JP2002506014A - New contraceptive kit - Google Patents

Abstract

(57) Abstract: The present invention relates to a contraceptive kit comprising a means for daily administration of a contraceptive agent, wherein the single contraceptive agent has an active property that uniquely combines progestogen activity and estrogen activity. The present invention relates to a contraceptive kit characterized by having a steroid compound. Among the common classes of known steroid compounds, steroids have been found that have a remarkable combination of biological properties used in contraception, especially in monotherapy. Such steroids are selected from the group consisting of steroids and their prodrugs satisfying structural formula (I), wherein the dashed lines each independently represent an optionally present bond: . Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

(A) Field of the Invention The present invention is in the field of hormonal contraception, and relates to a contraceptive kit including a means for daily administration of a contraceptive. The present invention also relates to certain steroid compounds that have significant biological properties for use as contraceptives. More specifically, the present invention relates to the prevention of pregnancy by "monotherapy", i.e., the administration of a single active substance to a woman of childbearing age, which itself has the activity required to prevent pregnancy. And compounds having characteristics such that they are suitable for use in the prevention of pregnancy.

(B) Background of the Invention Many conventional contraceptive kits provide for the administration of two different drugs to women of childbearing age, usually progestogens and estrogens. Depending on the particular kit, these agents can be administered in different ways and according to different dosing regimes. Most commonly, a daily dosage unit containing both progestogens and estrogens is administered for 21 consecutive days in one or more phases distinguished by different amounts and ratios of both actives. It is a kit that provides a so-called “combined contraceptive” type contraceptive regimen that is administered and receives placebo for the remaining days of the 28-day cycle, or is provided with a “pill-free” interphase.

[0003] Contraceptive kits in which a single active substance is provided are known. Such kits are typically of the "progestogen alone" type. While such "progestogen-only pills" (POPs) have the advantage that administration of estrogens is avoided, in many cases, as can be understood from irregular bleeding as well as intrinsic amenorrhea, It has the disadvantage that the management of the cycle is inadequate.

Accordingly, it is desirable to include an estrogenic component, usually ethinyl estradiol. In the art, some less desirable properties (with respect to the risk of congestion and carcinogenesis) of combined contraceptives are mainly due to this estrogenic component. It is an object of the present invention to be exposed to the above less desirable properties by employing a single compound having an activity profile that includes both the required progestogen activity and the required estrogen activity. It is an object of the present invention to provide a contraceptive agent which can obtain good cycle management without using it. Further, the object of the present invention is
It is to provide a contraceptive which has the advantage of omitting ethinyl estradiol but at the same time retains the beneficial effects of ethinyl estradiol on lipid properties.

[0005] In the art, estrogen receptor binding is usually described in relation to steroids having an aromatic A ring, just like estradiol.
Thus, for example, a review by Anstead et al. (Anstead et al., Stereo)
ids, 1997, 62, 269-303) describe the in vitro estrogen receptor binding of numerous such steroid structures with various substituents. Such disclosure, in addition to being unrelated to in vivo activity, makes any predictions about estrogen receptor binding of other non-aromatic structures, let alone mixed estrogen / progestogen activity. Can not do.

(C) Disclosure of the Invention SUMMARY The present invention provides a contraceptive kit comprising a means for daily administration of a contraceptive agent, wherein a single contraceptive agent is a steroid compound having an activity characteristic of uniquely combining progestogen activity and estrogen activity. A contraceptive kit is provided. The present invention also relates to the use of a steroid compound having an active property having an intrinsic combination of progestogen activity and estrogen activity, wherein said compound is a single contraceptive agent for producing a pharmaceutical preparation for contraception. Is in the use of More specifically, the present invention relates to the use of a steroid compound selected from the group consisting of a steroid satisfying the following structural formula I, a prodrug thereof, and a pharmaceutically acceptable salt thereof, wherein the steroid compound is used for contraception. It is in the use for producing a pharmaceutical preparation.

