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Europäisches Patentamt *EP000792152B1* (19) European Patent Office

Office européen des brevets (11) EP 0 792 152 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: A61K 31/565, A61P 15/18, of the grant of the patent: A61P 15/00 14.04.2004 Bulletin 2004/16 // (A61K31/565, 31:565) (21) Application number: 95940773.5 (86) International application number: PCT/US1995/015131 (22) Date of filing: 21.11.1995 (87) International publication number: WO 1996/015794 (30.05.1996 Gazette 1996/25)

(54) METHODS OF CONTRACEPTION VERFAHREN ZUR EMPFÄNGNISVERHÜTUNG METHODES DE CONTRACEPTION

(84) Designated Contracting States: (56) References cited: AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL EP-A- 0 659 432 WO-A-93/21926 PT SE WO-A-93/21927 WO-A-95/17194 WO-A-95/26730 (30) Priority: 22.11.1994 US 343383 • GUIAN CHEN, JUN RONG HUANG, JAMES (43) Date of publication of application: MAZELLA, LINDA TSENG: "Long-term effects of 03.09.1997 Bulletin 1997/36 progestin and RU 486 on and synthesis in human endometrial stromal cells" HUMAN (73) Proprietor: BALANCE PHARMACEUTICALS, INC. REPRODUCTION, vol. 4, no. 4, 1989, pages Pacific Palisades, CA 90272 (US) 355-358, XP000944177 • FERTILITY AND STERILITY, Vol. 53, No. 4, (72) Inventors: issued April 1990, KEKKONEN R. et al., • SPICER, Darcy V. "Interference With Ovulation by Sequential Pasadena, CA 91103 (US) Treatment With the Antiprogesterone RU486 and • PIKE, Malcolm Cecil Synthetic Progestin", pages 747-750, Long Beach, CA 90803 (US) XP000569448 • DANIELS, John R. • FERTILITY AND STERILITY, Vol. 60, No. 4, Pacific Palisades, CA 90272 (US) issued October 1993, KEKKONEN R. et al., "Sequential Regimen of the Antiprogesterone (74) Representative: Grünecker, Kinkeldey, RU486 and Synthetic Progestin for Stockmair & Schwanhäusser Anwaltssozietät Contraception", pages 610-615, XP000569447 Maximilianstrasse 58 80538 München (DE)

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 792 152 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 0 792 152 B1 2

