Novel Pharmaceutical Compositions Endowed With Anti-Progesteronic Properties and a Process for Making the Same

I. Field of the Invention

This invention relates to novel pharmaceutical compositions intended to prevent the effects of natural progesterone.

More precisely it relates to novel pharmaceutical compositions containing as their active ingredient an anti-progesterone effective amount of a .DELTA.-2 androstenic derivative of formula I: ##STR1## wherein: R is a hydrogen, the acyl residue of an organic carboxylic acid, a lower alkyl radical or the tetrahydropyranyl radical,

in admixture or conjunction with an inert, nontoxic and pharmaceutically acceptable carrier or vehicle.

II. Description of the Prior Art

These compounds and most particularly the 17.beta.-acetoxy derivative have already been disclosed in the literature, specifically in British Pat. No. 1492746. More recently, processes for their purification have been disclosed, for example, in European Pat. No. 66 601, or in European Patent Application No. 86-4006226, filed on Mar. 25, 1986, in the name of Laboratoire Theramex. The known biological properties of these compounds are defined by gonadotropic curbing actions on the hypophysis and the gonads, and are evidenced by the involution of the ovaries and testes in laboratory animals.

Previously disclosed therapeutic uses for the compounds of formula I related to endometriosis, to benign disease of the breast and to pseudogestation in animals, namely in female dogs.

More recent biological studies have shown that these compounds when given orally or by injection under the hereinafter mentioned conditions strongly interfere with the physiological effects of progesterone, acting as an antagonist of this hormone when administered to mammals in a physiologically effective amount.

Even at high doses (25 mg in rabbits) the compounds of formula I (the main representative of which is 17.alpha.-ethynyl-17.beta.-acetoxy-5.alpha.-androst-2-ene) induce only a weak pseudogestative action, i.e. <2.5% of that of progesterone. To the contrary, they antagonize the action of progesterone in rabbits after administration either orally or parenterally. Evaluation of the inhibiting action on endometrium proliferation due to progesterone was based on a determination according to Clauberg's test and Mac Phail's index, well-accepted evaluative criteria.

The observed inhibition was statistically significant when the compounds were administered by sub-cutaneous route at single doses of 5 mg, and total doses of 10 mg, against 1.9 mg of injected progesterone.

The action of 17.beta.-acetoxy-17.alpha.-ethynyl-5.alpha.-androst-2-ene is more significant by oral administration. The observed inhibition was practically total at 5 mg against 0.24 mg of injected progesterone. Inhibition was also very marked at doses of 10 mg against 1.9 mg of injected progesterone.

Given to rats by mouth before nidation (one to five days after mating of gestating rats) at doses of 5 mg/kg/day, the compounds of formula I made gestation impossible. Under the same conditions of treatment they decreased the number of fetuses which implanted, comparison to a dose of 1.25 mg/kg/day in the rat.

In rabbits, gestation was prevented by a dose as low as 5 mg/kg/day, given from the time of mating.

Moreover, 17.beta.-acetoxy-17.alpha.-ethynyl-5.alpha.-androst-2-ene also showed an anti-nidatory and an abortive action at the same time.

The pharmaceutical compositions according to this invention are hence efficient medicines to impede nidation and gestation in humans when given at the start of the pregnancy. They can be used either orally or parenterally.

The necessary dosages range from 50 to 200 mg/pay administered for several days. The daily administration may be fractionated into several smaller doses.

Another therapeutic use of the compositions according to this invention, as a result of this anti-progestative action, is the voluntary induction of menses in mammals before the end of the luteal phase of a normal cycle.

This anti-progesteronic effect, which induces an anti-progestative action, is surprising since it does not result either from an anti-gonadotropic action, or from a competitive action at the molecular level. The compounds of general formula I do not show any affinity for the specific receptors of progesterone, as is the case with Roussel Uclaf's compound RU 38486 (Mifepristone) (trademark).

