WO1992010194A1 - Use of antigestagenes for producing medicaments - Google Patents

Use of antigestagenes for producing medicaments Download PDF

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Publication number
WO1992010194A1
WO1992010194A1 PCT/EP1991/002358 EP9102358W WO9210194A1 WO 1992010194 A1 WO1992010194 A1 WO 1992010194A1 EP 9102358 W EP9102358 W EP 9102358W WO 9210194 A1 WO9210194 A1 WO 9210194A1
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treatment
antigestagens
sperm
antigestagenes
ejakulat
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PCT/EP1991/002358
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German (de)
French (fr)
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Chander P. Puri
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Schering Aktiengesellschaft Berlin Und Bergkamen
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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

Definitions

  • the present invention relates to the use of antigestagens (competitive progesterone antagonists) for the production of medicaments for controlling male fertility and / or for the treatment of andrological clinical pictures.
  • RU 486 11ß- [4-N, N- (Dimethylamino) phenyl] -17ß-hydroxy-17 ⁇ -propynyl-estra-4,9 (10) -dien-3-one; EP-A-0057115) and others 11ß -aryl- or 11ß.l9-arylene-substituted steroids are substances that can displace progesterone and glucocorticoids from their respective receptors. Pharmacologically, these substances are characterized by strong progesterone and glucocorticoid antagonistic effects. These properties determine the therapeutic application so far practiced. EU 486 is e.g. as a progesterone antagonist for the therapeutic termination of pregnancy, but also as a glucocorticoid antagonist for the treatment of
  • Cushing's syndrome used in the wake of a pathologically increased secretory activity of the adrenal cortex.
  • antigestagens competitive progesterone antagonists
  • FSH pituitary hormone
  • Blood sample collection Every fifth day, before, during and after the treatment period. Two samples (10:00 a.m. and 10:00 p.m.) were taken on the day of blood collection.
  • Morphological abnormalities such as spiral tails and defective sperm heads
  • Testosterone didhydrotestosterone and FSH. The diurnal rhythm of testosterone and dihydrotestosterone levels is not affected.
  • Ejaculate volume, ejaculate weight, sperm concentration per ejaculate, volume concentration of the sperm and the motility of the sperm of the animals in the treated and in the control group are shown in the following Tables 1-6.
  • Prostate hypertrophy and prostate cancer the observed phenomena can only be explained by inhibitory effects in the accessory sex glands, which also includes the prostate.
  • Trigger menstruation a reversible inhibition of male fertility is achieved.
  • progestogen receptor progesterone receptor
  • the antigestagens can be used according to different treatment regimens.

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  • 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)
  • Steroid Compounds (AREA)

Abstract

Antigestagenes (competitive progesterone antagonists) reversibly inhibit at very low doses various parameters of the masculine sexual function and are useful to produce medicaments for controlling masculine fertility and/or for treating andrological pathologies.

