EP0799042A1 - Compounds with progesterone-antagonistic and anti-oestrogen properties intended for combined use in female contraception - Google Patents

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

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Publication number
EP0799042A1
EP0799042A1 EP95943194A EP95943194A EP0799042A1 EP 0799042 A1 EP0799042 A1 EP 0799042A1 EP 95943194 A EP95943194 A EP 95943194A EP 95943194 A EP95943194 A EP 95943194A EP 0799042 A1 EP0799042 A1 EP 0799042A1
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EP
European Patent Office
Prior art keywords
hydroxy
phenyl
estra
dien
llß
Prior art date
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EP95943194A
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German (de)
French (fr)
Inventor
Kristof Chwalisz
Klaus Stöckemann
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Bayer Pharma AG
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Schering AG
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Publication of EP0799042A1 publication Critical patent/EP0799042A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of at least one compound with progesterone-antagonistic (PA) and at least one compound with anti-estrogenic (A ⁇ ) activity, in each case in non-ovulation-inhibiting dosage in a single dose unit, for the production of medicaments for female contraception.
  • PA progesterone-antagonistic
  • a ⁇ anti-estrogenic
  • the medicaments produced according to the invention develop their contraceptive effect on the basis of the receptivity inhibition by preventing a fertilized egg from implanting in the uterine mucosa without disturbing the ovulation or the cycle.
  • the contraceptive effect of a progesterone antagonist is due on the one hand to the ovulation-inhibiting effect and on the other hand to direct effects on the endometrium.
  • RU 486-type progesterone antagonists are poorly dissociated compounds with a strong ovulation-inhibiting effect.
  • Progesterone antagonists of the onapristone type are endometrium-specific (strongly dissociated) compounds that only inhibit ovulation at high doses. Chronic treatment with such progesterone antagonists leads to growth retardation of the endometrium, whereby the ovarian and menstrual cycle is not disturbed. In the endometrium, endometrial glands degenerate and the stroma is compressed, so that the implantation of a fertilized egg is prevented (inhibition of receptivity).
  • RU 468 can be used for a therapeutically induced termination of pregnancy (the human abortive dose in combination with a Prostaglandin is 200-600 mg; EP-A 0 139 608), but on the other hand can also be used for the therapy of Cushing's syndrome due to its antagonistic effect on the glucocorticoid receptor.
  • EP-A 0 219 447 describes the effects of daily administration of a progesterone antagonist during the follicular or, optionally, also the luteal phase of the female cycle in a period of up to 4 days in one dose of 10-200 mg with respect to the endometrial differentiation state.
  • the resulting changes in the endometrium are used for in vitro fertilization with regard to the time of nidation.
  • the hormonal control of the implantation depends on the species. In all mammals examined so far, the presence of ovarian progesterone is necessary for successful implantation. In postcoital ovariectomized rats and mice that are substituted with progesterone, there is no implantation without estrogen administration (Finn CA, Porter DG [1975] Implantation of ova [Chapter 6] and The control of implantation and the decidual reaction [Chapter 8] ; In Finn CA and Porter [eds] The Uterus, Elek Science, L.ondon, pp 57-73; 86-95). If estrogen is injected into these animal species, the blastocyst is immediately implanted (delayed implantation model).
  • ovarian estrogen induces rodent implantation in the presence of progesterone. It was already known that in guinea pigs and primates, ovarian estrogens are not essential for implantation. In guinea pigs that were ovariectomized after mating, the implantation only takes place after progesterone substitution (without additional estrogen treatment) (Deansley R [1972] Retarded embryonic development and pregnancy termination in ovariectomized guinea pigs: progesterone deficiency and decidual collapse; J Reprod Fert [1972 ] 28: 241-247).
  • DE-A 42 13 005 shows the use of aromatase inhibitors for contraception in female primates of reproductive age in a dosage at which the menstrual cycle of the female primate remains essentially unaffected.
  • Aromatase inhibitors block the biosynthesis of estrogens from their metabolic precursors.
  • the absolute amount of the daily doses required for the contraceptive effect depends entirely on the type of aromatase inhibitor used. For highly active aromatase inhibitors, the daily doses are usually between about 0.05 to about 30 mg. With less active aromatase inhibitors, the daily doses can also be higher.
  • the present invention has for its object to provide a preparation for endometrial contraception (inhibition of endometrial receptivity, post-coital use, "need pill”), which does not show the undesirable side effect mentioned above and at the same time a higher contraceptive Security as the separate application of the corresponding individual components.
  • a “need pill” is to be understood as an orally administered medicament which prevents a conception when it is preferably used once and precoitally as required.
  • Such an agent, produced using only a competitive progesterone antagonist, is described in the unpublished German patent application P 44 38 820.9.
  • At least one compound with progesterone-antagonistic (PA) and at least one compound with anti-estrogenic (A ⁇ ) activity are used together for the production of medicaments for female contraception.
  • Agent containing at least one compound with antigestagenic and at least one compound with anti-estrogenic activity, in particular for induction of birth and termination of pregnancy and for the treatment of gynecological disorders, and the use of at least one compound with antigestagenic and at least one compound with anti-estrogenic activity for the production of medicaments for the indicated indications are already the subject of EP-A 0 310 541.
  • compositions for post-coital fertility control which contain a competitive progesterone antagonist (antigestagen) and a progesterone and estrogen synthesis blocker, have already been described in US Pat. No. 4,670,426.
  • Typical representatives of the competitive progesterone antagonist to be used are fluocrnolone acetonide, triamcinolone acetonide, steroids with a cyclic 16,17 acetal with acetone and IIß- [4- (dimethylamino) phenyl] -17ß- hydroxy-17 ⁇ - (l-propynyl) estra-4,9-dien-3-one (RU 38 486) and equivalent derivatives mentioned.
  • the typical content is between 20 and 50 mg.
  • Examples of the progesterone and estrogen synthesis blocker are aminoglutethimide, 4 ⁇ , 17 ⁇ -dimethyl-17ß-hydroxy-3-oxo-4 ⁇ , 5-epoxy-5 ⁇ -androstan-2-carbonitrile, 20.25-
  • Diazocholesterol and compounds with equivalent activity are listed in a dose of 300 to 1000 mg.
  • the composition must be used as early as possible within the first week after sexual intercourse over a period of 3 days; it is best to continue treatment for 2 to 6 days.
  • the prevention of nidation and thus pregnancy is achieved by the synergistic effect when the two components of the composition are used together, with a success rate of the order of 90% or more.
  • the main advantages of the present invention lie not least in the low dosage of the active ingredients, on the one hand due to the possible reduction in the effective amounts required for monotherapy due to the synergistic effect, and on the other hand through the use of lower, non-ovulation-inhibiting dosages.
  • the cyclicality of the female menstrual cycle is in no way impaired (as caused by ovulation-inhibiting substances such as RU 486) and the organism is not burdened by unnecessarily high amounts of the competitive progesterone antagonist or the anti-estrogen.
  • progesterone antagonist / anti-estrogen combination offers safe contraception, ie the regular use of such a medication (daily, regularly every 3 to 7 days) prevents the blastocyst from implanting without affecting the cycle. Furthermore, the contraceptive security is increased after a one-time, needs-based precoital intake regardless of the intake day in the cycle ("need pill") or after postcoital treatment.
  • estrogen deprivation Due to the dose reduction of the anti-estrogen, estrogen deprivation is not to be expected. In this way, an endometrium-selective effect of the anti-estrogen can be achieved and an unfavorable effect due to estrogen deprivation on other organs, for example on the bone, can be avoided.
  • the weight ratio of both components in the new drug can be varied within wide limits. Both the same amounts of PA and A ⁇ and an excess of one of the two components can be used. PA and A ⁇ are used together, separately, simultaneously in a weight ratio of essentially 50: 1 to 1:50, preferably 25: 1 to 1:25, and in particular 10: 1 to 1:10. Co-administration is preferred. PA and A ⁇ can preferably be applied in combination in one dose unit.
  • the two components can be applied once a day or intermittently every 3-6 days over the entire cycle. They can also be used once precoitally (as required; "pill on demand") regardless of the time of the menstrual cycle or postcoitally. In the case of precoital use, the progesterone antagonist is dosed higher, but below the ovulation-inhibiting dose.
  • progesterone receptor progestogen receptor
  • progesterone antagonists All compounds which competitively block the effect of progesterone on the progestogen receptor (progesterone receptor) and which do not show their own progestogen activity are possible as competitive progesterone antagonists; the blockage can be brought about by the substance administered itself or by its metabolites.
  • the competitive progesterone antagonists are preferably endometrium-specific (dissociated) compounds which at most have weak antiovulatory activity.
  • Non-dissociated progesterone antagonists can also be used, in which case their Dosage is below the ovulation-inhibiting dose.
  • the following steroids are possible:
  • typical examples of competitive progesterone antagonists to be used according to the invention are: IIß- [4- (dimethylamino) phenyl] -17 ⁇ -hydroxy-17ß- (3-hydroxypropyl) -13 ⁇ -estra-4,9-dien-3-one (EP-A-0 129 499);
  • the latter PAs are of the dissociated type, in which changes in the endometrium are observed at a certain threshold dose, while the ovulation (central effect) is not inhibited.
  • the quotient of the ovulation-inhibiting and abortive dose (dissociation factor) can serve as a measure of the dissociation. Dissociated PAs are preferred in the context of the present invention.
  • the competitive progesterone antagonists can, for example, be applied locally, topically, enterally, transdermally or parenterally.
  • tablets, dragees, capsules, pills, suspensions or solutions are particularly suitable, which can be prepared in the usual way with the additives and carrier substances customary in galenics.
  • vaginal suppositories, vaginal gels, implants, vaginal rings, intrauterine release systems (IUDs) or transdermal systems such as skin patches are suitable.
  • One unit dose contains about 0.25 to 50 mg of llß- [4- (dimethylamino) phenyl] - 17 ⁇ -hydroxy-17ß- (3-hydroxypropyl) -13 ⁇ -estra-4,9-dien-3-one or a biologically equivalent Amount of another competitive progesterone antagonist. Effective amounts are determined in the niditation inhibition test on guinea pigs (treatment day 1-7 post coitum).
  • the pharmaceutical agent produced according to the invention is applied by means of an implant, a vaginal ring, an IUD or a transdermal system, these application systems must be designed in such a way that the dose of the competitive progesterone antagonist released by them daily in this range of 0.25 to 50 mg lies.
  • the dose of a competitive progesterone antagonist to be applied according to the invention can be in the non-ovulation-inhibiting and non-abortion-triggering dose range of the progesterone antagonist in question.
  • the most suitable compounds having an anti-estrogen effect are estrogen antagonists (competitive anti-estrogens).
  • Estrogen antagonists according to the present invention can either be derived from steroids or be non-steroidal compounds.
  • Estrogen antagonists according to the present invention are only to be understood as those compounds which act as selectively as possible, i.e. which essentially only inhibit the effect of estrogens and / or lower their concentration. The estrogen antagonists work by displacing estrogen from the receptor.
  • estrogen antagonists All common compounds with a competitive anti-estrogenic effect on the receptor can be considered as estrogen antagonists. They can be used in approximately the same amounts as the estrogen antagonists already on the market, that is to say the daily dose is about 5-100 mg for tamoxifen or the biologically equivalent amount of another estrogen antagonist.
  • non-steroidal estrogen antagonists are: (Z) -N r N-dimethyl-2- [4- (1,2-diphenyl-l-butenyl) phenoxy] ethanamine (tamoxifen), l- [2- [4- (3,4-dihydro-6-methoxy-2-phenyl-l-naphthalinyl) phenoxy] ethyl] pyrrolidine hydrochloride ( ⁇ afoxidin), ⁇ .
