WO1995005828A1 - Progesterone-antagonistic and anti-oestrogen compounds for the therapy of leiomyomata uteri - Google Patents

Progesterone-antagonistic and anti-oestrogen compounds for the therapy of leiomyomata uteri Download PDF

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Publication number
WO1995005828A1
WO1995005828A1 PCT/EP1994/002854 EP9402854W WO9505828A1 WO 1995005828 A1 WO1995005828 A1 WO 1995005828A1 EP 9402854 W EP9402854 W EP 9402854W WO 9505828 A1 WO9505828 A1 WO 9505828A1
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progesterone
compound
methyl
hydroxy
antagonistic
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PCT/EP1994/002854
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German (de)
French (fr)
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Klaus Stöckemann
Kristof Chwalisz
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Schering Aktiengesellschaft
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Priority to AU76917/94A priority Critical patent/AU7691794A/en
Publication of WO1995005828A1 publication Critical patent/WO1995005828A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • Progesterone antagonistic and anti-estrogenic compounds for the treatment of Leiomyomata uteri
  • 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 for the production of medicaments for the treatment of Leiomyomata uteri (uterine fibroid)
  • PA progesterone-antagonistic
  • a ⁇ anti-estrogenic
  • Leiomyomata uteri is a benign tumor of the myometrium that occurs with a frequency of 15 to 25% in women over 30 years of age. 20 to 50% of women with fibroids show related symptoms, such as changed menstrual bleeding behavior and depending on the size of the fibroid or uterus, pain. In addition to the possible influence of fibroids on fertility, fibroids represent a risk for a successful pregnancy that should not be underestimated. The increased risk of premature birth has been described in women with fibroids (Buttram VC and Reiter RC (1981): Uterine leiomyomata: Etiology, sympathomatology and management; Fert.
  • Hysterectomy is the most commonly used therapy (National Center of Health Statistics (1987): Hysterectomy in the United States 1965-1984; National Health Survey Series 13, No. 12 Publications (PHS): 88-1753). In women who have not yet completed their family planning, a myomectomy has usually been performed so far. However, this therapy also contains risks that should not be underestimated (Stovall TG (1992): Abdominal and vaginal hysterectomy for uterine myomas: Surgery combined with medical treatment; Seminars in Reproductive Endocrinology, 10/4: 385-389). So far, there is no established and validated drug therapy for fibroids. However, such therapy is urgently needed to enable women who have not yet completed their family planning or women who are excluded from surgery for medical reasons to become pregnant at a later date. In addition, the risk usually associated with surgery would be avoidable.
  • Drug treatment is currently limited to preoperative methods (before the myomectomy), such as with gonadotropin-releasing hormones (Lumsden MA and Baird DT (1987): Goserelin therapy before surgery for uterine fibroids; Lancet, 1: 36-37). This treatment is said to facilitate surgery (myomectomy) and reduce the amount of bleeding during surgery.
  • Progesterone antagonists represent a new medicinal approach.
  • First clinical studies (Murphy AA et al. (1993): Regression of uterine leiomyomata in response to the antiprogestin RU 486; J. Clin. Endocrinol. Metab., 76/2: 513 -517; Murphy AA et al. (1991): Response of uterine fibroids to the antiprogestin RU 486: A pilot study; AFS meting 1991, Abstract 0071; Murphy AA et al.
  • the invention has for its object to provide a medicament for the indicated indication, which does not have the above-mentioned undesirable effect or only has it to a small extent, at the same time has a high, possibly higher, effectiveness in comparison with the agents already known for the treatment of myomas and in the sense the undesirable effect of long-term treatment, has a protective function (has a protective effect on the endometrium).
  • the medicaments produced according to the invention are therefore highly suitable for preoperative use (before a myomectomy) and for long-term treatment of Leiomoymata uteri, since, due to the progesterone dependency, the PA component leads to an inhibition of the growth of the fibroids and with a combination with an anti-estrogen, the anti-estrogenic component has a protective function on the endometrium.
  • these drugs can thus be used continuously or intermittently as long-term therapy.
  • progesterone-antagonistically active compounds in combination with anti-estrogenic compounds can be used for the production of medicaments for induction of birth, for the termination of pregnancy and for the treatment of gynecological disorders (dysmenorrhea and endometriosis).
  • 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 and / or sequentially, 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. In the case of sequential administration, the second compound given can be given at any time after the first compound is administered, as long as it becomes bioavailable in the patient at the same time as an effective amount of the compound first applied. For example, the A ⁇ can be given from the 2nd day after the application of PA, whereby both PA and A ⁇ can then be applied from the 3rd day.
  • PA and A ⁇ can preferably be applied in combination in one dose unit. In general, a single daily application of the two components is sufficient.
  • the duration of treatment with the medicament according to the invention can, for example, in the preparative application. B. once or twice a day over a longer period, for example 3 to 4 months.
  • Chronic treatment can also be carried out intermittently, i.e. a longer period of time in which the components are applied is followed by a shorter break from taking the tablets; For example, treatment is given for 3 to 6 months, followed by an approximately 2-month break in medication.
  • 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.
  • steroids are suitable: IIß - [(4-N, N-Dimethylamino) -phenyl] -17ß-hydroxy-17 ⁇ -propinyl-4,9 (10) -estradien-3-one
  • Some of the above-mentioned PA are those 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.
  • 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.
  • 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 11 ⁇ - [(4-N, N-dimethylamino) phenyl] -17 ⁇ -hydroxy-17ß- (3-hydroxypropyl) -13 ⁇ -methyl-4.9 (10) -gonadiene -3-one or a biologically equivalent amount of another competitive progesterone antagonist.
  • 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 ovulation-inhibiting or in the non-ovulation-inhibiting and non-abortion-triggering dose range of the progesterone antagonist in question.
  • anti-estrogenic compounds include both competitive anti-estrogens and aromatase inhibitors infirage.
  • Anti-estrogens and aromatase inhibitors according to the present invention can either be derived from steroids or non-steroidal compounds.
  • Anti-estrogenic compounds 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 anti-estrogens act as competitive estrogen antagonists by displacing estrogen from the receptor, while aromatase inhibitors suppress the biosynthesis of the estrogen.
  • Compounds of the aminoglutethimide type, ie 3- (4-aminophenyl) piperidine-2,6-diones alkylated in the 3-position and others which, in addition to the estrogen level, also reduce other sex hormone serum concentrations act, are not suitable as anti-estrogenic compounds according to the present invention.
  • anti-estrogens can be considered as anti-estrogens. They can be used in approximately the same amounts as the anti-estrogens already on the market, i.e. the daily dose is about 5-100 mg for tamoxifen or biologically equivalent amounts of another anti-estrogen.
  • non-steroidal anti-estrogens are:
  • Mer 25 l- [p- (2-diethylaminoethoxy) phenyl] -2- (p-methoxyphenyl) -l-phenylethanol
  • Raloxifene 6-hydroxy-2- (p-hydroxyphenyl) benzo [b] thien-3-yl-p- (2-piperidinoethoxy) phenyl ketone, hydrochloride
  • Suitable as aromatase inhibitors are all compounds which come as a substrate for the aromatase, such as, for example, the 1-methyl-androsta-1,4-diene-3J7-dione described in German Offenlegungsschrift 33 22 285, which is published in the Journal of Clinical Endocrinology and Metabolism. 49, 672 (1979)
  • non-steroidal aromatase inhibitors are [4- (5,6,7,8-tetrahydroimidazo [1,5a] -pyridin-5-yl) benzometril-mono-hydrochloride] (Cancer Res., 48, pp. 834-838 , 1988) and the cycloalkylenazoles described in EP-A-0 411 735.
