DE1593337C - Process for the preparation of 3 Oxo 7 alpha methyl gona 4.9 are used - Google Patents

Description

The present invention relates to a process for the preparation of 3-oxo-7a-methyl-gona-4,9-dienes the general formula

in which R is a C ₁ - to C ^ alkyl radical, X is a hydrogen atom, the radical of an organic carboxylic acid, the radical of a substituted carbonic acid or a substituted or unsubstituted cyclic, heterocyclic or non-cyclic hydrocarbon group and Y is a hydrogen atom, a substituted or unsubstituted saturated or Unsaturated ^ hydrocarbon radical means which is characterized in that a 3-ketal-7'-methyl-17-oxo-gona-5 (10), 9 (II) -diene of the general formula

-CH ₃

in which R has the meaning given above and K is a ketal radical, according to known ones Methods reduced, the obtained 3-ketal-7a-melhylgona-5 (10) .9 (l l) -diene of the general formula

-CH,

in which R, K and Y have the meaning given above, decetalized with a strong mineral acid and the 3-oxo-7a-methyl-gona-4,9-diene of the general type formula

known androgenic anabolic compounds are markedly superior. In particular 3-oxo-7'-methyl-17 / I-acetoxy-oestra-4,9-diene develops its activity in the animal at a daily dose of 1 y / kg.

Likewise, the 3-oxo-7a-methyl-17a-äthinyl-17p ¹ -hydroxy -estra-4,9 -diene shows a very clear anabolic effect when used buccally. It also has a progestomimetic and an antizygotic effect. It's practically free from

ίο estrogenic effects.

Other important compounds that correspond to general formula I are the following:

The 3-oxo-7 <I-methyl-17 / ^ hydroxy-öslra-4.9-diene and the corresponding

Hexahydrobenzyl carbonate;
the 3-oxo-7 <i-methyl-l7 / i-allyloxy-estra-

4,9-diene;

3-oxo-7'-methyl-13 /> '- ethyl-l7f>' - acetoxygona-4,9-diene;

the 3-0x0-7 «. 17 «-dimethyl-l 7 / i-methoxy-

methoxy-öslra-4,9-diene;
the 3-oxo-7fi, 17 «-dimethyl-17 /) '- tetrahydro-

pyranyloxy-estra-4,9-diene;
the 3-Oxo-7 <i-methyl-17u-vinyl-17 / i-hydiOxy-

östra-4.9-diene;
the 3-oxo-7fi-methyl-17 «[l'-propynyl] -

17f> '- hydroxy-estra-4,9-diene.

One can assume that the insertion of the Meihylrestes in 7 «position in the molecule of _{3-oxo-13-R-17"} Y-17 / i-OX-gona-4,9-dienes substantial modification of the natural the physiological activity of the basic molecule.

Not only can the intensity of the effect change through the addition of the methyl radical, but also the kind of the effect can also be modified by the diminution or the noticeable Disappearance of the estrogenic effect according to the nature of the substituent in the 17u position.

The steroids with the structure 3-keto-gona-4,9-diene generally show a very marked estrogenic effect Effect, and there is therefore between the anabolic and / or androgenic effects of these dienes and the estrogenic effects a balance, resulting in a marked decrease in their biological Activity leads.

The 7'-methyl-gona-4,9-dienes, which have no estrogenic effect, show an androgenic effect or an anabolic effect that is pure and therefore much more intense.

The method according to the invention can also be carried out by the following features can be characterized:

in which R and Y have the meaning given above, isolated and then, if appropriate, into the corresponding 3-oxo-7 «-methyl-17ß-ether- or -17 / * - ester-gona-4,9-diene transferred.

The new compounds of general formula I have remarkable hormonal properties fitted.

