CA2163878A1 - Agents containing a compound with an anti-androgen effect and a compound with a competitive, progesterone-antagonistic effect - Google Patents
Agents containing a compound with an anti-androgen effect and a compound with a competitive, progesterone-antagonistic effectInfo
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- CA2163878A1 CA2163878A1 CA 2163878 CA2163878A CA2163878A1 CA 2163878 A1 CA2163878 A1 CA 2163878A1 CA 2163878 CA2163878 CA 2163878 CA 2163878 A CA2163878 A CA 2163878A CA 2163878 A1 CA2163878 A1 CA 2163878A1
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- beta
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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
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- Pharmacology & Pharmacy (AREA)
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- 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
Agents contain at least one compound with an anti-androgen effect (AA) as well as at least one compound with a competitive, progesterone-antagonistic effect (PA). These agents are suitable for preparing medicaments for the prophylaxis and therapy of prostate carcinome and benign prostate hyperplasia (BPH). Also disclosed is the use of at least one compound with a PA effect to prepare medicaments for the prophylaxis and therapy of BPH.
Description
W0 9~/27'610 PCT/EP9~/01756 Agent:s that Contain a Compound with Anti-AndrogeniG Effect a~ Well a~ a Compound with Competitive~ Progesteron~-Antagonistic Effect Thi.s invention relates to agents that contain at least one compound with anti-androgenic (AA) effect as well as at least one compound with competitive, progesterone-antagonistic (PA) effect.
It relat:es especially to agents of the indicated type for prophyl~xis and for treatment of carcinoma of the prostate as well as of benign prostatic hyperplasia (BPH).
Even before suitable anti-androgens were available, Dorfman postulat:ed that systemically effective anti-androgens could be of great benefit in the treatment of androgen-dependent tumors of the prostate. A multicentric, controlled study at the end of the 1970s definitely confirmed, keeping in mind rational inclusion criteria and differentiated monitoring of the course (carcinoma of the prostate is only at times and partially androgen-dependent), that treatment with cyproterone acetate, which is regarded as a standard anti-androgen, represents a good and advantageous alterative to other palliative processes in the treatment of inoperable, metastasized carcinoma of the prostate.
In the case of prostatic hyperplasia., this is a non-malignant enlargement of the prostate, wh.ich originates in the so-called "inner" prostate. The symptoms are attributable mainly to the obstructions of the urethra that occur. Voiding of the 2163878 ~
bladder is impeded, and residual urine ret:ention results. Urea poisoning can occur without operative intervention.
In ~he case of enlargement of the prostate, interstice (stroma) and epithelium are involved to a changing extent. As causes, i.a., a shifting of the estrogen/androgen ratio in favor of estrogen can be considered. In various studies, it has been shown that in the case of older males, the serum testosterone concentrations decrease; at the same time, the portion of SHBG
(sex hor~one binding globulins, specific conveying protein for steroids) increases, so that the biologic~l availability of androgens decreases still further.
Also, for the treatment of prostatic hyperplasia, the use of gestagenically and anti-androgenically effective esters of 6-chloro-17-hydroxy-lct,2~-methylene-pregna-4,6-diene-3,20-dione (cyproterone ester, i.a., cyproterone acetate) is already described (US-A-3,423,507). It has been shown, however, that only a partial remission of the hyperplasia occurs with this treatment.
Also, combinations of various antihormones or hormonic synthesis inhibitors are part of the treatment of the prostatic hyperplasia in the prior art, for example, combination of an aromatase inhibitor with an anti-androgen (DE-A-31 21 152), an anti-estrogen with a substance having an anti-androgenic effect (DE-A-28 17 157) or an aromatase inhibitor with a 5~-reductase inhibit~r (W087/05216; WO91/00731; WO92/18132).
In certain models for the study of c:arcinoma of the prostate, an effective inhibition of tumor growth was observed in 216387~
the case of a sole administration of a competitive progesterone antagonist [Betty Mobbs, I. Johnson, J. of Steroid. Biochem. Mol.
Biol., 39, pp. 713-722, 1991; tumor model: R3327H; test substance: llB-[(4-N,N-dimethylamino)-phenyl]-17B-hydroxy-17~-propiny]-4,9(10)-estradien-3-one (RU-486, EP-A-O 057 115)].
Androgen-independent prostate carcinoma subtypes exist, which do not respond to the single administration of an anti-androgen. The monotherapy of prostate carcinomas is therefore unsatisfactory.
The object of this invention is to provide phar~Laceutical agents that make possible an effective treatment of prostate carcinomas and in general also those which have become androgen-independent. At the same time, it would be desirable if such an agent were also suitable for prophylaxis and treatment of benign prostatic hyperplasia.
Such pharmaceutical agents are made available by this invention.
It has now been found that in the case of treatment of prostate carcinoma with a combination of at least one compound with anti-androgenic effect and at least one compound with competitive, progesterone-antagonistic effect, tumor growth of the prostate carcinoma -- even that whichL has also become androgen-independent -- is more greatly inhibited than would correspond to the sum of the individual effects of AA and PA.
In treating prostatic hyperplasia (~PH) with the agent according tc~ the invention, a greater re~uction of size of the ~ 4 hyperplastically enlarged prostate occurs than in the case of monotherapy with an anti-androgen.
The agent according to the invention thus has a synergistic effect in the case of the indications provided. A
(pharmaceutically effective) combination that contains AA and PA
was not yet known.
This invention also relates to,the use of at least one compounc~ with anti-androgenic (AA) effect as well as at least one compounc~ with competitive, progesterone-antagonistic (PA) effect for the production of pharmaceutical agents.
In particular, the invention relates to the use of the above-mentioned compounds for the production of pharmaceutical agents f'or prophylaxis and for treatment of prostate carcinoma and for prophylaxis and for treatment of benign prostatic hyperplasia (BPH).
The sole use of a compound with competitive, progesterone-antagonistic (PA) effect for the production of pharmaceutical agents ~or prophylaxis and for treatment of benign prostatic hyperplasia (BPA) has not previously been known.
Th~s invention therefore also relates to the use of at least one compound with competitive, progesterone-antagonistic (PA) effect ~or the production of pharmaceutical agents for prophylaxis and treatment of BPH.
