FI91158B - Process for Preparation of Therapeutically Active 6,21-Dimethyl-19-Norprogestone Derivatives - Google Patents

Description

91158

Process for the preparation of pharmacologically active 6,21-dimethyl-19-norprogesterone derivatives

This invention relates to a process for the preparation of pharmacologically active 19-progesterone derivatives having a methyl substituent on carbon 6 of the steroid core, a free, etherified or esterified hydroxyl radical on carbon 17or and a chain attached to the 17S carbon is propan-3-one chain 10 and having the general formula I

-CO-CH2-CH3 CH2 wherein R is a hydrogen atom, lower alkyl, methoxymethyl, tetrahydropyranyl or an acyl residue of an aliphatic or aromatic organic carbon or carboxylic acid having 1 to 10 carbon atoms.

Particularly preferred compounds of the formula I are: 17α-hydroxy-6,21-dimethyl-3,20-dioxo-19-norpregna-4,6-diene, 30-17α-acetoxy-6,21-dimethyl-3,20 -dioxo-19-norpregna-4,6-diene, - 17α-butyryloxy-6,21-dimethyl-3,20-dioxo-19-norpregna-4,6-diene, - 17α-tetrahydropyranyloxy-6,21-dimethyl-3 , 20-dioxo-19-35 norpregna-4,6-diene, - 17α-caproyloxy-6,21-dimethyl-3,20-dioxo-19-norpregna-4,6-diene, - 17α-heptanoyloxy-6,21 -dimethyl-3,2-dioxo-19-norpreg-na-4,6-diene.

40 2

Derivatives of 19-norprogesterone with a 6-methyl substituent have been known for a long time, such as nome-gestrol, which is a good progesterone derivative of pure progesterones.

5

Derivatives of 19-norprogesterone having 3 carbon atoms in the carbon 17 chain are also known, and in particular the 3,20-dioxo-17α, 2,1-dimethyl-19-norpregna-4,9-diene described in French Patent 2,077,887. type-10 that compound has only minor properties of progesterone compared to its lower homologues.

It has now been found that the compounds of general formula I have very interesting progesterone properties, especially when administered via the gastrointestinal tract, and that their strong binding to progesterone receptors provides potent progestative activity.

The efficacy of these new compounds is due to the steroid structure substituted with two strong substituents, methyl on carbon 6 and 21, without altering the ability to bind to receptors, they inhibit or slow the metabolism of the compound by reducing or hydrogenating enzymes.

25

In the general formula I, the group R may be lower alkyl, such as methyl, ethyl or isopropyl. It may also be an acyl residue derived from an alkyl or arylcarboxylic acid, such as acetyl, propionyl, butyryl, pentanoyl, hexanoyl, benzoyl or naphthoyl. It may also be derived from an unsaturated acid such as crotonic, senescent or 2-methylpentenoic acid. It may also be derived from an alkyl or cycloalkyl carbonic acid, such as cyclohexyl or cyclopentyl carbonic acid.

The compounds of formula I according to the invention can be prepared by reacting 17-keto-18-methylgonadiene, which is 3-alkoxyestra-1,3,5-triene of formula Ha 35 351158 3

O

(IIa) 10 wherein R 1 is a lower alkyl radical having 1 to 6 carbon atoms, or a 3-alkoxyestra-3,5-diene of formula Hb 0 (lib) 20 R 0 wherein R 1 has the same meaning as above, is reacted with a triarylpropylphosphonium halide of the general formula Π -η Θ

Ar \ Θ 30 Ar-P - CH2 - 0¾ - CHj Hai /

With Ar 35 or an equivalent ylide of the general formula Ar 40 \ 0 Θ

Ar-P - CH - CHj - CH3 /

Ar 45 wherein Ar is a substituted or unsubstituted phenyl radical and Hal is a halogen atom other than fluorine; to give a propylidene derivative of the estra-1,3,5-triene derivative of the general formula IIIa 4 - CH - CH2 - CH3 (IIIa) 10 as the isomer E or Z, wherein R1 has the same meaning as above, or estra-3,5 -dadiene derivative propylidene derivative of the general formula IIIb> * CH-CH2-CH3 15 i - \

Ή I I

(IIIb)

RJO

as isomer E or Z, wherein R 1 has the same meaning as above, the compound of formula IIIa is hydrogenated by the Birch method to form 3-oxoestra-4-ene, which is converted to the compound of formula IIIb using an alkylating agent in an acidic environment; the compound of formula IIIb is reacted with a Vilsmeier-Hack type formylating agent to give the corresponding 6-formyl derivative of general formula IV - 0¼ - CH3

35 H I

/ NI / VAs / (iv) 40 R, 0 |

CHO

as isomer E or Z, wherein R 1 has the same meaning as above; The 6-formyl derivative is reduced with a mixed alkali metal hydride and the resulting 6-hydroxymethyl derivative I! 91158 5 is treated in an acidic environment to give 3-oxo-

A 6-methylene derivative of formula V.

^ CH-CH, -CH3 5 _f

B

CH 2 as isomer E or Z;

The compound of formula V is isomerized with an isomerization catalyst to give a 3-oxo-6-methylester-4,6-diene compound of formula VI

.CH-CH2-CH3 20 f

B

(vi) 25 ch3 as isomer E or Z; The compound of formula VI is bishydroxylated using a bishydroxylation reagent prepared from osmium tetroxide and hydroperoxide under an inert environment to give the corresponding 17α-hydroxy-20-ketone derivative of formula 35

/ CO-CH 2 -CH 2 s' -f - OH

"jCy CH3 45 6 which can be alkylated with an alkyl halide in a basic environment or tetrahydropyranylated using dihydropyran in an acidic environment or acylated with a carboxylic or carbonic acid functional derivative in the presence of an acidic reagent.

Reaction of a compound of formula Ha or Hb with a triarylpropylphosphonium halide or ylide thereof results primarily in isomer Z on carbon 17. However, isomer E, which is formed in a smaller amount, can be isolated by physical methods and can be synthesized without significant difference between isomer Z or E.

The method according to the invention can also be determined by the following preferred embodiments.

The reaction of a 17-oxogonane of formula IIa or Hb with a triarylpropylphosphonium halide takes place in a basic environment in a polar solvent.

2. The basic substance is sodium hydride, lithium isopropylamide, potassium terbutylate or sodium amide.

3. The polar solvent is dimethyl sulfoxide or hexamethylphosphoric triamide.

4. The purple reduction of a compound by the Birch method takes place in liquid ammonia, followed by treatment with a strong acid such as hydrochloric acid.

5. The alkylation of the 3-oxoestra-4-ene compound takes place with an alkanol or alkyl orthoformate in an acidic environment.

6. The Vilsmeier-Hack reagent is obtained by the reaction of phosphorus oxychloride with a tertiary amine such as dimethylaniline or a disubstituted amide such as dimethylformamide.

Il 91158 7 7. The reduction of the 6-forithyl derivative takes place with an early metal by means of aluminum or borohydride in an unreacted solvent such as cyclic ether or alkanol.

8. Dehydration of the 6-hydroxymethyl derivative to give the 6-methylene derivative is accomplished by treatment with a strong acid such as hydrochloric, perchloric or sulfuric acid.

9. An isomerization reagent is a metal of the platinum or palladium type attached to an inert support, such as palladium on carbon, platinum on carbon, or palladium on calcium carbonate.

10. The bishydroxylation reaction is performed with osmium tetroxide and N-oxide hydroperoxide with a tertiary or secondary amine such as trimethylamine, triethylamine or morpholine.

11. The acylation of the 17α-hydroxyl derivative takes place with an acid chloride or acid anhydride in the presence of a strong mineral acid such as hydrochloric or sulfuric acid or a Lewis acid such as boron trifluoride.

12. Alkylation of the 17α-hydroxyl derivative takes place with methoxymethanol or dihydropyran in the presence of paratoluenesulfonic acid in an inert solvent.

Pharmaceutical compositions may be formulated in which the active ingredient is at least one compound of general formula I in admixture with or in combination with an inert, non-toxic pharmaceutically acceptable medium or carrier.

These pharmaceutical compositions are intended for parenteral, oral, rectal, mucosal, dermal or nasal administration.

8

For parenteral use, the compounds of general formula I are in the form of injectable solutions or suspensions in ampoules, multidose vials or auto-injectable syringes.

5

For oral administration, the compounds of general formula I are in the form of bare or packaged tablets, granules, various capsules, pills or powders.

10 through rectal administration the compounds of the invention are in the form of suppositories or capsules of the general formula I.

For transmucosal administration, the compounds of general formula I are in the form of oily solutions, creams, gels or capsules. The compounds of general formula I can be administered as a spray or gel to the vaginal or nasal mucosa.