  • steroidal estrogen antagonists which may also be used are, for example: 17 ⁇ -ethynyl-11 ⁇ -methylestra-1,3,5 (10) -triene-3,17ß-diol and 16ß-ethyltra-1,3,5 (10) -triene-3, 17ß-diol,
  • estrogen antagonists which act particularly strongly and as selectively as possible on the endometrium (for example tamoxifen, ifenafoxidin, 7 ⁇ - [9 - [(4, 4,5,5, 5-pentafluoropentyl) sulfinyl] nonyl] estral , 3,5 (10) -triene-3,17 ⁇ -diol).
  • the threshold dose for endometrium-selective action is determined in ovariectomized, estradiol-substituted rats. Mitotic activity serves as a parameter (proliferation marker: PC ⁇ A).
  • the threshold dose is the amount of the estrogen antagonist at which only an effect on the uterus, namely an inhibition of the estrogen-induced proliferation of the endometrium, is observed.
  • Aromatase inhibitors in connection with progesterone antagonists can also be used as anti-estrogens according to the present invention.
  • Aromatase inhibitors suppress the synthesis of estrogens from their precursors.
  • the use of estrogen antagonists is preferred over that of aromatase inhibitors in any case, since the estrogen antagonists reduce the serum Do not affect estrogen concentration
  • An A ⁇ dose unit contains 0.01-100 mg tamoxifen or a biologically equivalent amount of another anti-estrogenic compound.
  • Progesterone antagonistic and anti-estrogenic compounds can e.g. B. locally, topically, enterally or parenterally.
  • the progesterone antagonist and the anti-estrogen are preferably used in a common dosage unit.
  • Tablet press is manufactured. If appropriate, the active compounds according to the invention, each with half of the additives indicated above, can also be pressed separately into a two-layer tablet.
  • Tablet press is manufactured. If appropriate, the active compounds according to the invention, each with half of the additives mentioned above, can also be pressed separately into a two-layer tablet.
  • Example 5 the active compounds according to the invention, each with half of the additives mentioned above, can also be pressed separately into a two-layer tablet.
  • the solution is filled into an ampoule
  • Tablet press is manufactured. If appropriate, the active compounds according to the invention, each with half of the additives indicated above, can also be pressed separately into a two-layer tablet.
  • the experiments were carried out on intact guinea pigs with a normal cycle. Treatment started on day 1 post coitum. The animals were treated with vehicle (benzyl benzoate / castor oil) or the tamoxifen in a dose of 0.3, 1, 3 mg / day animal or the progesterone-antagonistically active compound onapristone (0.3, 1.0, 3.0 mg / Day / animal), each alone, or treated with a combination of both compounds. The substances were applied subcutaneously. The number of implantation sites on day 12 post coitum serves as a parameter.
  • Tamoxifen 0.5 mg leads to a significant increase in effectiveness (synergism).
  • Receptivity inhibition means a complete avoidance of

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Abstract

The invention concerns the use of at least one compound with progesterone-antagonistic properties and at least one compound with anti-oestrogen properties, each in a dose which would not in itself inhibit ovulation, in a single dosing unit, in order to prepare medicaments for female contraception.

Description

Progesteronantagonistisch- und antiöstrogen wirksame Verbindungen zur gemeinsamen Verwendung für die weibliche Kontrazeption Progesterone antagonistic and anti-estrogenic active compounds for common use in female contraception
Die vorliegende Erfindung betrifft die Verwendung mindestens einer Verbindung mit progesteronantagonistischer (PA) und mindestens einer Verbindung mit antiöstrogener (AÖ) Wirkung, jeweils in nicht-ovulationshemmender Dosierung in einer einzelnen Dosiseinheit, zur Herstellung von Arzneimitteln zur weiblichen Kontrazeption.The present invention relates to the use of at least one compound with progesterone-antagonistic (PA) and at least one compound with anti-estrogenic (AÖ) activity, in each case in non-ovulation-inhibiting dosage in a single dose unit, for the production of medicaments for female contraception.
Die erfmdungsgemäß hergestellten Arzneimittel entfalten ihre empfängnisverhütende Wirkung auf der Basis der Rezeptivitätshemmung, indem eine Einnistung einer befruchteten Eizelle in die Uterusschleimhaut verhindert wird, ohne daß die Ovulation bzw. der Zyklus gestört wird.The medicaments produced according to the invention develop their contraceptive effect on the basis of the receptivity inhibition by preventing a fertilized egg from implanting in the uterine mucosa without disturbing the ovulation or the cycle.
Bereits auf der ganzen Welt hat sich der Gebrauch von oralen Kontrazeptiva zu einem gesellschaftlichen Faktor entwickelt, der nicht mehr wegzudenken ist. Besonders unter dem Aspekt der sich nach wie vor rasant entwickelnden Weltbevölkerung ist eine Weiterentwicklung der bislang bewährten Methoden zur Fertilitätskontrolle unbedingt erforderlich.Throughout the world, the use of oral contraceptives has become a social factor that has become indispensable. Particularly in view of the still rapidly developing world population, a further development of the previously proven methods for fertility control is absolutely necessary.
Der Einsatz von kompetitiven Progesteronantagonisten in der weiblichen Fertilitätskontrolle wird sowohl bei diversen Tierspezies als auch am Menschen schon seit einigen Jahren diskutiert, wie den nachfolgend aufgeführten Publikationen entnommen werden kann, wobei insbesondere der Einsatz von RU 486 (llß-[4- (Dimethylamino)phenyl]-17ß-hydroxy-17α-(l-propinyl)estra-4,9-dien-3-on; EP-A- 0057115) in diesem Zusammenhang aufgeführt wurde:The use of competitive progesterone antagonists in female fertility control has been discussed in various animal species and in humans for several years, as can be seen from the publications listed below, in particular the use of RU 486 (IIß- [4- (dimethylamino) phenyl ] -17ß-hydroxy-17α- (l-propynyl) estra-4,9-dien-3-one; EP-A-0057115) was listed in this connection:
Collins et al., Blockade of the spontaneous mid-cycle gonadotropin surge in monkeys by RU 486; A progesterone antagonist or agonist. J. Cli. Metab., 63:1270- 1276 (1986);Collins et al., Blockade of the spontaneous mid-cycle gonadotropin surge in monkeys by RU 486; A progesterone antagonist or agonist. J. Cli. Metab., 63: 1270-1276 (1986);
Croxatto, H.B., Salvatierra 1990 Cyclic use of antigestagens for fertility control. Illrd International Symposium on Contraception, Heidelberg, June 19-23, Danford et al., Contraceptive potential of RU 486 by ovulation inhibition. III. Preliminary observations on once weekly administration. Contraception 40: 195-200 (1989);Croxatto, HB, Salvatierra 1990 Cyclic use of antigestagens for fertility control. Illrd International Symposium on Contraception, Heidelberg, June 19-23, Danford et al., Contraceptive potential of RU 486 by ovulation 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. Fertil Steril [Fertile Sterile] ≤3: 4747 (1990);Kekkonen et al., Lrahteoenmäki P 1990 Interference with ovulation by sequential treatment with the antiprogesterone RU 486 and synthetic progestin. Fertil Sterile [Fertile Sterile] ≤3: 4747 (1990);
Puri et al., Gonadal and pituitary responses to progesterone antagonist ZK 98 299 during the follicular phase of the menstral cycle in bonnet monkeys. Contraception 39(1): 227-243 (1989);Puri et al., Gonadal and pituitary responses to progesterone antagonist ZK 98 299 during the follicular phase of the menstral cycle in bonnet monkeys. Contraception 39 (1): 227-243 (1989);
Puri et al., Contraceptive potential of a progesterone antagonist ZK 98 734 ((Z)-llß-[4-(Dimethylamino)phenyl]-17ß-hydroxy-17α-(3-hydroxy-l-propenyl)estra- 4,9-dien-3-on): Effect on folliculogenesis, ovulation and corpus luteum function in bonnet monkeys. In Moudgal et al., (eds) (1990).Puri et al., Contraceptive potential of a progesterone antagonist ZK 98 734 ((Z) -llß- [4- (Dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-l-propenyl) estra-4,9 -dien-3-on): Effect on folliculogenesis, ovulation and corpus luteum function in bonnet monkeys. In Moudgal et al., (Eds) (1990).
Der kontrazeptive Effekt eines Progesteronantagonisten ist einerseits von der ovulationshemmenden Wirkung anderseits von direkten Effekten auf das Endometrium bedingt.The contraceptive effect of a progesterone antagonist is due on the one hand to the ovulation-inhibiting effect and on the other hand to direct effects on the endometrium.
Hierbei ist zu erwähnen, daß diejeniege Dosierung eines kompetitiven Progesteronantagonisten, welche einen ovulationsinhibierenden Effekt hervorruft, sehr stark von dem jeweiligen kompetitiven Progesteronantagonisten abhängt:It should be mentioned here that the dosage of a competitive progesterone antagonist, which produces an ovulation-inhibiting effect, depends very much on the respective competitive progesterone antagonist:
Bei Progesteronantagonisten vom RU 486-Typ handelt sich um wenig- dissozierte Verbindungen mit einer stark ausgeprägten ovulationshemmenden Wirkung.RU 486-type progesterone antagonists are poorly dissociated compounds with a strong ovulation-inhibiting effect.
Bei Progesteronantagonisten vom Onapriston-Typ handelt sich um endometriumsspezifische (stark-dissozierte) Verbindungen, die die Ovulation erst bei hohen Dosierungen hemmen. Eine chronische Behandlung mit derartigen Progesteronantagonisten führt zur Wachstumsretardierung des Endometriums, wobei der ovarielle und menstruelle Zyklus nicht gestört wird. Im Endometrium kommt es zur Degeneration von endometrialen Drüsen und zur Verdichtung des Stromas, so daß die Implantation eines befruchteten Eies verhindert wird (Hemmung der Rezeptivität).Progesterone antagonists of the onapristone type are endometrium-specific (strongly dissociated) compounds that only inhibit ovulation at high doses. Chronic treatment with such progesterone antagonists leads to growth retardation of the endometrium, whereby the ovarian and menstrual cycle is not disturbed. In the endometrium, endometrial glands degenerate and the stroma is compressed, so that the implantation of a fertilized egg is prevented (inhibition of receptivity).
Die Klasse von llß-Aryl- oder llß,19-Arylen-substituierten Steroiden wird pharmakologisch nach ihrem stark progesteron- bzw. glukocortikoid-antagonistischen Effekt unterschieden. So kann RU 468 einerseits für einen therapeutisch induzierten Schwangerschaftsabbruch (die humane abortive Dosis in Kombination mit einem Prostaglandin liegt bei 200-600 mg; EP-A 0 139 608), andererseits aber auch über seine antagonistische Wirkung am Glucocortikoid-Rezeptor zur Therapie des Cushing-Syndroms eingesetzt werden.The class of llß-aryl- or llß, 19-arylene-substituted steroids is differentiated pharmacologically according to their strong progesterone- or glucocorticoid-antagonistic effect. On the one hand, RU 468 can be used for a therapeutically induced termination of pregnancy (the human abortive dose in combination with a Prostaglandin is 200-600 mg; EP-A 0 139 608), but on the other hand can also be used for the therapy of Cushing's syndrome due to its antagonistic effect on the glucocorticoid receptor.
