DE1593334C3 - 11-substituted steroid derivatives, process for their preparation and pharmaceutical formulation - Google Patents

Description

wherein R _{1 is} hydrogen or a methyl radical, R 'is a methyl radical, R _{2 is} an ethynyl radical and R _{4 is} an alkoxy radical with 1 to 4 carbon atoms, an alkylthio radical with 1 to 4 carbon atoms, an azido radical, a benzyloxy radical or a thio radical.

2. S-Oxo-11ß-methoxy-IT / S-hydroxy-na-ethinylestra-4,9-diene.

3. S-Oxo-II / i-ethoxy-n / S-hydroxy-Ua-ethinylestra-4,9-diene.

4. S-Oxo-11ß-methoxy-TÄ-methyl-Na-ethinyl-17 /? - hydroxy-estra-4,9-diene.

5. Process for the preparation of the steroid derivatives of claims 1 to 4, characterized in that that one has the corresponding Al / 5-hydroxy compound in the presence of a strong acid and with the help of an aprotic solvent of action a corresponding alcohol, alkyl mercaptan, alkali metal azide or hydrogen sulfide subject.

6. Pharmaceutical formulation containing a compound of the general formula according to Claim 1 as an active ingredient.

The invention relates to steroid derivatives of the general formula which are substituted in the 11-position

wherein R _{1 is} hydrogen or a methyl radical, R 'is a methyl radical, R _{2 is} an ethynyl radical and R _{4 is} an alkoxy radical with 1 to 4 carbon atoms, an alkylthio radical with 1 to 4 carbon atoms, an azido radical, a benzyloxy radical or a thio radical.

It is known that in the steroid derivatives the alcohol is relatively little reactive in the 11-position, in particular because of its steric hindrance. However, under certain precisely defined conditions and with the help of strong acylating agents, it is possible to to esterify him.

So far, however, no ethers of this 11-alcohol, which remains inert under the classical etherification conditions, are known. The same applies to the thioether, thio and azido functions.
It has now been found that the 3-oxo-II / Miydroxy-gona-4,9-diene steroid derivatives, some representatives of which are described in Belgian patents 6 49 223 and 6 49 224, when exposed to an alcohol or a mercaptan or from

ίο hydrogen sulfide or an alkali metal azide in Presence of a strong acid to products with corresponding ether or thioether or thio or Lead azido function in II /? Position. This unexpected reaction allows a new process that creates access to undescribed 'structures in steroid chemistry and that position of derivatives with interesting physiolo-;

gical properties. I.

Thus, according to the present invention, there is provided a method for producing the above steroid derivatives according to the present invention created, which is characterized in that the corresponding 11/9-Hydroxyverbin- * in the presence of a strong acid and with the help of an aprotic solvent, the action of a appropriate alcohol, alkyl mercaptans, alkali metal azide or hydrogen sulfide.

The compounds according to the invention have interesting physiological properties; they show in particular an endocrine and / or metabolic activity to a generally greater degree than the 11-hydroxyl compounds of the same structure.

In particular, they have a significant hypocholesterolemic Activity as well as an estrogenic activity and an inhibitory effect on the pituitary gonadotropins.

The method according to the invention can also be characterized by the following points:

In relation to the steroid molecule, the reaction with alcohol or mercaptan or hydrogen sulfide or amounts of alkali metal azide between 1 and 25 moles inclusive.

The strong acid is selected from the mineral acids, such as perchloric acid, sulfuric acid, phosphoric acid, organic acids such as p-toluenesulfonic acid or a Lewis acid, such as boron trifluoride, etc., and these acids are allowed to act in very small amounts. On the other hand, the use of hydrochloric acid, which is mainly used for flavoring, is avoided of ring A.

The reaction is carried out near room temperature. It usually happens very quickly practically instantaneously, so that after a few minutes of being together, the reactants concerned can isolate the product formed. can be performed. This isolation can be carried out, for example, by adding Water, decant the organic phase and evaporate to dryness in vacuo, followed by purification of the product follows, for example by chromatography.

