Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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ANTIGESTA~:ENS FOR '1'~; INHIBITION OF
UTERINE SYNT~SIS OF PROSTA&I~NDIN
8ackground of the Invention
The invention relates to the use of antigestagens
and the production of drugs containing antigestagens for
the inhibition of uterine synthesis of prostaglandin,
especially for thé treatment and prevention of
dysmenorrheic symptoms.
Effective antigestagens are known, for example,
~rom European patent speci~ication 57,115 (Roussel-
Uclaf).
Studied especially thoroughly was 11-beta-t4-N,N-
dimethylamino)-phenyl]-17-beta-hydroxy-17-alpha-
propinyl-4,9(10)-estradien-3-one designated as RU 486.
Data on the therapeutic mechanism of RU 486 are found in
"Human Reproduction," Vol. 1 (1986), 107-110. According
to it, antigestagen causes a blocking of progesterone
activity and an increase of the formation of
prostaglandin, and the prostaglandin stimulates uterine
~- 20 contractility. With RU 486, clinical studies to the end
of pregnancy have just been conducted.
Prostaglandins play a key role in normal and
pathological menstruation:
They are viewed in relation to changes in the blood
supply of the mucous coating o~ the uterus and to the
laborlike contractions of the uteru~ during
menstruation. Increased release of PG and increased
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uterine contractions, which can be felt as extremely
painful, are the essence of dysmenorrhea.
Summary of the Invention
It is an object of the invention, therefore, to
provide a method for the inhibition of dysmennorhea and
prophalactic treatment of individuals with a history of
such smyptons.
It has now been found that, contrary to the
previous assumption, antigestagens inhibit uterine
- prodction of prostaglandins (PG). These objects
therefore have been satisfied by the provision of a
method for the use of antigestagens and the production
of drugs containing antigestagens used in the inhibition
of uterine synthesis of prostaglandin.
The invention further relates to the use of
antigestagens ~or treatment and prevention of
dysmenorrheic symptoms.
Detailed D~scussion
Inhibition of uterine PG through the use of
antigestagens eliminates or at least substantially
lessens the symptoms which accompany dysmenorrhea.
Since uterine synthesis o~ PG occurs essentially in the
endometrium, di~turbances and pains resulting from
endometriosis will also be benef~cially af~ected by
antigestagens.
The inhibitory effect of antigestageus was observed
in nonpregnant guinea pigs.
Luteolysis resulting from uterine PG at the end of
the approximately 16-day cycle was blocked by
antigestagens. A progression of serum progesterone
values resulted which otherwise occurs only during
pregnancy. Corresponding ef~ects of inhibited uterine
PG production would not be observed in human beings as a
result of antigestagens, since in a woman the lifespan
of the corpus luteum is not controlled by the uterus.
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However, with inhibition of uterine PG release in
humans, a calming effect of the uterine motor system in
the presence of dysmenorrhea will occur.
The advantage of this treatment course is that a
desirable degree of inhibition is attained without
affecting the PG function in other organs. A high
degree of organ selectivity is achieved through the
treatment of dysmenorrhea with antigestagens.
Antigestagens can be used at the onset of
dysmenorrheic symptoms, such as "pains in the lower
abdomen." It is sometimes appropriate to set the
beginning of the treatment at somewhat earlier phases of
the luteal phase to achieve a sufficient degree of
inhibition. In such prophylactic treatment, typical
hosts are those with a prior history of dysmenorrheic
symptoms, and treatment is commenced be~ore the onset of
estrus or menstruat~on.
According to a pre~erred embodiment, the
antigestagen treatment is given as a rule over 1 to 6,
pre~erably 1 to 4 days, preférably startin~ at thé
beginning o~ the estrual or menstrual period or upon the
appearance o~ symptoms,
As antigestagens, all compounds which have a strong
affinity for the gestagen receptor (progesterone
receptor) and at the same time show no gestagenic
activity of their own are suitable. As competitive
progesterone antagonists, the following steroids, for
example, are suitable:
beta-t(4-N,N-dimethylamino)-phenyl]-17-beta-hydroxy-
17-alpha-propinyl-4,9(10)-estradien-3-one,
11-beta-t(4-N,N-dimethylamino)-phenyl]-17-beta-hydroxy-
18-methyl-17-alpha-propinyl-4,9(10)-estradien-3-one,
ll-beta-t(4-N,N-dimethylamino)-phenyl]-17a-beta-hydroxy-
17a-alpha-propinyl-D-homo-4,9(10)-16-estratrien-3-one
(European Patent Application 82400025.1 - Publication
Number 57,115), 11-beta-methoxyphenyl-17-beta-hydroxy-
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17-alpha-ethinyl-4,9(10)-estradien-3-one, (Steroids 37 (1981)
361-382), 11-beta-~(4-N,N-dimethylamino)-phenyl]-17-beta-
hydroxy-17-alpha-hydroxyprop-l(Z)-enyl)- 4,9(10)-estradien-3-
one (European Patent Application 847300147.0 - Publication
Number 147,361), 11-beta-[(4-N,N-dimethylamino)-phenyl]-17-
alpha-hydroxyl7-beta-(3-hydroxypropyl)-13-alpha-methyl-
4,9(10-gonadien-3-one (European Patent Application 84730062.1
- Publication Number 129,49g). Other antigestagens which are
disclosed in US-4,536,401; US Patent No. 4,814,327 and US
Patent No. 4,829,060 are useful.
