DE1493174B - 6-chloro-1,2 alpha; 16.17 alphabismethylene delta high 4,6-pregnadiene-3,20-dione, a drug containing this compound and process for the preparation of 1,2 alpha; 16.17 alpha-bismethylene delta high 4,6-pregnadienes - Google Patents

Description

C = O

wherein R represents hydrogen or halogen, characterized in that the ^ "- double bond in the corresponding Δ ¹⁶ - steroid with R meaning hydrogen is methylenated by methods known per se and then in the resulting 1,2ix; 16,17a-bismethylene compound if desired, the Δ ^ double bond is epoxidized with a percarboxylic acid in a manner known per se and the 6,7'-oxido compound formed primarily, depending on the ultimately desired meaning for R

a) if it is chlorine, bromine or iodine, with the corresponding hydrohalic acid with simultaneous cleavage of both cyclopropane rings and the epoxide ring to give the la, 16a-bis- (halomethyl) -6-halo -Δ * · ^6-3 - keto compound or

b) if R denotes fluorine, with hydrofluoric acid primarily to the 6 / S-fluoro-7 "-hydroxyl, 2"; 16,17 "-bismethylene intermediate and this by means of hydrochloric, bromic or hydroiodic acid with elimination of the 7" -hydroxy group converted into the 1, 16a-bis (halomethyl) -6-fluoro-zl ⁴ - ^e -3-keto compound according to procedures known per se

and finally the la- and 16a-halomethyl groups closes with bases to form the cyclopropane ring.

2. 6-chloro-1,2α; 16,17α-bismethylene-J ⁴ - ⁶ -pregnadiene-3,20-dione.

3. Medicaments containing the compound according to claim 2 as an active ingredient.

The invention relates to 6-chloro-l, 2a; 16,17 '-bismethylen ^{Zl-4' e} -Pregnadien-3,20-diene, this compound-containing pharmaceutical compositions and methods for the preparation of l, 2a; 16,17a-Bismethylen- zi ⁴ ' ⁶ -pregnadienes

10

15 in which R represents hydrogen or halogen, which is characterized in that the Δ "double bond in the corresponding Δ " steroid with R meaning hydrogen is methylenated by methods known per se and in the resulting 1,2 "; 16, 17a-bismethylene compound then, if desired, epoxidized the Δ ″ double bond with a percarboxylic acid in a manner known per se and the 6,7a-oxido compound formed primarily, depending on the ultimately desired meaning for R

a) if R is chlorine, bromine or iodine, with the corresponding hydrohalic acid below simultaneous cleavage of both cyclopropane rings

and of the epoxy ring to the la, 16 "-Bis- (halomethyl) -6-halo-zl ⁴ · ⁶ -3-keto compound or

b) if R denotes fluorine, with hydrofluoric acid primarily to give the 6 /? - fluoro-7a-hydroxy-1,2 "; 16,17abismethylene intermediate and this by means of

Procedures known in the la, 16a-bis (halomethyl) -6-fluoro-id ^{4 'e} transferred -3-keto compound chlorine, bromine or hydriodic acid, with elimination of the 7a-hydroxy group according to per se

40

and finally closes the 1cc- and 16a-halomethyl groups with bases to form the cyclopropane ring.

The methylenation of the -d "double bond is expediently carried out either by using methods known per se
A. Diazomethane attaches and the resulting [Δ ! '- PyrazolinoH' ^ 'jlö,!? α-steroid

45

a) at high temperature, preferably about 220 to 250 ° C, and advantageously either im High vacuum or using a high-boiling base, for example quinoline or aniline, as a solvent and in the presence of an inert protective gas, for example nitrogen, or

b) by the action of acidic catalysts such as fluoroboric acid, Boron trifluoride etherate or especially perchloric acid in organic solvents, for example in acetone, preferably at room temperature

converted into the corresponding 16.17 a-methylene compound or that one can also use known methods

B. introduces the methylene group directly with dimethylsulfoxonium methylide.

To prepare compounds with R meaning halogen, the 6,7α-Οχί-do compound is first prepared. For this purpose, the Δ ^β double bond with the usual percarboxylic acids such as

Peracetic acid, perbenzoic acid, or monoperphthalic acid, as in this case it is a selective reaction acts, preferably with m-chloroperbenzoic acid, epoxidized.

