Concentraceptive method using competing progesterone antigonists, and new compounds suitable for its application

BACKGROUND OF THE INVENTION The present invention relates to a novel contraceptive method using a competitive progesterone antagonist and to novel progetterone antagonists suitable for the administration of WT. Inhibiting the formation of endometrial glands and epithelial development, the implantation of a uterus fertilized in the uterus / inhibition of uterine invasiveness. Thus, the use of competitive progesterone antagonists since the invention can be applied to contraception in a woman. HU 486 (11?) - 4- (N, N- (Dimethylamino) phenyl) -17? -hydroxy- 17? -propynyl-estra-4,9 A-0057115 and other113-aryl or 11β10 -arylene-substituted steroids represent compounds, which may displace progesterone and glucocorticoids from the respective receptors. These substances are characterized by their strong progesterone and glutathione-antagonist antagonists. These properties have so far defined their therapeutic application. 4Q6 is used as a progesterone antagonist for the therapeutic termination of pregnancy as well as a glucocorticoid antagonist for the treatment of Cushing's syndrome of anapathetically increased secretory activity of the adrenal cortex. The woman's abortive dose for RU 486 is 200-600 mg. It has also been widely known that competitive progesterone antagonists are able to inhibit ovulation in various animal species as well as in women. (Collins et al., & Quot; Blocadano spontaneous gonadotropin burst mid-cycle in May-muni by RU 486;

Croxatto, H.B. "Salvatierra 1990, Cyclic use of anti-gestagens for fertility control", 3rd International Symposium on Contraception "Heidelberg, 19-23. 1990";

Panford et al., The potential of HJ 486 for the ingestion of ovulation. III. Preliminary Observation Once Weekly, "Contraception 40: 195-200 (1989);

Kekkonen et al., & Quot; LShteonmaki P 1990 Interbronson Vulvation by Continuous Treatment with Antipoveasterone and Synthetic Progestin & quot ;, pertii jteril, 55,4747}

Purl etal Leuctions of the gonadal and pituitary progesterone antagonist 2k 98 299 of the mammary gland of the macaque menstrual cycle, Contraception 39, 2: 227-245 (1989);

Puri et al. "Contraceptive Potential of a Progesterone-NON-BREAKING HYPHEN (8209) antagonist% 98 754: K" Bact on the Gibliculogenesis, Ovulation and Puncture of the Body of the Macaque ". In Moudgal et al., (Eda) (1990); U.S. Pat. No. 4,764,513 discloses that the susceptibility of the endometrium to the implantation / irrigation prognosis of a woman can be varied by the administration of a progesterone antagonist in order to increase the likelihood of a successful implantation of an egg fertilized in vitro. 11β, 1y-in "phenylene-bridged steroids pointing osobenosilna competitive progesterone antagonistic effectiveness in significantly reduced antiglgkokortikoidalna activity against comparative-tional compound content 11 4 '. dimethylamino-phenyl) -hydroxy-17,10-propin-1-yl] 9 (10) -estradien-3-ones 486 and EP-A-0057 115 are described for the first time in U.S. Patent No. 5,095,115,5, the novel compounds (compounds I and II) the scope of the general formula of U.S. Patent 5,095,129, but are not disclosed by name or by way of example. The dose of a competitive pgosterone antagonist with the effect on ovulation depends largely on the susceptible species. For women, 50-100 mg is for the woman. / Croxatto et al. cit. »Ledge et al. /1992/. "Ovulation Incubation Using Very Low Dose of Mfeston"; Summary: A second congressional European contraceptive society, ki 486, shows little or no diolysis of its central endometrial effector in the human body. / ledge WL et al., Terra Sympoeimn for progesterone antagonists, May 25-29, 1922, Mohawk, State of York. One treatment (LH + 2) was proposed to inhibit implantation, with the initials being a "luteinizing hormone" or "luteinizing hormone". / gWahn et al., & quot; The Effect of Acceptance of Kib 4b in the Early Luteal Phase A First Bleeding Subject, Hormonal Papers and Endometrium & quot ;, Hvuaan Reproduction 5, 402-408 (1990) s two days after the peak in the menstrual cycle / occurrence of the LH peak in a woman corresponds vremetona ovulation / toeot of 14, 15 or 16 day OE takes a inhibited ovulation dose gjj 435 once. Thus, the active composition-ka re intake side after the time of ovulation in lutealna- Menstrual Cycle Phase / Luteal Contraception / It has just been reported recently, that an endometrial desynchronization in a woman without hormonal alterations (progesterone and etradiol concentrations) can be achieved by the competitive progesterone antagonist, etc., when it is on the fifth day and on the eighth day after the onset of the peak in the menstrual cycle / dosage in each case 10 mg orally / g. • Reliable conception without ovulation inhibition can not be achieved if a competitive progesterone antagonist is taken only after the luteinizing hormonal monovalent peaks in the menstrual It has now been found that according to the present invention, conjugated progesterone antagonists are capable, in a dosage regimen