FR2594830A1 - New 13-epi or D-homo steroids substituted in position 10 beta with a radical containing a double or triple bond, process for their preparation, their application as medicaments and the pharmaceutical compositions which contain them - Google Patents

Abstract

Products of formula I: in which R represents especially: H or optionally substituted alkyl, alkenyl, alkynyl, aryl and aralkyl radicals or alkoxy, carboxyl, dialkylamino and trialkylsilyl radicals, R6 and R7 represent especially either, together, a cyclopropyl or R6 = H and R7 = R1, R1 = H, alkyl, alkenyl, alkynyl or acetylthio, R2 = CH3 or ethyl, X and Y represent especially - either X = OH and Y = CH2CH2CO2M or CH2CH2CH2OH, - or X and Y together represent - or X = OH and Y = H or R4, R4 = alkyl, alkenyl or alkynyl, n = 1 when R2 is in position alpha and n = 2 when R2 is in position beta , process for their preparation, their application as medicaments and the pharmaceutical compositions which contain them.

Description

 The present invention relates to novel steroids 13-iso or homo steroids substituted in the 10-position by a radical having a double or triple bond, their method of preparation, their use as medicaments and the pharmaceutical compositions containing them.

dans laquelle R représente : - soit un atome d'hydrogène, - soit un radical alkyle, alkényl ou alkynyle ayant au plus 8 atomes de carbone, éventuellement substitué, - soit un radical aryle ou aralkyle éventuellement substitué, - soit un radical alkoxy, carboxy éventuellement estérifié ou dialkylamino, - soit un atome d'halogène, - soit un radical trialkylsilyle.The subject of the invention is the products of general formula I:

in which R represents: either a hydrogen atom, or an alkyl, alkenyl or alkynyl radical having at most 8 carbon atoms, optionally substituted, or an optionally substituted aryl or aralkyl radical, or an alkoxy or carboxy radical; optionally esterified or dialkylamino, - either a halogen atom, - or a trialkylsilyl radical.

- soit X et Y représentent ensemble un radical

lequel alk représente un radical alkyle renfermant au plus 8 atomes de carbone, - soit X et Y représentent ensemble un radical

ou X représente un radical hydroxyle et Y un radical

R6 and R7 are such that either R6 and R7 together with the carbons carrying them form a cyclopropyl radical, or R6 represents a hydrogen atom and R7 represents the radicaL R1, R1 representing - either a hydrogen atom, - or a alkyl, alkenyl or alkynyl radical having at most 6 carbon atoms, optionally substituted, - or an acetylthio radical,
R2 represents a methyl or ethyl radical,
X and Y are such that: either X represents a hydroxyl radical, optionally acylated or etherified, and Y represents either a radical -CH 2 CH 2 CO 2 M in which M represents a hydrogen atom, an alkali metal atom or an ammonium radical, or radical -CH 2 CH 2 -CH 2 OH, or X and Y together represent a radical ::

- X and Y together represent a radical

which alk represents an alkyl radical containing at most 8 carbon atoms, - or X and Y together represent a radical

where X represents a hydroxyl radical and Y represents a radical

M is defined as above, - or X represents a hydroxyl radical optionally acylated or etherified and Y represents, or a hydrogen atom or Y represents R4, R4 represents an alkyl, alkenyl or alkynyl radical having at most 6 atoms of carbon, n represents the integers 1 or 2, the dashed lines in position 1 (2) and 6 (7) indicate the possible presence of a second antrium bond The carbons which carry them, it being understood that it can not there having a second bond in position 6 (7) when R6 and R7 form with the carbons which carry them a cyclopropyl radical, the dotted line on the substituent RC = C- in position 10 indicates the possible presence of a third bond between the carbons wearing them, the undulating features in position 6, 7 and 13 indicate that the substituents
R6, R7 and R2 may be in one of the possible positions or where it is understood that when R represents the value 1, the wavy line at position 13 indicates the presence of a radical R2 in position and When n represents the value 2 , the line. corrugated in position 13 indicates the presence of a radical R2 in position (3
The invention also relates to the products of formula I indicated above in which the X and Y values at position 17 are reversed.

dans laquelle R, R2, R6, R7, X, Y et n, les traits pointillés et ondulés ont la signification indiquée ci-dessus et plus particulièrement les produits de formule

dans laquelle R, R2, R6, R7, X, Y et n, les traits pointillés et ondulés ont la signification indiquée ci-dessus.These products correspond to the following general formula

in which R, R2, R6, R7, X, Y and n, the dashed and wavy lines have the meaning indicated above and more particularly the products of formula

in which R, R2, R6, R7, X, Y and n, the dashed and wavy lines have the meaning indicated above.

In these products, the radicals X and Y can then form together the radicals

 These products can be prepared by the processes described above.

et des produits de formule I"

dans lesquelles les substituants R, R2, R6, R7, X, Y, Les traits pointillés et les traits ondulés ont la signification précédente.The formula I can be represented by the sum of the formulas I ':

and products of formula I "

in which the substituents R, R2, R6, R7, X, Y, the dashed lines and the wavy lines have the preceding meaning.

dans laquelle R représente : - soit un atome d'hydrogène, - soit un radical alkyle, alkényle ou alkynyle ayant au plus 8 atomes
de carbone, éventuellement substitués, - soit un radical aryle ou aralkyle éventuellement substitué, - soit un radical alkoxy, carboxy éventuellement estérifié ou dialkylamino, - soit un atome d'halogène, - soit un radical trialkylsilyle.The subject of the invention is, among the products of formula I, those corresponding to formula I 1:

in which R represents: - either a hydrogen atom, - or an alkyl, alkenyl or alkynyl radical having at most 8 atoms
of carbon, optionally substituted, - is an optionally substituted aryl or aralkyl radical, - is an alkoxy, optionally esterified carboxy or dialkylamino radical, - is a halogen atom, - is a trialkylsilyl radical.

- soit X1 représente un radical hydroxyle éventuellement acylé ou éthérifié et Y1 représente, ou bien un atome d'hydrogène ou bien Y1 représente R4, R4 représentant un radical alkyle, alkényle ou alkynyle ayant au plus 6 atomes de carbone, n représente les entiers 1 ou 2, les traits pointillés en position 1 (2) et 6 (7) indiquent la présence éventuelle d'une seconde liaison entre les carbones qui les portent, étant entendu qu'il ne peut pas y avoir de seconde liaison en position 6 (7) lorsque R6 et R7 forment avec les carbones qui les portent un radical cyclopropyle, le trait pointillé sur le substituant RC::C en position 10 indique la présence éventuelle d'une troisième liaison entre les carbones qui les portent, les traits ondulés en position 6, 7 et 13 indiquent que les substituants
R6, R7 et R2 peuvent se trouver dans l'une des positions 0( et (3. R6 and R7 are such that either R6 and R7 form with the carbons which carry them a cyclopropyl radical, or R6 represents a hydrogen atom and R7 represents the radical R1, R1 representing: - either a hydrogen atom, - or an alkyl, alkenyl or alkynyl radical having at most 6 carbon atoms which may be substituted, or an acetylthio radical,
R2 represents a methyl or ethyl radical;
X1 and Y1 are such that - either X1 represents a hydroxyl radical and Y1 represents either a -CH2CH2CO2- radical in which M represents a hydrogen atom, an alkali metal atom or an ammonium radical, or a radical -CH2CH2 -CHZOH, - or X1 and Y1 together represent a radical ::

or X 1 represents an optionally acylated or etherified hydroxyl radical and Y 1 represents, or a hydrogen atom, or Y 1 represents R 4, R 4 represents an alkyl, alkenyl or alkynyl radical having at most 6 carbon atoms, n represents the integers 1 or 2, the dashed lines in position 1 (2) and 6 (7) indicate the possible presence of a second bond between the carbons carrying them, it being understood that there can not be a second link in position 6 ( 7) when R6 and R7 together with the carbons carrying them a cyclopropyl radical, the dashed line on the substituent RC :: C in position 10 indicates the possible presence of a third bond between the carbons which carry them, the wavy lines in position 6, 7 and 13 indicate that the substituents
R6, R7 and R2 may be in one of the positions 0 (and (3.

it being understood that when n represents the value 1, the wavy line at position 13 indicates the presence of a group R2 in position pÇ and when n represents the value 2, the wavy line at position 13 indicates the presence of a radical R2 in position 0.

 Among the values of R, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, secondary butyl and tert-butyl radicals, and the optionally branched pentyl, hexyl, heptyl or octyl radicals.

 Mention may also be made of the following alkenyl radicals: vinyl, allyl, 1-propenyl, butenyl and alkynyl radicals such as ethynyl or propargyl or butynyl.

These different radicals may be substituted, for example by hydroxyl, optionally esterified carboxy radicals such as methoxycarbonyl, ethoxycarbonyl, optionally protected amino such
that tritylamino, chloroacetylamino, trifluoroacetylamino, trichloro
ethoxycarbonylamino, monoalkyl or dialkylamino such as methylamino and
dimethylamino, the halogen atoms, preferably chlorine or bromine.

Aryl and aryl radicals that can also represent
R are preferably phenyl, benzyl or phenylethyl.

These radicals can also be substituted, for example by
hydroxyl, optionally esterified carboxy, amino, mono radicals
or dialkylamino, alkyl such as methyl, alkoxy such as methoxy,
alkylthio such as methylthio.

The alkoxy value that can represent R can be for example a
methoxy, ethoxy or tert-butyloxy radical.

The preferred trialkylsilyl value is the trimethylsilyl value. The values that can represent the radical R1 can also be
chosen in the values mentioned above for R. The same is true for R4.

M preferably represents a sodium, potassium or
lithium.

 When X is an acylated or etherified hydroxyl radical, the preferred values are acetyloxy, propionyloxy, methoxy or ethoxy.

When R1 represents a substituent different from an atom
of hydrogen, the substituent is preferably in position 79.
The cyclopropyl radical which R 6 and R 7 can form with the carbons which carry them is preferably 6 6, 7 (3.

The compounds of formula I in which X and Y together represent a radical

/ O-S0
Existing <tb> / <SEP> L <SEP>
<tb> in the form of two diastereoisomers at the level of the sulfur atom, optionally separable from each other and referred to conventionally as isomers A and, the isomer A being the isomer whose melting point is the most high.

dans laquelle R, R1, R2, X, Y et n, les traits pointillés et les traits ondulés ont la signification indiquée ci-dessus.Among the products of formula I, the products of formula:

in which R, R 1, R 2, X, Y and n, the dashed lines and the wavy lines have the meaning indicated above.

 The invention more particularly relates to the products of Formula I as described above in which the substituents that may comprise the radicals R and R1 are chosen from the group formed by hydroxyl radicals, carboxy optionally esterified, amino, protected amino , mono or dialkylamino and halogen atoms.