[0007] 2. DETAILED DESCRIPTION The present invention is directed, in particular, to compounds of the type having a rare activity profile in that the compounds are simultaneously progestogenic (P) and estrogenic (E) and both activities are at relatively high levels. It is made possible by unexpected discoveries. Thus, a single contraceptive that can be used in the kit according to the invention has a minimum active dose in both the Allen-Doisy test for estrogen activity and the McFail test for progestogen activity (McPhail test). MAD) is a steroid compound having an activity characteristic of intrinsically having progestogen activity and estrogen activity at a level of not more than 250 μg / kg. The term "single contraceptive" refers to the incorporation of such compounds with any other progestogens and / or estrogens in trace amounts that are not active in contraception and to the extent desired to fine-tune the active properties. It will be clear to those skilled in the art that it does not prevent Preferably, a steroid of mixed nature is the only active compound present.

[0008] Suitable compounds according to the present invention include those that satisfy the following structural formula I:

[0009]

Embedded image (Where the dashed lines independently represent any additional bonds).

[0010] In one embodiment, the invention relates to the use of such compounds for the manufacture of a pharmaceutical preparation for contraception. In another embodiment, the present invention is a contraceptive kit comprising a means for daily administration of any one of the above steroids as a contraceptive. In yet another embodiment, the present invention provides a method of contraception comprising administering to a woman of childbearing age an effective amount of a steroid compound as described above. Compounds of Formula I, and prodrugs thereof, ie, related compounds having substituents that are readily metabolized to an active compound of Formula I, or are readily cleaved into such compounds upon administration, are included in the invention. Shall be Accordingly, the present invention relates to compounds satisfying Formula II, together with the most routine prodrugs, and pharmaceutically acceptable salts thereof.

[0011]

Embedded image Wherein each dotted line independently represents any additional bond; Y is (H, H),
X represents (—H) or —C, and represents (O), (N—OH) or (H, OH);
(= O) represents such CH ₃ a _(-C 2 -C ₇ acyl). Preferred are 3-keto compounds, ie, compounds wherein Y is (O). As its main characteristics according to the present invention,
With respect to the substituent at the carbon atom at position 3, there is another possibility that they are preferred precursors (prodrugs) of the 3-keto compounds. Similar considerations are made for the X substituent, in which case the optional ester group is the precursor of the preferred active compound, where the OX group is OH. For clarity, the invention will be described below with reference to the active compounds of the formula I, but will at least include the prodrugs described with reference to the formula II.

In a preferred embodiment, the compound used in the present invention has the following structural formula III: (11β, 17α) -11-ethyl-17-hydroxy-19
-Norpregna-4-en-20-in-3-one (Org4060).

[0013]

Embedded image

This compound is known from US Pat. No. 3,325,520 as a component of a mixture and from US Pat. No. 5,710,144 as a medicament in the treatment of menopause complaints, and Although it is known from patent 1,190,240 as a starting material for the synthesis of other steroids, it surprisingly has properties which make its use in contraception very advantageous.

[0015] A still further preferred embodiment of the present invention is a compound that satisfies the following structural formula IV:

[0016]

Embedded image

This compound is (11β, 17α) -11-ethenyl-17-hydroxy-19
-Norpregna-4-en-20-in-3-one (Org 4325)
Among the steroid compounds of the type generally known from U.S. Pat. No. 4,292,251. This patent describes a class of compounds having a range of properties. This patent does not relate to compounds having particular mixed E / P properties, nor does it relate to monotherapy contraception. In this preferred embodiment, the present invention provides:
This time, we provide compounds that show significant differences in the characteristics of their biological properties as compared to the structurally related compounds known from US Pat. No. 4,292,251. Due to this difference itself, that is, due to unexpected mixed E / P characteristics, O
rg4325 and its prodrugs and its pharmaceutically acceptable salts will be very suitable for use in monotherapy contraception.

