Compounds with progesterone-antagonistic and anti-oestrogen properties intended for combined use in female contraception

The present invention relates to the use of at least one compound with progesterone antagonist activity and at least one compound with anti-estrogen activity, each in a non-ovulation suppressant dosage form, for use in a single dosage unit for the manufacture of a female contraceptive.

The medicaments of the invention protect against conception on the basis of suppression of susceptibility by preventing the implantation of a fertilized egg into the lining of the uterus without interfering with ovulation or menstrual cycle.

The use of oral contraceptives has become a societal factor worldwide, and it cannot be imagined that this is not the case. Particularly in view of the fact that the very fast-growing population necessarily requires improvements in the methods used to control female fertility so far.

The use of competing progesterone antagonists for the control of female fertility has been discussed for several years in various animal species, including humans, as can be seen from the following publications; more particularly provided is RU 486 (lipo [4-dimethylamino) phenyl] -173-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one; EP-A-0 057 15). In connection with this, the following is provided:

Collins et al., Blockade of spontaneous mid-cycle gonadotropin surge in monkeys by RU 486; A progesterone antagonist or agonist. J. Cli. Metab., 63: 12701276 (1986);

Croxatto, HB, Salvatierra 1990 Cyclic mustache of antigestagens for fertility control. Illrd Internal Symposium on Contraception, Heidelberg, June 19-23, 1990;

Danford et al., Contraceptive potential of RU 486 by ovulation inhibition.

IlI.Preliminary observations on once weekly administration. Contraception 40: 195200 (1989);

Kekkonen et al., Lahteoenmaki P 1990 Interference with ovulation by sequential treatment with the antiprogesterone RU 486 and synthetic progestin. Fertile Sterile 53: 4747 (1990);

Puri et al., Gonads and pituitary responses to the progesterone antagonist ZK 98 299 during the follicular phase of the menstrual cycle in bonnet monkeys. Contraception 39 (2): 227-243 (1989);

Puri et al., Contraceptive potential of the progesterone antagonist ZK 98 734 ((Z) -113- [4- (Dimethylamino) phenyl] -17b-hydroxy-17α- (3-hydroxy-1-propenyl) estra-4,9 diene). 3-on): Effect on folliculogenesis, ovulation and corpus luteum function in bonnet monkeys. In Moudgal et al., (Eds) (1990).

The contraceptive efficacy of progesterone antagonists is mediated, on the one hand, by the effect of inhibiting ovulation and, on the other hand, by direct action on the lining of the uterus. It should be recalled that the dose of competing progesterone antagonists that inhibit ovulation is highly dependent on the available competing progesterone antagonists:

Progesterone antagonists of type RU 486 are low dissociated compounds with potent ovulation inhibitory activity.

In the case of onapristone-type antagonists, there are specific (strongly dissociated) compounds in the lining of the uterus which inhibit ovulation only at high doses. Constant use of such progesterone antagonists slows down the growth of the lining of the uterus and does not disrupt the ovulatory and menstrual cycles. In the lining of the uterus, the development of the lining of the uterine lining is impaired and the stroma is thinned out, thus preventing the implantation of the fertilized egg (suppression of receptivity).

The class of ßβ-aryl or 11β, 19-aryl substituted steroids exhibits a pharmacologically distinct class of potent antagonistic efficacy against progesterone or glucocorticoids. Therefore, RU 486 can be used, on the one hand, to terminate a therapeutically induced pregnancy (in humans, the abortion-inducing dose in combination with prostaglandin is 200600 mg; EP-A 0 139 608) and, on the other hand, to treat Cushing's syndrome .

Another possibility to use progesterone antagonists to control female fertility, the so-called "LH 2" treatment, was suggested by Swan et al. The effect of RU 486 administration during the early luteal phase on bleeding pattern, Hormone parameters and endometrium, Human Reproduction 5 (4): 402-408 (1990)], given on the second day after the increase in corpus luteum hormone (LH) in the menstrual cycle on day 14, 15, or 16) a single dose of RU 486 (a corpus luteum contraceptive) to inhibit ovulation. The use of RU 486 in this period of the menstrual cycle does not disrupt the cycle. Use of RU 486 in other phases of the cycle at doses of about 1 mg / day causes amenorrhea or bleeding. True, this method has no practical significance, as the simple and accurate determination of LH peak momentum is still a problem.