that does not inhibit ovulation or induce abortion, to inhibit the formation of endometrial glands in the proliferation phase, and the function of glands in the luteal phase of the menstrual cycle, thus Dacia achieved kontpatseptsiya if dosing OE performed at least once before and optionally after the onset pissed. Summary of the Invention In a methodical aspect, the present invention relates to a single contraceptive method encompassing for the purpose of taking the follicular phase from the menstrualcycle but the woman and optionally Factually and through the luteal phase of a certain amount of is a competitive progesterone antagonist that is less than one dose inhibiting ovulation and one dose causing abortion and which dose is capable of inhibiting the formation of endometrial glands , which glands are a prerequisite for the implantation of a fertilized egg into the uterus. In a composite aspect, the present invention relates to a compound of the formula: wherein R 1, R 2, R 3, R 3, R 3, R 3, R 3,

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where R is

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In another embodiment, the present invention relates to a pharmaceutical composition comprising a mixture of a pharmaceutically acceptable excipient, a known amount of a unit dose of a competitive progesterone antagonist at a dosage lower than the ovulation inhibiting dose, and less than a pre-dose abortion dose, and which is capable of inhibiting the formation of endometrial glands and the development of epithelium. In the phase of proliferation, in the normal menstrual cycle, the enzimetry occurs in the formation of secretory glands caused by phyllo-lievia, while in the luteal phase (also called). as the secretory activity / secretion of the glands is pre-invoked by the progesterone. The disclosed antagonist progesterone antagonists in the proliferative pathway, i.e. prior to administration, is therefore not based on the progesterone inhibitor eRect, since the proliferation of the endometrial glands is bound by the bupulculin. In addition, phygoteron concentrations are very low in the prolongation period of the menstrual cycle. Using competitive progesterone antagonists according to the invention, selective inhibition of uterine amputation is achieved without adversely affecting the menstrual cycle, and the doses are abnormally low to cause abortion if planting of the egg has already taken place. The ability to achieve contraception at doses lower than the doses causing abortion and doses resulting in inhibition of ovulation is of great importance for some women who do not have abortions or are worried by the long-term medical efficacy of ovulation induction . The decisive advantage of the proposed administration is the very high contraceptive reliability of the used progestogen antagonist, since the endometrium is not capable of receiving a fertilized egg receiving a respective very low dose of the competitor piogene-erython antagonist, and optionally Optionally After ovulation, the progesterone phase of normal menstrual cycles will not be excluded, as endometrial effusion secretions are suggestive of endometrial opiates. peshna imploitatsiya will be impossible if atvoFnya of eidometonalnite glands and epithelium. Thanks to providing contraceptives-dezhdnost and in women with irregular menstrual cycle. as the endometrium is unable to accept a fertilized egg receiving either a very low dose of the competitor phegeo-heron antagonist and optional Optionally after ovulation Not to be excluded as well as the progesterone Phase of the normal menstrual Because secretion of endometrial jelly is a symptom of endometrial attractiveness, a successful implantation will be impossible in the case of the esophagus of the epididymal glands and the epithelium, thereby providing a contraceptive also in women with irregular menstrual cycles. as the endometrium is unable to accept a fertilized egg receiving either a very low dose of the competitor phegeo-heron antagonist and optional Optionally after ovulation Not to be excluded as well as the progesterone Phase of the normal menstrual Because secretion of endometrial jelly is a symptom of endometrial attractiveness, a successful implantation will be impossible in the case of the esophagus of the epididymal glands and the epithelium, thereby providing a contraceptive also in women with irregular menstrual cycles. There will be no exclusion of the proliferation phase of normal menstrual cycles. Since endometrial secretions are susceptible to endometrial arrhythmia, a successful implantation will be impossible in the case of entomophilic epithelial glands and epithelium. Thanks to this, contraception is also provided for women with irregular menstrual cycles. There will be no exclusion of the proliferation phase of normal menstrual cycles. Since endometrial secretions are susceptible to endometrial arrhythmia, a successful implantation will be impossible in the case of entomophilic epithelial glands and epithelium. Thanks to this, contraception is also provided for women with irregular menstrual cycles.

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Two new competitive progesterone antagonists, namely 11?, 19? - (4-cyano-phenyl) -phenylsilane-17? -hydroxy- 17? -hydroxyprop- -3-one and 11β, 19- [4- (3-pyridinyl) -o-phenylethyl] -4- androsten-3-one (II) have surprisingly high peripheral selectivity, i.e. the effect of compounds I and II on the endometrium is very pronounced, whereas at the same dose, only a slight central effect on the pituitary- ovarian axis Such competitive progesterone antagonists can be referred to as dissociations because at a specific threshold dose, although changes in the endometrium are observed, ovulation (central effector) is not inhibited.A proportion in one dose inhibiting ovulation and one dose, inhibition, and implantation (Dissociation Factor) as determined in rats after oral administration may be used to measure dissociation. This ratio varies depending on the species but is at least about 30 or more in a dissociated or competitive progestin antagonist. One advantage of the dioxinated or competitive progesterone antagonists is found in the fact that they can be taken in sufficiently high doses to achieve endometrial Fect without inhibiting ovulation. As a result of the above observation, the normal menstrual cycle is maintained. Competitive progesterone antagonists are pre-chitally administered under the arc at individual doses at certain intervals, for example, preferably 4 to 10 days at regular intervals, for example every week of the menstrual cycle, each time a dose is taken, which is insufficient to inhibit ovulation or to cause abortion if imitation is already present. Another adverse effect may occur on the eyelid, lower doses are acceptable, orally dosed once a day. It is also possible to use slow release systems / crystalline suspensions, transdermal patches and subcutaneous implants /, the amount of progesterone antagonist released therein is sufficient. to sacrifice the effect of the egg during the predicted life but the system is lower than the dose that would frustrate the possible ovulation that would occur during this period. The above-described administration of competitive progesterone antagonists was demonstrated by the use of onnapristone 11β- (4-dimethylamino-phenyl) -17β-hydroxy- β- (3-hydroxy-propyl) -13β-methyl-4,9-octadiene &amp; lt; / RTI &amp; gt; n-3-one; EP-A-01S0400), a type of competitive progesterone antagonist, on adult female mammals (Iasasa radiata). The scheme of experiments is set out below: macaques: adult female animals weighing 3.5-4.5 kg groups treated with onopoiston (1, 3) 5 mg and 10 mg per animal from each group subcutaneously with an oily- Benzoyl Benzoate / Reduccinic Oil 1:10 / Initial Non-Treatment and Treatment Diagram: Day 1 of the Menstrual Cycle. Taking one week and one week duration Non-Treatment: 2 Cycles Controlling the Viscous Blood Collection: n = e): endometrial histology: 1 ml 1 x daily for the first 10 days of the menstrual cycle followed by 2 g and; also through cycles and treatments, - cachets. the biopsy is sutured under ketamine anesthesia (10 mg / kg withdrawn from the animal) in the 20th second cycle, i.e., after 7 administrations of the progesterone antagonist, progesterone and estradiol / phospholipid were determined by radioimmunoassay (determination of hormones). Observations on endothelial and hormonal changes: Table 1 shows that both the duration of the cycle, and the menstrual period in the control group were not altered from the treatment according to the invention. The level of estradiol / erythropoietin and progesterone clearly states that oligolucogeneity and ovulation have occurred normal in all animals: normal pre-ovarian estaddiol peak, normal progesterone level in the luteal-Rase. 1). Hyatology shows that, unlike control animals, the endometrium was atrophied in the two treated groups. Particularly affected were the oedematous glands: atrophied and inactive glands, increased by abnormal tissue. 