Description

Verwendung von Antigestagenen zur Herstellung von Arzneimitteln  Use of antigestagens for the manufacture of pharmaceuticals
Die vorliegende Erfindung betrifft die Verwendung von Antigestagenen (kompetitiven Progesteronantagonisten) zur Herstellung von Arzneimitteln zur Kontrolle der männlichen Fertilität und/oder zur Behandlung andrologischer Krankheitsbilder. The present invention relates to the use of antigestagens (competitive progesterone antagonists) for the production of medicaments for controlling male fertility and / or for the treatment of andrological clinical pictures.
RU 486 (11ß-[4-N,N-(Dimethylamino)phenyl]-17ß-hydroxy-17α-propinyl-estra-4,9(10)-dien-3-on;EP-A-0057115) und andere 11ß-aryloder 11ß.l9-arylen-substituierte Steroide sind Substanzen, die Progesteron und Glucocorticoide von ihren jeweiligen Rezeptoren verdrängen können. Pharmakologisch zeichnen sich diese Substanzen durch starke Progesteron- und Glucocorticoid-antagonistische Wirkungen aus. Diese Eigenschaften bestimmen die bisher praktizierte therapeutische Anwendung. EU 486 wird z.B. als Progesteronantagonist zum therapeutischen Abbruch von Schwangerschaften, aber auch als Glucocorticoidantagonist zur Behandlung des RU 486 (11ß- [4-N, N- (Dimethylamino) phenyl] -17ß-hydroxy-17α-propynyl-estra-4,9 (10) -dien-3-one; EP-A-0057115) and others 11ß -aryl- or 11ß.l9-arylene-substituted steroids are substances that can displace progesterone and glucocorticoids from their respective receptors. Pharmacologically, these substances are characterized by strong progesterone and glucocorticoid antagonistic effects. These properties determine the therapeutic application so far practiced. EU 486 is e.g. as a progesterone antagonist for the therapeutic termination of pregnancy, but also as a glucocorticoid antagonist for the treatment of
Cushing-Syndroms im Gefolge einer pathologisch erhöhten sekretorischen Aktivität der Nebennierenrinde eingesetzt. Cushing's syndrome used in the wake of a pathologically increased secretory activity of the adrenal cortex.
Es wurde nunmehr gefunden, daß Antigestagene (kompetitive Progesteronantagonisten) verschiedene Parameter der männlichen Sexualfunktionen in einer Weise beeinflußen, die eine reversible Hemmung der männlichen Fruchtbarkeit bewirken. Aus den erhobenen Befunden ergibt sich ferner, daß Antigestagene (unter den gewählten Versuchsbedingungen) eine starke selektive Suppression männlicher akzessorischer Geschlechtsorgane bewirken. Dies wird belegt durch unveränderte Konzentrationen des hypophysären Hormons FSH im Blut, das neben LH die Funktion des Hodens aufrecht erhält. Unter der Behandlung wurde eine unveränderte Größe der Hoden sowie ein unveränderter Blutspiegel der wichtigsten männlichen Sexualhormone Testosteron und 5α-Dihydrotestosteron, die vom Hoden sezerniert werden, festgestellt. Die Anwesenheit letzterer Hormone in unveränderten Konzentrationen ist die Voraussetzung für die Erhaltung einer normalen Libido. It has now been found that antigestagens (competitive progesterone antagonists) influence various parameters of male sexual functions in a manner which reversibly inhibits male fertility. The results also show that antigestagens (under the chosen experimental conditions) cause a strong selective suppression of male accessory genital organs. This is evidenced by unchanged concentrations of the pituitary hormone FSH in the blood, which in addition to LH maintains the function of the testicle. An unchanged testicle size and unchanged blood level of the most important male sex hormones testosterone and 5α-dihydrotestosterone, which are secreted by the testes, were found during the treatment. The presence of the latter hormones in unchanged concentrations is a prerequisite for maintaining a normal libido.
