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

PROGESTERONE ANTAGONISTIC AND ANTI-STROGENIC

COMBINATIONS WITH CHARACTERISTICS FOR COMBINED USE

WOMEN CONCEPT

The present invention relates to the use of at least one progesterone antagonist (PA) and at least one anti-estrogenic (AO) compound, each in a single dose, in a non-inhibiting dose of ovulation, for the manufacture of a female contraceptive.

The medicaments of the invention exhibit their contraceptive effect by inhibiting receptivity by preventing the fertilized egg from adhering to the endometrium without disturbing ovulation or the cycle.

The use of oral contraceptives has already become a worldwide social factor that can no longer be bypassed. Particularly in view of the still-growing population of the world20, further development of the tried-and-tested methods of delay control is essential.

The use of competing progesterone antagonists in female slug control has been debated for several years in both animal species and man, as can be inferred from the following publications, in which particular reference is made to RU 486 (11β- [4- (dimethylamino) phenyl] -17β-hydroxy- 17a- (1-Propynyl) estra-4,9-dien-330one, EP-A-0057115):

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Collins et al., Blockade of spontaneous mid-cycle gonadotropin surge in monkeys by RU 486; A progesterone antagonist or agonist. J. Cli. Metab., 63: 1270-1276 (1986);

Croxatto, HB, Salvatierra 1990 Cyclic Use of Antigen Agents for Fertility Control. Illrd International Symposium on Contraception, Heidelberg, June 19-23, 1990;

Danford et al., Contraceptive potential of RU 486 by ovulation 10 inhibition. III. Preliminary observations on once weekly administration. Contraception 40: 195-200 (1989);

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

Puri et al., Gonadal and pituitary responses to the progesterone antagonist ZK 98 299 during the follicular phase of the menst20 rai cycle in bonnet monkeys. Contraception 39 (2): 227-243 (1989);

Puri et al., Contraceptive potential of a progesterone antagonist ZK 98 734 ((Z) -11β- [4- (Dimethylamino) phenyl] -173-hyd25 roxy-17α- (3-hydroxy-1-propenyl) estr-4,9- dien-3-on): Effect on folliculogenesis, ovulation and corpus luteum function in bonnet monkeys. In Moudgal et al., (Eds) (1990).

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The contraceptive effect of the progesterone antagonist is due, on the one hand, to the inhibition of ovulation and, on the other hand, to the direct effect on the endometrium.

It should be noted here that the dosage of a competing progesterone antagonist that produces an ovulation-inhibiting effect is highly dependent on the particular competing progesterone antagonist:

The progesterone antagonists of RU 486 are low dissociative compounds with a pronounced ovulation inhibiting effect.

Onapristone-type progesterone antagonists are potent mucosal-specific, highly dissociable compounds that inhibit ovulation only at high dosing. Prolonged treatment with such progesterone antagonists results in retardation of the endometrial growth without disturbance of the ovarian and menstrual cycles.

This leads to degeneration of the endometrial glands and increased flow in the endometrial mucosa so that implantation of the fertilized egg is prevented (inhibition of receptivity).

Compounds of the ßβ-aryl or ΐΐβ, 19-arylene substituted steroid class differ in their potent progesterone or glucocorticoid antagonist activity. Thus, RU 486 can be used to treat Cushing's syndrome, on the one hand, due to a therapeutically-induced termination of pregnancy (human abortion vaEE 03421 B1 has a reasonable dose in combination with prostaglandin of 200-600 mg, EP-A 0 139 608) and, on the other hand.

Swahn et al., The Effect of RU 486 Administration during Early Luteal Phase on Bleeding Pattern, Hormonal Parameters and Endometrium, Human Reproduction 5 (4): 402-408 (1990), suggest another way to test competing progesterone antagonists for female slug control.

Treatment with LH + 2, in which a single dose of RU 486 (luteal contraception) is administered orally in a woman's menstrual cycle 2 days after the increase in luteinising hormone (LH) (generally on days 14, 15 or 16). Treatment with RU 486 during this period of the menstrual cycle does not interfere with the cycle. Use of RU 486 in other phases of the cycle at doses higher than 1 mg / day causes either amenorrhea or menstruation. However, this method is of no practical importance as the simple and accurate determination of the LH peak is still a problem.