If end products with R meaning chlorine, bromine or iodine are desired, the 6,7a-oxido compound is opened with the corresponding hydrohalic acid. The reaction is carried out in an organic acid as solvent, preferably in glacial acetic acid. Under these reaction conditions, the 7α-hydroxyl group formed primarily is eliminated with the escape of water to form the desired A ^ double bond, and at the same time both cyclopropane rings are cleaved by addition of hydrogen halide. The resulting 1, 16a-bis (halomethyl) compound can then be converted back into the 1, 2 "; 16,17a-bismethylene compound by treatment with bases. Suitable agents for splitting off hydrogen halide are, in particular, inorganic bases, such as, for example, sodium or potassium hydroxide. The reaction is expediently carried out in alcoholic solution, preferably using methanol, in particular at boiling temperatures. But you can also selectively convert the 1 a-halomethyl group into the 1,2oc-methylene group by heating the corresponding 1 a, 16 <x -bis (halomethyl) compound in organic bases such as collidine. This must be followed by a treatment with inorganic bases as described above.

If end products with R meaning fluorine are desired, the 6.7% - oxido compound with Hydrofluoric acid in an organic solvent or solvent mixture, preferably in Dimethylformamide, opened. In this case, the 6/9 fluoro-7'-hydroxy compound is formed, which is responsible for splitting off water is treated with mineral acids. As mineral acids, for example, chlorine, bromine or Hydriodic acid dissolved in organic acids,

ίο preferably used in acetic acid. Under These conditions are both the spin-off of Water as well as the opening of the two cyclopropane rings, which then, as above, with bases again to form the cyclopropane ring getting closed.

The compounds which can be prepared according to the invention have strong ovulation-inhibiting and low gestagenic activities, as shown in the following table using the example of 6-chloro-1,2a; 16.17'-bismethylene- Δ ^4> * -pregnadiene-3,20-dione in comparison with known ovulation inhibitors is shown.

The gestagenic effectiveness is determined in the well-known oral Clauberg test, the inhibition of ovulation by tube inspection. For the inhibition of ovulation that dose (WD ₅₀₎ is specified, (normal female rats) is not output after the peroral administration, at 50 ° / ₀ of the animals ovulation. In the case of gestagenic efficacy, the minimum amount that is just sufficient to achieve a positive Clauberg test in infantile rabbits is given.

table

Substance Clauberg p. O.

Threshold dose

(mg)

Ovulation inhibition po WD ₅₀ (mg)

6-chloro-1,2 «; 16,17 a-bismethylene-zl ⁴ ·" -pregnadiene-3,20-dione (I)

6-chloro-1,2 «-methylene-zl ⁴ ' ⁶ -pregnadien-17a-ol-3,20-dione-17-acetate (II)

6-chloro-Zl ⁴ ' ⁶ -pregnadiene-17 «-ol-3,20-dione-17-acetate (III)

17a-ethynyl-19-nor-testosterone (IV)

17a-ethynyl-19-nor-testosterone-acetate (V)

17 a-ethynyl-Λ ⁵ ( ¹⁰ > -19-nor-androsten-17ß-ol (VI)

0.3
inactive

0.01

0.03

0.1

0.03

0.3

Ibis 3

3 to 10

The table clearly shows the superior anti-ovulatory and the lack of gestagenic activity of the compound I according to the invention at one dose of 0.3 mg. While with the previously known gestagen ovulation inhibitors (II to VI) the effective dose for ovulation inhibition is ten to one hundred times is higher than the threshold dose in the Clauberg test, one already finds inhibition of ovulation with I. at a dosage at which the gestagenic effect does not yet appear. With that, the new compounds, for example for the treatment of climacteric complaints, can be of great use.

