Note: Descriptions are shown in the official language in which they were submitted.
~3~2~
This invention relates to a pharmaceutical agent, which
comprises a progesterone synthesis inhibitor (ProI) of the
type of trilostane and epostane, and an antigestagen (AG).
It is sometimes necessary, in order to avert dangers to
the mother and/or child, to induce labor artificially or
terminate pregnancy prematurely. Surgical techniques and
pharmacological methods are available for this purpose.
One possible pharmacological method is the vaginal or
intramuscular administration of prostaglandins, which, in the
0 case of termination of pregnancy, i~ carried out in the first
or second trimester of pregnancv (Contraception 1983, Vol.
27, 51-60 and Int. J. Gynaecol. Obstet. 1982 t Vol. 20, 383-
386).
The advantage of prostaglandin use is the possibility of
employing it over a long period of the pregnancy.
Disadvantages of prostaglandins which should be mentioned are
acute side effects such as pain and nausea. In addition in
the case of the termination of pregnancy in advanced phases
of pregnancy, the success rate does not exceed 90%, even with
0 prolonged duration of prostaglandin treatment.
Another possibility for terminating pregnancy comprises
administration of an antigestagen (Med. et Hyg. 1982, Vol.
40, 2087-2093). Antigestagens are better tolerated than are
prostaglandins, but are less effective, and have a longer
latency period and greater individual variability of the
onset of action compared with prostaglandins. In addition,
it has been observed clinically that they have a tendency to
cause hemorrhages, which can be severe.
Although the conjoint use of prostaglandins and
0 antigestagens (EP 84730108O2) has uncontestable advantages
over administration of the individual active substances alone
(especially reduction in the amount of each active
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substance), it does not, for example, solve the problems
which generally occur when prostaglandins are used:
undesired side effects, such as gastrointestinal effects or
uterine pain, the necessity for inpatient treatment, the
storage and shelf-life of the pharmaceutical, owing to a lack
of stability, being limited and/or elaborate, the
impossibility o~ the most user-friendly administration form,
namely oral, and thus the impossibility of combining the two
active substances in a tablet, pill or coated tablet.
It has also been suggested to use the combination of
prostaglandins, glucocorticoids and antigestagens for the
induction of labor or for termination of pregnancy. The
antigestagens can be either receptor competitive progesterone
antagonists or compounds which antagonize the effect of
gestagens by a different route, e.g, the derivatives of
trilostane of U.S. patent 4,160,027. (See U.S. S.N. 790,020,
filed October 22, 1985; DOS 3438994.6, filed October 22
1984).
Another possibility which has been suggested for
premature termination of pregnancy is treatment with
progesterone synthesis inhibitors such as epostane
derivatives (also US Patent 4,160,027). However, it has been
found that it is impossible to induce abortion in guinea pigs
in advanced pregnancy even with doses high enough to cause a
marked reduction in the serum progesterone level~ In early
human pregnancy, the success rate even with the maximum
epostane doses is not 100%. Once again, clinical treatment
is successful only in combination with prostaylandins, but
very large amounts of active substances (30 mg of PGE2, 5 X
600 mg of epostane) are necessary for this. In addition to
this disadvantage, the method is subject to the problems
associated with the use of prostaglandins which have been
discussed above.
Pharmaceutical compositions for post-coital fertility
control, which contain a competitive progesterone antagonist
(antigestagen~ as well as a progesterone and estrogen
synthesis blocker are already generically described in US
patent 4,670,426. Typical representatives of the competitive
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progesterone antagonists to be used are fluocinolone
acetonide, triamcinolone acetonide, steroids with a cyclic
16,17-acetate with acetone and 17~-hydroxy-11~,l4-
dimethylaminophenyl~ 7~ prop-lynyl-estra-4,9-dien-3-one
and equivalent derivatives. The stated dosages for these
compounds is between 20 and 100 mg per person per day. As
examples for the progesterone and estrogen synthesis blocker
there are cited aminogluthetimide, ~-cyano-4,4,17~-
trimethyl-5-androst-5-ene-17B-ol-3-one, 20,25-
0 diazacholesterol, and compounds with equivalent activity.Doses of 300 to 1000 mg are stated. The use of the agent
according to US patent 4,670,426 has to take place as early
as possible within the first week after sexual intercourse
over a period of 3 days; the treatment should best be
continued 2 to 6 days. Prevention of nidation and thus of a
pregnancy is caused by the synergistic effect in the combined
use of the two components of the composition, and with a
success rate on the order of 90% or more.
