CN1292702A - Newcontraceptive kit for monotherapy - Google Patents

Abstract

This invention relates to a contraceptive cartridge comprising a device for daily administration of a contraceptive agent, characterized in that the single contraceptive agent is a steroid compound with an inherent combination of progestinic and estrogenic activities. Among conventionally known steroid compounds, steroids have been found to possess a combination of bioactive properties for contraception, particularly through monotherapy. These steroids are selected from the group consisting of steroids satisfying structural formula (I) and their prodrugs, wherein the dashed lines respectively represent selective bonds.

Description

new contraceptive kit

The present invention is in the field of hormonal contraception and relates to contraceptive kits comprising means for daily administration of a contraceptive agent. The present invention also relates to steroid compounds having outstanding biological performance properties for use as contraceptive agents. More specifically, the present invention relates to compounds having properties which make them suitable for use in contraception by "monotherapy", ie by administering to women of reproductive age a single active substance which itself has the desired activity for preventing conception.

Many traditional contraceptive kits consist in administering two different agents, usually a progestin and an estrogen, to a woman of childbearing age. Depending on the particular kit, these agents can be administered in different ways and according to different mechanisms. The most common are kits that provide a contraceptive mechanism of the so-called "combination contraceptive" type, in which daily dosage units containing a progestogen and an estrogen are administered in single or multiple phases over usually 21 consecutive days through two Different amounts and ratios of the active substances were distinguished, while placebo was given or a "no pill" interval was given on the remaining days of the 28-day cycle.

Contraceptive kits providing a single active substance are known. These are usually the "progestin-only" types. Although such "progestogen-only pills" (POPs) have the advantage of avoiding the administration of estrogen, they have the disadvantage that cycle control is often unsatisfactory, as seen in irregular bleeding and idiopathic menses.

Therefore, it is desirable to include an estrogenic component, for which ethinyl estradiol is often administered. In this technology, several undesirable properties of combination contraceptives (blood pooling and cancer risk) are mainly attributed to this estrogenic component. The object of the present invention is to provide a contraceptive which, by administering a single compound with an active profile comprising the desired progestogenic activity and the desired estrogenic activity, allows good cycle control without exposing the unwanted properties mentioned above. Furthermore, it is an object of the present invention to provide contraceptives which have the advantage of being free of ethinyl estradiol while maintaining the favorable effect of ethinyl estradiol on the lipid profile.

In the art, estrogen receptor binding is often described in relation to the aromatic A-ring possessed by steroids such as estradiol. Thus, for example Anstead et al. in Steroids, 1997, vol. 62, the review article on pages 269-303 describes the in vitro estrogen receptor binding of a large number of these steroid structures with different substituents. This publication, besides not referring to in vivo activity, does not make any predictions about estrogen receptor binding of other non-aromatic structures, while only referring to the activity of mixed estrogen/progestogens alone.

The present invention now provides a contraceptive kit comprising means for daily administration of a contraceptive agent, characterized in that the single contraceptive agent is a steroid compound with an activity profile inherently combined progestogenic and estrogenic activity. The invention also consists in the use of a steroid compound having an activity profile inherently combined with progestogenic and estrogenic activity for the production of a contraceptive pharmaceutical preparation, wherein said compound is the single contraceptive agent. More specifically, the present invention resides in the use of a steroid compound selected from the steroids satisfying the structural formula I given below, its prodrugs and pharmaceutically acceptable salts thereof for the production of contraceptive pharmaceutical preparations.

The present invention can be realized in particular by the unexpected discovery of a class of compounds with an unusual spectrum of activity, wherein such compounds are both progestogens (P) and estrogens (E), and both activities are at relatively high levels. Thus, the single contraceptive agent to be used in the kit of the present invention is a steroid compound having an activity profile inherently combined progestogenic and estrogenic activity reaching the Allen-Doisy test for estrogenic activity. and the minimum active dose (MAD) in the McPhail test for progesterone activity are both ≤ 250 μg/kg. It will be clear to those skilled in the art that the term "single contraceptive agent" does not exclude the mixing of said steroid with small amounts of any other progestogen and/or estrogen without contraceptive activity to the extent desired to fine-tune the activity profile. Preferably the steroid of the mixed profile is the only active compound present.