The subject of the invention is more particularly the products of formula I as described above in which the dotted line on the substituent at position 10 represents a third bond and
R2 is selected from the group consisting of a hydrogen atom, an alkyl radical having 1 to 3 carbon atoms, a hydroxymethyl radical or phenyl radical and the products of formula I in which the substituent
R 1 is selected from the group consisting of a hydrogen atom, an alkyl radical having 1 to 4 carbon atoms and an acetylthio radical and X and
Y are such that either X represents a hydroxyl radical and Y represents either a CH 2 CH 2 CO 2 M 'radical in which M' represents a hydrogen atom or an alkali metal atom, or Y represents a hydrogen atom, ie X and Y represent a radical

Even more particularly, products in which
R represents a hydrogen atom or a methyl radical, R2 represents a methyl radical and X and Y are such that either X represents a radical;
OH and Y represents a hydrogen atom, ie X and Y together represent a radical

The subject of the invention is more particularly the products described hereinafter in the examples, namely: ## STR5 ## The lactam of 10ss-ethynyl acid 17ss-hydroxy 3-oxo 13 &alpha;, 17 &alpha; -19-nor 4.9 (11) -dien-21-carboxylic acid; 10β-ethynyl 17β-hydroxy 13α-estra-4,9 (11) -dien-3-one; 17-hydroxy-3-oxo-10ss- (1-propynyl) -α, 17α-19-nor-pregna-4,9 (11) -dien-21-carboxylic acid t-lactone; 17-hydroxy-10- (1-propynyl) 13α-estra-4,9 (11) -dien-3-one; - 10ss-ethynyl 17ass-hydroxy 3-oxo 19-nor (17a &alpha;-)&gamma; lactone
D-homo-pregna-4,9 (11) dien-21-carboxylic acid; 10β-thynyl-17α-hydroxy-D-homo-estra-4,9 (11) -dien-3-one; 17a-β-hydroxy-3-oxo-100- (1-propynyl) 19-nor 17α-α-D-homo-pregna 4,9- (11) -dien-21-carboxylic acid; 17α-hydroxyl 100- (1-propynyl) D-homo-estra 4.9 (11) -dien-3-one.

ou bien un produit de formule Il" :

dans lesquelles R' représente soit R, R ayant la signification indiquée ci-dessus soit le substituant R dans lequel les fonctions réactives sont protégées, R2 a la signification indiquée ci-dessus et K représente un groupement protecteur de la fonction cétone.The subject of the invention is also a process for the preparation of the products of formula I as defined above, characterized in that either a product of formula II 'is treated.

or a product of formula II ":

in which R 'represents either R, R having the meaning indicated above or the substituent R in which the reactive functions are protected, R2 has the meaning indicated above and K represents a protecting group of the ketone function.

dans lequel Alk représente un radical alkyle ayant de 1 à 4 atomes de carbone en présence d'une base forte puis par un acide pour obtenir ou bien un produit de formule 1,A

ou bien un produit de formule I"A :

II- soit par un réactif de formule
XMg-CH2CH2CH2OB dans lequel X représente un atome d'halogène et B représente un groupement protecteur du radical hydroxyle ou un alcoolate de magnésium pour obtenir apres traitement par un acide ou bien un produit de formule 1,2A :

ou bien un produit de formule I"2A ::

produits de formule I'2A ou 1,A que l'on traite éventuellement par un halogénure d'acide sulfonique en présence d'une base pour obtenir ou bien un produit de formule I"'2A :

ou bien un produit de formule I""2A:

I- firstly with a trimethylsulfonium halide in the presence of a strong base and then with a metal derivative of acetonitrile and finally with a base and then with an acid, or with a reagent of formula:

in which Alk represents an alkyl radical having 1 to 4 carbon atoms in the presence of a strong base and then an acid to obtain either a product of formula 1, A

or a product of formula I "A:

II- or by a reagent of formula
XMg-CH2CH2CH2OB wherein X represents a halogen atom and B represents a protecting group for the hydroxyl radical or a magnesium alkoxide to obtain after treatment with an acid or a product of formula 1.2A:

or a product of formula I "2A ::

products of formula I'2A or 1, A which is optionally treated with a sulfonic acid halide in the presence of a base to obtain either a product of formula I "2A:

or a product of formula I "" 2A:

ou bien un produit de formule I"3A :

III either with a reducing reagent and then with an acid to obtain a product of formula I'3A:

or a product of formula I "3A:

ou bien un produit de formule I" & ::

IV or with an organo-metal R4MgX, X representing a halogen atom, then with an acid to obtain either a product of formula 1,4A:

or a product of formula I "& ::

ou bien un produit de formule I"5A ::

V / firstly with a trimethylsulfonium halide in the presence of a strong base, then with a primary amine of formula H 2 N -alk, alk being defined as above, in the presence of an acid, with an alkyl chloroformate, by a strong base and finally by an acid, to obtain either a product of formula I'5A:

or a product of formula I "5A ::

ou bien un produit de formule

sous forme d'un mélange de deux diastéréoisomères au niveau de l'atome de soufre, sépare si désiré les deux diastéréoisomères, puis soumet soit leur mélange, soit chacun d'eux séparément, à l'action d'un acide, pour obtenir ou bien un produit de formule

ou bien un produit de formule

sous forme d'un mélange de deux diastéréoisomères ou un diastéréoisomère, sépare le cas échéant, les diastéréoisomères, puis soumet soit leur mélange, soit chacun d'eux séparément, à l'action du N-chloro ou du Nbromo succinimide, pour obtenir ou bien un produit de formule I'6A :

ou bien un produit de formule I"6A :

et que, si désiré, l'on traite les produits de formules I'A' I"A'
I'2A' I"2A' I"'2A' I""2A' I'3A' I"3A' I'4A' I"4A' I'5A'
I"5A' I'6A et I"6A par un orthoformiate d'alkyle en présence d'un acide puis par un agent de déshydrogénation pour obtenir ou bien les produits de formule I'B' I'2B' I"'2B' I'3B' I'4B' I'5B et
I'6B de formules suivantes :

VI / firstly with a trimethylsulfonium halide in the presence of a strong base, then with methyl terbutyl sulfoxide in the presence of n-butyllithium to obtain either a product of formula

or a product of formula

in the form of a mixture of two diastereoisomers at the level of the sulfur atom, separates, if desired, the two diastereoisomers, and then subjects either their mixture or each of them separately to the action of an acid, to obtain or well a product of formula

or a product of formula

in the form of a mixture of two diastereoisomers or a diastereoisomer, optionally separates the diastereoisomers, then subjects either their mixture or each of them separately to the action of N-chloro or Nbromo succinimide, to obtain or although a product of formula I'6A:

or a product of formula I "6A:

and that, if desired, the products of formulas IAA 'I "A' be processed
2A, 2A, 1A, 2A, 1A, 3A, 4A, 4A, 5A
5A, 6A and 6A with an alkyl orthoformate in the presence of an acid and then with a dehydrogenating agent to obtain the products of formula IB 'I'2B' I "'2B'I'3B'I'4B'I'5B and
I'6B of the following formulas:

ou bien les produits de formules I"B' I"2B' I""2B' I"3B' I"4B'
I"5B et I"6B de formules suivantes ::

produits de formule I'B' I'2B' I"'2B' I'3B' I'4B' I'5B'
I'6B' I"B' I"2B' I""2B' I"3B' I"4B' I"5B et I"6B que l'on traite si désiré - ou bien par un organo magnésien de formule R1MgX' éventuellement en présence d'un sel de cuivre, formule dans laquelle R1 a la signification indiquée ci-dessus et X' représente un atome d'halogène, - ou bien par un organo métallique de formule (R1)2 CuLi puis par un acide, pour obtenir ou bien les produits de formules I'C' I'2C' I"'2C'
I'3C' I'4C' I'5C et I'6C :

ou bien les produits de formule I"C' I"2C' I""2C' I"3C' I"4C'
I"5C et I"6C ::

sous forme d'un mélange d'isomères 7&alpha;et 7ss, mélange que, si désiré, l'on sépare et que, si désiré,l'on soumet les produits 7ss à å un réactif de déshydrogénation pour obtenir les produits t6 (7) correspondants; - ou bien l'on soumet les produits de formules I'B, I'2B' I"'2B'
I'3B' I'4B' I'5B' I'6B' I"B' I"2B' I""2B' I"3B' I"4B'
I"5B et et I"6B à l'action d'un réactif choisi dans le groupe constitué par l'iodure de triméthylsulfonium et l'iodure de triméthylsulfoxonium en présence d'une base forte pour obtenir ou bien les produits de formules I'D' I'2D' I"'2D' I'3D' I'4D I'5D et I'6D :

or the products of formula I "
I "5B and I" 6B of the following formulas:

products of formula I'B 'I'2B' I "'2B'1'3B'I'4B'I'5B'
1B, 2B, 4B, 5B and 1B, which are treated if desired - or by an organo magnesium of formula R1MgX ' optionally in the presence of a copper salt, formula in which R 1 has the meaning indicated above and X 'represents a halogen atom, - or by an organo metal of formula (R 1) 2 CuLi then by an acid, to obtain either the products of formulas I'C 'I'2C' I "'2C'
I'3C 'I'4C'1'5C and 1'6C:

or the products of formula I ## STR2 ##
I "5C and I" 6C ::

in the form of a mixture of 7α and 7β isomers, a mixture which, if desired, is separated and, if desired, subjected to a dehydrogenation reagent to obtain the t6 products (7). ) corresponding; or else the products of formulas I'B, I'2B 'I "' 2B 'are subjected
I'3B 'I'4B'1'5B'I'BB' I 'B' I '2B' I '"2B'I" 3B 'I "4B'
5B and 6B to the action of a reagent selected from the group consisting of trimethylsulfonium iodide and trimethylsulfoxonium iodide in the presence of a strong base to obtain either the products of formulas I ' From DID'I''D 2D 'I'3D 1'4D 1'5D and 1'6D:

ou bien les produits de formule I"D' I"2D' I""2D' I"3D' I"4D'
I"5D et I"6D ::

sous forme d'un mélange 6&alpha;, 7&alpha; et 6ss, 7ss et sépare, si désiré, les isomères ainsi obtenus et que si désiré l'on traite les produits 1,A'
I"A' I'2A' I"2A' I"'2A' I""2A' I'3A' I"3A' I'4A' I"4A'
I'5A' I"5A' I'6A' I"6A' I'B' I'2B' I"'2B' I'3B' I'4B'
I'5B' I'6B' i"B' I"2B' I""2B' I"3B' I"4B' I"5B' I"6B'
I'C' I'2C' I"'2C' I'3C' I'4C' I'5C' I'6C' I"C' I"2C'
I""2C' I"3C' I"4C' I"5C' I"6C' I'D' I'2D' I"'2D' I'3D'
I'4D' I'5D' I'6D' I"D' I"2D' I""2D' I"3D' I"4D' I"5D et
I"6D par un réactif de déshydrogénation ou par un microorganisme susceptible de déshydrogéner la molécule en position 1 (2) pour obtenir les produits correspondants comportant une insaturation en position 1 (2) et que, si désiré,l'on traite les produits de formules IA, IB' IC et 1D et les produits correspondants comportant une insaturation en position 1 (2) à l'aide d'un hydroxyde alcalin ou de l'ammoniaque pour obtenir les produits correspondants dans lesquels X représente un radical hydroxyle et Y représente un radical -CH2CH2CO2M' dans lequel M' représente un atome de métal alcalin ou un radical ammonium et, si désiré, soumet les produits ainsi obtenus à l'action d'un agent acide pour obtenir les produits dans lesquels X représente un radical hydroxyle et Y représente un radical-CH2CH2CO2H, et que si désiré l'on traite les produits dans lesquels le substituant en position 10 comporte un substituant R du type hydroxyalkyle, par un tétrabromure ou tetrachlorure de carbone, en présence de triphénylphosphine, pour obtenir les dérivés bromés et chlorés correspondants, et que si désiré, L'on traite les produits dans Lesquels le substituant en position 10 comporte une triple liaison par un agent d'hydrogénation sélective pour obtenir les produits correspondants dans lesquels le substituant en position 10 comporte une double liaison, et que si désiré, l'on traite les produits comportant en position 10 un substituant éthynyl par un halo-succinimide pour obtenir les produits correspondant comportant en position 10 un substituant -C#C-Hal, et que si désiré, l'on acyle ou éthérifie Le radical hydroxyle en position 17 ss des produits comportant en position 17 &alpha; un atome d'hydrogene, un radical R4 ou un radical -CH2-CH2-CH2OH.

or the products of formula I "D" I "2D" I "" 2D "I" 3D "I" 4D '
I "5D and I" 6D ::

as a 6 &alpha;, 7 & alpha mixture; and 6ss, 7ss and separates, if desired, the isomers thus obtained and if desired the products 1, A 'are treated
1A, 2A, 2A, 2A, 1A, 3A, 4A, 4A, 1A.
I'5A 'I "5A'I'6A'I"6A'1'B'I'2B' I "'2B'I'3B'I'4B'
I'5B 'I'6B' I 'B' I '2B' I '"2B'I" 3B 'I "4B'I" 5B 'I "6B'
I'C 'I'2C' I '' 2C 'I'3C'I'4C'I'5C'I'C'I' C 'I' 2C '
1 "2C 'I"3C' I "5C 'I"5C' I?
1DD '' D '''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''
6D by a dehydrogenation reagent or by a microorganism capable of dehydrogenating the molecule at the 1 (2) position to obtain the corresponding products having unsaturation at the 1 (2) position and, if desired, treating the products of formulas IA, IB 'IC and 1D and the corresponding products having unsaturation in position 1 (2) using an alkaline hydroxide or ammonia to obtain the corresponding products in which X represents a hydroxyl radical and Y represents a radical -CH 2 CH 2 CO 2 M 'in which M' represents an alkali metal atom or an ammonium radical and, if desired, subjects the products thus obtained to the action of an acidic agent to obtain the products in which X represents a hydroxyl radical and Y represents a radical -CH 2 CH 2 CO 2 H, and if desired one treats the products in which the substituent at the 10-position comprises a substituent R of the hydroxyalkyl type, with a tetrabromide or tetrachloride of carbon, in the presence of triphenylphosphine, to obtain the corresponding brominated and chlorinated derivatives, and that if desired, the products in which the substituent at the 10-position is triple bonded by a selective hydrogenation agent to obtain the corresponding products are treated. wherein the substituent at the 10-position has a double bond, and if desired, the products having an ethynyl substituent substituted with a halosuccinimide are treated to give the corresponding products having a C # -C substituent at the 10-position. -Hal, and if desired, is acylated or etherified The hydroxyl radical in position 17 ss of products having position 17 &alpha; a hydrogen atom, a radical R4 or a radical -CH2-CH2-CH2OH.