Die vorstehend beschriebenen Eigenschaften von Antigestagenen ergeben sich aus Versuchen, die mit RU 486 (11ß-[(4-N,N-Dimethylamino)-phenyl]-17ß-hydroxy-17α-propinyl-4,9(10)-estradien-3- on) an adulten Bonnet-Makaken (Makaka radiata) durchgeführt wurden. RU 486 gilt als Standardverbindung für die Wirkstoffklasse der Antigestagene. The properties of anti-gestagens described above result from experiments with RU 486 (11β - [(4-N, N-dimethylamino) phenyl] -17β-hydroxy-17α-propynyl-4,9 (10) -estradien-3 - on) were performed on adult Bonnet macaques (Makaka radiata). RU 486 is the standard compound for the active ingredient class of the antigestagens.
Das Versuchsdesign und die Ergebnisse gehen aus der nachstehenden Aufstellung hervor. The experimental design and the results are shown in the list below.
Bonnet-Makaken erwachsene männliche Tiere Bonnet macaque adult male animals
Mit RU 486 behandelte 1 mg/Tag in 0,2 ml Vehikel, 1 mg / day treated with RU 486 in 0.2 ml vehicle,
Gruppe (N = 4): subcutan auf öliger Basis  Group (N = 4): subcutaneously on an oily basis
(Benzylbenzoat: Rizinusöl 1:10)  (Benzyl benzoate: castor oil 1:10)
Vehikelkontrolle (N = 3) 0,2 ml Vehikel 1 × täglich Vehicle control (N = 3) 0.2 ml vehicle once daily
Behandlungsdauer: 75 Tage Treatment duration: 75 days
Sammlung von Blutproben: Jeden fünften Tag, vor, während und nach der Behandlungsdauer. Es wurden am jeweiligen Tag der Blutentnahme zwei Proben (10.00 Uhr und 22.00 Uhr) entnommen. Blood sample collection: Every fifth day, before, during and after the treatment period. Two samples (10:00 a.m. and 10:00 p.m.) were taken on the day of blood collection.
Sammlung der Spermien und Jeden 10. Tag durch pineale Collection of sperm and every 10th day by pineale
-proben: Elektroejakulation Hormonbestimmungen: Bestimmung von Testosteron, -samples: electro ejaculation Hormone determinations: determination of testosterone,
Dihydrotestosteron und FSH nach der Radioimmunoassay-Methode  Dihydrotestosterone and FSH using the radioimmunoassay method
Beobachtungen bezüglich der Spermieneigenschaften und der Hormonspiegel: Observations regarding sperm properties and hormone levels:
1. Abnahme des Ejakulationsgewichtes bei allen 4 Tieren 1. Decrease in ejaculation weight in all 4 animals
2. Abnahme der Spermienanzahl pro Ejakulat  2. Decrease in the number of sperm per ejaculate
3. Abnahme der Beweglichkeit der Spermien  3. Decrease in sperm motility
4. Morphologische Anomalitäten wie spiralförmige Schwänze und defekte Köpfe der Spermien  4. Morphological abnormalities such as spiral tails and defective sperm heads
5. Verlust/Beeinträchtigung der Akrosomen geht aus FITC-Anfärbung und der Ultrastruktur der Spermatozoen hervor  5. Loss / impairment of the acrosomes results from FITC staining and the ultrastructure of the spermatozoa
6. Keine signifikante Änderung der Serumspiegel von  6. No significant change in serum levels from
Testosteron, Didhydrotestosteron und FSH. Der diurnale Rythmus der Spiegel von Testosteron und Dihydrotestosteron wird nicht beeinträchtigt.  Testosterone, didhydrotestosterone and FSH. The diurnal rhythm of testosterone and dihydrotestosterone levels is not affected.