Suitable compounds of the invention include those satisfying the following formula I:

Formula I wherein the dashed lines each show an optional additional bond, respectively.

In one embodiment, the invention relates to the use of these compounds for the manufacture of a contraceptive pharmaceutical preparation. In another embodiment, the invention is a contraceptive kit comprising means for daily administration of any one of the above steroids as a contraceptive agent. In yet another embodiment, the present invention provides a method of contraception, comprising administering an effective amount of the above-mentioned steroid compound to a woman of childbearing age. Included in the present invention are compounds of formula I and prodrugs thereof, ie, related compounds in which substituents are readily metabolized to active compounds of formula I or are readily attached to such compounds given such compounds. Together with the most conventional prodrugs, the present invention therefore provides compounds satisfying formula II and pharmaceutically acceptable salts thereof,

Formula II wherein the dotted lines each show an optional additional bond, Y represents (H, H), (O), (N-OH) or (H, OH); and X represents (-H) or (-C ₂ - C ₇ acyl), such as -C(=O)CH ₃ . 3-keto compounds, ie Y is (O), are preferred. Another possibility of the substituents at carbon number 3 is that they have the main property of the invention, so that they are precursors (prodrugs) of the preferred 3-keto compounds. The same concept holds for the X substituent, where the optional ester group is a precursor to the preferred active compound, where the OX group is OH. For clarity, the invention is described herein below in terms of active compounds of formula I, but is intended to include at least prodrugs according to formula II.

In a preferred embodiment, the compound used in the present invention is (11β, 17α)-11-ethyl-17-hydroxyl-19-norpregna-4-en-20-yn-3-one (Org 4060), It has the following structural formula III:

The compound of formula III, known from US3325520 as a component of a mixture, known from US5710144 as a drug for the treatment of menopausal disease, known from GB1190240 as a starting compound for the synthesis of other steroids, unexpectedly has very good contraceptive properties performance.

Another preferred embodiment of the present invention is a compound satisfying the formula IV.

Formula IV

The compound (11β,17α)-11-vinyl-17-hydroxy-19-norpregna-4-en-20-yn-3-one (Org 4325) is a class of steroid compounds generally known from US4292251 . This document describes a group of compounds with possible properties. The document does not mention compounds with specific mixed E/P profiles (properties), nor does it mention monotherapy contraception. In this preferred embodiment, the present invention now provides a compound which exhibits a significantly different biological property profile compared to a compound of related structure known from US4292251. This striking difference, the unexpected mixed E/P profile, makes Org 4325, as well as its prodrugs and its pharmaceutically acceptable salts, very suitable for monotherapy contraception.

According to the present invention, the above steroids are preferred for monotherapy contraception. However, it will be clear to those skilled in the art that the remarkable biological properties of these steroids of the present invention can also be obtained from admixture of any of these steroids with another active substance such as a progestin or estrogen steroid.

The present invention also provides a contraceptive kit for administration of a single active substance having progestogenic and estrogenic properties for eg 18-30, preferably 21-25 days, with a "pill-free" or placebo interval for the remainder of the cycle. In principle, any other number of days is possible, but for practical reasons this is rarely desirable. A pill-free or placebo interval may also be dispensed with, ie, providing continuous (daily) administration of the aforementioned mixed estrogen/progestogen compound. This would share several of the advantages of the compounds above, but such a sequential mechanism would result in inherent amenorrhea, preferably involving no pill or placebo intervals.

The kit according to the invention provides contraception by "monotherapy" and not by "combination of components with individual activity, but includes an estrogenic component in order to achieve a contraceptive effect and cycle control comparable to combined contraception. A no-pill or placebo interval would allow bleeding to be avoided, which is generally considered desirable, both because it mimics the normal cycle as much as possible, and because it ensures non-pregnancy.

