EP0296160A1 - COMBINATION OF AROMATASE INHIBITORS AND 5$g(a)-REDUCTASE INHIBITORS - Google Patents

COMBINATION OF AROMATASE INHIBITORS AND 5$g(a)-REDUCTASE INHIBITORS

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Publication number
EP0296160A1
EP0296160A1 EP19870901381 EP87901381A EP0296160A1 EP 0296160 A1 EP0296160 A1 EP 0296160A1 EP 19870901381 EP19870901381 EP 19870901381 EP 87901381 A EP87901381 A EP 87901381A EP 0296160 A1 EP0296160 A1 EP 0296160A1
Authority
EP
European Patent Office
Prior art keywords
methyl
testosterone
inhibitor
dione
aza
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP19870901381
Other languages
German (de)
French (fr)
Inventor
M. Fathy El Etreby
Ursula-F. Habenicht
Helmut Schröder
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
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Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP0296160A1 publication Critical patent/EP0296160A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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 invention relates to the use of aromatase inhibitors and testosterone 5-t reductase inhibitors and pharmaceutical compositions containing them for the prophylaxis and therapy of benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • prostate hyperplasia or prostate adenoma
  • internal prostate the so-called "internal prostate”.
  • the complaints are above all due to the obstructions of the urethra that occur.
  • the emptying of the bladder is difficult and residual urinary retention occurs. Without surgical intervention, urea poisoning can occur.
  • DE-OS 31 21 152 describes a combination preparation which consists of an aromatase inhibitor and an antiandrogen.
  • This agent represents a major advance in the prophylaxis and therapy of prostate hyperplasia, but is associated with the disadvantage, which is characteristic of anti-androgen genes, of causing potency and libido disorders in the patients.
  • an agent which consists of an aromatase inhibitor and a testosterone 5c £ reductase inhibitor in a weight ratio of essentially 20: 1 to 1:20, preferably 10: 1 to 1: 10.
  • testosterone 5c_ reductase inhibitors surprisingly not only act organ-specifically as partial antiandrogens, but also produce a synergistic effect.
  • Aromatase inhibitors and testosterone 5- ⁇ -reductase inhibitors can be used both in combination in a uniform application form and separately in two different application forms.
  • the use of an aromatase inhibitor inhibits the formation of biologically active estrogens and thus reduces or prevents an estrogen effect in the prostate.
  • the testosterone 5cL reductase inhibitor leads to a "prostate-specific" androgen deprivation.
  • Treatment with a combination of an aromatase inhibitor and a testosterone 5ct reductase inhibitor inhibits both types of prostate tissue, which are responsible for the development of the disease, from growing.
  • Aromatase inhibitors work, i.e. which can be used as a substrate for aromatase, without estrogenic or other hormonal agents after aromatization
  • Testosterone-5ot reductase inhibitor should be understood to mean all compounds which block the conversion of testosterone into the more androgen-active 5 ⁇ t-dihydrotestosterone by testosterone 5 ⁇ , reductase, such as 4-androstene-3 -on-17-carboxylic acid or
  • the testosterone-5___-reductase inhibitors are administered per day for oral administration in amounts of 70 to 100 mg, preferably 70 to 700 mg, for p._renteral administration in amounts of 70 to 500 mg, preferably 70 to 350 mg the treatment administered to humans.
  • the active ingredients can be processed with the additives, carrier substances and / or taste correctives customary in pharmaceutical pharmacy according to methods known per se to give the usual forms of administration.
  • tablets, tablets, capsules, pills, suspensions or solutions are particularly suitable.
  • Oily solutions such as sesame oil or castor oil solutions are suitable for parenteral, in particular intramuscular and subcutaneous, application.
  • Solubilizers such as benzyl benzoate or benzyl alcohol can be added to increase the solubility.
  • the formulated pharmaceuticals preferably contain 10 to 100 mg of 1-methyl-androsta-1,4-diene-3,17-dione and 10 to 100 mg of 17 ⁇ -N, N-diethylc-ramoyl-4-methyl- 4-aza-5-L-androstan-3-one and for parenteral administration 10 to 200 mg 1-methyl-androsta-1, 4-diene-3,17-dione and 10 to 200 mg 17ß-N, N- Diethylcarbamoyl-4-methyl-4-aza-5_-androstan-3-one or in each case the biologically equivalent doses of another aromatase inhibitor and testosterone 5q reductase inhibitor.
  • the two active substances can be administered in identical or different application forms.
  • the active compounds according to the invention each with half of the additives specified above, can also be pressed separately to form a two-layer tablet.

