EP0437552A1

EP0437552A1 - Alkyl derivates in 17/21 of 19-nor progesterone

Info

Publication number: EP0437552A1
Application number: EP90907142A
Authority: EP
Inventors: Claude Chemin Des Revoirs Tchernatinsky; Nejib Mohamed Apt. 3.2 - Bât. 4/7 NASRAOUI
Original assignee: Laboratoire Theramex SAM
Current assignee: Laboratoire Theramex SAM
Priority date: 1989-04-13
Filing date: 1990-04-13
Publication date: 1991-07-24
Also published as: FR2645864B1; JPH04500523A; NO174393C; AU5552590A; OA09632A; NO905344D0; TNSN90053A1; AU635739B2; FI906116A0; HU208152B; FR2645864A1; HUT56579A; KR920700219A; NO905344L; RU1836379C; HU904373D0; NO174393B; WO1990012027A1

Abstract

L'invention se rapporte au domaine de la chimie et plus particulièrement à celui de la chimie thérapeutique. Elle a particulièrement pour objet les 6-méthyl 19-nor pregna 4,6-diènes 17alpha, et éventuellement, 21- alcoylés de formule générale (I), dans laquelle R'' et R' identiques ou différents représentent de l'hydrogène ou un radical alcoyle ayant de 1 à 3 atomes de carbone en chaîne droite ou ramifiée et R1 représente un radical alcoyle inférieur ayant de 1 à 6 atomes de carbone, en chaîne droite ou ramifiée. Elle a également pour objet un procédé d'obtention des composés de formule générale (I) et leur emploi comme principes actifs de médicaments.The invention relates to the field of chemistry and more particularly to that of therapeutic chemistry. It particularly relates to 6-methyl 19-nor pregna 4,6-dienes 17alpha, and optionally, 21-alkylated of general formula (I), in which R '' and R 'identical or different represent hydrogen or an alkyl radical having from 1 to 3 carbon atoms in a straight or branched chain and R1 represents a lower alkyl radical having from 1 to 6 carbon atoms, in a straight or branched chain. It also relates to a process for obtaining the compounds of general formula (I) and their use as active principles of medicaments.

Description

17/21 ALCOHOL DERIVATIVES OF 19-NOR PROGESTERONE

The present invention relates to the field of therapeutic chemistry and in particular steroid chemistry.

It relates more particularly to new steroids derived from 19-nor progesterone having at 17 and possibly at 21 an alkyl substituent.

It specifically relates to 6-methyl 19-nor pregna 4,6-dienes 17α and possibly, 21-alkylated of general formula

I

in which R 'and R ", identical or different, represent hydrogen or a lower alkyl radical, having from 1 to 3 carbon atoms, in straight or branched chain

and R ₁ represents a lower alkyl radical, identical or different from R 'or R ", having from 1 to 6 carbon atoms in a straight or branched chain.

In the general formula I the group

is preferably a 1-oxo ethyl chain (R 'H ₃ and R "H) 1-oxo propyl (R'" CH ₃ and R "H), 1-oxo butyl (R '- C ₂ H ₅ and R" = H)

1-oxo 2-methyl propyl (R '= CH ₃ and R "- CH ³ or 1-oxo 2-ethyl butyl

(R '= CH ₂ CH ₃ and R "= CH ₂ CH ₃ ) In the general formula I, R ′ and R ″ are preferably a methyl, ethyl or isopropyl radical. They can also be a propyl radical.

Derivatives of 19-nor progesterone were already known and more particularly those having a characteristic “6-methyl Dienone” sequence on the A and B cycles of the steroid molecule (Patent FR. 2,271,833) such as for example 6-methyl 17α-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, carrying on carbon 17 and / or 21 of alkyl radicals are known as progestogen molecules (cf. French patent 2,077,877), such as for example 3,20- dioxo 17α-methyl 19-nor pregna 4,9-diene.

The object of the present invention is to provide new compounds of general formula I, possessing very advantageous progestomimetic properties, links to improved progesterone receptors and slower hepatic metabolism.

The effectiveness of these new compounds can be attributed to the structure derived from 19-nor progesterone, characterized, in fact, by a steroid system carrying, at the same time, a sequence known as "6-methyl-dienone" and by the presence of three substituents R ′, R ″, R1 as defined above which prevent or delay the metabolism of the product in the organism 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:

- 6.17α, 21-trimethyl 3.20-dioxo 19-nor pregna 4,6-diene

- 17α-ethyl 6,21-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 pregna 4,6-diene

- 17α, 21-ethyl 6-methyl 3,20-dioxo 19-nor pregna 4,6-diene which are the currently preferred compounds. The raw materials of general formula IV,

necessary for the implementation of 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

in which Ac is the acyl residue of an organic carboxylic acid having from 1 to 4 carbon atoms

the wavy line indicates a spatial orientation α or β

and ring A is fully aromatic type 3 alkyloxy

Δ 1,3,5 (10) estratrienique or partially unsaturated type 3-oxo

Δ4 estrenic, possibly blocked in the form of a functional derivative with or without tilting of the double bond to the action of a strong base and then of an alkylating agent to darken a mono- or bis-alkyl derivative of partial formula III

in which R ', R "and R ₁ have the meanings given above.

