FR2645864A1 - NOVEL 17/21 ALKYLATED DERIVATIVES OF 19-NOR PROGESTERONE, PROCESSES THEREOF AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME - Google Patents

Abstract

The invention, which relates to the domain of chemistry and in particular therapeutic chemistry, essentially has as its subject matter b-methyl 19-nor pregna 4,6-dienes 17 alpha , and if necessary, 21-alkylates of general formula (I) in which R'' and R', identical or different represent hydrogen or an alkyl radical having 1 to 3 carbon atoms in linear or branched chain and R1 represents a lower alkyl radical having 1 to 6 carbon atoms, in a linear or branched chain. Said invention is also concerned with a process for production of compounds of general formula (I) and their use as active principles in medication.

Description

NEW ALCOHOL DERIVATIVES IN
17/21 OF 19-NOR PROGESTERONE,
METHODS OF OBTAINING THEM AND COMPOSITIONS
PHARMACEUTICALS INCLUDING
The present invention relates to the field of therapeutic chemistry and in particular steroid chemistry.

More particularly, it relates to new steroids derived from 19-nor progesterone having in 17 and optionally in 21 an alkyl substituent.

dans laquelle R' et R", identiques ou différents représentent de l'hydrogène ou un radical alcoyle inférieur, ayant de 1 à 3 atomes de Carbone, en chaîne droite ou ramifiée et R1 représente un radical alcoyle inférieur, identique ou différent de R' ou de R", ayant de 1 à 6 atomes de carbone en chaine droite ou ramifiée.It relates specifically to 6-methyl 19-nor pregna 4,6-dienes 17 and optionally 21-alkyls of general formula
I

in which R 'and R ", which may be identical or different, represent hydrogen or a lower alkyl radical having from 1 to 3 carbon atoms, in a straight or branched chain and R 1 represents a lower alkyl radical, which is identical to or different from R'; or R ", having from 1 to 6 carbon atoms in straight or branched chain.

est de préférence une chaine l-oxo éthyl (R' - H3 et R" = H) 1-oxo propyl (R' - CH3 et R" = H), 1-oxo butyl (R' = C2H5 et R" = H) l-oxo 2-méthyl propyl (R' - CH3 et R" = CH ou 1-oxo 2-éthyl butyl ( R' = CH2CH3 et R" w CH2CH3)
Dans la formule générale I, R1 et R" sont de préférence un radical méthyl, éthyl ou isopropyl. Ils peuvent également être un radical propyl.In the general formula I

is preferably 1-oxoethyl (R '- H 3 and R "= H) 1-oxopropyl (R' - CH 3 and R" = H), 1-oxo-butyl (R '= C 2 H 5 and R "= H) 1-oxo-2-methylpropyl (R '-CH 3 and R "= CH or 1-oxo-2-ethylbutyl (R' = CH 2 CH 3 and R" w CH 2 CH 3)
In the general formula I, R 1 and R "are preferably a methyl, ethyl or isopropyl radical and may also be a propyl radical.

19-Nor progesterone derivatives, and more particularly those possessing a characteristic 2 '6-methyl-Dienone chain, were known on the A and B rings of the steroid molecule (Patent FR 2,271,833), for example the 6- methyl 17O-hydroxy-3,20-dioxo-19-nor pregna 4,6-diene and its esters and ethers.

Several steroid derivatives having the carbon skeleton of nor-19 progesterone, carriers on carbon 17 and / or 21 alkyl radicals are known as progestational molecules.

(see French Patent 2,077,877), such as for example 3,20-dioxo 17o-methyl 19-nor pregna 4,9-diene.

It is an object of the present invention to provide novel compounds of general formula I having very good progestomimetic properties, improved progesterone receptor binding and slowed liver resabolization.

The effectiveness of these new compounds can be attributed to the structure derived from 19-nor progesterone, characterized, in fact, by a steroidal system carrying, at the same time, a so-called "methyl-6 dienone" chain and by the presence of three substituents R ', R ", RI as defined above which prevent or delay the metabolism of the product in the body by the enzymes without preventing the binding to the progesterone receptors.

Among the compounds of general formula I, mention may be made in particular of: 6,17a, 21-trimethyl-3,20-dioxo-19-nor pregna 4,6-diene-17c-ethyl-6,2-dimethyl-3,20- dioxo 19-nor pregna 4,6-diene 17α-ethyl-3,20-dioxo 6-methyl 19-nor pregna 4,6-diene 6,17α-dimethyl-3,20-dioxo-19-nor 4,6-diene pregna-17a, 21-ethyl-6-methyl-3,20-dioxo-19-non-pregna 4'-6-diene which are the presently preferred compounds.

nécessaires pour la mise en oeuvre du procédé de préparation des composés de formule I sont préparées conformément à la littérature en soumettant un dérivé 19-nor stéroïde de formule partielle II

dans laquelle Ac est le reste acyle d'un acide organique carboxylique ayant de 1 à 4 atomes de Carbone le trait ondulé indique une orientation spatiale α; ou ss et le cycle A est entièrement aromatique du type 3 alcoyloxy
A 1,3,5(10) estratriénique ou partiellement insaturé du type 3-oxo a4 estrénique, éventuellement bloqué sous forme de dérivé fonctionnel avec ou sans basculement de la double liaison à l'action d'une base forte puis d'un agent d'alcoylation pour former un dérivé mono- ou bis alcoylé de formule partielle III

dans laquelle Rt, R" et R1 ont les significations fournies précédemment.Raw materials of general formula IV,

necessary for carrying out the process for the preparation of the compounds of formula I are prepared in accordance with the literature by subjecting a 19-nor steroid derivative of partial formula II

wherein Ac is the acyl residue of an organic carboxylic acid having 1 to 4 carbon atoms the wavy line indicates a spatial orientation α; or ss and cycle A is entirely aromatic type 3 alkyloxy
A 1,3,5 (10) estratrenic or partially unsaturated 3-oxo-4-estrene, optionally blocked as functional derivative with or without tilting of the double bond to the action of a strong base and then an agent for alkylating to form a mono-or bis-alkylated derivative of partial formula III

wherein Rt, R "and R1 have the meanings previously provided.

The strong base may be an alkali metal alkoxide derived from a lower alcohol of 1 to 5 carbon atoms, linear or branched, and a metal such as lithium, sodium or potassium, such as, for example, sodium teramylate, tert-butylate or potassium, sodium ethanolate, alkali or alkaline earth metal amide, lithium, potassium sodium, calcium or barium. In a preferred manner, sodium amide or lithium isopropylamide is used. Dimsyl sodium can still be used.

The alkylating agent may be a dialkyl sulfate, such as dimethyl sulfate for example, or an alkyl halide, the halogen being iodine or bromine.

The solvent may be alone or a mixture selected from the list: liquid ammonia, ether, THP, benzene, toluene, hexane, alcohol, the preferred solvents being liquid ammonia and tetrahydrofuran.

The strong base and the alkylating agent are used in excess of stoichiometry. The reaction is followed by acid hydrolysis.

