FR2586021A1 - New products derived from the structure 5 alpha -OH- DELTA <9(10)>-19-norsteroids - Google Patents

Abstract

New products of formula: R'1 = in particular an optionally substituted thienyl, a furyl, a cycloalkyl, an optionally substituted phenyl, a naphthyl or a diphenyl naphthyl, R2 = a methyl or an ethyl, R''3 = in particular H, an alkyl, an alkenyl or an optionally substituted alkenyl, a hydroxyl, an acetyl or a hydroxyacetyl, R'4 = in particular H, OH, an alkyl, an alkenyl or an optionally substituted alkenyl, R5 = H or CH3 K = a blocked ketone group.

Description

 The present invention relates to novel products derived from the 3-keto structure A 4.9 19-nor-steroids, their method of preparation and their use as medicaments.

dans laquelle soit R1 représente un radical thiényle éventuelle- ment substitué, un radical furyle ; un radical cycloalkyle ayant de 3 à 6 atomes de carbone ; un radical phényle éventuellement substitué par un ou plusieurs radicaux choisis parmi les radicaux hydroxyhalogène, trifluorométhyle, aikyle, alkoxy, alkylthio éventuellement oxydé sous forme de sulfoxyde ou de sulfone, ou alkényloxy ayant au plus 6 atomes de carbone et phényloxy soit
R1 représente un radical naphtyle ou diphényle ou un radical aikyle ou alkényle portant éventuellement plusieurs insaturations ayant au plus 6 atomes de carbone;;
R2 représente un radical méthyle ou éthyle
R3 représente un atome d'hydrogène, un radical alkyle, alkényle ou alkynyle éventuellement substitué, un radical hydroxyle, acétyle, hydroxyacétyle,carboxyalkoxy ayant de 2 à 4 atomes de carbone éventuellement estérifié ou salifié, hydroxyalkyle éventuellement estérifié
R4 représente un atome d'hydrogène, un radical hydroxyle, un radical alkyle, alkényle ou alkynyle ayant au plus 12 atomes de carbone éventuellement substitué par un radical alkyle amino, dialkyle amino, ou par un halogène, un radical alkylthio, alkoxy ou trialkylsilyl
R5 représente un atome d'hydrogène ou un radical méthyle en position a ou ss
X représente un atome d'oxygène ou un radical hydroxyimino ou alkoxyimino ayant de 1 à 4 atomes de carbone en position syn ou anti;;
A et B représentent une fonction a époxy ou la présence d'une seconde liaison entre les carbones 9 et 10, ainsi que les sels de ces produits avec les acides lorsque R4 représente un radical comportant une fonction amino
A l'exception de ces produits dans lesquels A et B représentent une seconde liaison entre les carbones qui les portent,
X représente un atome d'oxygène,
R5 représente un atome d'hydrogène et a) R2 représente un radical méthyle et
a) R3 représente un radical hydroxyle et
i)R1 représente un radical éthyle ou phényle et
R4 représente un atome d'hydrogène, ou
ii)R1 représente un radical éthyle, propyle, isopropyle, vinyle, allyle, isopropényle, phényle, parafluorophényle ortho ou méta méthoxyphényle ou thiényle et R4 représente un radical éthynyle, ou
iii)R1 représente un radical propyle, isopropyle, vinyle, allyle, isopropényle, p-méthoxyphényle ou thiényle et
R4 représente un radical méthyle,
ss) R3 représente un radical acétyle et
i)R1 représente un radical éthyle, vinyle ou phényle et
R4 représente un radical hydroxyle ou
ii)R1 représente un radical vinyle et R4 représente un radical méthyle.The subject of the invention is the products of general formula I

wherein either R1 is optionally substituted thienyl, furyl; a cycloalkyl radical having 3 to 6 carbon atoms; a phenyl radical optionally substituted with one or more radicals chosen from hydroxyhalogen, trifluoromethyl, alkyl, alkoxy, alkylthio radicals optionally oxidized in the form of sulphoxide or sulphone, or alkenyloxy having at most 6 carbon atoms and phenyloxy,
R1 represents a naphthyl or diphenyl radical or an alkyl or alkenyl radical optionally bearing several unsaturations having at most 6 carbon atoms;
R2 represents a methyl or ethyl radical
R3 represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical, a hydroxyl, acetyl, hydroxyacetyl or carboxyalkoxy radical having 2 to 4 carbon atoms, optionally esterified or salified, optionally esterified hydroxyalkyl;
R4 represents a hydrogen atom, a hydroxyl radical, an alkyl, alkenyl or alkynyl radical having at most 12 carbon atoms optionally substituted by an alkyl amino, dialkyl amino radical, or by a halogen, an alkylthio, alkoxy or trialkylsilyl radical;
R5 represents a hydrogen atom or a methyl radical in position a or ss
X represents an oxygen atom or a hydroxyimino or alkoxyimino radical having 1 to 4 carbon atoms in the syn or anti position;
A and B represent an epoxy function or the presence of a second bond between carbons 9 and 10, as well as the salts of these products with acids when R4 represents a radical having an amino function
With the exception of those products in which A and B represent a second bond between the carbons which carry them,
X represents an oxygen atom,
R5 represents a hydrogen atom and a) R2 represents a methyl radical and
a) R3 represents a hydroxyl radical and
i) R1 represents an ethyl or phenyl radical and
R4 represents a hydrogen atom, or
ii) R1 represents an ethyl, propyl, isopropyl, vinyl, allyl, isopropenyl, phenyl, ortho or meta-methoxyphenyl para-fluorophenyl or thienyl radical and R4 represents an ethynyl radical, or
iii) R 1 represents a propyl, isopropyl, vinyl, allyl, isopropenyl, p-methoxyphenyl or thienyl radical and
R4 represents a methyl radical,
ss) R3 represents an acetyl radical and
i) R1 represents an ethyl, vinyl or phenyl radical and
R4 represents a hydroxyl radical or
ii) R1 represents a vinyl radical and R4 represents a methyl radical.

b) R2 represents an ethyl radical and
R1 represents a vinyl radical, R3 represents a hydroxyl radical and R4 represents a hydrogen atom.

 Among the substituents of the thienyl radical, there may be mentioned halogen radicals such as fluoro, chloro, bromo, alkyl radicals such as methyl, ethyl, haloalkyl radicals such as trifluoromethyl. The cycloalkyl radicals may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radicals. Among the possible substituents of the phenyl radical that may represent R1 include alkyl radicals which may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl radicals. The alkoxy and alkylthio radicals derive from the above-mentioned alkyl radicals. Alkoxy and alkylthio radicals are preferred.

 The alkenyloxy radicals are preferably vinyl or allyloxy radicals.

 Among the values of R7, mention may be made of the preceding alkyl and alkenyl radicals.

 Radicals containing several unsaturations, such as the propa 1,2-dienyl radical, may also be mentioned.

 Among the values of R2, the methyl value is preferred.

 Among the values of R 3 other than those mentioned above, the tert-butoxycarbonylmethoxy, carboxy methoxy radicals which are optionally salified, for example in the form of an alkali metal or alkaline earth metal salt or an organic base, are preferred.

 There may be mentioned, for example, the sodium, potassium, lithium, calcium, magnesium or ammonium salts.

Among the organic bases, mention may be made of methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procalne, lysine, arginine, histidine, N-methylglucamine.

 The sodium salt is preferred.

 When substituted, R3 may be substituted with alkylamino or dialkylamino or dialkylaminotun halogen with alkylthio, alkoxy or trialkylsilyl.

 Among the values of R, mention may be made especially of methyl, ethyl, ethynyl and propylyl values.

 3-dimethylamino prop-1-ynyl, or the 3-amino prop 1-ynyl radical may also be mentioned.

 Among the values of R 3 or R 4, radicals having at most 4 carbon atoms and especially ethynyl or propynyl are preferred.

 Of the alkyloximes that may be X, the methyloxime value is preferred.

 As addition salts with acids, mention may be made of the salts formed with hydrochloric acid, acetic acid, trifluoroacetic acid, malenic acid, tartaric acid, methanesulfonic acid, benzenesulphonic acid, p-toluenesulphonic acid, phosphoric acid, sulfuric acid and hydrobromic acid.

The subject of the invention is in particular the products of formula I as defined above in which either the radical R 1 represents a cycloalkyl radical having from 3 to 6 carbon atoms or a substituted thienyl radical, or
X represents a hydroxyimino or alkoxyimino radical having from 1 to 4 carbon atoms in the syn or anti position, ie the letters A and B represent an epoxy function, or R5 represents a methyl radical.

The subject of the invention is more particularly the products of formula I as defined above in which
R 3 represents a hydroxyl radical, R 4 represents a propynyl radical, R 2 represents a methyl radical and R 5 represents a hydrogen atom and those in which R 3 represents an acetyl radical, R 4 represents a methyl radical or a hydrogen atom and R 1 represents a optionally substituted phenyl radical.

 Among the preferred products of the application, mention may be made of those in which the radical R 1 represents a cyclopropyl, a phenyl group optionally substituted by one of the radicals chosen from the group formed by the radicals chloro, fluoro methylthio, methylsulfonyl, methoxy, hydroxy and allyloxy or a chlorothienyl group and R4 represents a propynyl radical.

A class of preferred products is also constituted by the products of formula I in which the letters A and
B represent an epoxy group.

 Of course, the products described hereinafter in the examples are particularly preferred products.

This is also the case for the following products - 11ss - / (4-chloro) phenyl / 17ss-hydroxy 17α- (prop-1-ynyl) estra 4,9-dien-3-one-11ss / (5-chlorojthienyl / 17S hydroxy-17α- (prop-1-ynyl) estra 4,9-dien-3-one; 11ss / (3-chloro) phenyl / 17ss-hydroxy 17α-prop-1-ynyl) estra
4,9-dien-3-one-11ss / (4-methylthio) phenyl / 175-hydroxy 17a (prop-1-ynyl)
Estra 4,9-dien-3-one - [1- (3-fluoro) phenyl] -175-hydroxy-17α- (prop-1-ynyl) estra
4,9-dien-3-one - 11ss / (4-methylthio) phenyl / 17-alpha-methyl 19-nor, pregna 4.9
dienes 3,20-dione - 11ss / (4-methylthio) thienyl / 16a-methyl 19-nor, pregna 4.9
dienes 3,20-dione - 11ss-cyclopropyl 17ss-hydroxy 17 &alpha;;( prop-1-ynyl) estra 4.9
dien 3-one-11ss / (3 (2-propenyloxy) phenyl / 17ss-hydroxy 17α-prop-1-ynyl)
estra 4,9-dien-3-one-9a, 10a epoxy 17ss-hydroxy 115- (4-methoxyphenyl) 17a- (prop-
1-ynyl) estra 4-en 3-one - 9a, 10a epoxy 17ss-hydroxy 11ss - / (4-methylsulfonyl) phenyl
17α- (prop-1-ynyl) estra 4-en-3-one-11ss- (3-fluoro) phenyl-3-hydroxyimino 17α- (prop-1-ynyl)
estra 4.9-dien 175-ol isomeric anti-17ss-hydroxy 17 &alpha;-( prop-1-ynyl) 11ss- (4-hydroxyphenyl) estra
4,9-dien-3-one; and especially for 1α - ((4-methylthio) phenyl / 17ss-hydroxy 17α- (prop-1-ynyl)
estra 4,9-dien-3-one.

dans laquelle K représente un groupement cétonique bloqué sous forme de cétal, de thiocétal, d'oxime ou de méthyloxime,
R'3 a les valeurs de R3 indiquées ci-dessus, avec en plus la valeur acétyle bloquée > R1 a la valeur de R1 indiquée cidessus, avec en plus la valeur phényle substituée par un radical hydroxy protégé, R2, R4 et R5 ayant les valeurs indiquées ci-dessus, à l'action d'un agent de déshydratation susceptible de libérer la ou les fonctions protégées pour obtenir un produit de formule IA::

correspondant à un produit. de formule I dans laquelle X représente un atome d'oxygène et A et B forment ensemble une seconde liaison entre les carbones qui les portent, produit de formule IA que si désiré, l'on soumet, dans un ordre quelconque à l'une ou plusieurs des réactions suivantes a) oxydation de manière à obtenir les produits dans lesquels
A et B forment une fonction époxyde et, lorsque R1 comporte un atome de soufre, oxydation en sulfoxyde ou sulfone de cet atome b) Action de l'hydroxylamine ou d'un dérivé alkylé de l1hydro- xylamine de manière à obtenir les produits dans lesquels X représente un radical hydroxyimino ou alkoxyimino c) Hydrolyse et salification éventuelles des produits dans lesquels R3 représente un radical carboxyalkoxy estérifié ; d) Salification des produits dans lesquels R4 représente un radical alkyle, alkényle ou alkynyle substitué par un radical amino, alkyle amino ou dialkyle amino.The subject of the invention is also a process for the preparation of the products of formula I as defined above, characterized in that a product of general formula II is subjected to

in which K represents a blocked ketone group in the form of ketal, thioketal, oxime or methyloxime,
R'3 has the values of R3 indicated above, in addition to the value acetyl blocked> R1 has the value of R1 indicated above, with in addition the phenyl value substituted by a protected hydroxy radical, R2, R4 and R5 having the values indicated above, to the action of a dehydrating agent capable of releasing the protected function (s) to obtain a product of formula IA ::

corresponding to a product. of formula I wherein X represents an oxygen atom and A and B together form a second bond between the carbons which carry them, a product of formula IA which if desired, is subjected in any order to one or several of the following reactions a) oxidation so as to obtain the products in which
A and B form an epoxide function and, when R1 has a sulfur atom, oxidation to the sulfoxide or sulfone of this atom; b) Action of the hydroxylamine or of an alkylated derivative of 1-hydroxylamine so as to obtain the products in which X represents a hydroxyimino or alkoxyimino radical. C) Possible hydrolysis and salification of the products in which R3 represents an esterified carboxyalkoxy radical; d) Salification of the products in which R4 represents an alkyl, alkenyl or alkynyl radical substituted by an amino, alkylamino or dialkylamino radical.

 In a preferred embodiment of the process, the dehydrating agent capable of releasing the protected function (s) which are ketone or hydroxyl functional groups is a sulphonic resin (acid form), for example a commercial sulphonic resin with a polystyrene support. or styrene / divinylbenzene polymer support; but it is also possible to use a mineral acid such as hydrochloric acid or sulfuric acid in a lower alkanol, or perchloric acid in attic acid, or a sulphonic acid such as para-toluenesulphonic acid.

 The oxidizing agent is preferably a peracid such as metachloroperbenzoic acid, peracetic acid or perphthalic acid. It is also possible to use hydrogen peroxide alone or in the presence of hexachloro or hexafluoroacetone.

 Of course, depending on the number of functions that can be oxidized, one or more equivalents of oxidizing agent can be used.

 For example, if it is desired to oxidize the sulfur atom that R 1 comprises to sulfone and the epoxide double bond, it is of course necessary to use at least three equivalents of oxidizing agent.

 The action of hydroxylamine or an alkylated derivative of hydroxylamine, preferably 1-methylhydroxylamine is preferably carried out in an alcohol such as ethanol. A salt is also preferably used, in particular hydroxylamine hydrochloride.

 The possible hydrolysis and salification of the products in which R3 comprises an esterified carboxy radical is carried out under the usual conditions.

 The hydrolysis may be carried out under reflux of an organic solvent such as benzene, in the presence of an acid such as para-toluenesulphonic acid.

 Basic hydrolysis can also be used in the presence of a base followed by acidification.

 Salification is carried out under usual conditions. One can operate for example in the presence of ethanolic sodium hydroxide. It is also possible to use a sodium salt such as sodium or potassium carbonate or acidic carbonate.

 In the same way salification with an acid is carried out under the usual conditions. It is preferably carried out with hydrochloric acid, for example in ether solution.

 In a preferred embodiment, the above process is carried out using products of formula II in which R '3 represents a hydroxyl radical, R4 represents a propynyl radical, R2 represents a methyl radical and R5 represents a hydrogen atom. or those in which R '3 represents an acetyl radical, R 4 represents a methyl radical or a hydrogen atom and R 1 represents an optionally substituted phenyl radical, and finally those in which the radical R 1 represents a cyclopropyl, a phenyl group optionally substituted with 1 one of the radicals selected from the group consisting of chloro, fluoro, methylthio, methylsulfonyl, methoxy, hydroxy and allyloxy, or a chlorothienyl group and R4 represents a propynyl radical.

 The products of formula I as well as their addition with pharmaceutically acceptable acids are products of particular interest from the pharmacological point of view; they possess in particular a remarkable anti-glucocorticoid activity as shown by the results of the tests set out below.

 The study of the products on the hormonal receptors made it possible to highlight activities progestomimetics or anti progestomimetics, androgens or antiandrogens.

 The products of formula I and their addition salts with pharmaceutically acceptable acids can therefore be used as medicaments to fight mainly against the side effects of glucocorticoids, they also make it possible to fight against the disorders due to hypersecretion of glucocorticoids and in particular against aging in general and more particularly against hypertension, atherosclerosis, osteoporosis, diabetes, obesity as well as immunosuppression and insomnia.

 The products of formula I and their pharmaceutically acceptable acid addition salts which possess antiprogestomimetic properties may be used as contraceptives; they can be used against hormonal disorders; they may also be of interest in the treatment of hormone-dependent cancers.

 Certain products of formula I and their addition salts with pharmaceutically acceptable acids may also have progestomimetic properties and may thus be employed in the treatment of amenorrhea, dysmenorrhea and luteal insufficiency.

 The products of formula I and their pharmaceutically acceptable acid addition salts which have anti-androgenic properties can be used in the treatment of hypertrophies and prostate cancer, hyperandrogenism, anemia and the like. , hirsutism and acne.

 The subject of the invention is therefore, as a medicament, the pharmaceutically acceptable products of formula I, that is to say non-toxic at the doses used, as well as their addition salts with pharmaceutically acceptable acids.

