11beta substituted steroids,process for preparing them,medicaments and compositions containing them

New steroid derivatives substituted at position 11β, process and intermediates for preparing them, their use as medigamente and the compositions containing them.

Company named : RCVSSEL-UCLAF

The present invention relates to new 19-nor steroid or 19-nor D-homosteroid compounds substituted at position 11β, a process for preparing them, their use as medicaments, the compositions containing them and the new intermediates obtained.

The subject of the invention is the compounds of formula (I*):

in which R^ represents an organic radical containing from 1 to 18 carbon atoms, containing at least one nitrogen, phosphorus or silicon atom, the atom immediately ajacent the carbon at position 11 being a carbon atom, Rg represents a hydrocarbon radical containing fromll to 8 carbon atoms, Σ' represents the residue of a pentagonal or hexagonal ring, possibly substituted and possibly bearing an unsaturation״ the group C ־ A at position 5 represents an oxo group which is free or blocked in the form of a ketal, a

<img file="IL65680A_D0001.tif" />

a group C־NOH, a group C־NO-alkj or a group CHg, alkp alkg, and-alkj representing an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl group containing from 7 to 15 carbon atoms and B and C together form a double bond or an epoxide bridge.

Preferably Rg represents a straight or branched saturated alkyl radical, containing from 1 to 4 carbon atoms, for example a methyl, ethyl, n-propyl or butyl radical.

When alkjj alkg or alk^ represents an alkyl radical, this is preferably the methyl, ethyl, n-propyl or isopropyl radical.

When alkp alk₂ or alk^ represents an aralkyl radical, this is preferably the benzyl radical.

Preferably X represents the residue of a possiblysubstituted pentaganal ring.

The invention extends, of course, to the addition salts with acids of the compounds of formula (I’) such as, for example, the salts formed with hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, and aspartic acids, alkane sulphonic acids such as methane or ethane sulphonic acids, arylsulphonic acids such as benzene or paratoluene sulphonic acids and arylcarboxylic acids.

The subject of the invention is especially the compounds 15 of formula (I'), as defined before, corresponding to the formula (I) :

<img file="IL65680A_D0002.tif" />

(I) in which Rp R^, X and A are defined, as before.

The subject of the invention is, more particularly, the compounds of formula (I*), for which Rj represents a methyl radical.

The subject of the invention is especially the compounds of formula (I¹) for which X represents the residue of a ring of formula:

<img file="IL65680A_D0003.tif" />

in which R^ keeps the same meaning as before, the dotted line at 16 - 1? symbolizes the possible presence of a double bond.,

Y represents the radical in which

<img file="IL65680A_D0004.tif" />

n represents the number 1 or 2, represents a hydrogen atom, an alkyl radical containing from 1 to 8 carbon atoms, an alkenyl or alkynyl radical containing from 2 to 8 carbon atoms, an aryl radical containing from 6 to 14 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, Rg, being the same as or different from R^, can take one of the values indicated for R^ and can also represent a hydroxyl radical, R^ and R^, being the same or different, represent either a hydrogen atom, or a radical OH, Oalk^ or O-CO-alk^, alk^ and alk^ representing an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, or an alkenyl or alkynyl radical containing from 2 to 8 carbon atoms, or a radical 0 or a radical

-c-ch₂oh

-COCH^OCOalkg, in which alkg represents an alkyl radical containing from 1 to 8 carbon atoms, possibly substituted, or an aralkyl radical containing from 7 to 15 carbon atoms or a radical CO-C^H or CO-CO^alk? in which alk? represents an alkyl radical containing from 1 to 8 carbon atoms, or H NHalkg a radical -C'0־, or a radical -C0־־ , in which alkg represents an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, or a radical -C=N, or R^ and R^ together form a CH,

I ⁵ radical HC-0 in which Z^ represents a hydrogen atom, — C- Z., 1 2 an alkyl radical or an acyl radical containing from 1 to 8 carbon atoms and represents an alkyl radical containing from 1 to 8 carbon atoms.

R^ is preferably different from Rg.

When R^ or Rg represents an alkyl radical, this is preferably the methyl or ethyl radical. ..

When R- or Rg represents an alkenyl radical, this is preferably the vinyl, isopropenyl or allyl radical.

When R^ or Rg represents an alkynyl radical, this is preferably the ethynyl or propynyl radical.

When R^ or Rg represents an aryl or aralkyl radical, this is preferably the phenyl or benzyl radical.

When Rj or R^ represents a radical Oalk^ or OCOalk^, alk^ and alk^ represent preferably a methyl, ethyl, n-propyl, butyl, pentyl, hexyl or benzyl radical.

When Rj or R^ represent an alkenyl radical, this is preferably the ׳inyl, isopropenyl, allyl or 2-methylallyl radical.

When Rj or R^ representa an alkynyl radical, this is preferably the radical -CsCH or -CsC-alkg, alk^ representing preferably a methyl, ethyl, propyl, isopropyl, isopropenyl, butyl, benzyl or trifluoromethyl radical.

Alkg, alk? and alkg represent preferably one of the preferred values of alk^ or alk^.

־

The preferred compounds are those for which the radicals R^ and R^ are different except in the case in which Rj and R^ each represent a hydrogen atom.

Among the preferred values of the radical

<img file="IL65680A_D0005.tif" />

there may he mentioned the radicals:

<img file="IL65680A_D0006.tif" />

<img file="IL65680A_D0007.tif" />

QsC—

<img file="IL65680A_D0008.tif" />

<img file="IL65680A_D0009.tif" />

<img file="IL65680A_D0010.tif" />

<img file="IL65680A_D0011.tif" />

>NH(CH₂)₂CH₅ in which represents a hydrogen atom, an alkyl radical containing from 1 to 8 carbon atoms or an acyl radical containing from 2 to 8 carbon atoms, for example an acetyloxy or benzoyl radical and Zg represents an alkyl radical containing from 1 to 8 carbon atoms, for’ example a methyl radical.

The subject of the invention is especially the compounds of formula (I¹)' for which the ring D does not bear any ethylenic unsaturation, R^ and Κθ represent a hydrogen atom and n is equal to 1, as well as the compounds for which C־A represent an oxo group.

The subject of the invention is, more particularly, the compounds of formula (Τ’ ) far which R^ represents a hydrocarbon radical containing from 1 to 18 carbon atoms and containing at least one nitrogen atom.

Among .these compounds, there may ^-be mentioned especially the compounds for which R^ represents a primary, secondary or tertiary alkyl radical containing from 1 to 8 carbon atoms, containing one or more heteroatoms selected from the group constituted by oxygen, nitrogen and sulphur, of which at least one is a nitrogen atom, or substituted by a heterocycle containing at least one nitrogen atom.

By alkyl radical there is understood preferably the methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.

By heterocycle containing at least one nitrogen atom, there may be mentioned the 2-, 5- or /!-pyridyl radical, or the thiazolyl or piperidinyl radical.

There may also be mentioned as preferred compounds of the invention the compounds for which R^ represents a heterocyclic radical containing at least one nitrogen atom, possibly substituted by an alkyl radical containing from 1 to 8 carbon atoms.

By heterocyclic radical there is understood preferably one of the radicals mentioned above.

When Rj. represents a heterocyclic radical containing at least one nitrogen atom, substituted by an alkyl radical, this is most often a heterocycle substituted by a methyl, ethyl or n-propyl radical.

Among the preferred compounds of the invention there may be mentioned also the compounds for which R^ represents an aryl or aralkyl radical bearing an amine function

- xr^Z θ , in which R? and R&amp; represent an alkyl radical containing from 1 to 8 carbon atoms or a primary secondary or tertiary alkyl radical containing from 1 to 8 carbon atoms, containing one or more heteroatoms selected from the group constituted by oxygen, nitrogen and sulphur, of which at least one is a nitrogen atom, or substituted by a heterocycle containing at least one nitrogen atom.

By alkyl radical there is understood, preferably one of the radicals mentioned above.

By aryl or aralkyl radical there is understood preferably the phenyl or benzyl radical.

By heterocyclic radical there is understood preferably one of the heterocyclic radicals mentioned, above.

The subject 0Γ the invention is especially the compounds for which represents a 2-jJ-or 4-pyridyl radical, a radical - N

CH₃ (n>5) a radical a radical a radical or a radical

The subject of the invention is also, in particular, the compounds for which R^ represents a radical:

<img file="IL65680A_D0012.tif" />

Among the compounds of the invention there may also be mentioned the compounds in which R^ contains an oxidised nitrogen atom, as well as those in which B and C together form an epoxy bridge.

Among the preferred compounds of the invention there may of course be mentioned the compounds of which the preparation is given further on in the experimental part and especially the compounds of Examples 1, 3, 4, 8, 10, 11, 12, 14, 16, 17, 20, 22, 28 and 29.

The compounds of formula (Τ’) as well as their addition salts with the pharmaceutically-aceptable acids are products which are particularly interesting from the pharmacological point of view; they possess in particular remarkable antiglucocorticoid activity as is shown by the accompanying test results.

The study of the products on hormone receptors has enabled progestomimetic or anti-progestomimetic, androgenic or anti-androgenic activity to be made evident.

The compounds of formula (!’) as well as their addition salts with the pharmaceutically-aceptable acids can therefore be used as medicaments to control mainly side effects &lt; glucocorticoids; they also permit control of disorders due to hypersecretion of glucocorticoids and especially of ageing in general and more particularly of hypertension, atherosclerosis, osteoporosis, diabetes, obesity as well as .immunity depression and insomnia.

The compounds of formula (I.), as well as their addition salts with the pharmaceutically-aceptable acids, which possess anti-progestomimetic properties can be used to prepare original contraceptives; they can also be used against hormonal irregularities and, in addition, they can be of advantage in the treatment of hormone-dependent cancers.

Certain compounds of formula (I״) as well as their addition salts with the pharmaceutically-aceptable acids can also display progestomimetic properties and can thus be used in the treatment of amenorrhoea, dysmenorrhoea and luteal insufficiencies.

The compounds of formula (I‘), as well as their addition salts with the pharmaceutically-aceptable acids, which display anti-androgenic properties, can be used in the treatment of hypertrophia and of cancer of the prostate gland, of hyperandrogenia, of anaemia, of hirsutism and of acne.

The subject of the invention is, therefore, as medicaments, the compounds of formula (I’) which are pharmaceutically-aceptable, that is to say non-toxic at the doses used, as well as their addition salts with the pharmaceutically-aceptable acids.

' The usual dosage varies depending upon the complaint

10׳ to be treated and the route of administration; it can vary, for example, from 10 mg to 1 g and preferably from 100 mg to 1 g per day in the adult by oral route.

The new compounds of formula (I’) and their salts, as defined above, can be used to prepare pharmaceutical compositions containing, as active principle, one at least of the said compounds.

The compounds of formula (Τ’) and their salts are used by digestive, parenteral or local route. They can be prescribed in the form of plain or sugar-coated compressed tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, cream and gels which are prepared according to the usual methods.

The active principle or principles can be incorporated in excipients usually employed in pharmaceutical compositions such as talc, gum arable, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives.

The subject of the invention is, therefore, the pharmaceutical compositions containing as active principle at least one compound of formula (I‘).

The subject of the invention is also a process for preparing the compounds of formula (I*)» characterized ⁰ in that a compound of general formula (II) :

<img file="IL65680A_D0013.tif" />

OH (II)

- ל1 in which K represents a ketone group blocked in the form of a ketal, thioketal, oxime or methyloxime, and B R^ and X keep the same meaning as before, is subjected to the action of a dehydrating agent capable of releasing the ketone function, to obtain a? compound of formula

<img file="IL65680A_D0014.tif" />

10׳ which is subjected, if necessary, either to the action of a ketalisation agent to obtain the compound of formula (I’g) which the ketone function at position 5 is blocked in the form of a ketal:

ketal

<img file="IL65680A_D0015.tif" />

or to the action of the free hydroxylamine NI^OH or the hydroxylamine blocked in the form of NH^-O-alkj in which alkj keeps its previous meaning, to obtain the compound of formula (I^,¢-):

<img file="IL65680A_D0016.tif" />

(I’_o) in which R represents a hydrogen atom or a group alk^, or to the action of a reducing agent capable of reducing selectively the ketone function at position

3, to obtain the compound of formula (I'jj):

<img file="IL65680A_D0017.tif" />

which is subjected, if necessary, . either to the action of an etherification agent capable of introducing the radical al^ to obtain a compound of formula (I’_E):

<img file="IL65680A_D0018.tif" />

or to the action of an esterification agent capable of introducing the group CO alkg in which alkg keeps its previous meaning, to obtain a compound of formula (T’j,):

alkgCO'

<img file="IL65680A_D0019.tif" />

<img file="IL65680A_D0020.tif" />

or, which compound of formula (I’_A) is converted, if necessary, according to the known methods, into a derivative for which C־־A represents a group CHp and which compound of formula (Γ’_λ), (1¹¢)_עי1) י) (Γ’_Ε), ^or (¹’y) י necessary, is subjected to the action of an acid to obtain a salt or to the action of an oxidizing agent to obtain either, if the radical R^ contains a nitrogen atom, a derivative containing at position ΙΙβ a radical of which the nitrogen atom is oxidised and 10׳ in which the radicalgB and 0 form possibly an epoxide bridge, or, if the radical R^ does not contain a nitrogen atom, a derivative in which the radicals B and O' form an epoxide bridge and in which compound at the same time the radical R^ contains an oxidised nitrogen atom and B and C together form an epoxide bridge wh-ich, IT necessary, is reduced selectively at the level of the oxidised nitrogen atom contained in the radical and which, if necessary, is subjected to the action of an acid to obtain a salt.

The subject of the invention is, more particularly, 20 a process as defined before for preparing the products of formula (I*) for which X represents the residue of a ring of formula:

<img file="IL65680A_D0021.tif" />

in which R₂, ? and *he dotted line at position

16-17 are defined as before.

In a preferred method of carrying out the process, the dehydration agent capable of releasing the ketone function is a sulphonic resin (acid form), for example a commercial sulphonic resin with a polystyrene support or with a styrene / divinylbenzene polymer support; but a mineral acid such as hydrochloric acid or sulphuric acid in a lower alkanol or perchloric acid in acetic acid, or a sulphonic acid such as paratoluene sulphonic acid can also be used.

The ketalisation agent is preferably an selcohol or a dialcohol in the presence of an organic acid such as, for example, oxalic acid or paratoluene sulphonic acid.

The agent for reducing the ketone function is preferably an alkali, metal hydride. (See on this subject the article by E. R. Walkis in Chemical Society Reviews 1976, Vol. 5, no 1, page 25.)

The etherification agent is preferably an alkyl 20 halide in the presence of a base.

The esterification agent is preferably a carboxylic acid derivative, for example a chloride or an anhydride, in the presence of a base such as pyridine.