  • Progesterone antagonistic and anti-estrogenic compounds can e.g. B. locally, topically, enterally or parenterally.
  • An A ⁇ dose unit contains 1-100 mg tamoxifen or 10-200 mg 1-methyl-androstal, 4-diene-3,17-dione or a biologically equivalent amount of another anti-estrogenic compound.
  • Substances, each with half of the additives specified above, are pressed separately into a two-layer tablet.
  • the solution is filled into an ampoule
  • the solution is filled into an ampoule.
  • the active compounds according to the invention can also be filled separately in two chambers with half of the additives specified above.
  • the experiments are carried out on intact rats with a normal cycle.
  • the animals are treated with vehicle (benzyl benzoate / castor oil), the anti-estrogen tamoxifen (0.2 mg / day / animal) or the progesterone-antagonistic compound llß - [(4-N, N-dimethylamino) -phenyl] -17 ⁇ -hydroxy- for 8 weeks.
  • 17ß- (3-hydroxypropyl) -13 ⁇ -methyl-4,9-gonadien-3-one (2.0 mg day / animal) treated individually or in a combination of both compounds.
  • the substances are applied subcutaneously.
  • the weight and morphology of the uterus serve as parameters.
  • PA Progesterone Antagonistic Compound

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Abstract

At least one compound with a progesterone-antagonistic (PA) activity and at least one compound with an anti-oestrogen (AO) activity are used to prepare medicaments for the therapy of leiomyomata uteri (myoma of the uterus). When PA and AO are used in combination, the stimulation of the epithelium in the endometrium caused when only a progesterone-antagonistic compound is used is largely inhibited by the compound with anti-oestrogen activity.

Description

Progesteronantagonistisch- und antiöstrogen wirksame Verbindungen für die Behandlung des Leiomyomata uteri Progesterone antagonistic and anti-estrogenic compounds for the treatment of Leiomyomata uteri
Die vorliegende Erfindung betrifft die Verwendung mindestens einer Verbindung mit progesteronantagonistischer (PA) und mindestens einer Verbindung mit antiöstrogener (AÖ) Wirkung zur Herstellung von Arzneimitteln zur Behandlung des Leiomyomata uteri (Uterines Myom)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 for the production of medicaments for the treatment of Leiomyomata uteri (uterine fibroid)
Beim Leiomyomata uteri (Myom) handelt es sich um einen gutartigen Tumor des Myometriums, der mit einer Häufigkeit von 15 bis 25 % bei Frauen über 30 Jahren auftritt. 20 bis 50 % der Frauen mit Myomen zeigen damit verbundene Symptome, wie z.B. verändertes menstraelles Blutungsverhalten und abhängig von der Größe des Myoms bzw. Uterus, Schmerzen. Neben dem möglichen Einfluß von Myomen auf die Fertilität, stellen Myome ein nicht zu unterschätzendes Risiko für eine erfolgreiche Schwangerschaft dar. Die erhöhte Gefahr einer Frühgeburt ist bei Frauen mit Myomen beschrieben worden (Buttram VC and Reiter RC (1981): Uterine leiomyomata: Etiology, sympathomatology and management; Fert. Steril., 36: 433-445; Rossi G and Diamond MP (1992): Myomas, reproductive unction, and pregnancy; Seminars in Reproductive Endocrinology, 10/4: 332-338; Katz VL. et al. (1989): Complications of uterine leiomyomas in pregnancy; Obstet. Gynecol., 73: 593-596).Leiomyomata uteri (fibroid) is a benign tumor of the myometrium that occurs with a frequency of 15 to 25% in women over 30 years of age. 20 to 50% of women with fibroids show related symptoms, such as changed menstrual bleeding behavior and depending on the size of the fibroid or uterus, pain. In addition to the possible influence of fibroids on fertility, fibroids represent a risk for a successful pregnancy that should not be underestimated. The increased risk of premature birth has been described in women with fibroids (Buttram VC and Reiter RC (1981): Uterine leiomyomata: Etiology, sympathomatology and management; Fert. Steril., 36: 433-445; Rossi G and Diamond MP (1992): Myomas, reproductive unction, and pregnancy; Seminars in Reproductive Endocrinology, 10/4: 332-338; Katz VL. et al . (1989): Complications of uterine leiomyomas in pregnancy; Obstet. Gynecol., 73: 593-596).
Hysterektomie stellt die am häufigsten angewandte Therapiemethode dar (National Center of Health Statistics (1987): Hysterectomy in the United States 1965-1984; National Health Survey Series 13, No. 12 Publications (PHS): 88-1753). Bei Frauen, die ihre Familien¬ planung noch nicht abgeschlossen haben, wird bisher in der Regel eine Myomektomie durchgeführt. Jedoch auch diese Therapie beinhaltet nicht zu unterschätzende Risiken (Stovall TG (1992): Abdominal and vaginal hysterectomy for uterine myomas: Surgery combined with medical treatment; Seminars in Reproductive Endocrinology, 10/4: 385- 389). Bisher existiert keine etablierte und validierte medikamentöse Therapie für Myome. Eine solche Therapie ist jedoch dringend notwendig, um Frauen, die ihre Familienplanung noch nicht abgeschlossen haben, oder Frauen, bei denen eine Operation aus medizinischen Gründen ausgeschlossen ist, die Möglichkeit zu geben, zu einem späteren Zeitpunkt schwanger zu werden. Zusätzlich wäre das mit einer Operation in der Regel verbundene Risiko vermeidbar.Hysterectomy is the most commonly used therapy (National Center of Health Statistics (1987): Hysterectomy in the United States 1965-1984; National Health Survey Series 13, No. 12 Publications (PHS): 88-1753). In women who have not yet completed their family planning, a myomectomy has usually been performed so far. However, this therapy also contains risks that should not be underestimated (Stovall TG (1992): Abdominal and vaginal hysterectomy for uterine myomas: Surgery combined with medical treatment; Seminars in Reproductive Endocrinology, 10/4: 385-389). So far, there is no established and validated drug therapy for fibroids. However, such therapy is urgently needed to enable women who have not yet completed their family planning or women who are excluded from surgery for medical reasons to become pregnant at a later date. In addition, the risk usually associated with surgery would be avoidable.
Die medikamentöse Behandlung beschränkt sich zur Zeit auf präoperative Methoden (vor der Myomektomie), wie z.B. mit Gonadotropin-Releasing-Hormonen (Lumsden MA and Baird DT (1987): Goserelin therapy before surgery for uterine fibroids; Lancet, 1: 36-37). Diese Behandlung soll die Operation (Myomektomie) erleichtern und das Ausmaß der Blutungen während der Operation verringern.Drug treatment is currently limited to preoperative methods (before the myomectomy), such as with gonadotropin-releasing hormones (Lumsden MA and Baird DT (1987): Goserelin therapy before surgery for uterine fibroids; Lancet, 1: 36-37). This treatment is said to facilitate surgery (myomectomy) and reduce the amount of bleeding during surgery.
