-bis (tetrahydro-2H-2-pyranyl) oxy] -beta- (4-ethynylphenyl) -D-homo-estra-1,3,5 (10) -triene.

 2.39 g of product obtained according to the process described in Step C above are stirred in a solution of 1M potassium hydroxide in methanol under an argon atmosphere. The mixture is heated at 35 ° C. for 30 minutes, poured into ice water, the pH is adjusted to 7 with 2N hydrochloric acid, extracted with methylene chloride, washed with saturated sodium chloride solution, dried, The residue (2.14 g) is chromatographed on silica (eluent: ethyl cyclohexaneacetate 6-4) and 1.89 g of intermediate deacetylated product are obtained. above, dissolved in 60 cm3 of ethyl ether, 3.2 cm3 of dihydropyran and 50 mg of para-toluenesulphonic acid are added, and the mixture is stirred for 3 hours at room temperature and 30 cm3 of saturated sodium bicarbonate solution are added. extracted with ethyl acetate, washed, dried and evaporated to dryness under reduced pressure The residue is chromatographed (2.7 g) on silica (eluent: cyclohexane-ethyl acetate 9-1 at 0.5% triethylamine) and obtains 2,429 g of expected product.

3302 cm1 aromatique 1607, 1575, 1555, 1499 cm'l
Exemple 16 : N-butyl-8-(4-(3.17abéta-dihydroxy-D-homoestra- 1.3.5(10)-trien-ilbéta-vl) hénvl) -N-méthvl-7-octvnamide. IR spectrum: (CHC13)

3302 cm1 aromatic 1607, 1575, 1555, 1499 cm -1
Example 16: N-Butyl-8- (4- (3, 7-beta-dihydroxy-D-homoestra-1,3,5 (10) -trien-ilbeta-1-yl) phenyl) -N-methyl-7-octynamide.

The procedure is as in Step A of Example 10 starting from 0.8 g of product obtained in Step D of the above preparation, 6.5 cm 3 of hexamethylphosphoric triamide and 1.7 cm 3 of a solution of butyl lithium 1, 1 M, then add 530 mg of 6-bromo
N-butyl N-methyl hexanamide prepared as in the preparation of Example 2 starting from 6-bromohexanoic acid. It is poured into a saturated solution of sodium chloride and extracted with ethyl acetate. After chromatography of the residue (3 g), 844 mg of product is obtained, the pyrannyl group at 3 and 17 is removed in solution in 40 ml of methanol to which 8 ml of 2N hydrochloric acid is added. It is poured into a water-ice mixture (1-1) extracted with methylene chloride, washed, dried and evaporated to dryness under reduced pressure. The residue (610 mg) is chromatographed on silica (eluent: methylene chloride-acetone). 2) and obtains 536 mg of expected product.

Analvse: C38H51NO3 = 569.84
C% H% N%
Calculated 80.10 9.02 2.46
Found 80.1 9.2 2.4
IR spectrum: (CHC13)
OH 3603 cm 1
C = O 1625 cm -1 (amide III) aromatic 1580, 1556, 1507 cm -1
Example 17: N-Butyl-4- (3.17beta-dihydroxy-D-homoestra-1,3,5X10) -trien-11beta-yl) -N-methyl-benzeneoctanamide.

 The procedure is as for the reduction in Step B of Example 10 starting from 360 mg of product obtained in Example 16 and 180 mg of palladium on charcoal. The residue is chromatographed (375 mg) on silica (eluent: methylene chloride-acetone 9-1) and 336 mg of expected product is obtained.

talpha] D = -26 5 + 1 (C = 1% ethanol)
Analvse: C38H55NO3 = 573.87
C% HN%
Calculated 79.54 9.66 2.44
Find 79.2 9.8 2.4
IR spectrum: (CHC13)
OH 3606 cm
C = O 1622 cm -1 (aromatic amide III) 1585, 1500 cm -1
Example 18: N-Butyl-2- (5- (4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-vinyl) phenoxo) pentyl) thio) -N-methyl ethanethioamide.