 The groups protecting the functional groups that may comprise R, for example the hydroxyl or amino groups, are chosen from known groups.

 The protecting group of the ketone function that K represents may be a ketal, a thioketal, an oxime or an alkoxime. Preference is given to a ketal such as bis methoxy or a cyclic ketal such as ethylene dioxy. These groups are eliminated in acidic medium.

 The trimethylsulfonium halide which is preferably used is iodide. The strong base in the presence of which one acts is preferably potassium terbutylate.

 A metal derivative of acetonitrile is then used, which may, for example, be the lithium derivative prepared in the presence of butyllithium.

The derivative thus obtained, which has in position 17 a cyanoethyl radical, is then subjected to the action of a base which may be, for example, sodium hydroxide or potassium hydroxide and the product obtained is preferably acidified with hydrochloric acid.

 The action of allyl tetraalkyl phosphorodiamidate, preferably tetramethyl, on the products of formulas II 'or II "is carried out according to the method described by STURTZ and YAOUANC, Synthesis 1980 p 289. The strong base in the presence of which Butyl lithium is preferably used in the presence of diazabicyclooctane (DABCO) or a crowned ether and is then acidified with hydrochloric acid, preferably.

 The action of the product of formula XMg-CH 2 CH 2 CH 2 OB on the products of formulas II 'or II "is carried out according to the conventional methods of magnesium preparation.The radical B may represent a usual protective group of the hydroxyl radical, such as tetrahydropyranyl or ter-butyl B may also be a magnesium salt such as MgCl The preparation and use of such a moiety is described by CAHIEZ, ALEXAKIS and NORMAND Tetrelett nn 33, 1978 pp. 3013. then acidify with an acid, preferably hydrochloric acid.

 Transformation of the products of formulas I'2A or 1, 2A into products I "'2A or I" "2A is preferably carried out in the presence of tosyl chloride and an amine base such as pyridine.

 The reduction of the products of formulas II 'or II "into products of formulas I'3A or I" 3A is carried out by the conventional methods. For example, a hydride such as sodium borohydride can be used.

 The hydrolysis of the protective group K is carried out by conventional methods in acidic medium, for example, by the addition of hydrochloric acid.

 The addition of the magnesium XMgR4 is carried out according to the standard methods, it is carried out for example in an anhydrous solvent such as tetrahydrofuran or ethyl ether and at a temperature below room temperature. As for the other reactions indicated above, an acid such as hydrochloric acid is then reacted to regenerate the ketone function in position 3.

The strong base used in the cyclization leading to the product
I'5A or I "5A is preferably methanolic potassium hydroxide.

 The acid in the presence of the reaction with the amine is preferably para-toluenesulfonic acid.

 The trimethylsulfonium halide is preferably an iodide and the strong base used is sodium hydroxide, potassium hydroxide or potassium terbutylate.

 The separation of the diastereoisomers is carried out by conventional means of chromatography and crystallization.

The action of an orthoformate on the products I'A, I "A 'I'2A'
2A, 2A, 1A, 3A, 4A, 4A, 5A, 5A, 6A and 1,16A is intended to prepare 3-alkoxy products # # 3,5 of formulas:

 In the above formulas the radicals R, R2 and R4 have the above meaning, Alk3 represents an alkyl radical having 1 to 4 carbon atoms. The orthoformate used is preferably ethyl orthoformate in the presence of para-toluenesulfonic acid.

The dehydrogenation agent used is preferably chloranil (1,4-tetrachlorobenzoquinone). We can also use the
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone). The action of the product of formula R1MgX 'in which X' represents a chlorine, bromine or iodine atom is preferably carried out in the presence of a cupric salt such as acetate, chloride, cupric bromide or a cuprous salt such as chloride, bromide or cuprous iodide.

 The acid which is used after the action of a product of formula (R1) 2CuL; is hydrochloric, nitric or sulfuric acid.

 The possible separation of the different isomers is carried out by.

chromatography or by fractional crystallization. The possible dehydrogenation of the products 7ss is carried out under the preceding conditions.

 The base used to form the ylide corresponding to trimethylsulfonium iodide and trimethylsulfoxonium iodide is sodium hydride or potassium tert-butoxide.

 The optional preparation is carried out according to the conventional methods set out above.

 The transformation of the products IA to 14A 'IB to 14B, IC to 14C and ID to 14D to products comprising unsaturation in position 1 (2) is preferably carried out by acting biochemically, the bacterium "Arthrobacter simplex". Another microorganism can also be used. The reaction is preferably carried out in a buffered aqueous medium.

 It is also possible to use the chemical route by subjecting the products to the action of a derivative of p-benzoquinone or chloranil, the reaction taking place within, for example, a solution in an organic solvent such as dioxane. , acetone, benzene or tert-butyl alcohol.

 The selenous or phenylselenic anhydride may also be used as the dehydrogenation reagent.

 The alkali metal hydroxide which is optionally subjected to the products of formulas I and II, and the corresponding products comprising unsaturation in position 1 (2) is preferably soda or potash.

 The acidic agent to which the products thus obtained are optionally subjected is hydrochloric, sulfuric, nitric or acetic acid.

 The selective hydrogenation agent which is optionally subjected to the products having a substituent having a triple bond in position 10 is preferably hydrogen in the presence of a catalyst such as Lindlar's catalyst.

 The halosuccinimide which is reacted with the products having in position 10 an ethynyl substituent is N-bromo or N-chlorosuccinimide. The operation is preferably carried out in the presence of silver nitrate.

The optional acylation of the products comprising at position 17 a hydroxyl radical and at position 170 (a hydrogen atom or a radical
R4 is carried out according to the usual methods. For example, an anhydride or an acyl halide such as acetic anhydride or acetyl chloride may be used. The etherification of the same products is also carried out under the usual conditions, for example using an alkyl halide.

ou bien un produit de formule II"A :

dans lesquelles K, R' et R2 ont la signification indiquée ci-dessus et
R17 représente un atome d'hydrogène ou un groupement protecteur du radical hydroxyle par un acide et éventuellement par un réactif de déprotection du radical hydroxyle.The subject of the invention is also a process for preparing the product of formulas I'3A and I "3A as defined above, characterized in that either a product of formula II, A:

or a product of formula II "A:

in which K, R 'and R2 have the meaning indicated above and
R17 represents a hydrogen atom or a group protecting the hydroxyl radical with an acid and optionally with a hydroxyl radical deprotection reagent.

 When R17 represents a protecting group of the hydroxyl radical, it is chosen from known groups.

 Benzoyl or tetrahydropyranyl groups are preferred. These groups are normally removed by the acid treatment to obtain the 3-keto # 4 function. If this is not the case, the formula II-A molecules are treated with a conventional deprotection reagent.

The preferred acid is hydrochloric acid.

selon par exemple la méthode décrite dans Tetrahedron Letters1984, 25, 3425-3428. The products of formulas II 'and II'A can be prepared as follows:
The products of formula II 'can be prepared by epimerization of the corresponding product 13

according to for example the method described in Tetrahedron Letters1984, 25, 3425-3428.

 The products of formula II'A can be prepared by reduction of the corresponding products of formula II '. For example, it is possible to use a hydride such as sodium borohydride.

dans lequel R'17 représente un groupement protecteur du radical hydroxyle pour obtenir un produit de formule 11,,A :

dans laquelle R17 représente un atome d'hydrogène ou le radical R'17 précédent. The products of formula 11,, A used starting from the process of the present application can be prepared by reacting a lithien of formula R'-C # C-Li on a product of formula III:

in which R'17 represents a protecting group of the hydroxyl radical to obtain a product of formula 11,, A:

in which R17 represents a hydrogen atom or the radical R'17 above.

 The protective group that may represent R'17 is preferably an acyl group such as benzoyl. Lithium R'-CC-Li can be prepared by the usual methods; the hydrolysis of the R'17 group is also carried out by the usual methods if the cleavage has not already occurred during the previous reaction. Hydrolysis can be used in a basic medium. The oxidation at position 17 is carried out for example by using pyridinium chlorochromate prepared according to Tet. Letters. n31 (1975) p. 2647. Such an example of preparation is described in European Patent 0,023,856 tex. 5).

que l'on traite ensuite par un réactif d'oxydation tel que le chlorochromate de pyridinium pour obtenir le produit de formule II" :

In order to obtain the products of formula II, the products of formula I-3A obtained from the products of formula II A can be treated, for example, with a ketone-protecting reagent so as to obtain a product. of formula IV:

that is then treated with an oxidation reagent such as pyridinium chlorochromate to obtain the product of formula II ":

par action d'un dérivé halogéné du radical R' sur l'acétylure métallique du produit correspondant.Pour former L'acétylure du produit, on utilise de préférence un lithien tel que le méthyllithium ou le butyllithium.In a preferred embodiment of the preparation process above, the products of formula II, wherein R 'is different from a hydrogen atom are prepared from the corresponding product:

by action of a halogenated derivative of the radical R 'on the metal acetylide of the corresponding product.To form the acetylide of the product, a lithian such as methyllithium or butyllithium is preferably used.

 Examples of preparation as described above are given below in the examples.

The products of type A or III are known in the literature or can be prepared according to methods by analogy from known products. For example, there may be mentioned as a patent describing a product of type A, the European patent EP 0 023 856. The products of formula III may be prepared by a known method from the 3-keto derivatives 4,9 D-homo steroids described in the US patent
USP 3,555,096.

 The products of formula I as defined above have very interesting pharmacological properties; they are in particular antagonists of aldosterone and increase the diuresis hydrosodée with conservation of the organic potassium.

 The products of formula (I) also offer the advantage of having only very few secondary hormonal effects.

 In particular, tests carried out on the receptor and in vivo have shown that the products of formula (I) are less anti-androgens than anti-aldosterone products described above.

 The products of formula (I) can therefore be used advantageously to fight, in particular, against arterial hypertension and heart failure.

 The object of the invention is therefore, as medicaments, the products of formula (I) as described above.

The subject of the invention is more particularly, as medicaments, the products of general formula I 'in which R- is chosen from the group formed by a hydrogen atom, an alkyl radical
X and Y are such that either X represents a hydroxyl radical and Y represents either a CH 2 CH 2 CO 2 M 'radical in which M' represents a hydrogen atom or an alkali metal atom, or
Y represents a hydrogen atom X and Y represent a radical

 The subject of the invention is more particularly that, as medicaments, the products of general formula I, whose names follow: ## STR1 ## the lactam of 10ss-ethynyl acid 17ss-hydroxy-3-oxo-13-alpha, 17-alpha; 19-nor-pregna 4,9 (11) -dien-21-carboxylic acid; 10β-ethynyl 17β-hydroxy 13α-estra-4,9 (11) -dien-3-one; 17β-hydroxy-3-oxo-10β-β-1-propynyl) β-17-alpha-19β-nor-pregna-4,9 (11) -dien-21-carboxylic acid, β-lactone; 17ss-hydroxy 10ss- (1-propynyl) 13α-estra-4,9 (11) -dien-3-one.

g-lactone of 10ss-ethynyl 17a acid (9-hydroxy-3-oxo-19-nor (17a-alpha))
D-homo-pregna-4,9 (11) dien-21-carboxylic acid; 10ss-ethynyl 17a 4-hydroxy-D-homo-estra-4,9 (11) -dien-3-one; 17-hydroxy-3-oxo 10ss- (1-propynyl) 19-nor (17α-alpha) D-homo-prenga-4,9 (11) -dien-21-carboxylic acid lactam.

17α (3-hydroxy-10) - (1-propynyl) -D-homo estra-4,9-din-3-one.

 The dosage varies with the condition being treated and the route of administration; it may range for example from 5 mg to 500 mg and preferably from 10 to 200 mg per day in the adult orally for the product of Example 1.

 The compounds of formula (I) are used orally, rectally, transcutaneously, or intravenously. They may be prescribed in the form of tablets, coated tablets, cachets, capsules, granules, emulsions, syrups, suppositories and injectables.