Einen neuen medikamentösen Ansatz stellen Progesteronantagonisten (Antigestagene) dar. Erste klinische Studien (Murphy AA et al. (1993): Regression of uterine leiomyomata in response of the antiprogestin RU 486; J. Clin. Endocrinol. Metab., 76/2: 513-517; Murphy AA et al. (1991): Response of uterine fibroids to the antiprogestin RU 486: A pilot study; AFS meting 1991, Abstract 0071; Murphy AA et al. (1993): Regression of uterine leiomyomata to the antoprogesterone RU 486: Dose response effect; SGI meeting 1993, Abstract P-89) haben gezeigt, daß eine dreimonatige Behandlung mit einem Progesteron- Antagonisten zu einer 50%igen Reduktion der Myome führt. Voraussetzung für die Wirksamkeit ist die Progesteronabhängigkeit des Myomwachstums. Neben der zentralen Rolle des Progesterons beim Myomwachstum spielen auch Östrogene eine wichtige Rolle (Mitchell SR and Nowak A (1992): Biology of uterine myomas and myometrium in vitro; Seminars in Reproductive Endocrinology, 10/4: 310-319; Kawaguchi K et al. (1989): Mitotic activity in uterine leiomyomas during the menstrual cycle; Am. J. Obstet. Gynecol., 160: 637-641). Trotz der wachstumsinhibierenden Wirkung des Progesteron¬ antagonisten auf das Myom kommt es zu einer unerwünschten Stimulation des Epithels im Endometrium (Murphy AA et al. (1993): Endometrial effect of long teπn, low-dose administration of RU 486 in cycling women; SGI meeting 1993, Abstract S-138), möglicherweise verursacht durch den sogenannten "unopposed estrogen". Dies könnte für eine Langzeit-Behandlung mit Progesteronantagonisten alleine unter Umständen ein Risiko (chronische Stimulation → Risiko oder Entstehung eines Endometrium-Karcinoms) darstellen bzw. eine Präparateentwicklung verhindern.Progesterone antagonists (antigestagens) represent a new medicinal approach. First clinical studies (Murphy AA et al. (1993): Regression of uterine leiomyomata in response to the antiprogestin RU 486; J. Clin. Endocrinol. Metab., 76/2: 513 -517; Murphy AA et al. (1991): Response of uterine fibroids to the antiprogestin RU 486: A pilot study; AFS meting 1991, Abstract 0071; Murphy AA et al. (1993): Regression of uterine leiomyomata to the antoprogesterone RU 486: Dose response effect; SGI meeting 1993, abstract P-89) have shown that a three-month treatment with a progesterone antagonist leads to a 50% reduction in fibroids. Progesterone-dependent fibroid growth is a prerequisite for effectiveness. In addition to the central role of progesterone in fibroid growth, estrogens also play an important role (Mitchell SR and Nowak A (1992): Biology of uterine myomas and myometrium in vitro; Seminars in Reproductive Endocrinology, 10/4: 310-319; Kawaguchi K et al . (1989): Mitotic activity in uterine leiomyomas during the menstrual cycle; Am. J. Obstet. Gynecol., 160: 637-641). Despite the growth-inhibiting effect of the progesterone antagonist on the fibroid, there is an undesirable stimulation of the epithelium in the endometrium (Murphy AA et al. (1993): Endometrial effect of long teπn, low-dose administration of RU 486 in cycling women; SGI meeting 1993, abstract S-138), possibly caused by the so-called "unopposed estrogen". For long-term treatment with progesterone antagonists alone, this could possibly represent a risk (chronic stimulation → risk or development of endometrial carcinoma) or prevent the development of preparations.
Der Erfindung liegt die Aufgabe zugrunde, ein Arzneimittel für die angegebene Indikation bereitzustellen, welches die oben genannte unerwünschte Wirkung nicht oder nur in geringem Maße aufweist, gleichzeitig eine hohe, möglichst höhere Wirksamkeit im Vergleich zu den für die Myombehandlung bereits bekannten Mitteln hat und im Sinne der unerwünschten Wirkung bei einer Langzeit-Behandlung, eine Schutzfunktion ausübt (protektiv auf das Endometrium wirkt).The invention has for its object to provide a medicament for the indicated indication, which does not have the above-mentioned undesirable effect or only has it to a small extent, at the same time has a high, possibly higher, effectiveness in comparison with the agents already known for the treatment of myomas and in the sense the undesirable effect of long-term treatment, has a protective function (has a protective effect on the endometrium).
Diese Aufgabe wird durch die Erfindung gelöst. Es wurde gefunden, daß durch die kombinierte Verwendung von PA und AÖ die durch die PA-Komponente unerwünscht induzierte Stimulation des Endometriums im Uterus durch die Kombination mit einem AÖ inhibiert wird. Es konnte gezeigt werden, daß sich durch die erfindungsgemäß hergestellten Arzneimittel die Wirkungen von PA und AÖ (Abnahme des Uterusgewichtes bzw. -volumens) leicht verstärken und gleichzeitig den durch die PA- Komponente verursachten unerwünschten Effekt, im Sinne einer Schutzfunktion, unterbinden.This object is achieved by the invention. It was found that the combined use of PA and AÖ inhibited the stimulation of the endometrium in the uterus, which was undesirably induced by the PA component, by the combination with an AÖ. It could be shown that the medicaments produced according to the invention slightly increase the effects of PA and AÖ (decrease in uterine weight or volume) and at the same time prevent the undesired effect caused by the PA component, in the sense of a protective function.
Die erfindungsgemäß hergestellten Arzneimittel sind somit für den präoperativen Einsatz (vor einer Myomektomie) sowie bei der Langzeit-Behandlung des Leiomoymata uteri in hohem Maße geeignet, da, durch die Progesteronabhängigkeit bedingt, die PA- Komponente zu einer Wachstumshemmung der Myome führt und bei einer Kombination mit einem Antiöstrogen die antiöstrogene Komponente eine Schutzfunktion auf das Endometrium ausübt.The medicaments produced according to the invention are therefore highly suitable for preoperative use (before a myomectomy) and for long-term treatment of Leiomoymata uteri, since, due to the progesterone dependency, the PA component leads to an inhibition of the growth of the fibroids and with a combination with an anti-estrogen, the anti-estrogenic component has a protective function on the endometrium.
Neben einer präoperativen Anwendung können diese Arzneimittel somit als Langzeit- Therapie kontinuierlich oder intermittierend gegeben angewendet werden.In addition to preoperative use, these drugs can thus be used continuously or intermittently as long-term therapy.
Daß progesteronantagonistisch wirksame Verbindungen in Kombination mit antiöstrogen wirksamen Verbindungen zur Herstellung von Arzneimitteln zur Geburtseinleitung, zum Schwangerschaftsabbruch sowie zur Behandlung gynäkologischer Störungen (Dysmen- norrhoe und Endometriose) verwendet werden können, ist bereits aus der EP-A-0 310 541 bekannt.It is already known from EP-A-0 310 541 that progesterone-antagonistically active compounds in combination with anti-estrogenic compounds can be used for the production of medicaments for induction of birth, for the termination of pregnancy and for the treatment of gynecological disorders (dysmenorrhea and endometriosis).
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 und/oder zeitlich abgestuft (sequential), 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. Im Falle der sequentiellen Gabe kann die als zweite gegebene Verbindung zu jeder Zeit nach Gabe der zuerst applizierten Verbindung gegeben werden, solange sie noch in der Patientin gleichzeitig mit einer wirksamen Menge der zuerst applizierten Verbindung bioverfügbar wird. Beispielsweise kann das AÖ ab dem 2. Tag nach der Applikation von PA gegeben werden, wobei ab dem 3. Tag dann sowohl PA als auch AÖ appliziert werden können.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 and / or sequentially, 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. In the case of sequential administration, the second compound given can be given at any time after the first compound is administered, as long as it becomes bioavailable in the patient at the same time as an effective amount of the compound first applied. For example, the AÖ can be given from the 2nd day after the application of PA, whereby both PA and AÖ can then be applied from the 3rd day.
Vorzugsweise können PA und AÖ kombiniert in einer Dosiseinheit appliziert werden. Im allgemeinen ist eine einmalige tägliche Applikation der beiden Komponenten ausreichend.PA and AÖ can preferably be applied in combination in one dose unit. In general, a single daily application of the two components is sufficient.
Die Dauer der Behandlung mit dem erfindungsgemäßen Arzneimittel kann bei der prä- oparativen Anwendung z. B. einmal oder zweimal täglich über einen längeren Zeitraum, beispielsweise 3 bis 4 Monate lang, erfolgen.The duration of treatment with the medicament according to the invention can, for example, in the preparative application. B. once or twice a day over a longer period, for example 3 to 4 months.
Im Falle der chronischen Behandlung von Myomen kann die Behandlung bis zurIn the case of chronic fibroid treatment, treatment can be extended to
Menopause fortgesetzt werden. Mit dem Nachlassen der Progesteron- und Östrogen- produktion in der Menopause hört das Wachstum der Myome auf.Menopause to be continued. With the decline in progesterone and estrogen production in the menopause, the growth of the fibroids stops.
Eine chronische Behandlung kann auch intermittierend durchgeführt werden, d.h. an einen längeren Zeitraum, in dem die Komponenten appliziert werden, schließt sich jeweils eine kürzere Einnahmepause an; beispielsweise wird 3 bis 6 Monate lang behandelt, woran sich eine ungefähr 2 monatige Einnahmepause anschließt.Chronic treatment can also be carried out intermittently, i.e. a longer period of time in which the components are applied is followed by a shorter break from taking the tablets; For example, treatment is given for 3 to 6 months, followed by an approximately 2-month break in medication.
Auch andere Einnahmeschemata sind denkbar (z. B. 3 Monate Behandlung, 9 MonateOther dosage regimens are also conceivable (e.g. 3 months of treatment, 9 months
Pause).Break).
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.
Beispielsweise kommen folgende Steroide infrage: llß-[(4-N,N-Dimethylamino)-phenyl]-17ß-hydroxy-17α-propinyl-4,9(10)-estradien-3-onFor example, the following steroids are suitable: IIß - [(4-N, N-Dimethylamino) -phenyl] -17ß-hydroxy-17α-propinyl-4,9 (10) -estradien-3-one
(RU-38486), llß-[(4-N,N-Dimethylamino)-phenyl]-17ß-hydroxy-18-methyl-17α-propinyl-4,9(10)- estradien-3-on und llß-[(4-N,N-Dimethylamino)-phenyl]-17aß-hydroxy-17aα-propinyl-D-homo-4,9(10)J6- estratrien-3-on (alle EP-A-0 057 115), ferner llß-p-Methoxyphenyl-17ß-hydroxy-17α-ethinyl-4,9(10)-estradien-3-on(RU-38486), llß - [(4-N, N-dimethylamino) phenyl] -17ß-hydroxy-18-methyl-17α-propinyl-4.9 (10) - estradien-3-one and llß- [ (4-N, N-dimethylamino) phenyl] -17ass-hydroxy-17aα-propynyl-D-homo-4,9 (10) J6-estratrien-3-one (all EP-A-0 057 115), further llß-p-methoxyphenyl-17ß-hydroxy-17α-ethynyl-4,9 (10) -estradien-3-one
(Steroids 37 (1981), 361-382), llß-(4-Acetylphenyl)-17ß-hydroxy-17α-(prop-l-inyl)-4,9(10)-estradien-3-on (EP-A(Steroids 37 (1981), 361-382), llß- (4-acetylphenyl) -17ß-hydroxy-17α- (prop-l-inyl) -4.9 (10) -estradien-3-one (EP-A
0 190 759),0 190 759),
(6α,HßJ7ß)-ll(4-Dimethylaminophenyl)-6-methyl-4,,5,-dihydrospiro[estra-4,9-dien-(6α, HßJ7ß) -ll (4-dimethylaminophenyl) -6-methyl-4, 5, -dihydrospiro [estra-4,9-dien
17,2'(3,H)-furan]-3-on, ( 1 Iß, 17α)- 1 l-(4-Acetylphenyl)- 17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-on,17.2 '(3 , H) -furan] -3-one, (1 Iß, 17α) - 1 l- (4-acetylphenyl) - 17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-one,
(7ß,llß,17ß)-ll(4-Dimethylaminoρhenyl)-7-methyl-4,,5'-dihydrospiro[estra-4,9-dien-(7.beta., LLSs, 17ß) -ll (4-Dimethylaminoρhenyl) -7-methyl-4, 5'-dihydrospiro [estra-4,9-dien
17,2'(3Η)-furan]-3-on (alle US-A 4,386,085) sowie die in der EP-A 0 277 676 beschriebenen llß-Aryl-14ß-estradiene und -triene, die 19,llß- überbrückten Steroide, die Gegenstand der EP-A-0 283 428 sind, die aus der EP-A-0 28917,2 '(3Η) -furan] -3-one (all US-A 4,386,085) and the 11β-aryl-14ß-estradienes and trienes described in EP-A 0 277 676, the 19, 11ß-bridged steroids which are the subject of EP-A-0 283 428, which from EP-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-H-Steroide der EP-A-0 404 283, beispielsweise. (Z)-llß-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 10-H-steroids of EP-A-0 404 283, for example. (Z) -llß-
[4-(Dimethylamino)phenyl]-17α-(3-hydroxyprop-l-enyl)-estr-4-en-17ß- ol.[4- (dimethylamino) phenyl] -17α- (3-hydroxyprop-l-enyl) -estr-4-en-17ß-ol.
Weiterhin seien als typische Vertreter erfindungsgemäß zu verwendender, kompetitiver Progesteronantagonisten beispielsweise genannt: llß-(4-Dimethylamino)-17α-hydroxy-17ß-(3-hydroxy-propyl)-13α-methyl-4,9-gonadien- 3-on (EP-A-0 129 499); llß-(4-Acetylphenyl)-17ß-hydroxy-17α-(3-hydroxyprop-l(Z)-enyl)-4,9(10)-estradien-3- on (EP-A-0 190 759); llß,19-[4-(Cyanphenyl)-o-phenylen]-17ß-hydroxy-17α-(3-hydroxyprop-l(Z)-enyl)-4- androsten-3-on und llßJ9-[4-(3-Pyridinyl)-o-phenylen]-17ß-hydroxy-17α-(3-hydroxyprop-l(Z)-enyl)-4- androsten-3-on (beide EP-A-0 283 428).The following may also be mentioned as typical representatives of competitive progesterone antagonists to be used according to the invention: IIß- (4-dimethylamino) -17α-hydroxy-17ß- (3-hydroxypropyl) -13α-methyl-4,9-gonadien-3-one ( EP-A-0 129 499); IIß- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxyprop-l (Z) -enyl) -4.9 (10) -estradien-3-one (EP-A-0 190 759); llß, 19- [4- (cyanophenyl) -o-phenylene] -17ß-hydroxy-17α- (3-hydroxyprop-l (Z) -enyl) -4- androsten-3-one and 11ßJ9- [4- (3rd -Pyridinyl) -o-phenylene] -17ß-hydroxy-17α- (3-hydroxyprop-l (Z) -enyl) -4- androsten-3-one (both EP-A-0 283 428).