The compounds of general formula III, mono- or polyalkylated, are optionally purified by appropriate means such as, for example, by crystallization or by chromatography on a column consisting of an adsorbent suitable for chromatography, such as silica, talc or magnesium silicate or alumina.

The reaction temperature can vary widely between -60 and +50 ° C. It is preferably between -600 and -400, because of the preferred use of ammonia as the solvent.

To form a monoalkylated derivative (where R 'and R "are hydrogen), a lower concentration of basic agent (from 4 to 7 equivalents) and a lower concentration of alkylating agent are preferably employed. .

On the contrary, to form a 17,21-dialkylated derivative, it is necessary to introduce a higher amount of basic agent (from 10 to 50 equivalents) and a higher amount of alkylating agent (50 to 75 equivalents). ).

The choice of the base is not without influence. Experience has shown that lithium isopropylamide is the best reagent for alkylation at 21. Alkali alkoxides promote alkylation at 17, the preferred basic reagent in this case is the metal amide resulting from the attack. in situ "liquid ammonia with an alkali metal or alkaline earth metal such as lithium or calcium.

Alkylation at 17a from an alkaline enolate is a difficult reaction and requires the presence of a very large excess of basic agent.

Access to the methyl at 21 by the alkylating agent is more difficult when the position 17 is already occupied by an alkyl group. A mixture of mono- and dialkylated derivatives is obtained at 21 and therefore requires a large excess of metal and alkylating agent. Single-alkylation is promoted at 21 using a basic agent such as lithium isopropylamide in tetrahydrofuran as a result of the steric lining of this basic reagent.

On the other hand, in view of the different alkylation rates, it is possible to first alkylate at 17 by introducing a small excess of alkylating agent into the reaction medium and then again adding an alkylating agent. identical or different from performing the alkylation at 21 with an alkyl radical identical to or different from that at 17a.

It is also possible to use as raw material a 19-nor pregnadiene already methylated at 21 and to perform a bis-alkylation at 17 and 21 but in this case, it is the alkylation at 21 which is favored because the carbon in 21 forms a secondary carbanion more stable and more reactive.

The reaction can thus be written for an ethylation reaction

à une réduction selon la méthode de Birch-Nielsen suivie d'une hydrolyse en milieu acide fort puis d'une réoxydation par le réactif de Jones pour former le 3-céto 19-nor pregna 4-ène de formule IV
La réduction selon Birch-Nielsen est effectuée dans un solvant inerte comme un éther cyclique ou linéaire au moyen d'un métal alcalin en solution dans l'ammoniac liquide en présence d'un agent donneur de protons comme par exemple un alcanol tel que méthanol ou l'éthanol.On chasse ensuite l'ammoniac et on détruit l'excès de métal alcalin par addition d'un alcanol. L'éther énolique résultant est ensuite hydrolysé par action d'un acide minéral fort.When the starting material used is an estra-trienic derivative III, that is to say a compound for which the nucleus
A is aromatic, the conversion to a compound of formula IV is carried out by the following steps - a compound of general formula III is subjected

to a reduction according to the Birch-Nielsen method followed by a hydrolysis in a strong acid medium and then a reoxidation with the Jones reagent to form the 3-keto 19-nor pregna 4-ene of formula IV
The Birch-Nielsen reduction is carried out in an inert solvent such as a cyclic or linear ether by means of an alkali metal in solution in liquid ammonia in the presence of a proton-donating agent such as an alkanol such as methanol or Ethanol is then removed and the excess alkali metal is destroyed by the addition of an alkanol. The resulting enol ether is then hydrolysed by the action of a strong mineral acid.

dans laquelle R', R" et R1 sont définis comme précédemment.The invention also relates to a process which leads to the compounds of general formula I by using as starting materials an enol ether of 3,20-dioxo-19-nor pregna 4-ene, obtained from 3,20-dioxo 19-nor pregna 4-ene, raw materials, which have the following general formula IV

wherein R ', R "and R1 are defined as above.

dans laquelle R2 est un radical alcoyle inférieur et R', R" et RI sont définis comme précédemment que l'on soumet à l'action d'un agent de formylation du type
Vilsmeier-Hack pour obtenir un dérivé formylé de formule générale
VI

dans laquelle R', R", h et R1 ont les significations fournies antérieurement réduit celui-ci par un hydrure mixte de métal alcalin pour former un dérivé hydroxy méthylé de formule générale VII

dans laquelle R', R", R2 et R1 ont les significations antérieures que l'on traite par un acide minéral ou organique et obtient le dérivé 3-oxo 6-méthylénique de formule générale VIII

dans laquelle R', R" et R1 sont définis comme précédemment celui-ci, à son tour, est traité par un catalyseur d'isomérisation pour former le dérivé 6-méthyl 3oxo 19-nor pregna 4, 6-diénique correspondant de formule générale I.The compounds of general formula Iv are etherified to enol ether by an alkyl orthoformate to obtain a compound of formula V

in which R2 is a lower alkyl radical and R ', R "and R1 are defined as previously that is subjected to the action of a formylation agent of the type
Vilsmeier-Hack to obtain a formyl derivative of general formula
VI

wherein R ', R ", h and R1 have the previously provided meanings reduced by mixed alkali metal hydride to form a methylated hydroxy derivative of the general formula VII

in which R ', R ", R2 and R1 have the prior meanings which are treated with a mineral or organic acid and obtain the 3-oxo-6-methylenic derivative of general formula VIII

in which R ', R "and R1 are defined as previously this, in turn, is treated with an isomerization catalyst to form the corresponding 6-methyl-3-oxo-19-nor pregna 4,6-diene derivative of the general formula I.

The invention also extends to pharmaceutical compositions containing, as active principle, at least one compound of general formula I alone, in admixture with one or more excipients or an inert, non-toxic, pharmaceutically acceptable carrier.

The invention also comprises pharmaceutical compositions containing, in addition, another active ingredient of similar or synergistic or complementary action.

The pharmaceutical compositions according to the invention are intended for parenteral, oral, rectal, per mucous or percutaneous administration.

For parenteral administration, the compounds of general formula I are administered in the form of solutes or injectable suspensions packaged in ampoules, in multi-dose vials or in auto-injectable syringes.

For oral administration, the compounds of the general formula I are administered in the form of naked or coated tablets, dragees, capsules, soft capsules, pills, powders or granules.

For rectal administration, the compounds of the general formula I are presented in the form of suppositories or rectal capsules.

For administration by the mucosal route, the compounds of general formula I are presented in the form of oily solutions, creams, jellies or capsules. It is possible to administer the compounds of general formula I either by the vaginal mucosa, by the nasal mucosa in the form of spray or gel, or by the ocular mucosa.

For percutaneous administration, the compounds of the general formula I are presented as a solution or creams in a penetrating solvent such as benzyl alcohol, dimethylsulfoxide, 1-n-dodecylazacycloheptanone-2 (AZONE (R) ) or N-B-hydroxyethyl acetamide.