 The procedure is as for Steps D, E and F of Example 1 starting from 570 g of N-butyl- [5-t4- (3,17-beta-dihydroxy estra1,3,5 (10) -trien-11beta -yl) phenoxy] pentylthio] N-methylacetamide obtained in stage C of example 8 - for stage D, 0.57 cm 3 of acetic anhydride and 28 mg of 4-dimethylaminopyridine are used and 682 mg of residue are obtained crude product 3,17-diacetoxy expected.

IR spectrum: (CHC13) absence of OH

<tb> C = O <SEP> 1720, <SEP> 1760 <SEP>cm'l<SEP> (ester)
<tb><SEP> 1640 <SEP> cm-1 <SEP> (amide)
1605, 1580, 1500 cm -1 - for stage E, 680 mg of the crude product above, 250 mg of Lawesson's reagent are used, stirred for 4 hours at 50 ° C. and 560 mg of crude product residue are obtained. thioamide expected.

IR spectrum: (CHCl 3) acetate 1720 at 1760 cm -1
C = O (amide) absence ~,
C = S 1605 cm aromatic 1500, 1580 cm -1 - for Stage F use 560 mg of the previous crude product, 4 cm3 of 2N sodium hydroxide, gives 516 mg of crude residue and after chromatography (eluent: G-acetate gasoline). ethyl 6-4) isolates 395 mg of expected product.

talpha] D = -30 i 1 (C = 0.45% CHCl 3)
Analvse: C36H51NO382 = 609.94
C% H% N% S%
Calculates 70.89 8.43 2.30 10.51
Found 70.9 8.4 2.3 10.4
IR spectrum: (CHC13)
OH 3602 cm -1 aromatic 1610, 1578, 1512 cm -1
Pharmaceutical compositions
Tablets having the following formula were prepared - Product of Example 2 ............................. 50 mg - Excipient (talc, starch, magnesium stearate)
qs for one tablet finished at .................... 120 mg
Pharmacological study of the products of the invention 1 - Study of the activity of the products of the invention on the estrogen receptor of the mouse uterus
Impuberant female mice aged 18 to 21 days are sacrificed, the uteri are removed and then homogenized at 0 C using a teflon-glass Potter in a TS buffered solution (10 mM Tris, 0.25 M sucrose, HC1 pH 7.4 (1 g of tissue per 25 ml of TS) The homogenate is then ultracentrifuged (105,000 gx 90 min) at 0 ° C. Aliquots of the supernatant thus obtained are incubated at 0 ° C. or at 25 ° C. for a time (t) with a constant concentration (T) of tritiated estradiol in the presence of increasing concentrations (0 - 1000 × 10 -9 M) either of cold estradiol or of the cold product to be tested The concentration of bound tritiated estradiol ( B) is then measured in each incubate by the charbondextran adsorption technique.

Calculation of the relative binding affinity
The calculation of the relative binding affinity (ARL) is identical for all receivers.

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

The equation line I50 = (B max + B min) / 2 is determined. TT
B max = Percentage of bound tritiated hormone for an incu
Tation of this tritiated hormone at the concentration (T).

B min = Percentage of bound tritiated hormone for an incu
Tation of this hormone tritiee at the concentration (T) in the presence of a large excess of cold hormone (2500.109M).

 The intersections of the right I50 and the curves allow to evaluate the concentrations of the cold reference hormone (CH) and the cold product tested (CX) which inhibit by 50% the binding of the tritiated hormone on the receiver.

 The relative binding affinity (ARL) of the test product is determined by the equation ARL = 100 (CH).