The steroid can be administered in a variety of ways. For example, a sustained release device may be chosen, but preferably the delivery device is in the form of a continuous daily dosage unit, especially an oral tablet.

The term "dosage unit" generally refers to discrete units suitable as unitary dosages for humans, each containing a predetermined quantity of active material calculated to produce the desired effect, for example tablets, pills, powders, suppositories, capsules and the like.

Methods and compositions for the manufacture of such dosage units are well known to those skilled in the art. For example, traditional techniques for the preparation of active ingredient-containing tablets and pills are described in the standard reference Gennaro et al., Reminggton's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacturing).

For the preparation of dosage units such as tablets, attempts have been made to use conventional additives such as fillers, colorants, polymeric binders and the like. Any pharmaceutically acceptable additive that does not generally interfere with the function of the active compounds may be used in one or more of the components.

Suitable carriers with which these compositions are administered include lactose, starch, cellulose derivatives, and the like, used in suitable amounts. Lactose is a preferred carrier. Mixtures of carriers may also be used.

The method for producing the kit of the present invention comprises combining a predetermined amount of one or more of the aforementioned steroid compounds having progestogenic and estrogenic activity, optionally together with another estrogenic or progestogenic steroid, with a predetermined amount of excipient mixture and convert the mixture into dosage units. The resulting kit may contain any number of daily dosage units, but will generally have 18-30, and preferably 20-28 daily dosage units, to accommodate the length of the menstrual cycle. Preferably the kit is in a form adapted to the length of the normal menstrual cycle in humans and contains 21-25, most preferably 21, of said consecutive daily dosage units, optionally also containing placebo dosage units for a total of 28-32 daily dosage units.

Conversion of the mixture into dosage units generally involves molding the mixture into tablets, filling capsules with the dry mixture, or filling capsules with the wet mixture.

As noted above, the means for administering the steroids of the present invention may also be in forms other than daily tablets, such as implants or intravaginal inserts such as vaginal rings or another type of sustained release device.

Methods of making sustained release devices such as implants and vaginal rings are known in the art. In this regard, see Jorge Heller Drug Delivery in the Plastics Age, in "Innovations in Drug Delivery", Tom Sam and Jasper Fokkensed. , pages 134-145. Reference is made to EP303306 for a preferred contraceptive implant. Many designs of vaginal rings that release two substances are known to those skilled in the art. A preferred annular drug delivery system that may be used in the present invention comprises at least one compartment comprising a thermoplastic polymer core comprising the steroid compound of the mixed profile in an amount such that the biologically desired amount of the compound is released directly.

The daily dose of the steroid of the present invention can be up to 1 mg, usually 50-500 μg, preferably 100-300 μg. As for the compounds of formulas III and IV, the amount to be administered is preferably 50-250 µg/day, more preferably 100-200 µg/day. The most preferred daily dose in the case of monotherapy contraception is 140-160 μg. As for Org 37678, which is a compound satisfying formula I and lacking both optional additional bonds, the dosage is typically 1.5-2 times higher, preferably 200-300 μg.

The steroids used in the present invention can be prepared according to the general teaching of US5710144 and US4292251.

The present invention is further explained on the basis of the following examples.

Example 1

(11β,17α)-11-vinyl-17- Hydroxy-19-norpregna-4-en-20-yn-3-one:

i) - A suspension of 57.5 g of potassium tert-butoxide in 585 ml of dry THF was frozen to 0°C and acetylene was passed through the mixture for 2 hours, at which time the ice bath was removed. Next, a solution of 15.0 g (11β)-11-vinylestr-5-ene-3,17-dione ring 3-(1,2-oxalacetal) in 156 ml of dry THF was added dropwise and mixed in Acetylene was passed through the resulting mixture at room temperature. After 2 hours, 350 ml of a saturated aqueous solution of ammonium chloride were added slowly and the resulting mixture was extracted twice with about 2% pyridine in ethyl acetate. The mixed extract was washed twice with a saturated aqueous solution of sodium bicarbonate and once with a saturated aqueous solution of sodium chloride (brine), dried over sodium sulfate, and concentrated under reduced pressure to obtain 16.2 g of (11β, 17α)-11 -Vinyl-17-hydroxy-19-norpregna-5-en-20-yn-3-onecyclo 3-(1,2-ethylene diacetal).