Thus show the 3-oxo-7 " -methyl-Π β -acetoxyestra-4,9-diene and the 3-oxo-7a-methyl-17" -methyl-17 / i-hydroxy-estra-4,9-diene very intense anabolic and androgenic properties to which

The reducing agent is a mixed alkali metal hydride such as sodium borohydride, sodium trimethoxyborohydride or aluminum or lithium tri-t-butoxyhydride;

the reducing agent is an organometallic compound in which the organic radical Y means and which is an alkyl magnesium halide such as methyl magnesium bromide or iodide, an alkenyl magnesium or alkenyl zinc halide such as vinyl magnesium bromide, Allyl magnesium bromide, an alkynyl magnesium halide such as ethynyl magnesium bromide, Propynyl magnesium bromide or propynyl zinc

bromide, or an alkali metal acetylide such as potassium acetylide;

the strong mineral acid is perchloric acid, hydrochloric acid, or sulfuric acid;

the etherifying agent is a hydrocarbon halide such as methoxychloromethane, benzyloxychloromethane, methyl iodide or an ethylene derivative such as dihydropyran;
the acylating agent is an anhydride or chloride of an organic carboxylic acid having 1 to 18 carbon atoms or a halide of a carbonic acid such as hexahydrobenzyl chloroformate.

The organic carboxylic acids are aliphatic or cycloaliphatic saturated ones or unsaturated carboxylic acids, or aromatic or heterocyclic carboxylic acids, such as. B. formic acid, Acetic acid, dichloroacetic acid, isobutyric acid, valeric acid, isovaleric acid, trimethyl acetic acid, Caproic acid, /> - trimethylpropionic acid, cenantic acid, Caprylic acid, pelargonic acid, capric acid, undecylic acid, undecylenic acid, lauric acid, myristic acid, Palmitic acid, stearic acid, oleic acid, cyclopentylic acid, cyclopropylic acid, cyclobutylic acid and cyclohexylcarboxylic acid, Cyclopropylmethylcarboxylic acid, cyclobutylmethylcarboxylic acid, cyclopentylethylcarboxylic acid, Cyclohexylethylcarboxylic acid, cyclopentyl, cyclohexyl or phenylacetic acid or propionic acid. Benzoic acid, the phenoxyalkanoic acids such as phenoxyacetic acid, p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid, 4 - tert. - butylphenoxyacetic acid, 3-phenoxypropionic acid, 4-phenoxybutyric acid, the furan - 2 - carboxylic acids, 5 - tert. - butylfuran-2-carboxylic acid, 5-bromofuran-2-carboxylic acid, the nicotinic acids, the / ^ - ketocarboxylic acids, e.g. B. the acetyl acetic acids, propionyl acetic acid, butyrylacetic acid, Amino acids such as diethylaminoacetic acid.

The 3-ketal Ia- methyl-17-oxo-gona-5 (10), 9 (l I) - used as starting materials serve the general formula

45 formula

can by an analogous method as described in German Offenlegungsschrift 1,593,323 is. from Des-A-gonenen of the general formula

OAcyl

OAcyl

60

65

can be obtained, the gonene in turn by ketalization of Des-A-gonenen of the general described in U.S. Patent 3,115,507 can be obtained.

example 1

Preparation of 3-oxo-7a-methyl-17 / i-acetoxyöstra-4,9-diene

Level a

3,3-Dimethoxy-7a-methyl-17 / hydroxy-oestra-5 (10), 9 (II) -diene

1.570 g of 3,3-dimethoxy-7'-methy 1 -17-oxo-oestra-5 (10), 9 (11) -diene, which is described in German Offenlegungsschrift 1 593 323, are suspended in 24 ml under nitrogen Methanol and 2.4 ml of water, stir, slowly add ^{0.8 g of sodium borohydride without exceeding 30 °} C. and stir for 1 hour at room temperature, always under a nitrogen atmosphere. 100 ml of water are added, the mixture is extracted with methylene chloride, the organic phases are washed with water, dried over sodium sulfate and distilled to dryness; 1.620 g of 3,3-dimethoxy-7u-methyl-17 / i-hydroxy-oestra-5 (10), 9 (II) -diene, which is used as it is for the following synthesis stage, are obtained. As far as is known, the product has not yet been described in the literature.

Level B.

3-Oxo-7'-methyl-17 / f-acetoxy-oestra-4,9-diene
a) Decetalization

1.60 g of 3,3-dimethoxy- la- methyl-17 / i-hydroxy-oestra-5 (10), 9 (ll) -diene are dissolved in 32 ml of a solution of 5 ml of perchloric acid in a sufficient amount of acetic acid, to obtain 50 ml of solution, stir for 30 minutes at room temperature under an inert atmosphere, then pour the reaction mixture into 320 ml of a saturated aqueous solution of sodium bicarbonate; it is extracted with methylene chloride, the organic phases are washed with a solution of sodium bicarbonate and then with water, dried and evaporated to dryness; 1.560 g of crude S-oxo ^ a-methyl-n / f-hydroxy-estra-4,9-diene are obtained.