The invention therefore also relates to pharmaceutical compositions containing as active ingredient at least one compound of formula (I). These compositions 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 following examples illustrate the invention without limiting it.

 In the examples in particular 1 and 3 below, the indicated structure 17-hydroxy-17-alpha-pregnane is the most probable but could not be affirmed with certainty. The structure 17α-hydroxy 17ss-pregnane can not be excluded.

Example 1: gamma-lactone of 10ss-ethynyl acid 17ss-hydroxy-3-oxo-13α; 17α-19-nor-pregna 4.9 (11) -dien-21-carboxylic acid.

Step A: 3,3- (1,2-Ethanediyl) acetalcyclic 10ss-ethynyl-5-hydroxy-13α-estr-9 (11) -en-3,17-dione.

 The epimerization of carbon 13 is carried out photochemically.

A high pressure mercury vapor lamp of the type TQ 150 Z3 is used, mark: original Hanan.

 In the reactor equipped with a thermoprobe and a magnetic stirrer, the mercury vapor lamp is immersed under a double jacket of quartz. The lamp is cooled by a circulation of ice cold distilled water in a closed circuit. A peristaltic pump and a copper coil dipped in a water + ice bath are used. 2.55 g of 10β-ethynyl 5α-hydroxy-9 (11) -n-3,17-dione 3,3- (1,2-ethanediyl) acetalcyclic are dissolved in 500 ml of dioxane at 18 ° C. After 20 minutes of irradiation, the temperature is 23nC, it is left under irradiation at this temperature for 2 hours. It is concentrated to dryness by distillation under reduced pressure and 2.95 g of crude product is obtained. The crude product is chromatographed on silica, eluting with the gasoline G / ethyl acetate mixture (70-30) to obtain 1.62 g. of product sought, dissolved in the minimum of methyl chloride, filtered, added isopropyl ether, concentrated to early crystallization, ice, drained, washed, dried and obtained 1.46 g of pure desired product. Mp = 168 ° C.

Controls:
IR spectrum (chloroform)
OH associated 3490cm-1; C = CH 3305cm-1; C = C 2100cm-1; 17-keto 1732cm-1
NMR spectrum (deuterochloroform) 1.13 ppm: 18-methyl 2.23 ppm: acetylenic H 3.99 ppm: methylenes of the ketal 4.10 ppm: OH 5.42 ppm: H 11.

Analysis: C22H2804 = 356.46
Calculated: CX 74.13 HX 7.92
Found: 74.1 7.8.

Stage B: &lt; -Lactone of 10ss-ethynyl 17ss-hydroxy-3-oxo-13α, 17α-19-nor-pregna-4,9 (11) -dien-21-carboxylic acid.

 20 ml of n-butyllithium are introduced into a flask under an inert atmosphere, the temperature is brought to -60 ° C., 20 ml of tetrahydrofuran are introduced, a solution of 3.5 ml of tetramethylphosphorodiamidate is added at -60 ° C. in the course of 20 minutes. allyl in 10 ml of tetrahydrofuran, stirred for 1 hour at -30nC, added in about 15 minutes a solution of 1.10 g of product obtained in Step A of Example 1 in 15 ml of tetrahydrofuran, allowed to return to 20nC in 30 minutes. minutes, stirred at 20mC for 2 hours, poured the reaction mixture into 200 cm3 of a saturated aqueous solution of ice-cold NH4Cl, extracted with methylene chloride, dried, concentrated to dryness by distillation under reduced pressure and 2.5 g an orange resin.

Decetalisation and dehydration.

 The 2.5 g of orange resin obtained beforehand are dissolved in 25 ml of ethanol, 3 cm 3 of 6N aqueous hydrochloric acid solution is added, the temperature is brought to 50 ° C., maintained for 2 hours, cooled, concentrated by dry distillation under reduced pressure, the residue is added a saturated aqueous solution of sodium chloride, extracted with methylene chloride, washed with a saturated aqueous solution of sodium bicarbonate, dried, concentrated to dryness by distillation under reduced pressure, chromatography on residue on silica, eluting with a mixture of gasoline G and ethyl acetate (50-50), obtain 550 mg of parmesan crystals, dissolve in the minimum of methylene chloride, filter, add isopropyl ether , concentrated until crystallization, ice, drained, washed, dried and obtains 450 mg of desired product. Mp = 200 ° C.

Controls:
IR (chloroform) C = O spectrum of γ-lactone 1765cm-1; O = C # 1673cm-1; C = C 1622cm-1 864cm-1; -C = CH 3305cm-1; -C = C-2100 cm-1
We observe a strong band at 1185cm-1
UV spectrum (ethanol) max. 235 nm 6 = 16900 max. 310 nm # = 85
RtlN spectrum (deuterochloroform) 0.97 ppm: 18-methyl 2.25 ppm: acetylenic H 5.73 ppm: H 11 5.81 ppm: H 4.

Analysis: C 23 H 26 O 3 = 350.46.

Calculated: CX 78.8 H max 7.48
Found: 78 7.6.

Example 2: 10ss-ethynyl 17ss-hydroxy 13α-estra-4,9 (11) -dien-3-one.

Step A: Cyclic 3,3- (1,2-ethanediyl) acetal of 5α, 17ss-dihydroxy-10ss-ethynyl 13α-estr-9 (11) -en-3-one.

 900 mg of cyclic 3,3- (1,2-ethanediyl) acetal of 10β-ethynyl 5α-hydroxy-13α-estr-9 (11) en-3,17-dione are suspended in 20 ml of ethanol. , introduced at + 5 ° C. in the course of 10 minutes, approximately 200 mg of 95% sodium borohydride, a gas evolution and a gradual dissolution of the steroid, stirred for 1 hour at + 5 ° C., concentrated to dryness by distillation under reduced pressure, added water, extracted with methylene chloride, washed with a saturated aqueous solution of sodium chloride, dried, concentrated to dryness by distillation under reduced pressure, chromatography the residue on silica eluting with a mixture of sodium chloride methylene and ethyl acetate (90-10) to 1Z ethanol, obtains 800 mg of crude desired product, dissolved in the minimum of methylene chloride, filtered, added isopropyl ether, concentrated until crystallization , ice, drain, dry and obtains 680 mg of pure desired product. F = 110nC.

Controls:
IR spectrum (chloroform)
Free OH 3600cm-1; OH associated 3489cm-1; -C # CH 3305cm-1; -CC-2100cm-1; ketal 1085cm-1
NMR (deuterochloroform) spectrum 1.07 ppm: 18-methyl 2.23 ppm: acetylenic H 3.83 ppm: H 17 3.99 ppm: ketal methylenes 4.03 ppm: OH 5.51 ppm: H 11.

Stage B: 10ss-ethynyl 17ss-hydroxy 13α-estra-4,9 (11) -dien-3-one.

 600 mg of the product obtained in Step A of Example 2 are dissolved in 10 ml of ethane, 2 cm 3 of aqueous 6N hydrochloric acid solution are added; the temperature is raised to 50 ° C. and maintained at this value for 2 hours and 30 minutes, concentrated to dryness by distillation under reduced pressure, a saturated aqueous solution of sodium chloride, extracted with methylene chloride, washed with a saturated aqueous solution of sodium bicarbonate, dry, concentrated to dryness by distillation under reduced pressure, chromatography the residue on silica eluting with a mixture of methylene chloride and ethyl acetate (90-10) at 1% ethanol, gives 380 mg of white crystals dissolve them in the minimum of methylene chloride, filter, add isopropyl ether, concentrate until crystallization, ice, drain, wash, dry and obtain 350 mg of product research. Mp 156 ° C.

 The HOREAU method confirms the S configuration of carbon 17.

Controls:
IR spectrum (chloroform)
O = CC = C 1671cm-1; O = CC = C # 1621cm-1; Free OH 3615cm-1; -CCH 3305cm-1; -C = C-2100cm-1.

NMR spectrum (deuterochloroform) 1.02 ppm: 18-methyl 2.23 ppm: acetylenic H 3.83 ppm: H 17 5.72 ppm: H 11 5.78 ppm: H 4.

Analysis: C20H2402 = 296.41
Calculated: C% 81.04 H% 8.16
Found: 81.3 8.3.

Example 3: 17ss-Hydroxy-3-oxo-1013- (1-propynyl) -α, 17α-19-nor-pregna-4,9 (11) -dien-21-carboxylic acid lactone.

Step A: Cyclic 3,3- (1,2-ethanediyl) acetal of 5-hydroxy 10ss- (1-propynyl) 13α-estr-9 (11) -en-3,17-dione.

 The epimerization of carbon 13 is carried out photochemically.

A high pressure mercury vapor lamp of the TQ 150 Z3 type (Hanan original) is used.

 The reactor is equipped with a thermoworld and a magnetic stirrer, the mercury vapor lamp is immersed under a double jacket of quartz. This is cooled by a circulation of distilled water, frozen in a closed circuit. A peristatic pump and a copper coil plunging in an ice-water bath are used.

 3.0 g of cyclic 3,3- (1,2-ethanediyl) acetal of 5α-hydroxy 10ss- (1-propynyl) estr-9 (11) en-3,17-dione are dissolved in 500 ml of dioxane. at + 18nC. After 30 minutes of irradiation, the temperature is obtained at + 26 ° C., the mixture is stirred for a further hour at + 26 ° C., the mixture is concentrated to dryness by distillation under reduced pressure and the residue is chromatographed on silica, eluting with the gasoline mixture G and ethyl acetate (7-3) gives 1.67 g of white crystals which are dissolved in the minimum amount of methylene chloride, filtered, isopropyl ether added, concentrated until the beginning of crystallization, ice, drained, washed, dried and obtained 1.42 g of sought product pure.F = 180 # C.

Controls:
IR spectrum (chloroform)
OH associated 3490cm-1; C # C-Me 2140cm-1; 17-keto 1730cm-1.

NMR spectrum (deuterochloroform) 1.13 ppm: 18-methyl 1.81 ppm: Me of propynyl 3.34 ppm: OH 3.98 ppm: methylenes of ketal 5.38 ppm: H 11.

Analysis: C23H3004 = 370.49
Calculated: CX 74.56H% 8.16
Found: 74.3 8.3.

Stage B: &lt; -lactone of cyclic 1,2-ethandiyl acetal acid of 5,17ss-dihydroxy-3-oxo-10ss- (1-propynyl) 13 &alpha;, 17 &alpha; -19-nor-pregna-9 (11 ) - dien-21-carboxylic acid.

 45 ml of n-butyllithium, 40 ml of tetrahydrofuran and then, in approximately 20 minutes at -50 ° C., a solution of 8 ml of allyl tetramethylphosphorodiamidate dissolved in 30 ml of solution is introduced successively at -50.degree. ml of tetrahydrofuran, stirred for 1 hour at -30nC, added in 15 minutes about 2.58 g of compound obtained in Step A of Example 3, allowed to return to + 20aC in 30 minutes, stirred at 20 ° C for 2 hours the reaction mixture is poured into 400 ml of a mixture of saturated aqueous solution of ammonium chloride and ice, extracted with methylene chloride, dried, concentrated to dryness by distillation under reduced pressure, the residue is chromatographed on silica, eluting with a mixture of Esence G and ethyl acetate (3-2) gives 1.9 g of crude product, dissolved in the minimum of methylene chloride, filtered, added isopropyl ether, concentrated to crystallization, ice, wring, wash, dries and gets 1.52 gd the product sought pure. F = 170nC.

Controls:
IR spectrum (chloroform)
OH associated 3500cm-1; -lactone 1763Cm-1
We observe a strong band at 1188cm-1
NMR spectrum (deuterochloroform) 1.03 ppm: 18-methyl 1.82 ppm: Me of propynyl 4.00 ppm: methylenes of ketal 5.42 ppm: H 11.

Analysis: C26H3405 = 426.56
Calculated: C% 73.21 HX 8.04
Found: 73.2 8.2.

17ss-Hydroxy-3-oxo-10ss- (1-propynyl) -α, 17α-19-nor-pregna-4,9 (11) -dien-21-carboxylic acid C-1-lactone.

 The steroid obtained in Step B of Example 3 is suspended in 20 ml of ethanol, 4 cm 3 of 6N aqueous hydrochloric acid solution is added, the temperature is brought to + 50 ° C., the mixture is kept there for 2 hours, cooled, concentrated to dryness by distillation under reduced pressure, the residue poured into a saturated aqueous solution of sodium chloride, extracted with methylene chloride, washed with a saturated aqueous solution of sodium bicarbonate, dried, concentrated to dryness by distillation under pressure reduced, chromatography the residue on silica eluting with a mixture of gasoline G and ethyl acetate (3-2), gives 1.3 g of light yellow crystals, dissolved in the minimum of methylene chloride, filter, add isopropyl ether, concentrate until crystallization, ice, drain, wash, dry and obtain 1.08 g of pure research product. Mp 202nC.