Bei den vorstehend genannten PA handelt es sich teilweise 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.Some of the above-mentioned PA are those 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.
Die Aufzählung der PA 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. Die kompetitiven Progesteronantagonisten können zum Beispiel lokal, topisch, enteral, transdermal oder parenteral appliziert werden.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. The competitive progesterone antagonists can, for example, be applied locally, topically, enterally, transdermally or parenterally.
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.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.
Eine Dosierungseinheit enthält etwa 0,25 bis 50 mg llß-[(4-N,N-Dimethylamino)- phenyl]-17α-hydroxy-17ß-(3-hydroxypropyl)-13α-methyl-4,9(10)-gonadien-3-on oder eine biologisch äquivalente Menge eines anderen kompetitiven Progesteronantagonisten.One unit dose contains about 0.25 to 50 mg of 11β - [(4-N, N-dimethylamino) phenyl] -17α-hydroxy-17ß- (3-hydroxypropyl) -13α-methyl-4.9 (10) -gonadiene -3-one or a biologically equivalent amount of another competitive progesterone antagonist.
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 ovulationshemmenden oder 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 ovulation-inhibiting or in the non-ovulation-inhibiting and non-abortion-triggering dose range of the progesterone antagonist in question.
Als antiöstrogen wirkende Verbindungen kommen erfindungsgemäß sowohl kompetitive Antiöstrogene als auch Aromatasehemmer infirage. Antiöstrogene und Aromatasehemmer gemäß vorliegender Erfindung können sowohl von Steroiden abgeleitet oder nicht- steroidale Verbindungen sein. Unter antiöstrogen wirkenden Verbindungen 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.According to the invention, anti-estrogenic compounds include both competitive anti-estrogens and aromatase inhibitors infirage. Anti-estrogens and aromatase inhibitors according to the present invention can either be derived from steroids or non-steroidal compounds. Anti-estrogenic compounds 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.
Die Antiöstrogene wirken als kompetitive Östrogenantagonisten, indem sie Östrogen vom Rezeptor verdrängen, während Aromatasehemmer die Biosynthese des Östroge s unterdrücken. Verbindungen vom Typ des Aminoglutethimids, d. h. in der 3-Stellung alkylierte 3-(4-Aminophenyl)piperidin-2,6-dione und andere, die außer auf den Östrogenspiegel auch auf andere Sexualhormonserumkonzentrationen erniedrigend wirken, sind gemäß vorliegender Erfindung als antiöstrogen wirksame Verbindungen nicht geeignet.The anti-estrogens act as competitive estrogen antagonists by displacing estrogen from the receptor, while aromatase inhibitors suppress the biosynthesis of the estrogen. Compounds of the aminoglutethimide type, ie 3- (4-aminophenyl) piperidine-2,6-diones alkylated in the 3-position and others which, in addition to the estrogen level, also reduce other sex hormone serum concentrations act, are not suitable as anti-estrogenic compounds according to the present invention.
Als Antiöstrogene kommen alle gebräuchlichen Antiöstrogene in Betracht. Sie können etwa in gleichen Mengen eingesetzt werden wie die bereits im Handel befindlichen Antiöstrogene, das heißt die tägliche Dosis beträgt etwa 5-100 mg für Tamoxifen oder biologisch äquivalente Mengen eines anderen Antiöstrogens. Als nicht-steroidale Antiöstrogene seien beispielsweise genannt:All common anti-estrogens can be considered as anti-estrogens. They can be used in approximately the same amounts as the anti-estrogens already on the market, i.e. the daily dose is about 5-100 mg for tamoxifen or biologically equivalent amounts of another anti-estrogen. Examples of non-steroidal anti-estrogens are:
Tamoxifen = (Z)-2-[p-(l,2-Diphenyl-l-butenyl)-phenoxy]-N,N-dimethyl-äthylamin, Nafoxidin = l-2-[4-(6-Methoxy-2-phenyl-3,4-dihydro-l-naphthyl)-phenoxy]-äthyl- pyrrolidin, Hydrochlorid, Mer 25 = l-[p-(2-Diäthylaminoäthoxy)-phenyl]-2-(p-methoxyphenyl)-l- phenyläthanol Raloxifen = 6-Hydroxy-2-(p-hydroxyphenyl)benzo[b]thien-3-yl-p-(2-piperidino- ethoxy)phenylketon, HydrochloridTamoxifen = (Z) -2- [p- (1,2-diphenyl-l-butenyl) phenoxy] -N, N-dimethyl-ethylamine, nafoxidine = 1--2 [4- (6-methoxy-2- phenyl-3,4-dihydro-l-naphthyl) phenoxy] ethyl pyrrolidine, hydrochloride, Mer 25 = l- [p- (2-diethylaminoethoxy) phenyl] -2- (p-methoxyphenyl) -l-phenylethanol Raloxifene = 6-hydroxy-2- (p-hydroxyphenyl) benzo [b] thien-3-yl-p- (2-piperidinoethoxy) phenyl ketone, hydrochloride
N-n-Butyl-N-methyl-ll-(3J7ß-dihydroxyestra-l,3,5(10)-trien-7α-yl)- undecanamid undN-n-butyl-N-methyl-ll- (3J7ß-dihydroxyestra-l, 3,5 (10) -trien-7α-yl) - undecanamide and
7α-[9-(4,4,5,5,5-Pentafluorpentylsulfinyl)nonyl]estra-l,3,5(10)-trien-7α- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -triene-
3,17ß-diol.3,17β-diol.
Verbindungen vom 1,1,2-Triphenylbut-l-en-Typ, insbesondere das l,l-Bis-(3'-acetoxy- phenyl)-2-phenyl-but-l-en [J. Cancer Res. Clin. Oncol., (1986), 112, S. 119-124].Compounds of the 1,1,2-triphenylbut-1-ene type, in particular the 1,1-bis (3'-acetoxyphenyl) -2-phenylbut-1-ene [J. Cancer Res. Clin. Oncol., (1986), 112, pp. 119-124].
Ferner kommen als steroidale Antiöstrogene infirage: llα-Methoxy-17α-äthinyl-l,3,5(10)-östratrien-3J7ß-diol und l6ß-Äthylestradiol.Also available as steroidal anti-oestrogens infirage: llα-methoxy-17α-äthinyl-l, 3,5 (10) -estratrien-3J7ß-diol and l6ß-ethyltradiol.