 More particularly, the subject of the invention is, as medicaments, the following products: - (4-chloro) phenyl / 175-hydroxy-17α- (prop-1-ynyl) estra 4,9-dien-3-one - (- 5-chloro) thienyl / 17ss-hydroxy 17α- (prop-1-ynyl) estra 4,9-dien-3-one - (3-chloro) phenyl-173-hydroxy 17- ( prop-1-ynyl) estra 4,9-dien-3-one-lys- [(4-methylthio) phenyl] -175-hydroxy-17α- (prop-1-ynyl) estra 4,9-dien-3-one - 11β - [(3-fluoro) phenyl] -175-hydroxy-17α- (prop-1-ynyl) estra 4,9-dien-3-one-N - [(4-methylthio) phenyl] -17a-methyl-19-nor, Pregna 4,9-diene 3,20-dione - (- 4-methylthio) phenyl-16α-methyl 19-nor pregna 4,9-dien-3,30-dione cyclopropyl 175-hydroxy 17α- 1-ynyl) estra 4,9-dien-3-one -3β- (3-propenyloxy) phenyl-175-hydroxy-17α- (prop-1-ynyl) estra 4,9-dien-3-one-9a, αα-epoxy 175-hydroxy-11ss- (4-methoxyphenyl) -17α- (propyl-ynyl) estra 4-en-3-one-9α, 10α-epoxy 17β-hydroxy-11β- (4-methylsulfonyl) phenyl 17a (prop 1-ynyl) estra 4-en-3-one - (3-fluoro) phenyl-3-hydroxyimino 17α- (prop-1-ynyl) estra 4.9-dien-175-ol isomerized anti-175-hydroxy 17a - (prop-1-ynyl) 1 - 15- (4-hydroxyphenyl) estra 4,9-dien-3-one and especially 17β- (4-methylthio) phenyl / 175-hydroxy-1-propanol -ynyl) estra 4,9-dien-3-one.

 The dosage varies with the condition being treated and the route of administration; it may vary for example from 10 mg to 1 g per day in the adult orally.

 The new products of formula I, and their salts, as defined above can be used to prepare pharmaceutical compositions containing, as active ingredient, at least one of said products.

 The products of formula I and their salts are used digestive, parenteral or local. They may be prescribed in the form of simple or coated tablets, capsules, granules, suppositories, injectables, ointments, creams, gels, 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.

 The invention therefore relates to pharmaceutical compositions containing as active ingredient at least one product of formula I.

dans laquelle R'1 représente soit un radical thiényle éventuellement substitué, un radical furyle un radical cycloalkyle ayant de 3 à 6 atomes de carbone, un radical phényle éventuellement substitué par un ou plusieurs radicaux choisis parmi les radicaux halogène, hydroxyle éventuellement protégé, trifluorométhyle, alkyle, alkoxy, alkylthio ou alkényloxy ayant au plus 6 atomes de carbone et phényloxy soit R'1 représente un radical naphtyle ou diphényle ou un radical alkyle ou alkényle portant éventuellement plusieurs insaturations ayant au plus 6 atomes de carbone,
R2 représente un radical méthyle ou éthyle et ou bien R" 3 représente un atome d'hydrogène, un radical alkyle, alkényle ou alkynyle éventuellement substitué, un radical hydroxyle, acétyle éventuellement protégé sous forme de cétal, hydroxyacétyle, carboxy alkoxy ayant de 2 à 4 atomes de carbone estérifié, acyloxy alkyle et
R'4 représente un atome d'hydrogène, un radical hydroxyle, un radical alkyle, alkényle ou alkynyle ayant au plus 12 atomes de carbone, éventuellement substitué par un radical alkylamino ou dialkylamino,par un halogène, un radical alkylthio, alkoxy ou trialkylsilyl, ou bien R3 représente un radical cyano et R'4 un groupement OH bloqué sous forme d'éther facilement clivable
R5 représente un atome d'hydrogène ou un radical méthyleen position a OU ss ;
K représente un groupement cétonique bloqué sous forme de cétal, de thiocétal, d'oxime ou de méthyloxime à l'exception des produits dans lesquels K représente un radical (1,2éthanediyl) acétal et R5 représente un atome d'hydrogène et a) R2 représente un radical méthyle et
a) R"3 représente un radical cyano, R'4 représente un radical triméthylsilyloxy et R1 représente un radical phényle, méthyle, éthyle, propyle, isopropyle, tert-butyle,- vinyle, allyle, isopropényle o-ou p-méthoxyphényle, thiényle, méthoxyvinyle, p-fluoro phényle
8) 3 représente un radical hydroxy et R'4 représente un radical éthynyle et R'1 représente un radical éthyle, propyle, isopropyle, vinyle, isopropényle, allyle, o- ou p-méthoxyphényle ou thiényle
r) R" 3 représente un radical acétyle et i)R'4 représente un radical hydroxyle et R'1 représente un radical éthyle, phényle ou vinyle ou
ii)R'4 représente un radical méthyle et R'1 représente un radical vinyle ; b) R2 représente un radical éthyle et
R" 3 représente un radical hydroxyle, R'1 représente un
3 radical vinyle et R'4 représente un atome d'hydrogène.The subject of the invention is also, as new industrial products and especially as intermediates necessary for the preparation of the products of formula I, as defined above, the products of general formula IIa:

in which R'1 represents either an optionally substituted thienyl radical, a furyl radical, a cycloalkyl radical having from 3 to 6 carbon atoms, a phenyl radical optionally substituted by one or more radicals chosen from halogen, optionally protected hydroxyl, trifluoromethyl radicals, alkyl, alkoxy, alkylthio or alkenyloxy having at most 6 carbon atoms and phenyloxy or R'1 represents a naphthyl or diphenyl radical or an alkyl or alkenyl radical optionally bearing several unsaturations having at most 6 carbon atoms,
R2 represents a methyl or ethyl radical and either R "3 represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical, a hydroxyl radical, acetyl optionally protected in the form of a ketal, hydroxyacetyl or carboxyalkoxy having from 2 to 4 esterified carbon atoms, acyloxy alkyl and
R'4 represents a hydrogen atom, a hydroxyl radical, an alkyl, alkenyl or alkynyl radical having at most 12 carbon atoms, optionally substituted by an alkylamino or dialkylamino radical, with a halogen, an alkylthio, alkoxy or trialkylsilyl radical, or else R3 represents a cyano radical and R'4 a blocked OH group in the form of an easily cleavable ether
R5 represents a hydrogen atom or a methyl radical in a position s OR ss;
K represents a blocked keto group in the form of ketal, thioketal, oxime or methyloxime with the exception of the products in which K represents a (1,2-ethanediyl) acetal radical and R5 represents a hydrogen atom and a) R2 represents a methyl radical and
a) R "3 represents a cyano radical, R '4 represents a trimethylsilyloxy radical and R1 represents a phenyl, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, allyl, isopropenyl o- or p-methoxyphenyl, thienyl radical; , methoxyvinyl, p-fluoro phenyl
8) 3 represents a hydroxyl radical and R'4 represents an ethynyl radical and R'1 represents an ethyl, propyl, isopropyl, vinyl, isopropenyl, allyl, o- or p-methoxyphenyl or thienyl radical;
r) R "3 represents an acetyl radical and i) R'4 represents a hydroxyl radical and R'1 represents an ethyl, phenyl or vinyl radical or
ii) R'4 represents a methyl radical and R'1 represents a vinyl radical; b) R2 represents an ethyl radical and
R "3 represents a hydroxyl radical, R'1 represents a
3 vinyl radical and R'4 represents a hydrogen atom.

 Among these products, the substituents of the thienyl radical may be those described above. It is the same for cycloalkyl radicals and R'1 values identical to those of R1.

 The hydroxy radical can be protected by a conventional protective radical in organic chemistry. For example, acyl radicals such as acetyl, chloroacetyl, trifluoroacetyl and phenoxyacetyl radicals may be mentioned.

 Mention may also be made of radicals such as the tetrahydropyranyl, trityl, benzoyl, benzhydryl or trimethylsilyl radicals.

 The acyloxyalkyl radical that can represent R "3 is preferably the 1 acetoxyethyl radical.

 The easily cleavable ether that R'4 may represent is preferably trimethylsilyl.

 The keto group is preferably blocked as ethanediyl.

Among the products of formula 11a, those in which R "3 represents a hydroxyl radical, R '4 represents a propynyl radical, R5 represents a hydrogen atom and
R2 represents a methyl radical.

 With regard to the R '1 value, the cycloalkyl, especially cyclopentyl, values are preferably the phenyl value optionally substituted with one of the radicals chosen from the group formed by the chloro, fluoro, methylthio, methylsulfonyl, hydroxy methoxy and allyloxy radicals. finally chlorothienyl.

dans laquelle R2, R" 3, R'4 et R5 ont la signification indiquée ci-dessus d'un produit de formule (R'1)2 CuLi ou R'1 Mg Hal ou R'1Li
R'1 ayant la signification précédente et Hal représente un atome d'halogène, en présence d'une quantité catalytique d'halogénure cuivreux pour obtenir un produit de formule IIa, produit que si désiré l'on soumet, dans un ordre quelconque à l'une ou plusieurs des réactions suivantes a) action d'un complexe acétylure de lithium-éthylène diamine sur un produit dans lequel R''3 représente un radical cyano et R'4 un groupement OH bloqué sous forme d'éther facilement clivable pour obtenir un produit de formule Il a dans lequel R" 3 représente un radical hydroxyle et R'4 représente un radical éthynyle; ou b) action d'un halogénure de méthyl magnésium sur le même produit dans lequel R''3 représente un radical cyano et R'4 représente un groupement OH bloqué sous forme d'éther facilement clivable pour obtenir un produit dans lequel R" 3 représente un radical acétyle et R'4 représente un radical hydroxyle;
c) déprotection des groupements hydroxyle ou acétyle protégés.The products of formula IIa may be prepared by action on a product of formula III

in which R2, R "3, R'4 and R5 have the meaning indicated above of a product of formula (R'1) 2 CuLi or R'1 Mg Hal or R'1Li
R'1 having the above meaning and Hal represents a halogen atom, in the presence of a catalytic amount of cuprous halide to obtain a product of formula IIa, product that if desired is subjected, in any order to one or more of the following reactions: a) action of a lithium ethylenediamine acetylide complex on a product in which R '' 3 represents a cyano radical and R'4 a blocked OH group in the form of an easily cleavable ether to obtain a product of formula II in which R "3 represents a hydroxyl radical and R '4 represents an ethynyl radical, or b) action of a methyl magnesium halide on the same product in which R''3 represents a cyano radical and R'4 represents a blocked OH group in the form of an easily cleavable ether to obtain a product in which R "3 represents an acetyl radical and R '4 represents a hydroxyl radical;
c) deprotection of the protected hydroxyl or acetyl groups.

When the compound of formula (R'1) 2CuLi is used, the reaction is preferably carried out at a temperature of between -100 ° C. and 0 ° C.
When using the compound of formula R'1Mg Hal,
Hal is preferably a bromine or chlorine atom and the operation is carried out in the presence of a catalytic amount of cuprous chloride or bromide, preferably at a temperature between -400C and 0OC.

 When using the compound of formula R'1Li, the reaction is carried out in the presence of a catalytic amount of chloride or cuprous bromide at a temperature between -40 ° C and OOC.

 The cuprous halide is optionally provided in the form of a complex with a dialkyl sulfide.

 In all cases, the operation is preferably carried out in an organic solvent or a mixture of solvents such as, for example, ethyl ether, isopropyl ether or tetrahydrofuran. In a preferred embodiment of the process of the invention: when R'1 represents a radical different from the allyl radical, the compound of formula R'1b1gBr is used, in order to introduce the substituent la, in the presence of a catalytic amount of cuprous chloride, operating at a temperature between -400C and -200C in ethyl ether and / or tetrahydrofuran, when R'1 represents the allyl radical, the compound of formula (R'1) is used to introduce the substituent at 115 2Culi, operating at a temperature between -90 C and -100C.

dans laquelle K, R'1, R2 et R5 ont la signification précédente. Les produits de formule IV peuvent être préparés par action d'un produit de formule (R'1)2CuLi, R'1MgHal ou
R'1Li dans les conditions indiquées précédemment sur un produit de formule V

The products of formula II in which R "3 represents a hydroxyl radical and R '4 represents an alkyl, alkenyl or alkynyl radical having at most 12 carbon atoms can also be obtained by the action of an alkyl halide, alkenyl, or alkynyl magnesium on a product of formula IV

wherein K, R'1, R2 and R5 have the above meaning. The products of formula IV may be prepared by the action of a product of formula (R'1) 2CuLi, R'1MgHal or
R'1Li under the conditions indicated above on a product of formula V

 The products of formulas III or V are, for many of them known in the literature or can be easily prepared from products of the literature.

dans laquelle Ri3 et Ri4 ont les valeurs précédemment indiquées pour R" 3 et R'4 ou Ri3 et Ri4 forment ensemble un radical céto.These products are prepared, generally by the action of an oxidant such as hydrogen peroxide in the presence of a catalyst or an organic peracid on a product of formula

wherein R13 and R14 have the previously indicated values for R3 and R4 or R13 and R14 together form a keto group.

 Examples of the preparation of starting materials III or V are given in the experimental section below.

In addition to the following examples which illustrate the invention without however limiting it, the following products constitute products obtainable within the scope of the present invention.

<Tb>

<SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4
<tb> HO <SEP> CH3 <SEP> OH <SEP> -C = -CH
<tb><SEP> (I <SEP> -C = C-C1
<tb><SEP> -CH2-C = -CH
<tb><SEP> -CH2-CH3
<tb><SEP> -CaC-SCH
<tb><SEP> 3
<tb><SEP> n <SEP>"<SEP>"<SEP> -C = C-CH2- <SEP> CH3
<tb><SEP> -CCH <SEP> -OH
<Tb>

<tb><SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4
<tb> OH
<tb><SEP> CH3 <SEP> CH3 <SEP> -C = CH <SEP> -OH
<tb><SEP> n <SEP> s <SEP> 0C-CH2OH <SEP> H
<tb><SEP>"<SEP>"<SEP> OH <SEP> -CC-H
<tb><SEP> -CC-CH3
<tb><SEP>"<SEP> ri <SEP>"<SEP> -C = C-Cl
<tb><SEP> i '<SEP> -CH2-C = CH
<tb><SEP> -CH2-CH3
<Tb>

<SEP> I
<tb> CH3S <SEP> + <SEP> CH3 <SEP> OH <SEP> -CH2-CH3
<Tb>

<tb> s <SEP> n <SEP> tr <SEP> -C = CH
<tb><SEP>"<SEP> (I <SEP>"<SEP> -CC-Cl
<tb><SEP> -C = C-CH2-CH3
<tb> -CH <SEP> 2-C = CH
<tb><SEP>"<SEP>"<SEP> -CH2-CH = CH2
<tb><SEP> -C = -CH <SEP> -OH
<tb><SEP> -C-CH26H <SEP> -H
<tb><SEP> O
<Tb>

<tb><SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4
<tb> CH3 <SEP> CH3 <SEP> -C-CH20H <SEP> H
<tb><SEP> 0
<tb>"" -OH -C # CH """-CH2-C#CH""" -CH2-CH # CH2
"""-CH2CH3""" -CH2CN ""# C-CH3 -CH3
O

<tb><SEP> OH <SEP> -CH <SEP> 2-C = -CH
<tb><SEP> ll
<tb><SEP> n <SEP> n
<tb><SEP> -CH <SEP> CH = CH2
<tb><SEP> ll
<tb><SEP> ll <SEP>"<SEP> -CH2CH3
<tb><SEP> CH2 <SEP> 3
<tb><SEP> ll <SEP> -CH2CN
<tb><SEP> ll
<tb><SEP> CH2CN
<tb> 9 <SEP> CH <SEP> O
<tb> HE <SEP> CH3 <SEP> OH <SEP> -CH2-CH = CH2
<tb><SEP> ll
<tb><SEP> ll <SEP> ll
<tb><SEP> I '<SEP> -CH2-C = CH
<tb><SEP> ll
<tb><SEP> 11 <SEP> -CH-2CH3
<tb><SEP> L <SEP> J
<tb><SEP> ll
<tb><SEP> -CH2CN
<tb><SEP> CH2CN
<tb><SEP> gl <SEP> / C-CH3 <SEP> -CH3
<tb><SEP> O
<Tb>
Preparation 1: 3,3-Ethylenebis (oxy) 17α- (prop-1-ynyl) 11ss- (2'-thienyl) estr 9-en Sa, 17ss-diol
To -50 ° C nitrogen (0.82 g) of cuprous chloride is introduced into 162 cm3 of thienyl magnesium bromide in tetrahydrofuran (1.05 M / l).

 It is stirred for 15 minutes and introduced dropwise so that the temperature does not rise above -200C a solution of 15 g of 3,3-ethylene bis (oxy) Sa, 10a-epoxy 17a (prop-1). -ynyl) is 9 (11) in 17ss-01 in 80 cm3 of tetrahydrofuran.

 It is left under nitrogen, stirred at -250C for 17 hours and then 2 hours at 0OC. It is then poured into an ice-cold aqueous solution of ammonium chloride.

 It is stirred, extracted with ether, the organic phase is washed with water, dried and concentrated under reduced pressure to give 18.8 g of crude product. Purification is carried out by chromatography on silica / eluent: chloroform-ethyl acetate (9-1) / and isolates 9, 85 g of product F = 2500C.

Preparation of the starting product
The 3,3-ethylene bis (oxy) -α, 10α-epoxy 17α (prop-1-ynyl) estr 9 (11) to 17β-ol used from Preparation 1 was prepared as follows: a) 3.3 bis methoxy 17a (prop-1-ynyl) estra 5 (10) 9 (11) dien178-ol
a) Propyne magnesium bromide:
350 cm3 of ethyl magnesium bromide solution in tetrahydrofuran (1.1 M / l) are introduced under nitrogen. Cooled to OOC and bubbled propyne for 2 hours maintaining the temperature at + 100C by an ice bath.