Eine andere Möglichkeit der Verwendung kompetitiver Progesteronantagonisten für die weibliche Fertilitätskontrolle, die sogenannte "LH+2"-Behandlung, wird von Swahn et al. [The effect of RU 486 administration during the early luteal phase on bleeding pattern, hormonal parameters and endometrium, Human Reproduction 5(4") : 402-408 (1990)] vorgeschlagen, indem 2 Tage nach dem Anstieg des luteinisierenden Hormons (LH) im Menstruationszyklus der Frau (das ist im allg. am Tag 14, 15 oder 16) einmalig eine ovulationshemmende Dosiseinheit RU 486 verabreicht wird (luteale Kontrazeption). Eine Behandlung mit RU 486 in diesem Abschnitt des Menstruationszyklus führt nicht zur Störung des Zyklus. Applikation von RU 486 in anderen Phasen des Zyklus führt bei Dosierungen oberhalb von 1 mg/Tag entweder zur Amenorrhoe bzw. zu einer Abbruchblutung. Allerdings besitzt dieses Verfahren keine praktische Bedeutung, da die einfache und genaue zeitliche Bestimmung des LH-Peaks immer noch ein Problem darstellt.Another possibility of using competitive progesterone antagonists for female fertility control, the so-called "LH + 2" treatment, is described by Swahn et al. [The effect of RU 486 administration during the early luteal phase on bleeding pattern, hormonal parameters and endometrium, Human Reproduction 5 (4 " ): 402-408 (1990)] suggested by 2 days after the increase in luteinizing hormone (LH) an ovulation-inhibiting dose unit RU 486 (luteal contraception) is administered once in the woman's menstrual cycle (generally on day 14, 15 or 16) Treatment with RU 486 in this section of the menstrual cycle does not lead to a disturbance of the cycle RU 486 in other phases of the cycle will either lead to amenorrhea or to stop bleeding at doses above 1 mg / day, but this procedure is of no practical importance since the simple and accurate timing of the LH peak is still a problem.
Von 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)] wird auch die Verwendung von RU 486 für die postkoitale Kontrazeption (emergency postcoital contraception) beschrieben. Die Methode zeigt neben einer hohen Wirksamkeit ein geringes Ausmaß von Nebenwirkungen. Bei einem hohen Prozentsatz der Frauen dieser Studie trat eine Verlängerung des Zyklus auf. Dieser Effekt ist primär auf die antiovulatorische Wirkung von RU 486 zurückzuführen.By 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 uses RU 486 for post-coital contraception (emergency postcoital contraception). In addition to its high effectiveness, the method shows a low degree of side effects. A prolongation of the cycle occurred in a high percentage of women in this study. This effect is primarily due to the antiovulatory effects of RU 486.
Des weiteren wird in WO 93/23020 beschrieben, daß kompetitive Progesteronantagonisten in einer Dosis, die sowohl unterhalb der abortiven als auch ovulationsinhibierenden Dosierung liegt, zur weiblichen Fertilitätskontrolle verwendet werden können. Es handelt sich hier um eine im allgemeinen wöchentliche, bzw. mehrfache und damit regelmäßige Applikation.Furthermore, it is described in WO 93/23020 that competitive progesterone antagonists can be used for female fertility control in a dose that is both below the abortive and ovulation-inhibiting dosage. It is a generally weekly or multiple and therefore regular application.
Ebenso beschreibt die EP-A 0 219 447, welche Effekte die tägliche Gabe eines Progesteronantagonisten während der follikulären, bzw. optional auch der lutealen Phase des weiblichen Zyklus in einem Zeitraum von bis zu 4 Tagen in einer Dosierung von 10-200 mg bezüglich des endometrialen Differenzierungszustandes auslöst. Die hierbei resultierenden Veränderungen am Endometrium werden hinsichtlich des Nidationszeitpunktes für die in-vitro-Fertilisation genutzt.Likewise, EP-A 0 219 447 describes the effects of daily administration of a progesterone antagonist during the follicular or, optionally, also the luteal phase of the female cycle in a period of up to 4 days in one dose of 10-200 mg with respect to the endometrial differentiation state. The resulting changes in the endometrium are used for in vitro fertilization with regard to the time of nidation.
Von 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)] wird auch die Verwendung von RU 486 für die weibliche Fertilitätskontrolle beschrieben, welche durch tägliche Einnahme, präkoital und den gesamten weiteren Zyklus hindurch, in einer ovulationshemmenden Dosis die Nidation beim Meerschweinchen verhindert.By Batista et al. [Daily administration of the progesterone antagonist RU 486 prevents implantation in the cycling guinea pig. At the. J. Obstet. Gynecol. 165: 82-86 (1991)] also describes the use of RU 486 for female fertility control, which prevents nidation in guinea pigs by daily intake, precoitally and throughout the entire cycle, in an ovulation-inhibiting dose.
Von Kawano et al. [Effect of RU 486 on Glycogen Metabolism in Endometrium. Acta Obstetrica et Gynaecologica Japonica, 41, : 1507-1511, (1989)] wird am Rattenmodell der Einfluß von RU 486 in einer Dosierung von 30 mg/kg Körpergewicht auf den endometrialen Glykogen-Metabolismus beschrieben, so daß eine erfolgreiche Eiimplantation gestört wird. Die Applikation erfolgt allerdings am Tag 2 oder 4 der Schwangerschaft.By Kawano et al. [Effect of RU 486 on Glycogen Metabolism in Endometrium. Acta Obstetrica et Gynaecologica Japonica, 41,: 1507-1511, (1989)] describes the influence of RU 486 in a dosage of 30 mg / kg body weight on the endometrial glycogen metabolism in the rat model, so that a successful egg implantation is disturbed. However, the application takes place on day 2 or 4 of pregnancy.
Die hormonelle Steuerung der Implantation ist speziesabhängig. Bei allen bisher untersuchten Säugetieren ist die Anwesenheit des ovariellen Progesterons für eine erfolgreiche Implantation notwendig. Bei postkoital ovariektomierten Ratten und Mäusen, die mit Progestron substituiert werden, kommt es allerdings ohne Östrogengabe zu keiner Implantation (Finn CA, Porter DG [1975] Implantation of ova [Chapter 6] and The control of implantation and the decidual reaction [Chapter 8]; In Finn CA and Porter [eds] The Uterus, Elek Science, L.ondon, pp 57-73; 86-95). Wird bei diesen Tierspezies Östrogen injiziert, kommt es sofort zur Implantation der Blastocyste (delayed implantation model). Diese Beobachungen deuten darauf hin, daß das ovarielle Östrogen bei Anwesenheit des Progesterons die Implantation bei Nagetieren induziert. Es war bereits bekannt, daß beim Meerschweinchen und Primaten die ovariellen Östrogene für die Implantation nicht essentiel sind. Bei Meerschweinchen, die nach Anpaarung ovariektomiert wurden, findet die Implantation nur nach einer Progesteronsubstitution (ohne zusätzlicher Östrogenbehandlung) statt (Deansley R [1972] Retarded embryonic development and pregnancy termination in ovariectomized guinea pigs: progesterone deficiency and decidual collapse; J Reprod Fert [1972] 28:241-247). Sowohl Antiöstrogene als auch Ostrogene in hoher Dosierung hemmen die Implantation bei Ratten und Mäusen (Martin L, Cox RJ, Emmens CW [1963] Further studies in the effects of estrogens and antiestrogens on early pregnancy in mice. J Reprod Fertil 5:239-247; Singh MM Kamboj VP [1992] Fetal resoption in rats treated with an antiestrogen in relation to luteal phase nidatory estrogen secretion. Acta endocrinol 126:444-50). Die implantationshemmende Wirkung von Antiöstrogenen mit östrogenen Partialwirkungen (Nafoxidine, Centchroman, Tamoxifen) wurde auch beim Meerschweinchen beschrieben (Wisel MS, Datta JK, Saxena RN [1994] Int J Fertil 39:156-163). Es ist unklar, ob die implantationshemmende Wirkung der oben genannten Antiöstrogene auf die antagonistische oder agonistische Wirkung zurückzuführen ist, da auch hochdosierte Ostrogene die Implantation beim Meerschweinchen verhindern.The hormonal control of the implantation depends on the species. In all mammals examined so far, the presence of ovarian progesterone is necessary for successful implantation. In postcoital ovariectomized rats and mice that are substituted with progesterone, there is no implantation without estrogen administration (Finn CA, Porter DG [1975] Implantation of ova [Chapter 6] and The control of implantation and the decidual reaction [Chapter 8] ; In Finn CA and Porter [eds] The Uterus, Elek Science, L.ondon, pp 57-73; 86-95). If estrogen is injected into these animal species, the blastocyst is immediately implanted (delayed implantation model). These observations indicate that ovarian estrogen induces rodent implantation in the presence of progesterone. It was already known that in guinea pigs and primates, ovarian estrogens are not essential for implantation. In guinea pigs that were ovariectomized after mating, the implantation only takes place after progesterone substitution (without additional estrogen treatment) (Deansley R [1972] Retarded embryonic development and pregnancy termination in ovariectomized guinea pigs: progesterone deficiency and decidual collapse; J Reprod Fert [1972 ] 28: 241-247). Both anti-estrogens and estrogens in high doses inhibit implantation in rats and mice (Martin L, Cox RJ, Emmens CW [1963] Further studies in the effects of estrogens and antiestrogens on early pregnancy in mice. J Reprod Fertil 5: 239-247 ; Singh MM Kamboj VP [1992] Fetal resoption in rats treated with an antiestrogen in relation to luteal phase nidatory estrogen secretion. Acta endocrinol 126: 444-50). The implant-inhibiting effect of anti-estrogens with estrogenic partial effects (nafoxidins, centchroman, tamoxifen) has also been described in guinea pigs (Wisel MS, Datta JK, Saxena RN [1994] Int J Fertil 39: 156-163). It is unclear whether the implant-inhibiting effects of the above-mentioned anti-estrogens can be attributed to the antagonistic or agonistic effects, since even high-dose estrogens prevent implantation in guinea pigs.
Die Verwendung von Östrogenantagonisten (Centchroman) zur Kontrazeption beim Menschen ist ebenfalls beschrieben (Nittyanand S, Kamboj VP [1992] Centchroman: contraceptive efficacy and safety profile. International Conference on Fertility Regulation, November 5-S, 1992 Bombay, India, Programme and abstracts). Allerdings treten bei wirksamen Dosierungen unerwünschte Nebenwirkungen vor, die auf die systemische Wirkung der Östrogenantagonisten zurückzuführen sind. Die Östrogendeprivation, die nach einer Langzeitbehandlung mit einem Antiöstrogen auftreten kann, limitiert zumindest deren regelmäßige Anwendung zur Kontrazeption.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-S, 1992 Bombay, India, Program and abstracts ). However, with effective doses there are undesirable side effects that are due to the systemic effects of the estrogen antagonists. The estrogen deprivation that can occur after long-term treatment with an anti-estrogen at least limits their regular use for contraception.
Schließlich geht aus der DE-A 42 13 005 die Verwendung von Aromatasehemmern zur Empfängnisverhütung bei weiblichen Primaten im fortpflanzungsfähigen Alter in einer Dosierung, bei der der menstruelle Zyklus des weiblichen Primaten im wesentlichen unbeeinflußt bleibt, hervor. Aromatasehemmer blockieren die Biosynthese von Estrgenen aus deren metabolischen Vorstufen. Die Absoluthöhe der für die kontrazeptive Wirkung erforderlichen Tagesdosen hängt dabei ganz von der Art des verwendeten Aromatasehemmers ab. Für hochaktive Aromatasehemmer liegen die Tagesdosen in der Regel zwischen etwa 0,05 bis etwa 30 mg. Bei weniger aktiven Aromatasehemmern können die Tagesdosen auch höher liegen.Finally, DE-A 42 13 005 shows the use of aromatase inhibitors for contraception in female primates of reproductive age in a dosage at which the menstrual cycle of the female primate remains essentially unaffected. Aromatase inhibitors block the biosynthesis of estrogens from their metabolic precursors. The absolute amount of the daily doses required for the contraceptive effect depends entirely on the type of aromatase inhibitor used. For highly active aromatase inhibitors, the daily doses are usually between about 0.05 to about 30 mg. With less active aromatase inhibitors, the daily doses can also be higher.