Controls:
IR spectrum (chloroform)
C = O &gamma; lactone 1765cm -1; O = CC = C-1672cm-1;
O = CC = C-1620cm-1; C = C (def) 864cm-1; -C # C- 2230cm-1.

NMR (deuterochloroform) spectrum 0.97 ppm: 18-methyl 1.83 ppm: Me of propynyl 5.68 ppm: H 11 5.74 ppm: H 4
Analysis: C24H2803 = 364.49
Calculated: C% 79.09 H% 7.74
Found: 78.9 7.6.

 The cyclic 3,3 (1,2-ethanediyl) acetal of 54-hydroxy 10ss- (1-propynyl) estr-9 (11) -En-3,17-dione used starting from Step A of Example 3 can be prepared as follows.

 In 25 cm3 of an ethereal solution of 1 M ethylmagnesium bromide diluted with 25 cm3 of anhydrous tetrahydrofuran, methylacetylene is bubbled between 0 and 5 ° C for 1 hour. 2.15 g of cyclic 1,2-acethanediyl acetal of 5α, 10α-epoxy-3-oxo-17α-trimethylsilyloxy estr-9 (11) -en-17ss-carbonitrile are added in 10 cm 3 of tetrahydrofuran, heated to 40 ° C. for 2 hours 30 minutes and leaves 16 hours at room temperature. Is added between 0 and 5nC, 20 cm3 of a solution of ammonium chloride, extracted with methylene chloride, washed with water, dried and concentrated to dry.The residue is dissolved in 30 cm3 of ethanol, added 3 cm3 of sodium hydroxide solution, stirred for 1 hour, diluted with 90 cm3 of water and extracted with chloroform, washed with water, dried and concentrated to dryness. The residue is recrystallized from methylene chloride-isopropyl ether and 1.21 g of expected product is collected. Mp = 204nC.

Example 4: 17ss-hydroxy 10ss- (1-propynyl) 13α-estra-4,9 (11) -dien-3-one.

Step A: 5α, 17α-Dihydroxy-10ss- (1-propynyl) 13α-estr-9 (11) -en-3-one cyclic 1,2-ethanediyl acetal.

 1 g of cyclic 3,3- (1,2-ethanediyl) acetal of 5-hydroxy 10ss- (1-propynyl) 13α- (-estr-9CI) -en-3,17-dione are suspended in 20 ml of methanol, introduced at + 5 ° C, in approximately 10 minutes 250 mg of sodium borohydride 95%, there is a gas evolution and gradual dissolution of the steroid in about 20 minutes, it is stirred for 1 hour, concentrated to dryness by distillation under reduced pressure, added water, extracted with methylene chloride, washed with saturated aqueous sodium chloride solution, dried, concentrated to dryness by distillation under reduced pressure, chromatography the residue on silica eluting with a mixture of G gasoline and ethyl acetate (3-2), obtains 880 mg of crude desired product, dissolved in the minimum amount of methylene chloride, filtered, added isopropyl ether, concentrated until crystallization, ice , wring, wash, dry and obtains 755 mg of pure desired product. Mp = 165 ° C and then 177 ° C.

Controls:
IR spectrum (chloroform)
OH free 3612Cm-1; OH associated 3490Cm-1; CEC 2030cm-1
NMR spectrum (deuterochloroform) 1.05 ppm: 18-methyl 1.79 ppm: propynyl 3.80 ppm: H 17 3.97 ppm: ketal methylenes 5.45 ppm: H 11.

Analysis: C29H3O4 = 372.50
Calculated: C% 74.16 H% 8.66
Found: 74.3 8.8.

Stage B: 17A-hydroxy 10ss- (1-propynyl) 13,130 (-estra-4,9 (li) -dien-3-one.

 870 mg of the steroid obtained in Step A of Example 4 is dissolved in 10 ml of ethanol, 1.6 cm 3 of 6N aqueous hydrochloric acid solution is added, the temperature is brought to 50 ° C. for 2 hours, the mixture is left stirring. at + 20nC overnight, distilled off the ethanol, poured the reaction mixture into saturated aqueous sodium chloride solution, extracted with methylene chloride, washed with saturated aqueous sodium bicarbonate solution, dried, concentrated to dryness by distillation under pressure relite, chromatography the residue on silica eluting with a mixture of gasoline G and ethyl acetate (1-1), obtains 650 mg of yellow crystals which are dissolved in the minimum of chloride of methylene, filter, add isopropyl ether, concentrate until crystallization, ice, drain, wash, dry and obtain 550 mg of pure desired product. Mp 156 ° C.

 / &alpha; / D20 = + 34.5 # (c = 1% chloroform).

 The HOREAU method confirms the S configuration of carbon 17.

Controls:
IR spectrum (chloroform)
C = O 1669cm-1; # 9 (11) 1634cm-1; O = CC = C-1619cm-1; -cc- 2218cm-1
NMR spectrum (deuterochloroform) 1.01 ppm: 18-methyl 1.82 ppm: Me of propynyl 3.81 ppm: H 17 5.69 ppm: H 11 5.74 ppm: H 4.

Analysis: C21H2602 = 310.44
Calculated: C% 81.25%% 8.44
Found: 81.0 8.4.

Example 5: 10ss-ethynyl 17α-hydroxy D-homo estra-4,9 (11) -dien-3-one.

Step A: 17-hydroxy-D-homo estra5 (10), 9 (11) -dien-3-one cyclic 1,2-ethanediyl acetal

 A mixture of 6.6 g of 17α-hydroxy-D-homo estra-4,9-dien-3-one, 660 cm 3 of benzene, 6 cm 3 of ethylene glycol, 50 mg of acid is refluxed for 4 hours. paratoluenesulphonic monohydrate, the condensed solvent being dried on silica gel and demoted into the reactor. It is cooled, triethylamine (1 cc) is added, the mixture is stirred for 10 minutes, diluted with water, extracted with ethyl acetate and washed with a solution. aqueous sodium chloride solution, dried, concentrated to dryness by distillation under reduced pressure, gives 8.1 g of brown oil which is filtered through 20 parts of silica eluting with a mixture of cyclohexane and ethyl acetate (6-4), to obtain 6.6 g of oil which is crystallized in ethyl acetate, obtains 3.544 g of desired product, F-160 ° C, dry concentrate mother liquors of crystallization, crystallizes in 4 volumes of isopropanol and obtains 1.995 g of desired product. F = 160nC.

Controls:
IR spectrum (chloroform)
Absence of C = O; OH 3615Cm-1; C = C 1640Cm-1; presence of ketal.

UV spectrum 1) In ethanol: infl. 230 nm E11 = 449; max. 236 nm ç = 17900 max. 242 nm # = 18800 max. 249 nm # = 12700 max. 270 nm f = 730 max. 300 nm # = 130 2) In ethanol, HCl, 0.1N: max. 234 nm # = 17500 max. 240 nm # = 18100 max. 320 nm # = 730
Stage e: 1,2-ethanediyl cyclic acetal of 17β-benzoyloxy 5α, 10α-epoxy D-homo estr-9 (11) -en-3-one and cyclic 1,2-ethanediyl acetal of 17α-benzoyloxy 5ss, 10β-epoxy D-homo estr-9 (11) -en-3-one.

1) Benzoylation.

 In a solution of 1 g of cyclic 1,2-ethanediyl acetal of 17ass-hydroxy-D-homo estra-5 (10), 9 (11) -dien-3-one obtained in stage A in 38 cm 3 of pyridine, a solution of 1.4 cm 3 of benzoyl chloride in 2 cm 3 of pyridine is added dropwise, the mixture is stirred for 30 minutes, poured into a saturated aqueous solution of sodium bicarbonate, stirred, extracted with methylene chloride, washed with water with a saturated aqueous solution of sodium chloride, dried, concentrated to dryness by distillation under reduced pressure, the residue is chromatographed on silica eluting with a mixture of cyclohexane and ethyl acetate (8-2) with 1X of triethylamine and collected 1.8 g of product used as such for epoxidation.

2) Epoxidation.

 1.8 g of the 17α-benzoyl product obtained in paragraph 1, 40 cm 3 of methylene chloride, 1.8 cm 3 of hexachloroacetone, brought to -30 ° C., are added dropwise 5.7 cm 3 of hydrogen peroxide to 50%, shake vigorously on overnight, carefully pour over 50 g of ice, 50 g of sodium thiosulphate pentahydrate and 8 g of sodium bicarbonate, add 100 cm3 of water, stir until the test is complete. for peroxide detection is negative for about 40 minutes, extracted with methylene chloride, washed with water with saturated aqueous sodium chloride solution, dried, concentrated to dryness by distillation under reduced pressure, chromatography the residue on silica in eluting with a mixture of cyclohexane and ethyl acetate (9-1) with 1n of triethylamine, obtains 390 mg of epoxide 5ss, 10 sec sought, F = 156nC and 520 mg epoxide 5 &alpha; 10 &alpha; research.

Controls: 1) Epoxide 5ss, 10ss.

IR spectrum (chloroform) absence of OH; OBz 1709cm -1, 1602cm -1; 1584cm -1; 1488cm-1
NMR spectrum (deuterochloroform) 1.04 ppm: 18-methyl 3.92 ppm: Methylenes from ketal 4.78 ppm: H 17a from the D-homo 5,78-5,87 ppm: H 7,36 to 7, 6 ppm and 8.3 to 8.13: H of the aromatic ring.

2) Epoxy 5 &alpha;, 10 &alpha;
IR spectrum (chloroform) absence of OH; OBz 1711cm-1, 1602cm-1; 1584cm -1; 1488cm-1.

NMR spectrum (deuterochloroform) 1.05 ppm: 18-methyl 3.93 ppm: cyclic acetal methylenes 6.03 ppm: H 11 7.37 to 7.67 ppm and from 8.02 to 8.13 ppm: H of the aromatic nucleus.

Stage C: cyclic 1,2-ethynyl 5α, 17α-dihydroxy-1,2-ethanediyl acetal D-homo estr-9 (11) -en-3-one.

1.2 g of 17α-benzoyloxy 5α, 10α-epoxy D-homo estr-9 (11) -en-3-one cyclic 1,2-ethanediyl acetal obtained in Stage B of Example 2 are mixed together. 18 cm3 of ethylenediamine, 2.48 g of lithium ethylenediamine acetylide complex, heated for 24 hours at 45 ° C., cooled, added 10 cm3 of ethylenediamine and 2.48 g of lithium acetylenide and ethylenediamine complex, heated at 45 ° C for 48 hours, cooled, poured in small portions on ice, extracted
The ethyl acetate, washed with water, with a saturated aqueous solution of sodium chloride, dried, concentrated to dryness by distillation under reduced pressure, chromatography the 1.1 g of residue on silica eluting with a mixture of hexane and ethyl acetate (6-4) to 1 # / ## triethylamine, crystallizes in isopropyl ether and obtains 680 mg of desired product. F = 189nC.

Controls:
IR spectrum (chloroform)
Free OH 3615cm-1; associated in 5 at 3487cm-1, #CH at 3305cm-1 C # C at 2110cm-1; C = C # 9 (11) 1660cm-1.

Stage D: 10ss-ethynyl 17ass-hydroxy D-homo estra-4.9 (11) -dien-3-one
660 mg of cyclic 1,2-ethanediyl acetal of 10β-ethynyl 5α, 17α-dihydroxy-D-homoestr-9 (11) -en-3-one obtained in Step C of
Example 2, 7 cm3 of ethanol and 1.2 cm3 of 5N aqueous hydrochloric acid solution, heated at 50nC for 2 hours, cooled to 0 ° C, added ice, basified to pH 9-10 with concentrated ammonia, extracted with methylene chloride, washed with water with a saturated aqueous solution of sodium chloride, dried, concentrated to dryness by distillation under reduced pressure, chromatography the 680 mg of residue on silica eluting with a mixture of hexane and ethyl acetate (6-4), obtains 440 mg of crude desired product, mp = 206 ° C., crystallizes in ethanol with hot filtration and obtains 400 mg of desired product. Mp 207 ° C.