 The temperature is allowed to rise to 200 ° C. while continuing the bubbling of propyne.

s) Condensation
In the preceding solution is introduced at 200C in 50 minutes a solution of 50 g of 3,3-bis methoxy estra 5 (10) 9 (11) dien-17-one in 240 cm3 of tetrahydrofuran and 2 drops of triethylamine, stirred 75 minutes then poured into an ice-cold aqueous solution of ammonium chloride.

 It is stirred for 15 minutes and then extracted with ether and washed with a saturated solution of sodium hydrogen carbonate in water containing 2 drops of pyridine. It is dried under reduced pressure and 62.4 g of crude product are obtained. 974 mg of this product are chromatographed on silica / ethyl ether / petroleum ether eluent (bp 600.degree.-800.degree. C.) to give 744 mg. purified product which is recrystallized hot in a mixture containing 5.5 cm3 of isopropyl ether, 0.4 cm3 of methylene chloride and traces of pyridine. The mixture is filtered, concentrated, crystallized, filtered, washed with isopropyl ether, dried and gives 444 mg of pure product F = 1380C.

b) 3,3-ethylenebisoxyl, 17α-prop-1-ynyl) estra (10) 9 (11) dien-17ss-ol:
88.5 g of the product obtained above in a) are introduced under nitrogen into 442.5 cm3 of glycol. The mixture is heated to 600 ° C. with stirring and nitrogen and 4,425 g of pyridine hydrochloride are introduced. The mixture is left stirring for 15 minutes at 60 ° C. and then cooled to 20 ° C., during cooling (at 40 ° C.) 17.7 cm 3 of triethylamine are added. The suspension at 200C is poured into 3 1 of ice water.

 OOC is kept for 1 hour and then drained, washed with water, dried and gives 75.4 g of product F = 135-1400C.

c) 3,3-ethylene bis (oxy) 5α, 10α-epoxy 17α; (prop-1-ynyl) estr 9 (11) to 17ss-ol:
30 g of the product obtained above in (b) in 150 cm 3 of methylene chloride containing 2 drops of pyridine are cooled to 0 ° C. and then 1.8 g of hexafluoroacetone sesquihydrate are added and the mixture is then added dropwise. 4.35 cm3 of 85% hydrogen peroxide are added, the mixture is stirred at 0 ° C. for 72 hours and then poured into a mixture of 250 g of ice in 500 cm 3 of 0.2 N sodium thiosulphonate. The mixture is stirred and then extracted with methylene chloride.

The organic phase is washed, dried and concentrated under reduced pressure to give 31.6 g of expected product.

Preparation 2: 3,3-Ethylenebis (oxy) 11β- (p -fluorophenyl) 17α- (prop-1-ynyl) estr 9-en 5α-17ss-diol
P-Fluorophenyl magnesium bromide is reacted under the same conditions as in Preparation 1 on the same product 3,3-ethylene bis (oxy) Sa, 10α-epoxy 17α (prop-1-ynyl) estra 9 (11) in the presence of cuprous chloride in tetrahydrofuran.

 After chromatography, the expected product is obtained = = 57, 50 + 1.50 (c = 1% CHCl 3).

Preparation 3: 3,3-Ethylenebis (oxy) 11B- (p-trifluoromethylphenyl) 17α- (prop-1-ynyl) estr 9-en Sa, 17ss-diol
The procedure is as in Preparations 1 and 2 using p-trifluoromethyl phenyl magnesium bromide on the same product.

We obtain the expected product / &alpha; / D = -56 + 2.50
(c = 0.4% CHCl3).

Preparation 4: 3,3-bis-methoxy 11ss-methyl 17α- (prop-1-ynyl) estr 9-en Sa, 17s-diol
A mixture of 11.4 g of cuprous iodide in 120 cm 3 of ether is cooled under nitrogen to OOC and 69 cm 3 of methyl lithium at 1.74 M in ether are added over 30 minutes. The mixture is stirred for a further 10 minutes and then added dropwise in the course of 30 minutes to 5.5 g of 3,3-bis-methoxy-5α, 10α-epoxy 17α-propyl-ynyl-estra 9 (11) -17β-ol in 50 cm3 of tetrahydrofuran is left stirring for 2 hours at 0 ° C. and then poured into an ice-cold aqueous solution of ammonium chloride. Stir one hour at room temperature. Extracted with ether, washed, dried, concentrated to dryness under reduced pressure and obtained 5.7 g of crude product.

6.8 g of the product obtained as indicated above is chromatographed on silica / eluent methylene chloride-acetone
(9-1) to 1 #. of triethylamine. 4.05 g of expected product is obtained, mp = 155 ° C. / a, = 800 ° C. (c = 1% CHCl 3).

Preparation of the starting product
3,3-bis-methoxy-5α, 10α-epoxy 17α- (prop-1-ynyl) estr 9 (11) to 17β-ol used starting from Preparation 4 was prepared as follows
62.4 g of 3,3-bis methoxy 17a are introduced under nitrogen.
(prop-1-ynyl) estra 5 (10) 9 (11) dien-17ss-ol prepared in Preparation 1 in 280 cm3 of methylene chloride. It is cooled to 00 ° C. with stirring and 8.5 cc of hexafluoroacetone sesquihydrate are added in one go and then dropwise.
10.1 cm3 of hydrogen peroxide at 85%. The mixture is left stirring for 41 hours at 0 ° C., poured into a mixture of 1.4 l of 0.5 M sodium bisulfite solution, 200 g of ice and 5 drops of pyridine. It is stirred for 15 minutes and then extracted with methylene chloride containing 2 drops of pyridine. The organic phase is washed with water containing traces of pyridine, dried, concentrated under reduced pressure and 63.8 g of expected product are obtained.

Preparation 5: 3,3-bis-methoxy-11ss- (propa-1,2-dienyl) 17α (prop-1-ynyl) estr 9 en Sa, 17ss-diol:
a) Allenyl lithium (CH2 = C = CHLi)
300 ml of dry tetrahydrofuran are cooled to 0 ° C. and allene gas is bubbled through to dissolve about 18 to 20 g. Then cooled to -700C and added dropwise in 30 minutes 180 cm3 of n-butyl lithium in n-hexane at 1.35 N. Stir 1 hour at -700C.

ss) Diallenyl cuprolithian / CH2 = C = CH) 2 CuLi /
To the previous suspension, 24.66 g of di-methylsulfide complex, copper bromide, are introduced in small portions over about 15 minutes. It is stirred for another hour at -700C.

y) Condensation on the epoxide
A solution of 11 g of 3,3-bis (methoxy) -sa, 10a-epoxy-17α- (prop-1-ynyl) estr 9 (11) in 17 μl-ol in 60 cm 3 of sodium chloride is added dropwise at -700 ° C. in 10 minutes. dry tetrahydrofuran and allowed to slowly return to -200C (approximately (+5 C) .There is a nitrogen under nitrogen for 18 hours at this temperature.

 It is then poured with stirring into an ice-cold aqueous solution of ammonium chloride. After stirring for 1 hour at ambient temperature, the mixture is extracted with ether, washed, dried and concentrated to dryness under reduced pressure.

 11.2 g of expected crude product are obtained.

 Chromatography on silica (eluent: methylene chloride-acetone 9-1 to 1 # triethylamine). 6.6 g of expected product are obtained.

= = -250 + 1 (c = 1%, CHCl3)
Preparation 6: 3,3-bis-methoxy 17α- (prop-1-ynyl) 11ss-tert-butyl estr 9-en 5α, 17s-diol
The procedure is as indicated in Preparation 1 starting from 13.8 cm3 of 0.65 M tert-butyl magnesium chloride in tetrahydrofuran and 1.1 g of 3,3-bis methoxy 5a, 10aepoxy 17a (prop-1). -ynyl) estra-9 (11) at 175-ol. After stirring for 3 hours at -20 ° C., the expected product is obtained.
Mp = 148-150C.

Preparation 7: 3,3-bis methoxy 11ss- (2-furyl) 17α- (prop-1-ynyl) estr 9-en Sa, 17s-diol
The procedure is as in Preparation 5, the cupolithian difuryl is condensed on the same product 3,3-bis methoxy Sa, 10a-epoxy 17a (prop-1-ynyl) estra 9 (11) to 17a-ol.

 The expected product is obtained / a / D = 620 + 1.50 (c = 1% CHCl 3).

Preparations 8 to 28
By operating as in Preparation 1, the following products are obtained: See tables on pages 24 to 27.

Preparation 29: 3,3-Ethylenebis (oxy) 17α-trimethylsilyloxy 11ss- (2'-methylprop-1'-enyl) 5-α-hydroxy-9-ene 17ss carbonitrile
A solution of 0.95 M of 2-methyl prop-1-enyl lithium in ether is added dropwise at -400 ° C. to a solution of 3.1 g of dimethylsulfide-copper bromide complex suspended in 30 cm3. of tetrahydrofuran. 4.16 g of 3 - [(1,2-ethanediyl) acetal] of 5α, 10α-epoxy 17α-trimethylsilyloxy-175-cyano estr-9 (11) -3-one are added.

 After 30 minutes at -300C poured into a solution of ammonium chloride and extracted with ether. The organic phase is dried and the solvent is removed under reduced pressure. 5.45 g of crude product is obtained, 570 mg of which is purified by chromatography on silica (eluent: ethyl benzeneacetate 8-2) and 450 mg of pure product F = 154 ° C. are isolated.

Analysis: C28H42O4NSi
Calculated: C%: 69.38H%: 8.73 N%: 2.89
Found: 69.4 9.0 2.9
Preparation 29 A: 3,3-Ethylene bis (oxy) -17-ethynyl-1- (2'-methyl-prop-1-enyl) estr-9-en Sa, 17B-diol
The 5.45 g of crude product obtained in Preparation 29 is dissolved in 50 cm 3 of ethylenediamine. It is stirred under nitrogen at 50 ° C. and 6 g of lithium ethylenediamine acetylide complex are added in small portions.

CONDITIONS
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> OPERATIVES
<tb> Preparation <SEP> 8 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (4-methyl)
<tb> Bromide <SEP> of <SEP> 4- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;<SEP> 10 &alpha; - <SEP> phenyl / <SEP > 17 &alpha;-( prop-1-ynyl) <SEP> estr <SEP> 9-èn- <SEP> 2 <SEP> hours
<tb> methyl <SEP> phenyl <SEP> epoxy <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estra <SEP> 5 &alpha; -17ss-diol <SEP> F <SEP> = <SEP> 172 C <SEP> to <SEP> -20 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -70 <SEP>#<SEP> 1, <SEP> (c <SEP> = <SEP> 0.9 <SEP>%, CHCl3)
<tb> Preparation <SEP> 9 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (3-methyl)
<tb> 1 <SEP> hour <SEP> 30
<tb> Bromide <SEP> of <SEP> 3- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;<SEP> 10 &alpha; - <SEP> phenyl / <SEP > 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;
<tb> methyl <SEP> phenyl <SEP> epoxy <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estra <SEP> 17ss-diol <SEP> F <SEP> = <SEP> 206 C <SEP > to <SEP> -20 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -72.5 <SEP>#<SEP> 1.5 <SEP> (c <SEP> = <SEP> 1 <SEP>%, CHCl3)
<tb> Preparation <SEP> 10 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- (4-chloro)
<tb> 1 <SEP> hour
<tb> Bromide <SEP> of <SEP> 4- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;<SEP> 10 &alpha; - <SEP> phenyl / <SEP > 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;
<tb> chloro <SEP> phenyl <SEP> epoxy <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estra <SEP> 17ss-diol <SEP> F <SEP> = <SEP> 180 C <SEP > to <SEP> -10 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -62 # <SEP> 2 <SEP> ( c <SEP> = <SEP> 1 <SEP>%, CHCl3)
<tb> Preparation <SEP> 11 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- (5-chloro
<tb> 18 <SEP> hours
<tb> Bromide <SEP> of <SEP> 2- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;<SEP> 10 &alpha; - <SEP> thienyl) <SEP > 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en
<tb> chloro <SEP> thien-5- <SEP> epoxy <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estra <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> F <SEP > = <SEP> 204 C <SEP> to <SEP> -10 C
<tb> yl <SEP> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = -23 <SEP>#<SEP> 1 <SEP> (c <SEP> = <SEP> 1 <SEP>%, CHCl3)
<tb> Preparation <SEP> 12: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- (3-chloro
<tb> 1 <SEP> hour
<tb> Bromide <SEP> of <SEP> 3- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;<SEP> 10 &alpha; - <SEP> phenyl) <SEP > 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en
<tb> chloro <SEP> phenyl <SEP> epoxy <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estra <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> F <SEP> = <SEP> 191 C <SEP> to <SEP> -20 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -67.5 <SEP>#<SEP> 2.5 <SEP> (c <SEP> = <SEP> 1 <SEP>%, <SEP> CHCl3)
<Tb>

CONDITIONS
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> OPERATIVES
<tb> Preparation <SEP> 13: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- (3-methoxy)
<tb> 1 <SEP> hour
<tb> Bromide <SEP> of <SEP> 3- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;<SEP> phenyl) <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;
<tb> methoxy <SEP> phenyl <SEP> epoxy <SEP> 17 &alpha;-(prop-1-ynyl)<SEP> estra <SEP> 17ss-diol <SEP> F <SEP> = <SEP> 228 C <SEP > to <SEP> -20 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -74 <SEP>#<SEP> 2 <SEP> (c <SEP> = <SEP> 0.5 <SEP>%, CHCl3)
<tb> Preparation <SEP> 14: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- (4-methoxy)
<tb> 2 <SEP> hours
<tb> Bromide <SEP> of <SEP> 4- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;<SEP> phenyl) <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr <SEP> 9-en <SEP> 5 &alpha;
<tb> methoxy <SEP> phenyl <SEP> epoxy <SEP> 17 &alpha;-(prop-1-ynyl)<SEP> estra <SEP> 17ss-diol <SEP> F <SEP> = <SEP> 226 C <SEP > to <SEP> -20 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -68 <SEP>#<SEP> 2, <SEP> (c <SEP> = <SEP> 1 <SEP>%, CHCl3)
<tb> Preparation <SEP> 15: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (3,4 <SEP> bis
<tb>#<SEP> 2 <SEP> hours
<tb> Bromide <SEP> of <SEP> 3,4- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;<SEP> methoxy) <SEP> phenyl / <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr
<tb> bis <SEP> methoxy <SEP> epoxy <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estra <SEP> 9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> F <SEP> = <SEP> 230 C <SEP> to <SEP> -15 C
<tb> phenyl <SEP> magnesium <SEP> 9 <SEP> (11) <SEP> en <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = -67 <SEP>#<SEP> 2 <SEP> (c <SEP> = <SEP> 0.85 <SEP>%, CHCl3)
<tb> Preparation <SEP> 16: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (3-trifluoro
<tb>#<SEP> 30 <SEP> minutes
<tb> Bromide <SEP> of <SEP> 3- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;<SEP> methyl) <SEP> phenyl / <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr
<tb> trifluoromethyl <SEP> epoxy <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estra <SEP> 9-en <SEP> 5 &alpha;<SEP> 17ss-diol <SEP> F <SEP> = <SEP> 179 C <SEP> to <SEP> - <SEP> 20 C
<tb> phenyl <SEP> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -58 <SEP>#<MS> 2 <SEP> (c <SEP> = <SEP> 0.8 <SEP>%, CHCl3)
<tb> Preparation <SEP> 17: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (3-trifloro)
<tb> 30 <SEP> minutes
<tb> Bromide <SEP> of <SEP> 3- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;,<SEP> methyl, <SEP > 4-chloro) <SEP> phenyl / <SEP> 17 &alpha; --( prop-1trifluoromethyl <SEP> epoxy <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> estra <SEP> ynyl) <SEP> estr -9-èn <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> to <SEP> -10 C
<tb> 4-chlorophenyl <SEP> 9 <SEP> (11) <SEP> εn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -47.5 <SEP>#<MS> 1.5 <SEP> (c <SEP> = <SEP> 0.9 <SEP>%, CHCl3)
<tb> magnesium
<Tb>

CONDITIONS
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> OPERATIVES
<tb> Preparation <SEP> 18: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- (2-naphthyl)
<tb> 30 <SEP> minutes
<tb> Bromide <SEP> of <SEP> 2- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;<SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;,<SEP> 17ss-diol
<tb> naphthyl <SEP> epoxy <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estra <SEP> F <SEP> = <SEP> 276.5 C <SEP> to <SEP> -15 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -14 <SEP>#<SEP> 2 <SEP> (c <SEP> = <SEP> 0.5 <SEP>%, CHCl3)
<tb> Preparation <SEP> 19: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (4-phenoxy)
<tb> 45 <SEP> minutes
<tb> Bromide <SEP> of <SEP> 4- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;<SEP> phenyl) <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;
phenoxy SEP phenyl SEP epoxy SEP 17 &alpha;> to <SEP> -10 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -68 <SEP>#<SEP> 1, <SEP> (c <SEP> = <SEP> 1 <SEP>%, CHCl3)
<tb> Preparation <SEP> 20: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss-phenyl <SEP> 17 &alpha; - <SEP> 3 <SEP> h. <SEP > 15 <SEP> mn
<tb> Bromide <SEP> of <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;<SEP> (prop-1-ynyl) <SEP> estr <SEP> 9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> to <SEP> -25 C
phenyl SEP magnesium SEP epoxy SEP 17 &alpha;<SEP> hours
<tb> 9 <SEP> (11) <SEP> èn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -74.5 <SEP>#<SEP> 2.5 <MS> (c <SEP> = <SEP> 0.5 <SEP>%, CHCl3) <SEP> to <SEP> 0 C
<tb> Preparation <SEP> 21: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss / (3-bromo)
<tb> 1 <SEP> night
<tb> Bromide <SEP> of <SEP> / (3- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;<SEP> 10 &alpha;<SEP> phenyl / <SEP> 17 &alpha;<SEP> (prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;
<tb> bromo) <SEP> phenyl / <SEP> epoxy <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> estra <SEP> 17ss-diol <SEP> to <SEP> -20 ° C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -61 <SEP>#<SEP> 1, <SEP> (c <SEP> = <SEP> 1.8, CHCl3)
<tb> Preparation <SEP> 22: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (4-bromo)
<tb> 30 <SEP> minutes
<tb> Bromide <SEP> of <SEP> / (4- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;<SEP> 10 &alpha;,<SEP> phenyl / <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr <SEP> 9-en <SEP> 5 &alpha;
<tb> bromo) <SEP> phenyl / <SEP> epoxy <SEP> 17 &alpha;-(prop-1-ynyl)<SEP> estra <SEP> 17ss-diol <SEP> to <SEP> -15 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -55 <SEP>#<SEP> 2 <MS> (c <SEP> = <SEP> 0.8 <SEP>%, CHCl3)
<Tb>