Der vorliegenden Erfindung liegt die Aufgabe zugrunde, ein Präparat für die endometriale Kontrazeption bereitzustellen (Hemmung der endometrialen Rezeptivität, postkoitale Anwendung, "Bedarfspille"), welches die oben genannte unerwünschte Nebenwirkung nicht zeigt und gleichzeiting eine höhere kontrazeptive Sicherheit aufweist als die getrennte Applikation der entsprechenden Einzelkomponenten.The present invention has for its object to provide a preparation for endometrial contraception (inhibition of endometrial receptivity, post-coital use, "need pill"), which does not show the undesirable side effect mentioned above and at the same time a higher contraceptive Security as the separate application of the corresponding individual components.
Unter "Bedarfspille" soll ein oral zu verabreichendes Arzneimittel verstanden werden, welches bei vorzugsweise einmaliger und praekoitaler bedarfsweiser Anwendung eine Konzeption verhindert. Ein derartiges Mittel, hergestellt unter ausschließlicher Verwendung eines kompetitiven Progesteronantagonisten, ist in der nicht veröffentlichten deutschen Patentanmeldung P 44 38 820.9 beschrieben.A “need pill” is to be understood as an orally administered medicament which prevents a conception when it is preferably used once and precoitally as required. Such an agent, produced using only a competitive progesterone antagonist, is described in the unpublished German patent application P 44 38 820.9.
Diese Aufgabe wird dadurch gelöst, daß mindestens eine Verbindung mit progesteronantagonistischer (PA) und mindestens eine Verbindung mit antiöstrogener (AÖ) Wirkung, jeweils in nicht-ovulationshemmender Dosierung in einer einzelnen Dosiseinheit, gemeinsam zur Herstellung von Arzneimitteln zur weiblichen Kontrazeption verwendet werden.This object is achieved in that at least one compound with progesterone-antagonistic (PA) and at least one compound with anti-estrogenic (AÖ) activity, in each case in non-ovulation-inhibiting dosage in a single dose unit, are used together for the production of medicaments for female contraception.
Es wurde nunmehr gefunden, daß die Kombination eines Progesteronantagonisten und Antiöstrogens synergistisch die Endometriumsproliferation und -differenzierung hemmt, so daß der antifertile Effekt der Einzelkomponenten bei entsprechender Dosierung in der Kombination entweder verstärkt wird oder zur Erzielung eines mit den Einzelkomponenten bei deren separaten Anwendung vergleichbaren Effektes die Einzelkomponenten in der Kombination entsprechend niedriger dosiert werden können.It has now been found that the combination of a progesterone antagonist and an anti-estrogen synergistically inhibits endometrial proliferation and differentiation, so that the antifertile effect of the individual components is either increased with the appropriate dosage in the combination or to achieve an effect comparable to that of the individual components when used separately Individual components in the combination can be dosed correspondingly lower.
Mittel, enthaltend mindestens eine Verbindung mit antigestagener und mindestens eine Verbindung mit antiöstrogener Wirkung, insbesondere zur Geburtseinleitung und zum Schwangerschaftsabbruch sowie zur Behandlung gynäkologischer Störungen sowie die Verwendung mindestens einer Verbindung mit antigestagener und mindestens einer Verbindung mit antiöstrogener Wirkung zur Herstellung von Arzneimitteln für die angegebenen Indikationen, sind bereits Gegenstand der EP-A 0 310 541.Agent containing at least one compound with antigestagenic and at least one compound with anti-estrogenic activity, in particular for induction of birth and termination of pregnancy and for the treatment of gynecological disorders, and the use of at least one compound with antigestagenic and at least one compound with anti-estrogenic activity for the production of medicaments for the indicated indications are already the subject of EP-A 0 310 541.
Pharmazeutische Zusammensetzungen zur postkoitalen Fertilitätskontrolle, die einen kompetitiven Progesteronantagonisten (Antigestagen) sowie einen Progesteron- und Östrogensyntheseblocker enthalten, sind bereits im US-Patent 4,670,426 beschrieben. Als typische Vertreter für den zu verwendenden kompetitiven Progeste¬ ronantagonisten sind Fluocrnolonacetonid, Triamcinolonacetonid, Steroide mit einem zyklischen 16,17-Acetal mit Aceton und llß-[4-(Dimethylamino)phenyl]-17ß- hydroxy-17α-(l-propinyl)estra-4,9-dien-3-on (RU 38 486) und äquivalente Derivate erwähnt. Der typische Gehalt liegt dabei zwischen 20 und 50 mg. Als Beispiele für den Progesteron- und Östrogensyntheseblocker sind Aminoglutethimid, 4ß,17α- Dimethyl-17ß-hydroxy-3-oxo-4α,5-epoxy-5α-androstan-2 -carbonitril, 20,25-Pharmaceutical compositions for post-coital fertility control, which contain a competitive progesterone antagonist (antigestagen) and a progesterone and estrogen synthesis blocker, have already been described in US Pat. No. 4,670,426. Typical representatives of the competitive progesterone antagonist to be used are fluocrnolone acetonide, triamcinolone acetonide, steroids with a cyclic 16,17 acetal with acetone and IIß- [4- (dimethylamino) phenyl] -17ß- hydroxy-17α- (l-propynyl) estra-4,9-dien-3-one (RU 38 486) and equivalent derivatives mentioned. The typical content is between 20 and 50 mg. Examples of the progesterone and estrogen synthesis blocker are aminoglutethimide, 4β, 17α-dimethyl-17ß-hydroxy-3-oxo-4α, 5-epoxy-5α-androstan-2-carbonitrile, 20.25-
Diazocholesterol und Verbindungen mit äquivalenter Aktivität angeführt und zwar in einer Dosis von 300 bis 1000 mg. Die Anwendung der Zusammensetzung hat gemäß US-Patent 4,670,426 möglichst früh innerhalb der ersten Woche nach dem Geschlechtsverkehr über einen Zeitraum von 3 Tagen zu erfolgen; am besten sollte die Behandlung 2 bis 6 Tage fortgesetzt werden. Die Verhinderung der Nidation und somit einer Schwangerschaft wird durch den synergistischen Effekt bei der gemeinsamen Anwendung der beiden Bestandteile der Zusammensetzung bewirkt, und zwar mit einer Erfolgsrate in der Größenordnung von 90% oder mehr.Diazocholesterol and compounds with equivalent activity are listed in a dose of 300 to 1000 mg. According to US Pat. No. 4,670,426, the composition must be used as early as possible within the first week after sexual intercourse over a period of 3 days; it is best to continue treatment for 2 to 6 days. The prevention of nidation and thus pregnancy is achieved by the synergistic effect when the two components of the composition are used together, with a success rate of the order of 90% or more.
Es wurde nunmehr gefunden, daß neben Antigestagenen (kompetitiven Progesteronantagonisten) auch reine Östrogenantagonisten, wie 7α-[9-[(4,4,5,5,5- Pentafluorpentyl)sulfinyl]nonyl]estra-l,3,5(10)-trien-3,17ß-diol (ICI 182780), die Implantation beim Meerschweinchen hemmen. Dieser Befund deutet darauf hin, daß beim Meerschweinchen, anders als bisher angenommen, auch Ostrogene eine wichtige Rolle bei der Implantation spielen.It has now been found that, in addition to antigestagens (competitive progesterone antagonists), pure estrogen antagonists such as 7α- [9 - [(4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl] estra-l, 3.5 (10) -trien-3,17ß-diol (ICI 182780), which inhibit implantation in guinea pigs. This finding suggests that in guinea pigs, contrary to previous beliefs, estrogens also play an important role in implantation.
Weiter wurde gefunden, daß beim Meerschweinchen überraschenderweise eine kombinierte Behandlung mit Progesteronantagonisten und Antiöstrogenen während der Periimplantationsphase (Tag 1-7 post coitum) eine synergistische Wirkung aufweisen. Diese .Beobachtungen deuten darauf hin, daß bei dieser Spezies die Ostrogene in der Blastozyste gebildet werden. Eine ähnliche Situation kann beim Menschen existieren.It has also been found that, surprisingly, combined treatment with progesterone antagonists and anti-estrogens during the peri-implantation phase (day 1-7 post coitum) has a synergistic effect in guinea pigs. This . Observations indicate that the estrogens are formed in the blastocyst in this species. A similar situation can exist in humans.
Die wesentlichen Vorteile der vorliegenden Erfindung liegen nicht zuletzt in der niedrigen Dosierung der Wirkstoffe begründet, einerseits durch die mögliche Verringerung der bei einer Monotherapie erforderlichen wirksamen Mengen durch den synergistischen Effekt, andererseits durch die Verwendung niedrigerer, nicht- ovulationsinhibierender Dosierungen. So wird der weibliche Menstruationszyklus in keiner Weise in seiner Zyklizität beeinträchtigt (wie durch ovulationshemmende Substanzen wie RU 486 verursacht) und der Organismus nicht durch unnötig hohe Mengen des kompetitiven Progesteronantagonisten bzw. des Antiöstrogens belastet. Die Verwendung einer solchen Progesteronantagonisten/Antiöstrogen-Kombination bietet eine sichere Empfängnisverhütung, d.h. die regelmäßige Einnahme eines derartigen Medikamentes (täglich, regelmäßig alle 3 bis 7 Tage) verhindert die Einnistung der Blastozyste ohne Beeinflußung des Zyklus. Ferner wird die kontrazeptive Sicherheit nach einer einmaligen, bedarfsorientierten präkoitalen Einahme unabhängig von dem Einnahmetag im Zyklus ("Bedarfspille") bzw. nach einer postkoitalen Behandlung erhöht.The main advantages of the present invention lie not least in the low dosage of the active ingredients, on the one hand due to the possible reduction in the effective amounts required for monotherapy due to the synergistic effect, and on the other hand through the use of lower, non-ovulation-inhibiting dosages. The cyclicality of the female menstrual cycle is in no way impaired (as caused by ovulation-inhibiting substances such as RU 486) and the organism is not burdened by unnecessarily high amounts of the competitive progesterone antagonist or the anti-estrogen. The use of such a progesterone antagonist / anti-estrogen combination offers safe contraception, ie the regular use of such a medication (daily, regularly every 3 to 7 days) prevents the blastocyst from implanting without affecting the cycle. Furthermore, the contraceptive security is increased after a one-time, needs-based precoital intake regardless of the intake day in the cycle ("need pill") or after postcoital treatment.
Durch die Dosisreduktion des Antiöstrogens ist nicht mit einer Ostrogendeprivation zu rechnen. Es kann so eine endometriumselektive Wirkung des Antiöstrogens erreicht und eine ungünstige Wirkung aufgrund einer Ostrogendeprivation an anderen Organen, beispielsweise am Knochen, vermieden werden.Due to the dose reduction of the anti-estrogen, estrogen deprivation is not to be expected. In this way, an endometrium-selective effect of the anti-estrogen can be achieved and an unfavorable effect due to estrogen deprivation on other organs, for example on the bone, can be avoided.
Das Gewichtsverhältnis beider Komponenten in dem neuen Arzneimittel kann dabei in weiten Grenzen variiert werden. So können sowohl gleiche Mengen PA und AÖ als auch ein Überschuß einer der beiden Komponenten eingesetzt werden. PA und AÖ werden gemeinsam, getrennt, gleichzeitig in einem Gewichtsverhältnis von im wesentlichen 50:1 bis 1:50, vorzugsweise 25:1 bis 1:25, und insbesondere 10:1 bis 1:10 verwendet. Die gleichzeitige Gabe ist bevorzugt. Vorzugsweise können PA und AÖ kombiniert in einer Dosiseinheit appliziert werden.The weight ratio of both components in the new drug can be varied within wide limits. Both the same amounts of PA and AÖ and an excess of one of the two components can be used. PA and AÖ are used together, separately, simultaneously in a weight ratio of essentially 50: 1 to 1:50, preferably 25: 1 to 1:25, and in particular 10: 1 to 1:10. Co-administration is preferred. PA and AÖ can preferably be applied in combination in one dose unit.