The pharmaceutical compositions according to this invention preferably contain from 25 to 250 mg of a compound of formula I per unit dosage.

The pharmaceutical compositions according to this invention are suitable for administration by oral, parenteral, rectal or vaginal route.

For this purpose pharmaceuticals containing these compounds can be administered in the form of tablets, coated tablets, dragees, capsules, lozenges, film-coated tablets, soft gelatin capsules, hard gelatin capsules (with a liquid phase inserted therein), pills, cachets, injectable solutions or suspensions divided in ampuls, auto-injectable syringes, or in multi-dose flasks.

Vehicles or carriers for pharmaceutical administration include water, saline, isotonic aqueous mediums, aqueous solutions containing polyethyleneglycols, and aqueous solutions of polyvinylpyrrolidone (for the injectable preparations); conventional carriers such as starches, cellulose, magnesium carbonate, calcium phosphate, silica, magnesium stearate, and talc; or binders, sweetening agents, flavoring agents, and agents which improve the taste of the solid preparations. The compounds can also be used in forms suitable for rectal administration such as suppositories or rectal capsules. Carriers for rectal administration include cocoa butter or polyethyleneglycol stearate.

This invention also provides a process for producing pharmaceutical compositions endowed with anti-progesteronic activity which is defined by incorporating an anti-progesteronic amount of a compound of formula I: ##STR2## wherein R has the above given definitions, admixed or put in conjunction with an inert, nontoxic and pharmaceutically acceptable carrier or vehicle.

This manufacture or this admixture is performed according to the known methods of pharmacology.

The experimental part which appears hereinafter summarizes the various assays performed in the animals and merely illustrates the invention.

Tablets of 17.alpha.-ethynyl-17.beta.-acetoxy-5.alpha.-androst-2-ene were prepared in the following proportions:

for 1000 tablets finished at a mean weight of 225 g.

An injectable solution of 17.alpha.-ethynyl-17.beta.-acetoxy-5.alpha.-androst-2-ene was prepared in the following proportions:

This solution was divided in 2 ml ampuls each containing 100 mg of active ingredient.

Progestomimetic and anti-progesteronic activity of the compounds of formula I:

The anti-progesteronic activity of the compounds of formula I was demonstrated using Clauberg's test, modified according to Mac Phail (J. Physiol. (London) 83 (1934) 145). Impubescent female rabbits of a means weight of 1.5 kg were, for 5 consecutive days, given a subcutaneous injection of 5 mg of Estradiol benzoate. After these five days of sensibilisation, the animals were given, from the sixth day and on every day for five days, a subcutaneous injection of the product to be tested, or of progesterone as a comparison.

The rabbits were sacrificed after the last administration. The uteri were excised, fixed in Bouin's solution and then embedded in paraffin. Chips of 5 m thickness were cut out by microtome and were stained using a mixture of Hemalun-Eosin-Saffron. The growth of the endometrial lacy structure observed by microscope was evaluated according to the scale given by Mac Phail.

The compounds of formula I did not cause any endometrial proliferation up to doses of 25 mg for 5 days. The pseudogestative action was less than 25% of that of progesterone.

The anti-progesteronic activity was also shown using a variant of Mac Phail's test. After the preliminary step of sensibilization using Estradiol benzoate, the animals were subcutaneously given an active amount of progesterone for five days. A compound of formula I was given at the same time, either subcutaneously or orally. 24 hours after the last administration the animals were sacrificed and the uteri analysed from a histological point of view. The endometrial proliferation was determined according to Mac Phail's Index.

(a) After oral administration of a compound of formula I:

(b) After subcutaneous injection of a compound of formula I:

The compounds of formula I, which were practically devoid of any progesteromimetic activity, show anti-progesteronic activity mainly by oral administration. This activity was observed to be dose-dependent and proportional to the administered dose.

The activity achieved by subcutaneous administration appeared to be somewhat less clear.