The strong base can be an alkaline alcoholate derived from a lower alcohol of 1 to 5 linear or branched carbon atoms and from a metal such as lithium, sodium or potassium, such as for example sodium teramylate, terbutylate of potassium, sodium ethanolate, an alkali or alkaline earth amide, lithium, potassium sodium, calcium or barium. Preferably, sodium amide or lithium isopropylamide is used. Dimsyl sodium can also be used.

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

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

The strong base and the alkylating agent are used in excess relative to the stoichiometry. The reaction is followed by acid hydrolysis. The compounds of general formula III, mono or polyalkyls, 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 -60 ° and -40º, due to the preferred use of ammonia as solvent.

To form a mono-alkyl derivative (case 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 used. .

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

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

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

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

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

The reaction can be written as follows for an ethylation reaction:

When an estra-triene derivative III, that is to say a compound for which the ring A is aromatic, is used as starting material, the conversion into compound of formula IV by the following stages:

- subjecting a compound of general formula III

in which R, R ₁ and R ₂ are defined as above

to a reduction according to the Birch-Nielsen method followed by hydrolysis in a strong acid medium then a reoxidation by the Jones reagent to form the 3-keto 19-nor pregna 4-ene of formula IV

The reduction according to Birch-Nielsen 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 donor agent such as for example an alkanol such as methanol or ethanol. The ammonia is then removed and the excess of alkali metal is destroyed by the addition of an alkanol. The resulting enolic ether is then hydrolyzed by the action of a strong mineral acid.

The invention also relates to a process which leads to the compounds of general formula I 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:

in which R ', R "and R ₁ are defined as above.

The compounds of general formula IV are etherified to enol ether with an alkyl orthoformate to obtain a compound of formula V

in which R ₂ is a lower alkyl radical

and R ', R "and R ₁ are defined as above

that we submit to the action of a formylating agent of the type

Vilsmeier-Hack to obtain a formylated derivative of general formula

VI

in which R ', R ", R ₂ and R ₁ have the meanings previously supplied

reduces this with a mixed alkali metal hydride to form a methylated hydroxy derivative of general formula VII

in which R ', R ", R ₂ and R ₁ have the previous meanings which are treated with a mineral or organic acid and obtain the 3-oxo 6-methylenic derivative of general formula VllI

in which R ', R "and R ₁ are defined as above, 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 general formula I.

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

The invention also includes pharmaceutical compositions further comprising another active principle of similar action or synergistic or complementary.

The pharmaceutical compositions according to the invention are intended for administration by parenteral, oral, rectal, per mucosa or per cutaneous route.

For parenteral administration, the compounds of general formula I are administered in the form of solutions or injectable suspensions packaged in ampoules, multidose vials or self-injecting syringes.

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

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

For administration via the mucosa, the compounds of general formula I are presented in the form of oily solutions, creams, jellies or capsules. The compounds of general formula I can be administered either through the vaginal mucosa, through the nasal mucosa in the form of a spray or gel, or through the ocular mucosa.

For administration by the cutaneous route, the compounds of general formula I are presented in the form of a solution or of creams in a penetrating solvent such as benzyl alcohol, dimethylsulfojgrde, 1-n dodecyl azacycloheptanone-2 (AZONE ^(R) ) or N-βhydroxyethyl 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 estrogen as a 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 for continuous or periodic administration.

The invention also extends to new intermediate products formed during the synthesis, namely:

- the compounds of general formula IV

in which R ', R "and R ₁ are defined as above, excluding the case where R' is methyl or ethyl, R 'and R" is hydrogen

-the compounds of general formula V

in which R ₂ is a lower alkyl radical

R 'and R ", identical or different, represent hydrogen or a lower alkyl radical, having 1 to 3 carbon atoms, in a straight or branched chain

R ₁ represents a lower alkyl radical, identical or different from R 'or R ", having from 1 to 6 carbon atoms in a straight or branched chain.

and in which R 'and R ", 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 VI

in which R ', R ", R ₁ and R ₂ have the meanings given previously.

- the compounds of general formula VII

in which R ', R ", R ₁ and R ₂ have the meanings given previously.

- the compounds of general formula VIII

in which R ', R "and R ₁ have the previous meanings

The following examples illustrate the invention without, however, limiting it.

EXAMPLE I

6.17α-dimethyl 3.20-dioxo 19-nor pregna 4,6-diene

Stage A: 17α-acetoxy 3-ethoxy 20-oxo 19-nor pregna 3,5-diene

Under an inert atmosphere and at room temperature, a solution of 126 g of 3.20-dioxo 17α-acetoxy 19-nor pregna 4-ene in 1.010 ml of ethanol, 115 g of ethyl orthoformate is added to the solution, then after stirring. for 10 min, addition of 0.63 g of p.toluene sulfonic acid.

Stirring is continued for 60 min and the reaction is stopped by adding 17 ml of triethylamine. We dilute the medium with

380 ml of ethanol and the mixture is heated to reflux until dissolved.