10 Table 1; S &amp; apos; - vehicle exposure and on-duty menstrual cycle duration (MG) and inpatient treatment period (MOC) in mahogany m Pre-cycle 1 of Cycle 2 of Post-cycle Cycle Treatment Treatment Due to the duration of the period of pregnancy (1) (1) (1) (1) (1) (1) (3) (1) (1) 28 2 27 2 126 25 1 24 Q 26 2 24 o 204 29 3 28 9 30 3 27 3 Group 2/8 mg / week / 246 2G 4 2 &lt;&lt;d&gt; 39 5 27 4 232 28 1 27 1 29 1 31 3 250 24 g ~ 3 26 1 26 1 27 4 &amp; lt; tb &amp; gt; 3 &amp; apos; 10 mg / gizzard / 203 26 4 25 3 53K 1 26 4 210 24 o ^ 7 26 1 25 1 48 1 180 30 o 28 1 28 2 27 3 and 2 oulpionic cycles in which bleeding is followed by a post-cycle The abovementioned observations clearly show that competitive antagonists are contraindicated for the contraception / inhibition of lactation (at individual doses having the effect of inhibiting the voritum effect), as well as the effect on each individual dosage unit, provided that the the dosage units will be turned on and on demand Optionally after the evaluation in each menstrual cycle Cycle - As competitive progesterone antagonists, all compounds having a high affinity for the gelatine receptor (progesterone receptor) are suitable and do not exhibit their own activity. for example, are the following steroids: 11? - [(4-n, N-dimethylamino) -4-methyl-17.beta.-hydroxy- 17,11,11,11,11,11,11,11 4 - [(4-i, gf-dimethylamino) -phenyl] -17.beta.-hydroxy- 18-methyl- 17.beta.-pyrrolidin- N, N-dimethylamino) -phenyl] -17? -hydroxy-17? -propyl-D-homo-4,9 (10) 0.057 1.15); 11β-methoxy-17β-hydroxy-17-ethynyl-4,10β-estradien-3-one (Steroids 37 (1981), 361-388) 17-propynyl-4,9 (10) -estradien-3-one (EP-A-0 190 759) and 11β-aryl-1β-etherodides and eotrippines described in EPA 0 877 676, 19, 11 beta-steroids constituting U.S. Pat. No. 5,095,129,113-aryl-6-alkyl or 1-alkenyl-estrodecyc, known from EP-A 0 289 073 and the aryl-7-methyl- or 7-ethyl-estradials known from EP-A 0 321 010 as well as 10 gH steroids from EP-A-0 404 283. The above list is exhaustive, as other competitive progesterone antagonists described in the above cited publications as well as in publications "not mentioned herein are suitable. An application according to the present invention is particularly suitable for those antagonists of progesterone antagonists which are distinguished by peripheral salivary activity, i.e., wherein the endo-ether c-Vkt is expressed even in the maximal vagina in a weak reaction centrally on the HYPOFFICE, the ovary axis . Such competitive progesterone antagonists may also be referred to as dissociated since, at a specific dose, no changes in the endometrium, but it is not inhibited by the &amp; lt; RTI ID = 0.0 &amp; gt; (s) &amp; lt; / RTI &amp; gt; The dose-response rate, the inhibition of the dose, and the dose, the implantable inhibitor, the dissociation factor, can be used for the measurement of the disease. It varies depending on the species and is about 30 days more of a competitive progesterone antagonist in the rat after oval administration to be used in isolation. The advantage of the dissociated competitive progesterone antagonists used in the present invention owing to the fact that they can be administered at higher doses to ensure that the necessary Fmoc osteotomy without inhibiting ovulation, preserves the "normal" flowing carpet rock cycle. Competitive progesterone antagonists can be administered, e.g., topically, topically, entepalio, trans doldalen gillipotrental. Oral administration is preferred. In oral administration, tablets, dragees, capsules, pills, suspensions or solutions which are to be prepared by conventional galenic propellant methods, with the aid of known additives and fillers, are suitable for oral administration. For topical or tonic administration, for example vaginal suppository, vaginal glands, implants, vaginal rings or traumatic dermal systems such as patches are suitable. It is possible for vaginal sprains, which can be removed after a certain amount of contraceptive withdrawal, for example after 14 days, and to be placed at the beginning of the next inter-contraceptive cycle. A dosage unit typically comprises about 0.25 g. Of 11? - [(4-dimethylamino) enyl) -L-hydroxy-17,11 (S-hydroxypropyl) -13-methyl-4,5 (10) -gonadien-3-one or Oligobenzoylglycylglycine A PCTGCHF antagonist, an otonocol antagonist. If the above-mentioned oral progesterone is present in the presence of an impingement, a vaginal ring and a transgenesis, these receiving systems have to bind t-phisposo such that each dose of the competitive progestin antagonist is in the range of 0.25 to 50 mg. The dose of competitive antagonist, an oncogene antagonist to be administered, should be below the dose of inhibitory ovulation as well as the dose causing the abortion. Usually, as a single cut, 0.25-20 Specifically, employing selectively competitive &amp; lt; RTI ID = 0.0 &amp; gt; of the oral antagonist: the single dose may be administered at a dose of 0.5 - 50 mg, as the permeable solubility of the compound allows a far higher dosage without producing an ovulatory