MXPA97004742A - Compounds with antagonist properties of progesterone and anti-estrogen for combined use in the femen contraception - Google Patents

Abstract

The present invention describes the use of at least one compound with an antagonistic effect of progesterone (PA) and at least one compound with antiestrogenic effect (AE), in a non-inhibitory dose of ovulation in a single dose unit, for the preparation of a medicine for female contraception

Description

COMPOUNDS WITH ANTAGONIST PROPERTIES OF PROGESTERONE AND ANTI-ESTROGEN FOR COMBINED USE IN FEMALE CONTRACEPTION. DESCRIPTION OF THE INVENTION The present invention relates to the use of at least one compound with progesterone antagonists (PA) and at least one compound with antiestrogen effect (AE), in a non-ovulatory dosage in a single dose unit, for the preparation of medicines for female contraception. The medicine prepared according to the invention bases its contraceptive effect on the basis of the inhibition of receptivity, thereby preventing the nidation of a fertilized egg in the mucous membranes of the uterus, without disturbing the ovulation or the cycle. Throughout the world, the use of oral contraceptives has become a commercial factor, to which he has no objection. Especially under the aspect of rapid global growth, a continuous development of the fertility control methods hitherto used is required. The use of progesterone antagonists competent in the control of female fertility has been discussed for some years for both animal species and humans, as can be taken from the publications mentioned below, especially the use of RU 486 ll -β- [4-N, N- (dimethylamino) phenyl] -17-β-hydroxy-l7-a-propynyl-estra-4, 9, 10-dien-2-one: EP-A-0057115: Collins and cois. Blocking the spontaneous gonadotropin increase in half monkeys by RU 486: An antagonist or progesterone agonist J.Cli.Metab. , 63, 1270-1276 (1986): Croxatto, H.B.M Salvatierra 1990 Cyclic use of antigestagens for the control of fertility, 3rd. International Symposium on Contraception, Heidelberg, June 19-23, 1990; Danford and cois. , Contraceptive potential of RU 486 due to the inhibition of ovulation, III. Preliminary observations with the weekly administration. Contraception 40: 195-200 (1989); Kekkonen and cois. Lahteien aki P 1990 Interference with ovulation through sequential treatment with the antiprogesterone RU 486 and synthetic progestin. Fertile Sterile 53: 4747 [1990]. Puri et al. , Responses of the gonads and the pituitary to the progesterone antagonist ZK 98 299 during the follicular phase of the menstrual cycle in capuchin monkeys. Contraception 19121: 227-243 [1989]; Puri et al. Contraceptive potential of a progesterone antagonist ZK 98 734: Effects on folliculogenesis, ovulation and function of the yellow body in capuchin monkeys. In Moidgal and cois (eds) (1990). The contraceptive effect of a progesterone antagonist is conditioned on the one hand by direct effects on the endometrium. It should be mentioned here that the dosage which shows an ovulation-inhibiting effect depends strongly on the competent progesterone antagonist used. In the case of progesterone antagonists of the type RU-486, these are slightly dissociated compounds with a strongly marked ovulation inhibiting effect. In the case of progesterone antagonists of the onapriston type, these are specific compounds for the endometrium (strongly dissociated), which inhibit ovulation only with strong dosages. A chronic treatment with this type of progesterone antagonist leads to the delay in the growth of the endometrium, without disturbing the ovarial and menstrual cycles. In the endometrium the degeneration of the endometrial glands and a thickening of the estrus is reached, in such a way that the implantation of a fertilized egg (inhibition of receptivity) is avoided. The class of steroids substituted with llß-aryl or llß, l9-arylene differs pharmacologically according to its strong progesterone antagonist effect or glucocorticoids. Thus RU 468 can be used on the one hand for the interruption of therapeutically induced pregnancy [the human abortive dose in combination with a prostaglandin is 200-600 mg; EP-A- 0 139 608], on the other hand also on its antagonist effect in the glucurotide receptor for the therapy of Cushing's syndrome. Another possibility of the use of competent progesterone antagonists for the control of female fertility, the so-called "LH + 2" treatment, is proposed by S ahn et al. [The effect of administration of RU 486 during the early yellow phase in bleeding models, hormonal parameters and endometrium. Human reproduction 5 (4): 402-408 [1990], in which the second day after the increase of the hormone leutenisant [LH] in the menstrual cycle of the woman (this is in general on day 14, 15 or 16) a single ovulation-reducing dose of RU 486 [leukoeconception] is administered. A treatment with RU 486 in that section of the menstrual cycle does not lead to disturbances of the cycle. The application of RU 486 in other phases of the cycle dosages below lmg / day leads to amenorrhea or irregular bleeding. This procedure has no practical meaning, since the easy and accurate temporal determination of the LH peak always represents a problem. Glasier and cois. [Mifepristone (RU 486) compared to high-dose estrogen and progesterone for post-coital emergency contraception. The New England J. of Med. 237 .: 1041-1044 (1992)] also describes the use of RU 486 for postcoital contraception (emergency postcoital contraception.) The method also shows a high degree of reduced side effects. In a high percentage of women in this study an extension of the cycle was present, which can be attributed to the anti-ovulatory effect of RU 486. Furthermore, in WO 93/23020 it is described that competent progesterone antagonists can be used in doses found in a dose, which is both below the abortive dose and inhibiting ovulation, certainly here in general a repeated and regular application is required to achieve the desired effect, likewise describes EP-A 0 219 447, which effect causes the daily administration of a progesterone antagonist during the follicular phase or optionally also leuteal of the female cycle in a period of up to 4 days in a dose of 1 0-200 mg in relation to the state of differentiation of the endometrium. The resulting variations of the endometrium are used considering the timing of nidation for in vitro fertilization. Batista and cois. [Daily administration of the progesterone antagonist RU 486 prevents implantation in cycle guinea pigs, Am.J.Obstet. Gynecol .165: 82-86 (1991)] also describes the use of RU 486 for the control of female fertility, which by daily, precoital and full cycle avoids nidation with an inhibitory dose of ovulation in guinea pigs. Kawano and cois. [Effect of RU 486 on glycogen metabolism in the endometrium. Obstetric Act and Gynaecologica Japónica, 41: 1507-1511 (1989)] describes the influence of RU 486 on a dosage of 30 mg / kg of body weight on glycogen metabolism, in such a way that successful implantation of the egg is disrupted . The application is made on day 2 or 4 of pregnancy. The hormonal control of the implantation depends on the species. In all the maminefors studied up to now, the presence of ovarian progesterone is necessary for successful implantation. In the case of rats and mice with postcoital ovariectomy, which is replaced by progesterone, implantation is not achieved without the administration of estrogen (Finn CA, Porter DG [1975] Implantation of ova. {Chapter 6] and Thecontrol of implantation and thhe decidual reaction { Chapter 8]; in Finn CA and Porter (eds.) The Uterus, Elk Science, London, p. 57-73; 86-95). If estrogen is injected into this animal species, the implantation of the blasts is reached immediately (model of delayed implantation). These observations indicate that ovarian estrogen in the presence of progesterone induces implantation in the case of rodents. It was already known that in the case of guinea pigs and primates ovarian estrogens are not essential for implantation. In the case of guinea pigs, which are ovariectomized after mating, implantation is performed after a substitution of progesterone (without additional estrogen treatment) (Deansley R [1972] Retarded embryonic development and pegnancy termination in ovariectomized giuinea pigs: prociesterone deficiency and decidual collapse; J. Reprod. Fert [1972] 28: 241-247). Both antiestrogen and estrogen in high doses inhibit implantation in rats and mice (Martin L, Cox RJ, Emmens cw [1963] Further studies in the effects of strogens and antiestrogens on early pregnancy in mice J. ZReprod Fertil 5: 239-247; Singh MM Kamboj VP [1992] Fetal resoption in rats treted with antiestrogen in relatio to luteal phase nidatory estrogen secretion Endocrinol act 126: 44-50). The inhibitory effect of the implantation of the antiestrogen with partial effects of estrogens (Nafoxidin, Centcroman, Tamoxifen) is also deduced for guinea pigs (Wlsel MS, Datta JK, Saxena RN [1974] Int. J. Fertile 39: 156-163). It is not clear if the inhibitory effect of the implantation of the aforementioned antiestrogens has to be attributed to the antagonistic or agonist effect, since the estrogens in high doses inhibit the implantation