For transdermal administration, the compounds of general formula I are in the form of a solution or cream in an absorbable solvent such as benzyl alcohol or dimethyl sulfoxide.

These pharmaceutical compositions are used in gynecological problems due to insufficient lutein, such as irregular or painful menstruation, premenstrual syndrome and menopausal problems.

The usual dosage is between 0.05 and 25 mg and the daily dose is between 0.1 and 50 mg given continuously or periodically.

Pharmacological experiments Measurement of relative affinity 35 For the progesterone receptor, determine the competitiveness of each steroid compared to a reference substance (cold progesterone).

li 91158 9

Labeled progesterone is incubated with uterine cytosol, alone or in combination with increasing concentrations of a cold steroid (including unlabeled progesterone) in an R ratio ranging from 1 to 1000 between the two agents.

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

10 steroi- Mit- R = 0 R = 1 R = 10 R = 100 Number of R-1000 ditations n

Proges- 10 100% 74 34 8 0 15 terons A 5 80 60 48 26 B 5 - 60 39 31 19 C 5 - 77 44 38 27 D 5 - 106 58 44 23 20 AMP * 4 62 35 20 11 TX66 * 4 73 25 5 0 TX71 * 4 - 96 17 8 0 * AMP = medroxyprogesterone acetate 25 * TX66 = 17or-acetoxy-3,20-dioxo-6-methyl-19-norpregna-4.6-diene * TX71 = 17a-hydroxy-3.20 -dioxo-6-methyl-19-norpregna-4.6-diene

Compound A = 3,20-dioxo-6-methyl-17or-hydroxy-21-methyl-30 19-norpregna-4,6-diene

Compound B = 3,20-dioxo-6-methyl-17α-acetoxy-21-methyl-19-norpregna-4,6-diene Compound C = 3,20-dioxo-6-methyl-17α-propionyloxy-21- methyl-19-nor-pregna-4,6-diene

Compound D = 3,20-dioxo-6-methyl-17a-benzoyloxy-21-methyl-19-norpregna-4,6-diene 5 Relative affinities can be deduced from this table.

Relative affinity is the ratio of the 50% inhibitory concentration (CI50) of a particular steroid to the specific cold hormone (here progesterone) used as a reference: AR = CI50 CI50r 15

The relative affinity is thus expressed as a percentage, assuming an AR of 100% for the reference hormone (or steroid).

The CI50 provides an estimate of the CI (inhibition constant) of the tested steroids for reference steroid binding.

Steroids CI50 (nM) AR%

Compound B 8.0 245 AMP 14.0 142 25 TX66 15.0 133

Compound A 8.5 235

Compound C 10.8 185

Compound D 13.1 160 TX71 600.0 3 30 Progesterone 20.0 100

Thus, the measurement of AR gives the following sequence:

Compound B> Compound A> Compound C> Compound D> TX66> progesterone> TX71 li 91158 11 These results clearly show that chain extension at position 21 with additional methyl results in a significant increase in receptor affinity for progesterone, a property that occurs only irregularly in prior art compounds.

5 It follows that the addition of a methyl group at position 21 surprisingly represents a significant increase in the affinity of steroids for cytosolic receptors and thus an indication of much longer efficacy.

10

When a steroid compound has a high degree of affinity for the hormone receptor, it is more difficult to transfer from it, so its effect is longer.

The following examples illustrate the invention.

Example 1 6,21-Dimethyl-17α-hydroxy-3,2-dioxo-19-norpregna-4,6-diene.

20

Step A: 3-Alkoxy-21-methyl-19-norpregna-3,5,17 (20) -triene A.M. In Krubiner et al., J. Org. Chem 33 (1968) 1713 25 starting from 3-methoxy-17-ketoestra-1,3,5 (10) -triene (IV), 3-methoxy-21-methylestra-1,3 , 5 (10), 17 (20) -tetraene (V) (m.p.

76 ° C, [α] D + 59 °), followed by 3-keto-21-methyl-19-norpreg-na-4,17 (20)-diene (VI) by reduction according to Birch-Nelson method to pale yellow as a running oil ([a] + 47 °). This compound is converted into 3-ethoxy-21-methyl-19-norpregna-3,5,17 (20) -triene (III) with triethyl orthoformate in the presence of a small amount of paratoluenesulfonic acid in ethanol.

Similarly, 3-methoxy-21-methyl-19-norpregna-3,5,17 (20) -triene is obtained from 3-keto-21-methyl-19-norpregna-4,17 (20) -diene (VI). (VII) trimethyl orthoformate in methanol in the presence of a small amount of paratoluenesulfonic acid.