For the sole use of at least one cornpound with PA effect for the production of such a pharmaceutical agent, all statements made concerning the combination hold true for this individual ~ 5 --- 2~63878 component, especially relative to the dose~, of exemplary compounds and formulation possibilities.
The weight ratio of both components of the agent according to the invention can be varied within wide limits for application for the two described indications.
Thus, both identical amounts of AA and PA and an excess of one of the two components can be present :in the agent. AA and PA
are used together, separately, simultaneollsly and/or graduated in time, in a weight ratio of 1:40 to 25:1, preferably 1:1 to 5:1, and especially 1:1 to 2:1. Simultaneous administration is preferred.
Also, a sequential treatment with the two components AA and PA of the combination according to the invention is possible.
The component provided as the second can :in this case be given at any time after administration of the component that is administered first, as long as it is still bio-available in the patient to be treated simultaneously with an effective amount of the component that is administered first. For example, the anti-androgenic component can be given first, and then the PA
component can be given.
The treatment program for a patient who is suffering from a prostate carcinoma or a BPH can also be arranged so that monotherapy with an anti-androgen is carried out as a first measure of treatment, specifically over a period of several weeks, until further growth inhibition of the prostate carcinoma can no longer be achieved. After that, the treatment with PA by '' 21~3878 itself or AA and PA in combination, simult:aneously, or sequentially is carried out.
The treatment with the combination ac:cording to the invention is carried out as long as, again, further growth inhibition is no longer observed.
In the case of simultaneous treatment;, AA and PA are administered in one dosage unit or in separate dosage units.
As a compound with anti-androgenic ei-fect, all compounds are suitable that act as competitive anti-androgens, i.e., those that mediate their AA effect by great affinity to the androgen receptor. These compounds with AA effect can be both of steroidal origin and non-steroids.
As steroids, for example, the compounds of general formulas I and II are suitable:
C_O
Y~
in which R1 and R2 each stand for a hydrogen atom or both together mean an additional carbon-carbon bond or the methyl group, ' ~ 2163878 R3 means the acyl radical of an acid that is commonly used in steroid chemistry, Y means an oxygen atom or the group H, OR~ with R4 meaning hydrogen, acyl or alkyl, X1 means a hydrogen or chlorine atom and X2 means a hydrogen, fluorine or chlorine atom.
~1 ~ ~ ~ 7~ ~17 o~
in which R1 and RZ each stand for hydrogen or both together mean the methylene group, X means hydrogen, fluorine or chlorine and A-B
I ;a 17 or C17 ~1 in which R3 and R~ represent the acyl radical of an acid that is commonly used in steroid chemistry.
The designation acyl radical is to be understood to encompass the radicals of the acids that are commonly used in . ~. 8 - 216387~
steroid chemistry for the esterification of secondary and tertiary hydroxy groups. Preferred are aliphatic carboxylic acids with 1-8 carbon atoms, such as, for example, acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, hexanoic: acid, heptanoic acid, etc. The esters of acetic acid are espe.cially preferred.
Alkyl is to be understood to be lower alkyl groups with 1-5 carbon atoms, and the methyl group is preferred.
Typical compounds of general formula I are the 17-esters of, for exannple, 6-('hloro-17-hydroxy-1~,21x-methylene-pregna-4,6-diene-3,20-dione;
6-chloro-17-hydroxy-pregna-4,6-diene-3,20-dione;
6-chloro-17-hydroxy-pregna-1,4,6-triene-3,20-dione;
6-chloro-3~,17-dihydroxy-la,2c~-methylene-pregna-4,6-dien-20-one;
6--chloro-3~-methoxy-17-hydroxy-1~,2c-methylene-pregna-4,6-dien-20--one;
6-~Eluoro-17-hydroxy-lc~,2~-methylene-pregna-4,6-diene-3,20-dione;
17 -hydroxy-l~x,2a!-methylene-pregna-4,6-diene-3,20-dione and 4,6-dichloro-17-hydroxy-lc~,2c~-methylene-pregna-4,6-diene-3,20-dione.
Preferred compounds of general formula I are 6--Chloro-17-hydroxy-lcc,2c~-methylene--pregna-4,6-diene-3,20-dione--a~etate (cyproterone acetate) and ~ :~ 9 2~63~78 6-chloro-17-hydroxy-pregna-4,6-diene-3,20-dione-acetate (chlormadinone acetate).
Typical compounds of general formula II are, for example, 6-Chloro-17aB-acetoxy-17a~-methyl-1~,2~-methylene-D-homo-4,6-androstadiene-3,17-dione and ~ -chloro-17a!-acetoxy-17B-methyl-la!,2~-methylene-D-homo-4,6-androstadiene-3,17a-dione.
Steroidopyrazoles and steroidotriazoles, described in patent applications EP-A-0 207 375 and W0-A-92/00992, are also suitable, for example, the (Sa!,17a!)-1'-(methylsulfonyl)-l'H-pregn-20-yno-(3,2-c)-pyrazol--17-ol;
4,17a!-dime~hyl-1'-mesyl-l'H-androst-4-eno[3,2-c]-pyrazol-17B-ol;
~ mesyl-17~-methyl-l'H-androsta-4,15-dieno[3,2-c]-pyrazol-17B-ol;
6,6-ethylene-1'-mesyl-17~-methyl-l'H-androst-4-eno[3,2-c]-pyrazol--17B-ol;
7~17~-dimethyl-1'-mesyl-l'H-androst-4-eno[3,2-c]-pyrazol-17B-ol;
2'--mesyl-17~-methyl-2'H-triazolo[4',5':2,3]-androsta-4,15-dien-17B-ol.
Suitable as nonsteroidal anti-androgens are, for example, 2163878 lo the compounds 2-methyl-N-t4-nitro-3-(trifluoromethyl)-phenyl]-propionamide (flutamide) ~ c~i 3 (~II);
2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)-phenyl]-propionamide ~;C ~ , IH
O~r ~ />~ 11 C~ and 2-methyl-4-[4-nitro-3-(trifluoromethyl)-phenyl]-5,6-dihydro-2H-1,2,4-oxadiazin-3-one O"~ ~.Y O
O .C~3 5,5-dimethyl-3-r4-nitro-3-(trifluoromethyl)-phenyl]-2,4-imidazo]idenedione;
5-[(3-chlorophenyl)-(lH-imidazol-1-yl)-methyl]-H-benzimidazole; hydrochloride, (RS)-4'-cyano-3-[(4-fluorophenyl)-sulfonyl]-2-hydroxy-2-methyl-3~-(trifluoromethyl)-propionanilide.