drug . The term &amp; quot; single dose &amp; quot; or &amp; quot; single dose &amp; quot; comprises a system which releases a competitively conjugated progestogen antagonist in an amount of 0.25 to 20 mg per day or equal to 0.5 to 50 mg per day. Without going into deeper detail, it is assumed that a person in this area could, by proceeding from the previous sansaudo, apply the rented invention to his complete endeavor. Therefore, the preferred embodiments, which will be hereinafter described, are to be construed as illustrative without limiting the scope of the invention, which is yet to be exposed. In the examples that have been given so far and which will be given in the following examples. - * * * * * * * * * * * * * * * * * * * * * * * (2-methylphenyl) -1- (2-methylpropyl) -1- [2 - [(4-

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The lazy nona-Phthalate (c.i.sub.2 SO.sub.2) is chromatographed on silica gel (9 g) with a mixture of ethyl acetate / hexane. 1.2. but the title compound was obtained under the following conditions. white foam. S? Melting point: 132-133 ° C; = + 25 ° C (CHCl3, c = 0.02 cm2) 3,3-Dimethyltrimethylenedioxy-11β, 19- (4-naphthalenbutylsulfonyloxy- α- phenylene) -androstan-17- one 63 g of chromium trioxide The mixture was cooled to 0 ° C to a solution of 210 ml of ethanol and 600 ml of ethyl acetate, followed by the addition of 89 g of the title compound, /, в 250 метилес тсг тт * '* * * * * * * * * * * * * * * * * * * * * ¿¿¿¿¿¿¿¿¿¨ ¨ ¨ ¨ ¨ ¨ ¨ ¨ ¨ ¨ ¨ ¨ ¨ ¨ ¨ ¨&gt; After the stirring is completed, fast-paced ·? and the residue is washed several times while remaining in the presence of ethyl acetate. The organic organic compounds are separated from the residual inorganic constituents by the addition of a 0.5 m solution of the hydroxide solution, washed with water, water, dried with sodium sulphate and evaporated in vacuo to evaporate in vacuo to give the title compound

The title compound is an azotropic distillate and toluene. Ж M f ·; The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give an off-white aluminum oxide (61 mg). The crude product was triturated with hexane to give 61.0 g of the title compound The title compound was obtained in the form of a mixture of the title compound and the title compound as a white solid: mp 77.7 DEG-77 DEG C .; : (+) - 3,3-dimethyltrimethylenedioxy-11B, 19- (4-nonyl) urea -butylsulphonyloxy-o-bilene) -17.beta .- [3- (tetrahydropyran-O-yloxy) -piperazin-1-ol, under a protective gas with 73.5 ml of 2- (8-propynyloxy) -tetradehyde oxy-2Y'-piran.Posle 328 ml of 1. 6 m of pyroboly-lithium solution (hexap) are slowly added dropwise to this solution without appreciably increasing the temperature. After stirring for 30 minutes, 50 g of a ketone solution produced in THF (50 ml) was dissolved in 500 ml of absolute tetrahydrofuran under cooling in an ice bath and the reaction was stirred for a further 30 minutes, after which the reaction mixture was quenched with a saturated solution of ammonium chloride and the aqueous 4-aze is extracted with ethyl acetate.The combined organic phases are washed with sodium chloride, dried with sodium sulphate and concentrated by suction under vacuum. chromatographed on alumina / neutral, melted with L / Z. there were obtained 50.3 g of the title compound as a white foam. a) 11β 19- [4- (4-thienyl) -o-4-ylidene] -3,3-dimethyl-trimethyl. 2-yloxy) -prop-1-yl] -androstane-17 g -diol 50 g of nicolate produced by e / is dissolved in a mixture of 400 ml of toluene and 155 ml of ethanol are mixed successively under a protective gas with 1.44 g of tetrakis (triphenylphosphine) palladium (0), 33 g of lithium chloride, 78 ml of 2? solution of sodium carbonate and 13.1 g of 4- (1,3,2-dioxaborinan-1-yl) benzonitrile. h. Takahashi, 62, 3896 (1989). Then, et al. , cd. Chen. See. Jpn. , the reaction mixture was stirred for 3 hours at 95 ° C in an oil bath, cooled to room temperature and mixed with water and ethyl acetate. Separate the aqueous layer and extract with ethyl acetate. The combined organic bases are selected from the group consisting of heptade and co-coprecipitates by the process of the invention. The residue is chromatographed in a slurry of ethyl acetate / hexane. 30 g of the title compound was added to the slurry of the foam. is 11β, 11β- [4- (4-cyclopenyl) -o-phenylene] -1β- ®-hidvot ccr 1? .....- H-hidpokstarott-1-ynyl) -'L-akloosten-3-one d) C / p 07 R0 TO IN GBg -OTSOTOL, ΠΌΟΤΤ3 Π ' "' D. The reaction mixture was cooled to 0 ml. Of Pd / C, and the mixture was stirred for 5 hours at room temperature. The solution was stirred for 2 hours at 50 ° C. is used in the ethylene-ethylenically unsaturated hydrocarbon feedstock and the more preferred catalyst is selected from the group consisting of ethylenically unsaturated hydrocarbons, ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿" oo thrust ON '

H * * * * * * * * * * * * * * * * ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿" (4-phenoxy) -o-phenoxy] -7,7-dihydro- (3-hydroxy-1 (2) -enyl) -propan-2-one The title compound was prepared as follows: tetrahydropyridine are mixed with 5 ml of pyridine and with hydrogen in the presence of palladium on barium sulphate for catalysis, too. equivalent water in the mixture to the reaction mixture (I), the reaction mixture is filtered, The residue was taken up in tetrahydrofuran and the residue was chromatographed overnight. Purification of the residue with acetone / tetrahydrofuran was carried out in a manner similar to that described above. with thionyl chloride. Yield 14.3 g of the title compound; ^^^^^^^^^^^^^^^^^^^^^^^^^ A solution of the title compound as a white solid: mp 268 ° C (decomp.): M.p. (A) 11B, 19- [4- (3-pyridinyl) -o-phenylene] -13,10-hexahydro-17.alpha. 3-one 11,10- [4- (3-pyridinyl) -o-phenylene] -1,3-diethyltrimethylenedioxy- 17- [3- (tethohydropypon- Oxo-1-pyrrolidin-5-one, 17-diol 13.7 g of the nona, was added dropwise in one portion with an amount of 140 ml of toluene and 70 ml of ethanol and the mixture was evaporated. (in the presence of a protective gas is 87.7 mg of tetrakis (triphenylphosphine) palladium (3.00 g), 1.20 g of lithium chloride, 17 ml of a 2 ml solution of sodium hydroxide, A solution of 2.46 g of diethyl (3-pyridyl) boron was added, and the reaction mixture was stirred at room temperature for 2 hours at -78 ° C. The aqueous solution was washed with water and extracted with ethyl acetate and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid. The combined organics were dried with sodium sulfate and concentrated in vacuo to give a residue which was chromatographed on silica gel ethyl acetate / hexane to give the title compound as an off-white solid (b) 11.beta. 19- [4- (3-pyridinyl) -o-Reninylene] -17.beta.-hydroxy- 17.beta.- (3hydroxyprop-1 -ynyl) 8.8 g of ketone cetaldehyde is dissolved in 869 parts by weight of the mixture under a protective gas with 6 ml of 4 parts of hydrochloric acid in the form of a hydrochloric acid, at 60 ° C, the reaction mixture is poured into a starch solution of IPB (basic pK) and the highest proportion of acetic acid deuterated. After centrifugation, the aqueous phase was separated and extracted with ethyl acetate. The combined organic phases are washed with a solution of triethylsulfate and evaporated to give an off-white solid. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate / hexane. There was obtained 6.0 g of the absent &amp; quot; r &amp; quot; you can use the wiki to copy the wiki. 22 = + 48.6 ° (cis) (C = O, 591). c) 11b, 1c; - [4- (3-pyridinyl) -octanone] -17β-hydroxy-17- (3hydroxyprop-1 (R) -propylglycine-8- nob) are dissolved under protective gas in 200 ml of tetrahydrofuran mixed with 5 ml of pyridine and hydrogenated using 800 mg of palladium on barium sulfate as a catalyst at atmospheric pressure. After one equivalent of hydrogen (in addition to Trisconazole) is absorbed, the reaction mixture is filtered, and the filtrate is concentrated in vacuo to give the title compound The residue was chromatographed on silica gel with one epoxidate acetate / hexane. The residue was chromatographed on silica gel using ethyl acetate / hexane to give the title compound as an off-white solid. There were obtained 3, 4 g of the title compound below the yellowish color, crystalline ethyl acetate 20 gave ethyl acetate 3.12 g of white crystals. Melting point! 219-221 ° C; 22 n -Hy = + 4H6 (CHCl3) i C = 0.530)