= i / D = + 67 # + 1.5n (c = 0.7% chloroform)
Controls:
IR spectrum (chloroform)
Free OH 3613cm-1; #CH 3305cm-1; C # C 2100cm-1; conjugated ketone 1672cm-1; -C = C-1624Cm-1.

UV spectrum (ethanol) max. 237 nm # = 16700 infl. 310 nm.

NMR spectrum (deuterochloroform) 0.85 ppm: 18-methyl 2.22 ppm: ethynyl 3.28 ppm: H 17a 5.71 to 5.79 ppm: H 11 5.84 ppm: H 4.

Analysis: C21H26O2 = 310.44
Calculated: C% 81.25%% 8.44
Found: 81.0 8.4.

Example 6: 17α-hydroxy 10ss- (1-propynyl) D-homo estr-4.9 (11) -dien-3one.

Step A: 17a - (2H-tetrahydropyranyl-2-oxy) D-homo estra-5 (10), 9 (11) -dien-3-one cyclic 1,2-ethanediyl acetal acetal.

Stirring is carried out for 5 hours and 30 minutes at 20 ° C., a solution containing 1 g of cyclic 1,2-ethanediyl acetal of 17α-hydroxy-D-homo estra-5 (10), 9 (11) -dien-3-one. obtained in Stage A of Example 5, 20 cm 3 of dihydropyran, 30 cm 3 of ethyl ether, 20 mg of para-toluenesulphonic acid, neutralized with 1 cm 3 of triethylamine, stirred for 10 minutes, the organic phase washed twice. water, dried, concentrated to dryness by distillation under reduced pressure, crystallizes the 2.025 g of residue in 3 volumes of isopropyl ether and obtains 594 mg of desired product
F = 136nC, filtering the mother liquors of crystallization on 35 parts of silica eluting with a mixture of cyclohexane and ethyl acetate (9-1), obtains 650 mg of desired product (2nd jet).

Controls:
IR spectrum (chloroform) absence of OH; presence of

du THP : dédoublement du H angulaire à 4,62 ppm et 4,77 ppm 0,83 ppm : 18-méthyle 3,03 à 4,11 ppm : H 17a et

4,0 ppm : méthylènes de l'acétal cyclique 5,61 ppm : H 11.NMR spectrum (deuterochloroform + 1 drop of C5D5N)
Mixtures of isomers at the level of

THP: resolution of angular H at 4.62 ppm and 4.77 ppm 0.83 ppm: 18-methyl 3.03 at 4.11 ppm: H 17a and

4.0 ppm: cyclic acetal methylenes 5.61 ppm: H 11.

Stage B: 5α, 10α-epoxy-17β- (2H-tetrahydropyranyl-2-oxy) D-homo-estr-9 (11) -en-3-one cyclic 1,2-ethanediyl acetal and 1,2-ethanediyl cyclic 5β, 10α-epoxy-17β- (2H-tetrahydropyranyl-2-oxy) -dhomo estr-9 (11) -en-3-one cyclic aceta I.

1.242 g of 17α- (2H-tetrahydropyranyl-2-oxy) D-homo estra-5 (10), 9 (11) -dien-3-one cyclic 1,2-ethanediyl acetal obtained from Step A of Example 6, 20 cm3 of dichloromethane, 1.2 cm3 of hexachloroacetone, cooled to -30nC, dropwise introduced 3 cm3 of oxygenated water at 50X (200 volumes), let the internal temperature back to
OnC, stirred for 2 hours at this temperature, poured into a mixture containing 130 cm3 of ice water, 66 g of sodium thiosulfate, 7 g of sodium bicarbonate, stirred until the medium is no longer oxidizing or about 2 hours, extracted with dichloromethane, washed with a saturated aqueous solution of sodium thiosulfate, with saturated aqueous sodium chloride solution, dried, concentrated to dryness by distillation under reduced pressure, filtering the 1.2 g of residue over 100 g of silica eluting with a mixture of cyclohexane and ethyl acetate (9-1) gives 239 mg of the desired 5ss isomer, 10ss-epoxy, F # 110 # C and 696 mg of isomer 5α, 10α -poxy searched.

Controls: 1) on the 5ss isomer, 10ss-epoxy.

IR spectrum (chloroform)
C = C 1660cm-1
NMR spectrum (deuterochloroform + 1 drop of C5D5N) 0.82 ppm: 18-methyl 3.0 to 4.23 ppm: H17 and CH2O THP 3.93 ppm: methylenes of cetal 4.61 and 4.75 ppm: H Ketalic 5.87 ppm: H 11.

2) on the isomer 5α, 10α-epoxy.

IR spectrum (chloroform)
O = C 1658cm-1.

NMR spectrum (deuterochloroform + 1 drop of C5D5N) 0.83 ppm: 18-methyl 3.92 ppm: methylenes from cetal 4.6 and 4.74 ppm: H THP ketallic 6.38 ppm: H 11 (90% d) epoxy &alpha;)
Stage C: 10ss-Ethynyl 5α-hydroxy-17β- (2H-tetrahydropyranyl-2-oxy) -D-homoestr-9 (11) -n-3-one cyclic 1,2-ethanediyl acetal acetal.

 10.4 g of cyclic 1,2-ethanediyl acetal of 5α, 10α-epoxy 17α- (2H-tetrahydropyranyl-2-oxy) D-homo estr-9 (11) -en-3-one are mixed together. (titrant 90% isomer 5α, 10α and 10% isomer 5ss, 10ss), 105 cm3 of ethylenediamine, added all at once to the solution obtained 16.4 g of lithium acetylide complex and of ethylenediamine and heated the suspension for 18 hours at 45nC, cooled, poured in small portions over 350 g of ice, extracted with methylene chloride, washed with a saturated aqueous solution of sodium chloride, dried, concentrated to dryness by distillation under reduced pressure, chromatography the 11.1 g of residue obtained on silica eluting with a mixture of n-hexane and ethyl acetate (7-3) to 5 # / ## triethylamine and obtains 8.25 g of sought product.

Controls:
IR spectrum (chloroform)
OH 3490cm-1 (associate); ECH 3305cm-1 (F); CC 2100cm-1 (f);
OTHP and probable ketal.

NMR spectrum (deuterochloroform + 1 drop of C5D5N) 0.83 ppm: 18-methyl 2.2 ppm: H ethynyl 3.05 to 4.3 ppm: H 17 and CH 2 O THP 4.42 ppm: methylenes of ketal 4, 60 to 4.75 ppm: H THP ketalic 5.5 ppm: H 11.

Step D: 5-Hydroxy-O-3- (1-propynyl) -17- (2H-tetrahydropyranyl-2-oxy) -D-homoestr-9 (11) -en-3-one cyclic 1,2-ethanediyl acetal acetal.

 2.23 g of cyclic 1,2-ethanediyl acetal of 10ss-ethynyl 50 (-hydroxy-17ass- (2H-tetrahydropyranyl-2-oxy) D-homo-estr-9 (11) -en-3 were mixed. one obtained in Step C of Example 6, 22 cm3 of tetrahydrofuran, introduced dropwise to OnC, 7.3 ml of methyl methacrylate at 1.6 mol / liter in ether, allowed to rise to room temperature, added drop 3.2 cm3 of methyl iodide are added dropwise, the mixture is stirred for 10 minutes, the mixture is cooled to 0 ° C. and a saturated aqueous solution of ammonium chloride is stirred dropwise, the mixture is extracted with ethyl acetate and washed with water. a saturated aqueous solution of sodium chloride, dried, concentrated to dryness by distillation under reduced pressure, chromatography on silica impregnated with silver nitrate, eluting with a mixture of n-hexane, ethyl acetate and TEA (7 -3-1 # / ##) and get 1.89 of wanted product.

Controls:
IR spectrum (chloroform)
Presence of OH in 3490cm-1; OTHP probable 1660cm-1 # 9 (11).

NMR Spectrum (deuterochloroform + 1 drop of C5D5N) 0.83 ppm: 18-methyl 1.81 ppm: H methyl propynyl 2.77 ppm: H 3.98 ppm: methylenes of ketal 4.59 and 4.75 ppm THP ketalic 5.47 ppm: H 11.

Stage E: 17α-hydroxy 10ss- (1-propynyl) D-homo estra-9 (11) -dien-3-one.

 820 mg of 5α-hydroxy-10ss- (1-propynyl) -17- (2H-tetrahydropyranyl-3-oxy) -D-homo-estr-9 (11) -3-one cyclic 1,2-ethanediyl acetal are mixed together. in Step D of Example 6, 10 cm3 of ethanol and 2 cm3 of 5N aqueous solution of hydrochloric acid, The solution obtained at 50 ° C for 2 hours, cooled, concentrated at low volume under reduced pressure, added the ice, basified to pH 9 with concentrated ammonia, extracted with methylene chloride, washed with a saturated aqueous solution of sodium chloride, dried, concentrated to dryness by distillation under reduced pressure and 630 mg of sought product. Mp = 152 ° C.

/ &alpha; / D = + 91 # # 2 # (c = 1% CHCl3)
Controls:
IR spectrum (chloroform)
OH 3614cm-1; conjugated ketone 1669Cm-1; -C 1621Cm-1.

UV spectrum max. 237 nm # = 15600
NMR Spectrum (CDCl 3) 0.85 ppm: 18-methyl 1.82 ppm: Methyl propynyl at 3.27 ppm: H 17 5.76 ppm: H 4.

Example 7: &gamma; 17aA-hydroxyl-10ss-ethynyl-3-oxo-19-nor (17a-alpha) D-homo-pregna-4,9 (11) -dien-21-carboxylic acid lactone.

Step A: cyclic 1,2-ethynyl-17α-hydroxy-homo-5,9 (11) -dien-3-one 1,2-ethanediyl acetal.

 1.9 g of cyclic 1,2-ethanediyl acetal of 10β-ethynyl 5α-hydroxy-17β- (2H-tetrahydropyranyl L-2-oxy) D-homo is mixed together. 3- one obtained in Step C of Example 6, 19 cm3 of ethanol, 2 cm3 of water, 190 mg of para-toluenesulphonic acid, stirred for 2 hours under reflux, cooled, concentrated to low volume, solubilized the oil obtained in 50 cm 3 of benzene, 2 cm 3 of ethylene glycol and 200 cm 3 of para-toluenesulphonic acid are added, refluxed, removing traces of water by azeotropic distillation, recycling the dried solvent, maintaining reflux for 5 hours, cooling neutralized by addition of 2 cm 3 of triethylamine, stirred for 10 minutes, diluted with water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried, concentrated to dryness by distillation under reduced pressure, crystallizes the 2.58 g of residue obtained in 10 cm3 of methanol, isolates 716 mg of desired product, mp = 194 ° C., c. Dry the mother liquors of crystallization dry, chromatography the 1.712 g of residue obtained on silica eluting with a mixture of cyclohexane and ethyl acetate (7-3) with 1n triethylamine and obtains 647 mg of desired product.

Controls:
IR spectrum (chloroform)
OH 3613cm-1; #CH 3304cm-1; -C = C-2100cm-1; C = C 1665cm-1
NMR spectrum (CDCl3 + 1 drop of C5D5N) 0.87 ppm: 18-methyl 2.17 ppm: H ethynyl 2.64 ppm: H hydroxyl 3.28 ppm: H 17a 3.98 ppm: methylenes of ketal 5.54 and 5.61 ppm: H 11 5.74-5.82 ppm: H 6.

Stage B: Cyclic 3,3- (1,2-ethanediyl) acetal of 10ss-ethynyl D-homo estra-5,9 (11) -dien-3,17a-dione.

80 mg of cyclic 1,2-ethanedjyl acetal of 10ss-ethynyl 17ass-hydroxy-D-homo estra-5,9 (11) -dien-3-one cyclic obtained from Step A of
Example 7, 2 cm3 of dichloromethane, introduced at once 120 mg of pyridinium chlorochromate, stirred for 2 hours at 20nC, added 2 g of hyflosupersel, stirred for 10 minutes, filtered, the filtrate was concentrated to dryness by distillation under reduced pressure, chromatography the 150 mg of residue obtained on silica eluting with a mixture of cyclohexane and ethyl acetate (7-3) and 70 mg of desired product. Mp 240 ° C.

Controls:
IR spectrum (chloroform)
Ketone 1700cm-1; C = CH 3304cm-1
RTlN spectrum (CDCl3 + 1 drop of C5D5N) 1.12 ppm: 18-methyl 2.17 ppm: H ethynyl 3.95 ppm: methylenes of the ketal 5.55 ppm: H 11 5.77 at 5.83 ppm: H 6.