The antigestagens can, for example, be administered locally,
topically, enterally or parenterally.
For the preferred oral administration, particularly tablets,
coated tablets, capsules, pills, suspensions or solutions
which can be produced in the standard way with the admixtures
and vehicles usual in galenic medicine are suitable. For
local or topical use, vaginal suppositories or transdermal
systems such as sXin plasters, for example, are suitable.
According to the present invention, the antigestagens are
used generally in amounts of about 2 to 50 mg/day, preferably
about 5 to 20 mg/day of 11-beta-[(4-N,N-dimethylamino)-
phenyl]-17-alpha-hydroxy-17-beta-(3-hydroxypropyl)-13-alpha-
methyl-4,9~10)-gonadien-3-one or in a biologically equivalent
amount of another antigestagen. Such amounts can be
routinely determined by differential dosage studies using a
conventional protocol determining antigestagenic activity;
- e.g. Fertility and Sterility 40,253 (1982), Steroids 37. 361
(1981).
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The compounds according to this invention when administered
to patients, e.g., humans to inhibit PG formation or treat
dysmenorrhea can be used analogously to the known agent
Cyclo-Progynova(R). Dosage amounts are analogous when
administered to prevent dysmenorrhea.
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Without further elaboration, it is believed that
one s~illed in the art can, using the preceding
description; utilize the present invention to its
fullest extent. The following preferred specific
embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the
disclosure in any way whatsoever.
In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees
Celsius and unless otherwise indicated, all parts and
percentages are by weight.
The entire text of all applications, patents and
publications, if any, cited above and below are hereby
incorporated by reference.
Example 1
Compo~ition o~ a tablet with 10 mg o~ 11-beta-[(4-
N,N-dimethylamino)-phenyl~-11-alpha-hydroxy-17-beta-(3-
hydroxypropyl)-13-alpha-methyl-4,9(10)-gonadien-3-one
~or o~al adm~ais~ation.
2010.0 mg 11-beta-t~4-N,N-dimethylamino)-phenyl]-
17-alpha-hydroxy-17-beta-(3-
hydroxypropyl)-13-alpha-methyl-4,9(ioj-
gonadien-3-one
140.5 mg lactose
2S69.5 mg corn starch
2.5 mg polyvinylpyrrolidone 25
2.0 mg Aerosil
_ O.S mg magnesium stearate
22S.0 mg Total Weight
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Example 2
Composition of an oily solution with So mg of 11-
beta-1(4-N,N-dimethylamino)-phenyl]-17-alpha-hydroxy-17-
beta-(3-hydroxypropyl)-13-alpha-methyl-4,9(10)-gonadien-
3-one for parente~al administration.
50 mg of the antigestagen is dissolved in 1 ml each
of castor oil/benzyl benzoate in a 6:4 ratio by volume.
Example 3
Nonpregnant guinea pigs received daily, from the
8th to the 16th day of the approximately 16-day cycle,
10 mg of 11-beta-~(4-N,N-dimethylamino)-phenyl]-17-
alpha-hydroxy-17-beta-(3-hydroxypropyl)-13-alpha-methyl-
4,9(10)-gonadien-3-one. The test substance was
dissolved in 1 ml of benzyl benzoate/castor oil (1:2)
and in~ected subcutaneously. The progesterone content
of the serum was determined daily.
It can be seen from the following table that the
serum progesterone values for the animals treated with
' 20 the antigestagen increase, while the serum progesterone
values for the controls treated with solvent fall
sharply toward the end of the cycle. Corresponding
dose-dependent findings were obtained for this substance
and also for other antigestagens in similar test
arrangements. The increase of progesterone in the blood
of animals treated with the antigestagen reflects an
inhibition of uterine release of PG.
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Treatment of Nonpregnant Guinea Pigs with 10 mg of
ll-beta-[~4-N,N-dimethylamino)-phenyl]-17-alpha-hydroxy-
17-beta-(3-hydroxypropyl)-13-alpha-methyl-4,9(10)-
qonadien-3-one _ _
Progesterone/nmol/l serum
Animal
No. do dl d4 d6 d8
Animals6637 1.3 23.2 7.2 10.2 19.9
Treated
With 6638 1.9 1.5 8.5 11.9 8.4
Anti-
Gestagen 6639 1.6 5.9 13.5 13.6 9.5
6640 0.4 4.8 8.2 17.6 22.2
________________________________________________________
Controls 6641 0.4 6.1 5.3 7.1 8.0
Treated
With 6642 3.7 2.3 11.7 8.7 18.1
Solvent
(Table Continued)
Animal
No. dlo dl2 dl4 d1s dl6 d17
Animals6637 20.5 18.810.2 --- 16.0 26.8
Treated
With 6638 14.3 16.117.4 --- 25.6 .Z~r 6
Anti-
Gestagen 6639 13.013.0 Z4.2 18.4 --- ---
6640 23.6 36.031.4 39.8 --- ---
____________ ___________________________________________
Controls 6641 9.5 10.6 5.2 --- 2.8 2.8
Treated
With 6642 5.3 1.3 0.8 1.1 --- ---
Solvent
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The preceding examples can be repeated with similar
success by substituting the generically or specifically
described reactants and/or operation conditions of this
invention for those used in the preceding examples.
From the foregoing description, one skilled in the
art can easily ascertain the essential characteristics
of this invention, and without departing from the spirit
and scope thereof, can make various changes and
modifications of the invention to adapt it to various
usages and conditions.