We crystallize by letting the solution return to temperature ordinary then cooling with an acetone / ice bath. 113 g of 3-ethoxy 17α-acetoxy 20-oxo 19-nor pregna 3,5-diene are thus collected, ie a yield of 83% compared to the theory.

Enol ether has the following characteristics:

IR spectrum:

1740 cm ^-1 CO of acetoxy

1710 cm ^-1 CO year 20,

1650, 1620 cm ^-1 delta-3,5

UV spectrum: λ max 243 nm, ε = 20840

NMR: (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 C6

(S, 1H) at 5.40 ppm H carried by C4

Stage B: 17α-methyl 3,20-dioxo 19-nor pregna 4-ene and 17α, 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. is prepared in advance and under an inert atmosphere, a solution of 30 g of enol ether of Stage A is added in a thin stream. in 495 ml of tetrahydrofuran. After 15 minutes of stirring, 363 ml of methyl iodide are added dropwise. a white-gray precipitate is formed. The end of the addition is followed by 60 min of stirring and then evaporation of the maximum possible ammonia under vacuum and under hot water bath. 1,000 ml of methanol and 6N hydrochloric acid are then added until the pH is acidic, while maintaining the temperature of the medium at 0 ° C. by immersion in an acetone / ice bath.

The mixture is still stirred for 60 min. The reaction products are precipitated by adding 2,000 ml of water and extracted with toluene. After evaporation of the solvent, 22.9 g of a crude oil is collected containing 68% of 17α-methylated derivative and 24% of 17α, 21-dimethyl derivative, determined by HPLC

By chromatography on silica with elution with Cyclohexane at 10% ether, 1.1 g of 17α, 21-dimethyl derivative are isolated in the top fractions then 6 g of 17os-methyl derivative in the bottom fractions. These two products are recrystallized separately from methanol. They present the following physical constants:

→ 3.20-dioxo 17α-methyl 19-nor pregna-4ene

IR: 1705 cm ^-1 CO in 20

1680 cm ^-1 CO in 3

1620 for conjugated c = c

UV: λ max 240 nm, ε = 17385

NMR: (S, 3H) at 1.2 ppm CH ₃ -17α

(S, 3H) at 2.2 ppm CH ₃ -21.

3,20-dioxo 17α, 21-dimethyl 19-nor pregna 4-ene

IR: 1697 cm ^-1 CO in 20

1670 cm ^-1 CO in 3

UV: λ max 240 nm, ε = 16515

NMR: (S, 3H) at 1.2 ppm CH ₃ -17α

(T, 3H) at 1.07 ppm CH ₃ -22

Multiplet at 2.55 ppm CH ₂ -21

Stage C: 3-ethoxy 17α-methyl 20-oxo 19-nor pregna 3,5-diene

This compound is prepared according to the same procedure as in Stage A, starting from 3,20-dioxo 17α-methyl 19-nor pregna 4-ene, 12 ml of ethanol 1.85 ml of ethyl orthoformate, 0.102 g of p.toluene sulfonic acid and then 0.2 ml of triethylamine. Obtained with 78% yield, the crystalline enolic ether having the following physical constants:

IR spectrum: 1695 cm CO in 20

1640, 1620 cm ^-1 delta-3,5

UV spectrum: λ max 243 nm, ε = 16520

NMR spectrum: (S, 3H) at 1.15 ppm CH ₃ -17α

(T, 3H) at 1.30 ppm CH ₃ of ethoxy

(S, 3H) at 2.15 ppm CH ₃ -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 in C4

Stage D: 3-ethoxy 6-formyl 17α-methyl 20-oxo 19-nor pregna

3,5-diene

A formylation reagent is prepared by dissolving dropwise under nitrogen and at 2 °, 3.15 ml of POCl ₃ freshly distilled in 28 ml of dimethylformamide followed by a stirring period of 5 min. 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 minutes.

Stirring is continued for 10 min 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 + 30 ° C. The solution, initially colored red, turns yellow with the start of crystallization. After 30 minutes of stirring, 105 ml of ice water are added. 7.2 g or 95% of the theory of 3-ethoxy 6-forroyl 17α-methyl 20-oxo 19-nor pregna 3,5-crude diene are thus isolated. It is recrystallized from ethanol to obtain 3.1 g of pure product, the constants of which are:

IR: 1700, CO in 20

1650 and 1615, delta-3,5 UV: λ 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 17α-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 continued for 2 hours. The temperature of the reaction solution is brought back to 0 ° and a solution of 0.4 ml of 2N sulfuric acid in 2 ml of water is added over 2 min. The temperature rises to 10 ° and a slight yellow precipitate appears in the form of an eraser. Stirring is continued for 20 min.

A solution of 0.88 g of potassium carbonate in 2 ml of water is then added dropwise. The precipitate increases. It is separated by filtration and washed thoroughly with water until the washings are neutral. 1.40 g of 3.20-dioxo 6-methylene 17α-methyl 19-nor pregna 4-ene are thus collected, ie a yield of 87%.