Glasier et al. [Mifepristone (RU 486) compared with high-dose estrogen and progesterone for emergency postcoital contraception, The New England J. of Med. 327: 1041-1044 (1992)] described the use of RU 486 in postcoital contraception (immediate postcoital contraception). Apart from being highly effective, this method has minor side effects. In this study, a large number of women had a prolonged cycle. This effect may be attributed primarily to the antiovulatory effect of RU 486.

Further, WO 93/23020 describes that competing progesterone antagonists can be used to control female fertility at a dose lower than the dose causing abortion and the dose inhibiting ovulation. These are general weekly or reusable and regular use.

EP-A-0 219 447 also describes the effect of daily administration of 10-200 mg of progesterone antagonists on the uterine mucosal differentiation state in the follicular formation of the female cycle or, although not necessarily, in the corpus luteum for up to 4 days. Concomitant lesions in the lining of the uterus are used to determine the moment of implantation during in vitro fertilization.

Batist et al. [Daily administration of progesterone antagonist RU 486 prevents implantation in cycling guinea pig. Am. J. Obstet. Gynecol. 165: 82-86 (1991)] also described the use of RU 486 in female fertility control, whereby guinea-pigs are prevented from implanting at daily mating and at an ovulation suppressing dose for the rest of the cycle.

Using a rat model, Kawano et al. [Effect of RU 486 is Glycogen Metabolism in Endometrium. Obstetrica et Gynaecologica Japonica, 41: 15071511 (1989)] described the influence of RU 486 on the glycogen metabolism of the endometrium; A dose of 30 mg / kg body weight is successful in preventing the implantation of the egg. True, the preparation is used on the 2nd or 4th day of pregnancy.

Hormonal regulation of implantation is species specific. In all mammals studied so far, the presence of ovarian progesterone is required for successful implantation. It is true that implantation does not occur in ovariectomized, progesterone-maintained rats and mice without estrogen delivery (Finn CA, Porter DG [1975] Implantation of the ova [Chapter 6]; In Finn CA and Porter [eds] The Uterus, Elek Science, London, pp. 57-73; 86-95). If estrogen is administered to these animal species, blastule implantation (delayed implantation model) occurs immediately. These observations indicate that when progesterone is present, ovarian estrogen induces implantation in mammals. It has been known in the past that ovarian estrogen is not essential for implantation in guinea pigs and primates. In guinea-pigs, which have had their pairs removed after pairing, implantation occurs only after the use of progesterone (without additional use of estrogen) (Deansley R [1972] Retarded embryonic deficiency and decidual collapse; J Reprod Fert [1972J28: 241-247).

High doses of both antiestrogens and estrogens inhibit implantation in rats and mice [Martin L, Cox RJ, Emmens CW [1963] Further studies on the effects of estrogens and antiestrogens on early pregnancy J. Reprod Fertil 5: 239-247; Singh MM, Kamboj VP [1992] Fetal resoption in rats treated with anti-estrogen in relation to luteal phase nidatory estrogen secretion (Endocrinol 126: 444-50). Implant-inhibiting effects of anti-estrogens with partial estrogenic effects (naphthoxidine, centchroman, tamoxifen) have also been described in guinea pigs. It is unclear whether the inhibitory effect of the aforementioned anti-estrogens is due to antagonistic or agonistic effects, since high doses of estrogen also interfere with guinea pig implantation.

The use of estrogen antagonists (centchroman) for contraception in humans is also described (Nittyanand S, Kamboj VP [1992] Centchroman: Contraceptive efficacy and safety profile. International Conference on Fertility Regulation, November 5-8, 1992, Bombay, India, Program and abstracts). . At the active dose, undesirable side effects occur due to the constant effects of estrogen antagonists. Estrogen deficiency, which can occur after long-term use of antiestrogen, at least limits their regular use for contraception.