Stage C: cyclic 1,2-ethanediyl acetal of the gamma-lactone of 17ass-hydroxy acid 10ss-ethynyl-3-oxo-19-nor (17α-alpha) D-homo pregna-5,9 (11) diene 21-carboxylic acid.

 2.6 cc of tetrahydrofuran (2.6 cc) are introduced into the mixture at -50 ° C. and then at 0.25 g of allyl tetramethylphosphorodiamidate dissolved in 2 cm3 of tetrahydrofuran, stirred for 1 hour at -30 ° C., 0.2 g of cyclic 3,3- (1,2-ethanediyl) acetal of 10β-ethynyl D-homo estra 5,9 (11) -dien-3,17- dione obtained in Step B of Example 7 in solution in 6 cm3 of tetrahydrofuran, allowed to return the temperature to 20nC, stirred for 2 hours and 30 minutes, added to OnC 5 cm3 of 2N aqueous solution of hydrochloric acid, stirred for 30 minutes. minutes, extracted with methylene chloride, washed with water, dried, concentrated to dryness by distillation under reduced pressure and 405 mg of crude desired product used as is for the next stage.

Stage D: &gamma; Lactone of 10ss-ethynyl 17a-hydroxy-3-oxo-19-nor (17α-alpha) D-homo pregna-4,9 (11) -dien-21-carboxylic acid.

- 78 mg de , F = 222nC

The 405 mg of crude product obtained in Step C of Example 7 is dissolved in 5 cm 3 of ethanol, 2 cm 3 of aqueous 1/2 Cl solution of hydrochloric acid are added under an inert atmosphere and heated at 50 ° C. for 1 hour. 30 minutes, cooled, concentrated to dryness by distillation under reduced pressure, methylene chloride added, washed with water, dried, concentrated to dryness by distillation under reduced pressure, 203 mg of residue obtained, chromatography 0.2 g of residue on silica, eluting with a mixture of cyclohexane and ethyl acetate (7-3) and obtaining 36 mg of QA

- 78mg of, F = 222nC

 The product is crystallized from a mixture of methylene chloride and isopropyl ether and gives 58 mg. Mp 222 ° C.

1761cm-1 &gamma;-lactame 1673cm-1 3-céto -C=C- 1624cm-1 ; HC# 3305cm-1 ; -C#C- 2100cm-1.Controls 1) On the product #:
IR spectrum (chloroform)

1761 cm -1 gamma-lactam 1673 cm -1--keto-C =C-1624cm-1; HC # 3305cm-1; -C # C- 2100cm-1.

NMR spectrum (deuterochloroform) 0.91 ppm: 18-methyl 2.22 ppm: H ethynyl 5.68 to 5.74 ppm: H 11 5.83 ppm: H 4.

2) On the product #:
IR (chloroform) spectrum -C # CH 3305cm-1; # 4 3-one 1674cm-1, 1624cm-1, 865cm-1; &gamma; -lactone 1759cm-1.

NMR spectrum (deuterochloroform) 1.07 ppm: 18-methyl 2.24 ppm: H ethynyl 5.71 and 5.76 ppm: H 11 5.84 ppm: H 4.

EXAMPLE 8 17a-Hydroxy-3-oxo 10ss- (1-propynyl) 19-nor (17a) D-homo-pregna-4,9 (11) -dien-21-carboxylic acid lactone.

Step A: 17α-Hydroxy-10ss- (1-propynyl) D-homo estr-5,9 (11) -dien-3-one cyclic 1,2-ethanediyl acetal.

 630 mg of product obtained in Step E of Example 6, 20 cm 3 of benzene, 80 mg of para-toluenesulphonic acid monohydrate, 2 cm 3 of ethylene glycol, refluxed for 2 hours, cooled, 20 cm 3 of solution are mixed. saturated aqueous sodium bicarbonate then 1 drop of pyridine, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride, dried, concentrated to dryness by distillation under reduced pressure, chromatography 710 mg of residue obtained on silica eluting with a mixture of n-hexane and ethyl acetate (7-3) to 2 # / ## triethylamine and obtained 500 mg of desired product.

F = 208nC.

Controls:
IR spectrum (chloroform)
OH 3614Cm-1
RNN spectrum (deuterochloroform + 1 drop of C5D5N) 0.86 ppm: 18-methyl 1.79 ppm: H methyl propynyl 2.45 ppm: H hydroxide 3.27 ppm: H 17a 3.97 ppm: ketone methylenes 5.68-5.74 ppm: H 6 5.67 ppm: H 11.

Step B: Cyclic 3,3- (1,2-ethanediyl) acetal of 10ss- (1-propynyl) -dhomo estra-5,9 (11) -dien-3,17a-dione.

470 mg of cyclic 1,2-ethanediyl acetal of 17ass-hydroxy 10ss- (1-propynyl) -D-homo estra-5,9C11-dien-3-one cyclic obtained from Step A of
Example 8.20 cm3 of methyl chloride, add 1.21 g of pyridinium chlorochromate in one go, stir the suspension for 1 hour at 20 ° C, add 5 g of silica, stir for 5 minutes, filter on hyflosupersel rinsed with methylene chloride and then with n-hexane-ethyl acetate (7-3) with 2 # / ## of triethylamine, concentrated to dryness by distillation under reduced pressure, chromatography the 430 mg of residue obtained on silica eluting with a mixture of n-hexane and ethyl acetate (7-3) to 2 # / ## triethylamine and 378 mg of desired product. Mp 193-194nC.

Controls:
IR spectrum (chloroform)
Ketone 1700cm-1; C = C 1665cm-1
NMR spectrum (deuterochloroform) 1.13 ppm: 18-methyl 1.78 ppm: H methyl propynyl 3.97 ppm: methylenes of the ketal 5.53 ppm: H 11 5.70-5.77 ppm: H 6.

 Stage C: cyclic 1,2-ethanediyl acetal of &gamma; 17-hydroxy-3-oxo-10ss- (1-propynyl) -19-nor (17α-alpha) D-homo pregna5,9 (11) -dien-21-carboxylic acid lactone.

 Working as in Step C of Example 7 from 1.47 g of the product obtained in the preceding stage, 2.47 g of crude product is obtained which is used as such for the next stage.

Stage D: Y-lactone of 17ass-hydroxy-3-oxo-10- (1-propynyl) 19nor (17α-alpha) D-homo pregna-4,9 (11) -dien-21-carboxylic acid.

 Working as in Step D of Example 8 from 2.47 g of crude product obtained in the preceding stage, 1.7 g of crude product is obtained which is purified by chromatography on 180 g of silica (eluent: hexane-ethyl acetate 6-4). 811 mg of expected product and 359 mg of mixture of the expected product are collected with 17α-hydroxy-3-oxo 10ss- (1-propynyl) 19-nor (17ass) -D-homo pregna-4 acid t-lactone. , 9 (11) dien-21-carboxylic acid. The 811 g of expected product are dissolved in hot absolute ethanol, filtered, concentrated until early crystallization and ice. After spinning and rinsing with ice-cold ethanol and then with isopropyl ether, 570 mg of expected pure product are obtained.

 F = 190nC.

 The 359 g of mixture are treated identically and 261 mg of colorless crystals of lactone epimer 17a is obtained.

- expected product 17ass-hydroxy.

IR & gamma spectrum; lactone 1758cm -1; C = O 1670cm-1; C = C 1623cm-1.

NMR Spectrum (CDCl 3) 1.06 ppm: 13-methyl 1.81 ppm: methyl propynyl 5.69 ppm: H 11 5.77 ppm: H 4.

- Lactone epimer 17a &alpha; -hydroxy.

IR-lactone spectrum 1760Cm-1; C = O 1670cm-1; C = C 1623Cm-1.

NMR Spectrum (CDCl 3) 0.91 ppm: 13-methyl 1.81 ppm: propynyl methyl 5.69 ppm: proton at 5.77 ppm: proton at 4.

Example 9: Example of a pharmaceutical composition
Tablets containing 50 mg of the product of Example 5 were prepared as the active ingredient.

Product of Example 5: .............................. 50 mg
Excipient (talc, starch, magnesium stearate).

 PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION

Study of the antialdosterone activity on the mineralocorticoid receptor of the rat kidney:
Male Sprague-Dawley EOPS rats, weighing 140 to 160 g, adrenalectomized for 4 to 6 days are sacrificed and their kidneys are perfused in situ with 50 ml of a 0.25 M Tris 10mM-sucrose buffer, pH 7.4 HCl. . The kidneys are then removed, decapsulated and homogenized with OnC using a polytetrafluoroethylene glass potter (1 g of tissue per 3 ml of buffer). The homogenate is centrifuged for 10 minutes at 800 g at 0nC.

 In order to eliminate the binding of tritiated aldosterone to the glucocorticoid receptor, the 11ss, 17ssdihydroxy 17 &alpha;-( 1-propynyl) androsta 1,4,6-trien-3-one steroid which binds only to the glucocorticoid receptor is added to the supernatant at the final concentration of 10-6M. This supernatant is centrifuged at 105,000 g for 60 minutes at OnC. 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 9 M) of cold aldosterone or of 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.

Calculation of the relative binding affinity:
The calculation of the binding relative affinity (ARL) is performed as follows:
The following 2 curves are drawn: the percentage of the tritiated hormone bound as a function of the logarithm of the concentration of the hormone
T concentration of the cold reference hormone and B depending on the
T
Logarithm of the concentration of the cold product tested.

We determine the line of equation f50 = (B-max + B min) / 2
TTE max = Percentage of bound tritiated hormone for an incubation of
T this hormone tritiated at the concentration (T).

B min = Percentage of bound tritiated hormone for incubation
T 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 make it possible 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 to the receptor.

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

<tb> T <SEP> Time <SEP> I <SEP> I
<tb> I <SEP> Incubation product <SEP> 1 <SEP> H <SEP> | <SEP> 24 <SEP> 24 <SEP> H
<tb> | <SEP> the example <SEP> I <SEP> ûnC <SEP> | <SEP> | <SEP> l
<tb> 1 <SEP> \ 1 <SEP> I <SEP> I
<tb><SEP> I <SEP> I <SEP> I
<tb> 1 <SEP> 5 <SEP> 1 <SEP> 56 <SEP> 1 <SEP> 9.1 <SEP>
<tb><SEP> I <SEP> I <SEP> I
<Tb>

Claims (10)