EXAMPLE 3 10.0 mg of 11β- (4-hydroxy-N, N-dimethylamino) -phenyl] -17,17β-3-hydroxypropyl- 13- methyl- 4,9-(10-tetrahydro- 3-one 140.5 mg of lactose 69.5 mg of corn starch / 2.5 mg of polyvinylpyrrolidone 25 2.0 mg of aerosil 0, -5 mg of magnesium stearate 22b, 0 mg of total weight To prepare from the above composition tablets of 10 mg for oral administration in the usual way. In order to use the medicament produced according to the present invention, it is critical that a smaller dosage unit be administered through the follicular period of the menstrual cycle (ovulation) and optionally at least facultatively one dosage unit to be taken into the intrauterine phase of the menstrual cycle (after ovulation). Preferably, the drug produced in accordance with the present invention, to be administered in individual dosage units every 4 to 10 days, preferably on a weekly basis, or on the same day, starting on each day before ovulation occurs in the first menstrual cycle of taking the opaque preparation. Preferably, the intake units between the individual dosatope units are constant. Preferably, the medication according to the present invention is taken once a week on the same day 21 of the week, for example on Monday ("Moon Pill"). the weekly rhythm of administration always provides a high degree of reliability at one and the same day of the week. However, it is advisable to take a dosage regimen every day, every 2 days or every 3 days, or only through the follicular larynx or in addition to the luteal self menstrual cycle. Based Mouna is " however, to vary the intervals between the intake of the individual dosage units of the medicament according to the invention or to be tamped by the implanted vesicle continuously by slow release of the preparation. To control the doses of competitive ovarian inhibitory progestin antagonists, the ovulation-inhibition experiment described below was performed on rats? the corresponding abortive efficacy doses are derived from the known (e.g., U.S. Pat. No. 5,095,129) abortion attempt. the ovulation inhibition described below was performed on rats? the corresponding abortive efficacy doses are derived from the known (e.g., U.S. Pat. No. 5,095,129) abortion attempt. the ovulation inhibition described below was performed on rats? the corresponding abortive efficacy doses are derived from the known (e.g., U.S. Pat. No. 5,095,129) abortion attempt.

The defined Dissociation Reagents for Compound I, IIa and IIIb of the Compound Disiacitivone Factor 1 100 II .. 30 RU 486 10 For both compounds I and II it was further found that despite their extremely potent antiviral efficiency (compound I) was filled efficiently with respect to of implantation inhibition in rats, even at a daily dose of 0.1 mg, and Compound II at a daily dose of 0.3 mg /, they are not simultaneously effective anti-glucocorticoids. This is seen from the thymolysis experience of the antiglucocorticoid effector (EP-A-0 283 428). The production of the compounds I and II is carried out by the pathway synthesis described in EP-A-0 S83 428 and referred to in the examples below. PRINCIPLE OF THE METHOD In order to detect the substances inhibiting ovulation, such as rats, as they ovulate spontaneously and the cycle can be easily observed by vaginal smears. This allows you to control the progress of the experiment and the in-fill of the treatment. METHOD EXAMPLE 4 Protocols Female rats weighing 190-210 g at a dose of 6 animals. The animals are kept in macrolon cells in controlled light exposure rooms (10 hours darkness: 14 hours light), fed standard diet / granulated feed (1 + 9 v / v), and the daily dose is taken in a volume of 0.2 ml of rat (s) and can drink water freely from the conduit of the wearer. Preparation and administration of test substance The test substance is dissolved in benzyl benzoate / castor oil Oral (oral) administration of the substance to be tested is suspeidiva liquid binder / 85 mg Myrj ^? in 100 ml0, (W / v solution of NaCl) and the daily dose is given in a volume of 0.5 ml. Charge of the test substance Two cycles are observed to start the test through vaginal smears. Only animals with a regular 4-day cycle are used in the experiment. Involvement in the experimental manes is done in a haphazard way. Start in the metastasis, the test substance is given for 4 days / day (4) and the cycle continues to be controlled. On the fourth day (after taking the substance), animals who have an ectus or metastasis during vaginal smears are subjected to ovariectomy on one side under anesthesia with ether. Prepare truncated preparations from the tubes and test them with a microscope for the presence of no egg cells. On the fifth day, all animals (untreated and unilateral) were killed with gaseous carbon dioxide, egg tubes are prepared in the same way. METHOD GENDER 5 Evaluation The percentage of animals in which ovulation was included in the individual dose groups was determined. Volunteers t Patients' status is as follows: their self-esteem, normocyclic women. Preferably voluntary after ligature of the two Fallopian tubes or after surgical excercise of the two