It is self evident that when one of the radicals R^ פס R^ of the products of formula (I') obtained previously represents a radical OH, the said radical OH of these products of formula (I') can be subjected to the action of an etherification or esterification agent.

This etherification or esterification agent is preferably ome of those which have been mentioned above.

When R, or R״ representsan acyloxy radical at ל * position 17, this acyloxy group can possibly be saponified.

The saponification agent used is preferably a base such as Sodium hydroxide, potassium hydroxide, potassium amide or potassium tert-butylate, the saponification reaction being carried out preferably in a lower alcohol such as methanol 10 or ethanol, it can also be lithium acetylide in ethylene diamine.

The oxydising agent is preferably a peracid such as metachloroperbenzoic acid, peracetic acid or perphthalic acid or else hydrogen peroxide alone or in the presence 15 of hexachloro- or hexafluoroacetone. When it is desired to obtain a compound in which only the nitrogen atom of the radical R^ is oxidised, one equivalent of oxidising agent is used.i When it is desired to obtain a compound in which, in addition, B and C form an epoxide bridge, two equivalents of oxidising agent are used.

The agent for selectively reducing the N-oxide function is preferablyrtriphenylphosphine and work can be carried out, for example, in acetic acid.

The subject of the invention is also a! preparation 25 process as defined before, characterised in that the starting product of formula (II) is prepared by subjecting a compound of. formula (III)::

<img file="IL65680A_D0022.tif" />

(III) to the action of a compound selected from the group constituted by the compounds formula (Rpp Cu Li, of formula RjMg Hal and of formula R^ Li, in which R^ keeps the same meaning as before and Hal represents a halogen atom, if necessary, in the presence of cuprous halide, to obtain the corresponding compoundiof formula (II).

In a preferred method of carrying out the process of -סו the invention:

- the reaction takes place at ambient temperature ,

- the compound of formula (III) is subjected to the action of a compound of formula RjMg Hal in the presence of copper salts.

The subject of the invention is also a preparation process as defined before, characterised in that the starting product, responding to the formula (II')

<img file="IL65680A_D0023.tif" />

OH in which Rp Rg and K are defined as before, R’^ represents a hydroxy radical or a radical 0R_c in which R_c represents the residue alk^ of an ether group or COalk^ of an ester group, alk^ and alk^ being defined as before and R'^ represents the hydrogen atom or an alkenyl or alkynyl radical containing from 2 to 8 carbon atoms, is prepared by subjecting a compound of formula (IV):

<img file="IL65680A_D0024.tif" />

(IV) to the action of a compound selected from the group constituted by the compounds of formula (Rpj of formula R^MgHal and of formula R^Li, in which R^ and Hal are defined as before, if necessary in the •5 presence of copper halide, to obtain the compound of formula (V):

<img file="IL65680A_D0025.tif" />

(V) which is subjected either to the action of. a reducing agent, to obtain the corresponding 17-hydroxy compound or to the action of an appropriate magnesium derivative, to obtain the corresponding !?«-substituted 17B-hydroxy compound or to the action of an organometallic derivative such as a lithium derivative or a potassium derivative, to obtain the corresponding !?«-substituted l?p-hydroxy compound, or a) to the action of a cyanidation agent, to obtain the corresponding 17B-cyano 17«-hydroxy compound, of which the hydroxy function is protected, then b) to the action of an organometallic derivative as described before, to obtain the corresponding !?«-substituted

17p-hydroxy compound and in that, if necessary, one or other of the 17-hydroxy compounds obtained above is subjected to the action of an esterification or etherification agent and that, if necessary, one or other of the 17-substituted compounds obtained above in which the substituent at position 17 contains a־ triple bond, is subjected to the action of a reducing agent, to obtain the corresponding ethylenic derivative.

In a preferred method of carrying out the process of the invention, the reaction of the compound (IV) with the compound R^ Mg Hal, (R^)2 ^or Ei is carried out under the conditions already described before.

The different reagents which are reacted with the compound of formula (V) are well known in the chemistry of the steroids. The experimental part hereinafter describes some of the reactions with the compound of formula (V).

The compounds of formula (II) as well as the compounds of formula (V) are new chemical products and the subject of the invention is the compounds of formula (II) as well as the compounds of formula (V) as new chemical products.

The subject of the invention is, more particularly, as new chemical products:

- 11β-[4-(trimethylsilyl) phenyl] 3,3-[l,2-ethane diyl bis (oxy)] 17^a-(prop-l-yn?1) estr-9-en 5^a,17P-diol,

-(4-pyridyl) 3,5-(1,2-6thane diyl bis (oxy)] l?a-(prop-

1-ynyl) estr-9-en 5^a, 170-diol,

-(5-(^,N-dimethylamino) propyl] 5,3-(1,2-ethane diyl bis (oxy)] 17a-(prop-l-ynyl) estr-9-βη 5^a,17P-diol,

- Ιΐβ-ι'4-dimethylaminophenyl) 3,5-(1,2-6 thane diyl bis (oxy) ] 17a-(prop-l-ynyl) estr-9-en 5», 170-diol,

3,5-(ethane diyl bis (oxy)] 110-(4-(N,N-dimethylaminoethyloxy) phenyl] 17*-(prop-l-ynyl) estr-9-en 5^a, 170-diol,

-chloro 3,5-(1,2-ethane diyl bis (oxy)] 110-(4-dimethyl aminophenyl) (17^a) 19-aor pregns9-en-20-yn 5^a,170-diol and

-(4-dimethylaminophenyl) 3,5-(l,2-ethane diyl bis (oxy)] 17a-(prop-2-ynyl) estr-9-en 5“, 170׳-diol.

The subject of the invention is, of course, more particularly, the compounds 0Γ formula (II) and (V*), especially the products of formulae (II) and (V) prepared in the experimental part, as new industrial products necessary for carrying out the process of the invention.

The compounds of formula (HI) and especially, among these the compounds of formula (IV), used to prepare the compounds of fonmula (II) or (V) are generally-known products, which can be prepared by subjecting the corresponding Δ5(10), 9(11) compounds to the action of an agent for selectively epoxidising the double bond 5(10). Thus the δ5(10) 9(11) compounds can be subjected, for example, to the action of hydrogen peroxide used in the presence of hexachloroacetom or hexafluoroacetone, according to the process described and claimed in French Patent 2,45,3 .86־23,4־Cl,2-ethane diyl bis (oxy)] 17a- (1-propynyl) estr-9-(ll)-en 5a,10a-epoxy 1?β-01 is a product which is not described, of which the preparation is given further on in the experimental part.

The subject of the invention is, therefore, also this product as a new chemical product and more particularly as an intermediate product necessary for carrying out the process of the invention.

In addition to the products described in the examples which illustrate the invention without,however, limiting it, the following products constitute products which can be obtained within the scope of the present invention.

A) The products of formula :

<img file="IL65680A_D0026.tif" />

in which the substituents A, R^, R^, R_z and have the following meanings. (The sign i^^icates that the substituent is the same as the one. abov^).

<img file="IL65680A_D0027.tif" />

<img file="IL65680A_D0028.tif" />

<td> A</td><td>^R1</td><td> מ to</td><td>^R3</td><td>^R4</td>

<td> HO-N=(£)</td><td> 1</td><td> ch₃</td><td> OH</td><td> -C=C-H</td>

<td> It</td><td> II</td><td> It</td><td> 11</td><td> -C=C-CH~ «3</td>

<td> II</td><td> II</td><td> II</td><td> II</td><td> -CH₂-C=C-H</td>

<td> II</td><td> It</td><td> II</td><td> -CSC-H</td><td> -OH</td>

<td> HO-N=(Z)</td><td> II</td><td> II</td><td> 11</td><td> II ,*</td>

<td> II</td><td> II</td><td> II</td><td> OH</td><td> -C-C-H</td>

<td> It</td><td> It</td><td> II</td><td> tt</td><td> -c=c-ch₃</td>

<td> tl</td><td> II</td><td> It</td><td> 11</td><td> -CH₂-C=C-H</td>

<td> 0</td><td></td><td> II</td><td> 11</td><td> -C^C-CH₂CH₃</td>

<td> tl</td><td> It</td><td> If</td><td> It</td><td> -C^C-CF₃</td>

<td> II</td><td> tl</td><td> II</td><td> -C=C-SiMe₃</td><td> -OH</td>

<td> 11</td><td> II</td><td> II</td><td> -ס-CH_nOH &amp;</td><td> -H</td>

<td> II</td><td> 11</td><td> II</td><td> II</td><td> »ס-</td>

<td> II</td><td> It</td><td> It</td><td> -C-CH</td><td> -«</td>

<td> It</td><td> « tl</td><td> .CH₂CH₃</td><td> 11 ³ 0 OH</td><td> -C=C-H</td>

<td> fl</td><td> II</td><td> II</td><td> 11</td><td> -c2c-c«₃</td>

<td> 11</td><td> It</td><td> II</td><td> 11</td><td> -C=C-C1</td>

<td> II</td><td> II</td><td> tl</td><td> II</td><td> -CSC-C«₂-C«₃</td>

<td> II</td><td> II</td><td> II</td><td> 11</td><td> -C=C-SiMe₃</td>

<td> II</td><td> If</td><td> II</td><td> II</td><td> -ch₂-c=c-h</td>

<td> II</td><td> It</td><td> II</td><td> 0 J:-CH₂OH</td><td> -H</td>

<td> HO-N=(E)</td><td> tl</td><td>^CH3</td><td> -C=C-H</td><td> »ס-</td>

<td> It</td><td> It /׳</td><td> It</td><td> -(J-Cf^OH</td><td> -«</td>

<td> 11</td><td> II</td><td> It</td><td> 0 OH</td><td> -C«₂־C=C-H</td>

HO-N=(Z) a R₁ R₂ R₃ R₄

H0-N=(2) »1

H0-N=(E) it II *l

<td> It</td><td> 11</td><td> II</td>

<td> It</td><td> II</td><td> !1</td>

<td> It</td><td> il</td><td> 1.</td>

<td> It</td><td> It</td><td> It</td>

<td> tt</td><td> II</td><td> It</td>

H0-N=(Z)

<td> tt</td><td> II</td><td> 1.</td>

<td> II</td><td> II</td><td> II</td>

<td> Π</td><td> It</td><td> 1.</td>

t> II '