7. Vollständige Rückbildung der beschriebenen Spermieneigenschaften in der behandelten Gruppe innerhalb von 6 Monaten nach Beendigung der Behandlung.  7. Complete regression of the described sperm properties in the treated group within 6 months after the end of treatment.
Ejakulatvolumen, Ejakulatgewicht, Spermienkonzentration je Ejakulat, Volumenkonzentration der Spermien und die Beweglichkeit der Spermien der Tiere in der behandelten und in der Kontrollgruppe sind in den folgenden Tabellen 1-6 wiedergegeben. Ejaculate volume, ejaculate weight, sperm concentration per ejaculate, volume concentration of the sperm and the motility of the sperm of the animals in the treated and in the control group are shown in the following Tables 1-6.
Die beschriebenen Beobachtungen zeigen eindeutig, daß Antigestagene zur Herstellung von Arzneimitteln zur Kontrolle der männlichen Fertilität geeignet sind. The observations described clearly show that antigestagens are suitable for the production of medicaments for controlling male fertility.
Sie sollten außerdem zur Herstellung von Arzneimitteln zur Behandlung andrologischer Krankheitsbilder wie der benignen  You should also use the benign for the manufacture of medicines for the treatment of andrological diseases
Prostatahypertrophie und des Prostatakarzinoms geeignet sein; die beobachteten Phänomene sind nur durch inhibitorische Effekte in den akzessorischen Geschlechtsdrüsen zu erklären, zu denen auch die Prostata gehört.  Prostate hypertrophy and prostate cancer; the observed phenomena can only be explained by inhibitory effects in the accessory sex glands, which also includes the prostate.
Entscheidend ist, daß mit Antigestagenen bei sehr niedrigen Dosierungen (bezogen auf Dosierungen, die bei Makaken die It is crucial that with antigestagens at very low doses (based on doses that are the same for macaques)
Menstruation auslösen) eine reversible Hemmung der männlichen Fertilität erreicht wird.  Trigger menstruation) a reversible inhibition of male fertility is achieved.
Als Anitgestagene kommen alle Verbindungen infrage, die eine starke Affinität zum Gestagenrezeptor (Progesteronrezeptor) besitzen und dabei keine eigene gestagene Aktivität zeigen. Als kompetitive Progesteronantagonisten kommen beispielsweise folgende Steroide infrage:  All compounds which have a strong affinity for the progestogen receptor (progesterone receptor) and do not show their own progestogen activity are possible antitagens. The following steroids are possible as competitive progesterone antagonists:
11ß-[(4-N,N-Dimetylamino)-phenyl]-17ß-hydroxy-17α-propinyl- 4,9(10)-estradien-3-on (RU-38486),  11ß - [(4-N, N-dimetylamino) phenyl] -17ß-hydroxy-17α-propinyl-4,9 (10) -estradien-3-one (RU-38486),
11ß-[(4-N,N-Dimetylamino)-phenyl]-17ß-hydroxy-18-methyl-17α-propinyl-4,9(10)-estradien-3-on und  11ß - [(4-N, N-Dimetylamino) phenyl] -17ß-hydroxy-18-methyl-17α-propinyl-4,9 (10) -estradien-3-one and
11ß-[(4-N,N-Dimetylamino)-phenyl]-17aß-hydroxy-17aα-propinyl-D- homo-4,9(10),16-estratrien-3-on (alle EP-A 0 057 115);  11ß - [(4-N, N-Dimetylamino) -phenyl] -17ass-hydroxy-17aα-propynyl-D-homo-4,9 (10), 16-estratrien-3-one (all EP-A 0 057 115 );
ferner  further
11ß-p-Methoxyphenyl-17ß-hydroxy-17α-ethinyl-4,9(10)-estradien-3-on (Steroids 37 (1981), 361-382),  11β-p-methoxyphenyl-17ß-hydroxy-17α-ethynyl-4,9 (10) -estradien-3-one (Steroids 37 (1981), 361-382),