The 1,2 κ- methylene- Δ ⁴ · ⁶ · ^{x β} -pregnatriene-3,20-dione, which is used as the starting material of the present process and has not been described in the literature, can be prepared by methods known per se, for example as follows:

10 g 1.2 a. - Methylene - Δ ⁴ > ^β - pregnadiene -17 α - ol-3,20-dione-17-acetate (prepared according to the process described in German Auslegeschrift 1 096 353) are boiled with 150 ml of distilled quinoline for 5 hours under nitrogen heated. After cooling, the mixture is stirred into excess ice-water with hydrochloric acid, extracted with ether and the organic phase is washed neutral with water. The residue remaining after drying over sodium sulfate and concentration to dryness is recrystallized from ethyl acetate. It will be 5.2 gl, 2a-methylene-Zl ^{4 'e} - ^ie -pregnatriene-3,20-dione of melting point 279 to 280.5 ° C was obtained.
UV: ε ₂₃₉ = 14,600; ε ₂₈₂ = 20,800 (methanol).

"··,.,

example 1

To 100 ml of ethereal diazomethane solution, prepared from 24.5 g of nitrosomethylurea, 3.2 g of 1,2 "-methylene-zl ⁴ ' ^e ' ^ie -prenatriene-3,20-dione, dissolved in 65 ml of methylene chloride, are added and 3 days stored closed at room temperature. Then precipitated polymers are filtered off and evaporated to dryness in vacuo. According to isopropyl ether

5 6

trituration will be 3.4 g of crude [A ¹ '-pyrazolino] 1.45 g of 6-chloro-loc, 16 «-bis- (chloromethyl) -zl ⁴ - ^e -pre-

4 ', 3'; 16,17- [1,2cx-methylene-zl ⁴ ' ^e -pregnadien-3,20-dione] Gnadien-3,20-dione obtained as a crude product

from a melting point of 180 to 182 ° C (decomposition) can be obtained.

th. 1.45 g of the crude chloromethyl compound are in

UV: ε ₂₈₀ = 19,000 (methanol). 5 50 ml collidine to the boil for 30 minutes under nitrogen

3.8 g of pyrazolino compound are heated with stirring. It is mixed with ether, with diluted

washed in portions to a solution of 105 ml of acetone and hydrochloric acid and water. After drying

1.5 ml of 70 ° / ₀ perchloric acid was added. After being over sodium sulphate, it is dried to dryness in a vacuum

The final addition is stirred into ice water, which is evaporated. The remaining residue is on

the precipitate which has fallen is suctioned off, washed and treated with silica gel with a 49: 1 benzene-ethyl acetate mixture

dries. Chromatographed on after chromatographic filtration. It will be recrystallized from

Silica gel, recrystallized from methanol, 2.1 g of ethyl acetate, 700 mg of ö-chloro-loa-chloromethyl-l ^ a-me-

1.2 oc; 16.17 α - bis - methylene - Δ ⁴ - ⁶ -pregnadiene-3,20-dione ethylene-zl ^{4> 6} -pregnadiene-3,20-dione from the melting point

obtained from melting point 198 to 199.5 ° C. 221.5 to 222.5 ⁰ C obtained.

UV: ε ₂₈₂ ■ = 21,200 (methanol). 15 UV: ε ₂₈₂ = 15,700 (methanol).

. -19 420 mg of loa-chloromethyl compound are in 42 ml

Example 2 Methanol with 126 mg of potassium hydroxide for 16 hours on

Another way of methylenation is reflux. Then the Zl ¹⁶ compound is diluted with methylene conversion with dimethyl sulf chloride, washed neutral with water and oxonium methylide. . 20 dried over sodium sulfate. After evaporation

For this purpose 1.58 g of trimethylsulfoxonium iodide are added and the remaining residue is removed to dryness

345 mg sodium hydride recrystallized than 50 ° / ₀ strength oil suspension in Essigester. 330 mg of 6-chloro

L 30 ml of dimethylsulfoxide for 30 minutes at Raumtempera-, 2a; 16,17a-bismethylene-z J ^{4 'e} -Pregnadien-dione 3,20-

door stirred under nitrogen. Subsequently, a melting point of 231 to 232 ° C. is obtained.