CONDITIONS
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> OPERATIVES
<tb> Preparation <SEP> 23: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss <SEP> / (4-methyl2 <SEP> hours
<tb> Bromide <SEP> of <SEP> 4- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;<SEP> thio) <SEP> pheyl / <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estrmethyl <SEP> thiophenyl <SEP> epoxy <SEP> 17 &alpha;-(prop-1-ynyl)<SEP> estra <SEP> 9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> F <SEP> = <SEP> 190 C <SEP> then <SEP> 214 C <SEP> to <SEP> - 20 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = -57 <SEP>#<SEP> 1.5 <SEP > (c <SEP> = <SEP> 1 <SEP>%, CHCl3)
<tb> Preparation <SEP> 24: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss (3-thienyl)
<tb> 1 <SEP> hour
<tb> Bromide <SEP> of <SEP> 3- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;<SEP> 10 &alpha;<SEP> 17 &alpha; (prop-1-ynyl) <SEP> estr <SEP> 9-en <SEP> 5 &alpha;,<SEP> 17ss-diol
<tb> thienyl <SEP> epoxy <SEP> 17 &alpha;-(prop-1-ynyl)<SEP> estra <SEP> F <SEP> = <SEP> 240 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -38 <SEP>#<SEP> 2, <SEP> (c <SEP> = <SEP> 1 <SEP>%, CHCl3)
<tb> Preparation <SEP> 25: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss-propyl <SEP> 17 &alpha;
<tb> 1 <SEP> hour
<tb> Bromide <SEP> of <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;<SEP> (prop-1-ynyl) <SEP> estr <SEP> 9-en <SEP> 5 &alpha;,<SEP> 17ss-diol
<tb> propyl <SEP> epoxy <SEP> 17 &alpha;-(prop-1-ynyl)<SEP> estra <SEP> F <SEP> = <SEP> 192 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -108.5 <SEP>#<SEP> 3 <SEP> (c <SEP> = <SEP> 1 <SEP>%, CHCl3)
<tb> Preparation <SEP> 26: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (3-fluoro
<tb> 1 <SEP> hour
<tb> Bromide <SEP> of <SEP> 3- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;<SEP> phenyl / <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr <SEP> 9-en <SEP> 5 &alpha;
<tb> fluoro <SEP> phenyl <SEP> epoxy <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estra <SEP> 17ss-diol <SEP> F <SEP> = <SEP> 228 C <SEP > to -15 C
<tb> magnesium <SEP> 9 <SEP> (11) <SEP> en <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -58.5 <SEP>#<SEP> 2.5 <SEP> (c <SEP> = <SEP> 1 <SEP>%, CHCl3)
<tb> Preparation <SEP> 27: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (3-phenyl45 <SEP> minutes
<tb> Bromide <SEP> of <SEP> 3- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;<SEP> oxy) <SEP> phenyl / <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr-9phenyloxy <SEP> epoxy <SEP> 17 &alpha; (prop-1-ynyl) <SEP> estra <SEP> èn-5 &alpha;,<SEP> 17ss-diol <SEP> F <SEP> = <SEP> 190 C <SEP> to <SEP> -20 C
<tb> phenyl <SEP> magnesium <SEP> 9 <SEP> (11) <SEP> en <SEP> 17ss-ol <SEP> / &alpha; / D <SEP> = <SEP> -59.5 <SEP>#<SEP> 1.5 <SEP> (c <SEP> = <SEP> 1 <SEP>%, <SEP> CHCl3)
<tb> Preparation <SEP> 28:
<tb> Bromide <SEP> of <SEP> 4- <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;,<SEP> 10 &alpha;<SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (4-phenyl)
<tb> 1 <SEP> hour
<tb> phenyl <SEP> phenyl <SEP> epoxy <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estra <SEP> phenyl / <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> estr-9-enmagnesium <SEP> 9 <SEP> (11) <SEP> εn <SEP> 17ss-ol <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> F <SEP> = <SEP> 165 C <SEP> to <SEP> -20 C
<tb> / &alpha; / D <SEP> = <SEP> -52 <SEP> + <SEP> 2 <SEP> (c <SEP> = <SEP> 1 <SEP>%, <SEP> CHCl3)
<tb> same temperature the reaction mixture is poured into a water-ice mixture and extracted with ether and then with chloroform.

The organic phases are dried and the solvent is evaporated under reduced pressure. The crude product is chromatographed on silica (eluent: benzene-ethyl acetate 7: 3 to 0.1% triethylamine) and 2.73 g of expected product is obtained
Rf: 0.3 which is recrystallized from isopropyl ether
M = 208 ° C. (0.26 g of 17-keto product is also obtained as a by-product).

Analysis: C26H3604
Calculated: C% 75.69 H% 8.80
Found: 75.9 8.8
Preparation 30: 3,3-Ethylene bis (oxy) 17α-trimethysilyloxy 11ss- (3-methoxyphenyl) 5α-hydroxy-9-en-17ss-carbonitrile:
The procedure is similar to that described in Preparation 1 from the same starting material as that of Preparation 29 and 3-methoxy phenyl magnesium bromide.

9.406 g of the desired product F = 1660C is thus obtained.

Analysis: C31H43N05Si
Calculated: C%: 69.23H%: 8.06 N%: 2.60
Found: 69.4 8.1 2.6
Preparation A: 3,3-ethylene bis (oxy) -α, 17α-dihydroxy-11β- (3-methoxyphenyl) 19-nor-pregn-9-en-20-one
20 cm3 of a solution of 1.3 M methyl magnesium bromide in tetrahydrofuran are concentrated to obtain a 2 M solution (7 cm 3 of tetrahydrofuran are removed). 2.79 g of the product obtained in Preparation 30 are added and refluxed overnight. 10 cm3 of 1.3 M magnesium solution are added and 5 cm3 of tetrahydrofuran are distilled off and the mixture is heated at 100 ° C. for 7 hours. It is hydrolyzed using an ice-cold aqueous solution of ammonium chloride, extracted with ether. dry and evaporate the solvent under reduced pressure.

 It is chromatographed on silica (eluent: benzene-ethyl acetate 6: 4 to 0.1% triethylamine) and 1.722 g of pure expected product is obtained which is recrystallized from an isopropyl ether / methylene chloride mixture. F 1900C.

Analysis: C293806
Calculated: C%: 72.17 H%: 7.94
Found: 72.5 8.0
Preparation 31: 3.20 bis ethylene ketal of 17α-methyl-11β-propyl Sa-hydroxy 19-nor pregn-9-en-3,20-dione
The procedure is similar to that described in Preparation 1 from the 3.20 bis ethylene ketal 17a-methyl 5 &alpha; α-epoxy 19-nor pregna-9 (11) η 3,20-dione and propylmagnesium bromide (2 hours at -300 ° C.).

Preparation of the starting product
The 3.20 bis ethylene ketal of 17α-methyl 5α, 10α-epoxy 19-nor pregna-9 (11) in 3.20 dione used from preparation 31 was prepared as follows a) 3.20 bis. ethylene ketal of 17α-methyl 19-nor pregna-5 (10) 9 (11) diene-3,20-dione:
1.5 g of para-toluenesulphonic acid monohydrate are added to a solution of 21 g of 17α-methyl 19-nor pregra 4,9-diene 3,20 dione in a mixture of 200 cm 3 of methylene chloride, 200 cm 3 of ethylene glycol and 100 cm3 of ethyl orthoformate. The reaction mixture is heated at reflux for 7 hours and 2 cm 3 of triethylamine are added. Part of the solvent is distilled off, water is added and the precipitate is collected by filtration, then washed with water, dissolved in methylene and dry. After addition of isopropyl ether and concentration, the expected product crystallizes (22.65 g). An analytical sample is obtained by chromatography then recrystallization from isopropyl ether F = 1750C.

Analysis: C25H3604
Calculated: C%: 74.96H%: 9.06
Found: 75.0 9.1 b) 3.20 bis ethylene ketal of 17α-methyl, 5α, 10α-epoxy 19-nor pregna-9 (11) -en 3.20 dione:
100 mg of the product obtained above in (a) are dissolved in 2 cm 3 of methylene chloride. 450 mg of sodium hydrogen carbonate are added and the mixture is stirred with OOC. 0.1 cc of chloral and then 0.1 cc of hydrogen peroxide (110 volumes) are added. The reaction is complete after 4 hours. The reaction mixture is poured into a solution of sodium thiosulfate, extracted with dry methylene chloride and the solvent evaporated under reduced pressure. 98 mg of expected epoxide is isolated.

Preparation 31 A: 3.20 bis ethylene ketal of 17α-methyl-11ss-vinyl 19-nor pregn-9-en-ol
The procedure is similar to that described in Preparation 1 starting from the starting material of Preparation 31 and vinyl magnesium bromide (2 hours at -30 ° C.).

 We obtain the expected product F = 192 C.

Analysis: C27H4005
Calculated: C%: 72.94% H: 9.07
Found: 72.7 9.2
Preparations 32 to 35: see table page 31
Preparation 36: N- (3,3-ethylenebisoxyl) -1ss- (3-methoxyphenyl) 17? - (proP-1-yns) 17S-estr-9-en? -Hydroxy-17-yl tert-butyl oxyacetate
A solution of 960 mg of 3,3-bis-bis-oxy-11- (3-methoxyphenyl) -17α- (prop-1-ynyl) estr-9-en-5α, 17β-diol prepared in Preparation 13 was cooled to -400 ° C. cm 3 of tetrahydrofuran, and 3.2 cm 3 of butyl lithium in n-hexane (1.25 M / l) are added dropwise, the mixture is allowed to come to room temperature and 1.3 cm 3 of tert-bromoacetate are added dropwise. butyl.

After 1 hour 30 minutes, it is poured into an aqueous solution of ammonium chloride, extracted with ether, washed, dried, evaporated to dryness, and the expected product is obtained.

CONDITIONS
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> OPERATIVES
<tb> Preparation <SEP> 32:
<tb> Bromide <SEP> of <SEP> 4- <SEP> 3,20-bis <SEP> ethylene <SEP> ketal <SEP> of <SEP> 17 &alpha;<SEP> 3,3, <SEP> 20, 20-bis <SEP> ethylene <SEP> bis <SEP> oxy <SEP> 17 &alpha; - <SEP> addition
<tb> methyl <SEP> thio- <SEP> methyl <SEP> 5 &alpha;,<SEP> 10 &alpha; -epoxy <SEP> 19-nor <SEP> methyl <SEP> 11ss- (4-methyl <SEP> thiophenyl) <SEP> 19- <SEP> drop <SEP> to
<tb> phenyl <SEP> megnium <SEP> pregna-9 (11) <SEP> en <SEP> 3,20-dione <SEP> nor <SEP> pregn-9-en-5 &alpha; -ol <SEP> drop
<tb> (prepared <SEP> as <SEP> to <SEP><SEP> prepared <SEP> to <SEP> -15 C
<tb> tion <SEP> 31)
<tb> Preparation <SEP> 33:
<tb> Dimethyl <SEP> 3,20-bis <SEP> ethylene <SEP> ketal <SEP> of <SEP> 16 &alpha;<SEP> 3,3, <SEP> 20,20-bis <SEP> ethylene <SEP > bis <SEP> oxy <SEP> 11ss,
<tb> 1 <SEP> hour
<tb> Cuprolithian <SEP> methyl <SEP> 5 &alpha;<SEP> 10 &alpha; -epoxy <SEP> 19-nor <SEP> 16 &alpha; -dimethyl <SEP> 19-nor <SEP> pregn-8-en <SEP > 5 &alpha; -ol
<tb> pregna-9 (11) <SEP> εn <SEP> 3,20-dione <SEP> F <SEP> = <SEP> 140 C <SEP> to <SEP> 0 C
<tb> describes <SEP> in <SEP> the <SEP> Patent <SEP> English
<tb> n <SEP> s.423.486
<tb> Preparation <SEP> 34:
<tb> Bromide <SEP> of <SEP> 4- <SEP> 3,30-bis <SEP> ethylene <SEP> ketal <SEP> of <SEP> 16 &alpha;<SEP> 3,3, <SEP> 20, 20-bis <SEP> ethylene <SEP> bis <SEP> oxy <SEP> 16 &alpha; 1 <SEP> hour
<tb> methyl <SEP> thio- <SEP> methyl <SEP> 5 &alpha;,<SEP> 10 &alpha; -epoxy <SEP> 19-nor <SEP> methyl <SEP> 11ss <SEP> (4-methyl <SEP> thiphenyl) <SEP> 19phenyl <SEP> magnesium <SEP> pregna-9 (11) <SEP> еn <SEP> 3,20-dione <SEP> nor <SEP> pregn-9-en-5 &alpha; -ol <SEP > F <SEP> = <SEP> 189 C <SEP> to <SEP> -15 C
<tb> describes <SEP> in <SEP> the <SEP> Patent <SEP> English
<tb> n <SEP> 2,423,486
<tb> Preparation <SEP> 35:
<tb> Cyclopropyl <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 5 &alpha;,<SEP> 10 &alpha; - <SEP> 11ss-cyclopropyl <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 30 <SEP> minutes
<tb> cuprolithian <SEP> epoxy <SEP> 17 &alpha;<SEP> (prop-1-ynyl) <SEP> estr-9 <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> estr-9-en-5 &alpha;,SEP> 17ss- <SEP> to <SEP> -70 C
<tb> (from <SEP> J. <SEP> Org <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> diol <SEP> and <SEP> 3 <SEP> h. <SEP> 30
<tb> Chem <SEP> 41, <SEP> p.3629 <SEP> to <SEP> -40 C
<tb> 1976)
<Tb>

CONDITIONS
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> OPERATIVES
<tb> Preparation <SEP> 39:
<tb> Bromide <SEP> of <SEP> 4- <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 5 &alpha;<SEP> 10 &alpha; - <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 11ss- (4-isopropyl <SEP> 1 <SEP> hour
<tb> isopropyl <SEP> epoxy <SEP> 17 &alpha;<SEP> (prop-1-ynyl) <SEP> estr- <SEP> phenyl) <SEP> 17 &alpha;-(prop-1-ynyl)<SEP> estr <SEP> 9-èn <SEP> 5 &alpha;,<SEP> to <SEP> -20 C
<tb> phenyl <SEP> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> 17ss-diol <SEP> F <SEP> = <SEP> 194 C <SEP> then
<tb> / &alpha; / D <SEP> = <SEP> -66.5 <SEP>#<SEP> 2.5 <SEP> (c <SEP> = <SEP> 0.5 <SEP>%, <SEP> CHCl3) <SEP> 1 <SEP> hour <SEP> 30
<tb> to <SEP> -0% C
<tb> Preparation <SEP> 40:
<tb> Bromide <SEP> of <SEP> 3- <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 5 &alpha;<SEP> 10 &alpha; - <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 11ss <SEP> (3-methyl <SEP> 1 <SEP> hour <SEP> 30
<tb> methyl <SEP> thio- <SEP> epoxy <SEP> 17 &alpha;<SEP> (prop-1-ynyl) <SEP> estr- <SEP> thiophenyl) <SEP> 17 &alpha; --( prop-1-ynyl ) <SEP> estr-9-en
<tb> to <SEP> -15 -20 C
<tb> phenyl <SEP> magnesium <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> 5 &alpha;<SEP> 17ss-diol <SEP> F <SEP> = <SEP > 250 C
<tb> / &alpha; / D <SEP> = <SEP> -65.6 <SEP>#<SEP> 2 <SEP> (c <SEP> = <SEP> 0.7%, <SEP> CHCl3)
<tb> Preparation <SEP> 41:
<tb> Bromide <SEP> of <SEP> 3- <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 5 &alpha;<SEP> 10 &alpha; - <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 11ss- / 3 (2-propenyl- <SEP> 16 <SEP> hours
<tb> (2-propenyl <SEP> epoxy <SEP> 17 &alpha;<SEP> (prop-1-ynyl) <SEP> estr- <SEP> oxy) <SEP> phenyl / <SEP> 17 &alpha;<SEP> ( prop-1-ynyl) <SEP> estr-9a <SEP> -20 C
<tb> oxy) <SEP> phenyl <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> еn <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> F <SEP> = <SEP> 165 C
<tb> magnesium <SEP> / &alpha; / D <SEP> = <SEP> -71 <SEP>#<SEP> 2.5 <SEP> (c <SEP> = <SEP> 0.8 <SEP>% , <SEP> CHCl3)
<tb> Preparation 42: 3,3-ethylene bis-oxy-11ss-thien-2-yl 17α-methyl-Sa, 21-dihydroxy-19-nor-pregn-9-en-20-one
300 mg of cuprous chloride are added to 40 cm 3 of 0.5 M thienyl magnesium bromide in tetrahydrofuran. Cooled to -200C - 250C and left in contact for 30 minutes. 2.02 g of 3,3-ethylenebis (oxy) 17α-methyl, 5α, 10α-epoxy 21-hydroxy-19nor pregn-9 (11) en-20-one are then added dropwise in 20 cm 3 of dry tetrahydrofuran solution. .

 Two hours are left in contact at -20 ° C. to 25 ° C. and then hydrolyzed with an aqueous solution of ammonium chloride.

Extracted with ethyl ether to obtain 2,218 g of resin which is chromatographed on silica (eluent: benzene-ethyl acetate 1: 1) and 701 mg of expected product. Rf = 0.29
F = 204 C.