According to the invention, the use of the above steroids in contraception by monotherapy is preferred. However, the remarkable biological properties of the steroids according to the invention are also obtained when one of these steroids is combined with another active substance, such as a progestogenic steroid or an estrogenic steroid. Will be apparent to those skilled in the art.

The present invention further provides that a single active substance having both progestogenic and estrogenic properties can be used, for example, for 18 to 30 days, preferably 21 to 25 days.
A contraceptive kit is given that is administered over days and the remaining days of the cycle are "pill free" or interphase of placebo. In principle any other number of days is possible, but for practical reasons this is less desirable. It is also possible to discontinue the interphase of pill-free or placebo, ie to define a continuous (daily) administration of the mixed estrogen / progestogen compound described above. Thus, although some of the benefits of the compounds described above can be enjoyed, it is preferred to include a pill-free or placebo interphase as such continuous dosing results in inherent amenorrhea.

The kits according to the invention provide contraception by "monotherapy" rather than by combination with components having distinct activities, but with contraceptive efficacy and cycle management comparable to that of combination contraceptives. Contains the estrogen component as obtained. Interphase between pill-free or placebo helps stop bleeding, which is generally considered desirable: especially since the natural cycle is therefore mimicked as much as possible, and ensuring that pregnancy does not result Because it is obtained.

The steroids of the present invention can be administered in various ways. For example, the means for sustained release may be chosen, but the means for administration will be in the form of continuous daily dosage units, particularly preferably tablets for oral administration.

The term “dosage unit” is generally a physically independent unit suitable as a unitary dosage form for humans, each of which is a defined amount of activity calculated to achieve a desired effect. Indicates a unit containing the substance, for example, tablets, pills, powders, suppositories, capsules and the like.

[0023] Methods and compositions for making such dosage units are well known to those skilled in the art. For example, conventional techniques for making tablets and pills containing the active ingredient are described in standard references such as Gennaro et al., Remington's.
s Pharmaceutical Sciences (18th edition, Mack
Publishing Company, 1990; in particular, see Part 8: Pharmaceutical preparations and their manufacture).

For making dosage units, for example tablets, the use of conventional additives such as fillers, coloring agents, polymer binders and the like is included. Generally, any pharmaceutically acceptable excipient that does not interfere with the function of the active compound can be used in one or more compositions.

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

The process of manufacturing the kit of the present invention comprises the step of combining a predetermined amount of one or more of the above steroid compounds having progestogenic and estrogenic activity with another estrogenic or progestogenic steroid as required. And mixing with a predetermined amount of excipients and converting the mixture into dosage units.
The resulting kit may contain any number of daily dosage units, but generally,
By having from 8 to 30, preferably 20 to 28 daily dosage units, it is adapted to a given length of menstrual cycle. Preferred kits are in a form adapted to the human menstrual cycle of normal length and contain from 21 to 25, most preferably 21 of said daily consecutive dosage units, and optionally And a total of 28
It further contains placebo dosage units to make up to 32 to 32 daily dosage units.

Converting the mixture into dosage units generally includes molding the mixture into tablets, filling capsules with the dry mixture, or filling capsules with the wet mixture.

As indicated above, the means for administering steroids according to the invention may be in a form other than that of a daily tablet, for example an implant or a vaginal product such as a vaginal ring Or another type of sustained release device.

[0029] Methods of making sustained release devices, such as implants and vaginal rings, are known in the art. In this regard, Jorge Heller's Drug Delivery in the Plastic Age ("Advances in Drug Delivery", Tom Sam and Jas
per Fokkens, eds., pages 134-145). For preferred contraceptive implants, reference is made to EP 303 306. Many designs of vaginal rings that release two substances are known to those skilled in the art. A preferred ring-shaped drug delivery system that can be used in the present invention is a thermoplastic polymer core that contains a fixed amount of a steroid compound of mixed-type properties and allows for direct release of the compound at physiologically required amounts. At least one area including:

The daily dosage of the steroids according to the invention can be up to 1 mg, but in general
It is in the range of 50 μg to 500 μg, preferably in the range of 100 μg to 300 μg. For compounds of formula III and formula IV, the dosage is preferably 50 μg to 250 μg per day, more preferably 100 μg to 200 μg per day.
μg. The most preferred daily dosage is between 140 μg and 150 μg for monotherapy contraception.
160 μg. In the case of Org 37678, a compound that satisfies Formula I, in which case no additional binding is both present, the dosage is typically 1.5
It is twice to twice as large, and 200 μg to 300 μg is preferably selected.