ii) - to 16.2 g (11β, 17α)-11-vinyl-17-hydroxyl-19-norpregna-5-ene-20-yn-3-one ring 3-(1, 2-ethanediacetal) solution was added 44 ml of 4N HCl, and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 3.5 hours. Next, the reaction mixture was poured into 3.5 l of water, which was extracted 3 times with ethyl acetate. The mixed extract was washed once with a saturated aqueous solution of sodium bicarbonate, twice with water and once with a saturated aqueous solution of sodium chloride (brine), dried over sodium sulfate, and concentrated under reduced pressure to obtain 14.0 g of crude material . The crude product is crystallized twice from a mixture of dichloromethane and acetone (K ₁ : 1.2 g, K ₂ : 4.8 g). The mother liquor of the second crystallization was concentrated under reduced pressure, and the residue was purified by flash chromatography (toluene:ethyl acetate=8:2) to obtain another 3.8 g of product. This material was mixed with _K1 and _K2 and 50ml diethyl ether was added. The resulting suspension was refluxed for 4 hours, cooled at 5°C for 60 hours, and the crystals, after rinsing with 3 ml of cold diethyl ether, were collected by filtration (9.0 g). Since repeating this step twice did not improve the purity of the product, flash chromatography (heptane:acetone=7:3) was used as the final purification step to obtain 6.3 g of pure (11β,17α)-11-vinyl -17-Hydroxy-19-norpregna-4-en-20-yn-3-one. M． p. 186.8°C. [α] _D ²⁰ =+29.5° (c=1, ethanol).

Example 2

From (11β,17α)-11-vinyl-17-hydroxy-19-norpregn-4-en-20-yn-3-one was prepared as follows (11β,17α)-17-acetoxy-11- Vinyl-19-norpregna-4-en-20-yn-3-one:

- To a solution of 460 mg (11β,17α)-11-vinyl-17-hydroxy-19-norpregn-4-en-20-yn-3-one in 4.6 ml acetic anhydride was added 156 mg p-methyl phenylsulfonic acid, and the resulting mixture was stirred at room temperature under nitrogen for 4.5 hours. Next, 0.4 ml of 36% HCl was added and the mixture was stirred overnight. The crude mixture was then poured into 46 ml of water and extracted 4 times with dichloromethane. The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride (brine), dried over sodium sulfate and concentrated under reduced pressure to obtain the corresponding 3-acetoxy-3,5- Diene-contaminated crude product.

The crude product was dissolved in a mixture of 28 ml acetone and 0.2 ml 36% HCl and the resulting solution was stirred at room temperature for 24 hours (0.7 ml water was added after 3 and 7.5 hours). Next, another 0.2 ml of 36% HCl was added, and the resulting mixture was stirred at room temperature for another night. Finally, the crude mixture was poured into 275 ml of water, which was extracted three times with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride (brine), dried over sodium sulfate, and concentrated under reduced pressure to obtain 550 mg of a crude product. Purification by flash chromatography (toluene:ethyl acetate=4:6) afforded 165 mg of pure (11β,17α)-17-acetoxy-11-vinyl-19-norpregn-4-ene-20- Alkyn-3-ones Amorphous solid.

M． p. 141.1-161.1°C. [α] _D ²⁰ = -1° (c = 0.5, dioxane).

Example 3

(3E/Z, 11β, 17α)-11-vinyl from (11β,17α)-11-vinyl-17-hydroxy-19-norpregn-4-en-20-yn-3-one was prepared as follows -17-Hydroxy-19-norpregna-4-en-20-yne-3-one oxime:

- To a solution of 500 mg (11β,17α)-11-vinyl-17-hydroxy-19-norpregna-4-en-20-yn-3-one in 2.6 ml of pyridine was added 1.18 g of hydroxylamine ． HCl, the resulting mixture was stirred at room temperature under nitrogen for 1 h. Next, the reaction mixture was poured into 46 ml of water and extracted 3 times with dichloromethane. The mixed extract was washed with water and a saturated aqueous solution of sodium chloride (brine), and concentrated under reduced pressure to obtain 480 mg of (3E/Z, 11β, 17α)-11-vinyl-17-hydroxy-19-norpregne -4-en-20-yn-3-one oxime.