Die beiden Komponenten können einmal täglich oder intermittierend alle 3-6 Tage über den gesamten Zyklus appliziert werden. Sie können auch einmalig präkoital (nach Bedarf; "Bedarfs-Pille") unabhängig vom Zeitpunkt des Menstruationszyklus oder postkoital angewandt werden. Bei der präkoitalen Anwendung wird der Progesteronantagonist höher dosiert, allerdings unterhalb der ovulationshemmenden Dosierung.The two components can be applied once a day or intermittently every 3-6 days over the entire cycle. They can also be used once precoitally (as required; "pill on demand") regardless of the time of the menstrual cycle or postcoitally. In the case of precoital use, the progesterone antagonist is dosed higher, but below the ovulation-inhibiting dose.
Als kompetitive Progesteronantagonisten kommen alle Verbindungen in Frage, die die Wirkung des Progesterons am Gestagenrezeptor (Progesteronrezeptor) kompetitiv blockieren und dabei keine eigene gestagene Aktivität zeigen; die Blockade kann durch die verabreichte Substanz selbst oder durch deren Metaboliten bewirkt werden.All compounds which competitively block the effect of progesterone on the progestogen receptor (progesterone receptor) and which do not show their own progestogen activity are possible as competitive progesterone antagonists; the blockage can be brought about by the substance administered itself or by its metabolites.
Bei den kompetitiven Progesteronantagonisten handelt sich gemäß vorliegender Erfindung vorzugsweise um endometriumsspezifische (dissozierte) Verbindungen die höchstenfalls eine schwache antiovulatorische Aktivität aufweisen. Es können auch nicht-dissozierte Progesteronantagonisten angewandt werden, wobei dann deren Dosierung unterhalb der ovulationsinhibierenden Dosis liegt. Beispielsweise kommen folgende Steroide infrage:According to the present invention, the competitive progesterone antagonists are preferably endometrium-specific (dissociated) compounds which at most have weak antiovulatory activity. Non-dissociated progesterone antagonists can also be used, in which case their Dosage is below the ovulation-inhibiting dose. For example, the following steroids are possible:
llß-[4-(Dimethylamino)phenyl]-17ß-hydroxy-17α-(l-propinyl)estra-4,9-dien-3-on (RU 38llß- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (l-propynyl) estra-4,9-dien-3-one (RU 38
486), llß-[4-(Dimethylamino)phenyl]-17ß-hydroxy-17α-(l-propinyl)-18a-homoestra-4,9-dien-3- on und llß-[4-(Dimethylamino)phenyl]-17aß-hydroxy-17aα-(l-propinyl)-17a-homoestra-4,9,16- trien-3-on (alle EP-A 0 057 115),486), llß- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (l-propynyl) -18a-homoestra-4,9-dien-3-one and llß- [4- (dimethylamino) phenyl] -17ass-hydroxy-17aα- (l-propynyl) -17a-homoestra-4,9,16-trien-3-one (all EP-A 0 057 115),
17α-Ethinyl-17ß-hydroxy-llß-(4-methoxyphenyl)estra-4,9-dien-3-on (Steroids 37 (1981),17α-ethynyl-17β-hydroxy-11ß- (4-methoxyphenyl) estra-4,9-dien-3-one (Steroids 37 (1981),
361-382), llß-(4-Acetylphenyl)-17ß-hydroxy-17α-(l-propinyl)estra-4,9-dien-3-on (EP-A 0 190 759),361-382), llß- (4-acetylphenyl) -17ß-hydroxy-17α- (l-propynyl) estra-4,9-dien-3-one (EP-A 0 190 759),
4',5'-Dihydro-llß-[4-(dimethylamino)phenyl]-6ß-methylspiro[estra-4,9-dien-17ß,2'(3'H)- furan]-3-on4 ', 5'-Dihydro-llß- [4- (dimethylamino) phenyl] -6ß-methylspiro [estra-4,9-dien-17ß, 2' (3'H) - furan] -3-one
4',5'-Dihydro-llß-[4-(dimethylamino)phenyl]-7ß-methylspiro[estra-4,9-dien-17ß,2'(3'H)- furan]-3-on4 ', 5'-Dihydro-llß- [4- (dimethylamino) phenyl] -7ß-methylspiro [estra-4,9-dien-17ß, 2' (3'H) - furan] -3-one
Uß-(4-Acetylphenyl)-19,24-dinor-17,23-epoxy-17α-chola-4,9,20-trien-3-on (alle US-AUß- (4-acetylphenyl) -19,24-dinor-17,23-epoxy-17α-chola-4,9,20-trien-3-one (all US-A
4,386,085) sowie die in der EP-A 0 277 676 beschriebenen llß-Aryl-14ß-estradiene und -triene, die 19,1 lß- überbrückten Steroide, die Gegenstand der EP-A-0 283 428 sind, die aus der EP-A-0 2894,386,085) and the 11β-aryl-14ß-estradienes and trienes described in EP-A 0 277 676, the 19.1 Lß-bridged steroids which are the subject of EP-A-0 283 428, which are known from EP-A A-0 289
073 hervorgehenden llß-Aryl-6-alkyl (bzw. 6-Alkenyl oder 6-alkinyl)-estradiene und - pregnadiene und die aus der EP-A-0 321 010 bekannten llß-Aryl-7-methyl (bzw. 7-ethyl)- estradiene sowie die lOß-Η-Steroide der EP-A-0 404 283, beispielsweise (Z)-llß-[4-073 resulting llß-aryl-6-alkyl (or 6-alkenyl or 6-alkynyl) -estradienes and pregnadienes and the llß-aryl-7-methyl (or 7-ethyl) known from EP-A-0 321 010 ) - estradienes and the lOß-Η steroids of EP-A-0 404 283, for example (Z) -llß- [4-
(Dimethylamino)phenyl]-17α-(3-hydroxy-l-propenyl)estr-4-en-17ß-ol.(Dimethylamino) phenyl] -17α- (3-hydroxy-l-propenyl) estr-4-en-17ß-ol.
Weiterhin seien als typische Vertreter erfindungsgemäß zu verwendender, kompetitiver Progesteronantagonisten beispielsweise genannt: llß-[4-(Dimethylamino)phenyl]-17α-hydroxy-17ß-(3-hydroxypropyl)-13α-estra-4,9- dien-3-on (EP-A-0 129 499);Furthermore, typical examples of competitive progesterone antagonists to be used according to the invention are: IIß- [4- (dimethylamino) phenyl] -17α-hydroxy-17ß- (3-hydroxypropyl) -13α-estra-4,9-dien-3-one (EP-A-0 129 499);
(-Z)-llß-(4-Acetylphenyl)-17ß-hydroxy-17α-(3-hydroxy-l-propenyl)estra-4,9-dien-3- on (EP-A-0 190 759);(-Z) -llß- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxy-l-propenyl) estra-4,9-dien-3-one (EP-A-0 190 759);
(Z)-6'-(4-CyanphenyI)-9,llα-dihydro-17ß-hydroxy-17α-(3-hydroxy-l-propenyl)-4'H- naphth[3',2*,l,:10,9,ll]estra-4,9(ll)-dien-3-on und (Z)-9,llα-Dihydro-17ß-hydroxy-17α-(3-hydroxy-l-propenyl)-6,-(3-pyridinyl)-4'H- naphth[3',2*,l':10,9,ll]estra-4,9(ll)-dien-3-on(Z) -6 '- (4-CyanphenyI) -9, llα-dihydro-17-hydroxy-17α- (3-hydroxy-l-propenyl) -4'H- naphth [3', 2 *, l,: 10.9, ll] estra-4.9 (ll) -dien-3-one and (Z) -9, llα-dihydro-17ß-hydroxy-17α- (3-hydroxy-l-propenyl) -6 , - (3-pyridinyl) -4'H-naphth [3 ', 2 *, l': 10.9, ll] estra-4.9 (ll) -dien-3-one
17α-Ηydroxy-17ß-(3-hydroxypropyl)-llß-[4-(l-methylethenyl)phenyl]-13α-estra-4,9-dien-17α-hydroxy-17ß- (3-hydroxypropyl) -llß- [4- (l-methylethenyl) phenyl] -13α-estra-4,9-diene
3-on (ZK 131 535) llß-[4-(3-Furanyl)phenyl]-17α-hydroxy-17ß-(3-hydroxypropyl)-13α-estra-4,9-dien-3-on3-one (ZK 131 535) llß- [4- (3-furanyl) phenyl] -17α-hydroxy-17ß- (3-hydroxypropyl) -13α-estra-4,9-dien-3-one
(ZK 135 695)(ZK 135 695)
(Z)-llß-[4-(Dimethylamino)phenyl]-17ß-hydroxy-17α-(3-hydroxy-l-propenyl)estr-4-en-3- on(Z) -llß- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-l-propenyl) estr-4-en-3- one
(E)-llß-[4-[[(Acetyloxy)imino]methyl]phenyl]-17ß-methoxy-17α-(methoxymethyl)estra- 4,9-dien-3-on(E) -llß- [4 - [[(acetyloxy) imino] methyl] phenyl] -17ß-methoxy-17α- (methoxymethyl) estra-4,9-dien-3-one
(E)-llß-[4-[[[(Εthoxycarbonyl)oxy]imino]methyl]phenyl]-17ß-methoxy-17 - (methoxymethyl)estra-4,9-dien-3-on(E) -llß- [4 - [[[(Εthoxycarbonyl) oxy] imino] methyl] phenyl] -17ß-methoxy-17 - (methoxymethyl) estra-4,9-dien-3-one
Bei den letztgenannten PAs handelt es sich um solche vom dissoziierten Typ, bei denen bei einer bestimmten Schwellendosis Veränderungen des Endometriums beobachtet werden, während die Ovulation (zentrale Wirkung) nicht gehemmt wird. Der Quotient aus ovulationshemmender und abortiver Dosis (Dissoziationsfaktor) kann als ein Maß für die Dissoziation dienen. Dissoziierte PAs sind im Rahmen vorliegender Erfindung bevorzugt.The latter PAs are of the dissociated type, in which changes in the endometrium are observed at a certain threshold dose, while the ovulation (central effect) is not inhibited. The quotient of the ovulation-inhibiting and abortive dose (dissociation factor) can serve as a measure of the dissociation. Dissociated PAs are preferred in the context of the present invention.
Die Aufzählung der PAs ist nicht abschließend; auch andere in den genannten Veröffentlichungen beschriebene kompetitive Progesteronantagonisten sowie solche aus hier nicht genannten Veröffentlichungen sind geeignet. Neuerdings sind auch nicht-steroidale, am Progesteronrezeptor als Antagonisten wirksame Verbindungen bekannt geworden (WO-A 93/21145), die für die Zwecke der vorliegenden Erfindung verwendet werden können.The PA list is not exhaustive; other competitive progesterone antagonists described in the publications mentioned and those from publications not mentioned here are also suitable. Recently non-steroidal compounds which act as antagonists on the progesterone receptor have also become known (WO-A 93/21145) which can be used for the purposes of the present invention.