These pharmaceutical compositions according to the invention find use in therapy for the treatment of gynecological disorders due to luteal insufficiency such as menstrual irregularity, dysmenorrhea, premenstrual syndrome and menopausal disorders. They can be used alone or in combination with an estrogen as a co-contraceptive agent.

The usual dosage ranges from 0.05 mg to 25 mg and the daily dosage ranges from 0.1 mg to 50 mg in continuous or periodic administration.

dans laquelle R', R" et R1 sont définis comme précédemment à l'exclusion du cas où R' est méthyl ou éthyl, R' et R" est de l'hydrogène - les composés de formule générale V

dans laquelle R2 est un radical alcoyle inférieur
R' et R", identiques ou di férents représentent de l'hydrogène ou un radical alcoyle inférieur, ayant de 1 à 3 atomes de Carbone, en chaîne droite ou ramifiée
R1 représente un radical alcoyle inférieur, identique ou différent de R' ou de R", ayant de 1 à 6 atomes de carbone en chaine droite ou ramifiée.The invention also extends to new intermediate products formed during the synthesis, namely - the compounds of general formula IV

in which R ', R "and R1 are defined as above except for the case where R' is methyl or ethyl, R 'and R" is hydrogen - the compounds of general formula V

in which R2 is a lower alkyl radical
R 'and R ", which are identical or different, represent hydrogen or a lower alkyl radical having from 1 to 3 carbon atoms, in a straight or branched chain
R 1 represents a lower alkyl radical, which is identical to or different from R 'or R ", having from 1 to 6 carbon atoms in the straight or branched chain.

dans laquelle R', R", R1 et R2 ont les significations fournies antérieurement.and in which R 'and R ", which may be identical or different, represent hydrogen or a lower alkyl radical having from 1 to 3 carbon atoms, in straight or branched chain - the compounds of general formula Vr

wherein R ', R ", R1 and R2 have the meanings previously provided.

dans laquelle R', R", R1 et R2 ont les significations fournies antérieurement.the compounds of general formula VII

wherein R ', R ", R1 and R2 have the meanings previously provided.

dans laquelle R', R" et R1 ont les significations antérieures
Les exemples suivants illustrent l'invention sans toutefois la limiter.the compounds of general formula VIII

in which R ', R "and R1 have the earlier meanings
The following examples illustrate the invention without limiting it.

EXAMPLE I 6,17 α -dimethyl-3,20-dioxo-19-nor pregna 4,6-diene
Stage A: 17O-acetoxy 3-ethoxy 20-oxo 19-nor pregna 3 '5-diene
Under an inert atmosphere and at ambient temperature, a solution of 126 g of 3,20-dioxo-17α-acetoxy-19-nor-pregna-4-ene in 1.010 ml of ethanol is added to 115 g of ethyl orthoformate and then after stirring. for 10 minutes, addition of 0.63 g of p-toluenesulphonic acid.

The mixture is stirred for 60 minutes and the reaction is stopped by the addition of 17 ml of triethylamine. The medium is diluted with 380 ml of ethanol and the mixture is refluxed until dissolved.

It is crystallized by allowing the solution to return to room temperature and then cooling with an acetone / ice bath. Thus 113 g of 3-ethoxy 17α-acetoxy 20-oxo-19-nor pregna 3,5-diene is collected, ie a yield of 83% relative to the theory.

The enol ether has the following characteristics
IR spectrum 1740 cm-1 CO of acetoxy 1710 cml CO at 20, 1650, 1620 cm-1 delta-3.5
Spectrum W: X max 243 nm, e-20840:: (T, 3H) at 1.3 ppm CH 3 of ethoxy
(Q, 2H) at 3.60 ppm CH 2 of ethyl
(S, 1H) at 5.25 ppm H carried by the C6
(S, 1H) at 5.40 ppm H carried by the C4
Stage B: 17α-methyl-3,20-dioxo-19-nor pregna-4-ene and 17,21-
dimethyl 3,20-dioxo 19-nor pregna 4-ene
A solution of 46 g of calcium in 1,000 ml of liquid ammonia cooled to -60 ° C. and inert atmosphere is prepared in advance, a solution of 30 g of enol ether of Stage A in 495 is added in a thin stream. ml of tetrahydrofuran. After stirring, 363 ml of methyl iodide are added dropwise. A white-gray precipitate is formed. The end of the addition is followed by 60 minutes of stirring and then evaporation of the maximum possible ammonia under vacuum and under hot water bath. 1000 ml of methanol and 6N hydrochloric acid are then added until that the pH is acidic, while maintaining the temperature of the medium at
OC by immersion in an acetone / ice bath.

It is kept stirring for 60 minutes. The reaction products are precipitated by the addition of 2.000 ml of water and extracted with toluene. After evaporation of the solvent, 22.9 g of a crude oil containing 68% of 17α-methyl derivative and 24% of 17α, 21-dimethyl derivative, determined by HPLC, are collected.
Chromatography on silica eluting with Cyclohexane at 10% ether, is isolated in the top fractions 1.1 g of 17a derivative, 21-dimethyl and then 6 g of 17α-methyl derivative in the tail fractions. These two products are recrystallized separately from methanol.They have the following physical constants: 4 3, 20-dioxo 17 α -methyl 19-nor pregna-4ene
IR: 1705 cm-1 CO in 20
1680 cm-1 CO in 3
1620 for the conjugate c = c
UV: X max 240 nm, # = 17385
NMR: (S, 3H) at 1.2 ppm CH 3-17a
(S, 3H) at 2.2 ppm CH3-21.

-> 3,20-dioxo 17a, 21-dimethyl 19-nor pregna 4-ene
IR: 1697 cm-i Co in 20
1670 cm1 Co in 3
W: X max 240 nm, E - 16515
NMR: (S, 3H) at 1.2 ppm CH 3-17a
(T, 3H) at 1.07 ppm CH3-22
Multiplet at 2.55 ppm CH2-21
Stage C: 3-ethoxy 17o-methyl 20-oxo 19-nor pregna 3,5-diene
This compound is prepared according to the same procedure as at Stade
A, starting from 3,20-dioxo-17α-methyl-4-butene-4-ene, 12 ml of ethanol, 1.85 ml of ethyl orthoformate, 0.102 g of p-toluenesulphonic acid and then 0 ml. , 2 ml of triethylamine.

With 78% yield, the crystallized enol ether has the following physical constants
IR spectrum: 1695 cm oe in 20
1640, 1620 cm-1 delta-3.5
Spectrum W: X max 243 nm, e = 16520
NMR Spectrum: (S, 3H) at 1.15 ppm CH3-17a
(T, 3H) at 1.30 ppm CH 3 of ethoxy
(S, 3H) at 2.15 ppm CH3-21
(Q, 2H) at 3.80 ppm CH 2 of ethoxy
(S, 1H) at 5.22 ppm H at C6
(S, 1H) at 5.32 ppm H at C4
Stage D: 3-ethoxy 6-formyl 17o-methyl 20-oxo 19-nor pregna 3,5-diene
A formylating reagent was prepared by dissolving under nitrogen and 20.35 ml of freshly distilled POCl3 in 28 ml of dimethylformamide followed by a stirring period of 5 minutes.