The aprotic solvent used is chlorinated solvents, e.g. B. methylene chloride, chloroform and carbon tetrachloride, aliphatic and cycloaliphatic hydrocarbons, e.g. B. n-hexane and cyclohexane, aromatic hydrocarbons, e.g. B. benzene and toluene, ethers, e.g. B. diethyl ether, Dioxane or tetrahydrofuran, esters of organic lower acids, e.g. B. ethyl acetate etc.

3 4

p.; .. · t ι which are insoluble in water, in ethanol and chloro-

are form-soluble.

Manufacture of 3-Oxo-l lÄ-methoxy-lTO-hydroxy-. , _ _TT _,. ",.

17 «-äthinylöstra-4,9-diene analysis C ₂₂ H ₂₈ O ₃ = 340.44:

5 Calculated ... C 77.61%, H 8.29%;

5 g of 3-oxo-II / ?, 17 /? - dihydroxy-17 "-ethi found ... C 77.4%, H 8.3%.

nyl-oestra-4,9-diene in 250 ecm of methylene chloride with

3 ° / ₀₀ methanol, then adds with vigorous stirring. As far as is known, this compound is in the literature

1 ecm 65% perchloric acid added, the stirring is not described,

continued for a few minutes after the addition and io _o .

pour into a mixture of ice-water. Example 3

It is decanted, the organic phase is washed with the production of S-Oxo-II / ff-isopropyloxy-n / I-hydroxy-water, filtered and evaporated to dryness in vacuo 17a-äthinyl-östra-4,9-diene

The residue obtained is chromatographed. 3 g of 3-oxo-II / ?, 17/3-dihydroxy-17: x-ethinyl are dissolved Silica gel. The product obtained is purified with oestra-4,9-diene in 150 ecm pure (of methanol Dissolve in methylene chloride, treat with animal-free) methylene chloride, add 1.8 ecm of isopropyl carbon, Filter and evaporate to dryness. The alcohol, then 0.8 ecm of 50% sulfuric acid, The residue crystallizes in ether and 2.6 g are obtained, stirred for 5 minutes, then poured into an ice cream

3-Oxo-II /? - methoxy-17 /? - hydroxy-17a-ethinyl-oestra- 20 water mixture and isolates the product formed, 4,9-diene. M.p. = 162 to 163 ° C, [cc] f = -93.5 ° (c as described in the previous examples. Man = 1.1% methanol). receives 1.8 g of S-Oxo-IIß-isopropyl-oxy-n / S-hydroxy-

. - 17 "-äthinyl-oestra-4,9-diene.

UV spectrum in ethanol: _{As far as be} fc _{annt) this} compound is in the literature

210 ΐημ E \? _m = 167, 25 not described.

33HH * £ 11 = 140, _Re · ·. _u

93πιμ ££ "= 628. Example 4

Analysis C ₂₁ H ₂₆ O ₃ = 326.42: Production of S-Oxo-II ^ benzyloxy-n / J-hydroxy-

^J 21 26 3 "17" -äthinyl-oestr-4,9-diene

Calculated ... C 77.27%, H 8.03%; . 30th

found ... C 77.3%, H 8.0%. 'Suspend 100 mg; 3-oxo-110.17 /? - dihydroxy-

17 "-äthinyl-oestra-4,9-diene in 5 ecm carbon tetrachloride-

The product falls in the form of needle-like crystals with substance containing 0.07 ecm of benzyl alcohol. One adds good stability, which is insoluble in water and in the 0.02 ecm 65% perchloric acid, stirs in the largest room Part of the usual organic solvent 35 temperature for 2 minutes, then poured into a are soluble. Mixture of ice and water. Isolate the product

If in the above-described preparation as described in Example 1, 44 mg of 3-oxo methylene chloride is obtained by cyclohexane, benzene, II /? - benzyloxy-17/3-hydroxy-17a-ethinyl-oestra-4,9-diene , Ether, carbon tetrachloride, chloroform replaced, he F. = 169 to 170 ⁰ C.

If you keep an identical product with similar characteristics 40 As far as is known, this compound is in the liteboot. rature not described.

As far as is known, this compound is not described in the literature. BeisDiel 5

B eisdie 1 2 ⁴⁵ Production of S-Oxo-II / S-methoxy-n / Miydroxy-

östra-4,9-dien

Manufacture of 3-oxo-llj5-ethoxy-17 /? - hydroxy-

17 "-äthinyI-oestra-4,9-diene Dissolve 0.5 g of 3-Oxo-II / S, 17y? -Dihydroxy-oestra-

4,9-diene in 25 ecm methylene chloride with 2% ₀ Me-

Dissolve 1 g of S-oxo-II / i-n / i-dihydroxy-na-ethinyl-50 ethanol, then add 0.1 cm of 65% perchloric acid Oestra-4,9-diene in 50 ecm chloroform with 1% ethanol, and stir for a few minutes at room adds then add 0.2 ecm of 65% perchloric acid and stir at temperature.

the reaction mixture for a few minutes at Man then pour the reaction mixture into ice

Room temperature, water, washes with water until neutral

It is then poured into ice water, the washing water is decanted, distilled to dryness in vacuo and the organic phase is extracted, the aqueous phase is extracted with the residue recrystallized from diethyl ether.
Chloroform, the organic solutions are combined, which gives 0.335 g of 3-Oxo-II / 9-methoxy-17 /? - hy-

it is washed with water, dried and droxy-oestra-4,9-diene to dryness, m.p. = 145 ° C.
evaporates. The product is obtained in the form of colorless needles

The residue is chromatographed on 60% in water, dilute aqueous acids and alkali silica gel cleaned. alkalis insoluble and in the greater part of the usual

The residue is then crystallized from organic solvents which are soluble
warm ethanol, treated with animal charcoal, filtered, as far as is known, this compound is in the lit-

brings to a small volume and cools. rature not described.

After suctioning off and drying, 343 mg of 65 are obtained. In an analogous manner, starting from 3-0x0-11 / 9; ethoxy-17 /? - hydroxy-17Ä-ethinyl-oestra-3-oxo-II / 9.17 / 9 -dihydroxy-17 "-methyl-estra-4,9-dien, 4,9-dien, mp = 100 to 110 ⁰ C. the S-oxo-ll / S-methoxy-na-methyl-n / S hydroxy

The product is obtained in the form of colorless rods, oestra-4,9-diene.

- As far as is known, this connection is in the literature not described. · ■ ·

In an analogous way, starting from 3-Oxoll) 3,17 /? - dihydroxy-estra-4,9-diene, the 3-oxo-li / S-ethoxy-17/3-hydroxy-estra-4,9-diene, M.p. = 128 ° C.

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

Example 6

Production of
SjlV-Dioxo-II / S-methoxy-estra - ^ - diene

0.5 g of 3,17-dioxole /? - hydroxy-estra-4,9-diene is dissolved at room temperature in 25 ecm methylene chloride with 2% methanol, then adds 5 mg p-toluenesulfonic acid and the reaction mixture is stirred for a few minutes.

It is then poured into ice water, washed with water until the wash water is neutral, distilled in Vacuum to dryness and the residue recrystallized from diethyl ether.

This gives 0.46 g of 3,17-dioxo-ll / S-methoxy-estra-4,9-dien, F. = 140 ⁰ C.

The product is obtained in the form of colorless prisms in water, dilute aqueous acids and alkaline solutions are insoluble and soluble in most common organic solvents.

As far as is known, this compound is not described in the literature. ·?

3,17-Dioxo-II / 3-hydroxy-oestra-4,9-diene is analogously converted into 3,17-dioxo-II _J o-oestra-4 by the action of methylene chloride with 2% ethanol in the presence of p-toluenesulfonic acid , 9-dien transferred.

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

Example 7

Production of 3-oxo-H / 9-methyl-thio-17a-ethinyl-17 /? - hydroxy-estra-4,9-diene

Dissolve 10 g

östra-4,9-diene in 800 ecm methylene chloride, the 10 ecm Contains methyl mercaptan. 5 cm of 32% perchloric acid are added. After a few minutes of stirring at An equal volume of water is added at ordinary temperature. The organic phase is separated washed with water, dried and brought to dryness in vacuo.

Purify by chromatography on silica gel to give 1.2 g of a compound which, upon uptake crystallized in isopropyl ether, m.p. = 136 ° C.

Analysis C ₂₁ H ₂₆ O ₂ S = 342.48:

Calculated ... C 73.64%, H 7.65%, S 9.36%;
found ... C 73.5%, H 7.6%, S 9.1%.

As far as is known, this compound is not described in the literature.
Based on the following connections:

S-Oxo-ll ^ -hydroxy-n / S-benzoyloxy-östra-

4,9-diene,
3-Oxo-II / 3.17) S-dihydroxy-17 «-chloro-ethinyl-

Austria,
3-Oxo-lly?, 17) S-dihydroxy-17 «-methyl-estra-

4,9-diene,
S-Oxo-llßn ^ -dinydroxy-na-ethyl-estra-

4,9-diene

the corresponding 11/9-methoxy-, 11/5-ethoxy-, "lljS-isopropyloxy-, 11/9-benzyloxy-, 11/9 methyl mercapto derivatives.

As far as is known, these compounds are not described in the literature.

Example 8

Production of 3-oxo-II) 9-thio-17a-ethinyl-17/9-hydroxy-estra-4,9-diene

3 g of 3-oxo-II / S, 17 / J-dihydroxy-17a-äthinylöstra-4,9-diene are dissolved in 30 ecm of methylene chloride containing 1.5 g of hydrogen sulfide per 100 ecm of solution. Man adds 1.5 ecm of 65% perchloric acid and stirs the mixture for 2 hours at ordinary temperature. The solution is then washed with water, dried and filtered. One brings to Dry.

The crude product is purified by chromatography on silica gel and 0.600 g of a product is obtained which crystallizes when taken up in isopropyl ether, mp = 190 ° C, [*]? = + 184.5 ° (c = 0.5% dioxane).

Analysis C ₂₀ H ₂₄ O ₂ S = 328.45:

Calculated
found

C 73.12%, H 7.37%;
C 73.20%, H 7.4%.

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

Example 9

Production of 3-Oxo-II)? - n-butylthio-17a-ethinyl-17 /? - hydroxy-estra-4,9-diene

500 mg of 3-oxo-II / ?, 17 /? -Dihydroxy-17a-ethinyl-oestra-4,9-diene are dissolved in 50 ecm of methylene chloride. 1.6 ecm of n-butyl mercaptan, then 0.25 ecm of 32% strength, are added Perchloric acid too. The mixture is stirred for 2 minutes at room temperature. An equal volume is then added Water too. After stirring, the organic phase is decanted, washed with water, over sodium sulfate dried, filtered and brought to dryness in vacuo.

The dry residue weighs 667 mg and is purified by chromatography on silica gel. In this way, 210 mg of a pure product are separated off, which crystallizes from isopropyl ether, mp = 140 ^° C.

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

The S-Oxo-II / S-terL-butyloxy-na-äthinyl- n ^ -hydroxy-estra-4,9-diene her, F. = about 100 ⁰ C.

UV spectrum (ethanol):

A _B ax 231 to 232 πψ. £ !? "= 134;
302 ηιμ. £}? » = 412.

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

Example 10

Manufacture of 3-oxo-7a-methyl-II /? - methoxy-17a-ethinyl-17 /? - hydroxy-estra-4,9-diene

760 mg of 3-oxo-7'-methyl-II / 5.17 / 3-dihydroxy-17'-ethinyl-oestra-4,9-diene are dissolved in 38 ecm methylene chloride with 0.5% methanol and 0.16 ecm 32% Perchloric acid, stir for 7 minutes, add one

Ice-water mixture to and makes by triethylamine alkaline; the organic phase is washed with water until the washing water is neutral, dried, filtered and evaporated to dryness; chromatographed the crude product on magnesium silicate, then crystallized from ethyl acetate in the Warmth and in the cold around; 520 mg h is obtained

droxy-estra-4,9-diene, m.p. 196 ° C.
A «oi ,, c _Q r · u r> IAn λλ.

Calculated ... C 77.61%, H 8.29%;
found ... C 77.9%, H 8.0%.

IR spectrum - chloroform:

Presence of OH at 3500 cm- \
Presence of C = CH at 3300 cm- *,
Presence of conjugated ketone.

UV spectrum - ethanol:

A _max 212n ^.

A 240 ηιμ

297 to 298 πιμ

£ 11 = 147.
£ 11 = 139.
£ 11 = 574.

As far as is known, this compound is not described in the literature. _

If the methanol is replaced by ethanol or isopropanol, 3-oxo-7 "- methyl-11/3 - ethoxy - 17a - ethinyl -17/3 - hydroxyestra-4,9-diene and S-oxo ^ are obtained in an analogous manner α-methyl-II / J-isopropoxy-17a-ethinyl-17 / S-hydroxy-estra-4,9-diene. _T

As far as is known, these products are in the literature not described.

Presence of 2 bands of the conjugated C = C type at 1643 cm " ¹ and 1612 cm" ¹ .

As far as is known, this connection is in the literature not described.

The 3,3-dimethoxy-7a-methyl-17-oxo-Östra-5 (10), 9 (II) -diene, the starting product of this preparation, can be obtained according to the Belgian patent 647178.

Stage B: Production of 3-oxo-7a-methyl-17a-ethhinyI-17 / Jh _y droxy-ostra-5 (10), 9 (ll) -diene

_{Suspen one} diert 6.1 g of 3,3-dimethoxy-7a-methyl-17 "- ethynyl - 170 - hydroxy - estr - 5 (10), 9 (ll) - diene ¹ ^ ³⁰ ^ m ⁱⁿ acetic acid with 5% water, stirred for 15 micro ^"ut f" ^at room temperature under an inert atmosphere

15 minutes. You add slowly, still at room temperature and under an inert atmosphere of 300 ecm an aqueous saturated sodium bicarbonate solution, cool for 30 minutes at ice temperature, filtered, sucks remove the precipitate, wash with water until the wash water is neutral and dry in vacuo. 5.2 g of 3 - oxo - 7 "- methyl-17" - ethinyl-17/3-hydroxy-estra-5 (10), 9 (II) -diene, F. = 226 ° C. This compound is obtained in the form of a product crystallized in colorless needles, which is found in the ordinary Soluble in organic solvents and insoluble in water and dilute aqueous acids and alkaline solutions is.

30th

Preparation of the starting product 3-oxo-7'-methylII / S, 17/3-dihydroxy-17a-ethinyl-oestra-4,9-diene UV spectrum - ethanol:

Inflexion at 237 ηιμ
X _max 241 to 242 ΐημ
Inflexion at 250 πιμ
Inflexion at 290 ΐημ

£ 11 = 610,
£ 11 = 630,
£ 11 = 440,
£ 11 = 4.7.

_{This spectrum}
lares dien.

characterizes a heteroannu-

Stage A: Preparation of 3,3-dimethoxy-7'-methyl-17'-ethinyl-17 £ -hydroxy-oestra-5 (10), 9 (II) -diene

It is cooled to -50 ⁰ C 105 cc of ammonia, with stirring under purging of inert gas 4 "1.750 g of potassium on, then passes through a stream of acetylene for 30 minutes. The precipitate is diluted with 28 ecm of ether, then 28 ecm of ether and 7 g of 3,3-dimethoxy-7 "-methyl-17-oxo-oestra-5 (10), 9 (ll) -diene are added, the temperature will hold at -50 ⁰ C 45 overall and stirring and flushing of the inert gas is continued, stirring is continued for 4 hours at -40 ⁰ C under acetylene. 3 ' ^{5 , t ammonium chloride is then introduced} , the temperature is brought to 0 ° C. and the ammonia is driven off; 50 30 ecm of water are added, extracted with methylene chloride, the organic phase is washed with water until the wash water is fresh, dried, filtered and evaporated to dryness; 7.7 g of the crude ethynyl are obtained. 1.2 g of 3-oxo-7a-methyl-17a-ethi are suspended

derivative, which is obtained by chromatography on 55 nyl-17 /? - hydroxy-oestra-5 (10), 9 (II) -diene in 30 ecm of eth-magnesium silicate and recrystallization from iso anol with 1% triethylamine. One conducts a sour propyl ether cleans; 5.2 g of 3,3-dimethoxy material are obtained over a period of 24 hours at room temperature. it is evaporated to dryness and 1.87 g of diene (yield 69%) are obtained in the form of a solid colorless derivative with a hydroperoxide group in the product which is in the usual organic solution ⁶ ° 11-position, which is obtained as such in the further course medium soluble, used in water and dilute aqueous synthesis.

Acids and alkalis is insoluble, F. = approximately "_. ,.

⁶ ' ⁶ 2nd reduction

The derivative obtained above with a gj _ner hydroperoxide group in the 11-position is introduced into 6.5 ecm of ethanol, 0.65 ecm of triethyl phosphite is added and the mixture is stirred under reflux for 1 hour; it is brought to room temperature and 1.3 ecm 30% is added

509 525/354

IR spectrum - chloroform:

Presence of OH at 3590 cm- ¹ ,
Presence of C s CH at 3300 cm- ¹ ,
Presence of unconjugated ketone.

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

_{Stage C:} Preparation of 3-oxo-7 "-methyl-II / 3.17 / S-dihydroxy-17" -ethinyl-oestra-4,9-diene

Introduction of the hydroperoxide group

IR spectrum:

Absence of C = O,
Presence of OH at 3950 cm " ¹ ,
Presence of C = CH at 3300 cm- ¹

Hydrogen peroxide and 1.3 ecm of distilled water are added, the mixture is stirred for 1 hour and 35 ecm are added Water too; it is extracted with methylene chloride, the organic phase is washed with water and dried over sodium sulfate and evaporated to dryness; the residue is heated with isopropyl ether stirred, it is then cooled, filtered, the precipitate is filtered off with suction, washed with water and dried him; 0.79 g of 3-oxo-7Ä-methyl-l 1) 5,17 / 9-dihydroxy-17 "-ethinyl-oestra-4,9-diene are obtained in the form of a solid product that is sparingly soluble in the ordinary organic solvents, in water and diluted is insoluble in aqueous acids and alkalis, m.p. = at 195 ° C.

IR spectrum - chloroform:

Presence of C ξ CH at 3300 cm " ¹ ,
Presence of conjugated ketone.

UV spectrum - ethanol:

A _max 213 to 214 πιμ £}? "= 149,

; Wx234m (x £ 15. = 141,
Inflexion at about 239

up to 240 πιμ £ & = 138,

Ä 299 ΐημ £}, = 556.

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

Example 11

Production of S-

droxy-estra-4,9-diene

2 g of 3-oxo-II ^, 17 /? -Dihydroxy-17 "-äthinylöstra-4,9-diene are dissolved in 100 ecm of pure methylene chloride at room temperature. 2 g of sodium azide are added under nitrogen to, stir for 1 minute, add 2 ecm of 65% perchloric acid and stir for 3 minutes. The reaction mixture is poured into 200 ecm of ice-water mixture, and the organic phase is washed with water, with a sodium bicarbonate solution and water and distilled to dryness in vacuo. Man dissolves the residue in 10 ecm of ether, filtered, sucks off the precipitate and washed with ether. You get 1.40 g of crude product, which is purified by chromatography on magnesium silicate. You get 3 - Oxo - HyS - azido - 17α - äthinyl -17/5 - hydroxy - estra-4,9-diene, F. = 152 ° C.

Analysis C ₂₀ H ₂₃ O ₂ N ₃ = 337.40:

Calculated ... C 71.19%, H 6.87%, N 12.45%;
found ... C 71.1%, H 7.0%, N 12.4%.