Description with exposure to the . [0007] PCT Patent Applications WO 93/21926 and [0001] This invention relates to methods useful for 93/21927 to Hodgen describes the protracted adminis- contraception in mammals, especially human females. tration of a progestogen, with administration of an anti- More particularly, the present invention is directed to 5 progestational compound on the 28th or 30th day of the contraceptive methods and methods of treating benign treatment cycle. The contraceptive compositions de- gynecological disorders which are effective for reducing scribed by Hodgen provides for an even greater number exposure to progestational agents. of days of exposure to the progestogen component than [0002] The first progestogen antagonist synthesized in the normal menstrual cycle. and tested was RU 486 [RU 38466; 17-hydroxy- 10 [0008] The breast has a tightly regulated pattern of 11-(4-dimethylaminophenyl)-17-(prop-1-ynyl)estra- growth primarily under the control of . 4,9-dien-3-one; beta-[(4-N,N-dimethylamino)-phenyl]- The effects of steroid hormones on the normal breast 17β-hydroxy-17α-propynyl-4,9(10)-oestradiene-3-one; are increasingly well understood. induces mefepristone]. Mefepristone has high affinity for the pro- some breast epithelial proliferation, but estrogen and gesterone receptor, with predominantly antiprogesta- 15 together produce even greater cell prolif- tional effects. Mefepristone is known to have growth-in- eration [Pike, M.C. et al., Epidemiol. Rev. 15:17-35 hibitory effects in cells in in vitro and in (1993)]. In non-pregnant premenopausal women the vivo preclinical studies and in human clinical trials [Klijn, breast epithelium undergoes repetitive periods of cell J. G. M. et al. Cancer Research 49:2851- 2856 (1989)]. proliferation and cell loss secondary to cyclic ovarian ac- Other antiprogestational agents have been synthesized 20 tivity. In the terminal duct lobular unit (TDLU) of the pre- and tested including ZK 98.299 () and ZK menopausal breast, cell proliferation is low during the 112,993, which also have antitumor efficacy [Michna, H. follicular phase of the menstrual cycle. Following ovula- et al., J. Steroid Biochem. Molec. Biol. 43:203-210 tion, progesterone is produced by the corpus luteum and (1992)]. TDLU cell proliferation increases two- to three-fold over [0003] Mefepristone is known to be useful as a med- 25 follicular levels [Pike et al. (1993), supra]. Consistent ical (because of its antiprogestational ac- with the breast cell proliferation rates, the size and tivities) and as a postcoital contraceptive. Mefepristone number of terminal ductules peak during the late-luteal has been evaluated as a potential contraceptive agent phase [Longacre, T.A. & Barlow, S.A., Am. J. Surg. Path. using several schedules. A single dose of mefepristone 10:382-393 (1986)]. If fertilization and pregnancy do not late in the menstrual cycle may be a useful contraceptive 30 ensue, progesterone levels fall, the rate of breast cell approach [Nieman. L. K. et al., N. Engl. J. Med. 316: division decreases, and a wave of cell death by apop- 187-191 (1987)]. tosis follows the peak in cell proliferation [Anderson, T. [0004] Protracted (i.e., 3 month) administration of 100 J. et al., Br. J. Cancer 46:376-382 (1982)]. mg per day mefepristone alone to premenopausal wom- [0009] Proliferating cell populations are more suscep- en has been shown to inhibit ovulation and ovarian pro- 35 tible to carcinogenic effects, and the rise in cancer risk gesterone production, while maintaining early follicular associated with cell proliferation is secondary to an in- phase levels of , and [Ket- creased chance of mutation and loss of tumor suppres- tel, L. M. et al. Fertil. Steril. 56:402-407 (1991)]. These sor genes [Preston-Martin, S. et al., Cancer Res. 50: effects may be mediated through a progesterone ago- 7415-7421 (1990)]. Thus, breast cancer risk would be nist effect of mefepristone on the hypothalamic-pituitary 40 predicted to increase the greatest during periods of ex- unit, although other mechanisms are possible. posure to both estrogen and progestogen, as in the pre- [0005] Several new regimens of progesterone antag- menopausal period or in women receiving combined onists and progestins have been described. One such oral contraceptives (COCs); less during periods of ex- regimen [Kekkonen, R. et al, Fertil. Steril. 53:747-750 posure only to estrogen, as in postmenopausal women (1990)] consists of 25 mg of mefepristone on days 1 to 45 receiving estrogen replacement therapy (ERT) or in 14 of a 28-day treatment cycle followed by norethister- obese postmenopausal women; and least during peri- one on days 15 to 24 of the cycle. A subsequent report ods of exposure to very low levels of both hormones, as describes a regimen consisting of 25 mg of mefepris- in non-obese postmenopausal Asian women. tone on days 1 to 21 of a 31-day treatment cycle followed [0010] The heretofore-identified regimens comprising by 5 mg per day or medroxyprogester- 50 administration of an antiprogestational agent in se- one 5 mg per day taken on days 22 to 31 [Kek- quence with a progestogen are thus not entirely satis- konen, R. et al., Fertil. Sterril. 60:610-615 (1993)]. factory. In particular, they result in exposure to pro- [0006] These administration sequences are designed gestogens for a period of time similar to a norma men- to mimic the physiological secretion of in the strual cycle, and to a similar or greater amount of pro- menstrual cycle, with a progestational steroid adminis- 55 gestational action. As such, they may result in a breast tered over a 10 day period following 14 to 21 days of cancer risk similar to or possibly greater than that of a administration of the progestogen antagonist. With such normal ovulating woman. a regimen, approximately 30% of days are associated [0011] U.S. Patent No. 5,211,952 describes adminis-