The reagent thus prepared is added dropwise to a solution of 7 g of 3-ethoxy 17α-methyl 20-oxo-19-nor pregna 3,5-diene in 56 ml of dimethylformamide in 10 to 15 min.

The mixture is kept stirring for 10 minutes and then the imonium ion is hydrolyzed by dropwise addition of a solution of 14 g of potassium acetate in 28 ml of water without the temperature exceeding + 300 ° C. The solution initially colored in red, turns yellow with beginning of crystallization. After stirring for 30 minutes, 105 ml of ice water are added. 7.2 g (95%) of the theory of crude 3-ethoxy-6-formyl-17-methyl-20-oxo-19-bromine-3,5-diene is thus isolated. It is recrystallized from methanol to obtain 3.1 g of pure product whose constants are
IR: 1700, this in 20
1650 and 1615 delta-3.5 WX max 220 and 320 nm
NMR: disappearance of (S, 1H) at 5.22 ppm.

Stage E: 17α-methyl-6-methylene-3,20-dioxo-19-nor pregna-4-ene
95 mg of sodium borohydride are added in small portions, under a nitrogen atmosphere and at room temperature, to a solution of 1.9 g of 3-ethoxy-17cr-methyl-6-formyl-19-nor 20-keto pregna 3,5 -diene in 5.7 ml of ethanol and 4.7 ml of dimethyl formamide. Stirring is maintained for 2 hours. The temperature of the reaction solution is reduced to 0 and a solution of 0.4 ml of 2N sulfuric acid in 2 ml of water is added over 2 minutes.

The temperature rises to 100 and a slight yellow precipitate appears in the form of an eraser. It is stirred for a further 20 minutes.

A solution of 0.88 g of potassium carbonate in 2 ml of water is then added dropwise. The precipitate is growing. It is separated by filtration and washed thoroughly with water until the washing water is neutral. 1.40 g of 3,20-dioxo-6-methylene 17a-methyl-19-nor pregna-4-ene are thus collected, ie a yield of 87%.

IR spectrum: 1700 cm 1 CO in 20
1660 cm ~ l CO in 3
1620, 1595 cm -1, c = c
UV spectrum: max X max 263 nm, e = 12280
NMR spectrum: appearance of two singlet not very well resolved at 5 ppm and at 5.25 ppm.

Stage F: 3,20-dioxo 6,17 α -dimethyl 19-nor pregna 4,6-diene
(compound of formula I)
A suspension of 0.65 g of 5% palladium on carbon in 33.5 ml of methanol is prepared and refluxed for 30 minutes, to which 1.34 g of 6-methylenic derivative of Stage E are added. maintains reflux heating. The reaction is followed by determination of the absorption in W. After stirring for 30 minutes, the mixture is allowed to return to ambient temperature. It is filtered on Clarcel. The filtrate is concentrated, chromatographed over 30 times its weight of silica and eluted with toluene. Fractions containing the 6-methyl derivative are recrystallized from methanol to give 0.83 g of 3,20-dioxo-6-yl dimethyl-19-nor pregna 4,6-diene, ie 62% of theory.

The analytical constants are as follows
IR spectrum: 1695 cm -1 CQ in 20
1650-cm-1 CO in 3
1622, 1576 cm 1 delta-4,6
Spectrum W: X max 289 nm, F = 23900
Mass: 326 molar mass
283 loss of CH3CO
43 CH3CO
[a] D: (dioxane) + 22032
pF: 164.60C
Centesimal composition: C22 H30 02
Found Calculated
C 80.26 80.93
H 8 9.20 9.26
NMR Spectrum: (S, 3H) at 0.76 ppm for CH3-18
(S, 3H) at 1.19 ppm for CH3-17a
(S, 3H) at 1.88 ppm for CH3 at 6
(S, 3H) at 2.16 ppm for CH3-21
(S, 1H) at 6.01 ppm for H in C7
(S, 1H) at 6.12 ppm for H in C4 EXAMPLE II 6,17a, 21-trimethyl-3,20-dioxo-19-nor pregna 4,6-diene
Stage A: 3-ethoxy 17a, 21-dimethyl 20-oxo 19-nor pregna 3,5-diene
The operation is carried out as in Step A of Example I, starting from 5.85 g of 3,20-dioxo-17a, 21-dimethyl-19-nor pregna-4-ene obtained in Step B of Example I in 12 ml. ethanol, 5.9 ml of ethyl orthoformate and 0.029 g of toluene sulfonic acid. When the reaction is complete, it is stopped by the addition of 0.6 ml of triethylamine. The enol ether obtained does not crystallize, it is exhausted with benzene and the benzene phase is washed with water. This gives 7.07 g of crude enol ether which, after purification by chromatography on basic alumina and elution with hexane and 1% of triethylamine, gives 5.8 g of 3-ethoxy 17a, 21 dimethyl 20-oxo. -Nor pregna 3, 5-diene is a yield of 91%.

Stage B: 3-ethoxy 6-formyl 17a, 21-dimethyl 20-oxo 19-nor pregna
3,5-diene
The formylation at 6 of the compound of Step A is carried out according to the procedure described in Step D of Example I. 5.1 g of enol ether of Step A are dissolved in 41 ml of dimethylformamide.

The formylating reagent is 2.15 ml POCl 3 in 20 ml dimethyl formamide. The hydrolysis reagent is 13.8 g of potassium acetate in 20 ml of water.

4.4 g is obtained, a yield of 77% crude 6-formylated derivative.

Stage C: 6-methylene 17a, 21-dimethyl-3,20-dioxo-19-nor pregna-4-ene
The same procedure as that described in Stage E of Example I is used. 4.3 g of 6-formylated derivative of Stage B are dissolved in 43 ml of ethanol. It is reduced with a solution of 0.273 g of sodium borohydride in 4 ml of dimethylformamide. It is stirred for 10 minutes and then the methylhydroxy derivative is dehydrated with a solution of 5.15 ml of 2N sulfuric acid in 40 ml of water.

This gives 1.9 g, a yield of 50% of crude 6-methylenic derivative
X max = 258 nm
Stage D: 6,17a, 21-trimethyl 3,20-dioxo 19-nor pregna 4,6-diene
(compound of formula I)
A suspension of 25 ml of ethanol and 0.14 g of palladium-carbon is refluxed for 60 minutes. 1.1 g of 6-methylenic derivative of Stage C are then added. The development of the reaction is monitored by spectrophotometry W. After stirring for 50 minutes at reflux temperature, a displacement of X max at 286 nm is observed. It is then filtered through Clarcel and the filtrate is then brought to dryness and the residue is chromatographed with toluene over 35 times its weight of silica. A fraction was collected which gave 0.83 g of 6,17a, 21-trimethylated derivative which was purified by recrystallization of 95% ethanol.

The 3,20-dioxo 6,17 α 21-trimethyl 19-nor pregna 4,6-diene melts at 1600C.