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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)

Abstract

Utilisation d'une combinaison d'un inhibiteur d'aromatase avec un inhibiteur de testérone-5alpha-réductase pour la prophylaxie et le traitement de l'hyperplasie bénigne de la prostate et agents basés sur cette combinaison. L'inhibiteur d'aromatase peut se présenter sous la forme de substances comme par exemple le 1-méthyle-androsta-1,4-dien-3,17-dione et l'inhibiteur de testérone-5alpha-réductase sous la forme de substances telles que le 17beta-diéthylcarbamoyle-4-méthyle-4-aza-5alpha-androstan-3-one.Use of a combination of an aromatase inhibitor with a testone-5alpha-reductase inhibitor for the prophylaxis and treatment of benign prostatic hyperplasia and agents based thereon. The aromatase inhibitor can be in the form of substances such as, for example, 1-methyl-androsta-1,4-dien-3,17-dione and the testone-5alpha-reductase inhibitor in the form of substances. such as 17beta-diethylcarbamoyl-4-methyl-4-aza-5alpha-androstan-3-one.

Description

Kombination von Aromatasehemmer und 5« -ßeάu tasehemmer Combination of aromatase inhibitor and 5 «-sseάu tasehemmer
Die Erfindung betrifft die Verwendung von Aromatasehemmern und Testoste- ron-5-t-Reduktasehemmern sowie diese enthaltenden pharmazeutische Mittel zur Prophylaxe und Therapie der benignen Prostatahyperplasie (BPH).The invention relates to the use of aromatase inhibitors and testosterone 5-t reductase inhibitors and pharmaceutical compositions containing them for the prophylaxis and therapy of benign prostatic hyperplasia (BPH).
Bei ca. 60% aller Männer jenseits des 50. Lebensjahres kommt es zu einer knotigen Vergrößerung der periurethalen Drüsen bzw. von Teilen des Gewe¬ bemantels um den Harnröhrenteil der Prostata. Diese als Prostatahyperpla¬ sie oder Prostataadenom bezeichnete gutartige Vergrößerung der Prostata nimmt ihren Ausgang von der sogenannten "inneren Prostata" . Die Beschwer¬ den sind vor allem auf die auftretenden Obstruktionen der Harnröhre zu¬ rückzuführen- Die Blasenentleerung ist erschwert und es kommt zu Rest- harnretentionen. Ohne operativen Eingriff kann es zu HarnstoffVergiftun¬ gen kommen.In about 60% of all men over the age of 50 there is a nodular enlargement of the periurethal glands or parts of the tissue around the urethral part of the prostate. This benign enlargement of the prostate, referred to as prostate hyperplasia or prostate adenoma, begins with the so-called "internal prostate". The complaints are above all due to the obstructions of the urethra that occur. The emptying of the bladder is difficult and residual urinary retention occurs. Without surgical intervention, urea poisoning can occur.
In der DE-OS 31 21 152 ist ein Kombinationspräparat beschrieben, das aus einem Aromatasehemmer und einem Antiandrogen besteht. Dieses Mittel stellt einen großen Fortschritt für die Prophylaxe und Therapie der Prostatahyperplasie dar, ist jedoch mit dem für Antiandro¬ gene charakteristischen Nachteil behaftet, bei den Patienten Potenz- und Libido-Störungen hervorzurufen.DE-OS 31 21 152 describes a combination preparation which consists of an aromatase inhibitor and an antiandrogen. This agent represents a major advance in the prophylaxis and therapy of prostate hyperplasia, but is associated with the disadvantage, which is characteristic of anti-androgen genes, of causing potency and libido disorders in the patients.
Es ist daher die Aufgabe der Erfindung, ein Mittel für den Mann zu ent¬ wickeln, das zu einer Rückbildung sowohl des epithelialen als auch des fibromuskulären Anteils der Prostata führt, ohne die Nachteile der be¬ kannten Hormonbehandliing aufzuweisen.It is therefore the object of the invention to develop an agent for men which leads to a regression of both the epithelial and the fibromuscular portion of the prostate, without having the disadvantages of the known hormone treatment.