Glasier et al., Mifepristone (RU 486) compared with high-dose estrogen and progestogen for emergency postcoital contraception, The New England J. of Med. 327: 1041-1044 (1992)] also describe the use of RU 486 for postcoital contraception. The method exhibits side effects in addition to high activity.

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A large percentage of women who completed this study showed a prolonged cycle. This effect is primary in explaining the antiovulatory effect of RU 486.

WO 93/23020 further discloses that competing progesterone antagonists can be used to control female fertility at both higher than abortion levels and at ovulation inhibiting doses.

Generally, weekly or multiple and thus continuous use is discussed here.

Similarly, EP-A 0 219 447 describes the effects produced by a daily dose of a progesterone antagonist during the follicular or, if desired, luteal phase of the female cycle at a dose of 10-200 mg relative to the endometrial distinguishing state. The resulting changes in the lining of the uterus are used for in vitro fertilization with respect to the time of nidation.

Batista et al., [Daily administration of the progesterone antagonist RU 486 prevents implantation in the cycling guinea pig. Am. J. Obstet. Gynecol. 165: 82-86 (1991)] also describes the use of RU 486 for female fertility control, which prevents guinea pig nidation by daily administration of copper at an ovulation-inhibiting dose, precytically and throughout the subsequent cycle.

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Von Kawano et al. [Effect of RU 486 on Glycogen Metabolism in Endometrium. Acta Obstetrica Gynaecologica Japonica, 41: 1507-1511, (1989)] describes the effect of RU 486 on rat endometrial glycogen metabolism at doses of 30 mg / kg body weight so that successful egg implantation can be impaired. Of course, treatment is on day 2 or 4 of pregnancy.

Hormonal implantation control is species dependent. In all mammals studied so far, the presence of ovarian progesterone is essential for successful implantation. Post-coital ovariectomized rats and mice treated with progesterone do not undergo implantation without estrogen administration (Finn CA, Porter DG [1975] Implantation of the ova [Chapter 6] and the control of implantation [Chapter 8]; In Finn CA and Porter [eds] The Uterus, Elek Science, London, pp. 5773; 86-95). If this animal species is injected with estrogen, it will immediately lead to delayed implantation of the blastocyst. These observations show

0 that ovarian estrogen induces implantation in rodents in the presence of progesterone. It was previously known that guinea pigs and primates are not essential for implantation. In guinea pigs that have been ovariectomized after mating, implantation occurs only after progesterone replacement (without additional estrogen treatment) (Deansley R [1972] J Reprod Fert [1972] 28 : 241-247).

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Both antiestrogens and estrogens inhibit high-dose implantation in rats and mice (Martin L, Cox RJ, Emmens CW [1963] Further studies on the effects of estrogens and antiestrogens on early pregnancy in mice).

J Reprod Fertil 5: 239-247; Singh MM Kamboj VP [1972] Fetal resoption in rats treated with an antiestrogen in relation to luteal phase nidatory estrogen secretion. Acetate endocrinol 126: 444-50). The inhibitory effect of anti-estrogen implantation along with the partial action of estrogens (naphthoxidine, centchroman, tamok10 siphene) was also described in guinea pigs (Wisel MS, Datta JK, Saxena RN [1994] Int J Fertil 39: 156163). It is not clear whether the inhibitory effect of the above-mentioned anti-estrogen implantation can be reduced to its antagonistic or agonistic action, since estrogens also inhibit the implantation of high doses of guinea pigs.

The use of estrogen antagonists (centchroman) for human contraception has also been described (Nittyanand S, Kamboj VP [1992] Centchroman: Contraceptive efficacy and sa20 fety profile. International Conference on Fertility Regulation, November 5-8, 1992, Bombay, India, Program and abstracts). However, effective dosing exhibits undesirable side effects, which are explained by the systemic action of estrogen antagonists. The deprivation of estrogens that may occur as a result of long-term treatment with anti-estrogens limits at least its regular use for contraception.

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Finally, DE-A 42 13 005 discloses the use of aromatase inhibitors for the prevention of pregnancy in primates of fertile females at doses that do not significantly disrupt the primate menstrual cycle. Aromatase inhibitors block the biosynthesis of estrogens in their metabolic precursors. The absolute value of daily doses required for contraceptive action is entirely dependent on the type of aromatase inhibitor. In the case of highly active aromatase inhibitors, the daily dose is usually about 0.05 to about 0.05

30th mg. Daily doses may also be higher for less active aromatase inhibitors.