<td> It</td><td> Π</td><td> It</td>

<td></td><td> It</td><td> II</td>

z ^Μ~©.~©־

<td> II</td><td> It</td><td> It</td>

<td> II</td><td> 11</td><td> tt</td>

-C=C-H-OH

-g-CH₂OH-H

IIII

-C=C-H-OH

OH -CH₂-C=C-H

-CSC-CH₂CH₃ . . -C=C-CF₃

-C=C-H

-CSC-SlMe₃

OH -C=C-H ״ ' -CSC-CH₃ ״ -C5C-CH₂CH₃

-C=C-C1

-C=C-SiMe₃

-CH₂־C=C-H

-C=C-H -OH

II II

OH -C=C-H ״ -CSC-CH₃ ״ -CSC-CH₂-CH₃

-CSC-C1

-C=C-SiMe₃ ״ -ch₂־csc-h

OH -CSC-H ״ -csc-cf₃ ״ -CSC-CH₃

CSC-Cl

<img file="IL65680A_D0029.tif" />

־5-

<td> A</td><td>^R1</td><td>^R2</td><td>^R3</td><td>^R4</td>

<td> ° €</td><td></td><td> ch₃</td><td> -OH</td><td> 1 a x K) 1 n 111 a 1 X</td>

<td> י.</td><td> Η</td><td> 11</td><td> -C=C—H</td><td> -OH</td>

<td> II</td><td> II</td><td> II</td><td> °^c-ch₂oh</td><td> -H</td>

<td> II</td><td></td><td> It</td><td> II</td><td> Π</td>

<td> Η</td><td> It</td><td> II</td><td> -C=C-H</td><td> OH</td>

<td> II</td><td> 1!</td><td> II</td><td> OH</td><td> -c2c-cf₃</td>

<td> II</td><td> 11</td><td> II</td><td> OH</td><td> -C=C-H</td>

<td> II</td><td> Η</td><td> It</td><td> II</td><td> '־ -ch₂-ch=ch₂</td>

<td> It</td><td> II</td><td> 11</td><td> It</td><td> ch₂-c=c-h</td>

<td> Η</td><td> Η</td><td> &gt;1</td><td> It</td><td> -CH,</td>

<td></td><td></td><td></td><td> 0.</td><td> 5</td>

<td> Π</td><td> II</td><td> If</td><td> /^C־^CH3</td><td> ־^CH3</td>

<td> II</td><td> 1</td><td> II</td><td> OH</td><td> -CH₂-CN</td>

<td> ΗΟ-Ν=(Ε)</td><td> u</td><td> It</td><td> OH</td><td> -C=C-H</td>

<td> II</td><td> II</td><td> 11</td><td> It</td><td> -C=C-CH₃</td>

<td> II</td><td> II</td><td> II</td><td> tl</td><td> -C^C-CH CH</td>

<td> II</td><td> II</td><td> II</td><td> tl</td><td> -C^C-Cl</td>

<td> II</td><td> II</td><td> If</td><td> 11</td><td> -CH₂-C2C־H</td>

<td> 11</td><td> tl</td><td> (t</td><td> -C=C-H</td><td> -OH</td>

<td> II</td><td> II</td><td> It</td><td> JC-CH-OH</td><td> -H</td>

<td></td><td></td><td></td><td>²</td><td></td>

<td> ΗΟ-Ν=(Ζ)</td><td> tl</td><td> II</td><td> It</td><td> 11</td>

<td> II</td><td> tl</td><td> It</td><td> -C-C-H</td><td> -OH</td>

<td> 11</td><td> II</td><td> It</td><td> OH</td><td> -C-C-H</td>

<td> Η</td><td> י It</td><td> II</td><td> II</td><td> -C=C-CH« J</td>

<td> 11</td><td> II</td><td> Π</td><td> tl</td><td> __C־C-CH₂-CH₃</td>

<td> II</td><td> 11</td><td> II</td><td> It</td><td> -C^C-C1</td>

<td> II</td><td> 11</td><td> It</td><td> It</td><td> -CH₂-C=C-H</td>

<td> 0</td><td> M</td><td> CH CH fc J</td><td> II</td><td> -C^C-H</td>

<td> II</td><td> II</td><td> 11</td><td> tt</td><td> -C=C-CH₃</td>

<td> A</td><td>^R1</td><td>^R2</td><td>^R3</td><td>^R4</td>

<td> 0</td><td></td><td> CH CH w W</td><td> OH</td><td> -CH₂-C=C-H</td>

<td> II</td><td> II</td><td> II</td><td> 11</td><td> -CH₂-CH־CH₂</td>

<td> II</td><td> II</td><td> It</td><td> ^C-CH-</td><td> -CH.</td>

<td></td><td></td><td></td><td> qS 3</td><td> 3</td>

<td> il</td><td> II</td><td> II</td><td> &gt;C-CH-OH</td><td> -H</td>

<td></td><td></td><td></td><td> 2</td><td></td>

<td> 11</td><td> 11</td><td> 11</td><td> -C=C־־H</td><td> -OH</td>

<td> ri</td><td></td><td> CH, «J</td><td> OH</td><td> -C=C-H</td>

<td> II</td><td> II</td><td> If</td><td> II</td><td> -c=c-ch₃</td>

<td> 11</td><td> II</td><td> II</td><td> 11</td><td> -C^C-C1</td>

<td> 11</td><td> II</td><td> II</td><td> II</td><td> -C-C-CH-CH,</td>

<td> 11</td><td> II</td><td> II</td><td> 11</td><td> -CH₂-C^C-H</td>

<td> it</td><td> II</td><td> 11</td><td> π</td><td> -CH₂-CH=CH₂</td>

<td> 11</td><td> II</td><td> 11</td><td> -C=C-H</td><td> -OH</td>

<td> II</td><td> It</td><td> It</td><td> lc-CH_nOH</td><td> -H</td>

<td></td><td></td><td></td><td></td><td></td>

<td> II</td><td> II</td><td> tl</td><td> \-CH_n</td><td> -CH_n</td>

<td></td><td></td><td></td><td> y 3</td><td> 3</td>

<td> II</td><td> tl</td><td> II</td><td> 1C-CH-</td><td> -H</td>

<td> II</td><td></td><td> II</td><td> 3 II</td><td> tl</td>

<td> II</td><td> 11</td><td> II</td><td> It</td><td> -CH-</td>

<td></td><td></td><td></td><td> 0</td><td> 3</td>

<td> II</td><td> It</td><td> II</td><td> ^-ch₂oh</td><td> -H</td>

<td> II</td><td> 11</td><td> II</td><td> -C=C-H</td><td> -OH</td>

<td> II</td><td> II</td><td> 11</td><td> OH</td><td> -C=C-H</td>

<td> 1*</td><td> II</td><td> It</td><td> It</td><td> -csc-ch₃</td>

<td> II</td><td> It</td><td> II</td><td> II</td><td> -C^C-Cl</td>

<td> II</td><td> II</td><td> II</td><td> tl</td><td> -C=C-CH₂CH₃</td>

<td> It</td><td> II</td><td> II</td><td> &gt;1</td><td> -CH₂-CSC-H</td>

<td> II</td><td> tl</td><td> It</td><td> It</td><td> -CH₂־CH=CH₂</td>

<td> 11</td><td> Me₃Si-CH^_N-^-</td><td> fl</td><td> It</td><td> -C=C-H</td>

<td> ft</td><td> 11</td><td> 11</td><td> II</td><td> -C=C-CH₃</td>

<td> 11</td><td> II</td><td> tl</td><td> II</td><td> -CH₂-CSC-H</td>

<img file="IL65680A_D0030.tif" />

<img file="IL65680A_D0031.tif" />

<td> A</td><td>^R1</td><td>^R2</td><td>^R3</td><td>^R4</td>

<td> HO-N=(E)</td><td> Me₃Si CH₂-</td><td> CH₃</td><td> OH</td><td> -CH₂-C=C-H</td>

<td> H0-N=(2)</td><td> II</td><td> tl</td><td> -C=C-H</td><td> -OH</td>

<td> II</td><td> It</td><td> II</td><td> OH</td><td> -C=C-H</td>

<td> II</td><td> tl</td><td> II</td><td> II</td><td> -c=c-ch₃</td>

<td> II</td><td> II</td><td> tl</td><td> It</td><td> -CH--C-C-H</td>

<td> 0</td><td> ^ΝΔΛΟ-φ.</td><td> 1.</td><td> II</td><td> -c־c-ch₃</td>

<td> 11</td><td> II</td><td> II</td><td> J3-CH OH CT ²</td><td> -H</td>

<td> II</td><td></td><td> II</td><td> II</td><td> II</td>

<td> II</td><td> II</td><td> II</td><td> OH</td><td> -C=C-H</td>

<td> II</td><td> II</td><td> 11</td><td> If</td><td> -C=C-CH₃</td>

<td> II</td><td> II</td><td> It</td><td> tl</td><td> -CH״-C=C-H 4.</td>

<td> 11</td><td> 1.</td><td> 11</td><td> II</td><td> Μ X</td>

<td> II</td><td> 11</td><td> II</td><td> It</td><td> -CH₂CN</td>

<td> tl</td><td> מ</td><td> II</td><td> -C=C-H 0</td><td> -OH</td>

<td> 11</td><td> It</td><td> II</td><td> x-ch₂oh 1</td><td> -H</td>

<td> 11</td><td> It</td><td> II</td><td> o=c-ch₇w</td><td> -ch₃</td>

<td> If</td><td> it . tie</td><td> 11</td><td> OH</td><td> -H</td>

<td> It</td><td></td><td> 11</td><td> OH</td><td> -C=C-H</td>

<td> 11</td><td> tl</td><td> it</td><td> II</td><td> -c^c-cf₃</td>

<td> It</td><td> II</td><td> II</td><td> If</td><td> -C=C-CH_CH M J</td>

<td> It</td><td> II</td><td> II</td><td> II</td><td> -C^C-Cl</td>

<td> It</td><td> II</td><td> II</td><td> II</td><td> -CH₂-C=C-H</td>

<td> It</td><td> II</td><td> tl</td><td> -C=C-H 0</td><td> -OH</td>

<td> II</td><td> II</td><td> II</td><td> ^C-CH₂OH</td><td> -H</td>

<td> 11</td><td> II</td><td> II</td><td> ^J:-ch₃</td><td> -CH, w</td>

<td> It</td><td> If</td><td> ch₉ch₇ M .J</td><td> OH</td><td> -C=C-H</td>

<td> If</td><td> tl</td><td> II</td><td> II</td><td> -C^C-CH.</td>

<td> It</td><td> tl</td><td> tl</td><td> II</td><td> -ch₂-c^c-h</td>

<img file="IL65680A_D0032.tif" />

<img file="IL65680A_D0033.tif" />

B) The products of formula !

<img file="IL65680A_D0034.tif" />

<td colspan="4"> in which Rp Rg, R^ and R^ have the following meEanings :</td>

<td> 1</td><td>^R2</td><td>^R3</td><td>^R4</td>

<td></td><td> ch₃</td><td> CH</td><td> -CaC-H</td>

<td> II</td><td> It</td><td> H</td><td> -C=C-CH₃־</td>

<td> II</td><td> II</td><td> tt</td><td> -C=C-C?₃</td>

<td> II</td><td> 1)</td><td> II</td><td> -CH,CH. M J</td>

<td> H 1</td><td> II</td><td> 41</td><td> -CH״-C־C-H 4M</td>

<img file="IL65680A_D0035.tif" />

<img file="IL65680A_D0036.tif" />

It is also possible to prepare the epoxides corresponding to the products appearing in list A above.

<img file="IL65680A_D0037.tif" />

Example-1; 17B-hvdroxv 17&lt;x-(proo-l-vnyl) HB-(4-pyridyl) estra-4.9-dien-3-0ne.

12°z£Br2Ezlrggyll_gstr^9-en_^q_17§7diol_A

At 20° C', 100 cm^ of a solution of 4-chloropyridinyl magnesium bromide: in tetrahydrofuran (0.5 - 0.6 M solution prepared from .15 g of 4-chloropyridine and 6g of magnesium) are added to a solution containing 6.16 g of dimethyl sulphide / copper bromide complex in 40 cm^ of tetrahydrofuran. The whole is agitated for 20 minutes at ambient temperature under inert atmosphere and over 10 minutes a solution containing J.7 g of 5,3-Cl,2-ethanediyl bis (oxy)] 5a 10a-epoxy 17a-(prop-l-ynyl) estr-9(ll)-en 17B-01 is added. The whole is agitated for one hour at ambient temperature and poured into a mixture of cold water and ammonium chloride. The reaction mixture is agitated for half an hour at ambient temperature and extracted with ether. The extract is washed with a saturated solution of sodium chloride, dried and concentrated to dryness under reduced pressure. 6 g are obtained of a product which is chromatographed on silica, elution being carried out with the methylene chloride / acetone mixture, 1:1 containing 1 per thousand of triethylamine. 5.15 g are thus isolated of a product which is dried under a vacuum of 0.1 mm of mercury at about 60° C. The product sought is thus obtained ^aD⁵²°“ ^־ ί ¹.5 (01%־ CHClj).

Stage_B_2_17^zhydrox2_122zi2I^,22rlzi2Z2)-¹l^-i^:2Zli^lL®stra iij.2z^i22z2222®i

For 3 hours at ambient temperature under inert atmosphere a solution containing 2.9 g of the product prepared in Stage A, 14 cm^ of methanol and 7 cm^ of 2N hydrochloric acid is agitated, .z x

A solution containing 200 cm⁷ of ether and 90cnr of a saturated solution of sodium acid carbonate is then added. The whole is agitated for 15 minutes at ambient temperature, decanted and extracted with ether. The extracts are washed with a saturated solution of sodium chloride then dried and concentrated to dryness under reduced pressure. 2.3 g are obtained of a product which is chromatographed on silica, elution being carried out with the methylene chloride / acetone mixture ; 6 : 41.7 .־ g of productaroisolated and dried under pressure of 0.1 mm of mercury for 24 hours of which 8 hours are at 80° 0. The product sought is thus obtained (&lt;_ע[ג « + 3O°5 -1° (c 1% ־ CHC1₃נ

Γη the same manner, 173־־hydroxy, 17^a“(prop«״l-ynyl) . . llp-(J-pyridyl) estra 4,9-dien 3־־oc.e (C&lt;x]^= +14° c 1* CHCI3) and 17p-hydroxy 17»(prop-l-ynyl) llB-(2-pyridyl) estra-4,9dien J-one ([a]p = 2°״ c = 1% CHCl^) are prepared.

Example 2 : 178-hydroxy llBU^Nrdimethyl amino) propyll 17&lt;x-(prop-l-ynyl) estra-4,9-dien 3-one.

Over 5 minutes at 0° C, 12.33 g of dimethyl sulphide 3 / copper bromide complex are added to 141 cm^y of 3׳־(N,N dimethylamino) propyl magnesium chloride (0.85 M solution prepared from 42 g of chloro 3-ΓΓ,Ν dimethylamino propane and 10.5 g of magnesium. The whole is kept under .

agitation for 25 minutes at 0° C and, drop by drop, J.70 g of 3,3[!,2-ethanediyl bis (oxy)2 5^a 10a epoxy 17a-(l-propynyl) estr-9( 11 )-en-17P-01 in solution in 50 cm^ of tetrahydro furan are added. The reaction mixture is kept under agitation for 3 hours at 0° C and poured into a mixture containing 40 g of ammonium chloride and 200 cm^ of iced water.

The whole is agitated for 15 minutes at ambient temperature then extracted with ether. The extract is washed with a saturated solution of sodium chloride, dried and concentrated to dryness under reduced pressure. 4.6 g of a product are obtained and chromatographed on silica, elution being carried out with a methylene chloride / methanol mixture (8 : 2). 2.55 g of product are isolated.

= -86° - 1.5 (0 1% ־־ in chloroform) Stage^B^^^g^hydro^^llg^C^-^N^N^dimethylamino^g^SEZlI 17^

2.4 g of the product prepared in Stage A, 14 cm^ of methanol and 7 cm of 2N hydrochloric acid are agitated at ambient temperature for 4 hours under inert atmosphere. 200 cm^ of isopropyl ether and 90 cm^ of a saturated solution of sodium acid carbonate are then added. The whole is agitated for half an hour at ambient temperature, decanted and extracted with ether. The extract is washed with a saturated solution of sodium chloride and dried. It is concentrated to dryness under reduced pressure and 1.8 g of a product are obtained and chromatographed on silica, elution being carried out with the chloroform / methanol mixture, 8:2. 1.30 g of a product are thus obtained and dried at about 30° - ¼0° 0 under reduced pressure of 0.1 mm of mercury. 1.25 8 of product sought are thus obtained, [a]_ = -114° + 2.5° (c = 1% CHOI,).

כ ע Example 3 : llg-C4-(N.N-dimethyl amino ethyloxy) ־phenyl) 17Bhydroxy 17«-(nron-l-ynyl) estra 4.9-dien-3-one, Stage-A-^-^A^ethane^diyl-bisCo^^llg-.t^^NjN^dimethyl-amino £i^Zl°?z2_21}®5Z12-12“zi2I22zlzZ?Zll_®stra29-9n__>52_A_17g3dioL.

a) magnesium derivative of 4-(N,N-dimethylamino ethyloxy) bromobenzene.

Drop by drop over 45 minutes a solution containing 24 g

ן / of 4-(N,N-dimethylamino ethyloxy) bromobenzene in 90 cm of anhydrous tetrahydrofuran is introduced. The reaction is catalysed by the addition of 0.2 cm^ of 1,2-dibromoethane. When the introduction is finished, the whole is agitated again for 1 hour at 25° 0. A 0.7 M solution is thus obtained and used as it is.

b) condensation.

The solution prepared above is added to a solution containing 6.16 g of dimethyl sulphide / copper bromide z complex in 20 cm of tetrahydrofuran. The whole is agitated for 20 minutes at ambient temperature and, drop by drop, over a few minutes, 3.7 8 of 5,3Cl,2-(ethanediyl bis (oxy)]

255«, 10a-epoxy 17a-(prop-1-ynyl) estr - 9(ll)-en 17β-01 in 5 cm of tetrahydrofuran are added. The whole is then agitated, for one hour under inert atmosphere, then the reaction mixture is poured into a solution containing 15 g of ammonium chloride in 200 cm^ of iced water. The whole is extracted with ether and the extract is washed with a saturated aqueous solution of sodium chloride. It is dried and concentrated under reduced pressure. 18.5 S of an oil are thus obtained and chromatographed on alumina and eluted with chloroform and 4.5 g of the product sought are thus obtained.

[a]_D 1.5° + 44°- ־ (c 1% ־ CHClj) ^^®-?-l-llSlihziN^N-dimethylamino^ethyloxy^^ghenyl] 17β^ISSZ-lZSziEISEzlzXBli^.sstra^^^-dien^^one^

9.5 cm^ of 2N hydrochloric acid are added to a solution containing 4.5 g of the product prepared in Stage A in 20 cm^ of methanol. The solution is kept under agitation for 2 hours at ambient temperature and 260 cm^ of ether and 110 cm^ of a saturated solution of sodium acid carbonate are added. The whole is kept under agitation for 15 minutes at ambient temperature, decanted, and extracted with ether. The extract is dried and concentrated to dryness under reduced pressure.

5.5 g of a product are obtained and chromatographed on silica, elution being carried out with the methylene chloride / methanol mixture (92.5 : 7.5). 1.8 g of amorphous expected product are thus obtained.