IR spectrum: 1700 cm ^-1 CO in 20

1660 cm ^-1 CO in 3

1620, 1595 cm ^-1 , c = c

UV spectrum: λ max 263 nm, ε = 12280

NMR spectrum: appearance of two singlets not very well resolved at 5 ppm and 5.25 ppm.

Stage F: 3.20-dioxo 6.17α-dimethyl 19-nor pregna 4,6-diene

(compound of formula I)

A suspension of 0.65 g of 5% palladium on charcoal is prepared in 33.5 ml of methanol which is brought to reflux for 30 min. 1.34 g of 6-methylene derivative of Stage E is added. Heating is maintained at reflux. The reaction is monitored by determining the UV absorption. After 30 minutes of stirring, the mixture is allowed to return to room temperature. We filter it on Clarcel. The filtrate is concentrated, chromatographed on 30 times its weight of silica and eluted with Toluene. The fractions containing the 6-methyl derivative are recrystallized from methanol and thus 0.83 g of 3.20-dioxo 6.17α-dimethyl 19-nor pregna 4,6-diene is obtained, ie 62% of theory.

The analytical constants are as follows:

IR spectrum: 1695 cm ^-1 CO in 20

1650 cm ^-1 CO in 3

1622, 1576 cm ^-1 delta-4.6

UV spectrum: λ max 289 nm, ε = 23900

Mass: 326 molar mass

283 loss of CH ₃ CO

43 OH ₃ CO

[α] _D : (dioxane) + 22 ° 32 pF: 164.6 ° C

Centesimal composition: C22 H30 02

Found Calculated

C% 80.26 80.93

H% 9.20 9.26

NMR spectrum (S, 3H) at 0.76 ppm for CH3-18

(S, 3H) at 1.19 ppm for CH3-17α

(S, 3H) at 1.88 ppm for CH3 in 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

6.17α, 21-trimethyl 3.20-dioxo 19-nor pregna 4,6-diene

Stage A: 3-ethoxy 17α, 21-dimethyl 20-oxo 19-nor pregna 3,5-diene

The procedure is as in Stage A of Example I, starting from 5.85 g of 3.20-dioxo 17α, 21-dimethyl 19-nor pregna 4-ene obtained in Stage B of Example I in 12 ml of ethanol, 5.9 ml of ethyl orthoformate and 0.029 g of p.toluene sulfonic acid. Once the reaction is complete, it is stopped by adding 0.6 ml of triethylamine. The enolic ether obtained does not crystallize, it is exhausted with benzene and the benzene phase is washed with water. 7.07 g of crude enolic ether are thus obtained which, after purification by chromatography on basic alumina and elution with hexane and 1% triethylamine, provides 5.8 g of 3-ethoxy 17α, 21 dimethyl 20-oxo 19 -nor pregna 3,5-diene, ie a yield of 91%.

Stage B: 3-ethoxy 6-formyl 17α, 21-dimethyl 20-oxo 19-nor pregna

3,5-diene

Formulation in 6 of the compound of Stage A is carried out according to the procedure described in Stage D of Example I. Starting from 5.1 g of enolic ether of Stage A in 41 ml of dimethyl formamide.

The formylation reagent consists of 2.15 ml of POCl, in 20 ml of dimethyl formamide. The hydrolysis reagent consists of 13.8 g of potassium acetate in 20 ml of water.

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

Stage C: 6-methylene 17α, 21-dimethyl 3,20-dioxo 19-nor pregna 4-ene

The same procedure is used as that described in Stage E of Example I. We start with 4.3 g of 6-forraylated derivative of Stage B in 43 ml of ethanol. Reduced with a solution of 0.273 g of sodium borohydride in 4 ml of dimethylformamide. The mixture is stirred for 10 min and then the hydroxy methyl derivative is dehydrated with a solution of 5.15 ml of 2N sulfuric acid in 40 ml of water.

1.9 g are thus obtained, ie a yield of 50% of crude 6-methylene derivative λ max = 258 nm

Stage D: 6.17α, 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 charcoal is brought to reflux for 60 min. 1.1 g of 6-methylene derivative of Stage C are then added. The development of the reaction is monitored by UV spectrophotometry. After 50 minutes of stirring at the reflux temperature, there is a displacement of the λ max at 286 nm. Filtration is then carried out on Clarcel, then the filtrate is brought to dryness and the residue is chromatographed with Toluene over 35 times its weight of silica. A fraction is collected which provides 0.83 g of 6,17α, 21-trimethylated derivative which is purified by recrystallization from ethanol at 95 °.

3,20-Dioxo 6,17α, 21-trimethyl 19-nor pregna 4,6-diene melts at 160 ° C.