in the guinea pigs. The use of estrogen antagonists (Centdroman) for contraception in humans is also described (Nuttyand S, Kamboj VP [1992] Centchroman: Contraceptive efficacious and safety profile, International Confrence on Fertility Regulation, November 5-8, 1992 Bombay Indica. and abstracts). However, undesirable side effects were present in effective dosages, which can be attributed to the systemic effect of the estrogen antagonists. Estrogen deprivation that occurs after prolonged treatment with an antiestrogen limits at least its regular use for contraception. Finally, from DE-A 42 13 005 the use of aromatic inhibitors for the prevention of pregnancy in the case of female primates of reproductive age is used in a dosage in which the menstrual cycle of female primates remains essentially unchanged. Aromatics inhibitors block the biosynthesis of estogens in their previous stages. The absolute extent of the daily dose required for the contraceptive effect depends on the type of aromatic inhibitor used. For the highly active aromatic inhibitor, daily doses are usually between 0.05 and about 30 mg. In case of less active dearomatics inhibitors can daily doses also be higher. The present invention proposes the task of preparing run prepared for endometrial contraception (inhibition of endometrial receptivity, postocital application, "Need Pill"), which does not present the aforementioned side effects and which simultaneously presents a greater contraceptive security than the separate application of the corresponding individual components. Under "necessity pill" it should be understood an oral administration medication that is preferably taken in a unique and precoiteal manner, avoids conception. An agent of that type prepared with the exclusive use of a competent progesterone antagonist is not described in published German patent application P 44 38 820.9. This task is solved because at least one compound with progesterone antagonist effect (PA) and at least one compound with antiestrogenic effect (AE) is used., in non-inhibiting dose of ovulation are used in an individual dose unit together for the preparation of drugs for female contraception. Now it was also found that the combination of a progesterone antagonist and an antiestrogen synegistically inhibits the proliferation and differentiation of the endometrium, so that the antiferil effect of the individual components at the corresponding dose in the combination is not increased or to achieve a effect comparable to the separate use of the individual components, can be used in smaller doses corresponding to the combination. EP-A 0 310 541 is already an agent containing at least one compound with antigestafen effect and at least one compound with antiestrogenic effect, especially for inducing labor and terminating pregnancy as well as for the treatment of serious problems as well as the use of at least one compound with antigestagenic effect and at least one compound with antiestrogenic effect for the preparation of medicaments for the given indications. Pharmaceutical compositions for the postcoital control of fertility, which contain a competent progesterone antagonist (antigestagen) as well as a blocker for the synthesis of progesterone and estrogen, are described in US Pat. No. 4,670,426. As a typical representative of progesterone-competent antoganists to be used are flocinolonacetonide, triamcinolonacetonide, steroids with cyclic 16,17-acetal with acetone and llß- [4- (di-ethylamino) phenyl] -17β-hydroxy-17a :-( 1- propinyl) is-4, 9-3-one (RU 38 486) and equivalent derivatives. The typical content is between 20 and 50 mg. As examples of the blockers of the synthesis of progesterone and estrogen, mention may be made of aminoglutethimide, 4β, l7a-dimethyl-17β-hydroxy-3-oxo-4,5-epoxy-5-androstan-2a-carbonitrile, 20, 25-diazo-cholesterol and with positions with equivalent activity and this in a dose of 300 to 1000 mg. The use of the composition should be carried out in accordance with the US patent 4,660,426 as soon as possible in the course of the first weeks after intercourse for a period of 3 days; It is best to extend the treatment 2 to 6 days. The inhibition of the nidation and with this of the pregnancy is realized by means of the synergistic effect to the joint use of both constituent parts of the composition, and this is with a success rate in the order of 90% or more. It has now been found that in addition to antigestagens (competent progesterone antagonists) also pure estrogen antagonists such as 7- [9 - [(4,4,5,5,5-pentaflioropentyl) sulfinyl] nonyl] estra-1, 3 , 5 (l?) Trien-3,17ß-diol (ICI 182780), inhinben the implantation in guinea pigs, different from what had been assumed until now, have estrogens also an important role in the implantation. It was also found that in the guinea pigs surprisingly a treatment combined with progesterone antagonists and antiestrogens during the peri-implantation phase (day 1-7 post coitum) have a synergistic effect. These observations indicate that in these species, estrogens are formed in blasts. A similar situation may exist for humans. The essential advantages of the present invention are not further based on the low dosage of the active ingredients, on the one hand by the possible reduction of the effective amounts required in a monotherapy by means of the synergistic effect, on the other hand by the use of lower dosages no inhibitors of ovulation. Thus the female menstrual cycle is modified in any way in regard to its cyclicity (as is the case with substances such as RU 486) and the organism is not loaded by means of unnecessarily high amounts of progesterone antagonist competent antiestrogen. The use of one of these progesterone / antiestrogen antagonist combinations offers a prevention of pregnancy, this is the regular intake of a drug of that type (daily, regularly every 3 to 7 days) prevents blastocyst nidation without influencing the cycle . In addition, the safe contraceptive is increased after the single taking, oriented to the precoital need regardless of the day of taking it in the cilo ["need pill"] or after a postcoital treatment. Estrogen deprivation is not available through dose reduction of the antiestrogen. Thus, an endometrioselective effect of the antiestrogen can suffice and an undesirable effect can be avoided due to an estrogen deprivation in another organ, for example in the bones. The proportion by weight of both components in the new medicament can thus vary between broad limits. Thus, equal amounts of PA and OE can be used as well as in excess of one of the two components. PA and AE are used together, separately, simulataneously in a weight ratio of essentially 50: 1 to 1:50, preferably 25: 1 to 1:25, and especially 10: 1 to 1:10. Simultaneous administration is preferred. Preferably PA and AE can be applied in combination in a dose unit. Both components can be applied once a day or intermittently every 3-6 days during the entire cycle. They can also be used once precoitally (according to the need "Pill according to need") independent of the moment of the menstrual cycle or postcoitally. In the case of precoital use, the progesterone antagonist is higher, in any way below the ovulation inhibiting dose. All competent progesterone antagonists which competently block the gestagen receptor (progesterone receptor) and which do not show gestagena activity thereby, are competent progesterone antagonists; Blocking can be done by means of the substance administered itself or by its metabolites. With the competent progesterone antagonists it is treated according to the present invention preferably in endometrial-specific compounds (dissociated) that at most have a low anti-ovulatory activity. Non-dissociated progesterone antagonists can also be used., of which its dose is below the inhibitory dose of ovulation. For example, the following steroids come into consideration. ll-ß- [4-N, N- (dimethylamino) phenyl] -17β-hydroxy-17- (1-propynyl) -estra-4,9,10-dien-2-one (RU 38 486) ll- β- [4-N, N- (dimethylamino) phenyl] -17β-hydroxy-17-a- (1-propynyl) -l8a-homoestra-4, 9, 10-dien-2-one and 11-β- [ 4-N, N- (dimethylamino) phenyl] -17aβ-hydroxy-17aa- (1-propynyl) -17a-homoestra-4,9,16-trien-3-one [all EP-A 0057 115], 17a- ethynyl-17β-hydroxy-11β- (4-methoxyphenyl) estra-4,9-dien-3-one (Steroids 37 (1981), 361-382), llß- (4-acetylphenyl) -17β-hydroxy-17a- (1-propynyl) estra-4,9-dien-3-one (EP-A 0 190 759), 4 ', 5'-dihydro-11β- [4- (dimethylamino) phenyl] -6β-methylspir 4, 9-dien-17β, 2 '(3'H) -furan] -3-one 4', 5'-dihydro-11β- [4- (dimethylamino) phenyl] -7β-methylspiro [estra-4, 9] -dien-17β, 2 '(3 H) -furan] -3-one llß- [- (acetylphenyl) -19, 24-dinor-17, 23-epoxy-17a-cola) 4, 9, 20-trien- 3-one (all US-A 4,386,085) as well as bridged steroids with 19, 11β-, 11β-aryl-14β-estradienes and threes described in EP-A 0277676, subject of EP-A-0 283 428 , the 11β-aryl-6-alkyl (or 6-alkenyl or 6-alkynyl estradienes and known pregnadienes of EP-A-0 289 073m the known 11β-aryl-7-methyl (07-ethyl) -estradiene of EP- A-0 321 010 as well as the lOß-H-steroids of EP-A-0 404 283, for example (Z) -ll- [4- (dimethylamino) phenyl] -17a- (3-hydroxy-1-propenyl) estr-4-en-17ß-oi. In addition, competent representatives