2 3 EP 0 792 152 B1 4 tration of a progestational agent every two months to six [0019] It is further preferred that said antiprogesta- months, with administration of a tional agent is selected from the group consisting of releasing hormone and an estrogen. mefepristone, onapristone, ZK 112.993, Org 31710, Org [0012] EP-A-0659 432 discloses a sugar-coated dos- 33628, Org 31806, , , epostane, age unit characterized in that it contains a composition 5 azastene and cyanoketone. comprising a steroid having two hydrogen atoms at po- [0020] It is also preferred that said antiprogestational sition 3 of the steroid skeleton, and a process for the agent is selected from the group consisting of mefepris- preparation of said dosage unit. tone, onapristone and ZK 112.993. [0013] WO-A-95-17194 discloses a composition and [0021] Furthermore, it is preferred that said first peri- use of it for a contraceptive comprising an estrogen se- 10 od of time is two to three months. lected from estradiol and ethinylestradid and a gestagen [0022] In addition, it is preferred that the second pe- selected from a group comprising and riod of time is ten days to fifteen days. , inter alia during a total period of time of [0023] Finally, it is preferred that the second period of 23-24 days. The individual dosage formulation contains time immediately follows or immediately precedes the a constant amount of estrogen and gestagen (see Ab- 15 first period of time. stract). [0024] In accordance with the present invention, there [0014] WO 95/26730 discloses a combined hormonal are provided methods for contraception which comprise contraception pharmaceutical preparation containing administering over an extended period of time (on the tow different hormonal components, separated in two order of 6 weeks to 26 weeks) an amount of an antipro- different types of dose unit taken sequentially for a total 20 gestational agent (e.g., a progestational antagonist or of 28 days, the first type containing an active hormone progesterone synthesis inhibitor) effective at suppress- component which is a combination of estrogen and ing ovulation or ovarian progesterone production and/or gestagen taken in mono or plural phase (23 to 24 days) at blocking the effects of progesterone, followed by a and the second type of dose unit containing only the es- short-term administration (on the order of 5 to 21 days, trogen preparation (4 to 10 days). 25 preferably 10 to 15 days) of an amount of a progesta- [0015] Human Reproduction, vol. 4, n°4, pp tional steroid effective to counteract the possibility of en- 355-358,1989 is a study of the long-term effects of pro- dometrial hyperstimulation, hyperplasia or carcinoma gestin and RU486 on prolactin production and synthesis which may develop during prolonged therapy with es- in human endometrial stromal cells. The MPA (medrox- trogenic steroids. The reduction in the amount of pro- yprogesterone acetate) and RU486 are administered 30 gestogen administered has the effect of reducing the alone or in sequence to stromal cells. projected rate of breast cancer incidence, as well as [0016] It is an object of the present invention to pro- treating or reducing tht incidence of various benign vide regimens for contraception which would obviate the gynecological disorders. problems attendant to the use of existing methods of [0025] The present invention eliminates problems in- birth control and treatment regimens. 35 herent in the heretofore-proposed gonadotropin releas- [0017] In particular, it is an object of the present in- ing hormone plus estrogen and periodic progestin treat- vention to reduce the risk of adverse consequences as- ment. The antiprogestational agents may be adminis- sociated with the heretofore known methods. tered by mouth. Furthermore, as the antiprogestational The invention relates to a method for preventing con- agents do not suppress ovarian estrogen and ception comprising: 40 production, there is no need for replacement of these steroid hormones. administering an antiprogestational agent at a level [0026] Pursuant to one preferred embodiment of the effective to inhibit ovulation over a first period of present invention, the contraceptive or treatment regi- time of 6 weeks to 26 weeks; and men comprises either a daily administration or a formu- administering a progestational agent at a level ef- 45 lation designed for continuous use over an extended pe- fective to inhibit endometrial proliferation over a riod of time. Typically, the formulations used in the in- second period of time of 5 days to 21 days immedi- vention are effective for use over at least 6 weeks. De- ately following, preceding or running concurrently pending on the composition, the formulation may be ef- with a portion of said first period of time. fective for as long as 6 months. It is presently preferred 50 that the formulation be effective over a 2 to 3 month pe- [0018] It is preferred that said progestational agent is riod. selected from the group consisting of , [0027] For purposes of the present invention, an "an- ethynodiol diacetate, hydroxyprogesterone caproate, tiprogestational agent" is defined as a composition acetate, norethindrone, nore- which impedes or eliminates the effects of progesterone thindrone acetate, norethynodrel, , progester- 55 in a patient being treated therewith. This may be effect- one, megesterol cicetate, , desogestrel, ed in one of two general ways. A progesterone antago- , , acetate and chlo- nist interacts with progesterone receptors to prevent a rmadinone. progestogen's biological effects on known target tissues