Finally, DE-A 42 13 005 discloses the use of aromatase inhibitors in adult primates at doses which do not substantially affect the monthly cycles of the primates. Aromatase inhibitors block estrogen biosynthesis in its metabolic pre-stage. The absolute daily dose required for contraceptive use depends entirely on the type of aromatase inhibitor used. The daily dose of high activity aromatase inhibitors is usually between 0.05 and 30 mg. With less active aromatase inhibitors, the daily dose may be much higher.

The object of the present invention is to provide a preparation for contraception of the lining of the uterus (suppression of the uterine lining, postcoital use, "need" pills) which does not have the above mentioned side effects and at the same time has greater contraceptive reliability than the separate use of the respective individual components.

The term "need pills" should be understood as an oral drug that, when best used once before sexual intercourse, would interfere with fertilization. Such a device, developed using only one of the competing progesterone antagonists, is described in unpublished German patent application P 44 38 820.9.

This task is solved as follows: at least one compound with a progesterone antagonist (PA) action and at least one compound with an antiestrogenic (AO) action, each corresponding to a non-inhibitory dose of ovulation, is used as a single dosage unit in the manufacture of medicaments for female contraception.

Currently, the combination of progesterone antagonists and antiestrogens has been found to synergistically inhibit uterine mucosal proliferation and differentiation, thereby enhancing the effect of the individual components against fertility at the respective dose in combination or to achieve similar effects obtained with the individual components alone in combination. may be dosed in smaller amounts.

A device comprising at least one compound active against gestagen and at least one compound active against estrogen, in particular for the initiation of life and termination of pregnancy and also for the treatment of gynecological disorders, or the use of at least one compound with anti-estrogenic activity for the development of medicaments for given indications. object of patent EP-A 0 310 541.

Pharmaceutical preparations for post -oital fertility control containing a competing progesterone antagonist (antigestagen) as well as progesterone or estrogen synthesis inhibitors are described in U.S. Patent 4,670,426. Fluoeinolonacetonide is a representative of the competing progesterone antagonists used. triamcinolone acetonide, steroids with cyclic 16,17-acetal with acetone and 1 ip [-4- (dimethylamino) phenyl] -173-hydroxy-17α- (1-propynyl) estra-4,9 dien-3-one (RU 38,486) and analogous derivatives. In addition, a typical amount is between 20 and 50 mg. Examples of progesterone and estrogen synthesis inhibitors include aminoglutethimide, 43,17a-dimethyl-173-hydroxy-3-oxo-4a, 5-epoxy-5a-androstane-2a-carbonitrile, 20,25-diazocholesterol, and compounds with equivalent activity (ranging from 300 to 1000 mg). According to U.S. Patent No. 4,670,426, the use of preparations may be successful, starting as early as possible within the first week after intercourse for a period of 3 days; ideally, continue treatment for 2 to days. When both components are used together, the synergistic effect of implantation and concomitant pregnancy is prevented; the success of this interruption is from 90% or higher in order.

It has now also been found that apart from antigestagens (competing progesterone antagonists), pure estrogen antagonists such as 7a- [9 [(4_j4₎5_?5_j5-pentafluoropentyl) sulfinyl] nonyl] estra-1,3,5 (10) -trien-3,173-diol (ICI 182780) also inhibits implantation in guinea pigs. This discovery demonstrates that in guinea pigs, estrogen also plays an important role in implantation, contrary to what has been thought to date.

It was also unexpectedly found that the administration of a combination of progesterone antagonists with antiestrogen in the guinea pigs in the preimplantation phase (day 1-7 post coitum) has a synergistic effect. These observations indicate that estrogens are formed in these species in the blastula. The situation is similar with people.

Finally, the great advantage of the present invention is not only based on a low dose of active ingredients; on the one hand, it is possible to reduce the amount of active substances used in monotherapy due to the synergistic effect and, on the other hand, lower doses which do not inhibit ovulation can be used. In this way, women's menstrual cycling is not compromised (as with ovulation suppressants such as RU 486) and the body is not overloaded with unnecessarily high levels of competing progesterone antagonists or antiestrogens. The use of such a progesterone antagonist / anti-estrogen combination provides good protection against conception, ie, regular use of such a drug (daily, regularly for 3 to 7 days) prevents blastula implantation without affecting the cycle. In addition, contraceptive reliability is increased by disposing on demand before sexual activity, regardless of use in the daily cycle (“need pill”), or after sexual activity.

Reducing anti-estrogen doses will no longer cause estrogen deficiency. In this way, the selectivity of the action of the antiestrogen on the lining of the uterus can be achieved and harmful effects on other organs, such as bone, due to estrogen deficiency can be avoided.

In addition, the weight ratio of both components in novel drugs can be varied within wide limits. Equal amounts of PA and AO or excess of one of the components can be used. PA and AO are used together, separately, at one time, generally in a weight ratio of 50: 1 to 1:50, most often 25: 1 to 1:25 and especially 10: 1 to 1:10. Concurrent use is preferred. In most cases, a combination of PA and AO in a dosage unit can be used.

Both components can be used once a day or intermittently throughout the cycle for 3-6 days. They can also be used once before sexual activity (on demand, “need pills”) regardless of the phase of your menstrual cycle, or post. coitum. In pre-sexual application, the progesterone antagonist is dosed at higher doses but lower than the ovulation suppressant dose.

Competing progesterone antagonists can be any compound that inhibits the action of progesterone on the gestagen receptor (progesterone receptor) and in addition has no gestagenic activity; inhibition may be induced by the substance itself or its metabolites.

The competing progesterone antagonists according to the present invention are usually dissociated, specifically acting on the lining of the uterus, which generally have mild antiovulatory activity. Non-dissociated progesterone antagonists may be used; then their doses are below the ovulation inhibiting dose. Examples include the following steroids:

113- [4- (dimethylamino) phenyl] -173-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one (RU 38,486),

Β- [4- (Dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) -18a-homoestra4,9-dien-3-one and

113- [4- (dimethylamino) phenyl] -17α-hydroxy-17α- (1-propynyl) -17α-homoester 4,9,16-trien-3-one (all from EP-A-0 057 115),

17c (-ethyl-173-hydroxy-lip- (4-methoxyphenyl) estra-4,9-dien-3-one (Steroids 37 (1981), 361-382),

113- (4-acetylphenyl) -17? -Hydroxy-17? - (1-propynyl) estra-4,9-dien-3-one (EP-A0 190 759),

4 ', 5'-Dihydro-11β- [4- (dimethylamino) phenyl] -63-methylspiro [estra-4,9-diene-173,2' (3'H) -furan] -3-one

4 ', 5'-Dihydro-1β- [4- (dimethylamino) phenyl] -73-methylspiro [estra-4,9-diene-173,2' (3R) -furan] -3-one

113- (4-acetylphenyl) -19,24-dinor-17,23-epoxy-17cc-chola-4,9,20-trien-3-one (all from US-A 4,386,085);

as well as

EP-A-0 279 676 describes 113-aryl-143-estradienes and -trienes, 19.1 Ιβ-bridged steroids, EP-A-0 289 073 1-ip-aryl-derived from EP-A-0 289 073 6alkyl (or 6-alkenyl or 6-alkynyl) estradienes and -pregnadienes and liparyl-7-methyl (or 7-ethyl) -estradienes known from EP-A-0 321 010 and also ΙΟβ-Η-steroids from EP -A-0 404 283, such as (Z) -1 H - [4- (dimethylamino) phenyl] -17α- (3-hydroxy-1-propenyl) estr-4-en-17β-ol.

The following, for example, competing progesterone antagonists may be used as representative agents of the invention:

113- [4- (dimethylamino) phenyl] -17α-hydroxy-17β- (3-hydroxypropyl) -13α-estra-4,9-dien-3-one (EP-A-0 129 499);

(Z) -113- (4-acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) estra-4,9 diene-3-one (EP-A-0 190 759);

(Z) -6 '- (4-cyanophenyl) -9,11a-dihydro-17β-hydroxy-17α- (3-hydroxy-1-propenyl) 4'H-naphth [3', 2 ', 1': 10 , 9.1 l] estra-4,9 (11) -dien-3-one and (Z) -9,11a-dihydro-17α-hydroxy-17α- (3-hydroxy-1-propenyl) -6′- (3-Pyridinyl) 4'H-naphtho [3 ', 2', r: 10.9,1 L] estra-4,9 (II) -dien-3-one