[a]_D 71° + ־־ (c־l% CHC1₃)

Example 4 ; 17B-hydroxy HB-(4-dimethylamino .phenyl) 17a(prop-l-ynyl) estra 4.9-dien-3-one, Stage_A_-:₁_llg3£4-dimethylamino_ghenyl2_2i^£14.§Z®i^5®^j:Zl 5i5_i22z21-i22£2£22zlzZSZ12-£5i£-2z®5z22A12§z^21A_

A solution containing 58 m.moles of p-dimethylamino phenyl magnesium bromide in tetrahydrofuran is added ־to a suspension containing 4.1 g of copper bromide / dimethyl sulphide complex in 20 cm^ of tetrahydrofuran. 2.45 g of 3»5-[l»2-ethanediyl bis (oxy)] 5^a, 10a epoxy 17^a-(prop10 1-ynyl) estr 9(H) en 175-01 in. solution in tetrahydrofuran are then added. The reaction mixture is kept under agitation a for 10 minutes and hydrolysed with 50 cm of a saturated solution of ammonium chloride. The whole is decanted and extracted with ether and the organid phase is washed with water and dried. The solvents are evaporated under reduced pressure and 11 g of crude product sought are obtained and chromatographed on silica, elution being carried out- with the cyclohexane / ethyl .acetate mixture, 6:40. 1.8 g of the product sought (11β) and 750 mg of the product Ila are thus obtained. The products are recristallised from isopropyl ether and ethyl acetate.

Hit. 210° ־ C [a]- 1%) 66°5- ־ CHC1,). 5 ע

Stage^B^: 12§^hydr0^^11g-^4-djjneth^larnin.o , ghenyl} 17^a-^PT0P-

1-ynyl} estra-4_A9-dien-5-one.

cnr of a solution of concentrated hydrochloric acid are added to a solution containing 1.53 g of the product prepared in Stage A in 60 cm^ of methanol. The whole is agitated for 30 minutes at ambient temperature and 150 cm^ of ether are added, then 50 cm^ of a N aqueous solution of sodium hydroxide. The reaction medium is agitated for 15 minutes and decanted and the organic phase is dried. The solvents are evaporated under reduced pressure and 1.4 g of crude product are obtained and purified on silica, elution being carried out with the cyclohexane / ethyl acetate mixture (7:3). 0.932gof the product sought are obtained with M. Pt. 0 150° ־ [a]_D 138.5° + ־ (c = 0.5% CHClj) Example 5 :_17B-hydroxy 17<x-(pron-1-ynyl) llg[(4-trimethylsilyl) phenyl] estra-4,9-dien-3-one, §iSS®_A_:_ll§[^4_:trimethylsilyl)2henyl)5_4>5[l_<12yethanediyl ii^-iSSZ^I-lZSziErSEzlzZSZl^-^str-^yen^^A.lZ^ydioL.

At -30° 0 under inert atmosphere there are added to 45 cm of a 0.65 M solution of 4-trimethylsilyl phenyl magnesium bromide in tetrahydrofuran, 200 mg of copper chloride then, drop by drop, the temperature being kept at -20° C, a solution of 3.3 g of 3,3-01,2-ethanediyl bis (oxy)] 54, 10a-epoxy 17a-(prop-l-ynyl) estr 9(U)-en 173-01 3 in 25 cet of tetrahydrofuran. After one hour the whole is hydrolysed by means of an aqueous solution of ammonium chloride, extracted with ether and dried and the solvents are evaporated under reduced pressure. The residue is chromatographed on silica, elution being carried out with the methylene chloride / acetone mixture (94:6) containing 0.1 % of triethylamine. 2.087 g of the product sought are ל isolated and purified by recristaUisation from isopropyl ether then from ethyl acetate, M.Pt . 226° C

[a]_D 1.5° + 60°- ־ (c 0.9% ־ CHCip

21?£2Ζ12_52ί£2ζ^Λ2ζ^122ζ^Ζ2224

1.7 g of Redex sulphonic resin are added to a solution containing 1.68 g of the product prepared in Stage A in 17 cm^ of boiling 90° alcohol. The whole is heated to refux for JO minutes, the resin is separated and rinsed with methylene chloride and the filtrate is evaporated under reduced pressure. The residue thus obtained is taken up with methylene chloride and dried and the solvent is driven off under reduced pressure. The residue obtained is chromatographed on'silica, elution being carried out with the benzene / ethyl acetate mixture (85:15). 1.21? g of the product sought are thus obtained, melting at 212° C.

[a] 94° + ־ (c 0.9% ־ CHC1₅)

In the same manner, 17£-hydroxy-17*-(prop-l-ynyl) 110-Γ(5-trimethylsilyl) phenyl) estra-4,9-dien-5-one was prepared.

⁼ °/ ²°^± 5°*52 ⁺ ר ²⁵

Preparation : 3.3-E1,2-ethanediyl bis (oxyll 17a-(prop-1-ynyl) estr- 9(H)-en 5.10-epoxy 170-01.

Stage_Ai_-J_>12_:Cl_A2-ethanediyl_-bis_£oxy)l_172_:£2ro2₌l_rynyl)_-estra 5iiQ)_9£ll)__z_d.ien__L2g-01^

Under agitation, 207 cm^ of a 1.15% solution of ethyl magnesium bromide in tetrahydrofuran are cooled to 0° 0 and propyne gas previously dried on calcium chloride is bubbled in for 1 hour 30 minutes at 0° C. The whole is allowed to return to ambient temperature and agitated again for 1 hour, the bubbling—in being maintained. Then at 2025° C over half an hour a solution containing 30 g of 3,3-Cl,2-ethanediyl bis (oxy)] estra 5(10^ 9(ll)-dien 17-one in 120 cm^ of anhydrous tetrahydrofuran and one drop of anhydrous triethyl-־. amine are added. The whole is agitated at ambient temperature for two hours and poured into a mixture of distilled water, ammonium chloride and ice. The whole is agitated and extracted three times with ethyl ether. The organic phase is washed with water, dried and concentrated under reduced pressure. The residue is dried under vacuum. 35.25 g of the product sought are obtained.

N.Ff.R, Spectrum GDC ppm

H of the methyl at 18 ¹.85 H of the methyl atcs c CH-

ל

5.65 H of the carbon at 11 * H of the ethylene ketal §i-5x_§_i_5_A53Cl_A22ethylenediox2־_bis__( oxy^J^lVa-^grop-l-jnjl)

Under agitation and bubbling-in of nitrogen, 30 g of the product prepared in Stage A are introduced into 150 cm of methylene chloride. The whole is cooled to 0° C

- ’49 5 then, all at once, 1.8 cm of hexafluoroacetone sesquihydrate z are added then, under agitation, 4.35 cur of 85% hydrogen peroxide. The reaction mixture is kept under agitation and bubbling-in of nitrogen at 0° 0 for ?2 hours. The reaction solution is then poured into a mixture containing z

250 g of ice and 500 cm of 0.2N sodium thiosulphate. The whole is agitated for a few moments then extracted with methylene chloride. The organic phase is washed with distilled, water, dried on sodium sulphate in the presence of pyridine, then concentrated under reduced pressure. The residue is dried under reduced pressure. 31.6 g of a product are obtained and chromatographed on silica, eluant: benzene / ethyl acetate, 90::10 . The product sought is thus obtained. NMR Spectrum CDCl^ ppm

0.82 H of the methyl at 18

1.83 H of the methyl of the radical

C = C -CH, 2

6.1 H of the carbon at 11

3.92 H of the ketal

Example 6 ; 176-ethynyl !?^-hydroxy llB-(4-dimethylaminophenyl) estra 4.9-dien 3-one, Stage^^^^dimet^xj^^^Szhydroxy^ll^iWimet^lamino^

Under inert gas 2,8 g of 3,3-dimethoxy 5^aa-epoxy

17p-ethynyl 17“-hydroxy estr-9(11)-ene,56 cm^ of anhydrous tetrahydrofuran and 80 mg of anhydrous copper chloride.are mixed. The mixture is agitated for 5 minutes at ambient temperature then placed in a bath of iced water and, drop by drop, 55 cm^ of a 0.95 M solution of (4-dimethylaminophenyl) magnesium bromide in tetrahydrofuran are added. The whole is then allowed to rise again to ambient temperature.

To a suspension of the copper bromide / dimethyl sulphide complex (6.15g) in 30cm^ of anhydrous tetrahydrofuran are added 63 cm^ of (4-dimethylaminophenyl) magnesium bromide so that the temperature remains below 28.5°. The whole is left for 30 minutes under agitation then, drop by drop, the solution obtained above is added. The whole is kept for 18 hours under agitation at ambient temperature, poured into a saturated solution of ammonium chloride, agitated for 10 minutes and extracted with chloroform, the organic phase is washed with water and dried and the solvent is evaporated. The residue is chromatographed on silica, elution beingr carried out with the petroleum ether / ethyl acetate mixture (1:1) containing 0.5 per thousand of triethylamine and 1.28 g of product are obtained. This product is purified again by chromatography on silica, elution being carried out with the same mixture, and 0,84 g of expected product is obtained.

®SiES-iL. 2ζ£ΐ ® 2ζ3ζ22®λ

0.76 g of the product obtained in Stage A is mixed with cm^ of methanol and 1.6 cm^ of 2N hydrochloric acid. The mixture is agitated for an hour and a half then poured into a saturated aqueous solution of sodium bicarbonate and extracted with chloroform, the organic phase is dried and the solvent is evaporated. 0.76 g of crude product is obtained and chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1) then with the ethyl ether / petroleum ether mixture (3:1). 0,435 g of expected product is obtained, which is crystallised from isopropyl ether.

K.Pt. 142° ־ C

[a)_D= * 235.5° * 4.5° (0 0.45% ־ chloroform)

The starting product of Stage A was prepared as follows: Stage a : 3,3־dimethoxy 17&lt;x-hydroxy 17P-ethynyl estra 5(10) 9 (ll)diene.

A mixture of 16.8 g of 3,3-dimethoxy 17p-hydroxy 17^a20 -ethynyl estra 5 (10) 9 (11) diene, 175 cm^ of anhydrous tetrahydrofuran and 4.35 g of lithium bromide is agitated for 5 minutes at ambient temperature then cooled to - 60° 0 and cm of a 1.55M solution of butyllithium in hexane are added.

z The whole is left for 30 minutes under agitation then J.9 cnr of methane sulphonyl chloride are added and the whole is left for 1 hour at -60° C under agitation. It is then poured into x

500 cm of a saturated aqueous solution of ammonium chloride, agitated for 10 minutes and extracted with methylene chloride the organic phase is dried, 2.5 cm^ of pyridine are added then the whole is evaporated to dryness under reduced pressure at 0 C. 75 cur of tetrahydrofuran are added to the residue obtained then 12.5 cm^ of water containing 0.75 g of silver nitrate. The whole is kept for 15 hours at -50° C, then for 4 hours at ambient temperature. It is poured into 500 cm^ of a half-saturated aqueous solution of ammonium chi οτ-ΐ containing 5 g of sodium cyanide. The whole is agitated for 50 minutes at 20° C, extracted with chloroform, washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture(9:l). J g of expected product are obtained.

M. Pt. /v 150° G (a]p = + 125 - 2.5° (c = 1% chloroform) Stage b : 5,3-dimethoxy 5«-10a-epoxy 170-ethynyl 17a-hydroxy estr-9(ll)-ene.

2.6 g of the product obtained in Stage a, 12 cm^ of methylene chloride and one drop of pyridina are mixed. The mixture is cooled to 0° C, and 0.12 cm^ of¹ hexachloroacetone and 0.65 cm^ of hydrogen peroxide (200 volumes) are added.

After one hour under agitation, 13 cm of chloroform are added then the agitation is continued for 18 hours. The whole is poured into 100 cm^ of a saturated solution of sodium thiosulphate, agitated for 10 minutes and extracted with chloroform, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. 2.8 g of expected product are obtained, which is used as it is for the following stage. (The product contains a small proportion of β epoxide).

Example 7 : 17B-hydroxy 17a-Phenyl 110(4-dimethylaminoohenyl) estra §taS^4H_JJ5!37Cl_j.2^ethane_diyl_ubis_(oxy) ] ,118-,,( ^-dimethylamino-

a) grg2aration^of_the_magnesium_derivative.

Under inert gas 29 g of magnesium turnings and 50 cm^ of anhydrous tetrahydrofuran are mixed. Over two and a half hours, the temperature being kept at 35° 0 - 5° 0, is introduced a mixture of 200 g of 4—dimethylamino bromo benzene z in 950 cnr of anhydrous tetrahydrofuran. A 0.8 M solution of expected magnesium derivative is thus obtained.

b) addition_of_the_magnesium_derivative₄

Under inert gas 25 g of 3,5-[l,2-ethane diyl bis (oxy)] 5^aa-epoxy estr-9(ll)-en 17-one, 500 cm^ of anhydrous tetrahydrofuran and 0.757 g of copper chloride are mixed. The mixture is cooled to 0° to +5° C and , drop by drop, over 1 x

hour 15 minutes, there are added 284. cm of the solution of magnesium derivative prepared above. The whole is then agitated for 15 minutes, poured into a saturated solution of ammonium chloride and extracted with ethyl acetate and the organic phase is washed with a saturated solution of ammonium chloride then with a saturated solution of sodium chloride. The .

organic phase is dried and evaporated to dryness under reduced pressure. 46 g of crude product are obtained and chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1) containing per thousand of triethylamine and 17.76 g of expected product ar© obtained. M. Pt. 173° ־ C.

The impure fractions of product obtained are again chromatographed on silica, elution being carried out with the petroleum ether / acetone mixture (8:2) containing 1 per thousand of triethylamine. 6.35 g of expected product are again obtained. M.Pt. 176° ־־ C. The product thus obtained is used as it is for the following stage.

έί2£ίΙ}Σ1^Βΐ2221ϊ£2Σ12-122ζ2^22Σ1_® ^{s tr}“9-®ne.

Over 30 minutes at +25° C there is added to a solution of 2

33.3 cm^y of phenyllithium (1.5 M), a solution of 4.5! g of the product obtained in Stage A in 45.1 cm^ of anhydrous tetrahydrofuran. The whole is agitated for 4 hours at ambient temperature, poured into a saturated aqueous solution of ammonium chloride and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. 5.6 g of crude product are obtained and chromatographed on silica, elution being carried out with the methylene chloride / acetone mixture (9:1) containing 1 per thousand of triethylamine. 1.16 g of expected product are obtained and crystallised from the methylene chloride / isopropyl ether mixture.