Preparation of the starting material a) A mixture of 120 cm 3 of tetrahydrofuran and 6.6 cm 3 of N-cyclohexyl isopropylamine is cooled to -50 ° C. and 19.6 cm 3 of n-butyl lithium in hexane are added over 12 minutes. 8.9 g of 3,3-ethylene bis (oxy) 17α-methyl-nor-prene S (10) 9 (11) dien-20-one are then stirred and added.

 The mixture is stirred for one hour at -35.degree. C. to 400.degree. C. and then 17.4 g of oxidation / oxodiperoxo pyridino (hexamethylphosphoramido) molybdenum VI reagent, described in Bull. Soc. 1481 (1969) and stirred at -300 ° C. to 350 ° C. for 1 hour 30 minutes, then poured into ice water, extracted with ethyl acetate, washed, then dried and concentrated to dryness.

 The residue is chromatographed on silica (eluent benzene) and 4.03 y of product used as is for the next stage.

b) A solution of 1.826 g of 3,3-ethylenedioxy-17α-methyl-21-hydroxy-19-nor pregn-5 (10) 9 (11) -dien-20-one obtained in 18 above is cooled to 00 / +5 ° C., 3 cm3 of methylene chloride and added 7.8 cm3 of a molar solution of hexafluoroacetone hydroperoxide in methylene chloride.

75 minutes are left at 00 / +5 ° C. and then 0.5M sodium thiosulfate is poured into a solution. It is extracted with chloroform, washed, dried and obtained 2.02 g of product used as such.

CONDITIONS
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> OPERATIVES
<tb> Preparation <SEP> 43:
<tb> Bromide <SEP> of <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 5 &alpha;,<SEP> 10 &alpha; - <SEP> 3,3-ethylene <SEP> bis <SEP > oxy <SEP> 11ss-cyclopentyl
<tb> immediate
<tb> cyclopentyl <SEP> epoxy <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr- <SEP> 17 &alpha;-(prop-1-ynyl)<SEP> estr-9-en <SEP> 5 &alpha; 17ssmagnesium <SEP> 9 <SEP> (11) <SEP> εn <SEP> 17ss-ol <SEP> diol <SEP> to <SEP> -30 ° C
###
<tb> Preparation <SEP> 49 ::
<tb> Bromide <SEP> of <SEP> 4 <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 5 &alpha;,<SEP> 10 &alpha; - <SEP> 3,3-ethylene <SEP > bis <SEP> oxy <SEP> 11ss / 4 (3-methyl)
<tb> 1 <SEP> hour
<tb> (3-methyl <SEP> butyl <SEP> epoxy <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr- <SEP> butyl <SEP> thiophenyl / <SEP> 17 &alpha; -1-ynyl)
<tb> to <SEP> -20 C
<tb> thio) <SEP> phenyl <SEP> 9 <SEP> (11) <SEP> еn <SEP> 17ss-ol <SEP> estr-9-en <SEP> 5 &alpha;<SEP> 17ss-diol
<tb> magnesium <SEP> / &alpha; / D <SEP> = <SEP> - <SEP> 52 <SEP>#<SEP> 1.5 <SEP> (c <SEP> = <SEP> 0.5 <SEP>%,<SEP> CHCl3)
<Tb>
Preparation 48: 2 R -acetoxy 3,3-ethylene bis (oxy) 11ss- (3-methyloxyphenyl) 17α-methyl 19-nor-pregn-9-en-5α-ol
The reaction is carried out as indicated above starting from 80 cm 3 of 3-methyloxyphenyl magnesium bromide at 0.9 M in tetrahydrofuran and 7.5 g of 20 R acetoxy 5a, 10 α-epoxy 3,3-ethylenebisoxygen 17α-methyl 19-nor pregn-9 (11) ene. After stirring for 18 hours at -200 ° C., 5.4 g of expected product which can be crystallized from ether are obtained after pressure chromatography. F = 1600C.

 / X / D = +19.50 + 1 (c = 1%, CHCl3).

Preparation of the starting material a) 2.7 g of paratoluene sulfuric acid hydrate and then 40 cm 3 of methylene chloride are added with stirring at 25 ° C. to a suspension of 45 g of 20 R acetoxy 17a-methyl pregna-4,9 dien -3-one in 180 cm3 of glycol and 180 cm3 of ethyl orthoformate.

 Stirred 45 minutes at room temperature under nitrogen and then added 10 cm3 of triethylamine.

 The solvent is removed under reduced pressure. 500 cm3 of ice-cold water are added over one hour and the mixture is poured with stirring into 2 liters of ice-cold water containing pyridine.

 After stirring at 0 ° C., the mixture is filtered off with suction, washed and dried to obtain 50.5 g of product which is recrystallized by dissolution at reflux in 10 cm 3 of isopropyl ether with 1 μl of triethylamine and cold recrystallization. 450 mg of expected product is obtained. F = 1480C.

 = = +1210 + 3.50 (c = 0.5%, CHCl3).

b) A mixture of 40 g of 20 R acetoxy-3,3-ethylenebisoxy-17a-methyl-19-norpregna 5-9 diene prepared above and 200 cm.sup.3 of methylene chloride containing 0.1 cm.sup.3 of pyridine was cooled to 0.degree. 2.5 cc of hexafluoroacetone sesquihydrate and 1 cc of 85% hydrogen peroxide are added, followed by 0.1 cc of pyridine. The mixture is stirred for 6 to 7 hours at 0 ° C., the mixture is poured into 1.5 l of 0.2 M sodium thiosulfate solution, 500 g of ice and 1 cm 3 of pyridine.

 The mixture is stirred for 10 minutes at ambient temperature and then decanted, extracted with methylene chloride, washed with 0.2 M sodium thiosulphate solution, dried, concentrated to dryness under reduced pressure and 44 g of crude product are obtained.

It is taken up in 40 cm 3 of 1% isopropyl ether of pyridine at 60 ° C. and then allowed to return to ambient temperature. 27.6 g of expected product are obtained. F = 1660C.

 = = 4.50 + 1 (c = 1%, CHCl3).

Preparation 55: 17α-3- (dimethylaminoprop-1-ynyl) 5α, 17ss-dihydroxy-11ss- (3-methoxyphenyl) estr-9-en-3-one / 17α-cyclic acid-1,2-ethanediyl acetal 3,3-ethylene bis-oxy-11ss- (3-methoxy) phenyl 5α-hydroxy-9-en-17-one
A mixture of 5 g of 3,3-ethylene bis (oxy) 5α, 10α-epoxy estr9 (11) en-17-one in 50 cm 3 of tetrahydrofuran containing 310 mg of cuprous chloride and 195 mg is stirred until dissolution at room temperature. of lithium chloride.

Cooled to -200C and added dropwise 31 cm3 of a 0.75 M solution of 3-methoxyphenyl magnesium bromide in tetrahydrofuran.

 Leave one hour at -20: C, warm to -150C then add the same amount of magnesium.

 It is poured into an ice-cold aqueous solution of ammonium chloride, stirred, extracted with ether and then with methylene chloride, the organic phase is washed with saturated aqueous sodium chloride solution, dried and the solvent is evaporated off.

 After chromatography, the expected product is obtained.

b) / 17α-β- (dimethylaminoprop-1-ynyl) 5α-alfa, 17ss-dihydroxy-11ss- (3-methoxyphenyl) estr-9-en-3-one: cyclic 1,2-ethanediyl acetal:
30 ml of 0.67 M / l lithium diisopropylamide in ether (made according to J. Org Chem, 43, 704 (1978)) and slowly adding 3.9 cm 3 of N, N- The temperature is allowed to rise to 0.degree. C. and then cooled to -400.degree. C. and then 4 g of 3,3-ethylenebisoxyl-11ss- (3-methoxy) -phenyl-6-hydroxy-estran-17-one are added dropwise. above in solution in 11 cm3 of tetrahydrofuran.

 The temperature is allowed to rise to OOC in 1 hour, poured into 500 cm3 of a saturated solution of ammonium chloride, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried, evaporated on solvent and 4.9 g of expected product. 600 mg of this product are chromatographed on silica (eluent: methylene chloride-methanol 92: 8) gives 200 mg of pure product.

 = -62 # 2.5 (c = 0.5%, CHCl3).

Analysis
Calculated: C%: 73.6H%: 8.3
Found: 73.3 8.3
Preparation 57: // 3,3-ethylene bis-oxy-11ss- (4-hydroxyphenyl) 17α- (prop-1-ynyl) estr-9-en-5α, 17ss-diol //: a) Preparation of 4-bromide trimethylsilyloxy phenyl magnesium
7.8 g of p-bromophenol dissolved in 15 cm3 of tetrahydrofuran and then 5.75 cm3 of trimethylsilyl chloride are added to 50 cm3 of a 0.9% solution of isopropyl magnesium chloride in tetrahydrofuran. The solution is poured onto 1.2 g of magnesium in turn. A little 1,2-dibromoethane and then 2 cm3 of hexamethyl phosphotriamide are added and the mixture is then refluxed for 2 hours 30 minutes.

b) // 3,3-ethylene bis-oxy-11ss- (4-hydroxyphenyl) 17α- (prop-1-ynyl) estr-9-en-5α, 17ss-diol //
350 mg of cuprous chloride and then 1.45 g of 3,3-ethylene bis (oxy) a, 10α-epoxy 17α- (prop-1-ynyl) estr9 (11) in 17β-ol dissolved in 15 cm3 of tetrahydrofuran are added. 75 cm3 of the magnesium solution described above.

 Poured into an aqueous solution of ammonium chloride, extracted with ether, the organic phase washed with N sodium hydroxide solution. Dry and evaporate the solvent under reduced pressure.

 After chromatography on silica (eluent: ethyl benzeneacetate 7-3), 207 mg of sought product is isolated.

Analysis: C29H3605
Calculated: C%: 74.97% H: 7.81
Found: 75.0: 7.9: &sub5; / D = = -58.50 + 2.50 (c = 0.5%, CHCl 3)
Example 1: 17ss-hydroxy 17α-prop-1-ynyl) 11ss- (2'-thienyl) estra 4,9-dien-3-one:
9.85 g of the product obtained in Preparation 1 are introduced into 330 cc of ethanol at 950. The mixture is refluxed and 9.85 g of Redex CF resin are added all at once. The mixture is refluxed under stirring and nitrogen for 4 hours. It is filtered, rinsed with absolute alcohol and concentrated under reduced pressure.

9 g of crude product are obtained, which is chromatographed on silica (eluent: chloroform-ethyl acetate 9-1). 6.5 g of expected product are isolated and recrystallized from isopropyl ether. It is filtered off with isopropyl ether, dried and obtained 5.315 g of pure product. F = 1920C.

Analysis: C25H2802S
Calculated: C%: 76.5H%: 7.18S z: 8.16
Found: 76.4 7.5 8.0 = = +830 + (1%, CHCl3).

DURATION
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> DU <SEP> REFLUX
<tb> Example <SEP> 2 <SEP>: <SEP> Ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss <SEP> (4- <SEP> 11ss- (4-fluorophenyl) <SEP> 17ss Hydroxyl-Sepharose 17-alpha-propfluorophenyl (SEP-17-alpha-prop-1-ynyl) SEP-estr-9-en SEP-1-ynyl) SEP-estra-SEP-4,9- dien <SEP> 3-one. <SEP> F <SEP> = <SEP> 135 -140 C <SEP> 2 <SEP> hours
<tb> 5 &alpha;<SEP> 17ss-diol <SEP> (preparation <SEP> 2) <SEP> then <SEP> 162 <SEP> / <SEP> 164 C
<tb> / &alpha; / D <SEP> = <SEP> +19 <SEP>#<SEP> 1.5 <SEP> (c <SEP> = <SEP> 0.8 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 3 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- (4- <SEP> 11ss - / (4-trifluoromethyl) <SEP> phenyl / <SEP> 17ss-hydroxy
<tb> tri <SEP> fluoromethyl <SEP> phenyl) <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> estra <SEP> 4,9- dien-3-one <SEP> 2 <SEP> hours
<tb> estr-9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 3) <SEP> F <SEP> = <SEP> 180 C <SEP> then <SEP> 218 C.
<Tb>

/ &alpha; / D <SEP> = <SEP> +29 <SEP>#<SEP> 1 <SEP> (c <SEP> = <SEP> 1 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 4 <SEP>: <SEP> 3,3-bis <SEP> methoxy <SEP> 11ss-methyl <SEP> 17 &alpha;<SEP> 11ss-methyl <SEP> 17ss-hydroxy <SEP> 17 &alpha;-(prop-1-ynyl)<SEP> 1 <SEP> hour
<tb> (prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;<SEP> 17ss <SEP> diol <SEP> estra <SEP> 4,9-dien-3-one <SEP > F <SEP> = <SEP> 213 C
<tb> 30 <SEP> minutes
<tb> (preparation <SEP> 4) <SEP> / &alpha; / D <SEP> = <SEP> -153 <SEP>#<SEP> 2.5 <SEP> (c <SEP> = <SEP> 1 , <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 5 <SEP>: <SEP> 3,3-bis <SEP> methoxy <SEP> 11ss- (propa-1,2- <SEP> 11ss- (propa <SEP> 1,2- dienyl) <SEP> 17ss-hydroxy <SEP> 17 &alpha;-( prop
<tb> dienyl) <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> estr <SEP> 9-en <SEP> 5 &alpha;<SEP> 17ss <SEP> 1-ynyl) <SEP> estra <SEP> 4,9-dien <SEP> 3-one <SEP> F <SEP> = <SEP> 133 C <SEP> 1 <SEP> hour
<tb> diol <SEP> (preparation <SEP> 5) <SEP> / &alpha; / D <SEP> = <SEP> +122 <SEP>#<SEP> 2 <SEP> (c <SEP> = <SEP > 0.9 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 6 <SEP>: <SEP> 3,3-bis-methoxy <SEP> 11ss-tert <SEP> butyl <SEP> 17 &alpha; - <SEP> 11ss-tert <SEP> butyl <SEP > 17ss-hydroxy <SEP> 17 &alpha;-( prop-1-ynyl)
<tb> 1 <SEP> hour
<tb> (prop-1-ynyl) <SEP> estr <SEP> 9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> estra-4,9-dien <SEP> 3-one <SEP > F <SEP> = <SEP> 168 C
<tb> (preparation <SEP> 6) <SEP> / &alpha; / D <SEP> = <SEP> - <SEP> 152 <SEP>#<SEP> 2.5 <SEP> (c <SEP> = <SEP> 1 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 7 <SEP>: <SEP> 3,3-bis <SEP> methoxy <SEP> 11ss- (2-furyl) <SEP> 11ss- (2-furyl) <SEP> 17ss-hydroxy <SEP> 17 &alpha;-( prop-1-ynyl)
<tb> 1 <SEP> hour
<tb> 17 &alpha;-( prop-1-ynyl) <SEP> estr <SEP> 9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> estra <SEP> 4,9-dien <SEP> 3-one <SEP> F <SEP> = <SEP> 208 C
<tb> (preparation <SEP> 7)
<tb> / &alpha; / D <SEP> = <SEP> +2.5 <SEP>#<SEP> 1 <SEP> (c <SEP> = <SEP> 1 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 8 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (4- <SEP> 11ss - / (4-methyl) <SEP> phenyl / <SEP> 17ss-hydroxy <SEP> 17 &alpha; 1 <SEP> hour
<tb> methyl) <SEP> phenyl / <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr <SEP> 9-en <SEP> (prop-1-ynyl) <SEP> estra <SEP> 4.9-dien <SEP> 3-one. <SEP> F <SEP> = <SEP> 232 C
<tb> 5 &alpha; -17ss-diol <SEP> (preparation <SEP> 8) <SEP> / &alpha; / D <SEP> = <SEP> +70 <SEP>#<SEP> 1.5 <SEP> ( c <SEP> = <SEP> 1 <SEP>%, <SEP> CHCl3) <SEP> 30 <SEP> minutes
<Tb>

DURATION
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> DU <SEP> REFLUX
<tb> Example <SEP> 9 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (3- <SEP> 11ss - / (3-methyl) <SEP> phenyl / <SEP> 17ss-hydroxy <SEP> 17 &alpha; methyl) <SEP> phenyl / <SEP> 17 &alpha;-(prop-1-ynyl)<SEP> estra-9- <SEP> (prop-1) -ynyl) <SEP> estra <SEP> 4,9-dien <SEP> 3-one <SEP> F <SEP> = <SEP> 182 C <SEP> 2 <SEP> hours
<tb> еn <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 9) <SEP> / &alpha; / D <SEP> = <SEP> +35 <SEP>#<SEP> 1 <SEP> (1 <SEP>% <SEP> in <SEP> CHCl3)
<tb> Example <SEP> 10 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (4- <SEP> 11ss - / (4-chloro) <SEP> phenyl / <SEP> 17ss-hydroxy <SEP> 17 &alpha; chloro) <SEP> phenyl / <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en <SEP> (prop- 1-ynyl) <SEP> estra <SEP> 4,9-dien <SEP> 3-one <SEP> F <SEP> = <SEP> 214 C <SEP> 45 <SEP> minutes
<tb> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 10) <SEP> / &alpha; / D <SEP> = <SEP> +87 <SEP>#<SEP> 2.5 <SEP> (c <SEP> = <SEP> 0.5 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 11 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- <SEP> 11ss (5-chlorothienyl) <SEP> 17ss-hydroxy <SEP> 17 &alpha;-( prop (5-chlorophenyl) <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> estr-9- (SEP) 1-ynyl) <SEP> estra <SEP> 4.9 -dinner <SEP> 3-one <SEP> 2 <SEP> hours
<tb> еn <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 11) <SEP> / &alpha; / D <SEP> = <SEP> +115.5 <SEP>#<SEP> 2 <SEP> (c <SEP> = <SEP> 1 <SEP>% <SEP> in <SEP> CHCl3)
<tb> Example <SEP> 12 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- (3- <SEP> 11ss- (3-chlorophenyl) <SEP > 17ss-bydroxy <SEP> 17 &alpha;-( propchlorophenyl) <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en <SEP> 1-ynyl) <SEP> estra <SEP> 4.9- dien <SEP> 3-one.Analysis <SEP>:
<tb> 45 <SEP> minutes
<tb> 5 &alpha;<SEP> 17ss-diol <SEP> (preparation <SEP> 12) <SEP> calculated <SEP> C% <SEP>: <SEP> 77.03 <SEP>, <SEP> H% <SEP>:

<SEP> 6.94 <SEP>, <SEP> Cl% <SEP>: <SEP> 8.42
<tb> Found <SEP>: <SEP> 76.8 <SEP> 7.0 <SEP> 8.4
#### CHCl3)
<tb> Example <SEP> 13 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- (3- <SEP> 11ss- (3-methoxyphenyl)] SEP > 17ss-hydroxy <SEP> 17 &alpha;-( propmethoxyphenyl) <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en <SEP> 1-ynyl <SEP> estra <SEP> 4.9 -dene <SEP> 3-one <SEP> F <SEP> = <SEP> 120 C <SEP> 1 <SEP> hour <SEP> 30
<tb> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 13) <SEP> / &alpha; / D <SEP> = <SEP> +45 <SEP>#<SEP> 1 <SEP> (c <SEP> = <SEP> 1 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 14 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- (4- <SEP> 11ss- <SEP> / 4-methoxyphenyl / <SEP> 17ss-hydroxy <SEP> 17 &alpha; methoxyphenyl) <SEP> 17 &alpha;-(prop-1-ynyl)<SEP> estr <SEP> 9-en <SEP> (prop-1-ynyl) <SEP> estra <SEP> 4,9-dien <SEP> 3-one <SEP> F <SEP> = <SEP> 120 C <SEP> 1 <SEP> hour <SEP> 30
<tb> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 14) <SEP> / &alpha; / D <SEP> = <SEP> +73 <SEP>#<SEP> 2 <SEP> (c <SEP> = <SEP> 1 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 15 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- <SEP> 11ss - / (3,4-bis <SEP> methoxy) <SEP> phenyl / <SEP> 17ss-hydroxy
<tb> / (3,4-bis <SEP> methoxy) <SEP> phenyl / <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> estra <SEP> 4.9 <SEP> dien <SEP> 3-one <SEP> 1 <SEP> hour <SEP> 15
<tb> estr <SEP> 9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 15) <SEP> F <SEP> = <SEP> 209 C
<tb> / &alpha; / D <SEP> = <SEP> +53.5 <SEP>#<SEP> 1.5 <SEP> (c <SEP> = <SEP> 1.2 <SEP>%, <SEP> CHCl3)
<Tb>

DURATION
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> DU <SEP> REFLUX
<tb> Example <SEP> 16 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- <SEP> 11ss - / (3-trifluoromethyl) <SEP> phenyl / <SEP> 17ss-hydroxy
<tb> / (3-trifluoromethyl) <SEP> phenyl / <SEP> 17 &alpha; --( prop-1- <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> estra <SEP> 4,9-dien <SEP> 3-one <SEP> 45 <SEP> minutes
<tb> ynyl) <SEP> estr-9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> F <SEP> = <SEP> 202 C
<tb> 16) <SEP> / &alpha; / D <SEP> = <SEP> +21.5 <SEP>#<SEP> 1 <SEP> (c <SEP> = <SEP> 0.9 <SEP> %, <SEP> CHCl3)
<tb> Example <SEP> 17 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- <SEP> 11ss - / (3-trifluoromethyl-4-chloro) <SEP> phenyl /
<tb> / (3-trifluoromethyl, <SEP> 4-chloro) <SEP> phenyl / <SEP> 17 &alpha; - <SEP> 17ss-hydroxy <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> estr -4.9-dien <SEP> 1 <SEP> hour
<tb> (prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> 3-one <SEP> F <SEP> = <SEP> 188 C
<tb> preparation <SEP> 17) <SEP> / &alpha; / D <SEP> = <SEP> +69 <SEP>#<SEP> 2.5 <SEP> (c <SEP> = <SEP> 0, 7 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 18 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- (2- <SEP> 11ss- (1-naphthyl) <SEP > 17ss-hydroxy <SEP> 17 &alpha;-( prop-1-ynyl)
<tb> naphthyl) <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;,<SEP> 17ss <SEP> estra <SEP> 4,9-dien <SEP > 3-one <SEP> F <SEP>##<SEP> 170 C <SEP> 30 <SEP> minutes
<tb> diol <SEP> (preparation <SEP> 18) <SEP> / &alpha; / D <SEP> = <SEP> +252 <SEP>#<SEP> 4 <SEP> (c <SEP> = <SEP > 1 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 19 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- <SEP> 11ss - / (4-phenoxy) <SEP> phenyl / <SEP> 17ss-hydroxy <SEP> 17 &alpha; / (4-Phenoxyphenyl) <SEP> 17 &alpha; - (prop-1-ynyl) <SEP> estr- <SEP> (prop-1-ynyl) <SEP> estra <SEP> 4,9-dien <SEP> 3 -one <SEP> 1 <SEP> hour
<tb> 9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 19) <SEP> / &alpha; / D <SEP> = <SEP> +73.5 <SEP>#SEP> 1.5 SEP (c <SEP> = <SEP> 0.8 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 20 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- <SEP> 11ss-phenyl <SEP> 17ss-hydroxy <SEP> 17 &alpha;-( prop-1-ynyl)
<tb> phenyl <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> estr <SEP> 9-en <SEP> 5 &alpha;,<SEP> 17ss- <SEP> estra <SEP> 4,9-dien -3-one <SEP> F <SEP> = <SEP> 190 C. <SEP> 1 <SEP> hour
<tb> diol <SEP> (preparation <SEP> 20) <SEP> / &alpha; / D <SEP> = <SEP> +35.5 <SEP>#<SEP> 2 <SEP> (c <SEP> = <SEP> 0.5 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 21 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss / (3- <SEP> 11ss - / (3-bromo) <SEP> phenyl / <SEP> 17ss-hydroxy <SEP> 17 &alpha; bromo) <SEP> phenyl / <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en <SEP> (prop-1) -ynyl) <SEP> estra <SEP> 4,9-dien <SEP> 3-one <SEP> Analysis:
<tb> 1 <SEP> hour
<tb> 5 &alpha;,<SEP> 17ss-diol <SEP> (Preparation <SEP> 21) <SEP> Calculated <SEP>: <SEP> C% <SEP>: <SEP> 69.67, <SEP> H % <SEP>: <SEP> 6.28, <SEP> Br% <SEP>: 17.17
<tb> Found <SEP>: <SEP> 69.7 <SEP> 6.3 <SEQ> 17.2
#### CHCl3)
<tb> Example <SEP> 22 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- <SEP> 11ss - / (4-bromo) phenyl / <SEP > 17ss-hydroxy <SEP> 17 &alpha;-( prop
<tb> / (4-bromo) <SEP> phenyl / <SEP> 17 &alpha; - (prop-1-ynyl) estr- (SEP) 1-ynyl) <SEP> estra <SEP> 4,9-dien <SEP > 3-one <SEP> F <SEP> = <SEP> 214 C <SEP> 1 <SEP> hour <SEP> 15
<tb> 9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 22) <SEP> / &alpha; / D <SEP> = <SEP> +88.5 <SEP># SEP 2 SEP (c SEP = SEP 1 SEP%, SEP CHCl 3)
<Tb>

DURATION
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> DU <SEP> REFLUX
<tb> Example <SEP> 23 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- <SEP> 11ss - / (4-methylthio) <SEP> phenyl / <SEP> 17ss-hydroxy <SEP> 17 &alpha;
<tb> / (4-methylthio) <SEP> phenyl / <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> (prop-1-ynyl) <SEP> estra <SEP> 4,9-dien <SEP> 3-one <SEP> F <SEP> = <SEP> 148-150C <SEP> 1 <SEP> hour
<tb> estr-9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 23) <SEP> / &alpha; / D <SEP> = <SEP> +135 <SEP>#<SEP> 2.5 <SEP> (c <SEP> = <SEP> 1 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 24 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- <SEP> 11ss- (3-thienyl) <SEP> 17ss- hydroxy <SEP> 17 &alpha;-( prop-1-ynyl)
<tb> (3-thienyl) <SEP> 17 &alpha; (prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;<SEP> estra <SEP> 4,9-dien <SEP> 3 -one <SEP> F <SEP> = <SEP> 202 C <SEP> 2 <SEP> hours
<tb> 17ss-diol <SEP> (preparation <SEP> 24) <SEP> / &alpha; / D <SEP> = <SEP> +91.5 <SEP>#<SEP> 2 <SEP> (1 <SEP >%, <SEP> CHCl3)
<tb> Example <SEP> 25 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- <SEP> 11ss-propyl <SEP> 17ss-hydroxy <SEP> 17 &alpha;-( prop-1-ynyl)
<tb> 1 <SEP> hour
<tb> propyl <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;<SEP> 17ss- <SEP> estr <SEP> 4,9-dien <SEP> 3-one <SEP> F <SEP> = <SEP> 141 C
<tb> diol <SEP> / &alpha; / D <SEP> = <SEP> -146.5 <SEP>#<SEP> 2.5 <SEP> (c <SEP> = <SEP> 0.75 <SEP >%, <SEP> CHCl3)
<tb> Example <SEP> 26 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- <SEP> 11ss - / (3-fluoro) <SEP> phenyl / <SEP> 17ss-hydroxy <SEP> 17 &alpha; / (3-fluoro) (SEP) phenyl / (SEP) 17α- (prop-1-ynyl) SE SEP-estr- (SEP) (prop-1-ynyl) SE SEP-estra-SEP-4,9- dien <SEP> 3-one <SEP> F <SEP> = <SEP> 172 C <SEP> 1 <SEP> hour <SEP> 30
<tb> 9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> / &alpha; / D <SEP> = <SEP> +25 <SEP>#<SEP> 2 <SEP> (0.5 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 27 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- <SEP> 11ss - / (3-phenyloxy) <SEP> phenyl / <SEP> 17ss-hydroxy <SEP> 17 &alpha; / (3-phenyloxy) <SEP> phenyl / <SEP> 17α-prop-1-ynyl) SEP> (prop-1-ynyl) SEP> estra <SEP> 4,9-dien <SEP> 3 -one. <SEP> Analysis
<tb> 1 <SEP> hour <SEP> 30
<tb> estr-9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 27) <SEP> Calculated <SEP>: <SEP> C% <SEP>: <SEP> 82.81, <SEP> H% <SEP>: <SEP> 7.16
<tb> Found <SEP>: <SEP> 82.6 <SEP> 7.3
#### CHCl3)
<tb> Example <SEP> 28 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss - / (4- <SEP> 11ss - / (4-phenyl) <SEP> phenyl / <SEP> 17ss-hydroxy <SEP> 17 &alpha; phenyl) &quot; SEP &quot;&quot; phenyl &quot; 17ss- <SEP> (prop-1-ynyl) <SEP> estra <SEP> 4,9-dien <SEP> 3-one <SEP> F = 240 C <SEP> 1 <SEP> hour
<tb> diol <SEP> (preparation <SEP> 28) <SEP> / &alpha; / D <SEP> = <SEP> +181.5 <SEP>#<SEP> 3 <SEP> (c <SEP> = <SEP> 1 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 29 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 11ss- (2'- <SEP> 11ss- (2'-methyl) SEP> prop-1-enyl) <SEP> 17ss-hydroxy
<tb> methyl <SEP> prop-1-enyl) <SEP> 17 &alpha; -ethynyl <SEP> estr-9-en <SEP> 17 &alpha; -ethynyl <SEP> estra <SEP> 4,9-dien <SEP> 3-one <SEP> F <SEP> = <SEP> 150 C
<tb> 35 <SEP> minutes
<tb> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 29A) <SEP> Analysis <SEP>: <SEP> Calculated <SEP> C% <SEP>: <SEP> 82,24 <SEP> H% <SEP>: <SEP> 8.63
<tb> Found <SEP> 82.1 <SEP> 8.5
<tb> / &alpha; / D <SEP> = <SEP> -212.5 <SEP>#<SEP> 3 <SEP> (c <SEP> = <SEP> 1%, <SEP> CHCl3)
<Tb>

DURATION
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> DU <SEP> REFLUX
<tb> Example <SEP> 30 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> (oxy) <SEP> 5 &alpha;, 17 &alpha; - <SEP> 11ss- (3-methoxyphenyl) <SEP> 17 &alpha; -hydroxy <SEP> 19-nor
<tb> dihydroxy <SEP> 11ss- (3-methoxyphenyl) <SEP> 19-nor <SEP> pregna <SEP> 4,9-dien-3,20-dione <SEP> F <SEP> = <SEP> 173 C <SEP> 1 <SEP> hour
<tb> pregn-9-en <SEP> 20-one <SEP> (preparation <SEP> 30A) <SEP> / &alpha; / D <SEP> = <SEP> +108.5 <SEP>#<SEP> 2.5 <SEP> (c <SEP> = <SEP> 0.5 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 31 <SEP>: <SEP> 3,20-bis <SEP> ethylene <SEP> ketal <SEP> of <SEP> 11ss-propyl <SEP> 17 &alpha; -methyl <SEP> 19- nor <SEP> pregna <SEP> 4,917 &alpha; -methyl <SEP> 5 &alpha; -hydroxy &quot; SEP &quot; 11ss-propyl &quot; SEP &quot;&quot; 19-nor &quot; SEP &quot; dien &quot; SEP &quot; 3,20-dione &quot; SEP &quot;> = <SEP> 122 C. <SEP> Analysis <SEP>:
<tb> 1 <SEP> hour
<tb> pregn-9-en <SEP> 3,20-dione <SEP> (Preparation <SEP> 31) <SEP> Calculated <SEP>: <SEP> C <SEP>% <SEP>: <SEP> 81 , 31 <SEP>, <SEP> H <SEP>% <SEP>: <SEP> 9.67
<tb> Found <SEP>: <SEP> 81.3 <SEP> 9.7
<tb> / &alpha; / D <SEP> = <SEP> -105 <SEP>#<SEP> 2 <SEP> (C <SEP> = <SEP> 1 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 32 <SEP>: <SEP> 3,3-20,20-bis <SEP> ethylene <SEP> bis <SEP> oxy <SEP> 11ss - / (4-methylthio <SEP> phenyl) ) 17α-methyl <SEP> 1917α-methyl <SEP> 11ss- (4-methylthiophenyl) <SEP> 19-nor <SEP> nor <SEP> pregn <SEP> 4.9-dien <SEP> 3.20 -dione. <SEP> Analysis <SEP>:
<tb> 2 <SEP> hours <SEP> 30
<tb> pregn-9-en-5 &alpha; -ol <SEP> (preparation <SEP> 32) <SEP> Calculated <SEP>: <SEP> C <SEP>% <SEP>: <SEP> 77.37, <SEP> H% <SEP>: <SEP> 7.88, <SE> S% <SEP> 7.38
<tb> Found <SEP>: <SEP> 77.6 <SEP> 8.0 <SEP> 7.4
<tb> / &alpha; / D <SEP> = <SEP> +263 <SEP>#<SEP> 4.5 <SEP> (c <SEP> = <SEP> 0.6 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 33 <SEP>: <SEP> 3,3-20,20-bis <SEP> ethylene <SEP> bis <SEP> oxy <SEP> 11ss, <SEP> 16 &alpha; -dimethyl <SEP > 19-nor <SEP> pregna <SEP> 4,9-dien <SEP> 1 <SEP> hour
<tb> 11ss, <SEP> 16 &alpha; -dimethyl <SEP> 19-nor <SEP> pregn-9-en <SEP> 5 &alpha; -ol <SEP> 3,20-dione <SEP> F <SEP> = <SEP> 155 C <SEP>, rf <SEP> = <SEP> 0.26
<tb> (preparation <SEP> 33)
<tb> Example <SEP> 34 <SEP>: <SEP> 3,3-20,20-bis <SEP> ethylene <SEP> bis <SEP> oxy <SEP> 16 &alpha; -methyl <SEP> 11ss- (4) methylthiophenyl) <SEP> 19-nor
<tb> 16α-methyl <SEP> 11ss (4-methylthiophenyl) <SEP> 19-nor <SEP> pregna <SEP> 4,9-diis <SEP> 3,20-dione. <SEP> Analysis <SEP>:
<tb> 1 <SEP> hour
<tb> pregn-9-en <SEP> 5 &alpha; -ol <SEP> (preparation <SEP> 34) <SEP> Calculated <SEP>: <SEP> C% <SEP>: <SEQ> 77.37 <SEP >, <SEP> H% <SEP>: <SEP> 7.88, <SE> S% <SEP>: <SEP> 7.38
<tb> Found <SEP>: <SEP> 77.6 <SEP> 8.0 <SEP> 7.4
<tb> / &alpha; / D <SEP> = <SEP> +290 <SEP>#<SEP> 5 <SEP> (c <SEP> = <SEP> 0.6 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 35 <SEP>: <SEP> 11ss-cyclopropyl <SEP> 3,3-ethylene <SEP> 11ss-cyclopropyl <SEP> 17ss-hydroxy <SEP> 17 &alpha; (prop-1-ynyl)
<tb> bis <SEP> oxy <SEP> 17 &alpha;<SEP> (prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;<SEP> estra <SEP> 4,9-dien-3-one <SEP> Analysis <SEP>:
<tb> 1 <SEP> hour
<tb> 17ss-diol <SEP> (Preparation <SEP> 35) <SEP> Calculated <SEP>: <SEP> C% <SEP>: <SEP> 82,24, <SEP> H% <SEP>: <SEP> 8.63
<tb> Found <SEP>: <SEP> 82.2 <SEP> 8.7
<tb> rf <SEP> = <SEP> 0.28
<Tb>
Example 36: 11β- (3-methoxyphenyl) 3-oxo 17α- (prop-1-ynyl) (17s) estra-4,9-dien-17-yl-oxy-tert-butyl acetate
40 cm 3 of methanol and 4 cm 3 of 2N hydrochloric acid are taken up in .beta.-3,3-ethylenebisoxyl-11ss- (3-methoxy-phenyl) -α-prop-1-ynyl (176). 9-tert-butyl α-hydroxy-17-yl-oxy-acetate obtained in Preparation 36.