3 5 EP 0 792 152 B1 6 such is breast, myometrium and endometrium. Proges- est dose of the composition that eliminates the known terone antagonists may additionally suppress ovulation rise in serum progesterone during the second half of the and ovarian progesterone production. Progesterone normal menstrual cycle is appropriate. With reference synthesis inhibitors block the ovarian production of pro- to the exemplary antagonist mefepristone (RU486), this gesterone without necessarily blocking the effect of the 5 dose would be in the range of 10 to 100 mg per day. progestogen at the tissue level. Similarly, with reference to the exemplary progesterone [0028] A number of compounds have been developed synthesis inhibitor epostane, this dose would be in the to act as progesterone antagonists, including the follow- range of 600 to 1000 mg per day. For antagonists that ing: mefepristone (RU 486; 17-hydroxy-11-(4-dimethyl- do not block ovulation, a dose of the composition that aminophenyl)-17-(prop-1-ynyl)estra-4,9-dien-3-oneβ- 10 eliminates the antimitotic effects of progesterone and [(4-N,N-dimethyl amino)-phenyl]-17β-hydroxy-17α-pro- decidualization of the endometrium during the second pynyl-4,9(10)-oestradiene-3-one); onapristone (ZK98. half of the normal menstrual cycle would be appropriate 299); ZK 112.993; Org 31710 [(6α,11β,17β)-11- [Ferenczy, A. et al., Am J. Obstet Gynecol 133, 859-67 (4-NMe2,-phenyl)-6-Me-4',5'-dihydrospiro[oestra-4,9- (1979)]. diene-17,2'(3'H)-furan]-3-one]; Org 33628 [(11β,17α)- 15 [0032] As would be readily understood by those work- 11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9, ing in the field, the amount of the antiprogestational 20-trien-3-one];Org31806 [(7β,11β,17β)-11-(4-NMe2,- agent effective to achieve the desired results may read- phenyl)-7-Me-4',5'-dihydrospiro(oestra -4,9-diene-17,2' ily be determined empirically with respect to any given (3'H)-furan)-3-one]; and lilopristone (ZK 98734). These antiprogestational agent and for any given mammal. and other potentially useful agents are described in, e. 20 The effective dose ranges, as well as being compound g., the following publications: the aforementioned PCT specific, may also depend upon patient characteristics, applications WO 93/21926 and WO 93/21927; U.S. Pat- such as age and weight. Further, the effective amount ent 4,386,085; U.S. Patent 4,027,019; U.S. Patent of the antiprogestational agent also depends upon route 4,000,273; U.S. Patent 3,890,356; U.S. Patent of administration. In general, it is expedient to administer 3,622,622; U.S. Patent 3,983,144; U.S. Patent 25 the active antiprogestational agent in an amount be- 3,462,466; U.S. Patent 3,790,564; U.S. Patent tween 0.001 and 10 mg/kg of body weight per day. 4,231,946; Pollow, K. et al., Contraception 40:213-32 [0033] The second component of the invention is a (1989); and Michna et al. (1992), supra. The progester- progestogen (progestational agent). Unlike the antipro- one antagonist mefepristone is commercially available gestational agent, which is administered at a continuous in a number of countries and is in clinical trials in the 30 level for an extended period of time, the progestogen is United States. administered in amount sufficient to provide suitable [0029] Also contemplated as within the scope of the systemic levels for only a second, more limited period present invention are inhibitors or antagonists of pro- of time. Typically, the progestogen is administered for a gesterone synthesis, which block the production of pro- period of time on the order of 5 to 21 days, and prefer- gesterone. Examples of suitable progesterone, synthe- 35 ably 10 to 15 days. The progestogen is provided in an sis inhibitors include the following: trilostane, epostane, amount effective to inhibit ovulation (and the rise in se- azastene and cyanoketone [PCT applications WO rum progesterone) and to minimize or eliminate the oc- 93/21926 and WO 93/21927; Haider, S. & Inbaraj, R.M., currence of endometrial hyperplasia by substantially re- Gen Comp Endocrino 73, 92-5 (1989)]. ducing the possibility of endometrial hyperstimulation [0030] To identify additional antiprogestational agents 40 which may occur during prolonged treatment with anti- suitable for use in the compositions and methods of the progestational agents without a period of exposure to present invention, it is further possible to employ here- the beneficial endometrial effects of a progestogen. tofore-known biological assays for such agents. An ex- [0034] Unlike the heretofore-proposed regimens, ad- emplary assay is described in Michra, H. et al., J.Steroid ministration of progestogen in preferred embodiments Blochem. Molec. Biol. 38:359-365 (1991) for progester- 45 of the present invention is generally not repeated every one antagonist. In this bioassay rats are subjected to 28-31 days (corresponding to the length of the normal ovariectomy on day 1. On day 8 the experimental rats menstrual cycle). Rather, the progestogen component are administered estrone, progesterone and the proges- is provided in these preferred embodiments only for a terone antagonist daily. On day 11 the animals are sac- short period of time comprising a portion of each extend- rificed and the number of tubular alveolar buds in the 50 ed treatment regimen cycle. Suitably, an extended treat- inguinal mammary gland counted in a whole mount ment cycle in accordance with the present invention preparation using a 40-fold magnification. Potent pro- comprises six weeks to 26 weeks, and most preferably gesterone antagonists inhibit the proliferative action of two or three months, with the progestogen administra- the progesterone and reduce the number of tubular al- tion comprising only 5 to 21 days, and preferably 10 to veolar buds by 30 to 35% or more. 55 15 days, of the extended treatment cycle. [0031] A suitable dose of the antiprogestational agent [0035] Suitable progestational agents () may be readily identified. For antagonists that block ovu- for use in accordance with the present invention are de- lation and for progesterone synthesis inhibitors, the low- scribed in greater detail in the aforementioned U.S. Pat-