IR spectrum: 1695 cm CO in 20

1680 cm CO in 3

1628, 1580 cm ^-1 , delta-4.6

UV spectrum: λ max 288.5 nm, ε = 24280

Mass: m / e 340 molar mass

283 (M-57) loss of COCH2CH3

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 CH3-17α

(S, 1H) at 5.95 ppm for H in C7

(S, 1H) at 6.05 ppm for H in C5

[α] _D + 18.9 (c = 0.53% dioxane)

EXAMPLE III

17α-ethyl 6-methyl 3,20-dioxo 19-nor pregna 4,6-diene

Stage A: 3.20-dioxo 17α-ethyl 19-nor pregna 4-ene

1 g of calcium is dissolved in 40 ml of liquid ammonia at -60 ° C and under an inert gas atmosphere. A solution of 1 g of 3-ethoxy 20-oxo 19-nor pregna diene 3.5 is then added, in a thin stream, in 18 ml of carefully dehydrated tetrahydrofuran. Stirring is continued 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 in vacuo in a warm water bath. A whitish paste is collected which is diluted in 100 ml of methanol and then a 3N solution of hydrochloric acid is added to acid pH while cooling with an acetone / ice bath.

After 60 minutes of stirring, the product is extracted with toluene, the toluene phase is separated and washed with water. After evaporation, 0.81 g (a yield of 95.5%) of crude 17α-ethyl derivative containing 41.6% of pure 17α-ethyl determined by HPLC is obtained.

The product is purified by chromatography, on 50 times its weight of silica, using 10% ether cyclohexane as 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 20 1670 cm ^-1 CO in 3

1620 cm ^-1 , delta-4 UV spectrum: λ max 240 nm, ε = 17520

NMR spectrum: (S, 3H) at 0.70 ppm CH3-18

(T, 3H) at 0.75 ppm CH3 of ethyl-17α

(S, 3H) at 2.05 ppm 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 17α-ethyl derivative of Stage A in 29 ml of ethanol, with 9.6 ml of ethyl orthoformate and 0.048 g of p.toluene sulfonic acid then 1 ml of triethylamine.

7.1 g are obtained, ie a yield of 68% of pure enolic ether.

IR spectrum: band at 1700 cm ^-1 (carbonyl in 20)

bands at 1650 and 1620 (double bonds at 3 and 5)

UV spectrum: λ max 243 nm, ε = 18520

NMR spectrum: (Q, 2H) at 3.7 ppm (CH ₂ of ethoxy)

(S, 3H) at 2.3 ppm (CH ₃ in 21)

(S, 1H) at 5.2 ppm (H in C ₆ )

(S, 1H) at 5.8 ppm (H in C ₄ )

Stage C: 3-ethoxy 6-formyl 17α-ethyl 20-oxo 19-nor pregna

3,5-diene

The formulation is carried out as in Stage D of Example 1:

. Formylation reagent: 0.5 ml POCl ₃ in 4.5 ml of dimethyl formamide

. Hydrolysis solution: 2 g of potassium acetate in 40 ml of water Starting from 1 g of 3-ethoxy 17os-ethyl 20-oxo 19-nor pregna 3,5-diene, 1.18 g of crude 6-formylated derivative are obtained, which by chromatography with dichloromethane on magnesium silicate provides 0, 7 g or a 65% yield of 3-ethσxy 6-formyl 17α-ethyl 20-oxo 19-nor pregna 3,5-pure diene λ max = 323 nm and 220 nm

Stage D: 3.20-dioxo 6-methylene 17α-ethyl 19-nor pregna 4-ene

The 6-methylene derivative is prepared from the 6-formylated derivative in Stage C, according to the same procedure as in Example I, Stage E starting from 0.5 g of 3-ethoxy 6-formyl 17α-ethyl 20-oxo 19-nor pregna 3,5-diene in 65 ml of ethanol and 0.419 g of sodium borohydride then hydrolysis and dehydration with 8 ml of 2N sulfuric acid and 55 ml of water. 4.4 g of crude 6-methylen derivative are thus isolated, ie a yield of 76%. This product contains small amounts of the intermediate 6-hydroxy methyl derivative.

IR spectrum: 3400 cm ^-1 weak, corresponds to H-0

3080 cm ^-1 very weak, corresponds to H2C of

methylene-6

1695 cm ^-1 CO in 20

1660 cm ^-1 CO in 3

UV spectrum: λ max 258 nm

NMR spectrum: (S, 3H) at 0.7 ppm CT3-18

(T, 3H) at 0.75 ppm CH3 of ethyl-17α (S, 3H) at 2.1 ppm CH3-21

Appearance of ethylenic 3H to:

4.95 ppm,

5.17 ppm

6.10 ppm

(Q) very low at 3.74 ppm corresponding to the CH2 of the ethoxy of the hydroxymethyl product, proof, taking into account the low IR band at 3400 cm ^-1 , of the presence of a certain amount of steroid hydroxymethyl.

Stage E: 3.20-dioxo 6-methyl 17α-ethyl 19-nor pregna 4,6-diene

(compound of formula I)

A suspension formed of 5.5 g of palladium charcoal in 820 ml of ethanol is brought to reflux for 60 min. Then 4.1 g of 3.20-dioxo 6-methylene 17α-ethyl 19-nor pregna 4-ene is added and the progress of the isomerization is monitored by UV spectrophotometry. After 8 min, 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 crystallized from its methanolic solution

The pure product melts at 162 ° C [α] _D ± 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, ε = 25880.

