NO127535B - - Google Patents

Abstract

Analogous process for the production of new, tera-. The present invention relates to an analogous process for the preparation of novel 17-hydroxy- and -alkanoyloxy-6B, 76-epoxy-1α, 2α-methylene-4-pregnene-3,20-diones. 6β, 7β-epoxy-1α, 2α-methylene-4-pregnene-3,20-diones of the general formula:

Description

where R is hydrogen or alkanoyl with 1-15 carbon atoms.

The new 6(3,7P-epoxy-1a,2a-methylene steroids have valuable

pharmacological properties. They exhibit a surprisingly strong progestagen activity, especially when administered orally. A particular advantage of the present process compounds lies in the fact that these have practically no antiandrogenic side effects. Surprisingly up-

the new progestogenic compounds also do not show any central hem-

ning effect (ovulation inhibition) in high doses.

The following tables show the superiority of the method for

the bonds exemplified by 17-acetoxy-6f3,7(3-epoxy-1a,2a-methylene-4-pregnene-3,20-dione (I). The known gestagenic compound 6-chloro-17-acetoxy-4 ,6-pregnadiene-3,20-

dione (II).

The progestogenic effect was tested in the usual Claubert test.

The threshold value was determined to be the total dose for at least two out of three cases

small rabbits caused a transformative transformation of the endometrium.

Ovulation inhibition was checked by tubal inspection.

When determining the antiandrogenic side effect, castrates were given

male rats during 7 days daily the test compound administered per us (p.o.). Over the same period, the animals received daily 0.1 mg of testosterone propionate subcutaneously. On the eighth day, the animals were killed and the weight of the gonads determined. The percentage inhibition of the growth of the seminal vesicle (Sbl.) and prostate (Pr.) caused by the test compound

was best emt.

The main area of application for the active substances produced by pre-

procedure is the treatment of the following gynecological

conditions: primary amenorrhoea and secondary amenorrhoea of longer duration

ity, cycle disturbances due to insufficient corpora lutea function,

Endometriosis, Uterine hypoplasia, premenstrual difficulties and Mastopathie.

The dose used will depend on the severity of the disease. In general, between 5 and 100 mg will be administered daily. The production of the medicinal preparations takes place in the usual way, as the active substances are prepared with suitable additives, carriers and flavor corrections for the usual commercial preparations. For oral administration, tablets, diragés, capsules, pills, suspensions or solutions are particularly suitable.

In the present method, the compounds of formula I are prepared by 6(3-hydroxy - , respectively 6|3-acyloxy-7a-halosteroids of the general formula:

where R<*> is hydrogen or alkanoyl with 1-15 carbon atoms, X is chlorine or bromine, and Ac is alkanoyl with 1-15 carbon atoms, is reacted with bases in a solvent that is inert towards the reactants, and a free 17-hydroxy group possibly esterified.

Solvents miscible with water, such as methanol, ethanol, acetone, tetrahydrofuran, dimethylsulfoxide or mixtures of these solvents, such as ethanol with acetone, are preferably used as inert solvents.

As bases for the oxirane ring closure according to the invention, e.g. alkali metal carbonates and hydrogen carbonates, such as potassium carbonate and sodium hydrogen carbonate, alkali metal hydroxides, such as potassium and sodium hydroxide, alkali metal alcoholates, such as potassium t-butylate and the like, in question.

Depending on the strength of the base used and the height of the reaction temperature, a greater or lesser proportion of the saponification product is obtained. By suitably choosing the reaction conditions, free or esterified 17a-hydroxy compounds can be obtained. Thus, with potassium carbonate in ethanol and acetone at room temperature, the 6(3,7(3-epoxide with the unchanged acyloxy group in the 17a position is obtained. With the same reagents in the heat after a reaction time of about 20 hours, an epoxide whose 17 -alkanoyloxy group is extensively saponified.With potassium hydroxide as a base, 6p,7P~epoxyd with the free 17a-hydroxy group is already formed after a short reaction time at room temperature.

The possibly subsequent esterification or reacylation of the 17a-hydroxy group is preferably carried out with a reactive acid derivative in the presence of basic reagents. In particular, mention can be made of the reaction with acid anhydride, respectively acid halide, in the presence of pyridine in the heat.

The previously described 6{3-hydroxy-, resp. 6|3-alkanoyloxy-7a-halo-steroids which can be prepared from the corresponding ^-unsaturated steroids.

Thus one obtains, for example, from 17-alkanoyloxy-1a,2a-methylene-4,6-pregnadiene-3,20-dione with N-bromo-, resp. N-Chlorosuccinimide and water in the presence of perchloric acid in dioxane the following 6(3-hydroxy-7a-halo-steroids:

7α-bromo-6β-hydroxy-17-acetoxy-1α,2α-methylene-4-pregnene-3,20-dione,

m.p. 185 - 185.5°C,

7α-bromo-6(3-hydroxy-17-hexanoyloxy-1α,2α-methylene-4-pregnene-3,20-dione as oil,

7α-chloro-6β-hydroxy-17-acetoxy-1α,2α-methylene-4-pregnene-3,20-dione,

m.p. 239 - 239.5°C.