More recently the use of antigestagens in the field of
0 tumor therapy, especially for treatment of mastocarcinoma,
has also been discussed. A first phase II study with the
already mentioned 17B-hydroxy-llB-(4-dimethylaminophenyl)-
17~-prop-1-ynyl-estra-4,9-dien-3-one-on postmenopausal or
ovariectomy endocrine-therapy-resistant patients with
metastasizing mastocarcinoma is reported by Maudelonde et al
in Hormonal Manipulation of Cancor, eds. J.G.M. Klijn, R.
Paridaens and J. A. Folkens in Raven Press, p.55 (1987).
This invention has found that the use of a combination
of progesterone synthesis inhibitors of the trilostane and
0 ~postane type(s) and antigestagens (competitive progesterone
antagonists), i.e. of substances which both act on the
principle of inhibition of the action of progesterone, (and
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each of which is, by itself, only incompletely effective or
entirely ineffective, even at high dosages), is surprisingly
completely effective even with a dramatic reduction in these
doses.
Progesterone synthesis inhibitors (ProI) of the
trilostane and epostane type and antigestagens (AG) can be
administered conjointly for inducing labor i.e., at term, in
humans and animals and for terminating normal or pathological
pregnancies therein. Further, the combination according to
0 the invention of progesterone synthesis inhibitors and
antigestagen is suitable for treatment of endometriosis,
dysmenorrhea and hormone-dependent tumors, for example,
carcinoma of the breast and durosarcoma.
A 100% effectiveness is absolutely necessary for the use
of these compounds for terminating pregnancy or inducing
labor, since an embryotoxic action of the involved compounds
can never be ruled out with certainty in practice. In the
treatment of hormone-dependent tumors, this invention proves
superior to the sole use of antigestagen.
0 Fig. 1 shows a comparison of the effect of an
antigestagen tRU-486) alone, a prostaglandin synthesis
inhibitor (epostane) alone, and the combination together in
inducing abortion in pregnant guinea pigs.
dpc = day post coitus
/d s.c. = per day subcutaneously
/d p.o. = per day by mouth
Progesterone synthesis inhibitors of the type of
0 trilostane or epostane and antigestagens are used for all
these purposes in one dose unit or separately, simultaneously
"f,~f`,
.,.i~.
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and/or sequentially, In a ratlo by welght whlch Is essentlally
1:40 to 60:1, preferably 1:30 to 30:1. The treatment wlth pro-
gesterone synthesls Inhlbltors and antlgestagens per thls Inven-
tlon Is, as a rule, carrled out for 1 to 4, preferably 1 to Z,
days. It Is possl~le and preferred for progesterone synthesls
Inhlbltor and antlgestagen to be admlnlstered comblned In one
dose unlt.
Sultable antlgestagens Include all compounds whlch have
a strong afFlnlty for the gestagen receptor (progesterone recep-
tor) and, moreover, have no Important Intrlnslc gestagenlc actlv-
l~y. Non-llmltlng examples o~ sultable compet~tlve progesterone
antagonlsts Include the followlng sterolds: 11~ -r l4-N,N-
dlmethylamlno)-phenyl]-17~ -hydroxy-17~ ~propynyl-4,9(10)-estra-
dlen-3-one (RU-486), 11~ -C(4-N,N-dlmethylamlno)-phenyl]-17 ~ -
hydroxy-18-methyl-17 ~ -propynyl-4,9-(10)-estradlen-3-one, and
~ (4-N,N-dlmethylamlno)-phenyl]-17a ~ -hydroxy-17a-propynyl-D-
homo-4,9(1n)16-estratrlen-3-one (European Patent ApplIcatlon
82,400,02~.1 - Publlcatlon No. 0,057,115); and furthermore 11~ -
p-methoxyphenyl-17~ -hydroxy-17~ -ethynyl-4,9(10)-estradlen-3-one
(Sterolds 37 (1981) 361-382) and 11 -[(4-N,N-dlmethylamlno)-
phenyl)-17 ~-hydroxy-17 ~(3-hydroxypropyl)-13~ -methyl-4,9-gona-
dlen-3-one (European Patent No. 0129 499 correspondlng to U.S.
Ser. No. 621,308).
~5
The foregolng llstlng Is exemplary only. Many other
antlgestagens can be used, e.g., as dlsclosed In Fertlll tY and
Sterlllty 40, 253 ~1982), Ste olds 37, 36~-382 ~1981) and
EP0057115.
The amounts of antlgestagens used accordlng to the pre-
sent Inventlon are thereby belo~ the amounts otherwlse customary
for termlnatlon of pregnancy ~and, nevertheless often Insuffl-
clent for a 100% success rate). In general, ~ to 200 mg oF 11~ -
[(4-N,N-dlmethylamlno)-phenyl]--17~ -hydroxy-17 ~-propynyl-
4,9(10)-estradlen-3-one per day Sand per dosls unlt), or a blo-
~,
,
:
"
,,
1 3 ~
loglcally equlvalent amount of ano~her antlgestagen, Is suffl-
cient. These bloavallably equlvalent amounts can be determlned
routlnely and conventlonaliy, e.~., by per f ormlng dl~ferentlal
potency studles uslng ~ully routlne pharmacologlcal protocols,
e.g., as dlsclosed In Fertll Itv and Sterl I Ity 40, 253 (1982~,
Stero/ds 37, 361 {19~
Progesterone synthesls Inhlbltors whlch can be used
accordlng to the Inventlon Include all Inhlbltors of the 3~ -
hydroxysterold dehydrogenase enzyme system whlch reduce the blood
progesterone level and are of the type of trllostane (4 ~,5-
epoxy-3,17 ~ -dlhydroxy-5 ~-androst-2-ene-2-carbonltrlle) and/or
epostane (4 ~,5-epoxy-3,17~ -dlhydroxy-4 ~ ,17~ -dlmethyl-5-
androst-2-ene-2-carbonltrlle). By compounds of the trllostane
and/or epostane type, there arP Included, among others, 5-
androstanes havlng the structural features: 2-cyano-4 ~ -5 ~ -
epoxy, and 17 ~ -hydroxy or -alkanoyloxy (1-6 C atoms). See USP
`4,160,027. In an especlally preferred subgenus, there are
Included such 5~ -androstanes whlch Includ~, Instead of a 3-one
f eature, the structural unlt 2-ene-3-hydroxy. In addltlon, all
of such compounds can have substltuents, e.~., those def,lned In
USP 4,160,027.
The amounts of these progesterone synthesls Inhlbltors
whlch are used are also far below the amounts otherwlse customary
for the mentloned Indlcatlons. When epostane Is used as the pro-
gesterone synthesls Inhlbltor, as a rule a total of 5 - 600 mg,
preferably 30 - 300 mg, wl I I suff Ice. One dose unlt contalns
about 5 - 300 mg of epostane or a blologlcally equlvalent amount
of another such progesterone synthesls Inhlbitor. These blo-
avallably equlvalent amounts can be determlned routlnely and
conventlonally, e.g., by performlng dlfferential potency studles
uslng fully routlne pharmacologlcal protocols, e.g., as dlsclosed
In Am. J. Obstet. Gynecol., SupP/., 1987, 157, ~065-74. The
actlvlty of the claImed comblnat30n In treatlng hormone-dependent
tumours can be determlned accordlng to already known methods,
131~
e.g. as dlsclosed In the mentloned reference to Maude londe et
al
The a~ounts of antlgestagen and progesterone synthesls
Inhlbltor can vary from 1:20 to 20:1 when treatlng a hormone-
dependent tumour or treatlng endometrlosls (dally dosage un1t 10
to 200 mg of each) or from 1:30 ~o 30:1 Y~hen treatlng dysmenor-
rhea (dally dosage unlt 10 to 300 mg of each). In every case the
upper llmlt of the dosage depends of the constltutlon of the
respectlve patlent and of ~he Intended duratlon of the respectlve
treatment.
The antlgestagens and progesterone synthesls In
Inhlbltors can be admlnlstered, for example, locally, toplcally,
enterally or parenterally. For the preferred oral admlnlstratlon
It Is posslble to use In partlcular, ~ablets, coated tablets,
capsules, pllls, suspenslons or solutlons, whlch can be prepared
In the customary manner uslng the addltlves and vehlcles custom-
ary In pharmacy. See e.g., the several references mentloned
above. Preparatlons sultable for local or toplcal admlnlstratlon
Include, for example, vaglnal supposltorles or transdermal sys-
tems such as skln plasters.
Accordlng to the present Inventlon for termlnatlng
pregnancy or Induclng labour the comblnatlon Is admlnlstered In
every case after nldatlon, preferably In the second or thlrd
trlmester of pregnancy, In the case of Induclng labour shortly
before or on the term of labour. The c~npounds can be admlnls-
tered In any sequence, preferably slmultaneously, In the case of
sequentlal admlnlstratlon the second may be admlnlstered at any
tlme after the fIrs$ so long as It becomes bloavallable In the
patlent at the same tlme as an effectlve dose of the fIrst Is
stlll bloavallable. For example, the ProI can be adminlstered
wlthln 1 or 2 days after AG.