This product is chromatographed on silica gel, eluting with a mixture of benzene-ethyl acetate (7: 3), then by recrystallization from a mixture of ethyl acetate-isopropyl ether (6: 4) cleaned. 3-Oxo-7a-methyl-17 / i-hydroxy-estra-4,9-diene is obtained, M.p. = 171 ° C.

UV spectrum: (ethanol)

?. _imr at 218 to 219 πΐμ El * = 198

Inflexion

at 230 πΐμ EjJ _n = 184

at 237 πΐμ E ^ _n , = 175

^λ , ηα.ν at 307 Πΐμ Ej * = 686

As far as is known, the product has not yet been described in the literature.

b) acetylation

1.545 g of crude 3-oxo-7a-methyl-17 ^ -hydroxy-oestra-4,9-diene are dissolved in 15.5 ml of pyridine and 1.6 ml of acetic anhydride and the mixture is stirred at 60 ^° C. for 1 hour; the reaction mixture is poured into 170 ml of a water-ice mixture, extracted with methylene chloride, the organic phases are washed with hydrochloric acid and then with water, dried and evaporated to dryness. 1.610 g of crude product are obtained, which is purified by chromatography.

It is eluted with a mixture of benzene and ethyl acetate (9: 1) and recrystallized from isopropyl ether; obtained in this way 930 mg of 3-oxo Ia - methyl -Πβ- acetoxy - estra - 4,9 - diene, which melts at 130 ⁰ C.

Analysis: C ₂₁ H ₂₈ O ₃ = 328.43.

Calculated ... C 76.79, H 8.59%;
found .... C 77.0, H 8.7%.

UV spectrum

7. _max at 217 ΐημ
Inflexion

= 181

at 230 ηΐμ E {* = 163

at 238 ΐη _μ EU = 151

¹ W ^{at 304 to 305 m} V- ^E ! ™ = ⁶²¹

IR spectrum

Absence of OH;
Presence of acetate;
Presence of conjugated ketone.

As far as is known, the product has not yet been described in the literature.

Example 2

Production of 3-oxo-7a, 17'-dimethyl-17 / i-hydroxy-estra-4,9-diene

Level a

3,3-Dimethoxy-7a, 17r.t-dimethyl-17 / f-hydroxyöstra-5 (10), 9 (II) -diene

To 110 ml of a 2.3-m-methylmagnesium bromide in ether is cooled to about 0 ⁰ C, is added within 20 minutes 1,732 g of 3,3-dimethoxy-7a-methyl-17-oxo-estra-5 (10 ), 9 (II) -diene, which is dissolved in 90 ml of anhydrous benzene, and the reaction mixture is stirred at room temperature for 20 hours.

Then it is poured into a saturated aqueous solution of ammonium chloride, cooled on ice, decanted, then washes with water until the wash water is neutral, dries and evaporates under vacuum to dryness.

In this way, 2.045 g of 3,3-dimethoxy - 7α, 17α - dimethyl - 17 / ϊ - hydroxy - östra - 5 (10), 9 (ll) -diene, which is used as it is for the following synthesis stage.

UV spectrum: (ethanol)

= 17 400.

The product is insoluble in water, in dilute aqueous acids and dilute aqueous alkalis and soluble in the majority of common organic solvents.

Level B.
3-Oxo-7a, 17a-dimethyl-17 / J-hydroxy-estra-4,9-diene

1.7 g of crude 3,3-dimethoxy-7a, 17'-dimethyl-17 /} -hydroxy-oestra-5 (10), 9 (II) -diene are dissolved in 17 ml of acetic acid and then 1.7 ml are added 65% perchloric acid added. The mixture is stirred for 30 minutes at room temperature under an inert atmosphere; the reaction mixture is then poured into a water-ice mixture, stirred for 15 minutes, filtered off with suction, washed and dried in vacuo. The product obtained is chromatographed on silica gel, eluting with a mixture of benzene-ethyl acetate (1: 1), and then purified by recrystallization from acetone under reflux. This gives 502 mg of 3-oxo-7 ", 17" -dimethyl-17 / f - hydroxy - estr - 4,9 - diene, mp = 210 ° C, [ «] = ⁰ -330 C (c = 0, 51% chloroform).