Als Aromatasehemmer sind alle Verbindungen geeignet, die als Substrat für die Aromatase infirage kommen, wie beispielsweise das in der deutschen Offenlegungsschrift 33 22 285 beschriebene l-Methyl-androsta-l,4-dien-3J7-dion, das in Journal of Clinical Endocrinology and Metabolism. 49, 672 (1979) beschriebeneSuitable as aromatase inhibitors are all compounds which come as a substrate for the aromatase, such as, for example, the 1-methyl-androsta-1,4-diene-3J7-dione described in German Offenlegungsschrift 33 22 285, which is published in the Journal of Clinical Endocrinology and Metabolism. 49, 672 (1979)
Testolacton (17a-Oxa-D-homoandrost-l,4-dien-3,17-dion), die in "Endocrinology" 1973. Vol. 92, No. 3, Seite 874 beschriebenen VerbindungenTestolactone (17a-oxa-D-homoandrost-l, 4-diene-3,17-dione), which is described in "Endocrinology" 1973. Vol. 92, No. 3, page 874 described connections
Androsta-4,6-dien-3,17-dion,Androsta-4,6-diene-3,17-dione,
Androsta-4,6-dien-17ß-ol-3-on-acetat,Androsta-4,6-dien-17ß-ol-3-one acetate,
Androsta- 1,4, 6-trien-3, 17-dion, 4-Androsten-19-chlor-3, 17-dion,Androsta-1,4, 6-triene-3, 17-dione, 4-androsten-19-chloro-3, 17-dione,
4-Androsten-3,6,17-trion, die in der deutschen Offenlegungsschrift 31 24 780 beschriebenen 19-alkynylierten4-Androsten-3,6,17-trione, the 19-alkynylated in German Offenlegungsschrift 31 24 780
Steroide, die in der deutschen Offenlegungsschrift 31 24719 beschriebenenSteroids described in German Offenlegungsschrift 31 24719
10-(l,2,-Propadienyl)-steroide, die in der euopäischen Patentanmeldung, Veröffentlichungs-Nr. 100 566 beschriebenen10- (1,2, -Propadienyl) steroids, which are described in the European patent application, publication no. 100 566
19-Thio-androstanderivate, das in "Endocrinology" 1977. Vol. 100, No. 6, Seite 1684 und der US-Patentschrift19-thio-androstanderivate, described in "Endocrinology" 1977. Vol. 100, No. 6, page 1684 and the US patent
4,235,893 beschriebene4,235,893
4-Androsten-4-ol-3,17-dion und dessen Ester, die in der deutschen Offenlegungsschrift 35 39 244 beschriebenen l-Methyl-15α-alkyl-androsta-l,4-dien-3J7-dione, die in der deutschen Offenlegungsschrift 36 44358 beschriebenen4-Androsten-4-ol-3,17-dione and its esters, the l-methyl-15α-alkyl-androsta-l, 4-dien-3J7-dione described in German Offenlegungsschrift 35 39 244, the German Laid-open specification 36 44 358
10ß-Alkinyl-4,9(ll)-östradien -Derivate und das in der europäischen Patentanmeldung10ß-alkynyl-4,9 (ll) estradiene derivatives and that in the European patent application
0 250 262 beschriebene l,2ß-Methylen-6-methylen-4-androsten-3,17-dion.0 250 262 described 1,2-methylene-6-methylene-4-androstene-3,17-dione.
Als nicht-steroidale Aromatasehemmer seien beispielsweise [4-(5,6,7,8-Tetrahydroimidazo [l,5α]-pyridin-5-yl)benzomtril-mono-hydrochlorid] (Cancer Res., 48, S. 834-838, 1988) und die in der EP-A-0 411 735 beschriebenen Cycloalkylenazole erwähnt.Examples of non-steroidal aromatase inhibitors are [4- (5,6,7,8-tetrahydroimidazo [1,5a] -pyridin-5-yl) benzometril-mono-hydrochloride] (Cancer Res., 48, pp. 834-838 , 1988) and the cycloalkylenazoles described in EP-A-0 411 735.
Im allgemeinen werden täglich 10-200 mg l-Methyl-androsta-l,4-dien-3,17-dion bzw. biologisch äquivalente Dosen von anderen Aromatasehemmern zur Behandlung von Myomen eingesetzt.In general, 10-200 mg of l-methyl-androsta-l, 4-diene-3,17-dione or biologically equivalent doses of other aromatase inhibitors are used daily for the treatment of fibroids.
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.
Für die bevorzugte enterale Applikation kommen insbesondere Tabletten, Dragees, Kapseln, Pillen, Suspensionen oder Lösungen infirage, die in üblicher Weise mit den in der Galenik üblichen Zusätzen und Trägersubstanzen hergestellt werden können. Für die lokale oder topische Anwendung kommen beispielsweise Vaginalzäpfchen oder transdermale Systeme wie Hautpflaster infrage. Eine AÖ-Dosiseinheit enthält 1-100 mg Tamoxifen oder 10-200 mg 1-Methyl-androsta- l,4-dien-3,17-dion oder eine biologisch äquivalente Menge einer anderen antiöstrogen wirksamen Verbindung. For the preferred enteral application, in particular tablets, coated tablets, capsules, pills, suspensions or solutions infirage come, 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 or transdermal systems such as skin patches are suitable. An AÖ dose unit contains 1-100 mg tamoxifen or 10-200 mg 1-methyl-androstal, 4-diene-3,17-dione or a biologically equivalent amount of another anti-estrogenic compound.
Beispiel 1example 1
10,0 mg llß-[(4-N,N-Dimethylamino)-phenyl]-17α-hydroxy-17ß*10.0 mg llß - [(4-N, N-dimethylamino) phenyl] -17α-hydroxy-17ß *
(3-hydroxypropyl)-13α-methyl-4,9-gonadien-3-on(3-hydroxypropyl) -13α-methyl-4,9-gonadien-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 me Magnesiumstearat0.5 me magnesium stearate
225,0 mg Gesamtgewicht der Tablette225.0 mg total tablet weight
Beispiel 2Example 2
50,0 mg l-Methyl-androsta-l,4-dien-3,17-dion50.0 mg l-methyl-androsta-1,4-diene-3,17-dione
115,0 mg Laktose115.0 mg lactose
50,0 mg Maisstärke50.0 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 ms Magnesiumstearat0.5 ms magnesium stearate
220,0 mg Gesamtgewicht der Tablette220.0 mg total tablet weight
Beispiel 3Example 3
25,0 mg l-Methyl-androsta-l,4-dien-3,17-dion25.0 mg l-methyl-androsta-l, 4-diene-3,17-dione
25,0 mg llß-[(4-N,N-Dimethylamino)-phenyl]-17α-hydroxy-17ß-25.0 mg llß - [(4-N, N-dimethylamino) phenyl] -17α-hydroxy-17ß-
(3-hydroxypropyl)-13α-methyl-4,9-gonadien-3-on(3-hydroxypropyl) -13α-methyl-4,9-gonadien-3-one
115,0 mg Laktose115.0 mg lactose
50,0 mg Maisstärke50.0 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 einer Tablettenpresse hergestellt wird. Gegebenenfalls können auch die erfindungsgemäßen Wirk- Stoffe mit jeweils der Hälfte der oben angegebenen Zusätze getrennt zu einer Zweischichtentablette gepreßt werden.220.0 mg total weight of the tablet, which is manufactured in the usual way on a tablet press. If appropriate, the active compounds according to the invention Substances, each with half of the additives specified above, are pressed separately into a two-layer tablet.