M.Pt. = 240° 0:

. +55° - 2.5° (c ^a 0.5% chloroform)

Sjage C_:_l?g-hydroxy !?»-phenyl llg-(4-dimethylaminophenyll

Under inert gas 1.5 g of the product obtained in Stage B are mixed into 45 cm^ of methanol. The mixture is cooled to o 3 to +5 C and 5 cr of 2N hydrochloric acid are introduced. The whole is agitated for 1 hour at 0° to +5° C, then 90 cm^ of ether and 90 cm^ of a 0.25 M aqueous solution of sodium bicarbonate are added. The whole is agitated for 5 minutes, decanted and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried ‘ and the solvent is evaporated. 1.30 g of product are obtained and purified by chromatography on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1). 0.95 g of expected product is obtained and crystallised from the methylene chloride / isopropyl ether mixture.

M.Pt. = 226° 0

[»]p » +151.5° (0 = 0.4% chloroform).

The starting product of Stage A was prepared as follows.

11.18 g of 3,3-£1.2-ethane diyl bis (oxy)] estr-5 (10) (11) dien~17“0ne and 56 cnr of methylene chloride are mixed two drops of pyridine are added, the whole is cooled to 0° 0 x and 4.3 cr of hexafluoroacetone sesquihydrate are introduced then 1.6 cm^ of 85% hydrogen peroxide are added. The whole is kept under agitation and under inert gas at 0° 0 for 25 x hours. It is then poured into a mixture containing 200 cnr of 0.5 M solution of sodium thiosulphate and 200 g of ice. The whole is kept for 30 minutes under agitation then extracted with methylene chloride containing a trace of pyridine. The organic phase is washed with water and dried and the solvent is evaporated. 11.4 g of expected product are obtained, which is used as it is for the following stage.

Example 8 : llB-(4-dimethylaminophenyl) 17B-hydroxy 23-methyl (17a) 19.21-dinorchola-4,9,23-trien-20-yn-3-one,

Stage A ׳; ^^x^El^^ethane^diyl^bis^^oxyl^l. llg-^^-d.imethylaminq^ 2^®2Σ12-.ί2ζδ£ί^Σ1-£12Ξ2_12Λϋζ^ίΒ2Σ9ίϊ212ζθΛ^^ίβη;2Ο;2η_-522 17g_zdi21.

Under inert gas 4.5 g of potassium tert-butylate are mixed with 90 cm^ of anhydrous tetrahydrofuran. The mixture is cooled to -10° 0 and 10.61 cm^ ofS 2-methyl 1-buten 3-yne are added. The whole is agitated for 15 minutes at -10° O', then, over 15 minutes, a solution of 4.5 g of־ product obtained x in Stage A of Example 7 in 45 cm of anhydrous tetrahydrofuran is added. The whole is agitated for 30 minutes at - 10° 0 o 3 then for 4 hours at 0 to +5 0. It is poured into 500 cm of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate and the organic phase is washed with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness. 5.56 g of crude expected product are obtained. M. Pt. =205° 0.

The product is used as it is for the rest of the synthesis.

The crude product is chromatographed on silica, elution being carried out with the methylene chloride / ethyl acetate mixture (9:1) containing 1 per thousand of triethylamine, then recrystalised from ethyl acetate, melting at 215° 0. Stage B : llg-^4-dimethylaminophenyl) !?g-hydroxj. 25-methyl

Under inert gas 5 g of the product obtained in Stage A

(7 ג are mixed with 500 on⁷ of methanol and 10 cm⁷ of 2N hydrochloric acid. The mixture is agitated for 15 minutes . at 20° C, 500 cm^ of methylene chloride are added then 500 cm^ of a 0.25 M aqueous solution of sodium bicarbonate. After 10 minutes under agitation, the whole is decanted and extracted with methylene chloride and the organic phase is washed with water, dried and evaporated to dryness.

4,5 g of crude expected product are obtained and chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1). After recrystallisation of the product from diisopropyl oxide 2.01 g of expected product are obtained.

M.Pt 0 185° ־ = +88.5° + 15°׳ (c = 1% chloroform).

Example 9 ; llg(4-dimethylaminophenyl) 176-methoxy 23-methyl (17«) 19.21-di norchola -4,9-23-trien-20yn-3-one.

Under inert gas 4.5 g of potassium tert-butylate 5 are mixed into 90 cm^ of anhydrous tetrahydrofuran The suspension is cooled to -10° C then, drop by drop, 10.61 cm^ of 2-methyl l-buten-5-yne are added. The whole is agitated for 15 minutes at -10° C, then, over 15 minutes, 4.5 g of the product obtained in Stage A of Example 7 in 45 cm of anhydrous tetrahydrofuran are added. The whole is agitated for 30 minutes at -10° C, then for 4 hours at 0° to +5° 0. 7.5 cm^ of methyl iodide are then added then the whole is kept for 30 minutes under agitation in an ice bath. The mixture is then poured into 500 cm^ of 0.1 N hydrochloric acid. The whole is agitated for 50 minutes at ambient temperature and extracted with ethyl acetate and the organic phase is washed with a saturated aqueous solution of sodium bicarbonate, then with a saturated aqueous solution of sodium chloride.

It is dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the methylene chloride / ethyl acetate mixture (95:5). 2.7 g of expected product are obtained and recrystallised from methanol. M.Pt. 0 105°־־ .

Example 10 : 21-chloro 17 β-hydroxy llg(4-dimethyl!.aminophenyl) (17») 19-nor pregna-4.9-dien-2C-yn 3-one, §ia£S_-A_j__212chloro_^_i3£l_J.23ethane_diyl_bis_^ox2;)2 ilii^r^iggt^g]:ggj.ngptenyl) ^17a)19-nor_pregnj^^en

Preparation of the lithium derivative

Under inert gas 77.5 cm^ of a IM solution of butyllithium in hexane are mixed with 310 cm^ 0£ anhydrous ethyl ether. The mixure is cooled to 0 to ♦5° C and, over 45 minutes, a solution of 7 cm^ of trichlorethylene in 28 cm^ of anhydrous ethyl ether is added. The whole is agitated for 1 hour, the temperature being allowed to return to 20° C, Condensation.

The mixture obtained above is cooled to 0 to +5° C and added to it, drop by drop, over thirty minutes is a solution of 7 g of the product obtained in Stage A z of Example 7 in 70 car of tetrahydrofuran. The whole is agitated for thirty minutes at 0 to ⁺5° C then the temperature is allowed to return to 20° C, the whole is poured slowly into a saturated aqueous solution of ammonium chloride, decanted and extracted with methylene chloride, the organic phase is washed with water and dried and the solvent is evaporated. 8.5 g of crude product are obtained (M.Pt. = 220° C) and introduced x into 42.5 cr of diisopropyl oxide. The whole is agitated for thirty minutes and separated and 6.58 g of expected product are obtained. M.Pt. 230° ־ C

The product can be purified by chromatography on silica, elution being carried out with the benzene / ethyl acetate mixture (7:3) containing 1 per thousand of triethylamine. By dissolution of this product in methylene chloride and the addition of diisopropyl oxide, a crystaline product is obtained melting at 240° C.

83.5°- ־ i 1.5° (c = 1% chloroform)

Stage B : 21-chl0r0_1767^dr0^_llg(4-jii1ne^hy^^ij1opj1enyl)

Under inert gas 6.38 g of the product obtained in the previous stage and 191.4 cm^ of 95% ethanol are x mixed. 15 cnr of 2N hydrochloric acid are added, 3 the whole is agitated for one hour and 300 cm of methylene chloride are added then 200 cm^ of a 0.25 M aqueous solution of sodium bicarbonate. The whole is decanted and extracted with methylene chloride, the organic phase is washed with water and dried and the solvent is evaporated. 6 g of crude product are obtained and chromatographed on silica, elution being carried out with the benzene / ethyl acetate mixture (7:3). 3.95 g of expected product are obtained and crystallised from ethyl acetate. M.Pt 240° ־ C.

[a]_D 2° - 111°+ ־ (c 1% ־ chloroform).

Example 11 : 21-chloro 178-hydroxy 118-C4-dimethylaminophenyl) (17°) 19״nor pregna 4.9“dien-20-yn-3one ΈΓ-oxide,

Under inert gas 1.2 g of the product obtained 2 in Example 10 are mixed into 24 cnr of methylene chloride. The mixture is cooled to 0 to +5° C and’ a mixture of 0.54 g of metachloroperbenzoic acid (at 85%) in 10.8 cm^ of methylene chloride is added. The whole is agitated for one hour at 0 to +5 C, poured into a 0.2 N solution of sodium thiosulphate and extracted with methylene chloride, the organic phase is washed with a saturated aqueous solution of sodium bicarbonate then with water and dried and the solvent iff evaporated. 1.3 g of crude product are obtained. This product is purified by chromatography- on silica, elution being carried out with the methylene chloride / methanol mixture (7:3). 1.15 g of expected product are obtained.

= +47.5° - 2.5° (c = 0.7 chloroform).

Example 12 : 21-chloro 9&lt;x-10°-epoxy 17B-hydroxy 116(4-dimethylaminophenyl) (17&lt;Ό 19-nor pregn-4-en-20yn-3-one N-oxide.

1.18 g of product obtained in Example 10 are 3 dissolved in 23.6 cur of methylene chloride, the solution is cooled to 0° to +5° 0 and, over 15 minutes, a mixture of 1.17 g of metachloroperbenzoic acid (at 85%) in 23•4 cm^ of meth lene chloride is added. The whole is agitated for 2 hours at 20° C, 10 0.117 g of metachloroperbenzoic are added again the whole is agitated again for one hour, the mixture is poured into a 0.2 N solution of sodium thiosulphate and extracted with methylene chloride, and the organic phase is washed with a saturated aqueous solution of sodium bicarbonate then with water, dried and evaporated to dryness. 1.14 g of crude product are obtained. M.Pt. 220° ־ O'.

The product is purified by chromatography on silica, elution being carried out with the methylene 20 chloride / methanol mixture (8:2) and 1 g of expected product is obtained. M.Pt. = 2?0° 0 [α]^ 2.5° - 39.5°+ ־ (c = 0.5% chloroform).

Example 13 ; 21-chloro 9&lt;*-10°-eooxy 17B-hydroxy 116-(4-dimethylaminophenyl) (17°0 19-nor pregn-425 -en-20-yn-3-one.

Under inert gas 0.63 g of the product obtained

X in Example 12 is mixed with 6.3 car of acetic acid. 0.34 g of triphenylphosphine is added, the whole is agitated for 45 minutes at ambient temperature, poured into water and extracted with methylene chloride, the organic phase is washed with water and dried and the solvent is evaporated. 0.9 g of product is obtained and chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1). The product thus obtained is recrystallised from a methylene chloride / isopropyl ether mixture and 0.346 g of expected product is obtained. M.Pt. = 265° O’.

= +45° - 2° (c 0.8% ־ chloroform) Example 14 : 17g-hydroxy HB-(4-dimethylaminophenyl) 21-phenyl (17a) 19-nor-pregna-4_t9-dien-20-yn-3-oae. §iage_A_£_21x2henyl_2_A2-[l_A2-ethane_diyl_bis_£oxy2] 19-nor-prsgn-9-en-20-yne.

Under inert gas 4.17 g of potassium tert-butylate are mixed into 83 cm^ of anhydrous tetrahydrofuran. The mixture is agitated for 5 minutes then cooled to -10° 0 and, drop by drop, 4,5 cm^ of phenyl acetylene are added. The suspension is agitated for 5 minutes then, drop by drop at -10° C, a solution of 4.17 g of product obtained in Stage A of Example 7 x in 41 cm of anhydrous tetrahydrofuran is added. At the end of the introduction the temperature is brought to 0° 0 then after 1 hour the mixture is poured into a saturated solution of ammonium chloride. The whole is extracted with ether, the organic phase is washed with the aid of a saturated aqueous solution of sodium chloride, dried and concentrated to dryness and 4.7 g of product are obtained and chromatographed on silica, elution being carried out with the methylena chloride / acetone mixture (9555). 3.71 g of expected product are obtained. M.Pt. » 168° C [a)_D= -119.5°- 2° (c = 1% chloroform).

Stage_B_£_17£3hydro^_llg-£^dimethylaminonhenyl) 21-phenyl_Q7a)_19-nor^grggua34_A9-dien320^yn-^-gne.

5.49 g of product obtained as described in the x previous stage are dissolved in 68 cur of methanol, x then 6.3 cm of 2N hydrochloric acid are added.After thirty minutes under agitation, the whole is poured

X X into a mixture of 180 cm of ethyl ether and 90 cnr of a 0.25 M solution of sodium bicarbonate. The whole is agitated for five minutes, decanted and extracted with ether and the organic phases are washed with a 0.25 M solution of sodium bicarbonate then with a saturated solution of sodium chloride. They are dried, the solvent is evaporated and 4.55 g of product are obtained and purified by chromatography on silica, elution being carried out with the methylene chloride / acetone mixture (95:5) 2.1? g of expected product are obtained.after crystallisation from isopropyl ether. [a]_D = +22.5° - 1° (c 1% chloroform).

Example 15 : 17B-hydroxy HB-(4-dimethylaminophenyl) 17^g(nr כוס a-1.2-dienyl) estra-4.9-dien-3-one.

S'tage^A^-llB-^^dimethyl^inophenyO^jJ^CljJ^ethane l^g-diql and.116-(4-dimethylamingphgnyl) _3,3ד_12?.£ך ethane_diyl_bis_^qxy)]_17«-(,2rop-2;ynyl)_a_estr_-9;enSSziZIzdiol^

Preparation of the lithium derivative, 5

Into 50 cm of anhydrous tetrahydrofuran at 0 to +5° C is bubbled allene until absorbtion of 2,1 g. The whole is cooled to -70° C and, over 15 minutes, 25.9 cm^ of a 3.3 M solution of butyllithiun in hexane are added. The mixture obtained is agitated for 15 minutes at -70° 0.

Condensation

To the solution of lithium derivative obtained^; above is added, at -70° C over 25 minutes, a solution of 3.5g of the product obtained in Stage A of Example 7 la 35 cm^ of anhydrous tetrahydrofuran. The whole is agitated for one hour at -70° C and poured slowly into a chilled saturated aqueous solution of ammonium chloride. The whole is extracted with ether, the organic phase is washed with a saturated, solution of sodium chloride and dried and the solvent is evaporated. 3.4 g of product are obtained and chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1) containing one per thousand of triethylamine, There are thus isolated:

a) 1.73 g of 17&lt;x-(propa-l, 2-dienyl) isomer

M.Pt. 178° ־ C 2° - 52°- ־ (c 0.7% ־ chloroform);

b) 1.5 g of 17a(prop-2-ynyl) isomer

M.Pt. = 150° 0 ^s° - 2° (c = 0.9% chloroform). ^gSg-^i-^^Thydroxyllg-C^dimethylaginochen;!}-^(^i2P22£zli22dienyl}_estra24_A93dien-5;0ne_A

Under inert gas 1.73 g of 17a-(propa-1,2-dienyl) isomer obtained in Stage A, 51.8 cm^ of 95% ethanol .

and 3.5 cm^ of 2N hydrochloric acid are mixed. The mixture is agitated at 20° C for one hour, 50 cm^ of methylene chloride are added then 50 cm^ of a 0.25 M solution of sodium bicarbonate; the whole is decanted, extracted with methylene chloride, washed with water and dried and the solvent is evaporated.