11ß-(4-Dimethylaminophenyl)-17α-hydroxy-17ß-(3-hydroxypropyl)- 13α-methyl-4,9-gonadien-3-on (EP-A 0 129 499), 11β- (4-dimethylaminophenyl) -17α-hydroxy-17ß- (3-hydroxypropyl) - 13α-methyl-4,9-gonadien-3-one (EP-A 0 129 499),
11ß-(4-Acetylphenyl)-17ß-hydroxy-17α-(prop-1-inyl)-4,9(10)-estradien-3-on (EP-A 0 190 759), sowie 11β- (4-acetylphenyl) -17ß-hydroxy-17α- (prop-1-ynyl) -4.9 (10) -estradien-3-one (EP-A 0 190 759), and
die in der EP-A 0 277 676 beschriebenen 11ß-Aryl-14ß-estradiene und -triene, die 19, 11ß-überbrückten Steroide, die Gegenstand der EP-A 0 283 428 sind, die aus der EP-A 0 289 073 hervor gehenden 11ß-Aryl-6-alkyl (bzw. 6-alkenyl oder 6-alkinyl)- estradiene und -pregnadiene und die aus der EP-A 0 321 010 bekannten 11ß-Aryl-7-methyl (bzw. 7-ethyl)-estradiene. 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 emerge from EP-A 0 289 073 outgoing 11ß-aryl-6-alkyl (or 6-alkenyl or 6-alkynyl) - estradienes and -pregnadienes and the 11ß-aryl-7-methyl (or 7-ethyl) known from EP-A 0 321 010 estradiene.
Diese Aufzählung ist nicht abschließend; auch andere in den genannten Veröffentlichungen beschriebenen Antigestagene sowie solche aus hier nicht genannten Veröffentlichungen sind geeignet.  This list is not exhaustive; other antigestagens described in the publications mentioned and those from publications not mentioned here are also suitable.
Die Antigestagene können dabei nach unterschiedlichen Behandlungsschemata angewendet werden. The antigestagens can be used according to different treatment regimens.
Anwendung zur reversiblen Unterdrückung der männlichen Fertilität; Application for reversible suppression of male fertility;
1. Intermittierende Behandlung a) Tägliche orale Behandlung über 4-12 Wochen bis zur 1. Intermittent treatment a) Daily oral treatment for 4-12 weeks until
Ausbildung einer Azoospermie. Dann: Behandlungsfreies  Formation of azoospermia. Then: treatment-free
Intervall von 3-5 Monaten. Erneute Behandlung usw. b) Intermittierende Applikation eines Depotpräparates  Interval of 3-5 months. Repeated treatment, etc. b) Intermittent application of a depot preparation
(Wirkstoff-Release über 2-6 Monate) ca. 6-12-monatige Applikationsintervalle.  (Active ingredient release over 2-6 months) approx. 6-12 month application intervals.
2. Die Behandlung erfolgt kontinuierlich a) Durch tägliche orale Applikation, 2. The treatment takes place continuously a) by daily oral application,
b) durch orale Applikation in zwei- oder mehrtägigen b) by oral application in two or more days
Intervallen oder  Intervals or
c) durch die Applikation von Depotformulierungen in c) by applying depot formulations in
regelmäßigen Abständen (z.B. 1 × pro Monat, 1 × pro Quartal usw.) Anwendung zu andrologischen Störungen: a) Die Behandlung erfolgt kontinuierlich durch orale regular intervals (e.g. 1 × per month, 1 × per quarter, etc.) Use for andrological disorders: a) The treatment is carried out continuously by oral
Applikation wie unter Punkt 2a-c aufgeführt.  Application as listed under point 2a-c.
Für die unterschiedlichen Indikationen werden die For the different indications, the
nachstehenden Dosierungen gewählt:  following doses selected:
Männliche Fertilitatskontrolle: Male fertility control:
Täglich 0.1-10.0 mg/d p.o. oder  Daily 0.1-10.0 mg / d p.o. or
1 × 1.0-300 mg als Depotinjektion  1 × 1.0-300 mg as a depot injection
(Formulierung: Microkristallsuspension, ölige Lösung, wirkstoffhaltige Träger oder andere geeignete Applikations- systeme)  (Formulation: microcrystalline suspension, oily solution, active ingredient carriers or other suitable application systems)
Andrologjsche Krankheitsbilder: Andrological diseases:
Täglich 1-100 mg/d p.o. oder  Daily 1-100 mg / d p.o. or
Depotformulierungen in regelmäßigen Intervallen, die auch für die männliche Fertilitätskontrolle sinnvoll erscheinen. Depot formulations at regular intervals that also appear useful for male fertility control.
Tabelle 1 Table 1
SPERMIENANALYSE IN BONNET-AFFEN # 11 1 KONTROLLE SPERM ANALYSIS IN BONNET MONKEY # 11 1 CONTROL
EJAKULAT VOLUMEN EJAKULAT SPERMIEN SPERMIEN BEWEGLICHKEIT GEWICHT KONZENTRATION X106/ml EJAKULAT VOLUME EJAKULAT SPERMEN SPERMEN MOBILITY WEIGHT CONCENTRATION X10 6 / ml
TAG ( DATUM) ml g PRO EJAKULAT %  DAY (DATE) ml g PER EJACULATE%
× 106 × 10 6
- 9 (29.3.90) 1.20 1.60 144 120 40% - 9 (29.3.90) 1.20 1.60 144 120 40%
- 4 (5.4.90) 1.40 1.57 (0.78)* 197 141 50%  - 4 (5.4.90) 1.40 1.57 (0.78) * 197 141 50%
+ 9 (18.4.90) 1.20 0.90 (0.42) 144 120 60%  + 9 (18.4.90) 1.20 0.90 (0.42) 144 120 60%
+ 21 (30.4.90) 0.75 0.72 (0.38) 79 105 70%  + 21 (30.4.90) 0.75 0.72 (0.38) 79 105 70%
+ 31 (10.5.90) 0.80 0.81 (0.39) 128 160 80%  + 31 (10.5.90) 0.80 0.81 (0.39) 128 160 80%
+ 42 (21.5.90) 0.50 0.61 (0.31) 74 147 70%  + 42 (21.5.90) 0.50 0.61 (0.31) 74 147 70%
+ 51 (30.5.90) 0.75 0.73 (0.39) 108 145 55%  + 51 (30.5.90) 0.75 0.73 (0.39) 108 145 55%
+ 60 (8.6.90) 0.80 0.63 (0.23) 151 189 82%  + 60 (8.6.90) 0.80 0.63 (0.23) 151 189 82%
+ 72 (20.6.90) 0.75 0.68 178 238 69% * Gewicht des Koagulums + 72 (6/20/90) 0.75 0.68 178 238 69% * weight of the coagulum
Tabelle 2 Table 2
SPERMIENANALYSE IN BONNET-AFFEN # 113 KONTROLLE SPERM ANALYSIS IN BONNET MONKEY # 113 CONTROL
EJAKULAT VOLUMEN EJAKULAT SPERMIEN SPERMIEN BEWEGLICHKEITEJAKULAT VOLUME EJAKULAT SPERMEN SPERMEN MOBILITY
GEWICHT KONZENTRATION ×105/ml CONCENTRATION WEIGHT × 10 5 / ml
TAG (DATUM) ml g PRO EJAKULAT %  DAY (DATE) ml g PER EJACULATE%
× 105 × 10 5
-15 (23.3.90) 1.0 - 180 100 80% -15 (03/23/90) 1.0 - 180 100 80%
-9 (29.3.90) 0.9 1.50 342 380 80%  -9 (29.3.90) 0.9 1.50 342 380 80%
-4 (5.4.90) 1.5 1.10 (0.40) 465 310 60%-4 (5.4.90) 1.5 1.10 (0.40) 465 310 60%
+ 9 (18.4.90) 1.1 1.04 (0.5) 300 200 60%+ 9 (18.4.90) 1.1 1.04 (0.5) 300 200 60%
+21 (30.4.90) 1.7 1.40 (0.68) 442 260 80%+21 (30.4.90) 1.7 1.40 (0.68) 442 260 80%
+31 (10.5.90) 1.2 1.10 (0.57) 252 210 02%+31 (10.5.90) 1.2 1.10 (0.57) 252 210 02%
+42 (21.5.90) 1.1 1.56 (0.84) 257 234 82%+42 (21.5.90) 1.1 1.56 (0.84) 257 234 82%
+ 51 (30.5.90) 1.6 1.70 (0.90) 288 180 -+ 51 (30.5.90) 1.6 1.70 (0.90) 288 180 -
+60 ( 0.6.90) 2.0 1.73 (0.64) 204 102 70% +60 (0.6.90) 2.0 1.73 (0.64) 204 102 70%
+ 72 (20.6.90)  + 72 (6/20/90)
Hodenbiopsie am 9.6.1990 durchgeführt Testicular biopsy performed on June 9, 1990
Tabelle 3 Table 3
SPERMIENANALYSE IN BONNET-AFFEN # 1 03 BEHANDELT SPERM ANALYSIS TREATED IN BONNET MONKEY # 1 03
EJAKULAT VOLUMEN EJAKULAT SPERMIEN SPERMIEN BEWEGLICHKEITEJAKULAT VOLUME EJAKULAT SPERMEN SPERMEN MOBILITY
GEWICHT KONZENTRATION ×105/ml CONCENTRATION WEIGHT × 10 5 / ml
TAG ( DATUM) ml g PRO EJAKULAT %  DAY (DATE) ml g PER EJACULATE%
× 105 × 10 5
- 9 (29.3.90) 0.90 1.500 342 380 80% - 9 (29.3.90) 0.90 1.500 342 380 80%
- 4 (5.4.90) 2.20 2.57 0(1.16) 396 180 80%  - 4 (5.4.90) 2.20 2.57 0 (1.16) 396 180 80%
+ 9 (18.4.90) 1.50 1.056 (0.51) 120 80 70%  + 9 (18.4.90) 1.50 1,056 (0.51) 120 80 70%
+ 21 (30.4.90) Scanty 118 41%  + 21 (30.4.90) Scanty 118 41%