17? -Hydroxy-17? - (3-hydroxypropyl) -1? - [4- (1-methylethenyl) phenyl] -13a-estra-4,9-dien-3-one (ZK 131 535)? - [4- (3- furanyl) phenyl] -17? -hydroxy -? - (3-hydroxypropyl) -13c-estra-4,9 dien-3-one (ZK 135 695) (Z) -1p- [4- (dimethylamino) phenyl] -17? -hydroxy-17α- (3-hydroxy-1-propenyl) estr-4-en-3-one (E) -lip- [4 - [[(acetyloxy) imino] methyl] phenyl] -17β-methoxy-17α- (methoxymethyl) ) estra-4,9-dien-3-one (E) -113- [4 - [[[ethoxycarbonyl) oxy] imino] methyl] phenyl] -173-methoxy-17a (methoxymethyl) estra-4,9-diene -3-one.

The PAs listed above are of the dissociation type, where changes in the lining of the uterus are observed at fixed threshold doses, while ovulation (main action) is not inhibited. The dose divider (dissociation factor) used to inhibit ovulation and cause miscarriage may be a measure of dissociation. Dissociated PAs are preferred according to the present invention.

This list of PAs is not exhaustive; other competing progesterone antagonists described in the above-mentioned publications are also suitable, as well as antagonists from publications not mentioned herein. Recently, non-steroidal compounds acting as progesterone receptor antagonists (WO-A 93/21145) have become known and can be used for the purpose of the present invention.

Competing progesterone antagonists can be applied topically, topically, enterally, parenterally and transdermally. Oral administration is preferred, in particular tablets, dragees, capsules, pills, suspensions and solutions, which are conventionally prepared with additives and carriers used in galenical dosage forms. For topical or topical application, for example, vaginal suppositories, vaginal ointments, implants, vaginal rings, intrauterine systems (IUDs) or transcutaneous systems such as a patch are suitable.

The dosage unit contains about 0.25-50 mg of lipo [4- (dimethylamino) phenyl] -17cchydroxy-173- (3-hydroxypropyl) -13a-estra-4,9-dien-3-one or the bioequivalent to other competing progesterone amount of antagonist.

The active equivalent amounts are administered to guinea pigs in an implantation inhibitory test (1-7 dosing of dienaposf coitum).

If the inventive pharmaceutical agent is to be administered via an implant, vaginal ring, IUD, or transcutaneous system, the application system must be designed to provide a daily dose of the competing progesterone antagonist in the range of 0.25 to 50 mg.

According to the invention, the dose of competing progesterone antagonists administered can be in the range of the respective progesterone antagonists which do not inhibit ovulation or induce miscarriage.

According to the invention, the compounds which act against estrogen are, in particular, estrogen antagonists (competing antiestrogens). According to the present invention, estrogen antagonists may be steroid derivatives as well as non-steroidal compounds. According to the present invention, only compounds which are as highly selective as possible, ie which essentially inhibit and / or reduce the effect of estrogen, should be considered as estrogen antagonists.

Estrogen antagonists work by displacing estrogen from the receptor.

All compounds with competing anti-estrogenic effects on the receptor can be used as estrogen antagonists. They can be used in about the same amounts as commercial estrogen antagonists, which means that the daily dose is about 5-100 mg tomoxifen or a bioequivalent amount of another estrogen antagonist.

Examples of non-steroidal estrogen antagonists include: (Z) -N, N-Dimethyl-2- [4- (1,2-diphenyl-1-butenyl) phenoxy] ethanamine (tamoxifen), 1- [2- [4- (3,4-dihydro-6-methoxy) -2-phenyl-1-naphthalenyl) phenoxy] ethyl] pyrrolidine hydrochloride (naphthoxyne), α- [4- [2- (diethylamino) ethoxy] phenyl] -4-methoxy-α-phenylbenzenethanol (Mer-25), [ 6-hydroxy-2- (4-hydroxyphenyl) -3-benzothienyl] [4- [2- (1-piperidinyl) ethoxy] phenyl-methanone hydrochloride (raloxifene), (3R-trans) -3,4-Dihydro-2,2-dimethyl-7-methoxy-3-phenyl-4- [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] -2H-1-benzopyran ( centchroman), hereinafter 1,1,2-triphenylbut-1-ene type compounds, in particular 3,3 '- (2-phenyl-1-butenylilidene) bis [phenol] diacetate [J. Cancer Res. Clin. Oncol., (1986) 112, p. 119-124];

further, for example, steroidal estrogen antagonists include:

17α-ethynyl-11α-methyl estra-1,3,5 (10) -trien-3,7,7β-diol and 16β-ethylestra-1,3,5 (10) -trien3,173-diol,

N-Butyl-11- (3,17? -Dihydroxyestra-1,3,5 (10) -trien-7a-yl) -N-methylundecanecarboxylic acid amide and

7a- [9 - [(4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl] estra-1,3,5 (10) -trien-3,17β-diol.

In accordance with the invention, estrogen antagonists are particularly preferred in each case, which have a particularly potent and possibly more selective action on the lining of the uterus (for example, tamoxifen, naphthoxidine, 7a- [9 - [(4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl). estra-1,3,5 (10) -trien-3,17β-diol).

Threshold doses for selective action of the endometrium are determined in ovariectomized, estradiol-maintained rats. The indicator is mitotic activity (proliferation marker: PCNA). The threshold dose is the amount of estrogen antagonist at which only effects on the uterus are observed, namely, inhibition of estrogen-induced endometrial proliferation.

In accordance with the present invention, estrogens may be used in combination with aromatase inhibitors in combination with progesterone antagonists. Aromatase inhibitors inhibit estrogen synthesis in its primary state. Examples of aromatase inhibitors include atamestane = 1-methylandrosta-1,4-diene-3,17-dione (DE-A 33 22 285), pentrozole = 5 [cyclopentylidene (1H-imidazol-1-yl) methyl] -2-thiophenecarbonitrile. (EP-A 0 411 735) or 4- (5,6,7,8-Tetrahydroimidazo [1,5-a] pyridin-5-yl) benzonitrile monohydrochloride (Cancer Res., 48, S). 834-838 (1988). In any case, the use of estrogen antagonists is preferred to aromatase inhibitors, since estrogen antagonists do not affect serum estrogen concentrations and thus prevent cycle disruption.

AO unit dose contains 0.01-100 mg of tamoxifen or another bioequivalent amount of an anti-estrogen compound. Its formulation may be analogous to that of the progesterone antagonist.

Compounds that antagonize progesterone or anti-estrogen may be administered topically, topically, enterally or parenterally.

The use of progesterone antagonists and anti-estrogens in a single unit dose is desirable.

The following examples further illustrate the present invention:

example

10.0 mg of 1 ip- [4- (dimethylamino) phenyl] -17α-hydroxy-17β- (3-hydroxypropyl) -13aestra-4,9-dien-3-one

140.5 mg lactose

69.5 mg corn starch

2.5 mg polyvinylpyrrolidone

2.0 mg aerosil

0.5 mg of magnesium stearate

225.0 mg total tablet weight sample

Tamoxifen 20.0 mg (anti-estrogen with partial agonist effect)

50.0 mg of 1 ip- [4- (dimethylamino) phenyl] -17a-hydroxy-173 - ('3-hydroxypropyl) -13aestra-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 mg magnesium stearate

220.0 mg total weight of tablet, which is conventionally tablet pressed. If necessary, the active compounds of the invention may also be compressed, respectively, with half of the above additives separately into a two-layer tablet.

example

5.0 mg of 7α- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl ester-1,3,5 (10) -trien-3,17β14 diol (pure anti-estrogen)

50.0 mg of 1 ip- [4- (dimethylamino) phenyl] -17α-hydroxy-17β- (3-hydroxypropyl) -13α-testra-4,9-dien-3-one

110.0 mg lactose

50.0 mg cornstarch

2.5 mg of poly-N-vinylpyrrolidone 25

2.0 mg aerosil

0.5 mg of magnesium stearate

220.0 mg total weight of tablet, which is conventionally tablet pressed. If necessary, the active compounds of the invention may also be compressed, respectively, with half of the above additives separately into a two-layer tablet.