The steroids used in the present invention can be prepared according to the general teachings of US Pat. No. 5,710,144 and US Pat. No. 4,292,251.

The present invention is further described with reference to the following examples.

Example 1 (11β, 17α) -11-ethenyl-17-hydroxy-19-norpregna-4-en-20-yn-3-one was converted to (11β) -11-ethenyl ester (
estr) -5-ene-3,17-dione Prepared from cyclic 3- (1,2-ethanediyl acetal) as follows.

I) 585 ml of dry THF in which 57.5 g of potassium tert-butoxide were suspended was cooled to 0 ° C. with ice, followed by passing acetylene through the mixture for 2 hours and removing the ice bath after 2 hours. Next, 15.0 g of (11β) -11-ethenyl ester-
156 ml of dry THF in which 5-ene-3,17-dione cyclic 3- (1,2-ethanediyl acetal) was dissolved was added dropwise and acetylene was passed through the resulting mixture at room temperature. After 2 hours, 350 ml of a saturated aqueous solution of ammonium chloride was slowly added and the resulting mixture was extracted twice with ethyl acetate containing about 2% pyridine. Combine the extracts and twice with a saturated aqueous solution of sodium bicarbonate,
It is then washed once with a saturated aqueous solution of sodium chloride (brine), dried over sodium sulfate and concentrated under reduced pressure to give 16.2 g of (11β, 17α) -11.
Ethenyl-17-hydroxy-19-norpregna-5-en-20-yne-3
An -one cyclic (1,2-ethanediyl acetal) was obtained.

Ii) Dissolve 16.2 g of (11β, 17α) -11-ethenyl-17-hydroxy-19-norpregna-5-en-20-yn-3-one cyclic (1,2-ethanediyl acetal) 44 ml of 4N HCl in 870 ml of acetone
Was added and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3.5 hours. Subsequently, the reaction mixture was poured into 3.5 l of water and extracted three times with ethyl acetate. The combined extracts were 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 give 14%. 0.0 g of crude material was obtained. The crude product was crystallized twice from a mixture of methylene chloride 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), giving a further 3.8 g.
Was obtained. This material was combined with _{K 1} and _{K 2,} diethyl ether was added 50 ml. The resulting suspension was refluxed for 4 hours, cooled at 5 ° C. for 60 hours and, after washing with 3 ml of cold diethyl ether, the crystals were collected by filtration (9.
0 g). Repeating this procedure twice did not improve the purity of the product, so 6.3 g of pure (11β, 17α) was obtained using flash chromatography (heptane: acetone = 7: 3) as the final purification step. ) -11-ethenyl-17
-Hydroxy-19-norpregna-4-en-20-in-3-one was obtained.
Melting point: 186.8C. [Α] _D ²⁰ = + 29.5 ^° (c = 1, ethanol).

Example 2 (11β, 17α) -17-acetyloxy-11-ethenyl-19-norpregn-4-en-20-yn-3-one was converted to (11β, 17α) -11-ethenyl-17-hydroxy Prepared from -19-norpregna-4-en-20-in-3-one as follows.

460 mg of (11β, 17α) -11-ethenyl-17-hydroxy-19
156 mg of p-toluenesulfonic acid was added to 4.6 ml of acetic anhydride in which -norpregna-4-en-20-yn-3-one was dissolved, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4.5 hours. Stirred for hours. Subsequently, 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 four times with methylene chloride. The extracts were combined, 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 give a crude product. It still contained the corresponding 3-acetyloxy-3,5-diene.