+ 31 (10.5.90) 0.10 0.100 2.8 28 20%  + 31 (10.5.90) 0.10 0.100 2.8 28 20%
+ 42 (21.5.90) 0.20 0.194 29.8 149 10%  + 42 (21.5.90) 0.20 0.194 29.8 149 10%
+ 51 (30.5.90) 0.25 0.215 52 210 12%  + 51 (30.5.90) 0.25 0.215 52 210 12%
+ 60 (8.6.90) 0.10 0.083 20 198 5% (2%)  + 60 (8.6.90) 0.10 0.083 20 198 5% (2%)
+ 72 (20.6.90) 0.05 0.053 10 192 2% + 72 (6/20/90) 0.05 0.053 10 192 2%
Tabelle 4 Table 4
SPERMIENANALYSE IN BONNET-AFFEN # 1 07 BEHANDELT SPERM ANALYSIS TREATED IN BONNET MONKEY # 1 07
EJAKULAT VOLUMEN EJAKULAT SPERMIEN SPERMIEN BEWEGLICHKEITEJAKULAT VOLUME EJAKULAT SPERMEN SPERMEN MOBILITY
GEWICHT KONZENTRATION ×106/ml CONCENTRATION WEIGHT × 10 6 / ml
TAG (DATUM) ml g PRO EJAKULAT %  DAY (DATE) ml g PER EJACULATE%
× 106 × 10 6
- 9 (29.3.90) 1.60 1,350 256 160 90% - 9 (29.3.90) 1.60 1.350 256 160 90%
- 4 (5.4.90) 1.20 1.090 (0.6) 249 208 60%  - 4 (5.4.90) 1.20 1.090 (0.6) 249 208 60%
+ 9 1(8.4.90) 0.60 0.180 156 260 80%  + 9 1 (8.4.90) 0.60 0.180 156 260 80%
+ 21 (30.4.90) 0.25 - 47 190 72%  + 21 (30.4.90) 0.25 - 47 190 72%
+ 31 (10.5.90) 0.20 0.130 22 110 30%  + 31 (10.5.90) 0.20 0.130 22 110 30%
+ 42 (21.5.90) 0.10 0.073 19 192 15%  + 42 (5/21/90) 0.10 0.073 19 192 15%
+ 51 (30.5.90) 0.10 0.177 19 190 20%  + 51 (30.5.90) 0.10 0.177 19 190 20%
+ 60 (8.6.90) 0.10 0.232 22 225 0% (4%) + 60 (8.6.90) 0.10 0.232 22 225 0% (4%)
+ 72 (20.6.90) 0.15 0.260 24 162 10% + 72 (6/20/90) 0.15 0.260 24 162 10%
Tabelle 5 Table 5
SPERMIENANALYSE IN BONNET-AFFEN # 1 09 BEHANDELT SPERM ANALYSIS TREATED IN BONNET MONKEY # 1 09
EJAKULAT VOLUMEN EJAKULAT SPERMIEN SPERMIEN BEWEGLICHKEIT GEWICHT KONZENTRATION ×106/ml EJAKULAT VOLUME EJAKULAT SPERMING SPERMEN MOBILITY WEIGHT CONCENTRATION × 10 6 / ml
TAG ( DATUM) ml g PRO EJAKULAT %  DAY (DATE) ml g PER EJACULATE%
× 106 × 10 6
- 4 (5.4.90) Scanty - 4 (5.4.90) Scanty
+ 9 (18.4.90) 0.30 0.300 96 320 64% + 9 (18.4.90) 0.30 0.300 96 320 64%
+ 21 (30.4.90) 0.25 65 260 48%+ 21 (30.4.90) 0.25 65 260 48%
+ 31 (10.5.90) 0.10 0.073 8 80 16%+ 31 (10.5.90) 0.10 0.073 8 80 16%
+ 42 (21.5.90) 0.10 0.049 15 149 25%+ 42 (21.5.90) 0.10 0.049 15 149 25%
+ 51 (30.5.90) 0.15 0.146 26 176 10%+ 51 (30.5.90) 0.15 0.146 26 176 10%
+ 60 ( 8.6.90) 0.10 0.144 21 212 12% (7%)+ 60 (8.6.90) 0.10 0.144 21 212 12% (7%)
+ 72 (20.6.90) No sperm + 72 (20.6.90) No sperm
Hodenbiopsie am 9.6.1990 durchgeführt Testicular biopsy performed on June 9, 1990
Tabelle 6 Table 6
SPERMIENANALYSE IN BONNET-AFFEN # 115 BEHANDELT SPERM ANALYSIS TREATED IN BONNET MONKEY # 115
EJAKULAT SPERMIEN SPERMIEN BEWEGLICHKEIT GEWICHT KONZENTRATION ×106/ml EJACULATE SPERMING SPOTLIGHT MOBILITY WEIGHT CONCENTRATION × 10 6 / ml
TAG (DATUM) ml g PRO EJAKULAT %  DAY (DATE) ml g PER EJACULATE%
× 106 × 10 6
- 9 (29.3.90) 2.80 2.510 330 118 70% - 9 (29.3.90) 2.80 2,510 330 118 70%
- 4 (5.4.90) 2.40 2.47 (1.14) 216 90 80%  - 4 (5.4.90) 2.40 2.47 (1.14) 216 90 80%
+ 9 (18.4.90) 0.90 0.55 (0.19) 126 140 65%  + 9 (18.4.90) 0.90 0.55 (0.19) 126 140 65%
+ 21 (30.4.90) 0.50 0.320 40 80 51%  + 21 (30.4.90) 0.50 0.320 40 80 51%
+ 31 (10.5.90) 0.25 0.237 15 62 27%  + 31 (10.5.90) 0.25 0.237 15 62 27%
+ 42 (21.5.90) 0.20 0.094 39 194 10%  + 42 (21.5.90) 0.20 0.094 39 194 10%
+ 51 (30.5.90) 0.10 0.135 20 205 6%  + 51 (30.5.90) 0.10 0.135 20 205 6%
+ 60 (8.6.90) 0.10 0.151 17 172 8% (4%) + 60 (8.6.90) 0.10 0.151 17 172 8% (4%)
+ 72 (20.6.90) 0.05 0.090 7.8 156 2% + 72 (6/20/90) 0.05 0.090 7.8 156 2%
Hodenbiopsie am 9.6.1990 durchgeführt Testicular biopsy performed on June 9, 1990