This list of anti-androgens is not exhaustive.
Also, 5~-reductase inhibitors, which prevent the conversion of testosterone to dihydrotestosterone, are suitable according to the invention as a compound with AA effect.
The compounds with anti-androgenic effectiveness are administ:ered in amounts of about l to 500 mg of cyproterone acetate, preferably 50 to 500 mg per day or an effective equivalent amount of another anti-androgen.
As compounds with competitive, progesterone-antagonistic effect ~PA), all compounds that have a great affinity to the progesterone receptor and show no specific (gestagen receptor) gestagenic activity are suitable. As competitive progesterone antagonists, for example, the following steroids are suitable:
llf~-[(4-N,N-dimethylamino)-phenyl]-17~-hydroxy-17-(3-hydroxy propyl)-13~-methyl-4,9(10)-gonadien-3-one (onapristone;
EP-A-0 129 499);
llB-[(4-N,N-dimethylamino)-phenyl]-17B-hydroxy-17~-propinyl-4,9(10)~-estradien-3-one (RU-38486);
llf3-t(4-N,N-dimethylamino)-phenyl]-17f3-hydroxy-18-methyl-17~-propinyl-4,9(10-estradien-3-one and llf3-[(4-N,N-dimethylamino)-phenyl]-17af~-hydroxy-17a~-propinyL-D-homo-4,9(10),16-estratrien-3-one (all EP-A-0 057 115);
also ll~-p-(methoxyphenyl-17B-hydroxy-17~-ethinyl-4,9(10)-estradien-3-one [Steroids 37 (1981), 361--382];
llB-(4-acetylphenyl)-17f3-hydroxy-17c~-(prop-1-inyl)-4,9(10)-estradien-3-one (EP-A 0 190 759) as well as .
216387~
the llB-aryl-14~-estradienes and llB-aryl-14~-estratrienes, described in EP-A O 277 676, the l9,11B-bridged steroids as well as the l9,11B-bridged 8,9-ene steroids, which are the object of EP-A O 283 428 or WO 92/09618, the llB,19-~4-(4-cyanophenyl)-o-phenyle~e]-17B-hydroxy-17~-(3-hydroxyprop-l(Z)-enyl)-4-androsten-3-one described in DE-A 42 16 003 and 11~,19-~4-(3-pyridinyl)-o-phenylene]-17B-hydroxy-17~-(3-hydroxyprop-l(Z)-enyl)-4-androsten-3-one, the llB-aryl-6-alkyl (or 6-alkenyl or 6-alkinyl)-estradienes and -pregnadienes known from EP-A O 289 073 and the llB-aryl-7-methyl ~or 7-ethyl)-estradienes known from EP-A O 321 010 as well as the ~OB-H steroids of EP-A O 404 283. This list is not exhaustive; also other competitive progesterone antagonists described in the above-mentioned publications as well as those from publications not mentioned here are suitable.
The dosage of the compounds with competitive, progesterone-antagonlstic effect is approximately 20-200 mg of onapristone per day or an effective equivalent amount of another compound with PA
effect ~or the indications of prostate carcinoma and benign prostat~c hyperplasia.
The active ingredients can be processed according to methods known iI~ the art to the usual forms of administration with the additives, vehicles and/or flavoring additives that are usual in galenic pharmaceutics.
Fo]c the preferred oral administration, especially tablets, coated 1tablets, capsules, pills, suspensions or solutions are suitable.
~ 13 For the parenteral, especially intramuscular administration, oily so]utions, such as, for example, sesame oil or castor oil solutions, are suitable. To increase the solubility, solubilizers, such as, for example, benzyl benzoate or benzyl alcohol/ can be added.
The pharmaceutical agents that are formulated as indicated above contain, for oral administration, preferably 10 mg to 100 mg of onapristone and 50 mg to 100 mg of cyproterone acetate or respectively the effective equivalent dose of another competitive progesterone antagonist and anti-androgen.
. ~ 14 21~i~878 Ex~mpl~ 1 Composition of an AA tablet for oral administration 50.0 mg of cyproterone acetate 120~.0 mg of lactose 50l.0 mg of corn starch 2.5 mg of polyvinylpyrrolidone 25 2.0 mg of aerosil 0.5 mg of magnesium stearate 225.0 mg total weight Example 2 Composition of a PA tablet for oral administration 5~.0 mg of onapristone 115.0 mg of lactose 55.0 mg of corn starch 2.5 mg of polyvinylpyrrolidone 25 2.0 mg of aerosil 0.5 mg of magnesium stearate 225.0 mg total weight . ~ 15 2163878 Ex~mpl~ 3 Composition of an AA-/PA tablet for oral administration sa .0 mg of cyproterone acetate 50.0 mg of onapristone 110.0 mg of lactose 5al.0 mg of corn starch 2.5 mg of polyvinylpyrrolidone 2S
2.0 mg of aerosil 0.5 mg of magnesium stearate 264.0 mg the total weight of the tablet, which is produced in the usual way in a tablet press.
Optionally, the active ingredients according to the invention can also be pressed separately into a two-layer tablet with respectively half of the above-indicated additives.
Ex~mpls ~
Composit:ion of an oily AA-/PA solution 50.0 mg of cyproterone acetate SO.O mg of onapristone 353.4 mg of castor oil 61~.6 mq of benzyl benzoate 1072.0 mg = 1 ml ' 162163~7~
The tumor-inhibiting action of ths agQnt According to the ~nvention is examined in the androgen-dependent R3327~-prostate carcinoma of th~ rat:
The R3327H prostate carcinoma was found as a spontaneous tumor in the dorsal prostate of a Copenhagen (Cop) rat and retransplanted in series. The tumor is androgen-dependent, i.e., castration of animals with established tumors inhibits the tumor growth almost completely. After a few months, however, renewed growth (so-called "relapse") occurs. The R3327H tumor contains androgen and estrogen receptors as well as 5~-reductase. By its response to anti-androgens, estrogens or LHRH analogs as well as histologically, it is very similar to carcinoma of the human prostate and therefore an almost ideal tumor model for the development of new prostate carcinoma therapeutic agents.