Yield 79%, mp = 118 ° C.

5

Step B: 3-Ethoxy-6-formyl-21-methyl-19-norpregna-1,5,17 (20) -triene (Isomer Z) (VIII) to 30 g of 3-ethoxy-21-methyl-19- norpregna-3,5,17 (20) -triene-10 isomer Z (III) and to 300 ml of dimethylformamide are added Vilsmeier's reagent obtained from 15.5 ml of phosphorus oxychloride and 124 men of dimethylformamide at + 5 ° C: in.

The reaction mixture is stirred continuously for 1 h 15 min. 140 ml of saturated aqueous sodium acetate solution are added to form a yellow crystalline precipitate. After 15 minutes, filter and wash with water. 20.2 g of yellow 3-ethoxy-6-formyl-21-methyl-19-norpregna-20 1,5,17 (20) -triene crystals (isomer Z) (VIII) are then obtained.

Yield 62%. Mp = 99 ° C of pure product.

Rotation capacity [α] D = -21.5 ° (C = 1% dioxane).

25

Step C: 21-Methyl-6-methylene-3-oxo-19-norpregna-4,17 (20)-diene (Isomer Z) (IX) 14 g of 3-ethoxy-6-formyl-2'-methyl-19- norpregna-1,5,17 (20) -30 triene isomer Z (VIII) and 140 ml of methanol are stirred for 1 h 20 min together with 960 mg of sodium borohydride at 0 ° C. Slowly add 15 ml of 2N hydrochloric acid and stir until crystals are obtained. 8.7 g of 21-methyl-6-methylene-3-oxo-19-norpregna-4,17 (20)-diene, isomer 35-Z (IX) are obtained.

Yield 71%, mp = 110-114 ° C.

li 91158 13

Rotation capacity [α] D = + 218 ° (1% dioxane).

UV λmax = 261 nm, ε = 10,600.

Step D: 6,21-Dimethyl-3-oxo-19-norpregna-4,6,17 (20) -tri-5-ene (Isomer Z) (X) 3.5 g of 21-methyl-6-methylene-3 -oxo-19-norpregna-4,17 (20)-diene, isomer Z (IX), 3.5 g of sodium acetate, 1.4 g of 5% palladium on carbon in 350 ml of ethanol at reflux for 1 h 30 min time. The reaction mixture is filtered, extracted with chloroform and washed with water. The organic phases are chromatographed on silica. 3.1 g of isomer Z (X) of 6,21-dimethyl-3-oxo-19-norpregna-4,6,17 (20) -triene are obtained in the form of a slightly yellowish oil.

15

Yield 88%.

Rotation capacity [α] D = -31 ° (1% dioxane) UV λmax = 288 nm, € = 22,000.

20

Step E: 6,21-Dimethyl-17α-hydroxy-3,20-dioxo-19-norpregna-4,6-diene 2.9 g of 6,21-dimethyl-3-oxo-19-norpregna-4, 6.17 (20) -triene 25 (X), 29 ml of terbutanol, 0.58 ml of a 2.5% solution of osmium tetroxide in terbutanol and 4.04 g of triethylamine-N-oxide-hydroperoxide complex are stirred for 24 hours at ambient temperature . Add 3 g of celite and 2 g of sodium sulfite in water and stir for a further 2 h.

30

Extract with toluene and filter the organic phase onto silica for chromatography. Evaporate the filtrate to dryness and stir in methanol while hot. 1.66 g of 6,21-dimethyl-17β-hydroxy-3,20-dioxo-19-35 norpregna-4,6-diene are crystallized.

Yield 52%, mp = 204 ° C.

14

Example 2 17α-Acetoxy-6,21-dimethyl-3,2-dioxo-19-norpregna-4,6-diene 1 g of 6,21-dimethyl-17α-hydroxy-3,20-dioxo-19-norpregna -5,6,6-diene, 10 ml of chloroform, 0.8 ml of acetic anhydride and 0.15 g of paratoluenesulfonic acid are refluxed for 50 min. Add 2 ml of methanol and 0.1 ml of concentrated hydrochloric acid and reflux again for 1 h. Extract the reaction mixture with chloroform, wash with water, dry under sub-10 pressure.

The residue is crystallized from methanol. 780 mg of 17α-acetoxy-6,21-dimethyl-3,2-dioxo-19-norpregna-4,6-diene are obtained.