Die kompetitiven Progesteronantagonisten können zum Beispiel lokal, topisch, enteral, transdermal oder parenteral appliziert werden. Für die bevorzugte orale Applikation kommen insbesondere Tabletten, Dragees, Kapseln, Pillen, Suspensionen oder Lösungen in Frage, die in üblicher Weise mit den in der Galenik gebräuchlichen Zusätzen und Trägersubstanzen hergestellt werden können. Für die lokale oder topische Anwendung kommen beispielsweise Vaginalzäpfchen, Vaginalgels, Implantate, Vaginalringe, intrauterine Freisetzungssysteme (IUDs) oder transdermale Systeme wie Hautpflaster in Frage. Eine Dosierungseinheit enthält etwa 0,25 bis 50 mg llß-[4-(Dimethylamino)phenyl]- 17α-hydroxy-17ß-(3-hydroxypropyl)-13α-estra-4,9-dien-3-on oder eine biologisch äquivalente Menge eines anderen kompetitiven Progesteronantagonisten. Wirkäquivalente Mengen werden im Niditationshemmtest am Meerschweinchen (Behandlung Tag 1-7 post coitum) ermittelt.The competitive progesterone antagonists can, for example, be applied locally, topically, enterally, transdermally or parenterally. For the preferred oral application, tablets, dragees, capsules, pills, suspensions or solutions are particularly suitable, which can be prepared in the usual way with the additives and carrier substances customary in galenics. For local or topical use, for example, vaginal suppositories, vaginal gels, implants, vaginal rings, intrauterine release systems (IUDs) or transdermal systems such as skin patches are suitable. One unit dose contains about 0.25 to 50 mg of llß- [4- (dimethylamino) phenyl] - 17α-hydroxy-17ß- (3-hydroxypropyl) -13α-estra-4,9-dien-3-one or a biologically equivalent Amount of another competitive progesterone antagonist. Effective amounts are determined in the niditation inhibition test on guinea pigs (treatment day 1-7 post coitum).
Erfolgt die Applikation des erfindungsgemäß hergestellten pharmazeutischen Mittels durch ein Implantat, einen Vaginalring, ein IUD oder ein transdermales System, so müssen diese Applikationssysteme derart ausgebildet sein, daß die durch sie täglich freigesetzte Dosis des kompetitiven Progesteronantagonisten in diesem Bereich von 0,25 bis 50 mg liegt.If the pharmaceutical agent produced according to the invention is applied by means of an implant, a vaginal ring, an IUD or a transdermal system, these application systems must be designed in such a way that the dose of the competitive progesterone antagonist released by them daily in this range of 0.25 to 50 mg lies.
Die erfindungsgemäß zu applizierende Dosis eines kompetitiven Progesteronantagonisten kann im nicht-ovulationshemmenden sowie nicht- abortauslösenden Dosisbereich des betreffenden Progesteronantagonisten liegen.The dose of a competitive progesterone antagonist to be applied according to the invention can be in the non-ovulation-inhibiting and non-abortion-triggering dose range of the progesterone antagonist in question.
Als antiöstrogen wirkende Verbindungen kommen erfindungsgemäß in erster Linie Östrogenantagonisten (kompetitive Antiöstrogene) infrage. Östrogenantagonisten gemäß vorliegender Erfindung können sowohl von Steroiden abgeleitet oder nicht- steroidale Verbindungen sein. Unter Östrogenantagonisten gemäß vorliegender Erfindung sollen nur solche Verbindungen verstanden werden, die möglichst selektiv wirken, d.h. die im wesentlichen nur die Wirkung von Östrogenen hemmen und/oder deren Konzentration senken. Die Östrogenantagonisten wirken, indem sie Östrogen vom Rezeptor verdrängen.According to the invention, the most suitable compounds having an anti-estrogen effect are estrogen antagonists (competitive anti-estrogens). Estrogen antagonists according to the present invention can either be derived from steroids or be non-steroidal compounds. Estrogen antagonists according to the present invention are only to be understood as those compounds which act as selectively as possible, i.e. which essentially only inhibit the effect of estrogens and / or lower their concentration. The estrogen antagonists work by displacing estrogen from the receptor.
Als Östrogenantagonisten kommen alle gebräuchlichen Verbindungen mit kompetitiver antiöstrogener Wirkung am Rezeptor in Betracht. Sie können etwa in gleichen Mengen eingesetzt werden wie die bereits im Handel befindlichen Östrogenantagonisten, das heißt die tägliche Dosis beträgt etwa 5-100 mg für Tamoxifen oder die biologisch äquivalente Menge eines anderen Östrogenantagonisten.All common compounds with a competitive anti-estrogenic effect on the receptor can be considered as estrogen antagonists. They can be used in approximately the same amounts as the estrogen antagonists already on the market, that is to say the daily dose is about 5-100 mg for tamoxifen or the biologically equivalent amount of another estrogen antagonist.
Als nicht-steroidale Östrogenantagonisten seien beispielsweise genannt: (Z)-NrN-Dimethyl-2-[4-(l,2-diphenyl-l-butenyl)phenoxy]ethanamin (Tamoxifen), l-[2-[4-(3,4-Dihydro-6-methoxy-2-phenyl-l-naphthalinyl)phenoxy]ethyl]pyrrolidin- hydrochlorid (Νafoxidin), α.[4-[2-(Diethylamino)ethoxy]phenyl]-4-methoxy-α-phenylbenzenethanol (Mer-25), [6-Hydroxy-2-(4-hydroxyphenyl)-3-benzothienyl][4-[2-(l- piperidinyl)ethoxy]phenyl]methanon-hydrochlorid (Raloxifen), (3R-trflΛs)-3,4-Dihydro-2,2-dimethyl-7-methoxy-3-phenyl-4-[4-[2-(l- pyrrolidinyl)ethoxy]phenyl]-2H-l-benzopyran (Centchroman),Examples of non-steroidal estrogen antagonists are: (Z) -N r N-dimethyl-2- [4- (1,2-diphenyl-l-butenyl) phenoxy] ethanamine (tamoxifen), l- [2- [4- (3,4-dihydro-6-methoxy-2-phenyl-l-naphthalinyl) phenoxy] ethyl] pyrrolidine hydrochloride (Νafoxidin), α . [4- [2- (Diethylamino) ethoxy] phenyl] -4-methoxy-α-phenylbenzenethanol (Mer-25), [6-hydroxy-2- (4-hydroxyphenyl) -3-benzothienyl] [4- [ 2- (l-piperidinyl) ethoxy] phenyl] methanone hydrochloride (Raloxifene), (3R-trflΛs) -3,4-dihydro-2,2-dimethyl-7-methoxy-3-phenyl-4- [4- [ 2- (l-pyrrolidinyl) ethoxy] phenyl] -2H-l-benzopyran (centchroman),
weiter Verbindungen vom 1,1,2-Triphenylbut-l-en-Typ, insbesondere das 3,3'-(2- Phenyl-l-buten-l-yliden)bis[phenol]-diacetat [J. Cancer Res. Clin. Oncol., (1986), 112, S. 119-124];further compounds of the 1,1,2-triphenylbut-1-ene type, in particular the 3,3 '- (2-phenyl-1-buten-1-ylidene) bis [phenol] diacetate [J. Cancer Res. Clin. Oncol., (1986), 112, pp. 119-124];
ferner kommen als steroidale Östrogenantagonisten beispielsweise infrage: 17α-Ethinyl-llα-methylestra-l,3,5(10)-trien-3,17ß-diol und 16ß-Ethylestra-l,3,5(10)-trien- 3,17ß-diol,steroidal estrogen antagonists which may also be used are, for example: 17α-ethynyl-11α-methylestra-1,3,5 (10) -triene-3,17ß-diol and 16ß-ethyltra-1,3,5 (10) -triene-3, 17ß-diol,
N-Butyl-ll-(3,17ß-dihydroxyestra-l,3,5(10)-trien-7α-yl)-N-methylundecansäureamid und 7α-[9-[(4,4,5,5,5-Pentafluorpentyl)sulfinyl]nonyl]estra-l,3,5(10)-trien-3,17ß-diol.N-butyl-ll- (3,17ß-dihydroxyestra-l, 3,5 (10) -trien-7α-yl) -N-methylundecanoic acid amide and 7α- [9 - [(4,4,5,5,5- Pentafluoropentyl) sulfinyl] nonyl] estra-1,3,5 (10) -triene-3,17β-diol.
Erfindungsgemäß bevorzugt sind in jedem Fall solche Östrogenantagonisten, die besonders stark und möglichst selektiv am Endometrium wirken (beispielsweise Tamoxifen, Νafoxidin, 7α-[9-[(4, 4,5,5, 5-Pentafluorpentyl)sulfinyl]nonyl]estra- l,3,5(10)-trien-3,17ß-diol).In any case preferred according to the invention are those estrogen antagonists which act particularly strongly and as selectively as possible on the endometrium (for example tamoxifen, ifenafoxidin, 7α- [9 - [(4, 4,5,5, 5-pentafluoropentyl) sulfinyl] nonyl] estral , 3,5 (10) -triene-3,17β-diol).
Die Schwellendosis für endometriumselektive Wirkung wird an ovarektomierten, estradiolsubstituierten Ratten ermittelt. Als Parameter dient die mitotische Aktivität (Proliferationsmarker: PCΝA). Als Schwellendosis gilt diejeniege Menge des Östrogenantagonisten, bei der nur ein Effekt am Uterus, nämlich eine Hemmung der estrogeninduzierten Proliferation des Endometriums, beobachtet wird.The threshold dose for endometrium-selective action is determined in ovariectomized, estradiol-substituted rats. Mitotic activity serves as a parameter (proliferation marker: PCΝA). The threshold dose is the amount of the estrogen antagonist at which only an effect on the uterus, namely an inhibition of the estrogen-induced proliferation of the endometrium, is observed.
Als Antiöstrogene gemäß vorliegender Erfindung können auch Aromatasehemmer in Verbindung mit Progesteronantagonisten verwendet werden. Aromatasehemmer unterdrücken die Synthese der Ostrogene aus deren Vorstufen. Beispiele für Aromatasehemmer sind Atamestan = l-Methylandrosta-l,4-dien-3,17-dion (DE-A 33 22 285), Pentrozol = 5-[Cyclopentyliden(lH-imidazol-l-yl)methyl]-2- thiophencarbonitril (EP-A 0 411 735) oder 4-(5,6,7,8-Tetrahydroimidazo[l,5- --]pyridin-5-yl)benzonitril-monohydrochlorid (Cancer Res., 48, S. 834-838, 1988). Die Verwendung von Östrogenantagonisten ist aber gegenüber derjenigen von Aromatasehemmern in jedem Fall bevorzugt, da die Östrogenantagonisten die Serum- Östrogenkonzentration nicht beeinflussen und somit eine Beeinträchtigung des Zyklus vermieden wird.Aromatase inhibitors in connection with progesterone antagonists can also be used as anti-estrogens according to the present invention. Aromatase inhibitors suppress the synthesis of estrogens from their precursors. Examples of aromatase inhibitors are atamestane = l-methyllandrosta-1,4-diene-3,17-dione (DE-A 33 22 285), pentrozole = 5- [cyclopentylidene (lH-imidazol-l-yl) methyl] -2- thiophene carbonitrile (EP-A 0 411 735) or 4- (5,6,7,8-tetrahydroimidazo [l, 5- -] pyridin-5-yl) benzonitrile monohydrochloride (Cancer Res., 48, p. 834- 838, 1988). However, the use of estrogen antagonists is preferred over that of aromatase inhibitors in any case, since the estrogen antagonists reduce the serum Do not affect estrogen concentration and thus an impairment of the cycle is avoided.
Eine AÖ-Dosiseinheit enthält 0.01-100 mg Tamoxifen oder eine biologisch äquivalente Menge einer anderen antiöstrogen wirksamen Verbindung.An AÖ dose unit contains 0.01-100 mg tamoxifen or a biologically equivalent amount of another anti-estrogenic compound.
Ihre Formulierung kann analog wie die der Progesteronantagonisten erfolgen.Their formulation can be carried out analogously to that of the progesterone antagonists.