4 7 EP 0 792 152 B1 8 ent No. 5,211,952. These include the following: dydro- followed by the mefepristone over approximately 90 gesterone, ethynodiol diacetate, hydroxyprogesterone days. caproate, medroxyprogesterone acetate, norethin- drone, norethindrone acetate, norethynodrel, norg- estrel, progesterone, megesterol acetate, gestodene, 5 Claims desogestrel, cingestol, lynestrenol, quingestanol ace- tate and . Typical dose ranges for pro- 1. A method for preventing conception comprising: gestogens depend upon the choice of steroid and the individual patient. For example, for an adult human fe- administering an antiprogestational agent at a male administered norethindrone, typically 1 mg is given 10 level effective to inhibit ovulation over a first pe- by mouth daily during the period of progestogen admin- riod of time of 6 weeks to 26 weeks; and istration. Alternatively, systemic administration of the administering a progestational agent at a level progestogen component may be completely avoided, effective to inhibit endometrial proliferation over for example by the use of in which a second period of time of 5 days to 21 days releases the progestogen within the uterus. It is pres- 15 immediately following, preceding or running ently preferred that the progestogen be administered at concurrently with a portion of said first period a rate effective to provide serum levels equivalent to se- of time. rum levels of progesterone of from 5 to 20 ng/ml, and preferably 5 to 15 ng/ml, during the time interval of pro- 2. The method according to claim 1, wherein said pro- gestogen treatment. 20 gestational agent is selected from the group con- [0036] Administration of formulations in accordance sisting of dydrogesterone, ethynodiol diacetate, hy- with the present invention in depot form may be effected droxyprogesterone caproate, medroxyprogester- in a manner well known per se, for example as described one acetate, norethindrone, norethindrone acetate, in the aforementioned U.S. Patent No. 5,211,952. Sim- norethynodrel, norgestrel, progesterone, meges- ilarly, formulations for daily administration may be pre- 25 terol acetate, gestodene, desogestrel, cingestol, pared in a conventional manner by incorporating the ac- lynestrenol, and chlormadi- tive materials into suitable carrier substances. Carrier none. substances may be organic or inorganic materials which are suitable for enteral or parenteral application and 3. The method according to claim 1, wherein said an- which do not enter into reactions with the active agents. 30 tiprogestational agent is selected from the group Suitable carrier agents include, but are not limited to, consisting of mefepristone, onapristone, ZK water, alcohols, vegetable oils, polyethylene glycols, 112.993, Org 31710, Org 33628, Org 31806, lilo- lactose, starch, talcum, gelatin, stearate, pristone, trilostane, epostane, azastene and cy- sodium lauryl sulfate. anoketone. [0037] The invention may be better understood with 35 reference to the accompanying examples, which are in- 4. The method according to claim 1, wherein said an- tended for purposes of illustration only. tiprogestational agent is selected from the group consisting of mefepristone, onapristone and ZK Example 1 112.993. 40 [0038] In a contraceptive product for oral administra- 5. The method according to claim 1, wherein said first tion over a twelve week period, the antiprogestational period of time is two to three months. agent mefepristone is administered as a tablet in a daily dose sufficient to inhibit ovulation (50 mg) for 71 days, 6. The method according to claim 1, wherein the sec- followed by the progestogen norethisterone as a tablet 45 ond period of time is ten days to fifteen days. in a daily dose sufficient to induce a non-proliferative en- dometrium (1 mg) for 14 days. Both agents are suitably 7. The method according to claim 1, wherein the sec- provided in a convenient pill dispenser package. ond period of time immediately follows or immedi- ately precedes the first period of time. Example 2 50