(CX)
The results obtained are as follows

<tb> I <SEP> Products <SEP> Receptors <SEP> Estrogen <SEP> I
<tb> g <SEP> of <SEP> | <SEP><SEP> incubation time <SEP> I
<tb> Examples <SEP> to <SEP> 0 C
<tb><SEP> 2H <SEP> 5H
<tb> 1 <SEP> 20
<tb> 2 <SEP> 16
<tb> 5 <SEP> 0 <SEP> 23
<tb> 1 <SEP> 6 <SEP> 1 <SEP> 3,3 <SEP> 1 <SEP> 29 <SEP> j <SEP>
<tb> 9 <SEP> 9 <SEP> 1 <SEP> 1 <SEP> 11.7 <SEP> j <SEP>
<tb> 14 <SEP> 1 <SEP> 2,8 <SEP> 1 <SEP> 47 <SEP> j <SEP>
<tb> 18 <SEP> 16
<Tb>
Conclusion
The products studied, in particular the product of Example 14, have a marked affinity for estrogen receptors at the second time.

 In addition, most products lack uterotrophic activity.

2 - Anti-roliferation activity of the products of the invention on the growth of MCF-7 mammary tumor cells.

Description of the test a) Cell culture
The MCF-7 lines are maintained in culture in medium
SVF (1) at 37 C in a humid atmosphere containing 5% CO2. The subconfluent cells are harvested by trypsin (0.05% trypsin, 0.02% EDTA) and then rinsed by gentle centrifugation. A sample of the suspended cells is counted on Malassez cell.

b) Study of growth
The cells resuspended in the SVF medium were started at 30,000 cells per well in multiwell plates (24 wells of 2.5 cm 2). Twenty four hours after seeding (OJ), the product to be tested is added to the medium in ethanolic solution (final concentration of 0.1% ethanol), at the concentration of 10-12 to 106M, the wells control receiving the same. ethanol concentration. The media are renewed every 48 hours. At the end of the experiment (J6), the medium is aspirated and the cells are immediately fixed with 150 microliters of methanol in order to assay the DNA.

 The antiproliferative activity of the products is evaluated by their ability to inhibit the increase of DNA.

c) Dosaae of DNA
The DNA is assayed by a fluorimetric method using DABA (3,5 diaminobenzoic acid) (2): 150 microliters of
DABA are added to each well; the plates are then incubated for 45 minutes at 56 ° C., then 2 ml of 1N HCl are added The fluorescence is measured using a fluorimeter (exciter wavelength: 408 nm, wavelength emission 510 nm).

 The amount of DNA per well is evaluated with respect to a standard range obtained by treating under the same conditions a calf thymus DNA standard.

Results
The concentration in nm which inhibits by 50% the growth of MCF7 cells (IC50) was determined as indicated above. Results
Product of Example 1: IC 50 = 0.03 nM
Product of Example 2: IC50 = 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
In addition, the maximum inhibitory effect of the products is approximately 90%.

(1) The fetal calf serum (FCS) culture medium is prepared as follows
MEM medium (minimal Essential Medium) to which are added - non-essential amino acids (GIBCO), - peni-strepto (penicillin 100 U / ml, streptomycin 0.1 mg / ml), - fungizone 0.1%, - insulin (50 ng / ml), - esteroid fetal calf serum (10% final concentration).

(2) Puzas and Goodman, Analytical Biochemistry, Vol. 86, pp.

50, 1978.

Claims (15)

1) The products corresponding to the general formula (I) of the main patent application and whose names follow - Ilbéta- monobutanedioate (4 - ((7- (butylmethylamino) carbonyl) heptyl) oxy) phenyl) -3- hydroxy-estra-1,3,5 (10) trien-17beta-yl, - Ilbeta- (4 - ((7 - ((butylmethylamino) carbonyl) heptyl) oxy) phenyl) -3-hydroxy-estra-2-butanedioate 1,3,5 (10) - trien-17beta-yl and sodium, - N-butyl-a- (6- (4- (3,17beta-dihydroxy-estra-1,3,5 (10) - trien-11beta-yl) phenoxy) hexyloxy-N-methylacetamide, N-butyl-8- (4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-IIbeta-yl) phenoxy) -N-methyl-2-octynamide, N-butyl-4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) -N-methyl-benzenenonamide N-Butyl-2 - ((5- (4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) phenyl) pentyl) oxy) -N-methyl 2 - ((8- (3,17beta-dihydroxy-19-nor-17alpha-pregna 1,3,5 (10) -trien-20-yn-11beta-yl) octyl) oxy) -N-acetamide methyl-N- (1-methylethyl) acetamide, as well as related products according to formula (IA)