IR spectrum - chloroform:

Presence of N ₃ at 2090 cm ¹ ,
Presence of C = O at 1660 cm " ¹ ,
Presence of C = C at 1612 cm- ¹ ,
Presence of OH at 3590 cm- ¹ ,
Presence of C ξ CH at 3300 cm- ¹ .

UV spectrum - ethanol:

Amax 214 ΓΠμ

Inflexion at about 228 ma
ax 292 to 293 πιμ

£ icm = 151,

£!. "- = 141,
£ & = 581.

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

Example 12

Production of S-Oxo ^ a-methyl-II / J-benzyloxy-17 /? - hydroxy-17a-ethinyl-oestra-4,9-diene

5 g are introduced into 250 ecm of carbon tetrachloride 3 - Oxo - 7 <x - methyl -11 / 9.17 /? - dihydroxy -17 \ - äthinylöstra-4,9-diene, prepared as in Example 10, and 5.2 ecm of benzyl alcohol. Add 2 ecm 32% Perchloric acid and stir this mixture during

ίο a few minutes. One then dilutes with water, separates the organic phase by decanting, washing it with water, drying it over sodium sulfate and evaporates to dryness. This crude product is chromatographed on silica gel and one obtains 3-Oxo-7x-methyl-II / 3-benzyloxy-17 /? - hydroxy-17.v ethinyl-estra-4,9-diene.

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

B e i s ρ i e 1 13

a-methyl-II / i-thio-17 / S-hydroxy-estra-4,9-diene

In 40 ecm of methylene chloride containing 0.60 g of hydrogen sulfide, 4 g of 3-oxo-7 \ -metlv I-11 / 9.17 /? - dihydroxy-17 "-ethinyl-oestra-4,9-diene are introduced, prepared as in Example 10, add 2 ecm 65 "perchloric acid and stir the mixture for a few minutes at ordinary temperature. After dilution with water, the organic phase is separated off by decanting, washed with water, dried and added under reduced pressure The crude product is purified by chromatography on silica gel and 3-oxo-7a-methyl-II /? - thio-17 "-ethinyl-17 /? - hydroxy-estni-4,9-diene is obtained 268 ⁰ C.

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

Example 14

17/9-hydroxy-estra-4,9-diene

In 400 ecm of methylene chloride, the 5 ecm of methyl mercaptan contains, 5 g of 3-oxo-7 \ -methylll / ?, 17/3-dihydroxy-17 £ t-ethinyl-oestra-4,9-diene, prepared as in Example 10, add 2.5 cm of 32% perchloric acid, stir for a few minutes at the usual rate Temperature, diluted with water, separates the organic phase by decanting, washing them with water, dries them and concentrates them to dryness under reduced pressure. The raw product is purified by chromatography on silica gel, and S-oxo ^ Ä-methyl-II / I-methyl-thio-17 <x-ethinyl-17/9-hydroxy-estra-4,9-diene is obtained. F. = 166 ° C.

As far as is known, this product is in the literature

not described.

In an analogous manner, methyl mercaptan is obtained replaced by ethyl mercaptan, propyl mercaptan or butyl mercaptan, 3-oxo-7 \ -methyI-ll /? - ethyl-17 "-äthinyl-17 /? - hydroxy-oestra-4,9-diene, 3-oxo-7Ti-methyl-II / 9-propyl-thio-17x-ethinyl-17 / i-hydroxy- oestra-4,9-diene and 3-oxo-7 \ -methyl-II /? - butyl-thio-17a-ethinyl-17 /? - hydroxy-oestra-4,9-diene.

As far as is known, these products are not described in the literature.

Example 15

Production of S-Oxo-II / S-methoxy-O / J-ethyl-17 /? - hydroxy-17oc-äthinyl-gona-4,9-diene

? _o = 137,

£ !? "= 573.