It is an object of the present invention to provide a formulation for endometrial contraception (inhibition of endometrial receptivity, postcoital use, utility pills) which does not exhibit the above undesirable side effect and at the same time possesses high contraceptive safety as used with the individual components alone.

Consumables are to be understood as an orally administered drug, which preferably reduces the concept in a single and precoadical application as needed. This type of compound, using exclusively a competing progesterone antagonist, is described in unpublished German patent application P 44 38 820.9.

The object of the present invention is achieved by using at least one progesterone antagonist (PA) and at least one anti-estroEE 03421 B1 gene (AO) compound, each in a non-ovulating non-inhibiting amount, to provide female contraceptives.

It has now been found that the combination of a progesterone antagonist and an anti-estrogen synergistically inhibits uterine mucosal proliferation and differentiation, so that the contraceptive effect of the individual components may be increased by combined dosing, or the individual components may be respectively reduced by the effect of the individual components.

EP-A-0 310 541 relates to a medicament comprising at least one antigenic agent and at least one compound having anti-estrogenic activity, in particular to induce labor and termination of pregnancy, to treat gynecological disorders and to use at least one antigenic and at least one anti-estrogenic compound. .

Pharmaceutical compositions for postcoital fertility control containing one competing progesterone antagonist (antigestagen) as well as one progesterone and estrogen synthesis blocker are already described in U.S. Patent 4,670,426. Representative representative competing progesterone 25 antagonists include the fluoxinolone acetonide, triamcinolone acetonide, a steroid ring with 16,17-acetal acetone and 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) estr-4,9- diene-3-one (RU 38 486) and equivalent derivatives. Typical content

EE 03421 B1 is between 20 and 30 mg. As blockers of the synthesis of progesterone and estrogen, aminoglutethimide, 4β, 17α-dimethyl-17β-hydroxy-3-oxo-4α, 5-epoxy-5α-androstane-2a-carbonitrile, 20,25-diazocholesterol and equivalent compounds have been disclosed, namely 300 to 1000 mg in doses. Use of the dosage form according to U.S. Patent 4,670,426 should occur as early as possible, within the first week of the three days following meals, preferably within 2 to 6 days. The prevention of nidation, and thus pregnancy, is due to the synergistic effect of the combination of both ingredients of the formulation, namely, efficiency of 90% or more.

Pure estrogen antagonists such as 7a - [- 9 [(4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl] estr1,3,5 (10) have now been found to inhibit implantation in guinea pigs in addition to antigestagens (competing progestogen 15 antagonists). -triene-3,173-diol (ICI 182780). This finding suggests that, unlike in the past, estrogens play an important role in guinea pig implantation.

Thereafter, guinea pigs were found to exhibit a surprisingly synergistic effect during pre-implantation treatment with progesterone antagonists and estrogens (1-7 days after feeding). These observations suggest that this species produces estrogens in the blastocyst. A similar situation may occur in humans.

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The significant advantages of the present invention are not only due to the low dosage of the active ingredient but also to the reduction of the effective amount required for monotherapy due to the synergistic effect and to the lower doses which do not inhibit ovulation. In this way, the female menstrual cycle is not impaired in any way (as caused by ovulation inhibitors such as RU 486) and the body is not unnecessarily burdened with competing progesterone antagonists or anti10 estrogens. The combination of such progesterone antagonists / anti-estrogens allows for a definite contraception, ie regular administration of this type of drug (daily, regularly every 3 to 7 days) prevents blastocyst fibrillation without affecting the cycle. Later, contraceptive confidence is increased after a single, need-based pre-administration, regardless of the day of administration in the cycle (pill), or after post-administration.

Estrogen deprivation has not been taken into consideration when reducing the dose of anti-estrogen. In this way, endometrial selective action of the antiestrogen can be achieved and adverse effects based on estrogen deprivation in other organs, such as bones, can be avoided.