 in which n = 1 or 2, the rings A and B represent the grouping

RA or RAi, which may be identical or different, represent a hydrogen atom, a linear or branched alkyl radical containing from 1 to 8 carbon atoms, optionally substituted by an aryl, alkyl or dialkylamino, hydroxy, halogen or esterified carboxyl radical or RA and RA, form, with the nitrogen atom to which they are bonded, a saturated or unsaturated 5- or 6-membered heterocycle, optionally containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms and optionally substituted by an alkyl radical having from 1 to 4 carbon atoms, an aryl or aralkyl radical having from 6 to 10 carbon atoms, it being understood that at least one of the radicals RA or RA is not an atom hydrogen and that at least one of the following conditions is satisfied - either n = 2, - or K is a sulfur atom, - or X is an arylenethio radical bonded to the steroid by a carbon atom, - or Y is an aliphatic chain interrupted by an optionally oxidized sulfur atom, - or RA or RA, is an alkyl radical substituted by one or more halogen atoms, - or RA and RA, form with the carbon atom to which they are bound a 5-membered heterocycle. or 6-membered chain substituted by an aryl or aralkyl radical. X, Y and Z are such that: - X represents a methylene radical, an arylene group, a CH2-O, arylenoxy or arylenethio radical bonded to the steroid by a carbon atom, - Y represents a single bond or a linear aliphatic chain or branched, saturated or unsaturated, containing from 1 to 18 carbon atoms, optionally interrupted by one or more radicals selected from arylene, oxygen or sulfur radicals optionally oxidized in the form of sulfoxide or sulfone 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 may not be a methylene or CH 2 -O radical, R'17 represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical having at most 8 carbon atoms, optionally substituted, R'17 are such that - either R17 and R'17 together form a ketone function, - or R17 is a hydroxyl radical or an acyloxy radical and K represents an oxygen atom or a sulfur atom, R17 and 2) The products corresponding to the formula (IA) as defined in claim 1 for which n is equal to 1. 3) The products according to claim 2 wherein K is a sulfur 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. 4) The products according to claim 2 for which X is an arylenethio radical and Y represents a saturated linear chain containing from 5 to 10 carbon atoms. 5) The products according to claim 2 wherein X is an arylene or arylenoxy radical and Y is a saturated linear chain containing from 5 to 10 carbon atoms and interrupted by an optionally oxidized sulfur atom. 6) The products according to claim 2 wherein X is an arylene or arylenoxy radical, Y is a saturated or unsaturated aliphatic chain and RA or RA, is an alkyl radical substituted by one or more halogen atoms. 7) The products according to claim 2 for which X is an arylene radical, Y represents an unsaturated linear chain containing from 5 to 10 carbon atoms, RA and RA form, with the atom to which they are bonded, an N-substituted piperidine; an aralkyl radical. 8) The products of formula (IA) according to any one of claims 1 to 7 whose names follow - N-butyl-5- (4- (3,17beta-dihydroxy-estra-1,3,5) phenyl) pentyloxy) -N-methyl-ethanethioamide, N-butyl-8- (4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-llbeta) -yl) phenoxy) -N-methyl-octanethioamide, N-butyl-2 - ((5- (4- (3,17beta-dihydroxy-estra-1,3,5 (10) -trien-11beta-yl) ) phenyl) pentylthio) -N-methylacetamide, 9) Process for the preparation of the products of formula (IA) as defined in claim 1, characterized in that a compound of formula (IIA):