0.5 g of 3-i is dissolved
17 "-äthinyl-gona-4,9-diene in 25 ecm methylene chloride with 0.15% methanol and adds 0.1 ecm 65% perchloric acid. The mixture is stirred for a few minutes at room temperature, the solution is washed with water until the wash water is neutral and evaporated to dryness under reduced pressure. The crude product is chromatographed on silica gel, eluted with a mixture of benzene and ethyl acetate, and the product is purified by recrystallization from ether. 0.2 g of 3-oxo-11ß-methoxy-13 /? - ethyl-17/3-hydroxy-17 "-ethinyl-gona-4,9-diene, mp = 164 ° C; [«] § · = -110 ° to ± 2.5 ° (c = 0.58%, methanol).

UV spectrum - ethanol:.

^ max 231 Πΐμ.
Amax 295 Πΐμ

Analysis C ₂₂ H ₂₈ O ₃ = 340.44:

Calculated ... C 77.60%, H 8.29%;
found ... C 77.5%, H 8.6 <.

The product is soluble in alcohols, acetone, benzene and chloroform.

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

The starting compound not described in the literature, as far as known, the 3-oxo-II / 3.17 /? - dihydroxy -13/3 - ethyl - 17a - ethinyl - gona - 4.9 - diene (F. = 200 ⁰ C), based on the 3-oxo-13 / S-ethyl-17 /? -Hydroxy-17 * -äthinyl-gona-5 (10), 9 (ll) -diene described in Belgian patent specification 6 63 534, obtained by using the processes described in Belgian patents 6 49 223 and 6 49 224.

As indicated above, the new products of general formula I have interesting physiological Properties on. In particular, they have significant hypocholesterolemic activity and an inhibitory effect on pituitary gonadotropins.

They can be used to treat hypercholesterolemia and as a preventive or curative agent for arterial diseases, aortitis, coronary artery infections, Cerebral arteritis, angina pectoris and athesromatosis be used. They can also be used to treat pathological conditions due to Hypoestrogenia or due to an excess of pituitary hormones during castration or Menopause can be used.

The compounds of general formula I are applied buccal, perlingual, transcutaneous or rectal Routes administered.

They can be used in the form of injectable solutions or suspensions, in ampoules, vials repeated ingestion bottled, tablets, coated tablets, dragees, sublingual tablets, capsules or Suppositories are offered.

Depending on the compounds under consideration and the administration route under consideration the daily beneficial dose for adults is staggered between 0.5 and 20 mg for:

S-Oxo-II / S-methoxy-na-äthinyl-n / S-hydroxy-

östra-4,9-diene,
S-Oxo-ll ^ -ethoxy-na-äthinyl-n / S-hydroxy-

östra-4,9-diene,
3-Oxo-l l / J-methylthio-na-äthinyl-n / Miydroxy-

östra-4,9-diene,
3-Oxo-II ^ -tert.-butyloxy-17 «-äthinyl-17 /? - hy-

droxy-oestra-4,9-diene,

3-Oxo-lly? -Benzyloxy-17/3-hydroxy-17 ^ -äthinylöstra-4,9-diene,

3-Oxo-II ^ -methoxy-17/5-hydroxy-estra-4,9-diene,
3-Oxo-llß-thio-17 /? - hydroxy-17a-ethinyl-

östra-4,9-dien, and

3-Oxo-II / 9-n-butal-thio-17Ä-ethinyl-17 /? - hydroxyestr-4,9-diene;

the dose of 3-oxo-7 <x-methyl-II /? - methoxy-17x-ethinyl-17 /? - hydroxy-estra-4,9-diene staggered between 0.1 and 2 to 5 mg per day;

the dose of 3-oxo-II / 5-azido-17Ä-ethinyl-17/5-hydroxy-estra-4,9-diene staggered between 0.5 and 10 mg per day.

The pharmaceutical forms, such as injectable solutions or suspensions, tablets, coated tablets, Dragees, sublingual tablets, capsules and suppositories are produced using the usual methods.

Claims (1)

Patent claims: 1. Steroid derivatives substituted in the 11-position the general formula R ' ^v4 \ / \ ,OH