The ratio of the components of the new drug can be varied within wide limits. Thus, equal amounts of PA and AO can be used as well as both components of the two components. PA and AÖ are used together, separately, simultaneously

The weight ratio is essentially 50: 1 to 1: 50, preferably 25: 1 to 1: 5, and in particular 10: 1 to 1: 10. Concurrent administration is preferred. Preferably, PA and AO can be used in combination in a single unit dose.

Both components can be used once daily or alternately every 3 to 6 days throughout the cycle. They can also be used as a disposable pre-coital (as needed, utility pills), regardless of the time of the menstrual cycle or postcoital. In the case of pre-treatment, the progesterone antagonist is administered at a higher dose, however, at a dose lower than the ovulation inhibiting dose.

All compounds which competitively block the action of progesterone at the gestagen receptor (progesterone receptor) and do not themselves exhibit gestagenic activity are contemplated as competing progesterone antagonists; the block may be induced by the substance administered itself or its metabolites.

According to the present invention, the competing progesterone antagonists are preferably endometrial-specific (dissociating) compounds which, at most, exhibit weak antiovulatory activity. Non-dissociating progesterone antagonists may also be used, where they are administered at a dose below the ovulation inhibiting dose. By way of example, the following steroids are contemplated:

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11β- [4-dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one (RU 38,486),

11β- [4-dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) 18α-homoestra-4,9-dien-3-one and

11β- [4-dimethylamino) phenyl] -17α-hydroxy-17α- (1-propynyl) -17α-homoestra-4,9,16-trien-3-one (all EP-A-0 057 115),

17α-ethynyl-17β-hydroxy-11β- (4-methoxyphenyl) oestr-4,9-dien-3-one (Steroids 37 (1981), 361-382),

11β- (4-acetylphenyl) -173-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one (EP-A-0 190 759),

4 ′, 5′-dihydro-ΙΙβ- [4- (dimethylamino) phenyl)] -6β-methylspiro [estra-4,9-Oΐΐθηη-17β, 2 ′ (3Ή) -furan] -3-one,

4 ', 5'-Dihydro-β- [4- (dimethylamino) phenyl]] - 70-methylspiro [beta] [estra-4,9-diene-173,2' (3 H) -furan] -3-one,

11β- (4-Acetylphenyl) -19,24-dinor-17,23-epoxy-17a-chola 4,9,20-trien-3-one (all US-A 4 386 085), as well as in EP-A 0 11β-aryl-143β-estradienes and trienes described in 277,676, 19β-bridged steroids, which are the subject of EP-A-0 283 428, and 13-aryl-6-alkyl (or

6-alkenyl or 6-alkynyl) estradienes and pregnadienes and the H3-aryl-7-methyl (or 7-ethyl) estradienes known from EP-A-0 321 010 as well as the β-β-steroids of EP-A25 0 404 283 such as (R) -11β- [4- (dimethylamino) phenyl] -17α- (3-hydroxy-1-propenyl) estr-4-en-173-ol.

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The following are representative representatives of competing progesterone antagonists used in accordance with the invention, for example:

11β- [4-dimethylamino) phenyl] -17α-hydroxy-17β- (3-hydroxy-5 propyl) -13α-estra-4,9-dien-3-one (EP-A-0 129 499), (Z) - 11β- (4-Acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) estra-4,9-dien-3-one (EP-A-0 190 759), (Z) -6 '- (4-cyanophenyl) -9,11α-dihydro-17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4'H-naphth [3 ', 2', 1 ': 10,9,11] estrole 4,4, 9 (11)-diene-3-one and (Z) -9, 11α-Dihydro-17β-hydroxy-17α- (3-hydroxy-1-propenyl) 6 '- (3-pyridinyl) -4'H-naphth [3', 2 ', 1': 10,9,11] ester -4.9 (11) diene-3-one,

17α-hydroxy-17β- (3-hydroxypropyl) -11β- [4- (1-methylethyl) phenyl] -13α-estra-4,9-dien-3-one (ZK 131 535),

11β- [4- (3-furanyl) phenyl] -17α-Γ0ΜΐΓΓ3Κ-17β- (3-hydroxypropyl) -13α-estra-4,9-dien-3-one (ZK 135 695), (Ζ) -11β- [4- (Dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) estr-4-en-3-one, (E) -11β- [4 - [[(Acetyloxy) imino] methyl] phenyl] -17β-methoxy17α- (methoxymethyl) estra-4,9-dien-3-one, (R) -11β- [4 - [[[(ethoxycarbonyl) oxy] imino] methyl] phenyl] 173 -methoxy-17α- (methoxymethyl) estr-4,9-dien-3-one.