Es wurde gefunden, daß als Antiandrogen auch ein Testosteron-5*.-Reduk- tasehemmer genommen werden kann, der die g__τ__ττten Nachteile nicht hat.It has been found that a testosterone 5 *. Reductase inhibitor can also be used as antiandrogen, which does not have the disadvantages.
Die Aufgabe wird erfindiαngsgemäß dadurch gelöst, daß man ein Mittel ver¬ wendet, das aus einem Aromatasehemmer und einem Testosteron-5c£-Reduktase- hemmer in einem GewichtsVerhältnis von im wesentlichen 20:1 bis1:20, vorzugsweise von 10:1 bis 1:10, besteht.The object is achieved according to the invention in that an agent is used which consists of an aromatase inhibitor and a testosterone 5c £ reductase inhibitor in a weight ratio of essentially 20: 1 to 1:20, preferably 10: 1 to 1: 10.
Es stellte sich dabei heraus, daß die Testosteron-5c_-Reduktasehemmer überraschenderweise nicht nur als partielle Antiandrogene organspezifisch wirken, sondern auch einen synergistischen Effekt hervorrufen. Aromatasehemmer und Testosteron-5-ι-Reduktasehemmer können sowohl kombi¬ niert in einer einheitlichen Applikationsform als auch getrennt in zwei verschiedenen Applikationsformen angewendet werden. Durch die Anwendung eines Aromatasehemmers wird die Bildung von biologisch wirksamen Östro- gen gehemmt und damit eine Östrogenwirkung in der Prostata verringert bzw. verhindert. Darüberhinaus führt der Testosteron-5cL-Reduktase-Hemmer zu einem "prostata-spezifischen" Androgen-Entzug.It was found that the testosterone 5c_ reductase inhibitors surprisingly not only act organ-specifically as partial antiandrogens, but also produce a synergistic effect. Aromatase inhibitors and testosterone 5-ι-reductase inhibitors can be used both in combination in a uniform application form and separately in two different application forms. The use of an aromatase inhibitor inhibits the formation of biologically active estrogens and thus reduces or prevents an estrogen effect in the prostate. In addition, the testosterone 5cL reductase inhibitor leads to a "prostate-specific" androgen deprivation.
Durch die Behandlung mit einer Kombination eines Aromatasehemmers und eines Testosteron-5ct-Reduktase-Hemmers werden somit beide Gewebearten der Prostata, die für die Entstehung des Krankheitsbildes verantwortlich sind, im Wachstum gehemmt.Treatment with a combination of an aromatase inhibitor and a testosterone 5ct reductase inhibitor inhibits both types of prostate tissue, which are responsible for the development of the disease, from growing.
Für die erfindungsgemäße Anwendung sind alle Stoffe geeignet, die alsFor the application according to the invention, all substances are suitable which as
Aromatasehemmer wirken, d.h. die als Substrat für die Aromatase infrage kommen, ohne nach der Aromatisierung östrogene oder andere hormoneileAromatase inhibitors work, i.e. which can be used as a substrate for aromatase, without estrogenic or other hormonal agents after aromatization
Wirkungen zu besitzen, wie beispielsweise 1-Methyl-androsta-1 ,4-dien-To have effects such as 1-methyl-androsta-1,4-diene
3,1 -dion. Als weitere Aromatasehemmer seien beispielsweise folgende3.1-dione. Examples of other aromatase inhibitors are as follows
Verbindungen aufgeführt: das in z.B. Journal of Clinical Endocrinology and Metabolis _49_, 672Connections listed: that in e.g. Journal of Clinical Endocrinology and Metabolis _49_, 672
(1979) beschriebene Testolacton (17a-Oxa-D-homoandrost-1 ,4-dien-3,17- dion) , die in "Endocrinology" 1973, Vol. 92, No. 3, Seite 874 beschriebenen(1979) described testolactone (17a-oxa-D-homoandrost-1, 4-diene-3,17-dione), which is described in "Endocrinology" 1973, vol. 92, no. 3, page 874
Verbindungenlinks
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,Androsta-1, 4,6-triene-3,17-dione,
4-Androsten-19-chlor-3,17-dion,4-androsten-19-chloro-3,17-dione,
4-Androsten-3,6,17-trion, die in DE-OS 31 24 780 beschriebenen 19-alkynylierten Steroide, die in DE-OS 31 24 719 beschriebenen 10—(1 ,2-Propadienyl)-steroide und die in EP 100 566 beschriebenen 19-Thio-androstanderivate sowie 4-Androsten-4-ol-3,17-dion, dessen Ester, z.B. die Acetate, Hepta- noate, Dodecanoate, Hemisuccinate und Benzoate, die in "Endocrinology"4-androsten-3,6,17-trione, the 19-alkynylated steroids described in DE-OS 31 24 780, the 10- (1,2-propadienyl) steroids described in DE-OS 31 24 719 and those in EP 100 566 described 19-thio-androstand derivatives and 4-androsten-4-ol-3,17-dione, its esters, for example the acetates, hepta-noates, dodecanoates, hemisuccinates and benzoates, which are described in "Endocrinology"
1977, Vol. 100, No. 6, Seite 1684 und US-Patent 4.235.893 beschrieben sind. Bei oraler Applikation werden täglich 70 bis 1000 mg, vorzugsweise 70 bis 700 mg, bei parenteraler Applikation täglich 70 bis 500 mg, vorzugswei¬ se 70 bis 350 mg 1-Methyl-androsta-1 ,4-dien-3,17-dion bzw. biologisch äquivalenten Dosen von anderen Aromatasehemmern für die Behandlung am Menschen angewendet.1977, Vol. 100, No. 6, page 1684 and U.S. Patent 4,235,893. In the case of oral administration, 70 to 1000 mg, preferably 70 to 700 mg, and in the case of parenteral administration, 70 to 500 mg, preferably 70 to 350 mg, of 1-methyl-androsta-1, 4-diene-3,17-dione or biologically equivalent doses of other aromatase inhibitors for human treatment.
Unter Testosteron-5ot-Reduktase-Hemmer gemäß vorliegender Erfindung sollen alle Verbindungen verstanden werden, die die Umwandlung des Testosterons in das androgen-aktivere 5<t- Dihydrotestosteron durch die Testosteron- 5α,-Reduktase blockieren, wie zum Beispiel 4-Androsten-3-on-17-carbonsäure bzw.Testosterone-5ot reductase inhibitor according to the present invention should be understood to mean all compounds which block the conversion of testosterone into the more androgen-active 5 <t-dihydrotestosterone by testosterone 5α, reductase, such as 4-androstene-3 -on-17-carboxylic acid or
4-Androsten-3-on-17-carbonsäuremethylester (Neuroendocrinology 3J5, 277 (1983), Endocrinology 92^, 1216 (1973), Can. Patent No. 970,692) oder die in EP 4949 und US 4.179.453 beschriebenen 17-substituierten 4-Aza- 5 -andostran-3-one, wie zum Beispiel 17ß-N,N-Diäthylcarbamoyl-4-methyl- 4-aza-5j_-androstan-3-on.4-Androsten-3-one-17-carboxylic acid methyl ester (Neuroendocrinology 3J5, 277 (1983), Endocrinology 92 ^ , 1216 (1973), Can. Patent No. 970,692) or the 17-substituted ones described in EP 4949 and US 4,179,453 4-aza-5-andostran-3-ones such as 17ß-N, N-diethylcarbamoyl-4-methyl-4-aza-5j_-androstan-3-one.
Die Testosteron-5__-Reduktase-Hemmer werden bei oraler Applikation in Mengen von 70 bis löOC mg, vorzugsweise von 70 bis 700 mg, bei p._rentera- ler Applikation in Mengen von 70 bis 500 mg, vorzugsweise von 70 bis350mg, pro Tag für die Behandlung am Menschen verabreicht.The testosterone-5__-reductase inhibitors are administered per day for oral administration in amounts of 70 to 100 mg, preferably 70 to 700 mg, for p._renteral administration in amounts of 70 to 500 mg, preferably 70 to 350 mg the treatment administered to humans.
Die Wirkstoffe können mit den in der galenischen Pharmazie üblichen Zusät¬ zen, Trägersubstanzen und/oder Geschmackskorrigentien nach an sich bekann¬ ten Methoden zu den üblichen Applikationsformen verarbeitet werden.The active ingredients can be processed with the additives, carrier substances and / or taste correctives customary in pharmaceutical pharmacy according to methods known per se to give the usual forms of administration.
Für die bevorzugte orale Applikation kommen insbesondere Tabletten, Dra¬ gees, Kapseln, Pillen, Suspensionen oder Lösungen infrage.For the preferred oral application, tablets, tablets, capsules, pills, suspensions or solutions are particularly suitable.
Für die parenterale, insbesondere intramuskuläre und subcutane Applika¬ tion sind ölige Lösungen, wie zum Beispiel Sesamöl- oder Rizinusöllösungen, geeignet. Zur Erhöhung der Löslichkeit können Lösungsvermittler, wie zum Beispiel Benzylbenzoat oder Benzylalkohol, zugesetzt werden. Die wie oben angegebenen formulierten Arzneimittel enthalten für die orale Applikation vorzugsweise 10 bis 100 mg 1-Methyl-androsta-1 ,4-dien- 3,17-dion und 10 bis 100 mg 17ß-N,N-Diäthylc_rbamoyl-4-methyl-4-aza-5-L- androstan-3-on und für die parenterale Applikation 10 bis 200 mg 1-Methyl- androsta-1 ,4-dien-3,17-dion und 10 bis 200 mg 17ß-N,N-Diäthylcarbamoyl- 4-methyl-4-aza-5_-androstan-3-on oder jeweils die biologisch äquivalen¬ ten Dosen eines anderen Aromatasehemmers und Testosteron-5q-Reduktase- Hemmers. Die beiden Wirkstoffe können in identischen oder unterschiedli¬ chen Applikationsformen verabreicht werden. Oily solutions such as sesame oil or castor oil solutions are suitable for parenteral, in particular intramuscular and subcutaneous, application. Solubilizers such as benzyl benzoate or benzyl alcohol can be added to increase the solubility. For oral administration, the formulated pharmaceuticals preferably contain 10 to 100 mg of 1-methyl-androsta-1,4-diene-3,17-dione and 10 to 100 mg of 17β-N, N-diethylc-ramoyl-4-methyl- 4-aza-5-L-androstan-3-one and for parenteral administration 10 to 200 mg 1-methyl-androsta-1, 4-diene-3,17-dione and 10 to 200 mg 17ß-N, N- Diethylcarbamoyl-4-methyl-4-aza-5_-androstan-3-one or in each case the biologically equivalent doses of another aromatase inhibitor and testosterone 5q reductase inhibitor. The two active substances can be administered in identical or different application forms.
BEISPIEL 1EXAMPLE 1
50,0 mg 1 -Methyl- androsta-1 , 4-dien-3 , 17-dion50.0 mg of 1-methyl-androsta-1, 4-diene-3, 17-dione
5,0 mg 17ß-N,N-Diäthylcarbamoyl-4-methyl-4-aza-5.-androstan-3-on 115,0 mg Lactose 50,0 mg Maisstärke5.0 mg 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5.-androstan-3-one 115.0 mg lactose 50.0 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
225,0 mg Gesamtgewicht der Tablette, die in üblicher Weise auf einer Tablettenpresse hergestellt wird. Gegebenenfalls können auch die erfindungsgemäßen Wirkstoffe mit jeweils der Hälfte der oben angegebenen Zusätze getrennt zu einer Zweischichtentablet¬ te gepreßt werden.225.0 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, each with half of the additives specified above, can also be pressed separately to form a two-layer tablet.
BEISPIEL 2EXAMPLE 2
20,0 mg 1 -Methyl- androsta-1 ,4-dien-3,17-dion20.0 mg of 1-methyl-androsta-1,4-diene-3,17-dione
2,0 mg 17ß-N,N-Diäthylcarbamoyl-4-methyl-4-aza-5εC-androstan-3-on 135,0 mg Lactose 60,0 mg Maisstärke2.0 mg 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5εC-androstan-3-one 135.0 mg lactose 60.0 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 Magnesiurnstearat0.5 mg magnesium stearate
222,0 mg Gesamtgewicht der Tablette, die in üblicher Weise auf einer Tablettenpresse hergestellt wird. Gegebenenfalls können auch die erfindungsgemäßen Wirkstoffe mit jeweils der Hälfte der oben angegebenen Zusätze getrennt zu einer Zweischichtentablet¬ te gepreßt werden. BEISPIEL 3222.0 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, each with half of the additives specified above, can also be pressed separately to form a two-layer tablet. EXAMPLE 3
Zusammensetzung_einer öligen_Lösungj_Composition of an oily solutionj
100 , 0 mg 1 -Methyl- androsta- , 4-dien-3 , 1 7-dion100.0 mg of 1-methyl-androsta-, 4-diene-3, 17-dione
10 , 0 mg 1 7ß-N,N-Diäthylcarbamoyl-4-methyl-4-aza-5^-androstan-3-on 343 , 4 mg Rizinusöl 608 , 6 mg Benzylbenzoat10.0 mg 1 7β-N, N-diethylcarbamoyl-4-methyl-4-aza-5 ^ -androstan-3-one 343, 4 mg castor oil 608, 6 mg benzyl benzoate
1062 , 0 mg = 1 ml1062.0 mg = 1 ml
Die Lösung wird in eine Ampulle gefüllt. 1-Methyl-androsta-1 ,4-dien-3,17- dion tαnd 17ß-N,N-Diäthylcarbamoyl-4-methyl-4-aza-5q_-androstan-3-on können auch mit jeweils der Hälfte der oben angegebenen Zusätze getrennt in zwei Kammern abgefüllt werden. The solution is filled into an ampoule. 1-Methyl-androsta-1,4-diene-3,17-dione tαnd 17ß-N, N-diethylcarbamoyl-4-methyl-4-aza-5q_-androstan-3-one can also be used with half of the above Additives are filled separately in two chambers.

Claims

PATENTANSPRÜCHE PATENT CLAIMS
1. Verwendung von Aromatasehemmern und Testosteron-5_L-Reduktase-Hemmern in einem GewichtsVerhältnis von 20:1 bis 1:20 zur Prophylaxe und The¬ rapie der Prostatahyperplasie.1. Use of aromatase inhibitors and testosterone 5_L reductase inhibitors in a weight ratio of 20: 1 to 1:20 for the prophylaxis and therapy of prostatic hyperplasia.
2. Verwendung von 1-Methyl-androsta-1 ,4-dien-3,17-dion als Aromatasehem¬ mer nach Anspruch 1.2. Use of 1-methyl-androsta-1, 4-diene-3,17-dione as aromatase inhibitor according to claim 1.
3. Verwendung von 17ß-N,N-Diäthylcarbamoyl-4-methyl-4-aza-5-t-androstan- 3-on als Testosteron-5o*,-Reduktase-Hemmer nach Anspruch 1.3. Use of 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5-t-androstan-3-one as testosterone-5o * , reductase inhibitor according to claim 1.
4. Verwendung nach Anspruch 1 von täglich 70 bis 1000 mg 1-Methyl-andro- sta-1 ,4-dien-3,17-dion und 70 bis 1000 mg 17ß-N,N-4. Use according to claim 1 from daily 70 to 1000 mg of 1-methyl-andro-sta-1, 4-diene-3,17-dione and 70 to 1000 mg of 17ß-N, N-
Diäthylcarbamoyl-4-methyl-4-aza-5c.-androstan-3-on oder jeweils biolo¬ gisch äquivalente Dosen eines anderen Aromatasehemmers und Testoste¬ ron-5q.-Reduktase-Hemmers.Diethylcarbamoyl-4-methyl-4-aza-5c.-androstan-3-one or in each case biologically equivalent doses of another aromatase inhibitor and testosterone 5q. Reductase inhibitor.
5. Mittel zur Prophylaxe und Therapie der Prostatahyperplasie auf Basis von Aromatasehemmern und Testosteron-5-ϊ-Reduktase-Hemmern in einem Gewichtsverhältnis von 20:1 bis 1:20, vorzugsweise von 10:1 bis 1:10.5. Agents for the prophylaxis and therapy of prostate hyperplasia based on aromatase inhibitors and testosterone 5-Redu reductase inhibitors in a weight ratio of 20: 1 to 1:20, preferably from 10: 1 to 1:10.
6. Mittel nach Anspruch 5 auf Basis von 1-Methyl-androsta-1 ,4-dien-3,17- dion als Aromatasehemmer und 17ß-N,N-Diäthylcarbamoyl-4-methyl-4-aza- 5<--androstan-3-on als Testosteron-5<t-Reduktase-Hemmer.6. Composition according to claim 5 based on 1-methyl-androsta-1, 4-diene-3,17-dione as an aromatase inhibitor and 17ß-N, N-diethylcarbamoyl-4-methyl-4-aza- 5 <- androstane -3-one as testosterone-5 <t-reductase inhibitor.
7. Oral applizierbares Mittel nach Anspruch 5 enthaltend 70 bis 1000 mg 1-Methyl-androsta-1 ,4-dien-3,17-dion und 70 bis 1000 mg 17ß-N,N-Di- äthylcarbamoyl-4-methyl-4-aza-ΞL-androstan3-on oder jeweils biologisch äquivalente Dosen eines anderen Aromatasehemmers und Testosteron-5«. -Reduktase-Hemmers. 7. Orally administrable composition according to claim 5 containing 70 to 1000 mg of 1-methyl-androsta-1, 4-diene-3,17-dione and 70 to 1000 mg of 17β-N, N-diethylcarbamoyl-4-methyl-4 -aza-ΞL-androstan3-one or respectively biologically equivalent doses of another aromatase inhibitor and testosterone-5 « . Reductase inhibitors.
8. Parenteral applizierbares Mittel nach Anspruch 5 enthaltend 70 bis 500 mg 1-Methyl-androsta-1 ,4-dien-3,17-dion und 70 bis 500 mg 17ß-8. Parenterally administrable composition according to claim 5 containing 70 to 500 mg of 1-methyl-androsta-1, 4-diene-3,17-dione and 70 to 500 mg of 17ß-
N,N-Diäthylcarbamoyl-4-methyl-4-aza-5q.-androstan-3-on bzw. biologisch äquivalente Dosen eines anderen Aroamtasehemmersoder Testosteron-5q;- Reduktase-Hemmers.N, N-diethylcarbamoyl-4-methyl-4-aza-5q.-androstan-3-one or biologically equivalent doses of another aroamtase inhibitor or testosterone 5q; reductase inhibitor.
9. Mittel nach Anspruch 5 enthaltend 70 bis 1000 mg oral applizierbares 1-Methyl-androsta-1 ,4-dien-3,17-dion und 70 bis 500 mg parenteral applizierbares 17ß-N,N-Di.äthylcarbamoyl-4-methyl-4-aza-5q.-androstan- 3-on bzw. jeweils biologisch äquivalente Dosen eines anderen Aromata¬ sehemmers oder Testosteron-5ot-Reduktase-Hemmeιs.9. Composition according to claim 5 containing 70 to 1000 mg of orally administrable 1-methyl-androsta-1, 4-diene-3,17-dione and 70 to 500 mg of parenterally administrable 17ß-N, N-Di.äthylcarbamoyl-4-methyl -4-aza-5q.-androstan- 3-one or respectively biologically equivalent doses of another flavor inhibitor or testosterone 5ot reductase inhibitor.
10. Mittel nach Anspruch 5 enthaltend 70 bis 500 mg parenteral applizier¬ bares 1-Methyl-androsta-1 ,4-dien-3,17-dion und 70 bis 1000 mg oral applizierbares 17ß- , -Diäthylcarbamoyl-4-methyl-4-aza-_c_-androstan- 3-on bzw. jeweils biologisch äquivalente Dosen eines anderen Aroma¬ tasehemmers oder Testosteron-5cfc-Reduktase-Hemme_s. 10. Composition according to claim 5 containing 70 to 500 mg parenterally administrable 1-methyl-androsta-1, 4-diene-3,17-dione and 70 to 1000 mg orally administrable 17ß-, -diethylcarbamoyl-4-methyl-4 -aza-_c_-androstan- 3-one or respectively biologically equivalent doses of another aromatase inhibitor or testosterone 5cfc reductase inhibitor.
EP19870901381 1986-03-06 1987-03-03 COMBINATION OF AROMATASE INHIBITORS AND 5$g(a)-REDUCTASE INHIBITORS Withdrawn EP0296160A1 (en)

Applications Claiming Priority (2)

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DE3607651 1986-03-06
DE19863607651 DE3607651A1 (en) 1986-03-06 1986-03-06 COMBINATION OF AROMATASE INHIBITORS AND TESTOSTERONE-5 (ALPHA) REDUCTASE INHIBITORS

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EP0296160A1 true EP0296160A1 (en) 1988-12-28

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US5595985A (en) * 1989-03-10 1997-01-21 Endorecherche Inc. Combination therapy for prophylaxis and/or treatment of benign prostatic hyperplasia
US5372996A (en) * 1989-03-10 1994-12-13 Endorecherche, Inc. Method of treatment of androgen-related diseases
DK0595796T3 (en) * 1989-07-07 2003-05-05 Endorech Inc Method of treating androgen-related diseases
CA2062973C (en) * 1989-07-07 2003-09-23 Fernand Labrie Combination therapy for prophylaxsis and/or treatment of benign prostatic hyperplasia
IL101243A (en) * 1991-03-20 1999-12-22 Merck & Co Inc Pharmaceutical compositions for treatment of benign prostatic hyperplasia comprising a steroid derivative
AU1893492A (en) * 1991-04-17 1992-11-17 Merck & Co., Inc. Pharmaceutical combination for the treatment of benign prostatic hyperplasia comtaining a 5 alpha-reductase inhibitor
EP0641211A1 (en) * 1992-05-21 1995-03-08 Endorecherche Inc. INHIBITORS OF TESTOSTERONE 5$g(a)-REDUCTASE ACTIVITY
HU212459B (en) * 1992-10-02 1996-06-28 Richter Gedeon Vegyeszet Process for producing new 17-beta-substituted 4-aza-androstane-derivatives and pharmaceutical compositions containing them
GB9717428D0 (en) * 1997-08-19 1997-10-22 Glaxo Group Ltd Pharmaceutical composition

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AU527030B2 (en) * 1978-04-13 1983-02-10 Merck & Co., Inc. 4-aza-17-substituted-5a-androstan-3-ones
DE2817157A1 (en) * 1978-04-17 1979-10-25 Schering Ag USE OF ANTIOESTROGEN AND ANTIGONADOTROP ACTING ANTIANDROGEN FOR PROPHYLAXIS AND THERAPY OF PROSTATE HYPERPLASIA
DE3121152A1 (en) * 1981-05-22 1982-12-09 Schering Ag, 1000 Berlin Und 4619 Bergkamen "USE OF THE COMBINATION OF AN AROMATASE INHIBITOR WITH AN ANTIANDROGEN FOR PROPHYLAXIS AND THERAPY OF PROSTATE HYPERPLASIA"

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AU7086787A (en) 1987-09-28
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