WO1995005828A1 - Composes a action antagoniste de la progesterone et anti-×strogene pour la therapie de liomyomes uterins - Google Patents

Composes a action antagoniste de la progesterone et anti-×strogene pour la therapie de liomyomes uterins Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
progesterone
compound
methyl
hydroxy
antagonistic
Prior art date
Application number
PCT/EP1994/002854
Other languages
German (de)
English (en)
Inventor
Klaus Stöckemann
Kristof Chwalisz
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to AU76917/94A priority Critical patent/AU7691794A/en
Publication of WO1995005828A1 publication Critical patent/WO1995005828A1/fr

Links

Classifications

    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On utilise au moins un composé à action antagoniste de la progestérone (PA) et au moins un composé à action anti-÷strogène (AO) pour préparer des médicaments thérapeutiques des liomyomes utérins. Lors de l'utilisation associée de composés à action antagoniste de la progestérone et anti-÷strogène, le composé à action anti-÷strogène inhibe dans une large mesure la stimulation de l'épithélium de l'endomètre provoquée lorsque l'on utilise uniquement un composé à action antagoniste de la progestérone.
PCT/EP1994/002854 1993-08-27 1994-08-29 Composes a action antagoniste de la progesterone et anti-×strogene pour la therapie de liomyomes uterins WO1995005828A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU76917/94A AU7691794A (en) 1993-08-27 1994-08-29 Progesterone-antagonistic and anti-oestrogen compounds for the therapy of leiomyomata uteri

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19934329344 DE4329344A1 (de) 1993-08-27 1993-08-27 Progesteronantagonistisch- und antiöstrogen wirksame Verbindungen für die Behandlung des Leiomyomata uteri
DEP4329344.1 1993-08-27

Publications (1)

Publication Number Publication Date
WO1995005828A1 true WO1995005828A1 (fr) 1995-03-02

Family

ID=6496469

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/002854 WO1995005828A1 (fr) 1993-08-27 1994-08-29 Composes a action antagoniste de la progesterone et anti-×strogene pour la therapie de liomyomes uterins

Country Status (3)

Country Link
AU (1) AU7691794A (fr)
DE (1) DE4329344A1 (fr)
WO (1) WO1995005828A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0702961A2 (fr) * 1994-09-20 1996-03-27 Eli Lilly And Company Compositions pour réduire les effets utérotrophiques du tamoxifène et de ses analogues

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE187643T1 (de) * 1995-06-06 2000-01-15 Lilly Co Eli Verringerung von knochenschwund durch antiöstrogen-kombinationen
US6653297B1 (en) * 1997-07-03 2003-11-25 Medical College Of Hampton Roads Control of selective estrogen receptor modulators
EP1287817A1 (fr) * 2001-08-31 2003-03-05 Pantarhei Bioscience B.V. Méthode et dispositif intravaginal pour le traitement des myomes utérins
GB0120147D0 (en) * 2001-08-17 2001-10-10 Metris Therapeutics Ltd Treatment method
WO2003017973A1 (fr) * 2001-08-31 2003-03-06 Pantarhei Bioscience B.V. Traitement de troubles gynecologiques benins et vecteur d'administration a cet effet

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0310541A1 (fr) * 1987-10-01 1989-04-05 Schering Aktiengesellschaft Composés antigestagéniques et anti-oestrogéniques pour le déclenchement de la naissance et pour l'interruption de la grossesse ainsi que pour le traitement des troubles gynécologiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0310541A1 (fr) * 1987-10-01 1989-04-05 Schering Aktiengesellschaft Composés antigestagéniques et anti-oestrogéniques pour le déclenchement de la naissance et pour l'interruption de la grossesse ainsi que pour le traitement des troubles gynécologiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
E.M. COUTINHO: "Treatment of large fibroids with high doses of gestrinone", GYNAECOL. OBSTET. INVEST., vol. 30, 1990, pages 40 - 47 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0702961A2 (fr) * 1994-09-20 1996-03-27 Eli Lilly And Company Compositions pour réduire les effets utérotrophiques du tamoxifène et de ses analogues
EP0702961A3 (fr) * 1994-09-20 1999-11-10 Eli Lilly And Company Compositions pour réduire les effets utérotrophiques du tamoxifène et de ses analogues

Also Published As

Publication number Publication date
DE4329344A1 (de) 1995-03-02
AU7691794A (en) 1995-03-21

Similar Documents

Publication Publication Date Title
EP0723439B1 (fr) Combinaison d'antagonistes de la progesterone et d'anti- estrogenes a action partiellement agoniste pour l'hormonotherapie substitutive des femmes peri et postmenopausees
EP0310541B1 (fr) Composés antigestagéniques et anti-oestrogéniques pour le déclenchement de la naissance et pour l'interruption de la grossesse ainsi que pour le traitement des troubles gynécologiques
DE60216630T2 (de) Verwendung von östrogen in kombination mit progestogen für die hormonsubstitutiionstherapie
DE19739916C2 (de) Verwendung einer Kombination aus einem Gestagen und einem Estrogen zur kontinuierlichen Ovulationshemmung und ggf. gleichzeitigen Behandlung und/oder Prophylaxe von Tumoren der Brustdrüsen
DE4429398C2 (de) Verwendung von Estra-1,3,5(10)-trien-Derivaten zur hormonalen Kontrazeption
EP0799042A1 (fr) Composes a action antagoniste de la progesterone et anti strogene utilisees conjointement pour la contraception feminine
EP0772441B1 (fr) Utilisation d'un antagoniste de progesterone et d'un progestatif pour le traitement de l'endometriose ou des fibromiomes uterins
DE69729956T2 (de) Orale einstufige empfängnisverhütungsmethode und kombinationspräparat das gestagen und estrogen enthält
SK135296A3 (en) Compound remedy for contraception on natural estrogens base
EP0310542B1 (fr) Composés antigestagéniques et anti-oestrogéniques pour le traitement des tumeurs dépendant des hormones
WO1995005828A1 (fr) Composes a action antagoniste de la progesterone et anti-×strogene pour la therapie de liomyomes uterins
DE60036723T2 (de) Mesoprogestine zur behandlung und vorbeugung von hormonabhängigen gutartigen gynekologischen störungen
US20030176404A1 (en) Progestogen-anti-progestogen regimens
DE4216004B4 (de) Verwendung kompetitiver Progesteronantagonisten
DE19610635A1 (de) Sequentielle Estrogen/Progesteronantagonist-Kombination für die Hormonersatz-Therapie
EP0296097B1 (fr) Médicament contenant des inhibiteurs de synthèse de la progestérone du type trilostane ou épostane et des antigestagènes
DE19510862A1 (de) Verwendung von Antiestrogenen zur männlichen Fertilitätskontrolle
EP0495825B1 (fr) Utilisation d'antigestagenes pour l'obtention de medicaments
WO1996029078A1 (fr) AGENT INHIBITEUR D'OVULATION POUR CONTRACEPTION HORMONALE CONTENANT 50 A 70 νg DE LEVONORGESTREL ET PLUS DE 30 A 40 νg D'ETHINYLESTRADIOL
DE10134768A1 (de) Pharmazeutische Kombinationspräparate enthaltend Aromatasehemmer und Substanzen mit estrogener Wirkung sowie ihre Verwendung

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CN CZ FI HU JP KR NO NZ RU SK US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA