13-Alpha-alkyl-17-beta-(3-acyloxy-propyl)-gonane.

Novel 13α-alkyl-17β- (3-acyloxypropyl) -gonanes, their preparation and contraceptives containing them

The invention relates to novel 13α-alkyl-17β- (3-acyloxypropyl) gonanes of the general formula I, to a process for their preparation and to contraceptive preparations containing these compounds.

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wherein R is an acyl group of a carboxylic acid having up to 10 carbon atoms and X is an oxygen atom or a group N OH.

13α-Alkyl-17β- (3-hydroxypropyl) -4,9-gonadien-3-ones are known from European Patent Application No. 84730062.1 (FI Patent Publication 78,709). These compounds have a strong affinity for progestogen receptors without themselves having a progestogenic effect. They are competing antagonists (anti-gestagens) of progesterone, or luteinizing hormone, and are suitable for causing abortion because they cause the progesterone, which is needed to maintain the pregnancy, to leave the receptor. The compounds are therefore valuable and interesting in terms of their use in postpartum (pc) fertility control.

EP-A-116974 also discloses compounds of the same type which, however, differ from the invention

83039 (1) the substituent at the 13-position is in the B-configuration, while in the compounds of the present invention it is in the α-configuration, (2) they have the substituents 17B-OH and 17a- (CH) at the 17-position.₂ )₃-OH, while the compounds of the present invention have substituents 17α-OH and 17β- (CH₂)₃-O-acyl, and (3) they always contain an alkyl group at the 16- or 15-position, whereas the compounds of the present invention at each of the 16- and 15-positions have hydrogen. There are also differences in biological activity, the compounds known from EP 116974 are antigestagenic and antiminergic corticoids, while the compounds of the present invention are antigestagenic.

It has now been found that by converting the compounds known from FI patent publication 78 709 into 13α-alkyl-17β- (3-acyloxypropyl) gonanes of the general formula I, their utilization can surprisingly be substantially improved. As a result, they have a substantially prolonged or substantially longer duration of action compared to previously known 13α-acyl-17β- (3-hydroxypropyl) -4,9-gonadien-3-ones. As an additional advantage, it was further found that the crystallization properties of the new compounds were excellent. The preparation of pure active substances therefore causes considerably less difficulty for them than in the case of 13α-alkyl-17β (3-hydroxypropyl) -4,9-gonadien-3-ones.

Furthermore, they have excellent chemical stability. They can be stored at room temperature for an extended period of time without decomposition.

The acyl group R in the general formula I must contain at most 10 carbon atoms. Examples of acyl groups are formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, glycoloyl, cyclopentylacetyl, mono-, di-, trichloroacetyl, benzoyl, trifluoromethylbenzoyl and nicotinoyl; acetyl and benzoyl groups are preferred.

X is an oxygen atom or, when grouped, N OH, the hydroxyimino group may be in the syn or anti position.

The compounds of the general formula I according to the invention are prepared according to Claim 5 using methods known per se. Preferred bases for esterification are tertiary amines, such as pyridine. The preferred tertiary amine in the reaction used to prepare the oximes is py ridine.

Other suitable tertiary bases include, for example, trimethylamine, triethylamine, N, N-dimethylaminopyridine, 1,5-diazabicyclo [4.5.0] noneene-5 (DBN) and 1,5-diazabicyclo [5.4.0] undecene-5 (DBU).

The 13α-alkyl gonanes of the general formula I can be used as pharmaceuticals for the prevention of pregnancy. The preparations are prepared according to the methods of galenics known per se by mixing with an organic or inorganic inert carrier suitable for enteral, parenteral or transdermal administration.

The dosage of the active ingredients according to the invention in humans is about 10-1000 mg / day.

The invention is illustrated by, but not limited to, the following examples.

Example 1

A solution of 2.4 g of 11β- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-176- (3-hydroxypropyl) -4,9-gonadien-3-one in 7 ml of pyridine and 14 ml of acetic anhydride stirred for 14 hours at 25 ° C. Finally, pour int o warm water (100 ml) at about 50 ° C, stir for 15 min. time and the cooled emulsion is extracted with methylene chloride. The methylene chloride phase is washed with NaHCO₃solution to neutral, dried over Na₂SO₄and evaporated. Crystallization of the crude product from ethyl acetate / diisopropyl ether gives 2.24 g of 17β- (3-acetoxypropyl) -118- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-4,9-gonadien-3-one, m.p. is 162-164 ° C.

[A]²⁵ + 436.5 ° (CHCl 3₃, c = 0.515).

Example 2

To a solution of 700 mg of 11β- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-17β- (3-hydroxypropyl) -4,9-gonadien-3-one in 5 ml of pyridine is added dropwise 0.36 ml of ice water under cooling. benzoyl chloride in 4 ml of methylene chloride. Stir for 60 minutes at + 5 ° C, then pour into saturated NaCHO₃solution and extracted with ethyl acetate. Crystallization of the crude product from hexane / diisopropyl ether gives 630 mg of 17β- (3-benzoyloxypropyl) -11β- (4-dimethylaminophenyl) -17-hydroxy-13α-methyl-4,9-gonadien-3-one, m.p. is 114-116 ° C.

Example 3

A solution of 630 mg of 17β- (3-acetoxypropyl) -1β- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-4,9-gonadien-3-one in 10 ml of pyridine is stirred after the addition of 600 mg of hydroxylamine. hydrochloride for 1.5 hours at 0 ° C. Finally, pour into ice water / saturated NH₄Cl solution and extracted with ethyl acetate. After chromatography on silica gel using hexane / ethyl acetate, 410 mg of 17β- (3-acetoxypropyl) -HB- (4-dimethylaminophenyl) -1α-hydroxy-13α-methyl-4,9-gonadien-3-one anti-oxime are obtained, by sp. is 201-204 ° C. UV (MeOH):_Bax 288 nm (= 27400).

Example 4

An oral tablet containing 17β (3-acetoxypropyl) -11β - [(4-N, N-dimethylamino) phenyl] 17α-hydroxy-13α-methyl-4,9-gonadien-3-one is prepared from the following ingredients:

17β- (3-acetoxypropyl) -11β - [(4-N, N-dimethylamino) phenyl] -17α-hydroxy13α-methyl-4,9-gonadien-3-one 10 mg

<td></td><td>lactose</td><td>140.5 mg</td>

<td> 5</td><td>malssitärkkelystä</td><td>69.5 mg</td>

<td></td><td>polyvinylpyrrolidone 25</td><td>2.5 mg</td>

<td></td><td>aerosiiliä</td><td>2.0 mg</td>

magnesium stearate

0.5 mg

225.0 mg