Crystallization from dichloromethane gave 260 mg of a 85:15 mixture of 3E- and 3Z-oximes.

M． p. 257°C. [α] _D ²⁰ =+58.4° (c=0.5, dioxane).

Example 4

Preparation of (11β,17α)-11-vinyl-17-hydroxyl from (11β,17α)-11-vinyl-17-hydroxy-19-norpregn-4-en-20-yn-3-one was as follows -19-norpregna-4,20-dien-3-one:

- To a suspension of 175 mg of Lindlar catalyst in 15 ml of ethanol pretreated with hydrogen for 25 minutes was added 500 mg of (11β, 17α)-11-vinyl-17-hydroxy-19-norpregna in 5 ml of ethanol - 4-en-20-yn-3-one, and the resulting mixture was hydrogenated at atmospheric pressure for 1 hour. Next, the catalyst in the crude mixture was removed by filtration through decalide, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography with toluene/ethyl acetate (4/6) using silver nitrate impregnated silica as stationary phase to afford 162 mg of pure (11β,17α)-11-vinyl-17-hydroxy- 19-Norpregna-4,20-dien-3-one Amorphous solid.

M． p. 62.9-70.3°C. [α] _D ²⁰ =+74.1° (c=0.5, dioxane).

Example 5

Preparation of (3α, 11β, 17α)-11-vinyl-19 from (11β,17α)-11-vinyl-17-hydroxy-19-norpregna-4-en-20-yn-3-one was as follows -Norpregna-4-ene-20-yne-3,17-diol and (3β,11β,17α)-11-vinyl-19-norpregna-4-ene-20-yne-3,17- Diols:

- To a solution of 2.0 g (11β,17α)-11-vinyl-17-hydroxy-19-norpregna-4-en-20-yn-3-one in 25 ml dry THF was added 3.14 g Li( ^OtBu ) _3AlH , the resulting mixture was stirred at room temperature under nitrogen for 2 hours. Next, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and extracted with dichloromethane. The extract was washed with water and a saturated aqueous solution of sodium chloride (brine), concentrated under reduced pressure, and the crude mixture was purified by flash chromatography using dichloromethane/acetone (95/5), crystallized from diisopropyl ether Afterwards, 100 mg of pure (3α, 11β, 17α)-11-vinyl-19-norpregna-4-ene-20-yne-3,17-diol and 700 mg of pure (3β, 11β, 17α)-11- Vinyl-19-norpregna-4-ene-20-yne-3,17-diol.

3α-isomer: M. p. 178.5-179.1°C.

3β-isomer: M. p. 147.6-148.2°C.

Example 6

(11β,17α)-11-ethyl-17- Hydroxy-19-norpregna-4-en-20-yn-3-one:

i) - To a solution of 100 g of said diacetal in 3.5 l of dry tetrahydrofuran is added 5 g of platinum(IV) oxide and the mixture is hydrogenated at room temperature until no more hydrogen is absorbed. The mixture was filtered through celite, the residue was washed twice with tetrahydrofuran, and the combined filtrate was concentrated under reduced pressure to obtain 93 g of crude crystalline (11β)-11-ethylestr-5-ene-3,17-di The ketocyclic bis-(1,2-ethanediacetal) was used in the next step without further purification.

ii) - The bisketal (10 g) from the above step was suspended in 50 ml of acetone. A solution of 6.7 ml of water and 3.3 ml of sulfuric acid is carefully added to this suspension. The mixture was stirred at room temperature for 1 hour and then poured into a solution of 20 g of sodium acetate in 100 ml of water. The mixture was cooled in an ice bath; the resulting precipitate was filtered off, and the residue was washed with water until the washings were neutral; the residue was then collected and dried to obtain 7.5 g of crude (11β)-11-ethylestra-4- ene-3,17-dione, which was used in the following step without further purification.