The latter PAs are intended to be a dissociative type in which, at a fixed dose, changes in the lining of the uterus are observed, while ovulation (central effect) is not inhibited. The dividing factor for ovulation inhibition and abortion (dissociation factor) can also be used as a measure of dissociation. Dissociative PAs are preferred within the present invention.

The list of PAs is not exhaustive, other competing progesterone antagonists described in those publications as well as those not mentioned herein are also suitable. Recently, non-steroidal compounds (WOA 3/21145) which act as progesterone receptor antagonists have also become known and can be used for the purpose of the present invention.

For example, competing progesterone antagonists may be used topically, topically, enterally, transdermally or parenterally. Preferred oral uses include tablets, dragees, capsules, pills, suspensions and solutions, which may be conveniently prepared from the additives and bases used in galenics. For topical or topical application, vaginal suppositories, vaginal gels, implants, vaginal rings, intrauterine devices, or transdermal systems such as patches are contemplated.

A single dose contains from about 0.25 to 50 mg of 11β- [4- (dimethylamino) phenyl] -17α-hydroxy-17β- (3-hydroxypropyl) -13α-estrac-4,9-dien-3-one or a bioequivalent amount. another competing progesterone antagonist.

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Equivalent amounts are determined by a nidation inhibition test in guinea pigs (1-7 days post-treatment).

Following the use of a formulation according to the invention by implant, vaginal ring, intrauterine device or transdermal system, the application systems must be formulated to provide a daily dose of 0.25 to 50 mg pi10 of competing progesterone antagonists.

The dose of a competing progesterone antagonist of the present invention may be in the dose range of the respective progesterone antagonist in non-ovulation inhibition as well as in the non-abortifacient dose range.

Especially estrogen antagonists (competing anti-estrogens) are contemplated as anti-estrogen compounds. The estrogen antagonists of the invention may be derived from steroids or may be non-steroidal compounds. In accordance with the present invention, estrogen antagonists are to be understood as meaning only compounds which act as selectively as possible, i.e. which essentially inhibit the action of estrogens alone and / or reduce their concentration.

Estrogen antagonists work by displacing estrogen from the receptor.

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As estrogen antagonists, all compounds having anti-estrogenic activity that compete with the receptor are contemplated. They may be administered in about the same amount as commercially available estrogen antagonists, i.e. a daily dose of about 5-100 mg for tamoxifen or a bioequivalent amount to 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 (naphthoxidine), α- [4- [2- (diethylamino) ethoxy] phenyl] -4-methoxy-α-phenylbenzenethanol (Mer-25), [6-hydroxy-2- (4-hydroxyphenyl) -3-benzothienyl] [4- [2- (piperidinyl) ethoxy] phenyl] methanone hydrochloride (raloxifene),

0 (3R-trans) -3,4-Dihydro-2,2-dimethyl-7-methoxy-3-phenyl-4- [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] -2E-1-benzopyran (centroman ), further 1,1,2-triphenyl-1-butene-type compounds, especially 3,3'25 (2-phenyl-1-buten-1-ylidene) bis [phenol] diacetate [J. Cancer Res. Clin. Oncol., (1986), 112, pp. 119-124], as steroidal estrogen antagonists, for example, include:

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17α-ethynyl-11a-methylestra-1,3,5 (10) -triene-3,17β-άΐοο1 and Ιόβ-ethylestra-1,3,5 (10) -triene-3,173-diol,

N-Butyl-11- (3,173-dihydroxyestra-1,3,5 (10) -trien-7a-yl) -N-methylundecanoic acid amide and 7α- [9 - [(4,4,5,5,5-pentafluoro) pentyl] ) sulfinyl] nonyl] estra-1,3,5 (10) -triene-3,17βdiol.

In any case, estrogen antagonists which act particularly on the mucous membrane of the uterus and are as selective as possible (e.g., tamoxifen, naphthoxidine, 7a- [9 - [(4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl) estrogen are preferred according to the invention. 1,3,5 (10) -triene-3,17β-diol).