Analysis: C ₂₀ H ₂₈ O ₂ = 300.43.

Calculated ... C 79.96, H 9.38%, found ... C 80.3, H 9.6%.

UV spectrum: (ethanol)

/ at 219 m ^ E ^ = 191

Inflexion

at 230 to 231 ηΐμ E! ^ _m = 178

at 238 to 239 ΐημ Ε | * = 170

}. _imx at 306 to 307 ηΐμ Ej * = 667

The product results in the form of colorless prisms. It is insoluble in water, in dilute it aqueous acids, dilute aqueous alkalis and benzene; slightly soluble in ether and soluble in alcohols and chloroform.

As far as is known, the product has not yet been described in the literature.

Example 3

Production of 3-oxo-7 "-methyl-17" -äthinyl-17 / f-hydroxy-estra-4,9-diene

Level a

3,3-Dimethoxy-7iz-methyl-17 "-ethinyl-17 / hydroxy-estra-5 (10), 9 (II) -diene

It is cooled to -5o ⁰ C 105 ml of ammonia, with stirring and passing an inert gas to 1,750 g of potassium, and then initiates a ■ 30 minutes acetylene. The precipitate is diluted with 28 ml of ether, then 28 ml of ether and 7 g of 3,3-dimethoxy-7a-methyl-17-oxo-oestra-5 (10), 9 (1 l) -diene are added, whereby one Temperature of -50 C, maintaining stirring and introduction of an inert gas; the mixture is stirred for a further 4 hours at -40 ° C. under a stream of acetylene. 3.5 g of ammonium chloride are then added, the temperature is brought to 0 ° C. and the ammonia is expelled; 30 ml of water are added, the mixture is extracted with methylene chloride, the organic phases are washed with water until the wash water is neutral, dried, filtered and evaporated to dryness; 7.7 g of the crude ethynyl derivative are obtained, which can be purified by chromatography on magnesium silicate and recrystallization from isopropyl ether; 5.2 g of 3,3-dimethoxy-7a-methyl-17'-ethinyl-17 / i-hydroxyöstra-5 (10), 9 (II) -diene (yield 69%) are obtained in the form of a

Product that is solid, colorless, soluble in common organic solvents, insoluble in water and dilute aqueous acids and dilute aqueous alkalis. The melting point is about 130 ^° C.

IR spectrum

Absence of C = O;
Presence of OH at 3590 cm "¹;
Presence of C =. CH at 3300 cm "¹;
Presence of 2 bands, type conjugated C = C, at 1643 cm " ¹ and 1612 cm" ¹ .

Level B.

3-0x0-7 a-methyl-na-ethinyl-n ^ -hydroxyestra-4,9-diene

3.3 g of crude 3,3-dimethoxy-7a-methyl-17a-ethinyl- Πβ- hydroxy-oestra-5 (10), 9 (lI) -diene are dissolved in 33 ml of acetic acid and then 3.3 ml of 65 are added % perchloric acid too. The mixture is stirred for 30 minutes at room temperature under an inert atmosphere; the reaction mixture is then poured into a mixture of water and ice, stirred for 15 minutes, filtered off with suction, washed and dried in vacuo.

The product obtained is chromatographed on silica gel, eluting with a mixture of benzene-ethyl acetate (1: 1) and then purified by recrystallization from benzene. This gives 1.460 g of 3-oxo-7ri-methyl-17a-ethynyl-17-hydroxy-estra-4,9-dien, F. = 204 ⁰ C, [a] $ = ⁰ -346 C (c = 0.53 % Chloroform).

Analysis: C ₂₁ H ₂₆ O ₂ = 310.45.

Calculated ... C 81.25, H 8.44%;
found .... C 81.2, H 8.7%.