of progesterone antagonists according to the invention can be mentioned, for example: 11β- [4-N, N- (dimethylamino) phenyl] -17α-hydroxy-17β- (3-hydroxypropyl) -13α-methyl- 4.9 (10) gonadien-3-one (EP-A 0 129 499), (Z) -ll- (4-acetylphenyl) -l7β-hydroxy-l7 - (3-hydroxyprop-1 (Z) -enyl) -4.9 (10) -estradien-3-one (EP-A 0 190 759), (Z) -6 '- (4-cyanophenyl) -9, lla-dihydro-l7β-hydroxy-l7a- (3- hydroxy-l-propenyl) -4, H-naft [3, 2, 1 ': 10, 9,11] estra-4, 9 (11) -dien-3-one and (Z) -9, 11-dihydro -17β-hydroxy-17 - (3-hydroxy-1-propenyl) -6 '- (3-pyridinyl) -4'H-naft [3', 2 ', 1': 10,, 11] estra-4, 9 (11) -dien-3-one 17-hydroxy-17β-93-hydroxypropyl) -ll- [4- (l-methylethyl) phenyl] -13-tetra-4,9-dien-3-one [ZK 131 535] llß- [4-93-furanyl) phenyl] -17a-hydroxy-i7B- (3-hydroxypropyl) -13-tetra-4,9-dien-3-one (ZK 135 695) (Z) -ll- [4- (dimethylamino) phenyl] -17β-hydroxy-i7a- (3-hydroxy-l-propenyl) est-4-en-3-one (E) -ll- [4- [[(acetyloxy) im] ino] methyl] phenyl] -17β-methoxy-l7a- (methoxymethyl) estra-4, 9-dien-3-one (E) -ll- [4 - [[[(ethoxycarbonyl) oxy] imino] methyl] phenyl] -177-methoxy-17a- (methoxyethyl) estra-4,9-dien-3-one. In the last PA it is tritiated of those of the dissociated type, in which with certain threshold doses changes in the endometrium are observed, while ovulation is not inhibited (central effect). The quotient of the inhibitory dose of ovulation and abortifacient (dissociation factor) can serve as a measure for dosing. Dissociated PAs are preferred within the framework of the present invention. The count of the PAs is not conclusive, also other competent progesterone antagonists described in the mentioned publications, as well as the publications not mentioned, are adequate. Recently, effective non-steroidal compounds have become known as progesterone receptors (WO-A 93/21145), which can be used for the purposes of the present invention. Suitable progesterone antagonists can, for example, be applied locally, topically, enterally, transdermally or parenterally. For oral application, tablets, dragees, capsules, pills, suspensions or solutions, which can be prepared in the usual manner with the additives or carriers used in the galenic, are considered. For local or topical application, for example, vaginal ovules, vaginal gels, implants, vaginal rings, intrauterine delivery systems (IUD) or transdermal systems such as patches are considered. A dosage unit contains about 0.25 to 50 mg llß- [4- (dimethylamino) phenyl] -17-hydroxy-17β- (3-hydroxypropyl) -13a-estra-4, 9-dien-3-one or a biologically equivalent amount with another competent progesterone antagonist. Equivalent quantities in effect are determined in a test of inhibition of nesting in guinea pigs (treatment day 1-7 post coitum). If the application of the pharmaceutical agent prepared according to the invention is carried out by means of an implant, a vaginal ring, an IUD or a transdermal system, such application systems can be formed in such a way that the daily dose released by them as an antagonist of competent progesterone is found in the range of 0.25 to 50 mg. The dose to be applied according to the invention of a competent progesterone antagonist can be found in a non-inhibiting dose of ovulation or provoking abortion of the progesterone antagonist in question. Antioxidants of estrogens (competent antiestrogens) are used as first-line antiestrogen effect compounds according to the invention. Estrogen antagonists according to the present invention can both be derived from steroids or be non-steroidal compounds. Under estrogen antagonists according to the present invention should be understood only those compounds, with the most selective effect possible, this in that essentially only inhibit the effect of estrogens and / or their concentration. The estrogen antagonists act by displacing the estrogen from the receptor. Suitable estrogen antagonists are all customary compounds with a competent antiestrogen effect. They can be used in approximately the same amounts as commercially available estrogen antagonists, this means that the daily dose consists of approximately 5-100 mg for tamoxifen or the biologically equivalent amount of another estrogen antagonist. As non-steroidal estrogen antagonists, there can be mentioned, for example: (Z) -N, N-dimethyl-2- [4- (1, 2-diphenyl-1-butenyl) phenoxy] ethanamine (Tamoxifen), l- [2] hydrochloride. - [4- (3, 4-dihydro-6-methoxy-2-phenyl-1-naphthalenyl) phenoxy] eti; ] pyrrolidine (Nafoxidine), a- [4- [2- (diethylamino) ethoxy] phenyl] -4-methoxy-a-phenylbenzenemethanol (Mer-25), [6-hydroxy-2- (4-hydroxy-enyl) -hydrochloride] -3-benzothienyl] [4- [2- (l-piperidinyl) ethoxy] phenyl] methanone (Raloxifen), (3R-trans) -3,4-dihydro-2, 2-dimethyl-7-methoxy-3-phenyl-4- [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] -2H- l-benzopyran (Centrchroman), other compounds of type 1, 1, 2-triphenyl-but-l-ene, especially 3, 3H - (2-phenyl-l-buten-l-ylidene) bis [phenol] - diacetate [J. Cancer Res. Clin. Oncol., (1986), 112, pgs. 119-124]; In addition, steroidal estrogen antagonists are considered: 17a-ethynyl-lla-methylestra-l, 3,5 (10) -trien-3,17β-diol and I6β-ethyl-tetra-1, 3,5 (10) -trien- 3, 17β-diol, N-butyl-11- (3, 17β-dihydrostrat-1, 3,5 (10) -trien-7a-yl) -N-methylundecane and 7a- [9 - [(4 , 4, 5, 5, 5-pentafluoropentyl) fulfinyl] nonyl] estra-l, 3,5 (10) _rien-3, 17β-diol. According to the invention, estrogen antagonists, which act particularly strongly and most selectively in the endometrium (for example Tamoxifen, Nafoxidin, 7a- [9 - [(4,4,5,5), are preferred in each case. , 5-pentafluoropentyl) sulfinyl] nonyl] estra-l, 3,5 (10) -trien-3, 17β-diol). The threshold dose for the selective effect on the endometrium is determined in ovariectomized rats with estradiol replacement. The mitotic activity (proliferation marker: PCNA) serves as a parameter. The amount of the estrogen antagonist, with which only one effect in the uterus is observed, that is the inhibition of estrogen-induced proliferation of the endometrium, is used as the threshold dose. As antiestrogens according to the present invention, aromatic inhibitors can be used in combination with progesterone antagonists. Aromatic inhibitors reduce the synthesis of estrogen in the previous stages. Examples of aromatic inhibitors are Atamestan = l-metilandrosta-l, 4-dien-3, l7-dione (DE-A 3322285), Pentrozol = 5- [cis-pepentylidene (lH-imidazol-l-yl) -methyl] -2- thiophenylcarbonitrile (EP-A 0411735) or 4- (5,6,7,8-tetrahydroimidazo [1,5-a] pyridin-5-yl) benzonitrile monohydrochloride (Cancer Res., 4jS, pp. 834-838, 1988 ). The use of estrogen antagonists is preferred over that of aromatic inhibitors in any chaos, since estrogen antagonists do not influence the concentration of estrogen and this prevents the cycle from being impaired. One dosage unit AE contains 0.01-100 mg Tamoxifen or a biologically equivalent amount of another compound effective as an antiestrogen. Its formulation can be carried out analogously to progesterone antagonists. The effective compounds such as progesterone antagonist and anti-estrogen can be applied locally, topically, enterally or parenterally. Preferably, the progesterone antagonists and the antiestrofen are used in a joint dosage unit. The following examples serve to illustrate the invention in more detail: Example l 10.0 mg llß- [4- (dimethylamino) phenyl] -l7a-hydroxy-17β- (3-hydroxypropyl) -13-tetra-4, 9-dien-3- ona 140.5 mg lactose 69.5 mg corn starch 2.5 mg polyvinylpyrrolidone 2.0 mg Aerosil 0.5 mq magnesium stearate 225.0 mg total tablet weight Example 2 20.0 mg Tamoxifen (antiestrocjeno with partial agonistic effect) 50.0 mg llß- [4- (dimethylamino) phenyl] -l7a-hydroxy-l7β- (3-hydroxypropyl) -13a-estra-4, 9-dien-3-one 105.0 mg lactose 40.0 mg corn starch 2.5 mg poly-N-vinylpyrrolidone 25 2.0. mg Aerosil 0.5 ms magnesium stearate 265.0 mg total weight of the tablet, which is prepared in the usual way in a tablet press. Optionally, the active ingredients according to the invention can be used with half of the mentioned additives, to give a two-layer tablet. Example 3 5.0 mg 7a- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) -nonyl] estra-l, 3, 5 (10) -trien-3, 17β-diol (pure antiestrogen) 50.0 mg llß - [4- (dimethylamino) phenyl] -l7-hydroxy-17β- (3-hydroxypropyl) -l3a-estra-4, 9-dien-3-one 110.0 mg lactose 50.0 mg corn starch 2.5 mg poly-N-vinylpyrrolidone 25 2.0 mg Aerosil 0.5 ms magnesium stearate 220.0 mg total tablet weight, which is prepared in the usual way in a tablet press. Optionally, the active ingredients according to the invention can be used with half of the mentioned additives, to give a two-layer tablet. Example 4 0.5 mg llß- [4- (dimethylamino) phenyl] -17-hydroxy-17β- (3-hydroxypropyl) -l3a-estra-, 9-dien-3-one 0.2 mg 7a- [9- (4, 4 , 5,5, 5-pentafluoropentylsulfonyl) -nonyl] estra-l, 3,5 (10) -trien-3,17β-diol (pure antiestrogen) 159.5 mg lactose 54.8 mg corn starch 2.5 mg poly-N-vinylpyrrolidone 25 2.0 mg Aerosil 0.5 mg magnesium stearate 220.0 mg total weight of the tablet, which is prepared in the usual way in a tablet press. Optionally, the active ingredients according to the invention can be used with half of the mentioned additives, to give a two-layer tablet.