iii) - Pass acetylene gas through a suspension of 16.5 g of potassium tert-butoxide in 100 ml of dry tetrahydrofuran for 2 hours. To this suspension was added dropwise a solution of 10 g of the diketone from the previous step in 50 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 2 hours while passing acetylene continuously. Next, a solution of 15 ml sulfuric acid in 30 ml water was carefully added and the mixture was stirred for another 2 hours. Afterwards, a solution of 40 g of sodium acetate in 250 ml of water was added slowly and the mixture was heated at 75° C. for 15 minutes. The organic solvent was then distilled off and the residue was cooled to room temperature. A precipitate formed, which was removed by filtration and taken up in 600 ml of toluene. Activated charcoal was added and the mixture was heated to 65°C, filtered and concentrated under reduced pressure. The crude product was recrystallized from ethanol/water to give 6.5 g of (11β,17α)-11-ethyl-17-hydroxy-19-norpregn-4-en-20-yn-3-one.

M． p. 222°C. [α] _D ²⁰ =-16.1° (c=1, dioxane).

Comparative example

(A) is the same as Example II(b) of US4292251.

(B) is the same as Example XIII of US4292251 (including the steps of Example VI(a) and (b) therein).

Examples of Pharmaceutical Preparations

Pharmaceutical compositions containing steroids of the invention are prepared. As an illustration, the compound of Example 6 (Org 4060) was chosen. The compound is mixed with the other ingredients in a standard manner, and the mixture is granulated. The composition is as follows, the same formulation is suitable for other compounds including Org 4325: Org 4060 (active ingredient) 1-10wt. %Corn starch (disintegration) 15wt. % hydroxypropyl cellulose (binder) 3wt. % lactose 200M (diluent) to 100wt. %

Test Example A

Several steroids, compounds according to the invention as well as compounds not according to the invention, were tested for relevant biological properties, ie progestogenic and estrogenic activity tests. The progestogenic activity was determined by the McPhail test and the estrogenic activity by the Allen-Doisy test. Both assays are known in the art and can be described as follows:

McPhail test:

The progestational activity of test compounds was assessed by histological assessment of differentiation of endometrial tissue using in vivo assays in rabbits. Rabbits were primed with estradiol for 8 days, followed by oral administration of the progestogenic compound for 5 days. The animals were euthanized (60 mg iv pentobarbitone/rabbit) and hematoxylin-eosin-stained cross-sections of two different sections of each uterine horn were prepared. The progesterone-dependent endometrial development was evaluated microscopically and graded 0-4 (Van der Vies J., and De Visser, J. 1983. Endocrinological studies with desogestrel. Drug Res. 33:231-236).

Allen-Doisy test:

In vivo assay using rats Estrogenic activity of test compounds was assessed by evaluation of vaginal epithelial keratinization on vaginal smears. Mature female mice were ovariectomized before being primed with a single dose of 1 μg estradiol at the third week (day 1). Seven days after priming, the test compound was administered once on day 8 and twice on day 9. Additional vaginal smears were obtained on the afternoon of Day 10, twice on Day 11 and on the morning of Day 12. These smears were stained with Giemsa and the number of positive smears was determined (Van der Vies J., and De Visser, J. 1983. Endocrinological studies with desogestrel. Drug Res. 33:231-236).

result:

The test results are listed in the table below.

Test Example B

The compound of Example 6 was used in monkey studies.