fallopian tubes / ectopic pregnancies / or women exposed only to valectomized partners. Study on Women 1: Characterization of Biochemical and Morphological Markers of Endometrial Emphysema after Short-Term Treatment with Opadryptone, 8, 8, 8, ···································································································· This is piloted to investigate which bio-chemical methods, especially the identification of endometrial marker proteins, are beneficial in targeting the more recent and following with low doses of onapristone / daily and intertemporary thio /. Experimental protocol: Groups of volunteers: Two groups / control group and taking gauze / from 8 to 10 women each. Study duration; Three cycle evaluation: pre-treatment cycle, treatment cycle, and post-treatment cycle. TREATMENT · 50 mg onapristone daily on LH + 1 and LII + 2 days. It is known that this dose of onapristone causes premature menstruation in the woman when given in the late phase luteal. However, according to Bygdeman / 8wahn et al. (LH + 2) with a single dose of 200 mg of RU 486 does not affect the cycle time, R10, LH, RAS and progesterone through cycling over treatment, treatment cycles and post-treatment cycles. Endometrial biopsy and collection of the uterine fluid day LH + 3 and LH + LH + / treatment cycle see the Appendix for details / - presence of menstrual bleeding 25 Study on Women 2: Evaluation of daily administration of nappsitone on ovulation and endometrial morphology and biochemistry : Objective Study Objective The results of this study identify a single dose that does not reflect negatively on the cycle, reveals an effect on morphology and function (endometrial proteins) on an endometrium mind. A minimal dose that causes endometrial changes may occur in these nations. Study Scheme Groups of volunteers: four groups / three groups, under contraceptive treatment and one control group (from porcine - 10 women each). Study Duration »Evaluation of the three cycles: pre-treated cycle, treatment cycle and post-treatment cycle. Mode: 18 daily oral intakes of 20 mg / group ./, 10 mg / group 2 / and 5 mg zrnyna 3 / onapristone, starting from day 1 of the cycle. BIA, LH, RHH, and progetaevin and cortisol over the pre-treatment, treatment cycles and post-treatment cycles Evaluation of endometrial biopsies and collected umbilicals (fluid) on day 16 and day 23 of treatment (see annex for details ^. - Existence and duration of menstrual bleeding Investigated women 5: "* * * * * * * * * * * * WWMI · * * * * * * * * * * * * * &gt; II ················································ Inn · ····················································&gt; (A) The results of this determination determine the dose of the one. 9 КОЯОС "" * 0 Я Я 0 *. TS ^ '03 TITLE θ '? 1' * NF? K otlkilto. ^ Co kyal "&lt;y kikayal January pokppvp θ ^ όχτ tue ^ lku t? 0 · Λ'νΌ YAOGK ^^ P • t * ld &lt;;;. rt * jfr'm * | ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿* * * * * * * * * * * * * * * * * * * • * • * • * • * • * • * • * • * • * from more! - 10 g of the aliphatic moiety. N-butyldimethylsilylphenol isocyanate, isocyanates, isocyanates, isocyanates, isocyanates, isocyanates and the like, weekly, but at a time of 1 mg per day (group 1), 20 mg / group 2, 10 mg / day 3 /, 2 mg / group 4 / and 0.25 mg / influenza / cycle. o) Assessment of RIA, -LH, P3H, and Ep and progeterone during the pretreatment cycle of the third and the cycle after treatment of Endometrial Biopsy Assessment and Collection of Mature Fluids on Day 16 and Day 23 of two treatment cycles (see Appendix for details). Existence and duration of menstrual bleeding and abnormalities during cycles: • By performing the treatment regimen described, the following phenomena were given: better cycle control but group treatment regimen in comparison to the control group; high tolerance? high contraceptive reliability; and estrogen-free / oval contraception / oval contraception. The foregoing impurities can be repeated successively by substituting the generic and specifically described reagents and / or operative conditions of the present invention for use in the foregoing examples. From the foregoing description, it is within the scope of the present invention that one can readily ascertain the essential feature of the present invention and, without departing from the spirit and purpose of the invention, may make various modifications and modifications to the invention in order to adapt it to various applications and conditions - ya