The crude product was dissolved in a mixture of 28 ml of acetone and 0.2 ml of 36% HCl, and the resulting solution was stirred at room temperature for 24 hours (after 3 and 7.5 hours 0.7 ml of water Was added). Then another 0.2 ml of 36% HCl was added and the resulting mixture was stirred once more at room temperature overnight. Finally, the crude mixture was poured into 275 ml of water and extracted three times with ethyl acetate. The extracts were combined, 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 give 550 mg of crude product.
Purification by flash chromatography (toluene: ethyl acetate = 4: 6) gave 165 mg of pure (11β, 17α) -17-acetyloxy-11.
-Ethenyl-19-norpregna-4-en-20-yn-3-one was obtained as an amorphous solid. Melting point: 141.1-161.1 [deg.] C. [Α] _D ²⁰ = -1 ^o (c =
0.5, dioxane).

Example 3 (3E / Z, 11β, 17α) -11-ethenyl-17-hydroxy-19-
Norpregna-4-en-20-in-3-one oxime was converted to (11β, 17α)
11-ethenyl-17-hydroxy-19-norpregna-4-en-20-
Prepared from in-3-one as follows.

500 mg of (11β, 17α) -11-ethenyl-17-hydroxy-19
1.18 g of hydroxylamine HCl was added to 2.6 ml of pyridine in which -norpregn-4-en-20-in-3-one was dissolved, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. . Subsequently, the reaction mixture was poured into 46 ml of water and extracted three times with methylene chloride. The extracts were combined, washed with water and a saturated aqueous solution of sodium chloride (brine), concentrated under reduced pressure and 480 mg of crude (3E / Z
, 11β, 17α) -11-ethenyl-17-hydroxy-19-norpregn-4-en-20-in-3-one oxime. Crystallization from methylene chloride gave 260 mg of a 85:15 mixture of 3E-oxime and 3Z-oxime. Melting point: 257 [deg.] C. [Α] _D ²⁰ = + 58.4 ^o (c = 0.5, dioxane)
.

Example 4 (11β, 17α) -11-ethenyl-17-hydroxy-19-norpregna-4,20-dien-3-one was converted to (11β, 17α) -11-ethenyl-17
Prepared from -hydroxy-19-norpregna-4-en-20-in-3-one as follows.

A suspension of 175 mg of Lindlar catalyst in 15 ml of ethanol was added to water
The suspension was pre-treated for 25 minutes, and 500 mg of (11β, 17α)-
11-ethenyl-17-hydroxy-19-norpregn-4-en-20-i
5 ml of ethanol in which the -3-one was dissolved was added and the resulting mixture was large.
Hydrogenated at atmospheric pressure for 1 hour. Subsequently, the catalyst was filtered by filtering the crude mixture through dicalite.
After removal, the filtrate was concentrated under reduced pressure. Subsequently, the crude product was dissolved in toluene / ethyl acetate (4
/ 6) using flash chromatography (determining silica impregnated with silver nitrate)
(Used as normal phase) to give 162 mg of pure (11β, 17α
) -11-ethenyl-17-hydroxy-19-norpregna-4,20-die
N-3-one was obtained as an amorphous solid. Melting point: 62.9-70.3C. [Α]_D ²⁰ = + 74.1^o(C = 0.5, dioxane).

Example 5 (3α, 11β, 17α) -11-ethenyl-19-norpregna-4-en-20-yne-3,17-diol and (3β, 11β, 17α) -11-ethenyl-19- Norpregna-4-en-20-yne-3,17-diol is converted to (
11β, 17α) -11-ethenyl-17-hydroxy-19-norpregna
Prepared from 4-en-20-in-3-one as follows.