1.51 g of product are obtained and dissolved in 10 cm^ of methylene chloride with heating. To this are added cur of isopropyl ether and the whole is concentrated and left to stand. 1.23 g of expected product are thus isolated and crystallised again from the methylene chloride / isopropyl ether mixture. Finally 1.11 g of expected product are obtained. M.Pt. = 228° 0.

Εα]ρ = +139.5° - 3° (c « 0.8% chloroform).

Example 16 ; 176-hydroxy 118-(4-dimethylaminophenyl) 17&lt;*-(prop-2-ynyl) estra-4.9-dien-3-one,

0.94 g of 17^a-(prop-2-ynyl) isomer obtained in Stage A' of Example 15, 28.2 cm^ of 95% ethanol and 2 cm^ of

2N hydrochloric acid are mixed. The mixture is agitated at 0 3

0 for one hour, 50 cnr of methylene chloride and z cm of a 0.25 M solution of sodium bicarbonate are added and the whole is agitated for 5 minutes, decanted and extracted with methylene chloride. The organic phase is washed with water and dried and the solvent is evaporated. The product obtained is chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1). 0.42 g of amorphous expected product is thus obtained.

[a] jj3° + 145°♦ ־ (_c 0.8% ־ chloroform).

Example 17 : 17^a-ethynyl 178-hydroxy HB-(4-dimethylaminophenyl estra 4.9-dien-3-one,

Stage A : 17^-cyano llg-£4-dimethjrlaminophenyl2 3_A3“C1_A2&amp;01.

Under inert gas at ambient temperature, a solution of 18 m/moles of(4-dimethylaminophenyl) magnesium bromide in anhydrous tetrahydrofuran is added to a suspension of 2.05 g of copper bromide / dimethyl sulphide complex in z cur of anhydrous tetrahydrofuran, then the whole is agitated. Cor 20 minutes and 20 cm^ of anhydrous triethylamine are added. 0.95 g of !??״cyano 17&amp;(trimethyl siljfoxy) 3,3-[l,2-ethane diyl bis (oxy)3 5a- 10a-epoxy estr-911) ־־) ene in solution in anhydrous tetrahydrofuran is then added, the whole is agitated for 15 hours at ambient temperature, poured into 50 cm^ of a saturated solution of ammonium chloride, decanted and extracted with ether, the organic phase is washed with water and dried and the solvent is evaporated. The residue is purified: by chromatography on silica, elution being carried out with the benzene / ethyl acetate mixture(8:2). 1.1 g of expected product are obtained and recrystallised from isopropyl :ether. M.Pt. 247° ־־ C.

= -12.5° (c = 1% chloroform) §i2S2-2-i-lZiZ2i״I2Zl_5j.3zithane_diyl_bis_(oxy) 2 11^-^4-dimethylaminoghenyl) estr-9-en-5&lt;*-17g-diol.

To 0.8 g of product obtained in Stage A in 8 cm^ of ethylene diamine is added 1 g of lithium acetylide / ethylene diamine complex, then the whole is kept under agitation and under inert gas at ~50° O’ for an hour and a half. It is cooled to 20° C then poured into a solution of ammonium chloride. The whole is extracted with ether and with methylene chloride. The organic phase is dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the benzene / ethyl acetate mixture (7:5), the product obtained is recrystallised from isopropyl ether and 0.45 g of expected product is obtained.

W.Pt 199° ־ C.

1.5° + 43°- ־־ (c = 1% chloroform). Stage_0_2_lZa-ethynyl_17g-hydro^ ll[3-(4-dimethylaminoghenyl) estra-4_A9-dien-5-one.

To a solution of 0.25 g of product obtained in Stage H, in 6 cm^ of methanol is added 1 cm^ of 2N hydrochloric acid. The whole is agitated for 40 minutes at 20° C, poured into water containing 2.5 cm^ of IN sodium hydroxide and extracted with ether, the organic phase is dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with :;he benzene / ethyl acetate mixture (7:5) and 0.25 g of expected product is

<td rowspan="2"> obtained. Analysis : Calculated</td><td rowspan="2">^σ28^Η55^Ν02 : C% 80.92</td><td colspan="2"> (*15.54)</td>

<td> 8.00</td><td> 5.57</td>

<td> Found :</td><td> 80.7</td><td> 8.1</td><td> 3.1</td>

Example 18 : l^a-ethynyl 17P-hydroxy llg-(4-dimethylaminophenyl) estra 4,9-dien-3-one,

Stage_A; ^llg-^4-dimethylaminophenyl) [l_x2-ethane 0Χ£22_52217£2άϊ)}£άΓ0Χ£_17«2βϋΤ1^£1_β3ΐΓ292βηθ_.

Under inert gas 6 g of product obtained in Stage A of Example 7 are dissolved in 180 car of tetrahydrofuran then 12.25 g of lithitan acetylide / ethylene diamine complex are added. The temperature is taken to 55° 0 and the whole is agitated for 4 hours, cooled, then poured into 600 cm of a chilled saturated solution of ammonium chloride. The whole is extracted with ether, the organic phase ia washed with a saturated solution of sodium chloride and dried and the solvent is evaporated. The residue obtained is purified by chromatography on silica, elution being carried out with the benzene / ethyl acetate mixture (7:5) containing 1 per thousand of triethylamine and 4.5 g of expected product are obtained and recrystallised from the methylene chloride / diisopropyl oxide mixture. K.Pt. = 202° C. [a]p = -47.5° - 1.5° (c= 1% chloroform) SilSS-^.i-lZSzS^Kil-lZ^zhZ^ro^-llgiC^dimethylaininophen^l;) g of the product obtained in Stage A are mixed 2 into 50 cnr of 95% ethanol, To tha suspension are 2 added 5 cnr of 2N hydrochloric acid. The whole is kept under agitation for 1 hour at 20° C and 100 cm^ of ethyl

X ether are added then 100 cnr of a 0.25 M solution of sodium bicarbonate. The whole is decanted and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness; The residue obtained is chromatographed on silica, elution being carried out with the petroleum etheir / ethyl acetate mixture (6:4) and 1.52 g of expected product are isolated and recrystallised from diisopropyl oxide. M'.Pt. 0 172° ־ [a]^2.5° - 182°+ ־ (c » 1% chloroform)

Example 19 : 17g-hydroxy llg-(5-dimethylaminophenyl) 17»-(prop-l-ynyl) estr-4,9-dien-3~oae.

Stage-A-^llg^-dimethjrlaminothenjrl^-Jjj^CljJ^ethane

HZl_]2i®-i2xZ.ll_122zi2E22zlzZ2Zl)_22ji]:z9z22-:5“zl2£z£iol₄

Preparation of the magnesium derivative.

Under inert gas 1.46 g of magnesium and 5 cm^ of anhydrous tetrahydrofux'an are mixed. Over 45 minutes, the temperature being kept at about 50° 0, 10 g״ of x metabromodimethylaniline in 45 cnr of anhydrous tetrahydrofuran are introduced. (The reaction was initiated by the addition of dibromomethane). .The whole is kept for one hour under agitation and a 0.95 M solution oftiie expected magnesium derivative is obtained. 522122221222

Under inert gas 5.7 g of 3»3-[l_i2-ethylene dioxy bis (oxy)] 17^a-(prop-l-ynyl) estr-9 (11) en-5»-10a-epoxy X

17β-01> 74 cnr of anhydrous tetrahydrofuran .and 99 mg of copper chloride are mixed. The mixture is cooled to 0 to *5° C then, over thirty minutes, 42.2 cm^ of the solution of magnesium derivative obtained above are added. The whole is agitated for thirty minutes at 0 to +5° 0, poured inco a saturated aqueous solution of ammonium chloride and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is chomatographed on silica, elution being carried out with the methylene chloride / acetone mixture (9:1) containing 1 per thousand of triethylamine. J.5 g of expected product are obtained. M.Pt .0 262° ־

64°- ־ t 1.5° (c 1% ־ chloroform).

0.66 g of the corresponding 5βΟΗ isomer is also isolated. M.Pt. - 210° C.

[a)_D 1° - 32.5°+ ־ (c 0.8% ־ chloroform).

Stag^B^lTg-hydro^llBzGz^imethyaminopheny!)-!?^ ζί2£22ζ1ζΣ3Σ1 )_SSJ22_^j.Zz^ix2zZz22£x

Under inert gas 3.3 g of the product־ obtained in Stage A are mixed with 100 cm^ of methanol and cooled 0 3 to 0 to +5 0 and ID'carof 2N hydrochloric acid are added. The whole is agitated for 1 hour at 0 to *5° 0 3 3 and 200 cnr of diethyl oxide are added, then 200 cm of a 0.25 M solution of sodium bicarbonate. The whole is agitated for 5 minutes, decanted and extracted with diethyl oxide, the organic phase is־ washed with a saturated solution of sodium chloride and dried: and the solvent is evaporated. 3 g of product are obtained and chromatographed on silica, elution being carried out with the benzene / e-thyl acetate mixture (7:3).

1.43 g of amorphous expected product are isolated.

2.5° - 43°+ ־ (c » 1% chloroform).

Example 20 : 178-hydroxy llB-(4-dimethylaminophenyl) 17a-(prop~l-ynyl) estra 4,9-dien-3~oue N-oxide.

1.5 g of product obtained in Example 4 are mixed X with 30 cur of methylene chloride. The mixture is cooled to 0 to +5° C and, over 10 minutes, a solution of 0.71 g of metachloroperbenzoic acid ( at 85%) in

X

14.2 cur of methylene chloride is added. The whole

3 is agitated at 0 to +5 C for 1 hour, poured into 100 cnr of a 0.2 N solution of sodium thiosulphate, decanted and extracted with methylene chloride, the organic phase is washed with a 0.5 M solution of sodium bicarbonate and dried¹, and the solvent is evaporated. The residue is x x dissolved in 20 cnr of methylene chloride and 20 cur of diisopropyl oxide are added'. Crystallisation is initiated, the whole is left to stand and the crystals formed are separated and dried. 1.4 g of expected product are obtained. M.Pt. = 210° C. [a]^ = +73.5° - 2° (c 1% chloroform).

Example 21 : 116-(4-dimethylaminophenyl) 176-hydroxy estra 4,9-dien-5-ona.

g of the product obtained in Stage A of Example 7

ן is mixed into 20 car of tetrahydrofuran containing 10% of water. After dissolution, 106 mg of sodium borohydride are added, the whole is agitated for 1 hour , poured into 200 cur of water and extracted with methylene chloride, the organic phase is washed with a saturated solution of sodium chloride and dried and the solvent is evaporated. 1.5 g of 5^a-dihydroxy product are obtained.

0.65 g of product obtained above are introduced 3 3 into a mixture of 12 cur of methanol and 2.4 cnr of 2ΪΓ hydrochloric acid. The whole is agitated for 1 hour thirty minutes at ambient temperature, poured into a solution of sodium bicarbonate and extracted with ether, the organic phase is washed with a saturated solution of sodium chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (6:4). The residue is triturated in petroleum ether and separated and 0.58 g of expected product is obtained. M.Pt. 150° ־ C.’

C^a)p = +277° - 5° (c = 0.5% chloroform).

Example 22 ; 17S-hydroxy 113-(4-dimethylaminophenyl) 17a-(prop-2-enyl) estra 4.9-dien-3-one.

SiagS-A-i-^A^IliizSiljane^ixl^bis^^oxx^.llg^^dimethyl;

aminophenyl) !?¹¹-(prQn-S^enyl) _restr-9-ene _17B-di01.

Into 55.5 cm^ of a 0.7 M solution of allyl magnesium bromide in ether is introduced, under inert gas at 20° C over 15 minutes, a solution of 3.5 g of the product x obtained in Stage A of Example 7 in 55 csr of tetrahydrofuran. The whole is agitated, at 20° C for 1 hour,.

poured into a saturated aqueous solution of ammonium chloride and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue

X obtained is dissolved in 10 cnr of methylene- chloride.

To this are added 15 cm^ of diisopropyl oxide and the whole is concentrated then left to stand. The crystals formed are separated, rinsed with diisoprppyl oxide and dried and 2.76 g of expected product are obtained.

M.Ft. 198° ־ C.

Analysis : ¾5 (493.69)

Calculated : C% 74.42 H% 8.78 N% 2.83

Found : 74.0 8.7 2.9

Stage_B_£_12gzhz£E22i-li£z£⁴z£i®2ihZl^a5.inophenyl}

12“z2E2Bzi;z£2Z12~£2iE£-.it12z£i£2z2z2B£i

2.2 g of the product obtained in Stage A are put into suspension in 66 cm^ of ethanol, then 4.5 cm^ of 2N hydrochloric acid are added. The whole is agitated for thirty minutes at 20° C and 1J2 cm^ of diethyl oxide are added, then 132 cm^ of a 0,25 M aqueous solution of sodium bicarbonate. The whole is decanted, extracted with diethyl oxide, washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the benzene / ethyl acetate mixture (7:3) the product obtained is taken up in a: mixture of 15 cm of diisopropyl oxide and 7.5 cm⁵ of methylene chloride and the whole is concentrated then left to stand. It is separated and the crystals obtained are rinsed with diisopropyl oxide and 1.565 g*of expected product are obtained. M.Pt* = 182° C ^s +206.5° . 5° (0 ⁸ 1% chloroform)

Example 25 : 17B~hydroxy llB-[4-(N,N-dimethylaminomethvl) phenyl] 17&lt;x-(urop-l-ynyl) estra 4.9-dien-3-one, 2i252_A_i_21^Ii4.22ethane_diyl__bis_£oxy)]_113-[4-(Nj_N172^2^222^^^7^-) s str-9~2n-2£22E3il22-2X-il]2_225222 IP¹ derivative.

Under inert gas 5.5 g of magnesium and 10 cm^ of anhydrous tetrahydrofuran are mixed. Over 1 hour thirty minutes, the temperature being kept at 45° - 50° 0,

42.8 g of 4-(N,N-dimethylaminomethyl) bromo benzene in 190 cm^ of anhydrous tetrahydrofuran are introduced. The reaction was initiated by the addition of dibromoethane. After the end of the introduction, the whole is kept under agitation for 1 hour. The expected 0.S5 M solution of magnesium derivative is thus obtained!.