1. The products of general formula I: in which R represents: - either a hydrogen atom, - or an alkyl, alkenyl or alkynyl radical having at most 8 carbon atoms, optionally substituted, - either an aryl radical or optionally substituted aralkyl, - either an alkoxy, optionally esterified carboxy or dialkylamino radical, - or a halogen atom, - or a trialkylsilyl radical. R6 and R7 are such that either R6 and R7 together with the carbons which carry them form a cyclopropyl radical, or R6 represents a hydrogen atom and R7 represents the radical R1, R1 representing - either a hydrogen atom, - or a alkyl, alkenyl or alkynyl radical having at most 6 carbon atoms, optionally substituted, - is an acetylthio radical, R2 represents a methyl or ethyl radical, X and Y are such that: - either X represents a hydroxyl radical optionally acylated or etherified and Y represents either a radical-CH2CH2CO2M in which M represents a hydrogen atom, an alkali metal atom or an ammonium radical, or a radical -CH2CH2-CH20H, -where X and Y together represent a radical :: - either X and Y together represent a radical which alk represents an alkyl radical containing at most 8 carbon atoms, - or X and Y together represent a radical where X represents a hydroxyl radical and Y a radical M being defined as above, or X represents an optionally acylated or etherified hydroxyl radical and Y represents, or a hydrogen atom, or Y represents R4, R4 represents an alkyl, alkenyl or alkynyl radical having at most 6 carbon atoms, n represents the integers 1 or 2, the dashed lines at position 1 (2) and 6 (7) indicate the possible presence of a second bond between the carbons that carry them, it being understood that there can be no second linkage at position 6 (7) when R6 and R7 together with the cyclopropyl carbons form a dotted line on the substituent RCC- at position 10 indicates the possible presence of a third bond between the carbons carrying them, the wavy lines in position 6, 7 and 13 indicate that the substituents R6, R7 and R2 may be in one of the possible positions or where (3 being understood that when h represents the value 1, the line undulates in position 13 indicates the near With a radical R2 in position o (and when n represents the value 2, the wavy line in position 13 indicates the presence of a radical R2 in position n 2. The products of general formula I, as defined in FIG. Claim 1, corresponding to formula Ii: wherein R represents - either a hydrogen atom, - or an alkyl, alkenyl or alkynyl radical having at most 8 carbon atoms, optionally substituted, - or an optionally substituted aryl or aralkyl radical or an alkoxy, optionally esterified carboxy or dialkylamino radical, or a halogen atom, or a trialkylsilyl radical. R6 and R7 are such that either R6 and R7 together with the carbons carrying them have a cyclopropyl radical, or R6 represents a hydrogen atom and R7 represents the radical R1, R1 representing - either a hydrogen atom, - or a alkyl, alkenyl or alkynyl radical having at most 6 carbon atoms optionally substituted, - is an acetylthio radical, R2 represents a methyl or ethyl radical; X1 and Y1 are such that: either X1 represents a hydroxyl radical and Y1 represents either a radical-CH2CH2CO2M in which M represents a hydrogen atom, an alkali metal atom or an ammonium radical, or a radical - CH 2 CH 2 -CH 2 OH, - or X 1 and Y 1 together represent a radical - X 1 represents a hydroxyl radical optionally acylated or etherified and Y 1 represents, or a hydrogen atom or Y 1 represents R 4, R 4 representing an alkyl, alkenyl or alkynyl radical; having not more than 6 carbon atoms, n represents the integers 1 or 2, the dashed lines at position 1 (2) and 6 (7) indicate the possible presence of a second bond between the carbons carrying them, provided that there can not be a second bond in position 6 (7) when R6 and R7 form with the carbons carrying them a cyclopropyl radical, the dotted line on the substituent R-CC- in position 10 indicates the possible presence of a third Link between the carbons carrying them, The wavy lines in position 6, 7 and 13 indicate that the substituents R6, R7 and R2 can be in one of the positions 0 (and being understood that when n represents the value 1, the The corrugated line at position 13 indicates the presence of a radical R2 in position and when n represents the value 2, the corrugated line at position 13 indicates the presence of a radical R2 at position 3. The products of general formula 11, such as as defined in claim 2, having the formula wherein R, R 1, R 2, X, Y and n, the dashed lines and the wavy lines have the meaning as in claim 2. 4. The products of formula I, as defined in claim 1, 2 or 3, in which the substituents that may comprise the radicals R and R1 are chosen from the group formed by hydroxyl, optionally esterified carboxy, amino, protected amino, mono or dialkylamino and halogen atoms. 5. The products of formula I, as defined in any one of claims 1 to 4, wherein the dotted line on the substituent in position 10 represents a third bond and R2 is selected from the group formed by a d hydrogen, an alkyl radical having 1 to 3 carbon atoms, a hydroxymethyl radical and a phenyl radical. 6. The products of formula I, as defined in any one of claims 1 to 5, wherein the substituent R 1 is selected from the group consisting of a hydrogen atom, an alkyl radical having 1 to 4 carbon atoms and an acetylthio radical and X and Y are such that either X represents a hydroxy radical and Y represents either a CH2CH2CO2M 'radical in which M' represents a hydrogen atom or an alkali metal atom, or Y represents a hydrogen atom, - let X and Y represent a radical

 7.- The products of general formula I, the names of which follow-the gamma-lactone of 10ss-ethynyl acid 17ss-hydroxy 3-oxo 13 &alpha; 17α-19-nor-pregna 4.9 (11) -dien-21-carboxylic acid; - 10ss-ethynyl 17ss-hydroxy 13 &alpha; Estra-4,9 (11) -dien-3-one; 17β-hydroxy 3-oxo-10ss- (1-propynyl) -α, 17α-19-nor-pregna-4,9 (11) -dien-21-carboxylic acid-gamma lactone; 17ss-hydroxy 10ss- (1-propynyl) 13α-estra-4,9 (11) -dien-3-one; 10β-ethynyl 17β-hydroxy-3-oxo-19-nor (17α-alpha) -lactone D-homo-pregna-4,9 (11) dien-21-carboxylic acid; 10ss-ethynyl 17α-hydroxy D-homo-estra-4,9 (11) -dien-3-one; 17-hydroxy-3-oxo-10ss- (1-propynyl) -19-nor 17ad) -D-homo-pregna-4,9- (11) -dien-21-carboxylic acid gamma; 17ass-hydroxy 10ss- (1-propynyl) D-homo-estra 4.9 (11) -dien-3-one. 8. A process for the preparation of the products of formula I, as defined in Claim 1, characterized in that either a product of formula II 'is treated:

 or a product of formula II "

 in which R 'represents either R, R having the meaning indicated in claim 1, or the substituent R in which the reactive functions are protected, R2 has the meaning indicated in claim 1 and K represents a protecting group of the ketone function. I- firstly with a trimethylsulfonium halide in the presence of a strong base and then with a metal derivative of acetonitrile and finally with a base and then with an acid, or first with a reagent of formula

 in which Alk represents an alkyl radical having 1 to 4 carbon atoms in the presence of a strong base and then an acid to obtain either a product of formula I'A:

 or a product of formula I "A:

II- or by a reagent of formula:  XMg-CH2CH2CH2OB wherein X represents a halogen atom and B represents a protecting group of the hydroxyl radical or a magnesium alkoxide to obtain after treatment with an acid or a product of formula 1.2A ::

 or a product of formula 1,, 2A

 products of formula I'2A or I "2A which are optionally treated with a sulfonic acid halide in the presence of a base to obtain either a product of formula I" 2 ZA

 or a product of formula I "" 2A:

III either with a reducing reagent and then with an acid to obtain a product of formula I'3A:

 or a product of formula I "3A:

IV or with an organo-metal R4MgX, X representing a halogen atom, then with an acid to obtain either a product of formula 1,4A:

 or a product of formula I "4A ::

V / firstly with a trimethylsulfonium halide in the presence of a strong base, then with a primary amine of formula H 2 N -alk, alk being defined as above, in the presence of an acid, with an alkyl chloroformate, by a strong base and finally by an acid, to obtain either a product of formula I'5A:

 or a product of formula I "5A ::

VI / firstly with a trimethylsulfonium halide in the presence of a strong base, then with methyl terbutyl sulfoxide in the presence of n-butyllithium to obtain either a product of formula

 or a product of formula

 in the form of a mixture of two diastereoisomers at the level of the sulfur atom, separates if desired the two diastereoisomers, then submits either their mixture or each of them separately, to the action of an acid, to obtain or well a product of formula

 or a product of formula

  in the form of a mixture of two diastereoisomers or a diastereoisomer, separates, where appropriate, the diastereoisomers, then submits either their mixture or each of them separately, to the action of N-chloro or Nbromo succinimide, to obtain or a product of formula 1.6A:

 or a product of formula I "6A:

 and that, if desired, the products of formulas IAA 'I "A' be processed 2A, 2A, 1A, 2A, 1A, 3A, 4A, 4A, 5A 5A, 6A and 6A with an alkyl orthoformate in the presence of an acid and then with a dehydrogenating agent to obtain the products of formula IB 'I'2B' I "'2B' I'3B 'I'4B' 1'5B and 1'6B of the following formulas:

 or the foamed products I "B 'I" 2B' I "2B 'I" 3B' I "4B 'and and I" 6B of the following formulas:

 products of formula I'B 'I'2B' I "'2B' 1'3B 'I'4B' I'5B ' 1B, 2B, 4B, 5B and 1B, which are treated if desired - or by an organo magnesium of formula R1MgX ' optionally in the presence of a copper salt, in which formula R 1 has the meaning indicated above and X 'represents a halogen atom, - or by an organo-metal of formula (R 1) 2 CuLi and then by an acid, to obtain either the products of formulas 1C, 2C, 2C, I'3C 'I'4C' 1'5C and 1'6C:

 or the products of formula I ## STR2 ## I "5C and I" 6C ::

 in the form of a mixture of 7α and 7β isomers, a mixture which, if desired, is separated and, if desired, the 7ss products are subjected to a dehydrogenation reagent to obtain the products # 6 (7). ) corresponding; or else the products of formulas I'B, I'2B, I "'2B' are subjected to I'3B 'I'4B' 1'5B 'I'BB' I 'B' I '2B' I '"2B' I" 3B 'I "4B' 5B and 6B to the action of a reagent selected from the group consisting of trimethylsulfonium iodide and trimethylsulfoxonium iodide in the presence of a strong base to obtain either the products of formulas I ' From DID'I''D 2D 'I'3D 1'4D 1'5D and 1'6D:

 or the products of formula I "D" I "2D" I "" 2D "I" 3D "I" 4D ' I "5D and I" 6D ::

 as a 6 &alpha;, 7 & alpha mixture; and 6ss, 7sset separates, if desired, the isomers thus obtained and if desired the products 1'A 'are treated 1A, 2A, 2A, 2A, 1A, 3A, 4A, 4A, 1A. I'5A 'I "5A' I'6A 'I" 6A' 1'B 'I'2B' I "'2B' I'3B 'I'4B' I'5B 'I'6B' I 'B' I '2B' I '"2B' I" 3B 'I "4B' I" 5B 'I "6B' I'C 'I'2C' I '' 2C 'I'3C' I'4C 'I'5C' I'C 'I' C 'I' 2C ' 1 "2C 'I" 3C' I "5C 'I" 5C' I? 4D '1'DD' 1'D "I" 2D 'I "2D' I" 3D 'I "4D' I" 5D and 1, 6D by a dehydrogenation reagent or by a microorganism capable of dehydrogenating the molecule at position 1 (2) to obtain the corresponding products having unsaturation in position 1 <2) and that, if desired, the products of formulas IA 'IB' IC and ID and the corresponding products are treated having an unsaturation in position 1 (2) using an alkali hydroxide or ammonia to obtain the corresponding products in which X represents a hydroxyl radical and Y represents a radical -CH 2 CH 2 CO 2 M 'in which M' represents an atom of an alkali metal or an ammonium radical and, if desired, subjecting the products thus obtained to the action of an acidic agent to obtain the products in which X represents a hydroxyl radical and Y represents a -CH 2 CH 2 CO 2 H radical, and that if desired, the products in which the substituent at position 10 has a substituent R from hydroxyalkyl type, with a tetrabromide or carbon tetrachloride, in the presence of triphenylphosphine, to obtain the corresponding brominated and chlorinated derivatives, and that if desired, the products in which the substituent at position 10 comprises a triple bond by an agent are treated; selective hydrogenation to obtain the corresponding products in which the substituent in position 10 has a double bond, and if desired, the products having in position 10 an ethynyl substituent by a halosuccinimide to obtain the corresponding products comprising in position 10 a substituent -C = C-Hal, and if desired, is acylated or etherified the hydroxyl radical at position 17 p of the products having in position 17 &alpha; a hydrogen atom, a radical R4 or a radical -CH2-CH2-CH20H. 9. A process according to claim 8 for the preparation of the products of formulas I'3A and I "3A 'as defined in claim 8, characterized in that either a product of formula II'A is treated:

 or a product of formula II "A:

 in which K, R 'and R2 have the meaning indicated in claim 8 and R17 represents a hydrogen atom or a group protecting the hydroxyl radical with an acid and optionally with a hydroxyl radical deprotection reagent. 10.- As medicaments, the products of general formula I, as defined in claim 1. 11.- As medicaments, the products as defined in one of claims 2 to 6. 12.- As medicaments, the products of general formula I, whose names follow: - the gamma -lactone of 10p-ethynyl acid 17ss-hydroxy 3-oxo 130 (, 17i - 19-nor-pregna 4 9 (11) -dien-21-carboxylic acid-17ss-hydroxy 13β-ethynyl 13α-estra-4,9 (11) -dien-3-one 17β-acid t-lactone hydroxy-3-oxo-10ss- (1-propynyl) 13α, 17α-19-nor-pregna-4,9 (11) -dien-21-carboxylic acid 17ss-hydroxy 10ss- (1-propynyl) 13α Estra-4,9 (11) -dien-3-one; -Lactone of 10ss-ethynyl 17ass-hydroxy-3-oxo-19-nor (17a-alpha) acid; D-homo-pregna-4,9 (11) dien-21-carboxylic acid; ; 10-ethynyl 17α-di-hydroxy-D-homo-estra-4,9 (11) -dien-3-one; 17-hydroxy-3-oxo-10ss- (1-propynyl) -19-nor (17α-alpha) -D-homo-pregna 4,9- (11) -dien-21-carboxylic acid gamma-lactone; 17α-hydroxy-10- (1-propynyl) D-homo-estra 4.9 (11) -dien-3-one. 13. Pharmaceutical compositions containing, as active ingredient, at least one drug defined in any one of claims 10 to 13.