2.0 g of (11β, 17α) -11-ethenyl-17-hydroxy-19-
25 ml of dry TH in which norpregna-4-en-20-in-3-one is dissolved
3.14 g of Li (O ^t Bu) ₃ AlH was added to F, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. Subsequently, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride (brine) and concentrated under reduced pressure. The crude mixture was purified by flash chromatography using dichloromethane / acetone (95/5) and, after crystallization from diisopropyl ether, 100 mg of pure (3α
, 11β, 17α) -11-ethenyl-19-norpregna-4-en-20-
In-3,17-diol and 700 mg of pure (3β, 11β, 17α)
This gave -11-ethenyl-19-norpregna-4-en-20-yne-3,17-diol. 3α-isomer: melting point 178.5-179.1 ° C. 3β-isomer: melting point 147.6-148.2 ° C.

Example 6 (11β, 17α) -11-ethyl-17-hydroxy-19-norpregn-4-en-20-yn-3-one was converted to (11β) -11-ethenyl ester-5.
Prepared from -ene-3,17-dione cyclic bis (1,2-ethanediyl acetal) as follows.

I) 5 g of platinum (IV) oxide were added to 3.5 l of dry tetrahydrofuran in which 100 g of the above bisacetal were dissolved and the mixture was hydrogenated at room temperature until no more hydrogen was taken up. The mixture was filtered through celite, the residue was washed twice with tetrahydrofuran, and the combined filtrate was concentrated under reduced pressure to give 93 g of crude (11β) -11-ethyl estr-5-ene-3,17. -A dione cyclic bis (1,2-ethanediyl acetal) was obtained. This was used in the next step without further purification.

Ii) The diketal (10 g) obtained from the above step was suspended in 50 ml of acetone. To this suspension was carefully added a solution of 6.7 ml of water and 3.3 ml of sulfuric acid. The mixture was stirred at room temperature for 1 hour, then poured into 100 ml of water with 20 g of sodium acetate dissolved. The mixture was cooled in an ice bath; the resulting precipitate was filtered off and the residue was washed with water until the wash was neutral; the residue was collected, dried and treated with 7.5 g of crude (11β) -11-ethyl estr-4-ene-3
, 17-dione. This was used in the next step without further purification.

Iii) Acetylene gas was suspended in 16.5 g of potassium tert-butoxide.
Passed through 100 ml of cloudy dry tetrahydrofuran for 2 hours. In this suspension,
50 ml of dry tetrahydrogen in which 10 g of the diketone obtained from the above step were dissolved
Furan was added dropwise. The mixture is brought to room temperature at room temperature with continuous passage of acetylene.
Stirred for hours. Subsequently, carefully add 30 ml of water in which 15 ml of sulfuric acid is dissolved.
The mixture was then stirred for a further 2 hours. Then, dissolve 40 g of sodium acetate
250 ml of water was slowly added and the mixture was heated at 75 ° C. for 15 minutes. Then
The organic solvent was distilled off and the residue was cooled to room temperature. A precipitate is obtained, which is filtered
Then, the resultant was dissolved in 600 ml of toluene. Add activated carbon and heat mixture to 65 ° C
And filtered and concentrated under reduced pressure. Recrystallizing the crude product from ethanol / water,
6.5 g of (11β, 17α) -11-ethyl-17-hydroxy-19-nor
Pregna-4-en-20-in-3-one was obtained. Melting point: 222 [deg.] C. [Α]_D ²⁰ = -16.1^o(C = 1, dioxane).

Comparative Example (A) Same as Example II (b) of US Pat. No. 4,292,251.

(B) Identical to Example XIII of US Pat. No. 4,292,251 (including the procedure of Examples VI (a) and (b) of that patent).