Example 5 Composition of an oily solution: 100.0 mg Tamoxifen 343.4 mg Castor oil 608.6 mg Benzyl benzoate 1052.0 mg = 1 ml The solution is filled in an ampule. Example 6 5.0 mg llß- [4- (dimethylamino) phenyl] -17β-hydroxy-l7a- (l-propynyl) estra-4, 9-dien-3-one (RU-38486) . 0 mg (Z) -N, N-dimethyl-2- [4- (l, 2-diphenyl-l-butenyl) phenoxy] ethanamine, (Tamoxifen: antiestrogen with partial agonistic effect) 140.0 mg lactose 60.5 mg corn starch 2.5 mg poly-N-vinylpyrrolidone 25 2.0 mg Aerosil 220. 0 mg total weight of the tablet, which is prepared in the usual manner in a tablet press. Optionally, the active ingredients according to the invention can be used with half of the mentioned additives, to give a two-layer tablet.

PHARMACOLOGICAL OBSERVATIONS Test l: The tests were performed on cobayosintacts with normal cycle. The treatment was started on day 1 post coitum. The animals were treated for 6 days with vehicle (benzyl benzoate / castor oil) or with Tamoxifen in a dose of 0.3, 1, 3 g / day / animal or the effective compound such as Onapriston antgesterone (0.3, 1.0, 3.0 mg / dia.animal), alone or in combination with both compounds. The substances were applied subcutaneously. How parameto serves the number of implantation points on day 12 post coitum. The combination of the threshold doses of both components (AG 0.3, l mg / AE around 0.3, lmg) leads to a significant increase in effectiveness (inhibition of 100% implantation in 1 mg AG + 1 mg AE and 1 mg AG + 0.3 mg AE) after the treatment for six days (illustration 1). The synergistic effect of both components is more marked after the treatment of 8 days. Test 2 The tests were performed on intact guinea pigs with normal cycles. The treatment started on day 1 p.c. The animals (n = 6 / group) were treated for 6 days with vehicle (benzyl benzoate / castor oil) or Tamoxifen / antigestagen in an osis of 0.3, 1.3 mg / kg / animal or the compound effective as an antagonist of progesterone (Z) -1- L- [4- (dimethylamino) phenyl] -17β-hydroxy-17a- (3-hydroxy-1-propenyl) estr-4-en-3-one either alone or in combination of both compounds. The substances are applied sc, as parameters serve the number of animals not gravid on day 12. The combination of the threshold doses (0.3 mg (Z) -ll- [4- (dimethylamino) phenyl] -l7β-hydroxy-l7a - (3-hydroxy-l-propeni;) estr-4-en-3-one (ZK 137.316) + 0.3 mg AE) leads to a significant increase in effectiveness (about 80% inhibition of receptivity, illustration 2). Test 3 The tests were performed in intact guinea pigs with normal cycle during a treatment period of 2 cilos. Mating took place in the second cycle. Onapriston dose: 0.1, 0.25, 0.5, 1.0 and 3.0 mg per day s.c. Dosage of Tamaxifen: 0.1, 0.25, 0.5, 1.0, 3.0 and 10.0 mg per day s.c. The combination of only marginally effective individual doses (Onapriston 0.5 mg, Tamoxifen 0.5 mg) leads to a clear increase in effect (synergism). SOloc on the use of a combination in the sense of the present invention can be obtained only with the complete inhibition of pregnancies. In the range of mentioned doses of Tamoxifen (0.1-10.0 g / animal) a complete inhibition of receptivity could be achieved. Normal pregnancies were observed in 30% (10.0 g) and 90 to 100% (< 1.0 mg). Also after treatment with. high doses of onapriston sporadic pregnancies occurred. After a treatment combined with Onapriston and Tamoxifen (each 1.0 mg), a complete inhibition of receptivity is observed in all cases. Inhibition of 100% receptivity means complete prevention of pregnancies. In cases of lower doses of Tamoxifen and Onapriston (< 1.0 mg) which alone does not have an effect or only a marginal effect, the inhibition rate of receptivity was found in 80 to 100% of all animals.