UV spectrum: (ethanol)

?, _mx at 219 ΐημ E £, = 186

Inflexion at 230 ηΐμ Ej ^, = 170

λ _ιηαχ at 306 mμ EJ1 = 640

IR spectrum: (chloroform)

Presence of OH at 3600 cm "¹;
Presence of C =. CH at 3300 cm " ^1. '

Example 4

Production of 3-oxo-7a-methyl-17 /? - hydroxyöstra-4,9-diene-hexahydrobenzyl carbonate

neutralized with 1.25 ml of triethylamine. It is poured into ice water, extracted with methylene chloride and washed the combined extracts with water, dried over sodium sulfate and evaporated to dryness. The The crude product obtained is chromatographed on silica gel, eluting with a mixture of Benzene-ethyl acetate (9: 1), and then by recrystallization Purified from isopropyl ether. 0.5 g of 3-oxo-7a-methyl-17/9-hydroxy-estra-4,9-diene hexahydrobenzyl carbonate is obtained, M.p. = 104 ° C. The product obtained is soluble in ethanol, chloroform, Ethyl acetate and benzene and slightly soluble in ether and isopropyl ether.

Analysis: C ₂₇ H ₃₈ O ₄ = 426.57.

Calculated ... C 76.02, H 8.98%;

found .... C 75.6 to 75.7, H 9.0 to 9.1%.

As far as is known, this compound has not yet been described in the literature.

In the same way as in Example 1, S-Oxo ^ a-methyl-n / i-ethyl-n / i-hydroxy-gona-4,9-diene can be used 3-oxo-7'-methyl-13 / I-ethyl-17 / * -acetoxy-gona-4,9-diene receive.

As far as is known, this product has not yet been described in the literature.

As already stated above, the products of general formula I are valuable pharmacological Features fitted.

They can be used to treat complaints of protidic anabolism, asthenia, Leanness, osteoporosis, andropause, signs of aging, healing delay in fractures, metabolic Complaints with prolonged corticotherapy, genital fatty syndrome, functional menometrorrhagia, Fibroids, endometriosis and as an additional treatment for breast cancer.

The 7'-methyl derivatives of O'strans, those of the general Formula 1 can be used buccally, perlingually, transcutaneously or rectally.

The usable posology varies between 0.1 and 5 mg per day in adults on the route of administration.

The product is in the form of colorless platelets; it is insoluble in water, diluted aqueous acids and dilute aqueous alkalis; very little soluble in ether; sparingly soluble in acetone and benzene and soluble in alcohols and chloroform.

As far as is known, the product has not yet been described in the literature.

Claims (2)

Patent claims: 1. Process for the preparation of 3-oxo-7a-methyl-gona-4,9-dienes the general formula 0.650 g of crude S-droxy-oestra-4,9-diene, which was obtained in step B of Example 1, is dissolved in 33 ml of pyridine with stirring and under an inert atmosphere. 1.35 ml of hexahydrobenzyl chloroformate, which is described in German Patent 1,217,376, is added. The mixture is stirred for 2 hours, then cooled to 0 ⁰ C and new -CH, in which R is a C ₁ - to C ₄ -alkyl radical, X is a hydrogen atom, the radical of an organic carboxylic acid, the radical of a substituted carbonic acid or a substituted or unsubstituted cyclic, heterocyclic or non-cyclic hydrocarbon group, and Y is a hydrogen atom, a substituted or unsubstituted one means saturated or unsaturated hydrocarbon radical, thereby marked 109 528/365 net that one is an S-ketal-Ta-methyl-n-oxogona-5 (10), 9 (II) -diene the general formula IO in which R has the meaning given above and K is a ketal radical, reduced by methods known per se, the 3-ketal-7a-methyl-gona-5 (10), 9 (II) -diene of the general formula _{R obtained} OH CH, in which R, K and Y have the meaning given above have, decetalized with a strong mineral acid and the desired 3-oxo-7a-methyl-gona-4,9-diene the general formula OH -Y -CH, in which R and Y have the meaning given above, isolated, and then optionally in the corresponding S-Oxo-Ta-methyl-H / i-ether or -17ß-ester-gona-4,9-diene transferred. 2. The method according to claim 1, characterized in that one is used as acylating agent Halide of a carbonic acid, in particular hexahydrobenzyl chloroformate, is used.