Claims

Patentansprüche Claims
1. Verwendung von Antigestagenen (kompetitiven Progesteronantagonisten) zur Herstellung von Arzneimitteln zur Kontrolle der männlichen Fertilität und/oder zur Behandlung 1. Use of antigestagens (competitive progesterone antagonists) for the production of medicaments for controlling male fertility and / or for treatment
andrologischer Krankheitsbilder.  andrological clinical pictures.
2. Verwendung von Antigestagenen nach Anspruch 1 zur Behandlung der benignen Prostatahypertrophie. 2. Use of antigestagens according to claim 1 for the treatment of benign prostatic hypertrophy.
3. Verwendung von Antigestagenen nach Anspruch 1 zur Behandlung des Prostatakarzinoms. 3. Use of antigestagens according to claim 1 for the treatment of prostate cancer.
4. Verwendung von 11ß-[(4-N,N-Dimethylamino)-phenyl]-17ß-hydroxy-17α-propinyl-4,9(10)-estradien-3-on nach Anspruch 1, 2 oder 3. 4. Use of 11ß - [(4-N, N-dimethylamino) phenyl] -17ß-hydroxy-17α-propinyl-4,9 (10) -estradien-3-one according to claim 1, 2 or 3.
PCT/EP1991/002358 1990-12-07 1991-12-09 Use of antigestagenes for producing medicaments WO1992010194A1 (en)

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DE19904039561 DE4039561A1 (en) 1990-12-07 1990-12-07 USE OF ANTIGESTAGENS FOR THE MANUFACTURE OF MEDICAMENTS

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WO1994027610A1 (en) * 1993-05-28 1994-12-08 Schering Aktiengesellschaft Agents containing a compound with an anti-androgen effect and a compound with a competitive, progesterone-antagonistic effect
EP2664325A1 (en) * 2012-05-16 2013-11-20 PregLem S.A. Methods for preventing or treating androgen mediated diseases

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UY27301A1 (en) * 2001-05-25 2003-02-28 Schering Ag USE AND COMPOSITIONS OF ANTIPROGESTINES FOR THE TREATMENT OF PROSTATE DISEASES

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CHEMICAL ABSTRACTS, Vol. 109, Nr. 25, 19 December 1988, (Columbus, Ohio, US), LINDZEY J. et al., "Effects of Progestins on Sexual Behaviour in Castrated Lizards (Cnemidophorus Inornatus)", page 521, Abstract 227150s; & J. ENDOCRINOL., 1988, 119(2), 265-273. *
CHEMICAL ABSTRACTS, Vol. 113, Nr. 2, 9 July 1990, (Columbus, Ohio, US), KHOLKUTE S.D. et al., "Suppression of Bioactive Luteinizing Hormone and Testosterone by a Progesterone Antagonist ZK 98734 in Adult Male Common Marmosets, Callithrix Jaccus", page 82, Abstract 52723j; & BIOL. REPROD., 1990, 42(56), 808-814. *
CHEMICAL ABSTRACTS, Vol. 114, Nr. 5, 4 February 1991, (Columbus, Ohio, US), VAN DER SCHOOT P. et al., "Effects of Treatment of Male and Female Rats in Infancy With Mifepristone on Reproductive Function in Adulthood", page 94, Abstract 36156s; & J. REPROD. FERTIL., 1990, 90(1), 255-266. *
CHEMICAL ABSTRACTS, Vol. 116, Nr. 5, 3 February 1992, (Columbus, Ohio, US), MOBBS B.G. et al., "Suppression of the Growth of the Androgen-insensitive R3327 HI Rat Prostatic Carcinoma by Combined Estrogen and Antiprogestin Treatment", page 114, Abstract 34787r; & J. STEROID BIOCHEM. MOL. BIOL., 1991, 39(5A), 713-722. *
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994027610A1 (en) * 1993-05-28 1994-12-08 Schering Aktiengesellschaft Agents containing a compound with an anti-androgen effect and a compound with a competitive, progesterone-antagonistic effect
EP2664325A1 (en) * 2012-05-16 2013-11-20 PregLem S.A. Methods for preventing or treating androgen mediated diseases
WO2013171684A1 (en) * 2012-05-16 2013-11-21 Preglem Sa Progesterone receptor modulators for use in preventing or treating androgen mediated diseases

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