From 17-acetoxy-1a,2a-methylene-4,6-pregnadiene-3,20-dione with N-bromo- or N-chlorosuccinimide and the corresponding carboxylic acid in hydrogen chloride-saturated tetrahydrofuran are obtained, e.g. with acetic acid:

7α-bromo-6β,17-diacetoxy-1α,2α-methylene-4-pregnene-3,20-dione,

m.p. 194 - 195°C,

7α-chloro-6β,17-diacetoxy-1α,2α-methylene-4-pregnene-3,20-dione,

m.p. 237 - 238°C,

with formic acid: 7α-bromo-6β-formyloxy-17-acetoxy-1α,2α-methylene-4-pregnene-3,20-dione, m.p. 217 - 218.5°C,

7a-chloro-6f3-formyloxy-17-acetoxy-1a,2a-methylene-4-pregnene-3,20-dione, m.p. 247 - 248°C

17-hydroxy-, 17-acetoxy- and 17-hexanoyloxy-6(3,7P-epoxy-1a,2a-methylene-4-pr,egnen-3,2-dione are preferred process compounds due to their pharmacological and physico-chemical properties.

Example 1

10.0 g of 7α-bromo-6|3-hydroxy-17-acetoxy-1α,2α-methylene-4-pregnene-3,20-dione was dissolved in 200 ml of ethanol and 100 ml of acetone, to which was added a solution of 10 g potassium carbonate and 25 ml of water and stirred for 48 hours at 25°C. The reaction mixture was then poured into water, the precipitate was filtered off with suction, washed, dried and recrystallized from acetone/hexane. 7.15 g of 17-acetoxy-6β,7β-epoxy-1α,2α-methylene-4~pregnene-3,20-dione were obtained with m.p. 244 - 245°C UV: £24o = 15'8°0-

The same 6{3, 7|3-epoxide is formed analogously from 7a-bromo-6(3-formyloxy-17-acetoxy-1a,2a-methylene-4-pregnene-3,20-dione.

Example 2

A solution of 1.2 g of α-chloro-6β-hydroxy-17-acetoxy-la garnet hylene-4-pregnene-3,20-dione in 24 ml of methanol was added with 600 mg of potassium carbonate in 3 ml of water and heated in 3 hours by boiling. The reaction mixture was then poured into water, the precipitate that had formed was sucked off, taken up in methylene chloride, washed with water, dried and concentrated in vacuo. After chromatography on silica gel, the product was recrystallized from isopropyl ether, thereby obtaining 650 mg of 17-acetoxy-6(3,7(3-epoxy-1a,2a-methylene-4-pregnen-3,20-dione with m.p. 240 - 242 ° C. UV: e- 2k0 = 15-000'

The same 6p,7f5-epoxide was obtained analogously from 7a-chloro-6{3,17-diacetoxy-1a, 2a-methylene-4-pregnene-3,20-dione and from 7a-chloro-6|3-formyl- oxy-17-acetoxy-1α,2α-methylene-4-pregnene-3,20-dione. Example 3

3.0 g of 7α-bromo-6β-hydroxy-17-acetoxy-1α,2α-methylene-4-pregnene-3,20-dione was dissolved in 60 ml of ethanol, to which was added an aqueous solution of 1.5 g of potassium carbonate in 7 .5 ml of water and boiled for 24 hours. The reaction mixture was then poured into water, the precipitate was suctioned off, washed, dried and recrystallized from acetone/hexane. 1.56 g of 17-hydroxy-6p,7p-epoxy-1a,2a-methylene-4-pregnene-3,20-dione with m.p. 280 - 283°C. UV: E 2 Z f Q = 15,100.

Example 4

A solution of 500 mg of 7α-bromo-6|3-hydroxy-17-acetoxy-1α,2α-methylene-4-pregnene-3,20-dione in 10 ml of ethanol and 5 ml of acetone was added to 2.5 ml of 20% -ig aqueous potash and stirred for 30 minutes at room temperature. The mixture was poured into water, the precipitated material was suctioned off, washed with water, dried in vacuum and recrystallized from acetone/hexane. 297 mg of 17-hydroxy-6(3,7(3-epoxy-1a,2a-methylene-4-pregnene-3,20-dione with mp. 279 - 281°C) was obtained.

Example 5

1.0 g of 7α-bromoT6(3-hydroxy-17-hexanoyloxy-1α,2α-methylene-4-pregnen-3,20-dione was reacted under the conditions described in example 1. The crude product was chromatographed on silica gel. With In 9 - 11% acetone/pentane, 550 mg of 17-hexanoyloxy-6(3,7(3-epoxy-1a,2a-methylene-4-pregnene-3,20-dione) was eluted as a viscous oil.

UV: £ „> ~ 15-400. The oil solidified after some time into a crystalline mass which melted at 129 - 130°C.

Claims (4)

1. Analogous method for the production of therapeutically active 17-hydroxy- and 17-alkanoyloxy-6(3,7p-epoxy-1a,2a-methylene-4-pregnene-3,20-diones with the general formula: where R is hydrogen or alkanoyl with 1-15 carbon atoms, characterized in that 6|3-hydroxy- or 6(3-alkane- oyloxy-7a-halogen steroids of the general formula: where R<*> is hydrogen or alkanoyl with 1-15 carbon atoms, X is chlorine or bromine, and Ac is alkanoyl with 1-15 carbon atoms, is reacted with bases in a solvent that is inert to the reactants, and a free 17-hydroxy group optionally esterified. 2. Process according to claim 1 for the production of 17-hydroxy-6(3,7(3-epoxy-1a,2a-methylene-4-pregnen-3,20-dione, characterized in that a starting material is used where R' is hydrogen. 3^ Method according to claim 1 for the production of 17-acetoxy-6p,7(3-epoxy-1a,2a-methylene-4-pregnene-3,20-dione, characterized in that a starting material is used where R' is acetyl, or that an obtained compound where R is hydrogen is esterified with an acetyl compound. 4. Method according to claim 1 for the production of 17-hexanoyloxy-6|3,7(3-epoxy-1a,2a-methylene-4-pregirene-3,20-dione, characterized in that a starting material is used where R' is hexanoyl, or that a compound obtained where R is hydrogen is esterified with a hexanoic acid compound.