Claims (7)

1. CLAIMS 1.- Use of at least one compound with progesterone antagonist effect (PA) and at least one compound with estrogen antagonist effect (AE), both in a non-inhibitory dose of ovulation in a single dose unit, for the preparation of medicines for female contraception.
2. 2. Use of a compound with progesterone antagonist effect and a compound with estrogen antagonist effect according to claim 1 for the preparation of a medicament for the control of postcoital female fertility in a dose unit to be administered only once .
3. 3. Use of at least one compound with progesterone antagonist effect and a compound with estrogen antagonist effect according to claim 1 for the preparation of a medicament for the control of female fertility according to the need, which can used irrespective of the moment in the menstrual cycle, in a dose unit to be administered only once.
4. 4. Use according to one of claims 1-3, characterized in that the compound with progesterone antagonist effect is selected from the group of the following compounds: llß- [4- (dimethylamino) phenyl] -17a-hydroxy-17β- (3-hydroxypropyl) -13-methyl-4, 9 (10) gonadien-3-one, (Z) -ll- (4-acetylphenyl) -l7β-hydroxy-17a- (3-hydroxyprop-1 (Z) - enyl) -4,9 (10) -estradien-3-one (EP-A 0 190 759), (Z) -6 '- (4-cyanophenyl) -9, lla-dihydro-17β-hydroxy-17a- ( 3-hydroxy-1-propenyl) -4'H-naft [3 ', 2', 1 ': 10, 9, 11] estra-4, 9 (11) -dien-3-one and (Z) -9 , 11-dihydro-l7β-hydroxy-l7a- (3-hydroxy-l-propenyl) -6 '- (3-pyridinyl) -4'H-naft [3', 2 ', 1': 10,9, 11 ] estra-4, 9 (11) -dien-3-one 17a-hydroxy-17β-93-hydroxypropyl) -ll- [4- (1-methylethyl) phenyl] -13a-estra-4,9-dien-3 -one [ZK 131 535] llß- [4-93-f uranyl) f-enyl] -l7a-hydroxy-l7β- (3-hydroxypropyl) -13a-estra-4,9-dien-3-one (ZK 135 695 ) (Z) -ll- [4- (dimethylamino) phenyl] -l7β-hydroxy-17a- (3-hydroxy-l-propenyl) est-4-en-3-one (E) -ll β- [4- [[(acetyloxy) imino] methyl] phenyl] -17β-methoxy-17a- (methoxymethyl) estra-4,9-dien-3-one (E) -llβ- [4 - [[[( ethoxycarbonyl) oxy] imino] methyl] phenyl] -17β-methoxy-17 - (methoxymethyl) estra-4,9-dien-3-one.
5. 5. Use according to one of claims 1-4, characterized in that the compound with estrogen antagonist effect is selected from the group of the following compounds: (Z) -N, N-dimethyl-2- [4- (l , 2-diphenyl-1-butenyl) phenoxy] ethanamine 3p l- [2- [4- (3,4-Dihydro-6-methoxy-2-phenyl-1-naphthalinyl) phenoxy] ethyl] pyrrolidine hydrochloride [6-Hydroxy-2- (4-hydroxyphenyl) -3-benzothienyl] [4- [2- (l-piperidinyl) ethoxy] phenyl] methanone hydrochloride N-butyl-II- (3,77β-dihydrostramide) acid amide -l, 3, 5 (10) -trien-7 -yl) -N-methylundecane and 7a- [9 - [(4, 4, 5, 5, 5-pentafluoropentyl) fulfinyl] nonyl] estra-l, 3, 5 (10) _rien-3, 17β-diol.
6. 6.- Use of llß- [4- (dimethylamino) phenyl] -17a-hydroxy-i7β- (3-hydroxypropyl) -l3a-methyl-4,9 (lo) gonadien-3-one as progesterone antagonist and (Z ) -N, N-dimethyl-2- [4- (1, 2-diphenyl-1-butenyl) phenoxy] ethanamine as a estrogen antagonist according to one of claims 1-3.
7. 7. Use according to one of claims 1-3, characterized in that the compound with progesterone antagonist effect and the compound with estrogen antagonist effect are prepared in a drug for application locally, topically, enterally or parenterally. .