Mature female rhesus monkeys (cynomolgus monkeys) aged 5-20 weeks were used which had shown regular menstrual cycles. The monkeys were housed in colonies of approximately 35 females and one vasectomized male. The test was approved by the 'Animal Use Committee' (DEC, AEP No. E97A0801PVE). Three groups of these monkeys were administered the compound of Example 6 at a dose of 8 µg/kg per day. The first day of menstrual bleeding was considered Day 1 of the cycle, and these trials began with the pretreatment control cycle (Day 1 of the trial). Treatment started on day 2 of the treatment cycle (daily) until day 22. Compounds were administered orally via catheter under light anesthesia with Ketamine(R) (dose dependent on monkey, i.m. < 10 mg/kg). Dosed animals will then be housed alone to regain consciousness and check for regurgitation. The animals were returned to the colony 2 hours later. The post-treatment cycle begins after the menstrual bleeding of the treatment cycle (at the desired time). Blood samples for analysis of estradiol and progesterone were obtained twice a week (Monday and Thursday) throughout the trial. Blood samples were obtained from the venous femoris muscle using Vacutainer tubes (Venoject). Periodicity was also monitored by taking daily vaginal swabs using a cotton-tipped applicator. Vaginal bleeding was divided into main bleeding (rating=+) and secondary bleeding (rating=±).

All monkeys receiving the compound of Example 6 showed suppression of ovulation; 2/3 showed no bleeding; none showed intermittent bleeding. These results show that the mixed E/P compound is very suitable as a contraceptive: very good suppression of ovulation without the need for a separate estrogen, and a good bleeding pattern and cycle control.

Claims (16)

1. Contraceptive kit comprising means for daily administration of a contraceptive agent, characterized in that the single contraceptive agent is a steroid compound having an activity profile inherently combined progestogenic and estrogenic activity. 2. Contraceptive kit according to claim 1, characterized in that the steroid compound is selected from the group consisting of steroids satisfying the structural formula I, prodrugs thereof and pharmaceutically acceptable salts thereof, Formula I wherein the dashed lines each show an optional additional bond, respectively. 3. The contraceptive kit according to claim 2, characterized in that the steroid compound satisfies the structural formula III,

Formula III or its prodrug or pharmaceutically acceptable salt thereof. 4. The contraceptive kit according to claim 2, characterized in that the steroid compound satisfies the structural formula IV, Or its prodrug or pharmaceutically acceptable salt thereof. 5. Contraceptive kit according to any one of the preceding claims, characterized in that the means for daily administration is in the form of 18-30 consecutive daily dosage units, each containing 100-300 μg of the steroid. 6. Contraceptive kit according to claim 5, characterized in that the number of daily dosage units is 21-25. 7. Contraceptive kit according to claim 6, characterized in that a total of 28-32 daily dosage units is constituted by comprising placebo dosage units. 8. Contraceptive kit according to any one of claims 5-7, characterized in that the continuous daily dosage unit is an oral tablet. 9. Use of a steroid compound having an activity profile inherently combined with progestogenic and estrogenic activity for the manufacture of a contraceptive pharmaceutical preparation, wherein said compound is a single contraceptive agent. 10. The use of steroid compounds selected from steroids satisfying structural formula I, prodrugs thereof and pharmaceutically acceptable salts thereof for the production of contraceptive pharmaceutical preparations,

Formula I wherein the dashed lines each show an optional additional bond, respectively. 11. The use according to claim 10, characterized in that the steroid compound is one satisfying the structural formula II, or a pharmaceutically acceptable salt thereof: Formula II wherein the dotted lines each show an optional additional bond, respectively, Y represents (H, H), (O), (N-OH) or (H, OH); and X represents (-H) or (-C ₂ -C ₇ acyl). 12. Use according to claim 11, characterized in that the steroid compound satisfies structural formula III:

Formula III or its prodrug or pharmaceutically acceptable salt thereof. 13. According to the purposes of claim 11, it is characterized in that the steroid compound satisfies structural formula IV:

Formula IV or its prodrug or pharmaceutically acceptable salt thereof. 14. Use according to any one of claims 10-13, characterized in that the pharmaceutical preparation is a monotherapy contraceptive. 15. A contraceptive method, comprising administering an effective amount of a steroid compound selected from steroids satisfying structural formula I or prodrugs thereof to women of childbearing age. 16. A method of contraception according to claim 15, comprising administering 100-300 μg of a compound satisfying formula III for 21-25 consecutive days, followed by a pill-free or placebo-free interval of 3-7 days.