Execution of th~ Test Animal material 7- to 10-week-old male Cop or Cop-Fischer Rats:
Standard care conditions Formulation and Administration of Test Substance The test substances are dissolved in benzyl benzoate +
castor oil (1 + 4) and the single dose is administered in a volume of 0.1 ml/100 body weight s.c. or p.o. In the case of oral use, the test substance is suspended in a carrier liquid (85 mg of ~yrj in 100 ml of 0.9% w/v NaCl solution) and the daily dose is administered in a volume of 0.1 mg/100 g of body weight.
17 216 387a The treatment is begun with a tumor size of 10-25 mm2 (about 8 to 10 weeks after implantation) and carried out 6 times weekly over 6 to 8 weeks.
Tumor Stem Perpetuation Tumor fragments of a 2 mm edge length are implanted inguinally s.c. on both sides in intact rats. Depending on the growth of the tumor, a new stem perpetuation is begun every 4-6 months.
Test Batch At least 3 different tumors are removed from animals with the perpetuated stem, cut into pieces of a 2 mm edge length and implanted as described above. The rats are randomized in groups of 7-10 animals. One group is castrated for the control of androgen-dependence at the beginning of the treatment. The tumor growth is estimated by deteL in;ng the tumor surface area with the aid of a sliding gauge. The tumor surface area is calculated from the product of the longest diameter of the tumor and the diameter perpendicular to it. At the end of the test, the animals are killed, the tumors, prostates, seminal vesicles and testicles are prepared and weighed.
Evaluation Average values + SE of tumor surface areas, tumor weights and optionally organ weights are determined. The course of growth of the tumors is represented graphically.
18 216~878 The statistical evaluation is carried out with the Dunnett test.
The observed tumor growth inhibition or remission of the tumors during treatment with the agent according to the invention is greater than that of the sum of the respective monotherapies with AA and PA.
It relat:es especially to agents of the indicated type for prophyl~xis and for treatment of carcinoma of the prostate as well as of benign prostatic hyperplasia (BPH).
Even before suitable anti-androgens were available, Dorfman postulat:ed that systemically effective anti-androgens could be of great benefit in the treatment of androgen-dependent tumors of the prostate. A multicentric, controlled study at the end of the 1970s definitely confirmed, keeping in mind rational inclusion criteria and differentiated monitoring of the course (carcinoma of the prostate is only at times and partially androgen-dependent), that treatment with cyproterone acetate, which is regarded as a standard anti-androgen, represents a good and advantageous alterative to other palliative processes in the treatment of inoperable, metastasized carcinoma of the prostate.
In the case of prostatic hyperplasia., this is a non-malignant enlargement of the prostate, wh.ich originates in the so-called "inner" prostate. The symptoms are attributable mainly to the obstructions of the urethra that occur. Voiding of the 2163878 ~
bladder is impeded, and residual urine ret:ention results. Urea poisoning can occur without operative intervention.
In ~he case of enlargement of the prostate, interstice (stroma) and epithelium are involved to a changing extent. As causes, i.a., a shifting of the estrogen/androgen ratio in favor of estrogen can be considered. In various studies, it has been shown that in the case of older males, the serum testosterone concentrations decrease; at the same time, the portion of SHBG
(sex hor~one binding globulins, specific conveying protein for steroids) increases, so that the biologic~l availability of androgens decreases still further.
Also, for the treatment of prostatic hyperplasia, the use of gestagenically and anti-androgenically effective esters of 6-chloro-17-hydroxy-lct,2~-methylene-pregna-4,6-diene-3,20-dione (cyproterone ester, i.a., cyproterone acetate) is already described (US-A-3,423,507). It has been shown, however, that only a partial remission of the hyperplasia occurs with this treatment.
Also, combinations of various antihormones or hormonic synthesis inhibitors are part of the treatment of the prostatic hyperplasia in the prior art, for example, combination of an aromatase inhibitor with an anti-androgen (DE-A-31 21 152), an anti-estrogen with a substance having an anti-androgenic effect (DE-A-28 17 157) or an aromatase inhibitor with a 5~-reductase inhibit~r (W087/05216; WO91/00731; WO92/18132).
In certain models for the study of c:arcinoma of the prostate, an effective inhibition of tumor growth was observed in 216387~
the case of a sole administration of a competitive progesterone antagonist [Betty Mobbs, I. Johnson, J. of Steroid. Biochem. Mol.
Biol., 39, pp. 713-722, 1991; tumor model: R3327H; test substance: llB-[(4-N,N-dimethylamino)-phenyl]-17B-hydroxy-17~-propiny]-4,9(10)-estradien-3-one (RU-486, EP-A-O 057 115)].
Androgen-independent prostate carcinoma subtypes exist, which do not respond to the single administration of an anti-androgen. The monotherapy of prostate carcinomas is therefore unsatisfactory.
The object of this invention is to provide phar~Laceutical agents that make possible an effective treatment of prostate carcinomas and in general also those which have become androgen-independent. At the same time, it would be desirable if such an agent were also suitable for prophylaxis and treatment of benign prostatic hyperplasia.
Such pharmaceutical agents are made available by this invention.
It has now been found that in the case of treatment of prostate carcinoma with a combination of at least one compound with anti-androgenic effect and at least one compound with competitive, progesterone-antagonistic effect, tumor growth of the prostate carcinoma -- even that whichL has also become androgen-independent -- is more greatly inhibited than would correspond to the sum of the individual effects of AA and PA.
In treating prostatic hyperplasia (~PH) with the agent according tc~ the invention, a greater re~uction of size of the ~ 4 hyperplastically enlarged prostate occurs than in the case of monotherapy with an anti-androgen.
The agent according to the invention thus has a synergistic effect in the case of the indications provided. A
(pharmaceutically effective) combination that contains AA and PA
was not yet known.
This invention also relates to,the use of at least one compounc~ with anti-androgenic (AA) effect as well as at least one compounc~ with competitive, progesterone-antagonistic (PA) effect for the production of pharmaceutical agents.
In particular, the invention relates to the use of the above-mentioned compounds for the production of pharmaceutical agents f'or prophylaxis and for treatment of prostate carcinoma and for prophylaxis and for treatment of benign prostatic hyperplasia (BPH).
The sole use of a compound with competitive, progesterone-antagonistic (PA) effect for the production of pharmaceutical agents ~or prophylaxis and for treatment of benign prostatic hyperplasia (BPA) has not previously been known.
Th~s invention therefore also relates to the use of at least one compound with competitive, progesterone-antagonistic (PA) effect ~or the production of pharmaceutical agents for prophylaxis and treatment of BPH.
For the sole use of at least one cornpound with PA effect for the production of such a pharmaceutical agent, all statements made concerning the combination hold true for this individual ~ 5 --- 2~63878 component, especially relative to the dose~, of exemplary compounds and formulation possibilities.
The weight ratio of both components of the agent according to the invention can be varied within wide limits for application for the two described indications.
Thus, both identical amounts of AA and PA and an excess of one of the two components can be present :in the agent. AA and PA
are used together, separately, simultaneollsly and/or graduated in time, in a weight ratio of 1:40 to 25:1, preferably 1:1 to 5:1, and especially 1:1 to 2:1. Simultaneous administration is preferred.
Also, a sequential treatment with the two components AA and PA of the combination according to the invention is possible.
The component provided as the second can :in this case be given at any time after administration of the component that is administered first, as long as it is still bio-available in the patient to be treated simultaneously with an effective amount of the component that is administered first. For example, the anti-androgenic component can be given first, and then the PA
component can be given.
The treatment program for a patient who is suffering from a prostate carcinoma or a BPH can also be arranged so that monotherapy with an anti-androgen is carried out as a first measure of treatment, specifically over a period of several weeks, until further growth inhibition of the prostate carcinoma can no longer be achieved. After that, the treatment with PA by '' 21~3878 itself or AA and PA in combination, simult:aneously, or sequentially is carried out.
The treatment with the combination ac:cording to the invention is carried out as long as, again, further growth inhibition is no longer observed.
In the case of simultaneous treatment;, AA and PA are administered in one dosage unit or in separate dosage units.
As a compound with anti-androgenic ei-fect, all compounds are suitable that act as competitive anti-androgens, i.e., those that mediate their AA effect by great affinity to the androgen receptor. These compounds with AA effect can be both of steroidal origin and non-steroids.
As steroids, for example, the compounds of general formulas I and II are suitable:
C_O
Y~
in which R1 and R2 each stand for a hydrogen atom or both together mean an additional carbon-carbon bond or the methyl group, ' ~ 2163878 R3 means the acyl radical of an acid that is commonly used in steroid chemistry, Y means an oxygen atom or the group H, OR~ with R4 meaning hydrogen, acyl or alkyl, X1 means a hydrogen or chlorine atom and X2 means a hydrogen, fluorine or chlorine atom.
~1 ~ ~ ~ 7~ ~17 o~
in which R1 and RZ each stand for hydrogen or both together mean the methylene group, X means hydrogen, fluorine or chlorine and A-B
I ;a 17 or C17 ~1 in which R3 and R~ represent the acyl radical of an acid that is commonly used in steroid chemistry.
The designation acyl radical is to be understood to encompass the radicals of the acids that are commonly used in . ~. 8 - 216387~
steroid chemistry for the esterification of secondary and tertiary hydroxy groups. Preferred are aliphatic carboxylic acids with 1-8 carbon atoms, such as, for example, acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, hexanoic: acid, heptanoic acid, etc. The esters of acetic acid are espe.cially preferred.
Alkyl is to be understood to be lower alkyl groups with 1-5 carbon atoms, and the methyl group is preferred.
Typical compounds of general formula I are the 17-esters of, for exannple, 6-('hloro-17-hydroxy-1~,21x-methylene-pregna-4,6-diene-3,20-dione;
6-chloro-17-hydroxy-pregna-4,6-diene-3,20-dione;
6-chloro-17-hydroxy-pregna-1,4,6-triene-3,20-dione;
6-chloro-3~,17-dihydroxy-la,2c~-methylene-pregna-4,6-dien-20-one;
6--chloro-3~-methoxy-17-hydroxy-1~,2c-methylene-pregna-4,6-dien-20--one;
6-~Eluoro-17-hydroxy-lc~,2~-methylene-pregna-4,6-diene-3,20-dione;
17 -hydroxy-l~x,2a!-methylene-pregna-4,6-diene-3,20-dione and 4,6-dichloro-17-hydroxy-lc~,2c~-methylene-pregna-4,6-diene-3,20-dione.
Preferred compounds of general formula I are 6--Chloro-17-hydroxy-lcc,2c~-methylene--pregna-4,6-diene-3,20-dione--a~etate (cyproterone acetate) and ~ :~ 9 2~63~78 6-chloro-17-hydroxy-pregna-4,6-diene-3,20-dione-acetate (chlormadinone acetate).
Typical compounds of general formula II are, for example, 6-Chloro-17aB-acetoxy-17a~-methyl-1~,2~-methylene-D-homo-4,6-androstadiene-3,17-dione and ~ -chloro-17a!-acetoxy-17B-methyl-la!,2~-methylene-D-homo-4,6-androstadiene-3,17a-dione.
Steroidopyrazoles and steroidotriazoles, described in patent applications EP-A-0 207 375 and W0-A-92/00992, are also suitable, for example, the (Sa!,17a!)-1'-(methylsulfonyl)-l'H-pregn-20-yno-(3,2-c)-pyrazol--17-ol;
4,17a!-dime~hyl-1'-mesyl-l'H-androst-4-eno[3,2-c]-pyrazol-17B-ol;
~ mesyl-17~-methyl-l'H-androsta-4,15-dieno[3,2-c]-pyrazol-17B-ol;
6,6-ethylene-1'-mesyl-17~-methyl-l'H-androst-4-eno[3,2-c]-pyrazol--17B-ol;
7~17~-dimethyl-1'-mesyl-l'H-androst-4-eno[3,2-c]-pyrazol-17B-ol;
2'--mesyl-17~-methyl-2'H-triazolo[4',5':2,3]-androsta-4,15-dien-17B-ol.
Suitable as nonsteroidal anti-androgens are, for example, 2163878 lo the compounds 2-methyl-N-t4-nitro-3-(trifluoromethyl)-phenyl]-propionamide (flutamide) ~ c~i 3 (~II);
2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)-phenyl]-propionamide ~;C ~ , IH
O~r ~ />~ 11 C~ and 2-methyl-4-[4-nitro-3-(trifluoromethyl)-phenyl]-5,6-dihydro-2H-1,2,4-oxadiazin-3-one O"~ ~.Y O
O .C~3 5,5-dimethyl-3-r4-nitro-3-(trifluoromethyl)-phenyl]-2,4-imidazo]idenedione;
5-[(3-chlorophenyl)-(lH-imidazol-1-yl)-methyl]-H-benzimidazole; hydrochloride, (RS)-4'-cyano-3-[(4-fluorophenyl)-sulfonyl]-2-hydroxy-2-methyl-3~-(trifluoromethyl)-propionanilide.
This list of anti-androgens is not exhaustive.
Also, 5~-reductase inhibitors, which prevent the conversion of testosterone to dihydrotestosterone, are suitable according to the invention as a compound with AA effect.
The compounds with anti-androgenic effectiveness are administ:ered in amounts of about l to 500 mg of cyproterone acetate, preferably 50 to 500 mg per day or an effective equivalent amount of another anti-androgen.
As compounds with competitive, progesterone-antagonistic effect ~PA), all compounds that have a great affinity to the progesterone receptor and show no specific (gestagen receptor) gestagenic activity are suitable. As competitive progesterone antagonists, for example, the following steroids are suitable:
llf~-[(4-N,N-dimethylamino)-phenyl]-17~-hydroxy-17-(3-hydroxy propyl)-13~-methyl-4,9(10)-gonadien-3-one (onapristone;
EP-A-0 129 499);
llB-[(4-N,N-dimethylamino)-phenyl]-17B-hydroxy-17~-propinyl-4,9(10)~-estradien-3-one (RU-38486);
llf3-t(4-N,N-dimethylamino)-phenyl]-17f3-hydroxy-18-methyl-17~-propinyl-4,9(10-estradien-3-one and llf3-[(4-N,N-dimethylamino)-phenyl]-17af~-hydroxy-17a~-propinyL-D-homo-4,9(10),16-estratrien-3-one (all EP-A-0 057 115);
also ll~-p-(methoxyphenyl-17B-hydroxy-17~-ethinyl-4,9(10)-estradien-3-one [Steroids 37 (1981), 361--382];
llB-(4-acetylphenyl)-17f3-hydroxy-17c~-(prop-1-inyl)-4,9(10)-estradien-3-one (EP-A 0 190 759) as well as .
216387~
the llB-aryl-14~-estradienes and llB-aryl-14~-estratrienes, described in EP-A O 277 676, the l9,11B-bridged steroids as well as the l9,11B-bridged 8,9-ene steroids, which are the object of EP-A O 283 428 or WO 92/09618, the llB,19-~4-(4-cyanophenyl)-o-phenyle~e]-17B-hydroxy-17~-(3-hydroxyprop-l(Z)-enyl)-4-androsten-3-one described in DE-A 42 16 003 and 11~,19-~4-(3-pyridinyl)-o-phenylene]-17B-hydroxy-17~-(3-hydroxyprop-l(Z)-enyl)-4-androsten-3-one, the llB-aryl-6-alkyl (or 6-alkenyl or 6-alkinyl)-estradienes and -pregnadienes known from EP-A O 289 073 and the llB-aryl-7-methyl ~or 7-ethyl)-estradienes known from EP-A O 321 010 as well as the ~OB-H steroids of EP-A O 404 283. This list is not exhaustive; also other competitive progesterone antagonists described in the above-mentioned publications as well as those from publications not mentioned here are suitable.
The dosage of the compounds with competitive, progesterone-antagonlstic effect is approximately 20-200 mg of onapristone per day or an effective equivalent amount of another compound with PA
effect ~or the indications of prostate carcinoma and benign prostat~c hyperplasia.
The active ingredients can be processed according to methods known iI~ the art to the usual forms of administration with the additives, vehicles and/or flavoring additives that are usual in galenic pharmaceutics.
Fo]c the preferred oral administration, especially tablets, coated 1tablets, capsules, pills, suspensions or solutions are suitable.
~ 13 For the parenteral, especially intramuscular administration, oily so]utions, such as, for example, sesame oil or castor oil solutions, are suitable. To increase the solubility, solubilizers, such as, for example, benzyl benzoate or benzyl alcohol/ can be added.
The pharmaceutical agents that are formulated as indicated above contain, for oral administration, preferably 10 mg to 100 mg of onapristone and 50 mg to 100 mg of cyproterone acetate or respectively the effective equivalent dose of another competitive progesterone antagonist and anti-androgen.
. ~ 14 21~i~878 Ex~mpl~ 1 Composition of an AA tablet for oral administration 50.0 mg of cyproterone acetate 120~.0 mg of lactose 50l.0 mg of corn starch 2.5 mg of polyvinylpyrrolidone 25 2.0 mg of aerosil 0.5 mg of magnesium stearate 225.0 mg total weight Example 2 Composition of a PA tablet for oral administration 5~.0 mg of onapristone 115.0 mg of lactose 55.0 mg of corn starch 2.5 mg of polyvinylpyrrolidone 25 2.0 mg of aerosil 0.5 mg of magnesium stearate 225.0 mg total weight . ~ 15 2163878 Ex~mpl~ 3 Composition of an AA-/PA tablet for oral administration sa .0 mg of cyproterone acetate 50.0 mg of onapristone 110.0 mg of lactose 5al.0 mg of corn starch 2.5 mg of polyvinylpyrrolidone 2S
2.0 mg of aerosil 0.5 mg of magnesium stearate 264.0 mg the total weight of the tablet, which is produced in the usual way in a tablet press.
Optionally, the active ingredients according to the invention can also be pressed separately into a two-layer tablet with respectively half of the above-indicated additives.
Ex~mpls ~
Composit:ion of an oily AA-/PA solution 50.0 mg of cyproterone acetate SO.O mg of onapristone 353.4 mg of castor oil 61~.6 mq of benzyl benzoate 1072.0 mg = 1 ml ' 162163~7~
The tumor-inhibiting action of ths agQnt According to the ~nvention is examined in the androgen-dependent R3327~-prostate carcinoma of th~ rat:
The R3327H prostate carcinoma was found as a spontaneous tumor in the dorsal prostate of a Copenhagen (Cop) rat and retransplanted in series. The tumor is androgen-dependent, i.e., castration of animals with established tumors inhibits the tumor growth almost completely. After a few months, however, renewed growth (so-called "relapse") occurs. The R3327H tumor contains androgen and estrogen receptors as well as 5~-reductase. By its response to anti-androgens, estrogens or LHRH analogs as well as histologically, it is very similar to carcinoma of the human prostate and therefore an almost ideal tumor model for the development of new prostate carcinoma therapeutic agents.
Execution of th~ Test Animal material 7- to 10-week-old male Cop or Cop-Fischer Rats:
Standard care conditions Formulation and Administration of Test Substance The test substances are dissolved in benzyl benzoate +
castor oil (1 + 4) and the single dose is administered in a volume of 0.1 ml/100 body weight s.c. or p.o. In the case of oral use, the test substance is suspended in a carrier liquid (85 mg of ~yrj in 100 ml of 0.9% w/v NaCl solution) and the daily dose is administered in a volume of 0.1 mg/100 g of body weight.
17 216 387a The treatment is begun with a tumor size of 10-25 mm2 (about 8 to 10 weeks after implantation) and carried out 6 times weekly over 6 to 8 weeks.
Tumor Stem Perpetuation Tumor fragments of a 2 mm edge length are implanted inguinally s.c. on both sides in intact rats. Depending on the growth of the tumor, a new stem perpetuation is begun every 4-6 months.
Test Batch At least 3 different tumors are removed from animals with the perpetuated stem, cut into pieces of a 2 mm edge length and implanted as described above. The rats are randomized in groups of 7-10 animals. One group is castrated for the control of androgen-dependence at the beginning of the treatment. The tumor growth is estimated by deteL in;ng the tumor surface area with the aid of a sliding gauge. The tumor surface area is calculated from the product of the longest diameter of the tumor and the diameter perpendicular to it. At the end of the test, the animals are killed, the tumors, prostates, seminal vesicles and testicles are prepared and weighed.
Evaluation Average values + SE of tumor surface areas, tumor weights and optionally organ weights are determined. The course of growth of the tumors is represented graphically.
18 216~878 The statistical evaluation is carried out with the Dunnett test.
The observed tumor growth inhibition or remission of the tumors during treatment with the agent according to the invention is greater than that of the sum of the respective monotherapies with AA and PA.
Claims (15)
1. Agent that contains at least one compound with anti-androgenic (AA) effect as well as at least one compound with competitive, progesterone-antagonistic (PA) effect.
2. Agent according to claim 1 for prophylaxis and for treatment of carcinoma of the prostate.
3. Agent according to claim 1 for prophylaxis and for treatment of benign prostatic hyperplasia (BPH).
4. Agent according to claim 1, characterized in that AA and PA are in a weight ratio of 1:40 to 25:1.
5. Agent according to claim 1, wherein AA and PA are present in separate dosage units.
6. Agent according to claim 1, wherein AA and PA are present in a common dosage unit.
7. Agent according to claim 1, wherein as an anti-androgenically effective compound, it contains 6-Chloro-17-hydroxy-1.alpha.,2.alpha.-methylene-pregna-4,6-diene-3,20-dione-acetate;
6-chloro-17-hydroxy-pregna-4,6-diene-3,20-dione-acetate;
(5.alpha.,17.alpha.)-1'-(methylsulfonyl)-1'H-pregn-20-yno-(3,2-c)-pyrazol-17-ol;
4,17.alpha.-dimethyl-1'-mesyl-1'H-androst-4-eno[3,2-c]-pyrazol-17.beta.-ol;
1'-mesyl-17.alpha.-methyl-1'H-androsta-4,15-dieno[3,2-c]-pyrazol-17.beta.-ol;
6,6-ethylene-1'-mesyl-17.alpha.-methyl-1'H-androst-4-eno[3,2-c]-pyrazol-17.beta.-ol;
7.alpha.,17.alpha.-dimethyl-1'-mesyl-1'H-androst-4-eno[3,2-c]-pyrazol-17.beta.B-ol;
2'-mesyl-17.alpha.-methyl-2'H-triazolo[4',5':2,3]-androsta-4,15-dien-17.beta.-ol;
2-methyl-N-[4-nitro-3-(trifluoromethyl)-phenyl]-propionamide;
5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)--phenyl]-2,4-imidazolidenedione;
5-[(3-chlorophenyl)-(1H-imidazol-1-yl)-methyl]-H-benzimidazole; hydrochloride, (RS)-4'-cyano-3-[(4-fluorophenyl)-sulfonyl]-2-hydroxy-2-methyl-3'-(trifluoromethyl)-propionanilide.
6-chloro-17-hydroxy-pregna-4,6-diene-3,20-dione-acetate;
(5.alpha.,17.alpha.)-1'-(methylsulfonyl)-1'H-pregn-20-yno-(3,2-c)-pyrazol-17-ol;
4,17.alpha.-dimethyl-1'-mesyl-1'H-androst-4-eno[3,2-c]-pyrazol-17.beta.-ol;
1'-mesyl-17.alpha.-methyl-1'H-androsta-4,15-dieno[3,2-c]-pyrazol-17.beta.-ol;
6,6-ethylene-1'-mesyl-17.alpha.-methyl-1'H-androst-4-eno[3,2-c]-pyrazol-17.beta.-ol;
7.alpha.,17.alpha.-dimethyl-1'-mesyl-1'H-androst-4-eno[3,2-c]-pyrazol-17.beta.B-ol;
2'-mesyl-17.alpha.-methyl-2'H-triazolo[4',5':2,3]-androsta-4,15-dien-17.beta.-ol;
2-methyl-N-[4-nitro-3-(trifluoromethyl)-phenyl]-propionamide;
5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)--phenyl]-2,4-imidazolidenedione;
5-[(3-chlorophenyl)-(1H-imidazol-1-yl)-methyl]-H-benzimidazole; hydrochloride, (RS)-4'-cyano-3-[(4-fluorophenyl)-sulfonyl]-2-hydroxy-2-methyl-3'-(trifluoromethyl)-propionanilide.
8. Agent according to claim 1, wherein as a compound with competitive, progesterone-antagonistic effect, it contains 11.beta.B-[(4-N,N-dimethylamino)-phenyl]-17.alpha.-hydroxy-17-(3-hydroxy-propyl)-13.alpha.-methyl-4,9(10)-gonadien-3-one (onapristone;
EP-A-o 129 499);
11.beta.-[(4-N,N-dimethylamino)-phenyl]-17.beta.-hydroxy-17.alpha.-propinyl-4,9(10)-estradien-3-one (RU-38486);
11.beta.-(4-acetylphenyl)-17.beta.-hydroxy-17.alpha.-(prop-1-inyl)-4,9(10)-estradien-3-one (EP-A 0 190 759);
11.beta.,19-[4-(4-cyanophenyl)-o-phenylene]-17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1(Z)-enyl)-4-androsten-3-one;
11.beta.,19-[4-(3-pyridinyl)-o-phenylene]-17.beta.-hydroxy-17.alpha.-(3-hydroxypropyl-1(Z)-enyl)-4-androsten-3-one.
EP-A-o 129 499);
11.beta.-[(4-N,N-dimethylamino)-phenyl]-17.beta.-hydroxy-17.alpha.-propinyl-4,9(10)-estradien-3-one (RU-38486);
11.beta.-(4-acetylphenyl)-17.beta.-hydroxy-17.alpha.-(prop-1-inyl)-4,9(10)-estradien-3-one (EP-A 0 190 759);
11.beta.,19-[4-(4-cyanophenyl)-o-phenylene]-17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1(Z)-enyl)-4-androsten-3-one;
11.beta.,19-[4-(3-pyridinyl)-o-phenylene]-17.beta.-hydroxy-17.alpha.-(3-hydroxypropyl-1(Z)-enyl)-4-androsten-3-one.
9. Agent according to claim 1, wherein it contains 50 to 500 mg of cyproterone acetate or an effective equivalent amount of another compound with androgenic effect (AA) as a daily dosage unit.
10. Agent according to claim 1, wherein it contains 20 to 200 mg of onapristone (11.beta.-[(4-N,N-dimethylamino)-phenyl]-17.alpha.-hydroxy-17.beta.-(3-hydroxypropyl)-18.alpha.-methyl-4,9(10)-gonadien-3-one or an effective equivalent amount of another compound with competitive, progesterone-antagonistic effect (PA) as a daily dosage unit.
11. Use of the agent according to claim 1 for the production of a pharmaceutical agent for prophylaxis and for treatment of carcinoma of the prostate.
12. Use of the agent according to claim 1 for the production of a pharmaceutical agent for prophylaxis and for treatment of benign prostatic hyperplasia (BPH).
13. Combined use of at least one compound with anti-androgenic (AA) effect as well as at least one compound with competitive, progesterone-antagonistic (PA) effect for the production of pharmaceutical agents.
14. Combined use of AA as well as PA according to claim 13 for the production of pharmaceutical agents for prophylaxis and for treatment of carcinoma of the prostate.
15. Combined use of AA as well as PA according to claim 13 for the production of pharmaceutical agents for prophylaxis and for treatment of benign prostatic hyperplasia (BPH).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4318371.9 | 1993-05-28 | ||
| DE19934318371 DE4318371A1 (en) | 1993-05-28 | 1993-05-28 | Agent containing a compound with antiandrogenic and a compound with competitive, progesterone-antagonistic effect |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2163878A1 true CA2163878A1 (en) | 1994-12-08 |
Family
ID=6489489
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2163878 Abandoned CA2163878A1 (en) | 1993-05-28 | 1994-05-30 | Agents containing a compound with an anti-androgen effect and a compound with a competitive, progesterone-antagonistic effect |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0701445A1 (en) |
| AU (1) | AU6998494A (en) |
| CA (1) | CA2163878A1 (en) |
| DE (1) | DE4318371A1 (en) |
| WO (1) | WO1994027610A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0748220A4 (en) * | 1994-01-21 | 1997-09-10 | Sepracor Inc | Methods and compositions for treating androgen-dependent diseases using optically pure r-(-)-casodex |
| DE19825591A1 (en) * | 1998-06-09 | 1999-12-23 | Jenapharm Gmbh | Pharmaceutical combinations to compensate for a testosterone deficit in men while protecting the prostate |
| UY27301A1 (en) * | 2001-05-25 | 2003-02-28 | Schering Ag | USE AND COMPOSITIONS OF ANTIPROGESTINES FOR THE TREATMENT OF PROSTATE DISEASES |
| SE0103838D0 (en) * | 2001-11-16 | 2001-11-16 | Astrazeneca Ab | Pharmaceutical formulation & product |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991000733A1 (en) * | 1989-07-07 | 1991-01-24 | Endorecherche Inc. | Method of treatment of androgen-related diseases |
| DE4039561A1 (en) * | 1990-12-07 | 1992-07-09 | Schering Ag | USE OF ANTIGESTAGENS FOR THE MANUFACTURE OF MEDICAMENTS |
-
1993
- 1993-05-28 DE DE19934318371 patent/DE4318371A1/en not_active Withdrawn
-
1994
- 1994-05-30 CA CA 2163878 patent/CA2163878A1/en not_active Abandoned
- 1994-05-30 AU AU69984/94A patent/AU6998494A/en not_active Abandoned
- 1994-05-30 WO PCT/EP1994/001756 patent/WO1994027610A1/en not_active Application Discontinuation
- 1994-05-30 EP EP94918820A patent/EP0701445A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| DE4318371A1 (en) | 1994-12-01 |
| EP0701445A1 (en) | 1996-03-20 |
| AU6998494A (en) | 1994-12-20 |
| WO1994027610A1 (en) | 1994-12-08 |
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