[0039] In a contraceptive pellet for subcutaneous ad- Patentansprüche ministration, mefepristone is administered as a choles- terol pellet to achieve a daily dose of 25 mg for 90 days. 1. Verfahren zur Empfängnisverhütung, umfassend: The mefepristone/cholesterol pellet is coated with nore- 55 thisterone in palmitic acid to achieve a daily dose of 0.75 Verabreichen eines Antiprogestativums in ei- mg per day for 14 days. The superficial norethisterone ner Menge, die wirksam die Ovulation hemmt, coat is absorbed over approximately the first 14 days über einen ersten Zeitraum von 6 bis 26 Wo-

5 9 EP 0 792 152 B1 10

chen; und le caproate d'hydroxyprogestérone, l'acétate de Verabreichen eines Progestativums in einer médroxyprogestérone, la noréthindrone, l'acétate Menge, die wirksam die Proliferation des Endo- de noréthindrone, le noréthynodrel, le norgestrel, la metriums hemmt, über einen zweiten Zeitraum progestérone, le acétate de mégestérol, le gesto- von 5 bis 21 Tagen, unmittelbar folgend, vor- 5 dène, le désogestrel, le cingestol, le lynestrénol, ausgehend oder gleichzeitig mit einem Teil des l'acétate de quingestanol et la chlormadinone. ersten Zeitraums. 3. Procédé selon la revendication 1, dans lequel ledit 2. Verfahren nach Anspruch 1, in dem das Progesta- agent antiprogestatif est choisi dans le groupe tivum aus der Gruppe ausgewählt ist, die aus Dy- 10 constitué par la méfépristone, l'onapristone, ZK drogesteron, Ethynodioldiacetat, Hydroxyproge- 112.993, Org. 31710, Org 33628, Org 31806, la li- steroncaproat, Medroxyprogesteronacetat, Nore- lopristone, le trilostane, l'épostane, l'azastène et la thindron, Norethindronacetat, Norethynodrel, Nor- cyanocétone. gestrel, Progesteron, Megesterolacetat, Gestoden, Desogestrel, Cingestol, Lynestrenol, Quingestano- 15 4. Procédé selon la revendication 1, dans lequel ledit lacetat und Chlormadinon besteht. agent antiprogestatif est choisi dans le groupe constitué par la méfépristone, l'onapristone et ZK 3. Verfahren nach Anspruch 1, in dem das Antiproge- 112.993. stativum aus der Gruppe ausgewählt ist, die aus Mefepriston, Onapriston, ZK 112.993, Org 31710, 20 5. Procédé selon la revendication 1, dans lequel ladite Org 33628, Org 31806, Lilopriston, Trilostan, Epo- première période est comprise entre deux et trois stan, Azasten und Cyanoketon besteht. mois.

4. Verfahren nach Anspruch 1, in dem das Antiproge- 6. Procédé selon la revendication 1, dans lequel la stativum aus der Gruppe ausgewählt ist, die aus 25 deuxième période est comprise entre dix jours et Mefepriston, Onapriston und ZK 112.993 besteht. quinze jours.

5. Verfahren nach Anspruch 1, in dem der erste Zeit- 7. Procédé selon la revendication 1, dans lequel la raum zwei bis drei Monate beträgt. deuxième période suit immédiatement ou précède 30 immédiatement la première période. 6. Verfahren nach Anspruch 1, in dem der zweite Zeit- raum 10 bis 15 Tage beträgt.

7. Verfahren nach Anspruch 1, in dem der zweite Zeit- raum unmittelbar auf den ersten Zeitraum folgt oder 35 unmittelbar dem ersten Zeitraum vorausgeht.

Revendications 40 1. Procédé pour empêcher. la conception compre- nant:

- administrer un agent antiprogestatif à une te- neur efficace pour inhiber l'ovulation pendant 45 une première période de 6 semaines à 26 semaines ; et - administrer un agent progestatif à une teneur efficace pour inhiber la prolifération endomé- triale pendant une deuxième période de 5 jours 50 à 21 jours qui suit ou précède immédiatement ladite première période ou qui se déroule en même temps qu'une partie de ladite première période. 55 2. Procédé selon la revendication 1, dans lequel ledit agent progestatif est choisi dans le groupe consti- tué par la dydrogestérone, le diacétate d'éthynodiol,

6