example

0.5 mg of 1 ip- [4- (dimethylamino) phenyl] -17oc-hydroxy-17β- (3-hydroxypropyl) -13aestra-4,9-dien-3-one

0.2 mg 7ct- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -trien-3,17β-diol (pure antiestrogen)

159.5 mg lactose

54.8 mg cornstarch

2.5 mg poly-N-vinylpyrrolidone 25 2.0 mg aerosil

0.5 mg of magnesium stearate

220.0 mg total weight of tablet, which is conventionally tablet pressed. If necessary, the active compounds of the invention may also be compressed, respectively, with half of the above additives separately into a two-layer tablet.

example

Composition of the oil solution:

100.0 mg tamoxifen 343.4 mg castor oil 608.6 mg benzyl benzoate

1052.0 mg = 1 mL

The solution is filled into ampoules.

example

5.0 mg 113- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-dienone (RU-38486),

10.0 mg of (Z) -N, N- (dimethyl-2- [4- (1,2-diphenyl-1-butenyl) phenoxy] ethanamine, (tamoxifen; anti-estrogen with partial agonist action)

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 tablet, which is conventionally tablet pressed. If necessary, the active compounds of the invention may also be compressed, respectively, with half of the above additives separately into a two-layer tablet.

Pharmacological test

The tests were carried out on healthy guinea pigs with a normal cycle. The medication is prescribed from day one. Animals are dosed with either solvent (benzyl benzoate / castor oil) or tamoxifen at 0.3, 1.0, 3.0 mg / day / animal for 6 days, or onapristone (0.3, 1.0, 3), a progesterone antagonist. , 0 mg / day / animal) alone or in combination. Substances are administered subcutaneously. The indicator is the number of implantation sites after 12 days post coitum.

The combination of both threshold doses (AG 0.3, 1 mg / AO about 0.3, 1 mg) significantly increases efficacy (100 7c inhibition of implants using 1 mg AG + 1 mg AO and 1 mg AG + 0.3 mg AO) after six days of administration (Fig.l). The synergistic effect of both components is even more pronounced when administered over 8 days.

test

The tests were carried out on healthy guinea pigs with a normal cycle. Medication started 1 day post coitum. The animals (n = 6 / group) were treated with a solvent (benzyl benzoate / castor oil), tamoxifen / antigestagen 0.3, 1. 3 mg / kg / animal at a dose or progesterone antagonistic compound - (Z) -1 ip. [4- (Dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) estr-4-en-3-one, respectively, alone or in combination. Substances are administered subcutaneously. The indicator is the number of pregnant animals after 12 days.

Threshold Dose Combination (0.3 mg (Z) -lip- [4-Dimethylamino) phenyl] -17Phydroxy-17α- (3-hydroxy-1-propenyl) estr-4-en-3-one (ZK 137.316) + 0 , 3 mg AO) significantly increases efficacy (about 80% inhibition of receptivity, Fig. 2).

test

The test was performed on healthy guinea-pigs with a normal cycle for two cycles. Pairing occurred in the second cycle.

onapristone doses: 0.1, 0.25, 0.5, 1.0 and 3.0 mg daily sc of tamoxifen: 0.1, 0.25, 0.5, 1.0, 3.0 and 10, 0 mg daily sc

The combination clearly enhances the effect (synergism) at only the limit active single dose, respectively (onapristone 0.5 mg; tamoxifen 0.5 mg). Only the combination according to the invention can prevent pregnancy completely. Within the above-mentioned dose range of tamoxifen (0.1 - 10.0 mg / animal), complete suppression of susceptibility cannot be achieved. Normal pregnancies are observed in 30% (10.0 mg) and 90% to 100% (less 1.0 mg). Also when using high doses of onapristone, guinea pigs sometimes become pregnant.

In all cases complete suppression of susceptibility was observed with the combination of onapristone and tamoxifen (1.0 mg each). 100% receptivity suppression means complete avoidance of pregnancy.

At lower doses of tamoxifen and onapristone (less than 1.0 mg), which have no or limited effect alone, the magnitude of the suppression of susceptibility was between 80 * 7i and 100 9Ϊ for all animals.

DEFINITION OF INVENTION