Mass: m / e 340 mass

297 (M-43) loss of COMe

268 (M-72) loss of COMe and ethyl pF: 162 ° C

Centesimal composition: C23 H32 02

% found% calculated

C 81.34 81.13

M 9.41 9.47

O 9924 9.40 NMR spectrum: (S, 3H) at 0.70 ppm CH3-18

(T, 3H) at 0.75 ppm CH3 of ethyl-17α

(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 19-nor pregna 4,6-diene

Stage A: 3-methoxy 17α-acetyl 17β-acetoxy estra 1,3,5 (10) Triene

1250 ml of cation exchange resin of the sulfonic polystyrene type are added to 4 liters of water. The suspension is stirred for 12 hours, filtered and the resin is 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 min. The resin is filtered and thoroughly washed with water. 100 ml of the mercuric resin are removed and suspended in a solution of 100 g Mestranol acetate, 50 ml of dioxane and 1500 ml of ethanol. After 20 minutes of stirring, 20 ml of water are added and the mixture is brought to reflux 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 are thus obtained, ie a yield of 79% of 3-methoxy 17α-acetyl 17β-acetoxy estra 1,3,5 (10) pure triene.

IR spectrum:

- disappearance of the bands at 3265 cm ^-1 and 2100 cm ^-1

(C = C - H)

- band appearance at 1709 cm ^-1

(CO in 17α)

NMR spectrum:

- disappearance of (S, 1H) at 2.65 ppm corresponding to H of C = C - H in 17α

- appearance of (S, 3H) at 2.05 ppm

corresponding to Ch ₃ of COCH ₃ in 17α

Stage B: 3-methoxy 17α-ethyl 20-oxo 19-nor pregna 1,3,5 (10) triene

A solution of 3.75 g of lithium is prepared in 800 ml of liquid ammonia under argon and at -60 ° C. Then adding a solution of 50 g of 3-methoxy 17α-acetyl 17β-acetoxy estra 1,3,5 (10) Triene in 750 ml of Tetrahydrofuran. After 3 hours of stirring, 270 ml of ethyl iodide are added over 20 minutes and the mixture is stirred for 2 hours.

The ammonia is then evaporated using a hot water bath under vacuum. The reaction medium is neutralized by addition of dilute hydrochloric acid and then the aqueous phase is exhausted 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 at 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 17α-ethyl 20-oxo 19-nor pregna 1,3,5 (10) pure triene are obtained, ie a yield of 74%.

IR spectrum:

- disappearance of the band at 1738 cm ^-1

at 1268 cm ^-1

and at 1240 cm ^-1 (acetoxy)

NMR spectrum: (S, 3H) at 0.70 ppm CH3-18

(T, 3H) at 0.80 ppm CH3 of ethyl-17α

(S, 3H) at 2.10 ppm CH3-21

(S, 3H) at 3.70 ppm CH3 of methoxy Stage C: 3-methoxy 17α-ethyl 20-oxo 21-methyl 19-nor pregna 1,3,5 (10) Triene

Under a nitrogen atmosphere and at 0 ° C., a solution of 1 ml of diisopropylamine and 6.5 ml of anhydrous tetrahydrofuran is prepared, then 4 ml of a 5% methyllithium solution in 1 l are added dropwise. 'ether. After 5 minutes of stirring, 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 ambient temperature and stirring is continued for 80 min. Then allowed to cool to 0 ° C. 2 ml of methyl iodide are then added with vigorous stirring all at once and the 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 21-methyl derivative is obtained, ie a yield of 96% which is purified by recrystallization from 20 ml of methanol, 0.8 g is thus collected, ie a yield of 77% of 3-methoxy 17α-ethyl 20-oxo 21-methyl 19-nor pregna 1,3,5 (10) Triene.

Analysis C ₂₄ H ₃₄ O ₂

C H 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 17

(T, 3H) at 0.75 ppm CH ₃ of ethyl in 17α

(T, 3H) at 1.10 ppm OR in 22

(Dq, 2H) at 2.42 ppm CH ₂ in 21

(S, 3H) at 3.78 ppm CH, methoxy

Stage D: 3.20-dioxo 17α-ethyl 21-methyl 19-nor pregna 4-ene

At -50 ° C. and under an argon atmosphere, a solution of 172 g of 3-methoxy 17α-ethyl 20-oxo 21-methyl 19-nor pregna 1,3,5 (10) Triene in 1750 ml of anhydrous tetrahydrofuran to 3000 ml of ammonia. Then added, at 30 min intervals with stirring, 3 times 90 ml of ethanol and 17.2 g of lithium. After 60 minutes of stirring, the ammonia is removed by a bath of hot water under vacuum.

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

After 20 minutes of stirring, 400 ml of methanol and 4,000 ml of water are added. The steroid is extracted with methylene chloride and purified by chromatography on a silica column. 84 g of 3.20-dioxo 17α-ethyl 21-methyl 19-nor pregna 4-ene are isolated, ie a yield of 54%. The crystallization of isopropyl ether provides the pure product.

IR spectrum: 1705 cm ^-1 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 the peak (S, 3H) at 3.7 ppm (methoxy CH3) and the peaks at 7.2 ppm (aromatic nucleus).

Stage E: 3-ethoxy 17α-ethyl 21-methyl 20-oxo 19-nor pregna

3,5-diene

We proceed to the enol etherification of 5 g of 3,21-dioxo 17α-ethyl 21-methyl 19-nor pregna 4-ene in 10 ml of ethanol with 5 ml of ethyl orthoformate and extraction with benzene containing 1% triethylamine.

Chromatography on basic alumina with benzene as solvent gives 4.8 g of enolic ether, ie 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: ro / e 370 molar mass

342 loss C2H4

285 loss C2H4 and COC2H5.

NMR spectrum: (T, 3H) at 1.3 ppm CH3 of ethoxy

(solid, 2H) at 3.7 ppm CH2 of ethoxy (S, 1H) at 5.7 ppm H in C6

(S, 1H) at 5.8 ppm H in C4.

Stage F: 3-ethoxy 6-formyl 17α-ethyl 21-methyl 20-oxo 19-nor pregna 3,5-diene

12.5 g of 3-ethoxy 17α-ethyl 21-methyl 20-oxo pregna 3,5-diene in 87.5 ml of dimethyl formamide are formylated with a formylating reagent formed of 6.25 ml of POCl, 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 reaction product, colored yellow, crystallizes. It is filtered off, dried and 12.75 g of crude product is obtained, ie 95% of theory.

IR spectrum: band at 1699 cm ^-1 (CO in 20)

band at 1651 cm ^-1 and at 1610 cm ^-1 (C = C conjugate) Weight: m / e 398

341 (loss of COC ₂ H ₅ )

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 17α-ethyl 21-methyl 19-nor pregna

4-ene

In an ice bath, 40 mg of sodium borohydride are added to a solution of 0.5 g of 3-ethoxy 6-formyl 17α-ethyl 20-oxo 21-methyl 19-nor pregna 3,5-diene dissolved in 3, 8 ml of methanol and 2.2 ml of dimethyl formamide. Then allowed to return to room temperature and after 40 min with stirring, the UV spectrum indicates the tilting of the Max at 250 nm.

1 ml of a 2N solution of sulfuric acid and 0.8 ml of dimethyl formamide are then added at 0 ° C. After 30 minutes of stirring, neutralization is carried out by adding 2.5 ml of an aqueous solution of sodium carbonate. The crystallized 6-methylenic derivative of the medium is filtered and washed abundantly with water. It has an λmax at 262 nm.

Stage H: 3.20-dioxo 6,21-dimethyl 17α-ethyl 19-nor pregna 4,6-diene

(compound of formula I)

5 g of crude 6-methylene derivative in 245 ml of ethanol are subjected to isomerization with 5 g of palladium carbon at reflux.

After 25 min of stirring, the UV spectrum indicates the presence of the Max at 288 nm. It is then filtered on Clarcel and the filtrate is concentrated to dryness. The residue is chromatographed on 60 times its weight of silica with dichloromethane as solvent. The recrystallized product of Methanol provides pure 3.20-dioxo 6,21-dimethyl 17α-ethyl 19-nor pregna 4,6-diene, the analytical constituents of which are: F: 180 º

α _D : + 4º4 (c = 1.26% dioxane)

Centesimal analysis C ₂₄ H ₃₄ O ₂

C H 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 ^-1 , CO in 3

1630, 1580 delta-4.6

NMR spectrum: (S, 3H) at 0.70 ppm CH3-18

(T, 3H) at 0.75 ppm CH3 of ethyl-17α

(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 in C4

HEERHACOLOGICAL STUDY OF THE COMPOUNDS ACCORDING TO THE INVENTION

Measure of relative affinity:

Efforts have been made to determine, for the progesterone receptor, the competitive power of each steroid compared to the reference substance (cold progesterone).

Progesterone labeled with Carbon C ¹⁴ is incubated with the uterine cytosol, alone or in the presence of increasing concentrations of cold steroid (including unlabeled progesterone), in an R ratio varying 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.

Compound D is 17α-acetoxy 6.21 dimethyl 3-oxo 19-nor pregna

4,6- diene

Compound A is 3,20-dioxo 6,17α-dimethyl 19-nor pregna

4,6-diene

Compound B is 3,20-dioxo 6-methyl 17α-ethyl 19-nor pregna

4,6-diene

Compound C is 3,20-dioxo 6,17α-20-trimethyl 19-nor pregna

4,6-diene

The data in this table makes it possible to deduce the relative affinities.

Relative affinity (RA) is the ratio between the 50% inhibition concentrations (C150) of a given steroid and the specific cold hormone taken for reference (here progesterone):

AR =

This relative affinity is thus expressed as a percentage, considering that for the reference hormone (or steroid), the AR is equal to 100%.

The C150s constitute an estimate of the Kl (inhibition constant) of the steroids tested for the binding of the reference steroid.

The AR measurement thus gives the following sequence:

Compound B> nomégestrol acetate> Compound A> Progesterone> Compound C> Nomégestrol

Discussion:

The six products studied belong to a series of derivatives of nomegestrol acetate.

Two types of variation are to be considered:

- 17α alkyl

- extension of the chain at 21 with methyl.

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

However, the differences in affinity observed at this stage of study, seem to indicate a hierarchy between these three products. On the other hand, nomégestrol has the same side chain in 17β as the three products tested (compound A, compound B and Nomégestrol acetate) but having a hydrσxyl in 17α- shows a reduced affinity, from 40 to 60 times weaker than the three products cited above.

Taking AR - 1 for Nomégestrol Acetate as a reference, the following table can be established, passing from nomégestrol acetate to 0.17 for compound B and from 0.81 for compound A to 0.45 for compound C.

For the same substituent in 17α, the lengthening of the chain in 21 leads to a decrease in affinity for the progestogen receptor.

However, it should be noted that a decrease in affinity for the receptor in vitro 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 better bioavailability (more difficult degradation, increased enterohepatic cycle, reduced sequestration by plasma proteins ...), the resulting effect can therefore result in an increase in pseudogestagenic activity.

CONCLUSION:

Based on the fact that the lowest relative affinity of the series of alkylated derivatives according to the invention is of the order of 60% and that the replacement of the hydroxy group in 17β by a lower alkyl chain, it is found that the mono- or bis-alkylation of 6-methyl 19-nor pregnadiene has led to highly active progestins.

Claims

R E V E N D I C A T I O N S

The subject of the invention is:

1º- As new compounds, 6-methyl 19-nor pregna 4.6-dienes 17α-alkylated of 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 in a straight or branched chain

and R ₁ represents a lower alkyl radical having from 1 to 6 carbon atoms, in straight or branched chain

2º- A compound according to claim 1 °, namely 6,17α, 21- trimethyl 3,20-dioxo 19-nor pregna 4,6-diene

3 ° - A compound according to claim 1 °, namely 17ct-ethyl 6,21-dimethyl 3,20-dioxo 19-nor pregna 4,6-diene

4. A compound according to claim Ie, namely 17α-ethyl 3,20-dioxo 6-methyl 19-nor pregna 4,6-diene

5º- a compound according to claim 1 °, namely 6,17α-dimethyl 3,20-dioxo 19-nor pregna 4,6-diene

6º- A compound according to claim 1 °, namely 17α, 21-ethyl 6-methyl 3,20-dioxo 19-nor pregna 4,6-diene 7º- A process for obtaining the compounds of general formula I according to claim I which consists in that a 3-oxo 19-nor Δ4 pregnene derivative of formula IV

in which R ', R "and R ₁ have the previous meanings is subjected to an enol-etherification in an acid medium to form the enolic ether of general formula V

in which R ', R "and R ₁ have the previous meanings and in which R ₂ is a lower alkyl radical

treats the latter with a formulating agent of the Vilsmeier-Hack type to form a 6-formylated derivative of general formula VI

in which R ', R ", R ₁ and R ₂ have the meanings given previously.

reduces this with a mixed alkali metal hydride to form the hydroxy-methyl derivative of general formula VII

in which R ', R ", R ₁ and R ₂ have the meanings given previously.

which is treated with a mineral or organic acid and obtains the 3-oxo 6-methylenic derivative of general formula VIII

in which R ', R "and R ₁ have the previous meanings which in turn is treated with an isomerization catalyst to form the corresponding 6-methylated derivative of general formula I

in which R, R "and R ₁ have the previous meanings 8 ° - The pharmaceutical compositions containing as active principle at least one compound of general formula I according to one of claims 1 ° to 6 ° in association or in mixture with an inert, non-toxic, pharmaceutically acceptable excipient or vehicle.

9. A pharmaceutical composition according to claim 9, which also contains another active principle of complementary or similar synergistic action.

10. The pharmaceutical compositions according to claim 8e in which the amount of active principle of general formula I ranges from 0.05 to 25 mg per unit dose.

11 ° -The pharmaceutical compositions according to claims 8 ° to 10e in which the excipient or the vehicle are one of those which are suitable for administration by parenteral, oral, rectal, per mucous or per cutaneous route.

12 ° -As intermediate compounds the compounds of general formula IV

in which R ', R "and R ₁ are defined as above, excluding the case where R1 is methyl or ethyl, R' and R" are hydrogen. 13º-As intermediate compounds the compounds of general formula V

in which B ₂ is a lower alkyl radical

R 'and R ", identical or different, represent hydrogen or an alkyl radical having from 1 to 3 carbon atoms in straight or branched chain and R ₁ represents a lower alkyl radical having from 1 to 6 carbon atoms in chain straight or branched 14 ° -As intermediate compounds the compounds of general formula VI

in which R ', R ", R ₁ and R ₂ have the meanings previously supplied 15 ° -As intermediate compounds the compounds of general formula VII

in which R ', R ", R ₁ and R ₂ have the meanings previously supplied 16º-As intermediate compounds the compounds of general formula VIII

in which R ', R "and R ₁ have the previous meanings