Note: Descriptions are shown in the official language in which they were submitted.
-- 2163878 1
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
-- 2163878
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
OR3
Y~
X2
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
F3C
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.
- 2163878
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
.
12
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
2163878
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.