IR spectrum: 1695 cm-1 this in 20
1680 cm-1 this in 3
1628, 1580 cm-1, delta-4.6
Spectrum W: X max 288.5 nm, ee 24280
Mass: m / e 340 molar mass
283 (-57) loss of COoe2CH3
Centesimal composition: C23 H32 02
Found Calculated
C% 81.06 81.13
H% 9.46 9.47
NMR spectrum: (S, 3H) at 0.71 ppm for CH3-18
(T, 3H) at 1.05 ppm for CH3-22
(Dq) at 2.45 ppm for CH2-21
(S, 3H) at 1.13 ppm for CH3-17a
(S, 1H) at 5.95 ppm for H to C7
(S, 1H) at 6.05 ppm for H at C5
[α] D + 18.9 (c = 0.53 z dioxane) EXAMPLE III 17α-ethyl 6-methyl-3,20-dioxo 19nor pregna 4,6-diene
Stage A: 3,20-dioxo 17 α -ethyl 19-nor pregna 4-ene
1 g of calcium is dissolved in 40 ml of liquid ammonia at -600 ° C. and under an inert gas atmosphere. A solution of 1 g of 3-ethoxy-20-oxo-19-nor-pregna-diene 3 is then added in a thin stream, In 18 ml of carefully dehydrated tetrahydrofuran. Stirring is maintained for 1 hour and then 9.8 ml of ethyl iodide are added. The mixture is stirred for one hour and then the ammonia is evaporated under vacuum in a water bath of warm water. A whitish paste is collected which is stirred in 100 ml of methanol and then added a 3N solution of hydrochloric acid to acidic pH while cooling with an acetone / ice bath.

After 60 minutes stirring, the product is extracted with toluene, the toluene phase is separated and washed with water. After evaporation, a crude 17o-ethyl derivative containing 41.6% of pure 17?
HPLC.

The product is purified by chromatography on 50 times its weight of silica using 10% ethereal cyclohexane as the solvent. The fraction corresponding to the 17α-ethyl derivative is brought to dryness and the dry residue is recrystallized from cyclohexane.

IR spectrum: 1705 cm -1 CO in 1670 cm -1 CO 3
1620 cml, delta-4
Spectrum W: X max 240 nm, e = 17520
NMR Spectrum: (S, 3H) at 0.70 ppm CH 3-18
(T, 3H) at 0.75 ppm CH 3 of ethyl-17 α
(S, 3H) at 2.05 ppm the cH3-21
(S, 1H) at 5.80 ppm H in C4
Stage B: 3-ethoxy 17α-ethyl 20-oxo 19-nor pregna 3,5-diene
Ether-enolization is carried out according to the same procedure as that described in Stage A of Example 1 starting from 9.6 g of 17c-ethyl derivative of Step A in 29 ml of ethanol, with 9.6 ml of ethyl orthoformate and 0.048 g of toluene sulfuric acid and then 1 ml of triethylamine.

7.1 g is obtained, a yield of 68% of pure enol ether.

IR spectrum: band at 1700 cm 1 (carbonyl in 20)
bands at 1650 and 1620 (double bonds in 3 and 5)
Spectrum W: X max 243 nm, e = 18520
NMR spectrum: (Q, 2H) at 3.7 ppm (CH 2 of 1-methoxy)
(S, 3H) at 2.3 ppm (CH 3 in 21)
(S, 1H) at 5.2 ppm (H at C6)
(S, 1H) at 5.8 ppm (H at C4)
Stage C: 3-ethoxy 6-formyl 17o-ethyl 20-oxo 19-nor pregna
3,5-diene
Formylation is carried out as in Stage D of Example 1
Formylation reagent: 0.5 ml POC13 in 4,5 ira of
dimethylformamide
Hydrolysis solution: 2 g of potassium acetate in 40 ml of water
Starting from 1 g of 3-ethoxy 17α-ethyl-20-oxo-19-nor pregna-3,5-diene, 1.18 g of crude 6-formylated derivative is obtained which, by chromatography with dichloromethane on magnesium silicate, gives 0, 7 g is a yield of 65% of 3-ethoxy 6-formyl 17o-ethyl 20-oxo 19-nor pregna 3,5-diene pure
X max = 323 nm and 220 nm
Stage D: 3,20-dioxo 6-methylene 17 α -ethyl 19-nor pregna 4-ene
The 6-methylenic derivative is prepared from the 6-formyl derivative in Step C, according to the same procedure as in Example I, Stage
E from 0.5 g of 3-ethoxy-6-formyl-20-ethyl-20-oxo-19-nor pregna-3,5-diene in 65 ml of ethanol and 0.419 g of sodium borohydride and then hydrolyzed and dehydrated by 8 ml 2N sulfuric acid and 55 ml of water. 4.4 g of crude 6-methylenic derivative are thus isolated, ie a yield of 76%. This product contains small amounts of the intermediate 6-hydroxy methylated derivative.

IR spectrum: 3400 cm 1 low, corresponds to HO
3080 cml very low, corresponds to H2C of
methylene-6
1695 cm-1 this in 20
1660 cm ~ l this in 3
Spectrum W: X max 258 nm
NMR Spectrum: (S, 3H) at 0.7 ppm CH 3-18
(T, 3H) at 0.75 ppm CH 3 of ethyl 17a
(S, 3H) at 2.1 ppm CH3-21
Appearance of 3H ethylenic
4.95 ppm,
5.17 ppm
6.10 ppm
(Q) very low at 3.74 ppm corresponding to the CH 2 of the ethoxy of the hydroxymethylated product, proof, taking into account the weak IR band at 3400 cm -1, of the presence of a certain amount of hydroxymethyl steroid.

Stage E: 3,20-dioxo 6-methyl 17α-ethyl 19-nor pregna 4,6-diene
(compound of formula I)
A suspension of 5.5 g of palladium on carbon in 820 ml of ethanol is refluxed for 60 minutes. 4.1 g of 3.20-dioxo-6-methylene-17α-ethyl-19-nor-pregna-4-ene are then added, and the course of the isomerization is followed by spectrophotometry at W. After 8 minutes, the maximum has switched to 288 nm. The reaction is then stopped, the suspension is filtered on clarcel and the filtrate is brought to dryness. 3.65 g of crude 6-methylated product are collected.

It is purified by chromatography on 30 times its weight of silica and crystallizes from its methanolic solution
Pure product melts at 162 C [a3D + 0 (c = 1.26% dioxane)
IR spectrum: 1695 cm 1 CO in 20
1660 cm-1 CO in 3
1622, 1579 cm 1, delta-4,6
UV spectrum: λ max 288.5 nm, - 25880.

Mass: m / e 340 mass
297 (M-43) loss of COMe
268 (M-72) loss of COMe and ethyl, mp: 1620C
Centesimal composition: C23 H32 02
% found% calculated
C 81.34 81.13
H 9.41 9.47
9.24 9.40
NMR Spectrum: (S, 3H) at 0.70 ppm CH 3-18
(T, 3H) at 0.75 ppm CH 3 of ethyl 17a
(dd, 3H) at 1.83 ppm CH3 in C6
(s, 3H) at 2.10 ppm CH3-21
(S, 1H) at 5.95 ppm H in C7
(S, 1H) at 6.05 ppm C4 EXAMPLE IV 3,20-dioxo 6,21-dimethyl 17α-ethyl 19nor pregna 4,6-diene
Stage A :: 3-methoxy 17o-acetyl 17ss-acetoxy estra 1,3,5 (10) Triene
1250 ml of polystyrene sulfonic cation exchange resin are added to 4 liters of water. The suspension is stirred for 12 hours, filtered and resuspended in 3.5 liters of water.