The limit on endometrial selective activity is explained in ovariectomized, estradiol-substituted rats. The parameter is mitotic activity (proliferation marker: PCNA). The limitation is the same amount of estrogen antagonist, where the effect is observed only in the uterus, namely, the inhibition of estrogen-induced endometrial proliferation.

Aromatase inhibitors with respect to progesterone antagonists may also be used as antiestrogens according to the present invention. Aromatase inhibitors suppress estrogen synthesis during its precursors. Examples of aromatase inhibitors are atamestane, 1-methylandrosta-1,4-diene-3,17-dione (DE-A

22nd 285); pentrozole, 5- [cyclopentylidene (1H-imidazol-1-yl) methyl] -2-thiophenecarbonitrile (EP-A 0 411 735) or 4EE 03421 B1 (5,6,7,8-tetrahydroimidazo [1,5a] pyridine-5 yl) benzonitrile monohydrochloride (Cancer Res., 48, pp. 834-838, 1988).

However, the use of estrogen antagonists is in any case preferred over aroma5 reuptake inhibitors since estrogen antagonists do not affect the serum estrogen concentration and thus avoid cycle damage.

One unit dose of A0 contains 0.01-100 mg of tamoxifen or a bio10 equivalent logically equivalent amount of another anti-estrogen-acting compound.

They may be formulated in a manner analogous to progesterone antagonists.

The progesterone antagonist and anti-estrogen active compounds may be used, for example, topically, topically, enterally or parenterally.

The progesterone antagonist and the anti-estrogen are preferably used in a common dosage form.

The following examples are provided to further illustrate the present invention.

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Example 1

<td>10.0 mg</td><td>11β- [4- (Dimethylamino) phenyl] -17α-hydroxy-17ββ-3-hydroxypropyl) -13α-estra-4,9-dien-3-one</td>

<td>140.5 mg</td><td>lactose</td>

<td>69.5 mg</td><td>corn starch</td>

<td>2.5 mg</td><td>polyvinylpyrrolidone</td>

<td>2.0 mg</td><td>aerosol</td>

<td>0.5 mg</td><td>magnesium stearate</td>

<td>10 225.0 rags</td><td>total weight of the tablet</td>

Example 2

<td>20.0 mg</td><td>tamoxifen (a partial anti-agonist</td>

<td> 15</td><td>rogen)</td>

<td>50.0 mg</td><td>11β- [4- (Dimethylamino) phenyl] -17a-hydroxy-17β-3-hydroxypropyl) -13a-estra-4,9-dien-3-one</td>

<td>105.0 mg</td><td>lactose</td>

<td>40.0 mg</td><td>corn starch</td>

<td>2.5 mg</td><td>poly-N-vinylpyrrolidone 25</td>

<td>2.0 mg</td><td>aerosol</td>

<td>0.5 mcr</td><td>magnesium stearate</td>

<td>220.0 mg</td><td>- conventionally made by tablet press total weight of the tablet. If necessary, the present invention may be carried out</td>

<td> 25</td><td>also with each of the above mentioned additives compressed into separate bilayer tablets.</td>

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Example 3

<td>5.0 mg</td><td>7a- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) no. nyl] estra-1,3,5 (10) -triene-3,17β-άΐοο1 (pure</td>

<td> 5</td><td>anti-estrogen)</td>

<td>50.0 mg</td><td>11β- [4-Dimethylamino) phenyl] -17α-hydroxy-17β- (3-</td>

<td>110.0 mg</td><td>hydroxypropyl) -13a-estra-4,9-dien-3-one lactose</td>

<td>50.0 mg</td><td>corn starch</td>

<td>2.5 mg</td><td>poly-N-vinylpyrrolidone 25</td>

<td>2.0 mg</td><td>aerosol</td>

<td>0.5 mq</td><td>magnesium stearate</td>

<td>220.0 mg</td><td>- conventionally made by tablet press</td>

<td> 15</td><td>total weight of the tablet. If necessary, the present invention may be carried out also with each of the above mentioned additives compressed into separate bilayer tablets.</td>

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Example 4

0.5 mg

0.2 mg

159.5 mg

54.8 mg

2.5 mg

2.0 mg

0.5 mg

220.0 mg

11β- [4- (Dimethylamino) phenyl] -17a-hydroxy-173 (3-hydroxypropyl) -13a-estra-4,9-dien-3-one 7a- [9- (4,4,5,5,5) -pentafluoropentylsulfinyl) nonyl] oestr-1,3,5 (10) -triene-3,17β-άϊοο1 (pure anti-estrogen) lactose cornstarch poly-N-vinylpyrrolidone aerosil magnesium stearate

- the total weight of the tablet usually made by tablet press. If desired, the active compounds of the invention may also be compressed into each of the above-mentioned additives into separate bilayer tablets.