Under inert gas 10 g of 5,5-Cl,2-ethane diyl bis (oxy)] 17a-(prop-l-ynyl) estr-9, (ll)-en-54-10a-epoxy 17β-01,

200 cm^ of anhydrous tetrahydrofuran and 0.27 g of copper chloride are mixed. The mixture is cooled to 0 to +5° 0 and, over one hour, 127 cm^ of the solution of magnesium derivative prepared above are introduced. The whole is then agitated for 15 minutes, poured into a saturated aqueous solution of ammonium chloride and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the methylene chloride / methanol mixture (9:1) containing 1 per thousand of triethylamine. 10.1 g of product are obtained and crystallised by dissolution x in methylene chloride and the addition of a few err of methanol then of diisopropyl oxide. After concentration and keeping standing for six hours, the product obtained is separated and 7.57 g of expected product are obtained.

M.Pt. = 186° 0.

[a] 2.5° - 63°- ־ (c 0.5%־ chloroform).

Siage^i.^^hydro^llgyC^CN^N-dimethylaminomethyl)

2^22Σ12-12ίζί2£22Ζ^ΖΣ2Σϋ-22ίΓ2-^χ2ζ^ΐ£2ζ3ζ22®Λ

Under inert gas 7*37 g of the product obtained in

2

Stage A are mixed into 147,4 cur of methanol and 15 cm of 2N hydrochloric acid. The mixture is agitated at 20° C for one hour, 300 cm^ of diethyl oxide and 300 cm^ of a 0.25 M aqueous solution of sodium bicarbonate are 10 added, the whole is decanted and extracted with diethyl oxide, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The product obtained is recrystall ised by being dissolved in a mixture of diisopropyl 15 oxide and methylene chloride, then by concentrating the solution and leaving it to stand. It is separated and the crystals formed are dried. 3.74 g of expected product are thus obtained. M.Pt. = 190° C.

[&lt;x]_D = +84.5° - 2° (c 0.8% ־ chloroform).

Example 24 : 17g-hydroxy 11B-(4-pyrrolidinyl phenyl) 17a-(prop-l-ynyl) estra 4,9-dien-3-one. §52S®-^-i-2_J.5z£lj.2yethane_diyl_-bis_-£oxy2]_-llgy(42 ζ2ΣΕ2211^12ί1-2^®2Σ11_122ζί2£22ζ1ζΣ2Σ12-22ί£ζ2ζ£2Ζ5a-12£z*i21x

־ 79 5Γ222Ζ2ί122_2£_ί2®_22Ε2θ3ΐηη_άθηίν&amp;ίϊνθ_Λ x Under inert gas 4 g of magnesium and 10 cnr of anhydrous tetrahydrofuran are mixed. Over one hour, the temperature being maintained at 45 - 50° 0, X g of 4-pyrrolidinyl bromo benzene in 140 car of anhydrous tetrahydrofuran are introduced. The reaction was initiated by the addition of dibromoethane. AIM solution of expected magnesium derivative is thus obtained.

222^22S22222_22_22-21]2-222Si^2i

Under inert gas 8 g of 33_י-Cl,2-ethane diyl bis (oxy)] 5«-lOa-epoxy 17^a-(prop-l-ynyl) estr-9 (11) x en-175-01, 160 cnr of anhydrous tetrahydrofuran and 216 mg of copper chloride are mixed. The mixture is cooled to 0 to +5° C and, over one hour thirty minutes, x

86.4 cm of the solution of magnesium derivative .. prepared above are introduced. The whole is agitated for one hour, poured into a saturated aqueous solution of ammonium chloride and extracted with diethyl oxide, the organic phase is washed with a saturated aqueous solution of ammonium chloride then with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is purified by chromatography on silica, elution being carried out with the methylene chloride / acetone mixture (95:5) containing 1 per thousand of triethylamine. 8.3 g of expected product are thus obtained and recrystallised from a methylene chloride / isopropyl ether mixture. M.Pt. 0 185° ־

[a]p = -67° - 1.5° (c 1% ־ chloroform)

Stage_B_£ 12^zM222Z-ll£ziitz2ZP£2ii^A2Z12^®2Z12 12gz£22P2zlz2ggi)_gspra_^19“4j.en- 3-one.

6.4 g of product obtained in Stage A are dissolved in 128 cm^ of methanol then 13 cm^ of 2N hydrochloric acid are added. The whole is agitated at 20° 0 for one hour, then 26ל cm^ of diethyl oxide and 256 cm^ of a 0.25 M aqueous solution of sodium bicarbonate are added. The whole is decanted and extracted with diethyl oxide, the organic phase is washed with a 0.25 M aqueous solution of sodium bicarbonate, then with a saturated aqueous solution of sodium chloride and dried and .the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1) and 5.25 g of expected product are obtained and recrystallised from a methylene chloride / diisopropyl oxide mixture.

M.Pt. 190° ־ C

[ajjj » +120° - 2.5° (c 1.2% ־ chloroform).

Example 25 : 17S-hydroxy 116-(4-dimethylaminophenyl) ' 17»-ethenyl. estra 4,9-dien-3~one.

§ia5e_A_£_3i3zClj.22ethane_divl_bis_£ox2)]_11^3 _rdioL.

g of product obtained in Stage B of Example 17 are mixed with 60 cm^ of anhydrous pyridine and 0.6 g of 5% palladium on calcium carbonate is added. A current of hydrogen is passed into the mixture.at ambient temperature for one hour. The catalyst is separated, the.filtrate is evaporated to dryness and the residue is taken up with toluene and again evaporated to dryness. 2.94 g of expected product are thus obtained, which is used as it is for the rest of the synthesis. M.Pt = 181° C. The product can be recrystallised from a methylene chloride / diisopmpyl oxide mixture. M. Pt. = 182° C.

= -6.5° - 2° (c 0.7% ־ chloroform) Sta£e_B_2_12^Z£E0^_llg;(^dimethylamin0phenyl)_17a2

Under inert gas 2.94 g of the product obtained in 3 3

Stage A are mixed with 60 cnr of methanol, then 6.2 cm of 2N hydrochloric acid are added. The solution is 0 3 agitated at 20 C for one hour, 120 cnr of ether and 120 cm^ of a 0.25 M aqueous solution of sodium bicarbonate are added and the whole is kept under agitation for 10 minutes, decanted and extracted with ether. The organic phase is washed with a 0.25 M aqueous solution of sodium bicarbonate־ then with a saturated aqueous solution of sodium chloride. It is dried and the solvent is evaporated. 2.65 g of product are obtained and chromatographed on silica, elution being carried out with the benzene / ethyl acetate mixture (7:3), and then crystallised from a diisopropyl oxide / methylene chloride mixture. 1.51 g of expected product are finally obtained. M.Pt. = 150° 0

[a]jj » +243° i 3° (0 = 0.8% chloroform) Example 26 .: 170-hydroxy 116-(4-diethylaminophenyl) 17a-(prop-l-ynyl) estra 4,9-dien-3-one. Stage_eA_-2_>-3_i33£l_A23ethane_diyl_-bis_-£oxy2]_-ll^15 ί-Ζ^ί®2^Σ122ΐ222^22Σ12-122ζί2Ι22ζ1ζΣ2ΣΏ-£2ί£ζ2Σ22

5a_z17g_zdiol. Formation. _ of the magnesium derivative.

Under inert gas 3*9 g of magnesium are mixed into cm^ of tetrahydrofuran. Drop by drop,.34.2 g of

4-(N,N-diethylamino) bromo benzene in 110 cm^ of tetrahydrofuran are added, the temperature being kept at about 35° 0. AIM solution of the expected magnesium derivative is obtained.

222^22225A22x

7.4 g of 3,3-(1,2-ethane diyl bis (oxy)] 5^a&lt;גepoxy 17a-(prop-l-ynyl) estr-9 (11) ene 170-01 are x dissolved in 150 cm of anhydrous tetrahydrofuran.

0.25 g of copper chloride are added. The whole is agitated at 0 to +5° 0 under inert gas and 80 cm^ of the solution of magnesium derivative prepared above are added slowly. The whole is kept for 17 hours under agitation at 20° C, poured into an aqueous solution of ammonium chloride and extracted with ether, the organic phase is washed with an aqueous solution of sodium bicarbonate and dried and the solvent is evaporated. The residue is made into a paste with petroleum ether then treated with active charcoal in ether and recrystallised from isopropyl ether. 4 g of expected product are thus obtained.

[a]^ 2.5° - 61°- ־ (c = 0.790 chloroform)

Stage J5_£_12§3hzdro^_llj32i^iethzlaminc2henyl)_

To a solution of 3.12 g of product obtained in Stage A in 45 cm^ of methanol are added 8 cm^ of 2N hydrochloric acid and the whole is agitated at 20 20° C under inert gas for 45 minutes. It is poured into water, neutralised by the addition of 2N sodium hydroxide, extracted with methylene chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out 25 with the benzene / ethyl acetate mixture (1:1) and

1.34 g of expected product are obtained.

Ca]p = +144.5° t 5° (c 0.8% ־ chloroform) Analysis : C_?1 Η₃θ N0₂ (457.65) Calculated : C% 81.56 8.59 N% 5.06

Found : 81.7 8.8 2.09

The 4-(IF,N-diethylamino) bromo benzene used at the start of Stage A was prepared as follows.

To a solution of 86 g of 2F,N-diethylaniline in x

400 cnr of acetic: acid are added, drop by drop, 95 g of bromine. After the end of the introduction, the whole is poured into a water / ice mixture and extracted with methylene chloride, the organic phase is washed with an aqueous solution of sodium bicarbonate and dried and the solvent is evaporated. 125 g of expected product are obtained. B.Pt. : 0.6 0 97° ־.

Example 27 : 173-hydroxy llg-C4-[methyl(3-methylbutyl)^ aminojphenyl] 17a-(prop-1-ynyl) estra 4_<9-dien-3-ons, §52S2-A-i-5iJ3£112-ethane_diyl__>bis_£oxy)J_llg-[42[methyl £^Z?25־I2152521}-2S1221_2^22211-122z(2222zlz22211_2£52z2z22£ 22ζ1Ζ£ζ1121λ ?2222225122-25-5^2-222222122-12212251221.

X Under inert gas 4.12 g of magnesium and 10 cnr of tetrahydrofuran are mixed. A few cm^ of N-methyl N-(5-mephylbutyl) 4-bromo benzenamine in solution in tetrahydrofuran are introduced and the reaction is x initiated by the addition of 0.2 cnr of 1,2-dibromoethane.

Then over 40 minutes, the rest of the N-methyl N-(3-methylbutyl) 4-bromo benzenamine solution in anhydrous tetrahydrofuran (J2.6 g in 90 cm^>. is added. The whole is then alleged to return to ambient temperature then kept under agitation for 1 hour. A 0.9 M solution of the expected magnesium derivative is thus obtained.

Condensation^ g of 3,5-[l,2-ethane diyl bis (oxy) ] 5a-10aepoxy 17^a-(prop-l-ynyl) estr-9 (11) en 17β-01 are mixed with 90 cnr of anhydrous tetrahydrofuran and^:5.77 g of copper chloride. The mixture is agitated for 20 minutes at +5° C under inert gas, then 100 cm* of the solution of magnesium derivative prepared above are added. The mixture is then poured into an aqueous solution of ammonium chloride and extracted with ether mixed with triethylamine then with methylene chloride mixed with triethylamine. The combined organic phases are washed with a saturated aqueous. solution of sodium chloride, dried and evaporated to dryness.

51.2 g of expected product are obtained,which is used as it is for the following stage. The product can be purified by chromatography on silica, elution being carried out with the methylene chloride / acetone / triethylamine mixture (96.5::4.5:0.5), ⁼ 2.5° - 59.5°״ (c = 0.7% chloroform).

Stage Β : !?^-hydroxy 11^-[4-[methyl £3-methylbutyl) aminoJphenyl]17a-(prop-1-ynyl) estra 4,9-dien-3-one.

g of product obtained in Stage A are dissolved in 200 cm^ of methanol, then 52 cm^ of? 2N? hydrochloric acid, are added* After one hour under agitation,, the mixture is poured into an aqueous solution of sodium bicarbonate and extracted with ether then with methylene chloride, the combined organic phases are washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated.

The product is purified: by chromatography on silica, elution being carried out with the toluene / ethyl acetate mixture (92:8) and J.2? g of expected product are obtained.

[®Ip = 5°«3 - 125°־*־ (c » 0.6% chloroform) Analysis : 0,, H״, N0_o (485.71) ל י* ל לd

Calculated: C% 81.6 8.922.88

Found 81.4 9.02.7

The amine used at the start of Stage A was prepared as follows.

Siags.a^-Nymethyl^-^^methylbutyl^-aniline.

g of N-methyl aniline, 500 cm^ of anhydrous benzene and 81 g of anhydrous triethylamine are mixed. Drop by drop, 121 g of isoamyl bromide are added and the whole is taken to reflux for 100 hours. The mixture is filtered, the filtrate is washed with water and dried and the solvent is evaporated. The residue is distilled and 90 g of expected product are obtained. B.Pt. 18 = 132° O'.

g of product obtained in Stage a are mixed with 3 300 cm of acetic acid then, drop by drop, over 1 hour ο 3 at about 15 C, 58 g of bromine in solution in 60 csr of acetic acid are added. The temperature is taken to 80° 0, the whole is agitated for 8 hours then poured into iced water and extracted with methylene chloride, the organic phase is washed with a solution of sodium bicarbonate then wiih water ani dried and the solvent is; evaporated. The residue is distilled and 70 g of expected product are obtained. B.Pt 0.5 = 119° O'.

Example 28 ; 17g-hydroxy llg-[4-(N;N-dimethylaminoethylthio) phenyl] !?«-(prop-l-ynyl) estra 4,9-dien—3-one, Stage״A : 3,3C112^ethane_diyl £SAN-dimethylaminoethylthio2_e2henyl]_12azi2£22zizZ3Zil ]״ieEaration-Of-the-magnesium-derivative., 3 Under inert gas 2g of magnesium and 15 cur of anhydrous tetrahydrofuran are mixed. Then, over 45 minutes, the temperature being allowed to rise to 56° 0, a solution of 20 g of 4-(N,N-dimethylaminoethylthio)

1-bromo benzene in 40 cm^ of anhydrous tetrahydrofuran is introduced. The reaction was initiated bythe addition of

1,2-dibromoethane. The whole ir then allowad. to return to 20° C, then kept under agitation for 45 minutes under inert gas. A 1.05 M solution of the expected magnesium derivative is thus obtained.

Condensation.Under inert gas 58 cm^ of the solution of magnesium derivative obtained ateove is cooled to -20° C. To this are added 1.730 g of copper chloride, the whole is kept under agitation for 20 minutes, then 5 g of 5,5-[l,2-ethane diyl bis (oxy)[ 5a-10a-epoxy 17«-(prop-1-ynyl estr-9 (11) en 17g-al in 50 cm^ of anhydrous tetrahydrofuran are added. The whole is kept at 20° C under inert gas for 2 hours 45 minutes. The mixture is poured into 600 cm^ of iced water containing 60 g of ammonium chloride. The whole is kept under agitation for 45 minutes and decanted, the aqueous phase is extracted with diathyl oxide mixed with triethylamine, the combined organic phases are washed with s saturated aqueous solution of sodium chloride and: dried and the solvent is evaporated, '^he residua is chromatographed on alumina, elution being carried ojit with the methylene chloride / acetone mixture (95:5) and 10.5 g of expected product.axe obtained.