Examples of Pharmaceutical Formulations Pharmaceutical compositions containing steroids according to the invention are prepared. By way of example, the compound of Example 6 (Org 4060) is selected. This compound is mixed with the other ingredients in a standard manner and the mixture is granulated. The composition is as follows. The same formulation can be applied to other compounds, including Org 4325. Org 4060 (activator) 1-10 wt% Corn starch (disintegrant) 15 wt% Hydroxypropylcellulose (binder) 3 wt% Lactose 200M (diluent) Remaining up to 100 wt% Test Example A Some steroids (compounds according to the invention and invention) ) Were tested for relevant biological properties, ie, progestogenic and estrogenic activities. Progestogen activity was measured by the McFile test, and estrogen activity was measured by the Allen-Doisey test. Both tests are known in the art and can be described as follows.

The McFair Test The test compound is evaluated for its progesterone activity by assessing endometrial tissue differentiation histochemically using an in vivo test in rabbits. Rabbits are treated with estradiol for 8 days, followed by oral administration of progestogenic compounds for 5 days. Animals were euthanized (60 mg pentobarbitone / rabbit, iv) and hematoxylin in two different parts of each uterine horn.
Prepare eosin-stained transverse sections. Progestin-dependent endometrial development was assessed microscopically and on a scale of 0-4 (Van der V
ies J. And De Visser, J. et al. 1983, Endocrinological studies using desogestrel, Drug Res. 33: 231-236).

Allen-Doisey Test The test compound is evaluated for its estrogenic activity by evaluating the keratinization of vaginal epithelial cells in vaginal smears using an in vivo test in rats. Adult female rats are ovariectomized and then treated with a single dose of 1 μg estradiol (Day 1) during the third week. Seven days after treatment, test compounds are administered once on day 8 and twice on day 9. Vaginal smears are collected in the afternoon on day 10, twice on day 11, and again in the morning on day 12. Smears are stained with Giemsa to determine the number of positive smears (Van der Vies J. and De Vi).
sser, J. et al. 1983, Endocrinological studies using desogestrel, Drug Res. 33: 231-236).

Results The test results are shown in the table below.

[0055]

[Table 1]

Test Example B The compound of Example 6 was used in a monkey study.

Adult female Benigao monkeys (Ma) aged 5 to 20 years with regular menstrual periodicity
caca Arctoides) was used. Monkeys were housed in colonies consisting of approximately 35 females and one vasectomized male. The experiment was approved by the "Animal Use Committee" (DEC, AEP No. E97A0801PV E). Three of these monkeys received the compound of Example 6 at a dose of 8 μg / kg per day. The experiment was started with a pre-treated control cycle, with the first day of menstrual bleeding regarded as the first day of the cycle (day 1 of the experiment). Treatment (daily) started on the second day of the treatment cycle and continued until day 22. Compounds were administered orally via catheter under light anesthesia with Ketamine® (dose dependent on monkey, im < 10 mg / kg). After dosing, the animals were individually housed to restore consciousness and examined for regurgitation. Two hours later, the animals were returned to the colony. The post-treatment cycle started after (the expected time of) menstrual bleeding in the treatment cycle. Blood samples for estradiol and progesterone levels were analyzed twice a week throughout the experiment (
Monday and Thursday). Blood samples were obtained from the femoral vein using Vacuta.
The samples were collected using an inner tube (Venoject). Periodicity was also monitored by taking daily vaginal smears using a cotton tip applicator. Vaginal bleeding was divided into overt bleeding (score = +) and minimal bleeding (score = ±).