After stirring for one hour at room temperature, half of the water is poured into Ae, stirred for 5 minutes, extracted with ether, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure.

 The residue is chromatographed on silica (eluent petroleum ether 60-800C - ethyl acetate 7-3) Finally 720 mg of expected product 1 is obtained which is used as it is.

Example 37: 11β- (3-methoxyphenyl) -3-oxo-17α- (prop-1-ynyl) (176) estra-4,9-dien-17-yl-oxy-acetic acid
A mixture of 5 g of product obtained as in Example 36, 500 mg of para-toluenesulphonic acid and 100 cm 3 of benzene is refluxed for 5 hours. The resulting resin is evaporated to dryness and chromatographed on silica (eluent: methylene chloride-methanol 92.5-7.5). 886 mg of expected product are collected. / &alpha; / D20 = +50.5, c = 0.3%, in CHCl3
Example 38: Sodium salt of 11β- (3-methoxyphenyl) -3-oxo-17α-alpha (prop-1-ynyl) (17ss) estra 4,9-dien-17-yl-oxy-acetic acid
A mixture of 305 mg of acid obtained in example 37 and 3 cm 3 of ethanolic sodium hydroxide (0.2 M / l) is stirred until dissolution, the light insoluble filter is filtered off. It is evaporated to dryness under reduced pressure and the residue is triturated with isopropyl ether until concretion. It is stirred, drained and rinsed with isopropyl ether. It is dried and 280 mg of expected product is obtained> 2700C.

% calculated as Na: 4.63
% Found: 4,45

DURATION
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> DU <SEP> REFLUX
<tb> Example <SEP> 39 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 11ss- (4- <SEP> 11ss - / (4-isopropyl) <SEP> phenyl / <SEP> 17ss-hydroxy, <SEP> 17 &alpha;
<tb> isopropylphenyl) <SEP> 17 &alpha; - (prop-1-ynyl) <SEP> estr-9- <SEP> (prop-1-ynyl) <SEP> estra <SEP> 4,9-dien-3- one <SEP> F <SEP> = <SEP> 192 C <SEP> 45 <SEP> minutes
<tb> еn <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 39) <SEP> / &alpha; / D <SEP> = <SEP> +73 <SEP>#<SEP> 2 <SEP> (c <SEP> = <SEP> 0.7 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 40 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 11ss (3- <SEP> 11ss - / (3-methylthio) <SEP> phenyl / <SEP> 17ss-hydroxy <SEP> 17 &alpha;
<tb> methylthiophenyl) <SEP> 17 &alpha; - (prop-1-ynyl) <SEP> estr-9- <SEP> (prop-1-ynyl) <SEP> estra <SEP> 4,9-dien <SEP> 3-one. <SEP> Analysis
<tb> еn <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 40) <SEP> Calculated <SEP>: <SEP> C% <SEP>: <SEP> 77.73, <SEP> H% <SEP>: <SEP> 7.45 <SEP> 1 <SEP> hour
<tb> Found <SEP>: <SEP> 77.7 <SEP> 7.6
###
<tb> Example <SEP> 41 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 11ss / 3- (2- <SEP> 11ss- / 3 (2-propenyloxy) <SEP> phenyl / <SEP> 17ss-hydroxy
<tb> propenyloxy) <SEP> phenyl / <SEP> 17 &alpha; - (prop-1-ynyl) estr- <SEP> 17 &alpha; - (prop-1-ynyl) <SEP> estra <SEP> 4,9-dien -3-one
<tb> 40 <SEP> minutes
<tb> 9-en <SEP> 5 &alpha;<SEP> 17ss-diol <SEP> (Preparation <SEP> 41) <SEP> Analysis <SEP>: <SEP> Calculated <SEP> C%: 81.41 <SEP> H%: 7.74
<tb> Found <SEP> 81.7 <SEP> 7.9
### > in <SEP> CHCl3)
<tb> Example <SEP> 42 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 11ss-thien <SEP> 11ss-thienyl <SEP> 17 &alpha; -methyl <SEP> 21-hydroxy <SEP> 19-nor
<tb> 2-yl <SEP> 17 &alpha; -methyl <SEP> 5 &alpha;<SEP> 21-dihydroxy <SEP> 19-nor <SEP> pregna <SEP> 4.9 <SEP> (10) <SEP> diene-3,20-dione, <SEP> Analysis <SEP>: <SEP> 30 <SEP> minutes
<tb> pregn-9-en <SEP> 20-one <SEP> (preparation <SEP> 42) <SEP> Calculated <SEP>: <SEP> C% <SEP>: <SEQ> 73.3, <SEP > H% <SEP>: <SEP> 7.5, <SEP> S% <SEP>: <SEP> 7.6
<tb> to <SEP> 60 C
<tb> Found <SEP>: <SEP> 73.13 <SEP> 7.36 <SEP> 7.81
<tb> / &alpha; / D <SEP> = <SEP> +138.5 <SEP>#<SEP> 3.5 <SEP> (c <SEP> = <SEP> 0.57 <SEP>%, C2H5OH )
<tb> Example <SEP> 43 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 11ss-cyclo- <SEP> 11ss-cyclopentyl <SEP> 17ss-hydroxy <SEP> 17 &alpha;-( prop-1-ynyl)
<tb> pentyl <SEP> 17 &alpha;-( prop-1-ynyl) <SEP> estr-9-en <SEP> 5 &alpha;,<SEP> 17ss- <SEP> estra <SEP> 4,9-dien-3 -one. <SEP> Analysis <SEP>:
<tb> 1 <SEP> hour
<tb> diol <SEP> (preparation <SEP> 43) <SEP> Calculation <SEP>: <SEP> C% <SEP>: <SEP> 82.49 <SEP> H% <SEP>: <SEP> 9 .05
<tb> Found <SEP>: <SEP> 82.2 <SEP> 9.3
<tb> / &alpha; / D <SEP> = <SEP> +122 <SEP>#<SEP> 2.5 <SEP> (c <SEP> = <SEP> 0.9 <SEP>%, <SEP> CHCl3)
<Tb>

DURATION
<tb> PRODUCTS <SEP> FROM <SEP> START <SEP> PRODUCTS <SEP> FINALS
<tb> DU <SEP> REFLUX
<tb> Example <SEP> 48 <SEP>: <SEP> 20R-acetoxy, <SEP> 3,3-ethylene <SEP> bis <SEP> 20R-acetoxy <SEP> 11ss- (3-methoxyphenyl) <SEP> 17 &alpha; -methyl
oxy &quot; SEP &quot; 11ss- (3-methoxyphenyl) &quot; SEP &quot; 17 &alpha; -methyl &quot; SEP &quot; 19-nor &quot; SEP &quot; 19-nor &quot; SEP &quot;&quot; SEP &quot; 4,9-di-3-one &quot;SEP> F <SEP> + <SEP> 145 C. <SEP> 2 <SEP> hours
<tb> pregn-9-en <SEP> 5 &alpha; -ol <SEP> (preparation <SEP> 48) <SEP> Analysis <SEP>: <SEP> Calculated <SEP> C% <SEP>: <SEP> 77 , 88, <SEP> H% <SEP>: <SEP> 8.28
<tb> Found <SEP>: <SEP> 77.6 <SEP> 8.2
<tb> / &alpha; / D <SEP> = <SEP> +168 <SEP>#<SEP> 2.5 <SEP> (at <SEP> 1 <SEP>%, <SEP> CHCl3)
<tb> Example <SEP> 49 <SEP>: <SEP> 3,3-ethylene <SEP> bis <SEP> oxy <SEP> 11ss- / 4 (3- <SEP> 11ss / 4 / (3-methyl) <SEP> butylthio / <SEP> phenyl / <SEP> 17ssmethyl) <SEP> butylthiophenyl / <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> hydroxy <SEP> 17 &alpha; --( prop-1-ynyl) <SEP> estra <SEP> 4,9-dienestr-9-en <SEP> 5 &alpha;,<SEP> 17ss-diol <SEP> (preparation <SEP> 49) <SEP> 3-one. <SEP> Analysis <SEP>: <SEP> 45 <SEP> minutes
<tb> Calculated <SEP>: <SEP> C% <SEP>: <SEQ> 78.62, <SEP> H% <SEP>: <SEP> 8.25, <SEP> S% <SEP>: <SEP> 6.56
<tb> Found <SEP>: <SEP> 78.4 <SEP> 8.3 <SEP> 6.4
#### CHCl3)
<Tb>
Example 44: 9α, 17β-hydroxy-11ss- (4-methoxyphenyl) 17α-alpha-prop-1-ynyl) estr-4-en-3-one:
700 mg of 85% metachloroperbenzoic acid are added, with stirring, to a solution at 0 ° C. of 1.3 g of 11β- (4-methoxy) phenyl 17α-hydroxy-17α-propyl-1-ynyl) estra. 4,9-dien-3-one prepared as in Example 14 in 25 cm3 of methylene chloride.

After one hour at room temperature, the mixture is allowed to return to ambient temperature, washed with an aqueous solution of 0.5 N sodium thiosulphate and then with saturated sodium bicarbonate solution. Dry and evaporate the solvent. The residue is chromatographed on silica (eluent: 95-5 methyleneacetone chloride and 1.075 g of expected product is obtained which is recrystallized from a mixture of methanol and isopropyl ether.
Mp 185-189 C.

Example 45: 9α, 10α-epoxy 17ss-hydroxy 11ss- (4-methylsulfonyl) phenyl 17α- (prop-1-ynyl) estr 4-en 3-one
960 mg of 85% metachloroperbenzoic acid is added in 5 minutes to a solution of 570 mg of lys- (4-methylthio) phenyl / 175-hydroxy-17α- (prop-1-ynyl) estra 4,9- dien 3-one as obtained in Example 23 in 13 cm3 of methylene chloride cooled to OOC.

 The mixture is stirred for 1 hour 30 minutes at 0 ° C. under nitrogen and then, with stirring, poured into 100 cm3 of 0.5 M aqueous sodium thiosulfate solution and stirred for a few moments at room temperature.

 It is extracted with methylene chloride, washed with an aqueous solution of sodium bicarbonate, dried and concentrated to dryness.

 The product obtained is chromatographed on silica (benzene-ethyl acetate eluent 1: 1) to give 750 mg of the expected product which is recrystallized from a mixture of isopropyl ether and methylene chloride. F = 2050-2080C.

/ &alpha; / D = = +67.50 + 1.50 <c = 1%, CHCl3)
Example 46: 3-Methoxyimino 11ss- (4-bromophenyl) 17α- (prop-1-ynyl) estra 4,9-dien-17ss-ol / isomers syn (Z) and anti (E) /:
170 mg of methylhydroxylamine hydrochloride are added to a solution of about 700 mg of 11ss / (4-bromo) phenyl / 17ss-hydroxy-17α- (prop-1-ynyl) estra 4,9-dien-3-one, such as obtained in Example 22 in 10 cm3 of ethanol and stirred for 2 hours at room temperature. Poured into water, extracted with ether and then with methylene chloride. The organic phase is dried and the solvent is evaporated and the residue is chromatographed on silica (eluent: benzene-ethyl acetate 9: 1).

408 mg of anti isomer product is thus obtained (E)
F = 1850C then 200 mg of product isomer Z. F = 2170C.

Anti product analysis
Calculated C%: 68.01, H%: 6.52, N%: 2.83, Br%: 16.16
Found 68.3 6.6 2.9 16.0
Example 47: 11ss- (3-fluorophenyl) -3-hydroxyimino 17α (propyl-ynyl) estra 4,9-diene 17β-ol (syn (Z) and anti (E) isomers:
1.27 g of hydroxylamine hydrochloride are added in one go to a solution of 3.7 g of 11ss- [(3-fluoro) phenyl] -17ss-hydroxy-17-alpha-prop-1-ynyl) estra-4. , 9-dien-3-one as obtained in Example 26 in 44.4 cm3 of absolute ethanol and 7.6 cm3 of pyridine.

 The mixture is refluxed for 1 hour, cooled to 0.degree. C. and then poured into 450 cm.sup.3 of ice-water mixture with stirring. Methylene chloride is extracted, the organic phases are washed with water, dried and then concentrated under reduced pressure.

 The crude product is chromatographed under pressure (eluent cyclohexane-ethyl acetate 7-3). Finally, 2.7 g of isomer isomer (E) and 857 mg of syn isomer isomer (Z) are obtained.

 The anti product is recrystallized from a mixture of 20 cm 3 of isopropyl ether and 10 cm 3 of methylene chloride, and gives 2.145 g of pure product. Mp 2100 ° C.

= +35 C # 2.5 (c = 0.5%, CHCl3)
Analysis: Calculated C%: 77.3, H%: 7.21, N%: 3.34
Found: 77.3 7.5 3.3
Example 50: 11β-tert-butyl 9α, 17β-hydroxy-17β-alpha-epoxy 17β-alpha-prop-1-ynyl-estr-4-en-3-one
By operating as in Example 44 starting from 2.11 g of 115-tert-butyl 17ss-hydroxy 17α- (prop-1-ynyl) estra 4,9-dieno-3-one as obtained in Example 6 and 2.92 g of meta-chloroperbenzoic acid, 0.55 g of the expected product F = 186-187 ° C. are obtained after chromatography.

Analysis: Calculated C: 78.49, H% 8.96
Found: 78.4 9.0 / &alpha; / D = + 38 # 1 (c = 1%, CHCl3)
Example 51: 11ss-cyclopentyl 9α, 10α-epoxy 17ss-hydroxy 17α-prop-1-ynyl) estr-4-en-3-one:
The procedure is as in Example 44 starting from 1.5 g of 11β-cyclopentyl 17β-hydroxy-17α-prop-1-ynyl) estra 4,9-dien-3-one as obtained in Example 43 and 0.8 g of metachloroperbenzoic acid. 0.7 g of the expected product are obtained after chromatography. F = 1700C.

Analysis: Calculated C%: 79.15, H%: 8.68
Found: 79.6 8.7 / &alpha; / D = + 6.5% (c = 1%, CHCl 3)
Example 52: 11ss- (3-methoxyphenyl) 9α, 10α-epoxy 17ss-hydroxy 17α-prop-1-ynyl) estr-4-en-3-one:
The procedure is as in Example 44 starting from 1.05 g of 11ss- (3-methoxyphenyl) 17ss-hydroxy-17α- (prop-1-ynyl) estra4,9-dien-3-one as obtained from Example 13 and 0.608 g of metachloroperbenzoic acid. After chromatography, 0.65 g of expected product is obtained.

 ## STR3 ## (+ = 0.6%, CHCl 3).

Example 53: 11ss-phenyl 9α -10α-epoxy 17ss-hydroxy 17α-prop-1-ynyl) estr-4-en-3-one
The operation is carried out as in Example 44 starting from 1.15 g of 11ss-phenyl 17ss-hydroxy 17α-prop-1-ynyl) estr 4,9-dien-3-one as obtained in the example 20 and 0.608 g of metachloroperbenzoic acid.

 After chromatography, 0.85 g of crystals are obtained.

Mp 186-1870 ° C. Analysis: Calculated C%: 80.56H%: 7.51
Found 80.6 7.3 / λ / D = +47.5 # 1.5 (c = 1%, CHCl 3)
Example 54: 11? - [(3-methyl) butylsulfonyl] phenyl? 9a, 10? Epoxy? -175-hydroxy-17? - (prop-1-ynyl) estr 4-en-3-one
The procedure is as in Example 45 starting from 11ss / 4 - [(3-methyl) butylthio] -phenyl] -17ss-hydroxy-17α-prop-1-ynyl) estra-4,9-dien-3-one obtained in Example 49. The expected product is obtained. F = 1740C.

/ / D = +620 + 2.50 (c = 0.6%, CHCl3)
Example 55: 23-N, N-Dimethylamino 17s-hydroxy 11ss- (3-methoxyphenyl) 19,21,24-trinor 17α-chol 4,9-dien-20-yn 3-one
4 g of 17α-di-3-dimethylamino-propynyl / 5α, 17ss-dihydroxy-11β- [3-methoxyphenyl] estr-9-en-3-one cyclic 1,2-tethanediyl acetal are stirred for 1 hour at room temperature. obtained in Preparation 55 in 100 cm3 of methanol and 3 cm3 of 2N hydrochloric acid.

 It is poured into a mixture of 300 cm3 of ethyl acetate and 200 cm3 of 0.25 M aqueous sodium hydrogen carbonate solution. The organic phases are decanted, reextracted with ethyl acetate. Washed with saturated aqueous sodium chloride solution, dried, the solvent evaporated, and the residue chromatographed on silica / eluent (95: 5 methylene chloride-methanol) (acetone-ethyl acetate 3: 1) /. 1.7 g of the expected product used as such for the following stage are isolated.

/ / D = +400 + 10 (c = 1%, CHCl3)
Example 56: 23-N, N-dimethylamino hydrochloride 17ss-hydroxy 11ss- (3-methoxyphenyl) 19,21,24-trinor 17α-chola-4,9-dien 20-yn 3-one
1.5 g of product obtained in Example 55 is dissolved in 50 cm3 of ether, stirred for 10 minutes at room temperature and the insoluble light is removed. 16.5 cm3 of an ethereal solution of gaseous hydrochloric acid are then introduced dropwise. The suspension is stirred for 10 minutes and then filtered, rinsed with ether and 1.4 g of expected product. F = 1900C.

 / / D = +490 + (c = 5%, water).

Analysis: Calculated C96: 72.63, H%: 7.72, N%: 2.82
Found: 72.5 7.7 2.7
Example 57: 17ss-hydroxy 17α-prop-1-ynyl) 11ss- (4-hydroxyphenyl) estra 4,9-dien-3-one:
A solution of 90 mg of 3,3-ethylene bis-oxy-11ss- (4-hydroxyphenyl) -171- (prop-1-ynyl) estr-9-ene, 17ss-diol (as described above) is stirred for two hours at room temperature. obtained in Preparation 57) in 2 cm3 of methanol and 0.3 cm3 of 2N hydrochloric acid. It is poured into an ice-cold solution of half sodium hydrogen carbonate, extracted with ether and then with methylene chloride.