50 g of mercuric acetate and 1 ml of acetic acid are then added and the mixture is stirred for 60 minutes. The bath resin is thoroughly filtered and washed. 100 ml of the mercuric resin are removed and suspended in a solution of 100 g of Mestranol acetate, 50 ml of dioxane and 1500 ml of ethanol. After stirring for 20 minutes, 20 ml of water are added and the mixture is refluxed for 15 hours. The reaction mixture is then filtered hot and washed with ethanol.

The filtrate is concentrated to dryness and the residue is recrystallized from ethanol. 83 g is thus obtained, a yield of 79% of pure 3-methoxy 17α-acetyl-175-acetoxy estra 1,3,5 (10) triene.

IR spectrum
- disappearance of the bands at 3265 cm 1 and 2100 cm 1
(C n C - H)
- band appearance at 1709 cm 1
(CO in 17a)
NMR spectrum
- disappearance of (S, 1H) at 2.65 ppm
corresponding to H of C n C - H in 17
- appearance of (S, 3H) at 2.05 ppm
corresponding to CH3 of COCH3 at 17 α
Stage B: 3-ethoxy 17a-ethyl 20-oxo 19-nor pregna 1,3,5 (10) triene
A solution of 3.75 g of lithium in 800 ml of liquid ammonia under argon and at -600C is prepared. A solution of 50 g of 3-methoxy-17α-acetyl-17-acetoxy-estra-1,3,5 (10) triene in 750 ml of tetrahydrofuran is then added. After stirring for 3 hours, 270 ml of iodide are added over 20 minutes. of ethyl and stirred for 2 hours.

The ammonia is then evaporated using a hot water bath under vacuum. The reaction medium is neutralized by the addition of dilute hydrochloric acid and then the aqueous phase is extracted with methylene chloride. After separation and evaporation of the organic solution, 40 g of crude product are obtained (yield 87% of theory). This is taken up under reflux in a mixture of 400 ml of methanol and 80 ml of methylene chloride.

After partial concentration of the mixture and evaporation, 34 g of 3-methoxy-17-alpha-ethyl 20-oxo-19-nor-pregna-1,3,5 (10) pure triene is obtained, ie a yield of 74%.

IR spectrum
- disappearance of the band at 1738 cm-1
at 1268 cml
at 1240 -1 (acetoxy)
NMR Spectrum: (S, 3H) at 0.70 ppm CH 3-18
(T, 3H) at 0.80 ppm CH 3 of ethyl-17a
(S, 3H) at 2.10 ppm CH3-21
(S, 3H) at 3.70 ppm methoxy CH3
Stage C: 3-methoxy 17a-ethyl 20-oxo 21-methyl 19-nor pregna 1.3.5 (10) Triene
Under a nitrogen atmosphere and with OOC, a solution of 1 ml of diisopropylamine and 6.5 ml of anhydrous tetrahydrofuran is prepared, and then 4 ml of a solution of 5% methyllithium in ether are added dropwise thereto. After stirring for 5 minutes, a solution of 1 g of 3-methoxy-17α-ethyl-20-oxo-19-nor pregna-1,3,5 (10) triene in 22 ml of anhydrous tetrahydrofuran is added dropwise. The temperature of the solution is allowed to rise to room temperature and stirring is continued for 80 minutes. Then allowed to cool to 0 C. is then added with vigorous stirring 2 ml of methyl iodide at once and stirring is continued for 2 hours at room temperature. A precipitate of whitish salt is formed which is separated by filtration.

The filtrate is brought to dryness, exhausted with toluene. The toluene solution is washed with water, dried and evaporated to dryness. 1 g of crude 17α-ethyl-17-methylated derivative is obtained, ie a 96% yield which is purified by recrystallization from 20 ml of methanol, thus obtaining 0.8 g, ie a yield of 77% of 3- methoxy 17α-ethyl-20-oxo 21-methyl 19-nor pregna 1,3,5 (10) triene.

Analysis C24 H34 2
CH 0%
Calculated 81.31 9.37 9.03
Found 81.46 9.66 8.87
NMR spectrum: (S, 3H) at 0.65 ppm CH 3 in I7
(T, 3H) 3H> at 0.75 ppm CH 3 of ethyl at 17a
(T, 3H) at 1.10 ppm CH3 in 22
(Dq, 2H) at 2.42 ppm CH2 in 21
(S, 3H) at 3.78 ppm methoxy CH3
Stage D: 3,20-dioxo 17 α -ethyl 21-methyl 19-nor pregna 4-ene
At -50 ° C. under an argon atmosphere, a solution of 172 g of 3-ethoxy-17α-ethyl-20-oxo-21-methyl-19-nor-pregna-1,3,5 (10) triene in 1750 ml of tetrahydrofuran is added. anhydrous with 3000 ml of ammonia. Then, at intervals of 30 minutes with stirring, 3 times 90 ml of ethanol and 17.2 g of lithium are added. After stirring for 60 minutes, the ammonia is removed by a hot water bath under vacuum.

13 liters of water are then added and the mixture is stirred for 2 hours. The insoluble material is filtered off and the filtrate is washed to neutrality. It is diluted with 3000 ml of methanol, a 4N solution of hydrochloric acid is added until pH 2 and the mixture is stirred for 2 hours. Upon addition of water, the steroid is precipitated and filtered off. 145 g of crude product are obtained whose IR spectrum shows conjugated OH, CO and C = C bands, which is taken up in 1960 ml of acetone and reoxidized with 114 ml of Jones reagent.

After stirring for 20 minutes, 400 ml of methanol and 4,000 ml of water are added. The steroid is extracted with methylene chloride and purified by silica column chromatography. 84 g of 3,20-dioxo-17-ethyl-21-methyl-19-nor-pregna-4-ene are isolated, ie a yield of 54%. Crystallization of the isopropyl ether provides the pure product.

IR spectrum: 1705 cml CO in 20
1680 cm 1 CO in 3
1620 cm-1 delta-4
Mass: m / e 343 molar mass
285 loss of COC2H5
NMR spectrum: disappearance of peak (S, 3H) at 3.7 ppm <CH 3 from
methoxy) and peaks at 7.2 ppm (aromatic ring).

Stage E: 3-ethoxy 17α-ethyl-21-methyl 20-oxo 19-nor pregna 3,5-diene
The enol etherification of 5 g of 3,21-dioxo-17-alpha-methyl-21-methyl-4-pregna-4-ene in 10 ml of ethanol is carried out with 5 ml of ethyl orthoformate and extraction with 1% benzene. triethylanine.