Beispiel 4Example 4
20,0 mg Tamoxifen (Antiestrogen mit agonistischer Partialwirkung) 50,0 mg llß-[(4-N,N-Dimethylamino)-phenyl]-17α-hydroxy-17ß-20.0 mg tamoxifen (antiestrogen with agonistic partial action) 50.0 mg llß - [(4-N, N-dimethylamino) phenyl] -17α-hydroxy-17ß-
(3-hydroxypropyl)-13α-methyl-4,9-gonadien-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 einer Tablettenpresse ======= hergestellt wird. Gegebenenfalls können auch die erfindungsgemäßen Wirk(3-hydroxypropyl) -13α-methyl-4,9-gonadien-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, which is manufactured in the usual way on a tablet press =======. If necessary, the active ingredients according to the invention
Stoffe mit jeweils der Hälfte der oben angegebenen Zusätze getrennt zu einer Zweischichtentablette gepreßt werden.Substances, each with half of the additives specified above, are pressed separately into a two-layer tablet.
Beispiel 5Example 5
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-N,N-Dimethylamino)-phenyl]-17α-hydroxy-17ß-5.0 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-N, N-dimethylamino) phenyl] -17α-hydroxy-17ß-
(3-hydroxypropyl)-13α-methyl-4,9-gonadien-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 einer Tablettenpresse ======= hergestellt wird. Gegebenenfalls können auch die erfindungsgemäßen Wirk(3-hydroxypropyl) -13α-methyl-4,9-gonadien-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 manufactured in the usual way on a tablet press ======= . If necessary, the active ingredients according to the invention
Stoffe mit jeweils der Hälfte der oben angegebenen Zusätze getrennt zu einer Zweischichtentablette gepreßt werden. Beispiel 6Substances, each with half of the additives specified above, are pressed separately into a two-layer tablet. Example 6
Zusammensetzung einer öligen Lösung:Composition of an oily solution:
100,0 mg Tamoxifen100.0 mg tamoxifen
343,4 mg Rizinusöl343.4 mg castor oil
608,6 mg Benzylbenzoat608.6 mg benzyl benzoate
1052,0 mg = 1 ml1052.0 mg = 1 ml
Die Lösung wird in eine Ampulle gefülltThe solution is filled into an ampoule
Beispiel 7Example 7
Zusammensetzung einer öligen Lösung:Composition of an oily solution:
55,0 mg l-Methyl-androsta-l,4-dien-3J7-dion55.0 mg l-methyl-androsta-l, 4-diene-3J7-dione
55,0 mg llß-[(4-N,N-Dimethylamino)-phenyl]-17α-hydroxy-17ß- (3-hydroxypropyl)-13α-methyl-4,9-gonadien-3-on 343,4 mg Rizinusöl 608,6 mg Benzylbenzoat 1062,0 mg = 1 ml55.0 mg llß - [(4-N, N-dimethylamino) phenyl] -17α-hydroxy-17ß- (3-hydroxypropyl) -13α-methyl-4,9-gonadien-3-one 343.4 mg castor oil 608.6 mg benzyl benzoate 1062.0 mg = 1 ml
Die Lösung wird in eine Ampulle gefüllt. Die erfindungsgemäßen Wirkstoffe können auch mit jeweils der Hälfte der oben angegebenen Zusätze getrennt in zwei Kammern abgefüllt werden.The solution is filled into an ampoule. The active compounds according to the invention can also be filled separately in two chambers with half of the additives specified above.
Beispiel 8Example 8
5,0 mg llß-[(4-N,N-Dimethylamino)-phenyl]-17ß-hydroxy-17α-propinyl-4,9(10)- estradien-3-on (RU-38486), 10,0 mg (Z)-2-[p-(l,2-Diphenyl-l-butenyl)-phenoxy]-N,N-dimethyl-äthylamin, (Tamoxifen; Antiestrogen mit agonistischer Partialwirkung) 140,0 mg Laktose 60,5 mg Maisstärke 2,5 mg Poly-N-Vinylpyrrolidon 25 2,0 mg Aerosil 220,0 mg Gesamtgewicht der Tablette, die in üblicher Weise auf einer Tablettenpresse ======= hergestellt wird. Gegebenenfalls können auch die erfindungsgemäßen Wirk¬ stoffe mit jeweils der Hälfte der oben angegebenen Zusätze getrennt zu einer Zweischichtentablette gepreßt werden.5.0 mg llß - [(4-N, N-dimethylamino) phenyl] -17ß-hydroxy-17α-propinyl-4.9 (10) - estradien-3-one (RU-38486), 10.0 mg (Z) -2- [p- (1,2-Diphenyl-l-butenyl) phenoxy] -N, N-dimethylethylamine, (tamoxifen; antiestrogen with agonistic partial action) 140.0 mg lactose 60.5 mg corn starch 2.5 mg poly-N-vinylpyrrolidone 25 2.0 mg Aerosil 220.0 mg total weight of the tablet, which is manufactured in the usual way on a tablet press =======. If appropriate, the active compounds according to the invention can also be pressed separately into a two-layer tablet, each with half of the additives specified above.
Pharmakologische BeobachtungenPharmacological observations
Die Versuche werden an intakten Ratten mit normalem Zyklus durchgeführt. Die Tiere werden über 8 Wochen mit Vehikel (Benzylbenzoat/Rizinusöl), dem Antiöstrogen Tamoxifen (0.2 mg/Tag/Tier) oder der progesteronantagonistisch wirksamen Verbindung llß-[(4-N,N-Dimethylamino)-phenyl]-17α-hydroxy-17ß-(3-hydroxypropyl)-13α-methyl- 4,9-gonadien-3-on (2.0 mg Tag/Tier) jeweils alleine, oder in einer Kombination beider Verbindungen behandelt. Die Substanzen werden subkutan appliziert. Als Parameter dient das Gewicht und die Morphologie des Uterus.The experiments are carried out on intact rats with a normal cycle. The animals are treated with vehicle (benzyl benzoate / castor oil), the anti-estrogen tamoxifen (0.2 mg / day / animal) or the progesterone-antagonistic compound llß - [(4-N, N-dimethylamino) -phenyl] -17α-hydroxy- for 8 weeks. 17ß- (3-hydroxypropyl) -13α-methyl-4,9-gonadien-3-one (2.0 mg day / animal) treated individually or in a combination of both compounds. The substances are applied subcutaneously. The weight and morphology of the uterus serve as parameters.
Ergebnisse:Results:
1) Progesteronantagonistisch wirksame Verbindung (PA):1) Progesterone Antagonistic Compound (PA):
Die Behandlung mit dem kompetitiven Progesteronantagonisten führt zu einer leichten Gewichtsabnahme des Uterus (AbbJ) mit einer Inhibition des Myometriums und des stromalen Gewebes bei gleichzeitiger Stimulierung des luminaren Epithels und einer Vermehrung drüsiger Strukturen (Tab. 1).Treatment with the competitive progesterone antagonist leads to a slight weight loss of the uterus (FigJ) with an inhibition of the myometrium and the stromal tissue with simultaneous stimulation of the luminal epithelium and an increase in glandular structures (Table 1).