 The organic phase is washed with a saturated aqueous solution of dry sodium chloride, concentrated to dryness under reduced pressure and the residue is chromatographed on silica (eluent: methylene chloride-acetone 92.5-7.5). 71 mg of expected product is obtained.

 = = +67 (c = 0.25%, CHCl3).

Pharmacological study of the products of the invention 1 / Study of the activity of the products of the invention on the hormonal receptors
Mineralocorticoid receptor of rat kidney
Male Sprague-Dawley EOPS rats, weighing 140 to 160 g, adrenalectomized for 4 to 8 days are sacrificed and their kidneys are perfused in situ with 50 ml of 10 mM Tris buffer.
0.25 M sucrose, HCl pH 7.4. The kidneys are then removed, decapsulated and homogenized at OOC with a Potter teflon-glass (1 g of tissue per 3 ml of buffer). The homogenate is centrifuged for 10 minutes at 800 g at 0 ° C.

 In order to eliminate the binding of tritiated aldosterone to the glucocorticoid receptor, the lily, 17S dihydroxy-21 methyl pregna 1,4,6-trien 20-yn 3-one steroid binding only to the glucocorticoid receptor is added to the supernatant at the same time. final concentration of 10 M. This supernatant is ultracentrifuged at 105,000 g for 60 minutes at OOC. Aliquots of the supernatant thus obtained are incubated at 0 ° C. with a constant concentration (T) of tritiated aldosterone in the presence of increasing concentrations (0-2500.

 10 9M) cold aldosterone or the cold product to be studied.

After a time (t) of incubation, the bound tritiated aldosterone concentration (B) is measured by the carbon-dextran adsorption technique.

Receptor androgenic rat prostate
Male Sprague Dawley EOPS rats 160-200 g are castrated. 24 hours after castration, the animals are sacrificed, the prostates are removed, weighed and homogenized at OOC using a teflon-glass Potter in TS buffer solution (10 mM Tris, 0.25 M sucrose, pH HCl). 7.4) (1 g of tissue per 5 ml of TS). The homogenate is then ultracentrifuged (105,000 g for 60 minutes) at 0 ° C. Aliquots of the supernatant thus obtained are incubated at 0 ° C. for an incubation time E with a constant concentration (T) of tritiated testosterone in the presence of concentrations. The concentration of the bound tritiated tosterone (B) is then measured in each incubate by the carbon-dextran adsorption technique (O-1000, 10-9M), either cold testosterone or test product.

Proqestogen receptor of rabbit uterus
Impubberous rabbits of about 1 kg receive cutaneous application of 25 g of estradiol. 5 days after this treatment, the animals are sacrificed, the uteri are removed, weighed and homogenized at 0 ° C., using a teflon-glass Potter in a TS buffer solution (10 mM Tris, 0.25 M sucrose). , HCl pH 7.4) (1 g of tissue per 50 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. for a time t, with a constant concentration (T) of tritiated product R 17,21-dimethyl-19. nor-4,9-pregnadiene-3,20-dione) in the presence of increasing concentrations (0 - 2 500. 10-9M) of either cold R or cold progesterone, or the cold product to be tested. The bound tritiated R concentration (B) is then measured in each incubate by the dextran carbon adsorption technique.

Glucocorticoid receptor of the rat thymus
Male Sprague Dawley EOPS rats 160-200 g are adrenalectomized. 4 to 8 days after this ablation, the animals are sacrificed, and the thymuses are removed and homogenized at 00C in 10mM Tris buffer, 0.25M sucrose, 2mM dithiothreitol, HCl pH 7.4, using Potter polytetrafluoroethylene-glass (1 g of tissue per 10 ml of TS).

The homogenate is then ultracentrifuged (105,000 g × 90 min) at 0 ° C. Aliquots of the supernatant thus obtained are incubated at 0 ° C. for a time (t) with a constant concentration (T) of tritiated dexamethasone in the presence of concentrations. increasing (O - 2500x10M) either of cold dexamethasone, or of the cold product to be tested. The concentration of bound tritiated dexamethasone (B) is then measured in each incubate by the charbondextran adsorption technique.

Estrogen receptor of mouse uterus:
Impuberic female mice aged 18 to 21 days are sacrificed, the uteri are removed and then homogenized at OOC with a Teflon-glass Potter in a TS buffered solution (10mM Tris, 0.25M sucrose, pH 7 HCl). 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 250 ° C. for a time (t). a constant concentration (T) of tritiated estradiol in the presence of increasing concentrations (0-1000.

 9M) either cold estradiol or the cold product to be tested.

The concentration of bound tritiated estradiol (B) is then measured in each incubate by the carbon-dextran 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 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 tritiated at the concentration (T) in the presence of a large excess of cold hormone (2500.10-9M).

 The intersections of the I50 line 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 receptor.

The relative affinity binding (ARL) of the test product is determined by the equation
ARL = 100 (CH)
(CX)
The results obtained are as follows

<tb> Time
<tb><SEP> of ircubation <SEP> Mineralo <SEP> Pro- <SEP> Gluco
<tb><SEP> \ <SEP> to <SEP> 0 C <SEP> corticosteroid <SEP> Androgen <SEP> gestogen <SEP> aorticoid <SEP> Estrogen
<tb><SEP> gestogen <SEP> trogen
<tb> product <SEP> 5H
<tb><SEP>
<tb> Examples <SEP> 1 <SEP> H <SEP> 24 <SEP> H <SEP> i / 2H <SEP> 24 <SEP> H <SEP> 2 <SEP> H <SEP> 24 <SEP> H <SEP> 4 <SEP> H <SEP> 24 <SEP> H <SEP> 2 <SEP> H <SEP> (250C)
<tb><SEP> 10 <SEP> 0.9 <SEP> 0.01 <SEP> 1.3 <SEP> 3 <SEP> 274 <SEP> 536 <SEP> 213 <SEP> 217 <SEP> 4 <SEP> 0.01
<tb><SEP> it <SEP> 1 <SEP> 0.1 <SEP> 11.5 <SEP> 1 <SEP> r5 <SEP> 1 <SEP> 160 <SEP> 80 <SEP> 274 <SEP> 249 <SEP> 4 <SEP> 0.01
<tb><SEP> 12 <SEP> 3.4 <SEP> 0.4 <SEP> 9.6 <SEP> 0.3 <SEP> 63 <SEP> 126 <SEP> 189 <SEP> 125 <SEP> 4 <SEP> 0.01
<tb><SEP> 23 <SEP> 0.4 <SEP> 0.04 <SEP> 6.3 <SEP> 12.4 <SEP> 236 <SEP> 910 <SEP> 210 <SEP> 227 <SEP><<SEP> 0.01
<tb><SEP> 26 <SEP> 3.1 <SEP> 0.2 <SEP> 7.7 <SEP> 2.0 <SEP> 33 <SEP> 129 <SEP> 210 <SEP> 106 <SEP> c <SEP> 0.01
<tb><SEP> 28 <SEP> 0101 <SEP> 40.1 <SEP> 0.6 <SEP> 108 <SEP> 513 <SEP> 164 <SEP> 204 <SEP> 4 <SEP> 0.01
<tb><SEP> 32 <SEP> 1.9 <SEP> 0.7 <SEP>;<SEP> 1.1 <SEP> 3.0 <SEP> 66 <SEP> 230 <SEP> 42 <SEP> 27 <SEP> 4 <SEP> 0.01
<tb><SEP> 34 <SEP> O, <SEP> 0.1 <SEP> 0.4 <SEP> 1.6 <SEP> 38 <SEP> 176 <SEP> 65 <SEP> 43 <SEP> 4 <SEP> 0.01
<tb><SEP> 35 <SEP> 0.02 <SEP> 0.02 <SEP> 0.6 <SEP> 0.4 <SEP> 11 <SEP> 9 <SEP> 186 <SEP> 128 <SEP> 4 <SEP> 0.01
<tb><SEP> 41 <SEP>, 3 <SEP> 0.1 <SEP> 18 <SEP> 6.4 <SEP> 8.2 <SEP> 3.6 <SEP> 171 <SEP> 117 <SEP > d <SEP> 0.01
<tb><SEP> 44 <SEP> 1.4 <SEP> 0.1 <SEP> 13 <SEP> 5.6 <SEP> 41 <SEP> 67 <SEP> 136 <SE> 140 <SEP> b <SEP> 0.01
<tb><SEP> 45 <SEP>, <SEP> s <SEP> 0.07 <SEP> 8.3 <SEP> 2.4 <SEP> 24 <SEP> 62 <SEP> 40 <SEP> 64 <SEP> 4 <SEP> 0.01
<tb><SEP> 47 <SEP>, <SEP> 0.04 <SEP> 0.13 <SEP> 0.05 <SEP> 19 <SEP> 16 <SEP> 160 <SEP> 100 <SEP> 3 , 5 <SEP> 0.80
<tb><SEP> f <SEP>
<Tb>
Conclusion ::
The products studied, particularly the product of Example 23, have a very strong affinity for the glucocorticoid and progestogen receptors, as well as a moderate affinity for the androgen receptor.

 From the results obtained, it can be concluded that the products may exhibit agonist or antagonist activities of glucocorticolls, progestogens and androgens.

II / Antiglucocorticoid activities
The technique used derives from the method described by
Dausse et al in Molecular Pharmacology 13, 948-955 (1977) ("The relationship between glucocorticoid structure and effects upon thymoxides") for mouse thymocytes.

 Thymocytes of adrenalectomized rats are incubated at 370C for 3 hours, in a nutrient medium containing S108M dexamethasone in the presence or absence of a product to be studied at different concentrations. Tritiated uridine is added, and the incubation is continued for one hour. The incubates are cooled, treated with 5% trichloroacetic acid solution, filtered on Whatman GF / A paper, washed three times with a 5% trichloroacetic acid solution. The radioactivity retained by the filter is determined.

Glucocorticoids and in particular dexamethasone cause a decrease in the incorporation of tritiated uridine. The products of Examples 10, 11, 12, 23, 26, 32, 34, 35, 41, 44, 45 and 47 oppose this effect.

5.10-8 <SEP> Dexamethasone <SEP>% <SEP> of inhibition <SEP> of
<tb> Product <SEP> of
<tb><SEP> + <SEP> product <SEP> to <SEP> test <SEP> to <SEP> the <SEP> effect of <SEP> la
<tb> the example <SEP>:
<tb><SEP><SEP> concentration <SEP> of <SEP>: <SEP> Dexamethasone
<tb><SEP> 10 <SEP> 10-8M <SEP> 9
<tb><SEP> 10-7M <SEP> 42
<tb><SEP> 10-6M <SEP> 89
<tb><SEP> 11 <SEP> 10-8M <SEP> 19
<tb><SEP> 10-7M <SEP> 61
<tb><SEP> 10-6M <SEP> 75
<tb><SEP> 12 <SEP> 10-8M <SEP> 11
<tb><SEP> 10-7M <SEP> 54
<tb><SEP> 10-6M <SEP> 85
<tb><SEP> 23 <SEP> 10-8M <SEP> 26
<tb><SEP> 10-7M <SEP> 64
<tb><SEP> 10-6M <SEP> 85
<tb><SEP> 26 <SEP> -8
<tb><SEP> 26 <SEP> 10-8M <SEP> 11
<tb><SEP> 10-7M <SEP> 45
<tb><SEP> 10-6M <SEP> 93
<tb><SEP> 32 <SEP> 10-8M <SEP> 0
<tb><SEP> 10-7M <SEP> 4
<tb><SEP> 10-6M <SEP> 100
<tb><SEP> 34 <SEP> 10-8M <SEP> 0
<tb><SEP> 10-7M <SEP> 11
<tb><SEP> 10-6M <SEP> 68
<tb><SEP> 35 <SEP> 10-8M <SEP> 7
<tb><SEP> 10-7M <SEP> 22
<tb><SEP> 10-6M <SEP> 61
<tb><SEP> 41 <SEP> 10-8M <SEP> 15
<tb><SEP> 10-7M <SEP> 21
<tb><SEP> 10-6M <SEP> 100
<tb> 44 <SEP> 10-8M <SEP> 0
<tb><SEP> 10-7M <SEP> 23
<tb><SEP> 10-6M <SEP> 65.5
<tb><SEP> 45 <SEP> 10-8M <SEP> 13
<tb><SEP> 10-7M <SEP> 17
<tb><SEP> 10-6M <SEP> 49
<tb><SEP> 47 <SEP> 10-8M <SEP> 26
<tb><SEP> 10-7M <SEP> 76
<tb><SEP> 10-6M <SEP> 72
<Tb>
It has also been found that used only products tested do not cause any effect of the glucocorticoid type.

Conclusion
The products studied show a very marked anti-glucocorticoid activity while being devoid of glucocorticoid activity.

Pharmaceutical compositions
Tablets having the following formula were prepared - Product of Example 23 ....................... 50 mg
Excipient (talc, starch, magnesian stearate)
qs for a tablet finished at ............... 120 mg

Claims (6)

 R "3 represents a hydroxyl radical, R '1 represents a vinyl radical and R' 4 represents a hydrogen atom.  Y) R "3 represents an acetyl radical and i) R '4 represents a hydroxyl radical and R' represents an ethyl, phenyl or vinyl radical or ii) R'4 represents a methyl radical and R'1 represents a vinyl radical b) R2 represents an ethyl radical and  ss) R "3 represents a hydroxyl radical and R '4 represents an ethynyl radical and R' 1 represents an ethyl, propyl isopropyl, vinyl, isopropenyl, allyl, o-, p-methoxyphenyl or thienyl radical;  a) R "3 represents a cyano radical, R'4 represents a trimethylsilyloxy radical and R1 represents a phenyl radical methyl, ethyl, propyl, isopropyl tert-butyl, vinyl, allyl, isopropenyl o-or p-methoxyphenyl, thienyl, methoxyvinyl, pf luorophenyl I K represents a blocked keto group in the form of ketal, thioketal, oxime or methyloxime with the exception of the products in which K represents a (1,2-ethanediyl) acetal radical and R5 represents a hydrogen atom and a) R2 represents a methyl radical and R5 represents a hydrogen atom or a methyl radical in position a or B OH blocked as easily cleavable ether R2 represents a methyl or ethyl radical and either R''3 represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical, a hydroxyl radical, acetyl optionally protected in the form of a ketal, hydroxyacetyl or carboxyalkoxy having from 2 to to 4 carbon atoms esterified, acyloxy alkyl and R4 represents either a hydrogen atom, a hydroxyl radical, an alkyl radical, alkenyl or alkynyl having at most 12 carbon atoms optionally substituted by an alkyl amino, diaikyl amino radical, or by a halogen, an alkylthio, alkoxy or trialkylsilyl radical, ie R4 represents a cyanomethyl radical, or solen R''3 represents a cyano radical and R'4 a grouping  in which R'1 represents either an optionally substituted thienyl radical, a furyl radical, a cycloalkyl radical having from 3 to 6 carbon atoms, a phenyl radical optionally substituted by one or more radicals chosen from hydroxyl halogen radicals optionally protected, trifluoromethyl, alkyl, alkoxy, alkylthio optionally oxidized in the form of sulphoxide or sulphone or alkenyloxy having more than 6 carbon atoms and phenyloxy or R'1 represents a naphthyl or diphenyl radical or an alkyl or alkenyl radical optionally carrying more than one unsaturations having at most 6 carbon atoms,

 R E V E N D I C A T I N N 1) The products of general formula IIa: 2) The products of general formula 11a as defined in claim 1 wherein either the radical R'1 represents a cycloalkyl radical having from 3 to 6 carbon atoms or a substituted thienyl radical, or R5 represents m methyl radical.  3) The products of formula 11a as defined in one of claims 1 or 2 wherein R "3 represents a hydroxyl radical, R '4 represents a propynyl radical, R2 represents a methyl radical and R5 represents a hydrogen atom . 4) The products of formula 11a as defined in claim 1 characterized in that R "3 represents an acetyl radical, R '4 represents a methyl radical or a hydrogen atom and R' 1 represents an optionally substituted phenyl radical. 5) The products of formula 11a as defined in any one of claims 1 to 4 wherein the radical R '1 represents a cyclopropyl, a phenyl groupvenvenically substituted by one of the radicals selected from the group formed by the chloro, fluoro, methylthio, methylsulfonyl, methoxy, hydroxy and allyloxy radicals, or a chlorothienyl group and R'4 represents a propynyl radical. 6) The products of formula 11a as defined in claim 1 whose names follow: - 3, 3-ethylenebis (oxy) 11ss - [(4-chloro) phenyl] -17-alpha-prop-1-ynyl) 5α, 17ss-diol-3,3-ethylenebis (oxy) 11ss- (5-chlorothienyl) 17α- (prop-1-ynyl) estr-9-en-5α, 17ss-diol. -3,3-ethylenebis (oxy) 11ss- (3-chloro) phenyl-17α-prop-1-ynyl) estr-9-en-alpha-17β-diol. 3,3-ethylene bis (oxy) 11? - [(4-methylthio) phenyl] -17a (prop-1-ynyl) estr-9-en?,?, 17? -Diol. 3,3-ethylene bis (oxy) 11? - [(3-fluoro) phenyl] -17? - (propylmyl) estr-9-en?, 17? -Diol. 3,3,20,20-bis (ethylenebis) oxy-17α-methyl-11ss- (4-methylthiophenyl) 19-norpregn-9-en-5α-ol. 3,3,20,20-bis-ethylene bis (oxy) -α-methyl-11ss- (4-methylthiophenyl) -19-nor-pregn-9-en-5α-ol. 11β-cyclopropyl-3,3-ethylene bis-17α- (prop-1-ynyl) estr-9-en-5α, 17β-diol. 3,3-ethylenebisoxyl-11β- [3- (2-propenyloxy) -phenyl] -17a (prop-1-ynyl) estr-9-en-5α, 17β-diol.  3,3-ethylenebisoxyl-11ss- (4-hydroxyphenyl) -17α- (prop-1-ynyl) estr-9-en-5α, 17β-diol. 3,3-ethylenebis (oxy) 11? - [(4-methylthio) phenyl] -17? - (propyl-ynyl) estr-9-en?, 17? -Diol.