Chromatography on basic alumina with benzene as solvent gives 4.8 g of enol ether, a yield of 89%.

The analytical constants are as follows
IR spectrum: disappearance of 1680 cm 1, CO in 3
appearance of 1640 cm-1, delta-5
Mass: m / e 370 molar mass
342 loss C2H4
285 loss C2H4 and COC2H5.

NMR spectrum: (T, 3H) at 1.3 ppm CH 3 of ethoxy
(massive, 2H) at 3.7 ppm CH2 of ethoxy
(S, 1H) at 5.7 ppn H in C6
(S, 1H> at 5.8 ppm H at C4.

Stage F: 3-ethoxy-6-formyl 17α-ethyl-21-methyl-20-oxo-19β-pregna-3,5-diene formylation of 12.5 g of 3-ethoxy-17α-ethyl-21-methyl is carried out -oxo pregna 3, 5-diene in 87.5 ml of dimethylformamide with a formylating reagent formed of 6.25 ml of POCl3 in 37.5 ml of dimethyl formamide. The hydrolysis of the imonium salt is carried out by adding 3 successive fractions of a solution of 37.5 g of potassium acetate in water. The product of the reaction, colored yellow crystallizes. It is filtered off and dried to give 12.75 g of crude product, 95% of theory.

IR spectrum: band at 1699 cm -1 (CO at 20) at 1651 cm -1 and at 1610 cm -1 (Conjugated CnC)
Mass: m / e 398
341 (loss of COC2H5)
NMR spectrum: (S, 1H) at 6.20 ppm ethylenic
appearance of (S, 1H) at 10.25 ppm (CHO)
Stage G: 3,20-dioxo 6-methylene 17O-ethyl 21-methyl 19-nor pregna
4-ene
Under an ice bath, 40 mg of sodium borohydride is added to a solution of 0.5 g of 3-ethoxy-6-formyl-17-ethyl-20-oxo-21-methyl-9-pregna-3,5-diene dissolved in 3.8 ml. of methanol and 2.2 ml of dimethyl formamide. It is then allowed to return to ambient temperature and after 40 minutes with stirring, the spectrum W indicates the tilting of the max at 250 nm.

1 ml of a 2N solution of sulfuric acid and 0.8 ml of dimethylformamide are then added at 0 ° C. After stirring for 30 minutes, the mixture is neutralized by addition of. 2.5 ml of an aqueous solution of
Sodium carbonate The crystallized 6-methylenic derivative of the medium is filtered and washed extensively with water. It has an Amax at 262 nm.

Stage H: 3,20-dioxo 6,21-dimethyl 17o-ethyl 19-nor pregna 4,6-diene
(compound of formula I)
5 g of crude 6-methylenic drift in 245 ml of ethanol are subjected to isomerization with 5 g of palladium-bearing charcoal under reflux.

After stirring for 25 minutes, the spectrum W indicates the presence of Max at 288 nm. It is then filtered on Clarcel and the filtrate is concentrated to dryness. The residue is chromatographed over 60 times its weight of silica with dichloromethane as solvent. The recrystallized product of
Methanol provides the 3,20-dioxo 6,21-dimethyl 17α-ethyl 19-nor pregna 4, 6-diene pure whose analytical constants are
F: 180: + 404 (c = 1.26% dioxane)
Censual Analysis C24 H34 02
CH 0%
Calculated 81.31 9.67 9.03
Found 81.84 9.75 8.59
IR spectrum: 1700 cm 1, CO in 20
1660 cm l, CO in 3
1630, 1580 delta-4,6
RNN spectrum: (S, 3H) at 0.70 ppm CH 3-18
(T, 3H) at 0.75 ppm CH 3 of ethyl 17a
(T, 3H) at 1.05 ppm CH3-21
(Dd) at 2.40 ppm CH2-21
(dd, 3H) at 1.85 ppm CH3 in C6
(S, 1H) at 5.95 ppm H in C7
(S, 1H) at 6.05 ppm H at C4 PHARMACOLOGICAL STUDY OF COEES S ACCORDING TO INVENTION
Relative affinity measurement
Efforts have been made to determine the competing potency of each steroid for the progesterone receptor relative to the reference substance (cold progesterone).

The C14-labeled progesterone is incubated with the uterine cytosol, alone or in the presence of increasing concentrations of cold steroid (including unlabeled progesterone), at a ratio R ranging from 1 to 1000 between the two substances.

The following table shows the percentages of labeled progesterone still bound to the receptor in the presence of the cold competitor.

<tb><SEP> Steroids <SEP> No. <SEP> of <SEP> R = 0 <SEP> R <SEP> R-10 <SEP> R = 100 <SEP> R = 1000
<tb><SEP> metrics <SEP> n
<tb><SEP> Progesterone <SEP> 10 <SEP> 100 <SEP>% <SEP> 74 <SEP> 34 <SEP> 8 <SEP> 0
<tb><SEP> Compound <SEP> A <SEP> 5 <SEP> - <SEP> 80 <SEP> 28 <SEP> 17 <SEP> 12
<tb><SEP> Compound <SEP> B <SEP> 5 <SEP> - <SEP> 60 <SEP> 34 <SEP> 25 <SEP> 11
<tb><SEP> Compound <SEP> C <SEP> 5 <SEP> - <SEP> 77 <SEP> 44 <SEP> 17 <SEP> 7
<tb> Compound <SEP> D <SEP> 5 <SEP> - <SEP> 106 <SEP> 58 <SEP> 27 <SEP> 17
<tb> Acetate <SEP> of <SEP> 17 &alpha;; - methoxy4 <SEP><SEP> - <SEP> 62 <SEP> 35 <SEP> 20 <SEP> 11
<tb><SEP> Progesterone
<tb> Acetate <SEP> of
<tb> Nomegestrol <SEP> 4 <SEP> - <SEP> 73 <SEP> 25 <SEP> 5 <SEP> O <SEP>
<tb> Nomegestrol <SEP> 4 <SEP> - <SEP> - <SEP> 96 <SEP> 52 <SEP> 23
<Tb>

Compound D is 17α-acetoxy-2,2,2-dimethyl-3-oxo-19-nor pregna-4,6-diene
Compound A is 3, 20-dioxo 6,17 &alpha; dimethyl 19-nor pregna 4,6-diene
Compound B is 3,20-dioxo-6-methyl-17-alpha-ethyl 19-nor pregna-4,6-diene
Compound C is 3,20-dioxo 6,17o-20-trimethyl 19-nor pregna 4, 6-diene
The data in this table allow to deduce relative affinities.

Relative affinity (RA) is the ratio of the concentrations at 50 t of inhibition (Cl50) of a given steroid to the specific cold hormone taken for reference (here progesterone)
AR Cl50
IC50
This relative affinity is thus expressed as a percentage, considering that for the hormone (or the steroid) of reference, the AR is equal to 100%.

Cl50 is an estimate of the KI (inhibition constant) of the steroids tested for the binding of the reference steroid.