15 Yield 69%. Spectrum UV λmax 288 nm, e = 23400.

Mp = 203 ° C, rotation capacity [α] D = -34 ° (1% dioxane).

NMR spectrum in chloroform:

20 0.68 Hz 3H

singlet C18

1.05 Hz 3H

triplet J = 7 Hz C22

25 1.86 Hz 3H

singlet in methyl C6

2.08 Hz 3H

singlet CH3-CO

5.95 Hz 1H

30 singlets H in C7

6.05 Hz 1H

singlet H in C6.

By the same procedure, propionyl chloride is prepared using 6,21-dimethyl-17α-propionyloxy-19-norpregna-4,6-diene - caproyl chloride to give 6,21-dimethyl-17α-caproyloxy-19-norpregna-4, 6-diene,

II

91158 15 - using trimethylacetyl chloride to give 6,21-dimethyl-17α-trimethylacetyloxy-19-norpregna-4,6-diene, - using benzoyl chloride to give 6,21-dimethyl-17a-benzoyloxy-19-norpregna-4,6- using 6-monochloroacetyl chloride to give 6,21-dimethyl-17α-chloroacetoxy-19-norpregna-4,6-diene.

Example 3 Content of 2.5 mg 17α-acetoxy-6,21-dimethyl-3,20-dioxo-19-norpreg-10α-4,6-diene tablets: - active substance ......... ..... 2.5 g - lactose ..................... 110.0 g - maize starch ............ .. 17.5 g - cereal starch ............... 8.1 g 15 - sodium carboxymethyl starch 4.5 g - magnesium stearate .......... 12.4 g 1000 finished tablets with an average weight of 0.155 g.

Claims (5)