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131 82~
Wlthout further elaboratlon, It Is belleved that one
skllled In the art can, uslng the precedlng descrlptlon, utlllze
the present Inventlon to Its fullest extent. The followlng pre-
ferred speclflc embodlments are, therefore, to be construed as
5 merely Illustratlve, and not llmltatlve of the remalnder of the
dlsclosure In any way whatsoever.
EXAMPLE 1
Composltlon of a ta~let contalnlng 11~[(4 - N,N -
dlmethyl-amlno)-phenyl]-17 ~-hydroxy-17~ -propynyl-4,9~10)-estra-
dlen-3-one for oral admlnlstration
_ 7a -
2 ~ ~
10.0 mg of llB-[(4-N,N-dimethylamino)-phenyl]-17~-hydroxy-
17~-propynyl-4,9(10)-estradien-3-one
140.5 mg of lactose
69.5 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
EX~MPLE 2
Composition of a tablet containing 4~,5-epoxy-3,17B-dihy-
droxy-4B,17~-dimethyl-~-androst-2-ene-2-carbonitrile
(epostane) for oral administration
mg of 4~,5-epoxy-3,17B-dihydroxy-4B,1~-dimethyl-5~-
androst-2-ene-2-carbonitrile
201 mg of lactose
139 mg of corn starch
5.0 mg of polyvinylpyrrolidone 25
~~~ 4.0 mg of Aerosil Trale ~ar~
1.0 mg of magnesium stearate
380.0 mg total weight
.
EX~MPLE 3
Composition of a tablet containing 4~,5-epoxy-3,17~
dihydroxy-5~-androst-2-ene-2-carbonitrile (trilostane) for
oral administration
-
20.0 mg of 4~,5-epoxy-3,17B-dihydroxy-5~-androst-2-ene-2-
carbonitrile
281.0 mg of lactose
139.0 mg of corn starch
5.0 mg of polyvinylpyrrolidone 25
4.0 mg of Aerosil rra~e ~ar~
0 mg of magnesium stearate
450.0 mg total weight
~ 31 8%e~
Pharmacoloqical findinqs
I'he model substances selected for experiments on
pregnant guinea pigs were the progesterone synthesis
inhibitor epostane and the antigestagen llB-[(4-N,N-dimethyl--- -
amino)-phenyl]-17B-hydroxy-17~-propynyl-4,9(10t-estradién-3-
one (RU 486). The dosages tested are shown in the figure.
Investiqations on preqnant Quinea ~ias
Test of the combination
Description of the experiment
Pregnant guinea pigs weighing about 800 g were entered
in the experiment on day 42 of pregnancy (the 2nd day of
vaginal opening in the mating period was regarded as the
first day of pregnancy). Pregnancy was checked by palpation
before the start of the experiment. The treatment with the
selected test substances and the combination was effected by
oral (epostane) or subcutaneous (RU 486) administration each
day on days 43 and 44 of pregnancy. For this purpose, the
antigestagen was dissolved in benzyl benæoate + castor oil
(mixing ratio 2 + 4.5), and the daily dose was injected s~c.
,, 20 in a volume of 1.0 ml. The daily dose of epostane was
suspended as microcrystals in Myrj(R)/ saline solution and
administered divided into two equal doses in the morning and
afternoon. 'Any expulsion'of emhryos was checked-several
times a day during and a,fter the treatment. The animals were,
sacrificed on-day 50 of,pregnancy. The uteri were inspected,
and the fetuses were examined.
Results
The results of the experiments on the induction of
abortion in pregnant guinea pigs on combined administration
of antigestagens and progesterone synthesis inhibitors are
shown in the figure.
Proqesterone sYnthesis inhibitors
At an oral dose of 30.0 mg/day, epostane was totally
inactive in terms of an abortive effect (see Fig. 1).
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Antiqestagens
With the antigestagen RU 486 an existent pregnancy was
terminated with 10 mg/d s.c. in 3 of 9 treated animals. The
abortions took place after a latency period-of 4 to 6 days
after the start of treatment (see Fig.. 1).
Antigestagen~proaesterone svnthesis inhibitor combination
0 The combination of marginally effective antigestagen
doses (10.0 mg of RU 486/d s.c.) with an ineffective epostane
doses o~ 30 mg/d orally resulted in an abortion rate of 100%
and a far more rapid occurrence of the abortions. The
latency period was shortened to a maximum of 2 days ~see Fig.
1).
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