Progesteronantagonistisch- und antiöstrogen wirksame Verbindungen können z. B. lokal, topisch, enteral oder parenteral appliziert werden.Progesterone antagonistic and anti-estrogenic compounds can e.g. B. locally, topically, enterally or parenterally.
Vorzugsweise kommen der Progesteronantagonist und das Antiöstrogen in einer gemeinsamen Dosierungseinheit zur Anwendung.The progesterone antagonist and the anti-estrogen are preferably used in a common dosage unit.
Die nachfolgenden Beispiele dienen der näheren Erläuterung der vorliegenden Erfindung: The following examples serve to explain the present invention in more detail:
Beispiel 1example 1
10,0 mg llß-[4-(Dimethylamino)phenyl]-17α-hydroxy-17ß-(3-hydroxypropyl)-10.0 mg llß- [4- (dimethylamino) phenyl] -17α-hydroxy-17ß- (3-hydroxypropyl) -
13α-estra-4,9-dien-3-on13α-estra-4,9-dien-3-one
140,5 mg Laktose140.5 mg lactose
69,5 mg Maisstärke69.5 mg corn starch
2,5 mg Polyvinylpyrrolidon2.5 mg polyvinyl pyrrolidone
2,0 mg Aerosil2.0 mg Aerosil
0.5 mg Magnesiumstearat0.5 mg magnesium stearate
225,0 mg Gesamtgewicht der Tablette225.0 mg total tablet weight
Beispiel 2Example 2
20,0 mg Tamoxifen (Antiestrogen mit agonistischer Partialwirkung)20.0 mg tamoxifen (antiestrogen with agonistic partial effect)
50,0 mg llß-[4-(Dimethylamino)phenyl]-17α-hydroxy-17ß-(3-hydroxypropyl)-50.0 mg llß- [4- (dimethylamino) phenyl] -17α-hydroxy-17ß- (3-hydroxypropyl) -
13α-estra-4,9-dien-3-on 105,0 mg Laktose 40,0 mg Maisstärke 2,5 mg Poly-N-Vinylpyrrolidon 25 2,0 mg Aerosil 0.5 mg Magnesiumstearat 220,0 mg Gesamtgewicht der Tablette, die in üblicher Weise auf einer13α-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 mg magnesium stearate 220.0 mg total weight of the tablet in the usual way on a
Tablettenpresse hergestellt wird. Gegebenenfalls können auch die erfindungsgemäßen Wirkstoffe mit jeweils der Hälfte der oben angegebenen Zusätze getrennt zu einer Zweischichtentablette gepreßt werden.Tablet press is manufactured. If appropriate, the active compounds according to the invention, each with half of the additives indicated above, can also be pressed separately into a two-layer tablet.
Beispiel 3Example 3
5,0 mg 7α-[9-(4,4,5,5,5-Pentafluorpentylsulfinyl)nonyl]estra-l,3,5(10)-trien- 3,17ß-diol (reines Antiestrogen) 50,0 mg llß-[4-(Dimethylamino)phenyl]-17α-hydroxy-17ß-(3-hydroxypropyl)- 13α-estra-4,9-dien-3-on 110,0 mg Lactose 50,0 mg Maisstärke 2,5 mg Poly-N-Vinylpyrrolidon 25 2,0 mg Aerosil 0.5 mg Magnesiumstearat 220,0 mg Gesamtgewicht der Tablette, die in üblicher Weise auf einer5.0 mg 7α- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -triene-3,17β-diol (pure antiestrogen) 50.0 mg llß- [4- (dimethylamino) phenyl] -17α-hydroxy-17ß- (3-hydroxypropyl) - 13α-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 mg magnesium stearate 220.0 mg total weight of the tablet, which is in the usual way on a
Tablettenpresse hergestellt wird. Gegebenenfalls können auch die erfindungsgemäßen Wirkstoffe mit jeweils der Hälfte der oben angegebenen Zusätze getrennt zu einer Zweischichtentablette gepreßt werden.Tablet press is manufactured. If appropriate, the active compounds according to the invention, each with half of the additives indicated above, can also be pressed separately into a two-layer tablet.
Beispiel 4Example 4
0,5 mg llß-[4-(Dimethylamino)phenyl]-17α-hydroxy-17ß-(3-hydroxypropyl)-0.5 mg llß- [4- (dimethylamino) phenyl] -17α-hydroxy-17ß- (3-hydroxypropyl) -
13α-estra-4,9-dien-3-on13α-estra-4,9-dien-3-one
0,2 mg 7α-[9-(4,4,5,5,5-Pentafluorpentylsulfinyl)-nonyl]-estra-l,3,5(10)-trien-0.2 mg 7α- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -triene-
3,17ß-diol (reines Antiestrogen)3,17ß-diol (pure antiestrogen)
159,5 mg Lactose159.5 mg lactose
54,8 mg Maisstärke54.8 mg corn starch
2,5 mg Poly-N-Vinylpyrrolidon 252.5 mg poly-N-vinylpyrrolidone 25
2,0 mg Aerosil2.0 mg Aerosil
0.5 mg Magnesiumstearat0.5 mg magnesium stearate
220,0 mg Gesamtgewicht der Tablette, die in üblicher Weise auf einer220.0 mg total weight of the tablet in the usual way on one
Tablettenpresse hergestellt wird. Gegebenenfalls können auch die erfindungsgemäßen Wirkstoffe mit jeweils der Hälfte der oben ngegebenen Zusätze getrennt zu einer Zweischichtentablette gepreßt werden. Beispiel 5Tablet press is manufactured. If appropriate, the active compounds according to the invention, each with half of the additives mentioned above, can also be pressed separately into a two-layer tablet. Example 5
Zusammensetzung einer öligen Lösung:Composition of an oily solution:
100,0 mg Tamoxifen 343,4 mg Rizinusöl 608.6 mg Benzylbenzoat 1052,0 mg = 1 ml100.0 mg tamoxifen 343.4 mg castor oil 608.6 mg benzyl benzoate 1052.0 mg = 1 ml
Die Lösung wird in eine Ampulle gefülltThe solution is filled into an ampoule
Beispiel 6Example 6
5,0 mg llß-[4-(Dimethylamino)phenyl]-17ß-hydroxy-17α-(l-propinyl)estra-5.0 mg llß- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (l-propynyl) estra-
4,9-dien-3-on (RU-38486), 10,0 mg (Z)-N,N-Dimethyl-2-[4-(l,2-diphenyl-l-butenyl)phenoxy]ethanamin, (Tamoxifen; Antiestrogen mit agonistischer Partialwirkung) 140,0 mg Laktose 60,5 mg Maisstärke 2,5 mg Poly-Ν-Vinylpyrrolidon 25 2,0 mg Aerosil4,9-dien-3-one (RU-38486), 10.0 mg (Z) -N, N-dimethyl-2- [4- (1,2-diphenyl-l-butenyl) phenoxy] ethanamine, ( Tamoxifen; antiestrogen with agonistic partial effect) 140.0 mg lactose 60.5 mg corn starch 2.5 mg poly-Ν-vinylpyrrolidone 25 2.0 mg Aerosil
220,0 mg Gesamtgewicht der Tablette, die in üblicher Weise auf einer220.0 mg total weight of the tablet in the usual way on one
Tablettenpresse hergestellt wird. Gegebenenfalls können auch die erfindungsgemäßen Wirkstoffe mit jeweils der Hälfte der oben angegebenen Zusätze getrennt zu einer Zweischichtentablette gepreßt werden. Tablet press is manufactured. If appropriate, the active compounds according to the invention, each with half of the additives indicated above, can also be pressed separately into a two-layer tablet.
Pharmakologische BeobachtungenPharmacological observations
Versuch 1:Trial 1:
Die Versuche wurden an intakten Meerschweinchen mit normalem Zyklus durchgeführt. Die Behandlung wurde am Tag 1 post coitum angefangen. Die Tiere wurden über 6 Tage mit Vehikel (Benzylbenzoat/Rizinusöl), bzw. dem Tamoxifen in einer Dosis von 0,3, 1, 3 mg/Tag Tier oder der progesteronantagonistisch wirksamen Verbindung Onapriston (0.3, 1,0, 3,0 mg/Tag/Tier), jeweils alleine, oder mit einer Kombination beider Verbindungen behandelt. Die Substanzen wurden subkutan appliziert. Als Parameter dient die Zahl der Implantationstellen am Tag 12 post coitum.The experiments were carried out on intact guinea pigs with a normal cycle. Treatment started on day 1 post coitum. The animals were treated with vehicle (benzyl benzoate / castor oil) or the tamoxifen in a dose of 0.3, 1, 3 mg / day animal or the progesterone-antagonistically active compound onapristone (0.3, 1.0, 3.0 mg / Day / animal), each alone, or treated with a combination of both compounds. The substances were applied subcutaneously. The number of implantation sites on day 12 post coitum serves as a parameter.
Die Kombination von Schwellendosen beider Komponenten (AG 0,3, 1 mg/ AÖ ca. 0,3, 1 mg) führt zu einer signifikanten Zunahme der Wirksamkeit (100%ige Implantations hemmung bei 1 mg AG + 1 mg AÖ und 1 mg AG + 0,3 mg AÖ) nach sechstägiger Behandlung (Abb. 1). Die synergistische Wirkung beider Komponenten ist nach einer Behandlung über S Tage noch stärker ausgeprägt.The combination of threshold doses of both components (AG 0.3, 1 mg / AÖ approx. 0.3, 1 mg) leads to a significant increase in effectiveness (100% inhibition of implantation with 1 mg AG + 1 mg AÖ and 1 mg AG + 0.3 mg AÖ) after six days of treatment (Fig. 1). The synergistic effect of both components is even more pronounced after treatment over S days.
Versuch 2Trial 2
Die Versuche wurden an intakten Meerschweinchen mit normalem Zyklus durchgeführt. Die Behandlung wurde an Tag 1 p.c. angefangen. Die Tiere (n=6/Gruppe) wurden über 6 Tage mit Vehikel (Benzylbenzoat/Rizinusöl), bzw Tamoxifen/Antigestagen in einer Dosis von 0,3, 1, 3 mg/kg Tier oder der progesteronantagonistisch wirksamen Verbindung (Z)-llß-[4-The experiments were carried out on intact guinea pigs with a normal cycle. Treatment was started on day 1 p.c. started. The animals (n = 6 / group) were treated with vehicle (benzyl benzoate / castor oil) or tamoxifen / antigestagen in a dose of 0.3, 1, 3 mg / kg animal or the progesterone-antagonistically active compound (Z) -llß for 6 days - [4-
(Dimethylamino)phenyl]-17ß-hydroxy-17α-(3-hydroxy-l-propenyl)estr-4-en-3-on jeweils alleine oder mit einer Kombination beider Verbindungen behandelt. Die Substanzen wurden s.c. appliziert. Als Parameter dient die Zahl der nichtgraviden Tiere an Tag 12.(Dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-l-propenyl) estr-4-en-3-one treated individually or with a combination of both compounds. The substances were s.c. applied. The number of non-gravid animals on day 12 serves as a parameter.
Die Kombination von Schwellendosen (0,3 mg (Z)-llß-[4-(Dimethylamino)phenyl]- 17ß-hydroxy-17α-(3-hydroxy-l-propenyl)estr-4-en-3-on (ZK 137.316) + 0,3 mg AÖ) führt zu einer signifikanten Zunahme der Wirksamkeit (ca. 80% Rezeptivitätshemmung, Abb. 2) Versuch 3The combination of threshold doses (0.3 mg (Z) -llß- [4- (dimethylamino) phenyl] - 17ß-hydroxy-17α- (3-hydroxy-l-propenyl) estr-4-en-3-one (ZK 137.316) + 0.3 mg AÖ) leads to a significant increase in effectiveness (approx. 80% receptivity inhibition, Fig. 2) Trial 3
Die Versuche wurden an intakten Meerschweinchen mit normalem Zyklus über einenThe experiments were carried out on intact guinea pigs with a normal cycle over one
Behandlungszeitraum von 2 Zyklen durchgeführt. Die Anpaarung fand im zweitenTreatment period of 2 cycles carried out. The mating took place in the second
Zyklus statt.Cycle instead.