A process for the preparation of a pharmacologically active 6,21-dimethyl-19-norprogesterone derivative of the general formula I wherein R is a hydrogen atom, lower alkyl, methoxymethyl, tetrahydropyranyl or an aliphatic or an acyl residue of an aromatic organic carbon or carboxylic acid having 1 to 10 carbon atoms, characterized in that the 17-keto-18-methylgonadi-20-ene which is 3-alkoxyestra-1,3,5-triene of the formula Ha 25 J (IIa) 30 wherein R 1 is a lower alkyl radical of 1 to 6 carbon atoms or a 3-alkoxyestra-3,5-diene of formula Hb 35 (Hb) 40. I RjO II 91158 wherein R 1 has the same meaning as above, is reacted with a triarylpropylphosphonium halide of general formula 5 i - -, 0 Ar \ Θ Ar-P - CH 2 - CH 2 - CH 2 Hal / With Ar or a corresponding ylide of general formula Ar-P - CH - CH2 - CH3 20 / Ar wherein Ar is a substituted or unsubstituted phenyl radical-25 and Hal is a halogen atom other than fluorine; to give a propylidene derivative of the estra-1,3,5-triene derivative of the general formula IIIa-CH - CH2 - CH3 (IIIa) 35 as an R or O isomer E, wherein R1 has the same meaning as above, or estra-3 A 5-diene derivative propylidene derivative of the general formula IIIb -gTH - CH2 - CH3 45 (IIIb) R10 as the isomer E or Z, in which R1 has the same meaning as above, the compound of formula IIIa is hydrogenated by the Birch method 3- to form oxoestra-4-ene, which is converted to a compound of formula 5 IIIb using an alkylating agent in an acidic environment; reacting a compound of formula IIIb with a Vilsmeier-Hack type formylating agent to give the corresponding 6-formyl derivative of general formula IV 10 x. CH - CH 2 --CH 3 CHO 20 as isomer E or Z, wherein R 1 has the same meaning as above; The 6-formyl derivative is reduced to an early metal with a mixed hydride and the resulting 6-hydroxymethyl derivative is treated in an acidic environment to give a 3-oxo-6-methylene derivative of the formula Vx.CH - CH2 - CH3 35 as CH isomer E or Z; compounding a compound of formula V isomerized with an isomerization catalyst 40 to give a 3-oxo-6-methylester-4,6-diene compound of formula VI II 91158 ^ CH - CH 2 --CH 3 (VI) ch 3 as isomer E or Z; the compound of formula VI is bishydroxylated using a bishydroxylation reagent prepared from osmium tetroxide and hydroperoxide under an inert atmosphere to give the corresponding 17β-hydroxy-20-ketone derivative of formula / v CO - ch2 - ch3 f ^ - / - OK 20 H 25 OAVV ch3 which can be alkylated with an alkyl halide in a basic environment or tetrahydropyranylated using dihydropyran in an acidic environment or acylated with a functional derivative of a carboxylic or carbonic acid in the presence of an acidic reagent. 2. A patent according to claim 1, comprising triarylpropylphosphonium halides and propyltriphenylphosphonium bromide. 40 3. A process according to claim 1, which comprises a bishydroxylation reagent and osmium tetroxide and triethylamine-N-oxide hydroperoxide. Process according to Claim 1, characterized in that the triarylpropylphosphonium halide is propyltriphenylphosphonium bromide. Process according to Claim 1, characterized in that the bishydroxylation reagent is prepared from osmium tetroxide and triethylamine N-oxide hydroperoxide. Process according to Claim 1, characterized in that 17α-hydroxy-3,20-dioxo-6,21-dimethyl-19-norpregna-4,6-diene is prepared. Process according to Claim 1, characterized in that 17α-acetoxy-3,20-dioxo-6,21-dimethyl-11-19-norpregna-4,6-diene is prepared. 10 l. For the preparation of pharmacologically active 6,21-dimethyl-9-norprogesterone derivatives with the formula I / CO-CH2-CH2 15 f ^^ - - OR ch3 color R är en väteatom, lägre alkyl, methoximethyl , tetrahydro-25 pyranyl or acyl esters of aliphatic or aromatic organic co-carboxylic carbons with 1 to 10 cholatomers, supported by 17-keto-18-methylgonadines, to give 3-alkoxy esters-1,3,5 -trien with formula Hal (ΙΙ &) RjO color R, with 1 to 4 alkyl atoms or 40 3-alkoxyestra-3,5-dienes with formula Hb II 91158 Γ ^ ΗΓ ° (Hb) RjO 10 color R, in the case of angylated compounds having a triaryl-propylphosphonium halide in the form of a form | - -, Θ Ar 15 \ Θ Ar-P - CH2 - CH2 - CH3 Hal / Ar 20 or 20 times more than in the form of a form of 25 Ar \ Θ Θ Ar -P - CH - CH2 - CH3 / Ar 30 color Ar is a substituent or a substituent on a phenyl radical and halogen on the face gives a halogen atom and fluorine; colors of esters-1,3,5-friends-35 are derived from all forms of formula Ilia yCK-CE2-CH3 40 (Ilia) with isomer E or Z, color R, with an angular lettering, or with propylidene estra-3,5-dienders with the formula IIIb 45 ^ CH - CH2 - CH3 (nib) RjO 10 with isomer E or Z, color R, with an angular betydelse; in the case of formulas Ilia hydreras enligt Birch-methods for the preparation of 3-oxoestra-4-en, which are used for the formation of formulas Illb with the use of alkylation compounds in the environment; for the purposes of formula III, 15 of the formylation method of the Vilsmeier-Hack type, which may be used to give 6-formyl derivatives with all the formulas IV yCH-CHj-CHj 20 I ^ --- 1 (IV) 25 CHO is isomer E or Z # vari Ri har ovan angiven betydelse; Reduction of 6-formyl derivatives with anhydrous hydride of an alkali metal and the addition of a 6-hydroxymethyl derivative to the environment, coloring to give 3-oxo-6-methyl derivatives of formula V 35 ^ CH-CH2-CH3 (V) 40 s' ch2 45 is isomer E or Z; II 91158 for the preparation of formula V isomerized with a mixture of isomerization rings, a color is obtained with 3-oxo-6-methylester-4,6-diene with formula VI 5 ^ CH-CH2-CH3 (VI) "/ -V ch3 15 som isomer E or Z; For the preparation of formula VI bishydroxylers with the preparation of bishydroxylation reagents in the form of osmium tetroxide and hydroperoxide, in an inert environment, the color of the 17a-hydroxy-20-ketone derivative with the formula 20 ___ .co-ch2-ch3 f ^ -l OH 25 I ^ T ch3 30 are alkylers with alkyl halides and bases of tetrahydropyranyl with the addition of dihydropyrans and acetyls with functionally derivatized carboxyl or columns of the same reagent. 35 A compound according to claim 1, which can be converted into 17α-hydroxy-3,20-dioxo-6,21-dimethyl-19-norpregene-4,6-diene. 5. A preferred embodiment of claim 1 is the addition of 17α-acetoxy-3,20-dioxo-6,21-dimethyl-19-norpregna-4,6-diene. I!