 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 by the action of an oxidation agent for get the formula product

 that is subjected to the action of an agent for activating the carboxylic function, then to the action of a compound of formula (IVA)

 in which RA and RA 'have the same meaning as in claim 1, to obtain the product of formula (V)

  wherein Z is a single bond, products (VA) that, if necessary, is subjected to a deprotection reaction of the hydroxy function and that, if desired, or is subjected to a reducing agent when R17 and R ' 17 together form a ketone function, either it is subjected to an acylating agent when R 17 represents a hydroxyl function, or it is subjected to a saponification agent when R 17 represents an acyloxy function, and then subject to to a flavoring agent of the ring A, then to a mild saponification agent to obtain the products of formula (IA) if desired, - or, when R17 and R'17 together form a ketone function, it is subject to a reducing agent or which is subjected to a metal complex of formula (VIA) M-R'17 (VI) in which M represents a metal atom and R'17 has the same meaning as in claim 1, being understood that it is not a hydrogen atom, - or, when R17 is a radical hy and then, when RA or RA 'is a hydrogen atom, is subjected to an alkylating agent, or when Y represents an aliphatic chain. unsaturated, subjected to a hydrogenation agent, to obtain the products of formula (IA) wherein K is an oxygen atom which, if desired, is subjected to a sulphurizing agent to obtain the products of formula (IA) in which K is a sulfur atom. 10) Process for the preparation of the products of formula (IA ') corresponding to the products of formula (IA) as defined in claim 1 wherein 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 having at least 3 carbon atoms or bonded to the arylene group by an oxygen atom or a sulfur atom, characterized in that a compound of formula (XA) ::

 in which W represents either an -OH radical, an optionally protected mercapto radical or a radical

 n having the same meaning as that given in claim 1, Ra117 and Ra'17 having the same meanings as that indicated in claim 1 for R17 and R'17, the rings A 'and B' are - either

 - is

 or R3 represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms or an acyl radical, and in which the reactive functions at 3 and 17 are optionally protected, or else, in the case where W represents a radical

 to the action of a halogenated derivative of formula (XIA) ::

 in which Hal is a halogen atom, Z, RA and RA 'have the same meaning as that indicated in claim 1 and Y 'represents the aliphatic chain Y above having 2 less carbon atoms, in the presence of a strong base and subject, where appropriate, to the action of a deprotection agent, to obtain the product of formula (XIIA) al:

 product that, if desired, is subjected to a partial or total reduction agent of the triple bond to obtain the product of formula (XIIA) a2 ::

 or else, in the case where W represents an -OH radical, or in the case where W represents a mercapto radical or an optionally activated derivative of the mercapto radical, to the action of a halogenated derivative of formula (XIIIA)

  in which Hal, Y, Z, RA and R 'have the same meaning as that indicated in claim 1, in the presence of an alkaline agent, then, if appropriate, to the action of a deprotection agent to obtain a product of formula (XIIA) a3

 in which K 'represents either an oxygen atom or a sulfur atom, produced (XIIA) a1, (XIIA) a2 and (XIIA) a3, if desired, subject to any of the reactions indicated in claim 9 for (VA), and then the products (XIIA) a1, (XIIA) a2 and (XII) a3 in which the rings A 'and B' are

 to a flavoring agent of the ring A, then to a mild saponification agent to obtain the products of the formula (IA ') which, if desired, are subjected to any of the reactions indicated in claim 9 for IA). 11) As a medicament, the products of formula (I) and the products of formula (IA) as defined in any one of claims 1 to 8. 12) Pharmaceutical compositions containing as active principle at least one of the medicaments as defined in claim 1. 13) Pharmaceutical compositions containing as active ingredient at least one of the medicaments as defined in any one of claims 1 to 8. 14) As new intermediate products, the products of formula (IIA) and (IIIA) as defined in claim 9 being understood that at least one of the following conditions is fulfilled - either n = 2, - or Y is an aliphatic chain interrupted by an optionally oxidized sulfur atom. 15) As new intermediate products the products of formula (XA) as defined in claim 10 wherein W represents an optionally protected mercapto radical.