2) Antiöstrogen wirksame Verbindung (AÖ):2) Anti-estrogen-active compound (AÖ):
Die Behandlung führt zu einer deutlichen Gewichtsabnahme des Uterus (AbbJ) mit einer Inhibition des luminaren und glandulären Epithels (Tab. 1). 3) PA/AÖ-KombinationThe treatment leads to a significant weight loss of the uterus (FigJ) with an inhibition of the luminal and glandular epithelium (Tab. 1). 3) PA / AÖ combination
Nach einer Kombination der beiden Komponenten wird eine signifikante Gewichts¬ reduktion des Uterus gefunden (AbbJ). Es kommt zu einer Inhibition des Myometriums, des endometrialen Stromas mit einer Inhibition des luminaren und glandulären Epithels. Die histologischen Befunde zeigen, daß die Stimulierung des luminaren Epithels und die vermehrten drüsigen Strukturen, die unter der alleinigen PA-Behandlung beobachtet werden, durch die Kombination von PA mit AÖ aufgehoben werden (Schutzeffekt) können (Tab. 1).After a combination of the two components, a significant reduction in the weight of the uterus is found (FigJ). There is an inhibition of the myometrium, the endometrial stroma with an inhibition of the luminal and glandular epithelium. The histological findings show that the stimulation of the luminal epithelium and the increased glandular structures that are observed under the sole PA treatment can be canceled by the combination of PA with AÖ (protective effect) (Tab. 1).
Tabelle 1 Morphologische Veränderungen im UterusTable 1 Morphological changes in the uterus
Gr. l Substanz Myo- Endo¬ metrium metriumGr. l substance Myo- Endo¬ metrium metrium
Stroma EpithelStromal epithelium
1 Vehikel ++ ++ ++1 vehicle ++ ++ ++
2 AÖ _ + -2 AÖ _ + -
3 PA . - ++-_-3 PA. - ++ -_-
4 PA + AÖ - - -4 PA + AÖ - - -
+ = Stimulation = Inhibition + = Stimulation = inhibition

Claims

Patentansprüche claims
1. Verwendung mindestens einer Verbindung mit progesteronantagonistischer (PA) und mindestens einer Verbindung mit antiöstrogener (AÖ) Wirkung zur Herstellung von Arzneimitteln zur Behandlung des Leiomyomata uteri (Uterines Myom).1. Use of at least one compound with progesterone-antagonistic (PA) and at least one compound with anti-estrogenic (AÖ) activity for the production of medicaments for the treatment of Leiomyomata uteri (uterine myoma).
2. Verwendung von llß-[(4-N,N-Dimethylamino)-phenyl]-17ß-hydroxy-17α-propinyl- 4,9(10)-estradien-3-on oder llß-(4-Dimethylamino)-17α-hydroxy-17ß-(3-hydroxy- propyl)-13α-methyl-4,9-gonadien-3-on als Verbindung mit progesteronantagonistischer (PA) Wirkung nach Anspruch 1.2. Use of llß - [(4-N, N-dimethylamino) phenyl] -17ß-hydroxy-17α-propinyl-4,9 (10) -estradien-3-one or llß- (4-dimethylamino) -17α -hydroxy-17ß- (3-hydroxypropyl) -13α-methyl-4,9-gonadien-3-one as a compound with progesterone-antagonistic (PA) activity according to claim 1.
3. Verwendung von (Z)-2-[p-(l,2-Diphenyl-l-butenyl)-phenoxy]-N,N-dimethyl- äthylamin, l-2-[4-(6-Methoxy-2-phenyl-3,4-dihydro-l-naphthyl)-phenoxy]-äthyl- pyrrolidin, Hydrochlorid, 6-Hydroxy-2-(p-hydroxyphenyl)benzo[b]thien-3-yl-p-(2- piperidinoethoxy)phenylketon, Hydrochlorid, N-n-Butyl-N-methyl-ll-(3,17ß- dihydroxyestra-l,3,5(10)-trien-7α-yl)-undecanamid oder3. Use of (Z) -2- [p- (1,2-diphenyl-l-butenyl) phenoxy] -N, N-dimethylethylamine, 1--2 [4- (6-methoxy-2- phenyl-3,4-dihydro-l-naphthyl) phenoxy] ethyl pyrrolidine, hydrochloride, 6-hydroxy-2- (p-hydroxyphenyl) benzo [b] thien-3-yl-p- (2-piperidinoethoxy) phenyl ketone, hydrochloride, Nn-butyl-N-methyl-ll- (3,17ß-dihydroxyestra-l, 3,5 (10) -trien-7α-yl) -undecanamide or
7α-[9-(4,4,5,5,5-Pentafluorρentylsulfinyl)nonyl]estra-l,3,5(10)-trien-3,17ß-diol als7α- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -triene-3,17ß-diol as
Verbindung mit antiöstrogener (AÖ) Wirkung nach Anspruch 1.Compound with anti-estrogenic (AÖ) activity according to claim 1.
4. Verwendung von l-Methyl-androsta-l,4-dien-3J7-dion oder [4-(5,6,7,8-Tetrahydro- imidazo [l,5α]-pyridin-5-yl)benzonitril-mono-hydrochlorid] als Verbindung mit antiöstrogener (AÖ) Wirkung nach Anspruch 1.4. Use of l-methyl-androsta-l, 4-diene-3J7-dione or [4- (5,6,7,8-tetrahydro-imidazo [1,5a] -pyridin-5-yl) benzonitrile mono -hydrochloride] as a compound with anti-estrogenic (AÖ) activity according to claim 1.
5. Verwendung von llß-(4-Dimethylamino)-17α-hydroxy-17ß-(3-hydroxy-propyl)-13α- methyl-4,9-gonadien-3-on (PA) und (Z)-2-[p-(l,2-Diphenyl-l-butenyl)-phenoxy]-N,N- dimethyl-äthylamin (AÖ) nach Anspruch 1. 5. Use of 11β- (4-dimethylamino) -17α-hydroxy-17ß- (3-hydroxypropyl) -13α-methyl-4,9-gonadien-3-one (PA) and (Z) -2- [ p- (1,2-diphenyl-l-butenyl) phenoxy] -N, N-dimethylethylamine (AÖ) according to claim 1.
PCT/EP1994/002854 1993-08-27 1994-08-29 Progesterone-antagonistic and anti-oestrogen compounds for the therapy of leiomyomata uteri WO1995005828A1 (en)

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US6653297B1 (en) * 1997-07-03 2003-11-25 Medical College Of Hampton Roads Control of selective estrogen receptor modulators
EP1287817A1 (en) * 2001-08-31 2003-03-05 Pantarhei Bioscience B.V. Method of treating uterine leiomyomas and intravaginal drug delivery vehicle for use in such method
GB0120147D0 (en) * 2001-08-17 2001-10-10 Metris Therapeutics Ltd Treatment method
WO2003017974A1 (en) * 2001-08-31 2003-03-06 Pantarhei Bioscience B.V. Method of treating benign gynaecological disorders and a pharmaceutical kit for use in such method

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0702961A2 (en) * 1994-09-20 1996-03-27 Eli Lilly And Company Compositions for minimizing the uterotrophic effect of tamoxifen and its analogs
EP0702961A3 (en) * 1994-09-20 1999-11-10 Eli Lilly And Company Compositions for minimizing the uterotrophic effect of tamoxifen and its analogs

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