1.93 gl, 2 "-Methylene-zl ⁴ ' ^e ' ^ie -pregnatrien-3.20-dione 25 UV: ε ₂₈₂ = 17 100 (methanol),

added and 16 hours at room temperature.

stirs. fs example 4

It is then poured into ice-water with weak acetic acid, 3 gl, 2 "; 16,17a-bisniethylen-6,7oi-epoxy-zl ⁴ -prirred, the precipitate which has separated out is filtered off with suction, and 3,20-dione is added for 5 hours Wash at room temperature and dry. Recrystallized from metha- 30 in a solution of 15 ml of hydrofluoric acid in nol, 1.23 g of 1,2 ”; 16,17a-bis-methylene / ^{I 4} ' ⁶ -pre- 15 ml of dimethylformamide are stirred. It is then stirred into gnadiene-3,20-dione with a melting point of 198 to 199 ° C potassium hydrogen carbonate solution, extracted with sea hold, ethylene chloride, washed neutral with water

UV: ε ₂₈₂ = 21,300 (methanol). and dried over sodium sulfate. After entering

. 35 evaporate to dryness, the residue is composed

α e 1 s ρ 1 e Ι ό _aug 6 £ -Fluor-l, 2a; 16,17a-bismethylene-zl ⁴ -pregnen-

1.57 g 1,2α; 16,17α - bismethylene - zl ⁴ · ⁶ - pregna- 7a-ol-3,20-dione, dissolved in 30 ml glacial acetic acid and mixed with diene-3,20-dione in 15 ml ethylene chloride saturated with 1.9 g of dry hydrogen chloride gas. After 20stün-85 ° / _o solution of m-chloroperbenzoic acid in 10 ml of ether ended reaction time of 5 days, stirred into ice water, kept at room temperature. Then the precipitated precipitate is filtered off with suction, diluted in methylene with methylene chloride, taken up with weak sulfur chloride and washed with sodium hydrogen acid iron (II) sulfate solution, sodium hydrogen carbonate solution and water. It is washed over sodium solution and water. The dried after the sodium sulfate and evaporated to dryness in vacuo, drying over sodium sulfate and evaporation. The thus obtained crude 6-fluoro-1 «, 16a-to-dry residue is ^{recrystallized from ethyl acetate 45 (chloromethyl) -zl 4! E} -pregnadiene-3,20-djon is recrystallized in 300 ml. 1.4 g, 2oc; 16,17a-bis-methanol are taken up and refluxed with 1.05 g of potassium methylene -6.7 α-epoxy -Zl ⁴ -pregnen-3,20-dione of the hydroxide for 16 hours. Obtained after melting point 251 to 252 ° C, working analogously to Example 3, the residue is obtained

UV: ε ₂₁₆ = 12,200; ε ₂₃₀ = 12,100 (methanol). Silica gel with a benzene-ethyl acetate mixture (19: 1)

1.24 g of epoxide are dissolved in 62 ml of glacial acetic acid and chromatographed with 50%. It will be recrystallized from

saturated dry hydrogen chloride gas and ethyl acetate for 20 hours, 1.35 g of 6-fluoro-1,2 ”; 16.17 «-bismethylene-

stored at room temperature. Then Zl ^{4> e} -pregnadien-3,20-d ion obtained, F. from 250 ° C below

is stirred into ice water, the precipitated low - slow decomposition,

blow vacuumed, washed and dried. UV: ε ₂₈₂ = 17,300 (methanol).

Claims (1)

Patent claims: 1. A process for the preparation of l, 2 '; 16,17-bismethylene-zl ^{4' e} -pregnadienen of the general formula the general formula CH ₃