All monkeys to which the compound of Example 6 was administered showed inhibition of ovulation; two of three did not bleed; none of the monkeys showed temporary bleeding. These results indicate that the mixed E / P compounds of the present invention are very suitable as contraceptives: excellent inhibition of ovulation and the elimination of separate estrogens, Bleeding patterns and cycle management are good.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AU, BA, BB, BG, BR, CA, CN, CU, CZ , EE, GE, HU, ID, IL, IN, IS, JP, KP, KR, LC, LK, LR, LT, LV, MG, MK, MN, MX, NO, NZ, PL , RO, RU, SG, SI, SK, SL, TR, TT, UA, US, UZ, VN, YU (72) Inventor Hamelsma, Johannes Antonius Maria NEL-5345 FAE Zet Otus, Heisheedstraat 237 (72) Inventor Huerbost, Pieter Michel Nel-5384 ATE Haas, The Netherlands, Plantson 15 (72)・ Jan Teimen, N.L.-3971, Netherlands ・ B.A.Driebergen, Melville Juan Karnbergern ・ 38 F-term (reference) 4C086 AA02 DA10 MA01 MA04 MA35 MA52 NA14 NA15 ZA86 ZC03 4C091 AA01 BB05 CC01 DD01 EE07 FF01 GG01 HH01 JJ01 KK04 LL01 MM03 NN01 PA03 PA05 PA09 PB02 QQ01

Claims (16)

[Claims] 1. A contraceptive kit comprising a means for daily administration of a contraceptive agent, wherein said single contraceptive agent is a steroid compound having an active property that uniquely combines progestogen activity and estrogen activity. A contraceptive kit, comprising: 2. The method according to claim 1, wherein the steroid compound is selected from the group consisting of a steroid satisfying the following structural formula I, a prodrug thereof, and a pharmaceutically acceptable salt thereof. Contraceptive kit as described: (Where the dashed lines independently represent any additional bonds). 3. The method of claim 1, wherein the steroid compound satisfies the following structural formula III: Alternatively, the contraceptive kit according to claim 2, wherein the kit is a prodrug or a pharmaceutically acceptable salt thereof. 4. The method of claim 1, wherein the steroid compound satisfies the following structural formula IV: Alternatively, the contraceptive kit according to claim 2, wherein the kit is a prodrug or a pharmaceutically acceptable salt thereof. 5. The means for daily administration each comprises 100 μg to
The contraceptive kit according to any one of claims 1 to 4, characterized in that it is in the form of 18 to 30 consecutive daily dosage units containing 300 [mu] g of steroid. 6. The contraceptive kit according to claim 5, wherein the number of the daily dosage units is 21 to 25. 7. The contraceptive kit according to claim 6, comprising a placebo dosage unit such that the total number of daily dosage units is between 28 and 32. 8. The contraceptive kit according to any one of claims 5 to 7, wherein the continuous daily dosage unit is a tablet for oral administration. 9. Use of a steroid compound having an active property having an intrinsic combination of progestogen activity and estrogen activity, wherein said compound is a single contraceptive agent for producing a pharmaceutical preparation for contraception. Use of. 10. Use of a steroid compound selected from the group consisting of a steroid satisfying the following structural formula I, a prodrug thereof, and a pharmaceutically acceptable salt thereof, wherein: Wherein each dotted line independently represents any additional binding. Use for preparing a pharmaceutical preparation for contraception. 11. The use according to claim 10, wherein the steroid compound is a steroid compound satisfying the following structural formula II or a pharmaceutically acceptable salt thereof. (Where the dotted lines each independently represent any additional bond; Y is (H, H)
, (O), (N-OH) or (H, OH); X represents (-H) or (-
It represents a C ₂ -C ₇ acyl)). 12. The steroid compound according to claim 1, wherein: 12. Use according to claim 11, characterized in that it is a prodrug or a pharmaceutically acceptable salt thereof. 13. The method according to claim 13, wherein the steroid compound satisfies the following structural formula IV: 12. Use according to claim 11, characterized in that it is a prodrug or a pharmaceutically acceptable salt thereof. 14. The use according to any one of claims 10 to 13, wherein the pharmaceutical preparation is a monotherapy contraceptive. 15. A method of contraception comprising administering to a woman of childbearing age an effective amount of a steroid compound selected from the group consisting of steroids satisfying structural formula I and prodrugs thereof. 16. An amount of 100 μg to 300 μg of the compound satisfying the formula III is 2
16. The contraceptive method according to claim 15, wherein the method is administered continuously for 1 to 25 days, followed by an inter-pill or placebo interphase of 3 to 7 days.