Example 5

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 put in an ampoule.

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Example 6

5.0 mg of 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-Hail-propynyl) estra-4,9-dien-3-one (RU-38486),

10.0 mg of (Z) -N, N-dimethyl-2- [4- (1,2-diphenyl-1-butenyl) 140.0 mg

60.5 mg

2.5 mg

2.0 mg

220.0 mg phenoxy] ethanamine, (tamoxifen, anti-estrogen with partial agonist activity) lactose cornstarch poly-N-vinylpyrrolidone aerosil

- the total weight of the tablet usually made by tablet press. If desired, the active compounds of the invention may also be compressed into each of the above-mentioned additives into separate bilayer tablets.

PHARMACOLOGIST! SEP STUDIES

Test 1

The experiments were performed on normal cycle intact guinea pigs. Treatment was begun on the first day after fattening. Animals were treated for 6 days with vehicle (benzyl benzoate / castor oil) or tamoxifen at 0.3, 1, 3 mg / day / animal or with progesterone antagonist compound onapristone (0.3, 1.0, 3.0 mg / day / animal), each alone or a combination of both. Substances were administered subcutaneously. The parameter is the number of implantation sites on the 12th day after feeding.

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The combination of the limit doses of both components (AG 0.3, 1 mg / AÖ ca 0.3, 1 mg) leads to a significant increase in effect after six days of treatment (100% implantation inhibition 1 mg AG + 1 mg AÖ and 1 mg AG + 0.3 mg for AÖ) (Figure 1). The synergistic effect of both components is no longer pronounced after 8 days of treatment.

Test 2

The experiments were performed on normal cycle intact guinea pigs. Treatment was begun on the first day after fattening. Animals (n = 6 / group) were treated with vehicle (benzyl benzoate / castor oil) or tamoxifen / antigestagen 0.3, 1, 3 mg / kg / animal or progesterone antagonist (Z) -11β- [4- ( dimethylamino) phenyl] 17β-hydroxy-17α- (3-hydroxy-1-propenyl) oestr-4-ene-3-one, individually or in combination. The agents were administered subcutaneously. The parameter is the number of non-pregnant animals at day 12.

Limit Combination (0.3 mg of (Z) -1- [4- (dimethylamino) phenyl] -173-hydroxy-17α- (3-hydroxy-1-propenyl) estr-4-en-3-one (ZK 137 316) + 0.3 mg AÖ) leads to a significant increase in activity (ca 80% inhibition of receptivity, Figure 2).

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Test 3

The experiments were performed by treating with normal cycle intact guinea pigs for two cycles. Mating took place in the second cycle.

Doses of onapristone: 0.1, 0.25, 0.5, 1.0 and 3.0 mg daily subcutaneously.

Tamoxifen doses: 0.1, 0.25, 0.5, 1.0, 3.0 and 10.0 mg daily subcutaneously.

The combination of both alone in a marginally effective single dose (onapristone 0.5 mg, tamoxifen 0.5 mg) leads to a significant increase in activity (synergism). Only the combination according to the invention can be used to achieve complete contraception. Complete inhibition of receptivity could not be achieved at the said dose range of tamoxifen (0.1-10 mg / animal). Normal pregnancies were observed

30% (10.0 mg) and 90 to 100% (&lt;1.0 mg). Accidental pregnancies continue to occur after treatment with a high dose of onapristone.

After combined treatment with onapristone and tamox 25 phene (1.0 mg each), complete inhibition of receptivity was observed. 100% inhibition of receptivity means complete prevention of pregnancy.

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At lower doses of tamoxifen and onapristone (&lt;1.0 mg), which either have no or only marginal efficacy, a 80-100% reduction in receptivity was observed in all animals.