Dosen von Onapriston: 0,1, 0,25, 0,5, 1,0 und 3,0 mg täglich s.c.Doses of onapristone: 0.1, 0.25, 0.5, 1.0 and 3.0 mg daily SC
Dosen von Tamoxifen: 0,1, 0,25, 0,5, 1,0, 3,0 und 10,0 mg täglich s.c.Doses of tamoxifen: 0.1, 0.25, 0.5, 1.0, 3.0 and 10.0 mg daily SC
Die Kombination jeweils nur marginal wirksamer Einzeldosen (Onapriston 0,5 mg;The combination of only marginally effective single doses (onapristone 0.5 mg;
Tamoxifen 0,5 mg) führt zu einer deutlichen Wirkungsverstärkung (Synergismus).Tamoxifen 0.5 mg) leads to a significant increase in effectiveness (synergism).
Nur bei Verwendung einer Kombination im Sinne vorliegender Erfindung läßt sich eine vollständige Vermeidung von Schwangerschaften erzielen. In dem genanntenA complete avoidance of pregnancies can only be achieved when using a combination in the sense of the present invention. In the above
Dosisbereich von Tamoxifen (0,1 - 10,0 mg/Tier) konnte keine vollständigeDose range of tamoxifen (0.1-10.0 mg / animal) could not be complete
Hemmung der Rezeptivität erreicht werden. Normale Schwangerschaften wurden beiInhibition of receptivity can be achieved. Normal pregnancies have been reported
30% (10,0 mg) und 90% bis 100% (<1,0 mg) beobachtet. Auch nach der Behandlung mit hohen Onapriston-Dosen sind gelegentlich Schwangerschaften aufgetreten.30% (10.0 mg) and 90% to 100% (<1.0 mg) observed. Pregnancy has occasionally occurred even after treatment with high doses of onapristone.
Nach einer Kombinationsbehandlung mit Onapriston und Tamoxifen (jeweils 1,0 mg) wird in allen Fällen eine vollständige Hemmung der Rezeptivität beobachtet. 100%igeAfter combination treatment with onapristone and tamoxifen (1.0 mg each), complete inhibition of receptivity is observed in all cases. 100%
Rezeptivitätshemmung bedeutet eine vollständige Vermeidung vonReceptivity inhibition means a complete avoidance of
Schwangerschaften.Pregnancies.
Bei niedrigeren Dosen von Tamoxifen und Onapriston (<1,0 mg), die alleine keine bzw. eine marginale Wirkung aufweisen, lag die Rezeptivitätshemmrate bei 80% bisAt lower doses of tamoxifen and onapristone (<1.0 mg), which alone had no or only marginal effects, the receptivity inhibition rate was 80% to
100% aller Tiere. 100% of all animals.

Claims

Patentansprüche claims
1. Verwendung mindestens einer Verbindung mit progesteronantagonistischer (PA) und mindestens einer Verbindung mit antiöstrogener (AÖ) Wirkung, jeweils in nicht- ovulationshemmender Dosierung in einer einzelnen Dosiseinheit, zur Herstellung von Arzneimitteln zur weiblichen Kontrazeption.1. Use of at least one compound with progesterone-antagonistic (PA) and at least one compound with anti-estrogenic (AÖ) action, in each case in non-ovulation-inhibiting dosage in a single dose unit, for the production of medicaments for female contraception.
2. Verwendung mindestens eines kompetitiven Progesteronantagonisten und eines Antiöstrogens nach Anspruch 1 zur Herstellung eines Arzneimittels zur postkoitaler weiblichen Fertilitätskontrolle in einer einmalig zu verabreichenden Dosiseinheit.2. Use of at least one competitive progesterone antagonist and an anti-estrogen according to claim 1 for the manufacture of a medicament for post-coital female fertility control in a single dose unit to be administered.
3. Verwendung mindestens eines kompetitiven Progesteronantagonisten und eines Antiöstrogens nach Anspruch 1 zur Herstellung eines Arzneimittels zur bedarfsorientierten weiblichen Fertilitätskontrolle, welches unabhängig vom Zeitpunkt des Menstruationszyklus angewandt werden kann, in einer einmalig zu verabreichenden Dosiseinheit.3. Use of at least one competitive progesterone antagonist and an anti-estrogen according to claim 1 for the manufacture of a medicament for need-based female fertility control, which can be used regardless of the time of the menstrual cycle, in a single dose unit to be administered.
4. Verwendung nach einem der Ansprüche 1-3, dadurch gekennzeichnet, daß der kompetitive Progesteronantagonist aus der Gruppe der folgenden Verbindungen ausgewählt ist: llß-[4-(Dimethylamino)phenyl]-17α-hydroxy-17ß-(3-hydroxypropyl)-13α-estra-4,9-dien-3- on,4. Use according to any one of claims 1-3, characterized in that the competitive progesterone antagonist is selected from the group of the following compounds: IIß- [4- (dimethylamino) phenyl] -17α-hydroxy-17ß- (3-hydroxypropyl) - 13α-estra-4,9-dien-3-one,
(Z)-llß-(4-Acetylphenyl)-17ß-hydroxy-17α-(3-hydroxy-l-propenyl)estra-4,9-dien-3-on, (Z)-6'-(4-Cyanphenyl)-9,llα-dihydro-17ß-hydroxy-17α-(3-hydroxy-l-propenyl)-4'H- naphth[3',2',l':10,9,ll]estra-4,9(ll)-dien-3-on,(Z) -llß- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxy-l-propenyl) estra-4,9-dien-3-one, (Z) -6 '- (4-cyanophenyl ) -9, llα-dihydro-17ß-hydroxy-17α- (3-hydroxy-l-propenyl) -4'H-naphth [3 ', 2', l ': 10.9, ll] estra-4.9 (ll) -dien-3-one,
(Z)-9,llα-Dihydro-17ß-hydroxy-17α-(3-hydroxy-l-propenyl)-6'-(3-pyridinyl)-4'H- naphth[3',2',l,:10,9,ll]estra-4,9(ll)-dien-3-on,(Z) -9, llα-dihydro-17-hydroxy-17α- (3-hydroxy-l-propenyl) -6 '- (3-pyridinyl) -4'H- naphth [3', 2 ', l,: 10.9, ll] estra-4.9 (ll) -dien-3-one,
17α-Ηydroxy-17ß-(3-hydroxypropyl)-llß-[4-(l-methylethenyl)phenyl]-13α-estra-4,9-dien- 3-on,17α-hydroxy-17ß- (3-hydroxypropyl) -llß- [4- (l-methylethenyl) phenyl] -13α-estra-4,9-diene-3-one,
Hß-[4-(3-Furanyl)phenyl]-l7α-hydroxy-17ß-(3-hydroxypropyl)-13α-estra-4,9-dien-3-on (Z)-llß-[4-(Dimethylamino)phenyl]-17ß-hydroxy-17α-(3-hydroxy-l-propenyl)estr-4-en-3- on,Hß- [4- (3-furanyl) phenyl] -l7α-hydroxy-17ß- (3-hydroxypropyl) -13α-estra-4,9-dien-3-one (Z) -llß- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-l-propenyl) estr-4-en-3-one,
(E)-llß-[4-[[(Acetyloxy)imino]methyl]phenyl]-17ß-methoxy-17α-(methoxymethyl)estra- 4,9-dien-3-on, (E)-llß-[4-[[[(Ethoxycarbonyl)oxy]imino]methyl]phenyl]-17ß-methoxy-17α- (methoxymethyl)estra-4,9-dien-3-on,(E) -llß- [4 - [[(acetyloxy) imino] methyl] phenyl] -17ß-methoxy-17α- (methoxymethyl) estra- 4,9-dien-3-one, (E) -llß- [4 - [[[(ethoxycarbonyl) oxy] imino] methyl] phenyl] -17ß-methoxy-17α- (methoxymethyl) estra-4,9-dien-3-one,
5. Verwendung nach einem der Ansprüche 1-4, dadurch gekennzeichnet, daß die Verbindung mit antiöstrogener Wirkung ein Ostrogenantagonist ist.5. Use according to any one of claims 1-4, characterized in that the compound having an anti-estrogenic effect is an estrogen antagonist.
6. Verwendung nach Anspruch 5, dadurch gekennzeichnet, daß der Ostrogenantagonist aus der Gruppe der folgenden Verbindungen ausgewählt ist: (Z)-NN-Dimethyl-2-[4-(l,2-diphenyl-l-butenyl)phenoxy]ethanamin, l-[2-[4-(3,4-Dihydro-6-methoxy-2-phenyl-l-naphthalinyl)phenoxy]ethyl]pyrrolidin- hydrochlorid,6. Use according to claim 5, characterized in that the estrogen antagonist is selected from the group of the following compounds: (Z) -NN-dimethyl-2- [4- (1,2-diphenyl-l-butenyl) phenoxy] ethanamine, 1- [2- [4- (3,4-dihydro-6-methoxy-2-phenyl-l-naphthalinyl) phenoxy] ethyl] pyrrolidine hydrochloride,
[6-Hydroxy-2-(4-hydroxyphenyl)-3-benzothienyl][4-[2-(l- piperidinyl)ethoxy]phenyl]methanon-hydrochlorid (Raloxifen),[6-hydroxy-2- (4-hydroxyphenyl) -3-benzothienyl] [4- [2- (l-piperidinyl) ethoxy] phenyl] methanone hydrochloride (raloxifene),
N-Butyl-ll-(3,17ß-dihydroxyestra-l,3,5(10)-trien-7α-yl)-N-methylundecansäureamid, 7α-[9-[(4,4,5,5,5-Pentafluorpentyl)sulfinyl]nonyl]estra-l,3,5(10)-trien-3,17ß-diol.N-Butyl-ll- (3,17ß-dihydroxyestra-l, 3,5 (10) -trien-7α-yl) -N-methylundecanoic acid amide, 7α- [9 - [(4,4,5,5,5- Pentafluoropentyl) sulfinyl] nonyl] estra-1,3,5 (10) -triene-3,17β-diol.
7. Verwendung von (Z)-llß-[4-(Dimethylamino)phenyl]-17ß-hydroxy-17α-(3-hydroxy-l- propenyl)estr-4-en-3-on als PA und (Z)-NN-Dimethyl-2-[4-(l,2-diphenyl-l- butenyl)phenoxy]ethanamin als AÖ nach einem der Ansprüche 1-3.7. Use of (Z) -llß- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-l-propenyl) estr-4-en-3-one as PA and (Z) - NN-dimethyl-2- [4- (1,2-diphenyl-1-butenyl) phenoxy] ethanamine as AÖ according to any one of claims 1-3.
8. Verwendung nach einem der Ansprüche 1-3, dadurch gekennzeichnet, daß der kompetitive Progesteronantagonist und das Antiöstrogen in dem Arzneimittel zur Applikation in lokaler, topischer, enteraler oder parenteraler Weise hergerichtet ist. 8. Use according to any one of claims 1-3, characterized in that the competitive progesterone antagonist and the anti-estrogen in the medicament is prepared for application in a local, topical, enteral or parenteral manner.
EP95943194A 1994-12-23 1995-12-23 Compounds with progesterone-antagonistic and anti-oestrogen properties intended for combined use in female contraception Withdrawn EP0799042A1 (en)

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