<Tb>

<SEP> Steroids <SEP> Cl150 <SEP> (nM) <SE> AR
<tb> Compound <SEP> B <SEP> 12.5 <SEP> 160
<tb> Acetate <SEP> of
<tb> 17o-Methoxy <SEP> 14.0 <SEP> 142
<tb> progesterone
<tb> Acetate <SEP> of
<tb> Nomegestrol (DCI <SEP>) <SEP> 15.0 <SEP> 133
<tb> Compound <SEP> A <SEP> 18.5 <SEP> 108
<tb> Progesterone <SEP> 20.0 <SEP> 100
<tb> Compound <SEP> C <SEP> 33.0 <SEP> 60
<tb><SEP> Nomegestrol <SEP> 600.0 <SEP> 3
<Tb>
The dfAR measure thus gives the following sequence
Compound B> Nomegestrol acetate> Compound A>Progesterone>
Compound C> Nomegestrol
Discussion
The six products studied belong to a series of nomegestrol acetate derivatives.

Two types of variation are to be considered - alkyl at 17 - extension of the chain at 21 by a methyl.

The 17α-methyl (Compound A), 17α-ethyl (Compound B) and 17α-acetoxy groups as in nomegestrol acetate give molecules whose affinity for the progestin receptor is at least equal to that of progesterone and equivalent to that of
Medroxyprogesterone.

But, the differences in affinity observed at this stage of study, seem to indicate a hierarchy between these three products. On the other hand, nomegestrol has the same side chain at 176 that the three products tested (compound A, compound B and Nomegestrol acetate) but having a hydroxyl in 17or shows a reduced affinity, 40 to 60 times lower than the three products mentioned. above.

Using AR = 1 for Nomegestrol acetate as a reference, the following table can be made, passing from nomegestrol acetate to 0.17 for compound B and from 0.81 for compound A to 0.45 for compound C.

<Tb>

<SEP> AR <SEP> for <SEP> the <SEP> receiver <SEP> e <SEP>
<tb><SEP> Steroid <SEP> Progesterone <SEP> expressed as <SEP> by <SEP> 17 <SEP> ss <SEP> 17 <SEP> cr <SEP>
<tb><SEP> report <SEP> to <SEP> acetate <SEP> of
<tb><SEP> Nomegestrol
<tb> Compound <SEP> B <SEP> 1.20 <SEP> CQMe <SEP> And
<tb> Acetate <SEP> of
<tb> Nomegestrol <SEP> 1.00 <SEP> coMe <SEP>
<tb> Compound <SEP> A <SEP> 0.81 <SEP> COMe <SEP> Me
<tb> Compound <SEP> C <SEP> 0.45 <SEP> ceEt <SEP> Me
<tb> Nomegestrol <SEP> 0.02 <SEP> COMe <SEP> OH
<Tb>
For the same substituent at 17a, the extension of the chain at 21 causes a decrease in affinity for the progestin receptor.

However, it should be noted that a decrease in affinity for the in vitro receptor does not prejudge a decrease in biological activity in vivo or not.

Indeed, if the structural modification leads to a lower affinity, it can nevertheless be accompanied by a better bioavailability (more difficult degradation, increased enterohepatic cycle, sequestration reduced by plasma proteins ...), the resulting effect can therefore result in an increase in pseudogestagen activity.

CONCLUSION:
From the fact that the lower relative affinity of the series of alkylated derivatives according to the invention is of the order of 60% and that the replacement of the hydroxyl group at 176 by a lower alkyl chain, it is found that the mono- or bis-alkylation of 6-methyl-19-nor-pregnadienes led to highly active progestins.

Claims (1)

The invention relates to 1 - As new compounds, the 6-methyl 19-nor pregna  4.6-17-alpha-alkenyl dienes of the general formula I

 in which R "and R ', which are identical or different, represent  hydrogen or an alkyl radical having from 1 to 3 carbon atoms  carbon in straight or branched chain  and R1 represents a lower alkyl radical having from 1 to 6  carbon atoms, straight chain or branched chain 2- A compound according to claim 1, namely 6,17, 21-  trimethyl 3,20-dioxo 19-nor pregna 4,6-diene 30- A compound according to claim 10, namely 17α-ethyl  6,21-dimethyl-3,20-dioxo-19-nor pregna 4,6-diene 40- A compound according to claim 10, namely 17α-ethyl  3.20-dioxo 6-methyl 19-nor pregna 4,6-diene 5 - A compound according to claim 10, namely 6,17 &alpha;  dimethyl 3,20-dioxo 19-nor pregna 4,6-diene 60- A compound according to claim 10, namely 17,  21-ethyl 6-methyl-3,20-dioxo-19-nor-pregna-4,6-diene 7-A process for obtaining compounds of general formula  according to claim 1 which consists of a 3-oxo derivative  19-nor b4 pregnene of formula IV

 in which R ', R "and R1 have the above meanings is subjected to an enol etherification in an acid medium to form the enol ether of general formula V

 in which R ', R "and R1 have the above meanings and wherein R2 is a lower alkyl radical treats the latter by a formylating agent of the type Vilsmeier-Hack to form a 6-formyl derivative of general formula VI

 wherein R ', R ", R1 and R2 have the meanings previously provided. reduced by a mixed hydride of alkali metal to form the hydroxy-methyl derivative of general formula VII

 wherein R ', R ", R1 and R2 have the meanings previously provided. that is treated with an inorganic or organic acid and obtains the 3-oxo-6-methylenic derivative of general formula VIII

  wherein R ', R "and R1 have the above meanings which in turn is treated with an isomerization catalyst to form the corresponding 6-methylated derivative of the general formula I

 wherein R, R "and R1 have the above meanings. The pharmaceutical compositions comprising  active ingredient at least one compound of general formula I according to  one of claims 10 to 60 in combination or in admixture  with an excipient or an inert, non-toxic, pharmaceutically acceptable carrier.  90. A pharmaceutical composition according to claim 90 which  further contains another active ingredient of action  synergisticJ complementary or similar.  The pharmaceutical compositions of claim 80  in which the amount of active ingredient of formula  General I ranges from 0.05 to 25 mg per unit dose. The pharmaceutical compositions according to claims 80 to  100 in which the excipient or the vehicle is one of those  suitable for parenteral administration,  Oral, rectal, per mucous or percutaneous. 12 -As intermediates compounds of the formula  general IV

 in which R ', R "and R1 are defined as above  except where R1 is methyl or ethyl, R 'and Rlt are  hydrogen.  No. of Intermediates Formula Compounds  general V

 in which R2 is a lower alkyl radical  R 'and R ", which are identical or different, represent  hydrogen or an alkyl radical having from 1 to 3 carbon atoms  carbon straight or branched chain and R1 represents a  lower alkyl radical having 1 to 6 carbon atoms in  straight or branched chain.  14 = k as intermediate compounds compounds of formula  general VI

 in which R ', R ", R1 and R2 have the meanings provided  previously 15 g-k as intermediate compounds the compounds of formula  General VII

 in which R ', R ", R1 and R2 have the meanings provided  previously 16-As intermediate compounds the compounds of formula  General VIII

 in which R ', R "and R1 have the earlier meanings