I.R.Spectrum.

Absorption at 5600 cm ¹ (OH), 2240 cm¹ (c=C), 1705 and

ף«

16?0 cm (CO and conjugated CO), 1615 and 1490 cm“¹(aromatic bands).

Stage : 17£-hydroxy 11/S-C4-(N,N-dimethylaminoethylthio) phenyl 17*-(prop-1-ynyl) estra 4,9-dien-5-one.

Under inert gas 10.J g of product obtained in Stage A are mixed with 72 cm^ of methanol, then 20.6 cm^ of 2M hydrochloric acid are added. The whole is kept under agitation at 20°C for 1 hour 15 minutes and neutralised by the addition of a saturated aqueous solution of sodium bicarbonate, 200 cm^ of diethyl oxide are added, the whole is decanted and extracted with diethyl oxide, and the combined organic phases are washed with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness. The residue is chromatographed on silica, elution being carried out with the methylene chloride / methanol mixture (9:1) and 5 g of expected product are obtained and crystallized by making intoa paste in diisopropyl oxide. M.Pt. = 145°C.

Wp = +125° - 2° (c = 1% chloroform).

The amine used at the start of Stage A was prepared as follows.

g of sodium hydroxide in pellets are dissolved in X

500 cr of ethanol. In addition, 25.5 g of chloroethyldimethylamine are dissolved in 75 cm^ of ethanol, then 160 cm^ of the sodium hydroxide solution prepared above are added. In addition, JO g of parabromothiophenol are dissolved in 100 cm^ of ethanol, then 160 cm^ of the sodivr. hydroxide solution prepared above are added. Then, over 2 minutes,at ^0°&lt;3_י the amine solution prepared above is added. The whole is taken to reflux for 3 hours, the solvent is evaporated, water is added, the whole is extracted with methylene chloride, the organ־!c phase is washed with a 0.1 N aqueous solution of sodium hydroxide then with water and dried and the solvent is evaporated.

The residue is distilled and 35•5 g of expected product are obtained. B.Pt. 0.1 110° ־C.

Example : 11i3-(4-dimethylaminophenyl) 170-hydroxy 21-(trimethylsilyl) (1?x) 19-nor pregna 4,9-dien-20-yn-3-one.

Stage A : 110-(Λ-dimethylsminophenyl) 3,3-C1,2-ethane diyl bis (oxy)J 21-(trimethylsilyl) (1?°&lt;) 19-non pregn-9-en-2O-yn 5&lt;x-17g-diol.

Under inert gas 13 cm⁵׳ of a 1.6 M solution of ethyl magnesium bromide in tetrahydrofuran are mixed with 13 cm^ 15 of anhydrous tetrahydrofuran. The mixture is agitated for minutes at 0 to +5°C,then, drop by drop, 3-i cm^ of trimethylsilyl acetylene are added. The temperature is allowed to rise again to 20°0 and the agitation is continued for 20 minutes then, drop by drop, a solution of

1.12 g of the product obtained in Stage A of Example 7 in

X car of anhydrous tetrahydrofuran is introduced. The whole is kept for 16 hours at ambient temperature under agitation, poured into an aqueous solution of ammonium chloride, agitated for 10 minutes at ambient temperature 25 and extracted with methylene chloride, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (6:4) and 630 mg of expected product are obtained. [0&lt;0.5# = 0) 3° - 76.5°- = _ענ chloroform).

.5 Stage B : 11^-(4-dimethylaminophenyl) 170-hydroxy 21-(trimethylsilyl) (17*) 19-nor pregna 4,9-dien-20-yn-3-one.

562 mg of the product obtained in Stage A are mixed with 15 cm'* of methanol and 1 cm^ of 2N hydrochloric acid. The mixture is kept under agitation at ambient temperature for 40 minutes, poured into an aqueous solution of sodium bicarbonate and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (6:4) and 364 mg of expected product are obtained.

3° * 97.5°+ ־ (c = 0.35# chloroform).

Analysis : N0₂ Si (487.76)

Calculated : C# 76.55 H# 8.47 N# 2.87

Bound : 76.4 8.7 2.8

Example : 17^-hydroxy 11/?־ Γ4- (N, N-dimethylaminomethyl) phenyl] 17*-(prop-1-ynyl) estra 4,9-dien-3-one N-oxide.

1.4 g of product obtained in Example 23 are dissolved in 28 cm^ of methylene chloride then, over 15 minutes at

0 to +5°C, a solution of 0.64 g of metachloroperbenzoic acid in 12.8 cnr of methylene chloride is introduced. The whole is agitated for 1 hour at 0 to +5°C then poured into a 0.2 N aqueous solution of sodium thiosulphate, decanted., extracted, with methylene chloride, washed with an aqueous solution of sodium bicarbonate, dried and evaporated to dryness. The residue is chromatographed, on silica, elution being carried out with the methylene chloride / methanol mixture (8:2) and 1.28 g of expected product are obtained and dissolved in a methylene chloride / diisopropyl oxide mixture. The crystals formed are separated and dried and 1.075 g of expected product are obtained. H.Ft. . 215°C.

[74.5°+ = _ע[א>׳ ί 2.5° (c = 0.7$ chloroform).

Example 31 : Hemifumarate of 17&amp;־hydroxy 11&lt;S-C4-(N,ITdimethylaminomethyl) phenylJ 17*-(prop-1-ynyl) estra 4,9־ -d.ien-3-οΡ-θ.

44,ף g of the product obtained in Example 23 are mixed into 2.88 cm^ of ethanol then a mixture of 0.378 g of fumaric acid in 4.54 cm^ of ethanol is added. The suspension is agitated for 3θ minutes at 60°C, the temperature is allowed to return to 20°C and the whole is kept under agitation. The solvent is evaporated, the residue is taken up with ether, separated, and dried and

1.70 g of expected product are obtained. M.Pt. = 160°0.

205° ± 70.5°+ ־ (c«0.8$ chloroform).

Example : 170-hydroxy 11g-C4-(N,N-dipropylamino) phenyl] 17*-(prop-1-ynyl) estra 4,9-dien-3-one.

Stage A : 3.5-Γ1,2-ethane diyl bis (oxy)3 11^-^4-(N_J3-dipropylamino) phenyl] 17*-(-τορ-1-ynyl) estr-9-βπ ~ -17^-diol.

Preparation of the magnesium derivative.

Under inert gas 5 g of magnesium are mixed with 15 15 cm-׳ of anhydrous tetrahydrofuran. Lrop by drop, a solution of 52 g of 4-bromo Ν,Ν-dipropylaniline in 110 cm^ 5 of tetrahydrofuran is added, the temperature being kept at 40°C. A 1.1 M solution of expected magnesium derivative is thus obtained.

Condensation.

Under inert gas a solution of 5.55 g of 3,3-Γ1,210׳ -ethane diyl bis (oxy) J 5x-1C«&lt;-epoxy 17*-(prop-1-ynyl) estr-9 (11 )-en 17β-01 obtained in Stage A of Example 7 is mixed with 200 mg of cuprous chloride. The mixture is agitated at 0 to +5°C then, over 15 minutes, 50 cur’ of the solution of magnesium derivative obtained above are added. ¹5׳ The whole is then agitated for 1 hour at 20°C, poured into a saturated aqueous solution of ammon-j,קח chloride and extracted with ether, the organic phase is dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the toluene / ethyl 20 acetate mixture (7:5) and 6.5 g of expected product are obtained.

[*Ip ^s° - 2° (c = 0.8% chloroform).

£2®1ysis : c₃₅ e₄₉ no₄ (547.75) Calculated : C% 70.74 H% 9.02 2,56

Found : 76.6 9.2 2.5

Stage : 17^-hydroxy 11ft-C4-(N,N-dipropylamino) phenylj 17*-(prop-1-ynyl) estra 4,9-dien-3-one.

To a solution of 5*33 S product obtained in 3 3

Stage A m 80 cm^ of methanol are added 10 cnr of hydrochloric acid and the whole is agitated at 20°C for 0ל minutes. It is neutralised by the addition of 5 N sodium hydroxide, the solvent is evaporated under reduced pressure and the residue is taken up with methylene chloride. The organic phase is washed with water and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being 10 carried out with the toluene / ethyl acetate mixture (75:25) and 3.81 g of expected product are obtained. IR Spectrum (chloroform)

Absorption at 3600 cm“¹ (OH), 1654 cm”¹ (00־), 1610-1595-1558 and 1517 cm“¹ (44.9 + aromatic bands), 15 2240 cm“¹ (C2C).

The products below constitute examples of other products which can be obtained by the process of the invention :

^־r4-(N-ethyl N-methylamino) phenylO 17^-hydroxy

17*-(prop-1-ynyl) estra 4,9-dien-5-one (M.Pt. 174° ־C;

*_D 149°+ ־ i 2.5°, c 1% ־ CECI,);

/5-hydroxy 11/$-fN-methyl 2,3-dihydro 1H-indol-5-yll 1?x-(prop-1-ynyl) estra 4,9-dien-3-one (M.Pt. = 176°C,־

0.8% ־ 0 ,3° - 133°+ ־ CHC1₃);

4)-11$ ־-dimethylaminophenyl) 3-hydroxyimino 17*-(prop-1-ynyl) estra 4,9-dien-17/3-01, isomer Z (M.Pt. 260° ־C;

= 141° ί 3.5°, c 0.8% ־ CHClj);

-(4-dimethylaminophenyl) 3-hydroxyimino 17a-(prop-1-ynyl) estra 4,9-dien-17P-01, isomer E (M.Pt. =22O°C;

a_D - +164° i 5.5°, c 0.8% ־ CHCl^);

-hydroxy 110-(4-pyrrolidylphenyl) 17a-(prop-1-ynyl) estra 4»9-dien-3-one H-oxide, (M.Pt. . 220°C;

a_D - +88° - 2.5° , c ־ O.?5% CEClj);

-hydroxy 11P-C4-N-methyl N-(l-methylethyl) aminophenyl] 17a-(prop-l-ynyl) estra 4,9-dien-3-0ne (a^ » +140° - 3*5° » c 0.5% ״ OKClj).,

-C4-(N,N-dimethylaminoethyloxy) phenyl] 170-hydroxy 17a-(prop-l-ynyl) estra 4,9-dien-3-one N-oxide, (a_D . +60.5° , c 1.2% ־־ CHOI,);

-hydroxy 113-C(N-methyl) 2,3-dihydro lH-indol-5-yl3 17a-(prop-l-yn71) estra 4,9-dien-3-0ne N-oxide, (a_D = +103° t 2.5° , c 0.8% ־ CHCl^);

P-hydroxy 113-[4-(N-methyl N-trimethylsily!methyl) aminophenyl] 17a-(prop-1-ynyl) estra a,9-dien-3-one;

-hydroxy 110-C4-(N-methyl N-dimethylaminoethyl) aminophenyl] 17a-(prop-l-ynyl) estra 4,9-dien-3-one;

-hydroxy llg-C4-(N-methyl piperazin-l-yl) phenyl] 17a-(prop-l-ynyl) estra a,9-dien-3-one;

-hydroxyimino 11p-(4-dimethylaminophenyl) estra 4,9-dien-3-one, Ca]_D = +207.5° * 3.5°, (c 1% ״ CHCl^);

(E)-hydroxyimino 17-hydroxyimino 110-(4-dimethylaminophenyl) estra 21,9-dien-3-one, (a_D . +195° - 3° י c 1% ־ CHOI,); and (2)-hydroxyimino 17-hydroxyimino 110-(4-dimethylaminophenyl) estra 4,9-dien-3-one, (a-j = +163° - 2.5° » » 0.6% CHClj).

a PHARMACOLOGICAL

Study of the activity of the products on hormone receptors. Mineralocorticoid receptor of the rat kidney.

Male Sprague-Dawley EOPS rats, weighing 140 to 160 .g, 5 from which the suprarenal glands have been removed 4 to 8 days previously, are sacrificed and their kidneys are perfused in situ with 50 ml of a buffer of 10 mM of Tris, 0.25 M saccharose and HC1 at pH 7.4. The kidneys are then removed, decapsulated and homogenised at 0°C using a Potter 10 polytetrafluoroethylene glass (1 g of tissue to 5 211 of buffer). The homogenate is centrifuged for 10 minutes at 800 g, at 0°C.

So as to eliminate the fixing of tritiated aldosterone on the glucocorticoid receptor, the 11|5, 1-dihydroxy 15 21-methyl pregna 1,4,6-trien 20-yn 5-one steroid adhering solely to the glucocorticoid receptor is mixed with the —6 supernatant liquid at the final concentration of 10 M. This supernatant liquid is ultracentrifuged at 105,000 g for 60 minutes at 0°C. Aliquot parts of the supernatant 20 liquid thus obtained are incubated at 0°C with a constant concentration (T) of tritiated aldosterone in the presence -9 of increasing concentrations (0-2500 . 10 ⁷־M) of cold aldosterone or of the cold product to be studied. After a period (t) of incubation, the concentration of bonded, 25 tritiated aldosterone (B) is measured by the technique of adsorption to charcoal-dextran.

— 95b Androgen receptor of the rat prostate gland.

Male Sprague-Dawley ECPS rats of 160 to 200 g are castrated. 24 hours after castration, the animals are sacrificed; the prostate glands are removed, weighed ann homogenised at 0®C using a Potter polytetrafluoroethylene glass in a TS buffered solution (10 mH of Tris, 0.25 M saccharose and HCl at pH 7.4) (1 g of tissue to 5 ml of TS). The homogenate is then ultracentrifuged (105,000 g x 60 minutes) at 0°C. Aliquot parts of the supernatant liquid thus obtained are incubated at 0°C for two hours with a constant concentration (T) of product P (170-hydroxy-17^~n1ethyl-estra-4,9,11-trien-5-one) in the presence of increasing concentrations (0 - 1,000 10^-¾) either of cold P,or of cold testosterone, or of the product to be tested. The concentration of bonded tritiated P (3) is then measured in each incubate by the technique of adsorption to chareoal-dextran.

Progestogen receptor of the rabbit uterus.

Impubic female rabbits of about 1 kg receive a ²⁰ cutaneous application of 25 /*g of estradiol. ל days after this treatment, the animals are sacrificed; the uteri are removed, weighed and homogenised at 0°C using a Potter polytetrafluoroethylene glass in a TS buffered solution (10 mN of Tris, 0.25 M saccharose and HCl at 7.4) ²5 (1 g of tissue to 50 ml of TS).

The homogenate is then ultracentrifuged (105,000 g x 90 minutes) at 0°C. Aliquot parts of the supernatant liquid thus obtained are incubated at 0°C for a period (t)