NZ712670B2 - Progesterone receptor antagonist dosage form - Google Patents
Progesterone receptor antagonist dosage form Download PDFInfo
- Publication number
- NZ712670B2 NZ712670B2 NZ712670A NZ71267014A NZ712670B2 NZ 712670 B2 NZ712670 B2 NZ 712670B2 NZ 712670 A NZ712670 A NZ 712670A NZ 71267014 A NZ71267014 A NZ 71267014A NZ 712670 B2 NZ712670 B2 NZ 712670B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- treatment
- estra
- methylsulphonyl
- pentafluoroethyl
- hydroxy
- Prior art date
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- 239000002552 dosage form Substances 0.000 title claims description 9
- 102000003998 progesterone receptors Human genes 0.000 title abstract description 17
- 108090000468 progesterone receptors Proteins 0.000 title abstract description 17
- 239000002464 receptor antagonist Substances 0.000 title abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 39
- 206010046798 Uterine leiomyoma Diseases 0.000 claims abstract description 36
- 201000010260 leiomyoma Diseases 0.000 claims abstract description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 22
- 210000004291 Uterus Anatomy 0.000 claims abstract description 17
- 230000000069 prophylaxis Effects 0.000 claims abstract description 16
- 201000004458 myoma Diseases 0.000 claims abstract description 14
- 201000007954 uterine fibroid Diseases 0.000 claims abstract description 14
- 201000009273 endometriosis Diseases 0.000 claims abstract description 11
- 230000002175 menstrual Effects 0.000 claims abstract description 10
- 239000011780 sodium chloride Substances 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 32
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- -1 Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone Chemical compound 0.000 claims description 17
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 17
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- 239000008194 pharmaceutical composition Substances 0.000 abstract description 32
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Classifications
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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
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/36—Antigestagens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
Abstract
The invention is directed to a pharmaceutical composition comprising a progesterone receptor antagonist namely (11 β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one at the dosage of about 0.5 to 5 mg and more particularly 2 mg. Additionally, the invention is directed to the use of the novel pharmaceutical composition for treatment of and/or prophylaxis of gynaecological diseases, such as fibroids of the uterus (myomas, uterine leiomyoma), endometriosis or excessive menstrual bleeds, and method for obtaining such composition and oral dosage form. directed to the use of the novel pharmaceutical composition for treatment of and/or prophylaxis of gynaecological diseases, such as fibroids of the uterus (myomas, uterine leiomyoma), endometriosis or excessive menstrual bleeds, and method for obtaining such composition and oral dosage form.
Description
Progesterone receptor antagonist dosage form
The disclosure is directed to a pharmaceutical composition comprising a progesterone receptor antagonist
namely (11β,17β)Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone at
the dosage of about 0.5 to 5 mg and more particularly 2 mg. Additionally, the disclosure is directed to the
use of the novel pharmaceutical composition for treatment of and/or prophylaxis of gynaecological
diseases, such as fibroids of the uterus (myomas, uterine leiomyoma), endometriosis or excessive
menstrual bleeds, and method for obtaining such composition and oral dosage form.
Background
Uterine leiomyomas (also called fibroids or myomas) are common benign tumors of the myometrium, which
are reported to occur in approximately 30-40 % of all women of reproductive age. They may remain
asymptomatic, or cause bleeding abnormalities and/or bulk-related symptoms depending on their number,
size and location. Various medications are used for symptom-oriented therapy in minor disease (e.g.
combined oral contraceptives, progestogens, iron supplements). For short-term therapy and/or as a
precursor to surgery, gonadotropin-releasing hormone agonists represent the most effective medical
treatment. However, their use is restricted to 6 months due to hypoestrogenic side effects. For definite
treatment of symptomatic leiomyomas, therapeutic options are mainly surgical so far.
Various studies suggested steroid-dependence of fibroids growth in which progesterone has a critical role.
This is supported by the fact, that progesterone receptor (PR) antagonists – like mifepristone (RU 486) –
have been shown to decrease the size of fibroids and related symptoms. Therefore, PR antagonists might
offer a promising therapeutic alternative meeting the need for medical long-term treatment of symptomatic
fibroids with an orally effective agent lacking clinically relevant side effects. Mifepristone (RU 486) was
disclosed in EP57115. Additional competitive progesterone receptor modulators are shown below.
from Spitz et al. Current Opinion in Obstetrics and Gynecology, 2009, 21:318-324.
All these compounds as listed above are effective in the treatment of uterine fibroids where that are
associated with a reduction in pain, bleeding and improvement in quality of life and decrease in fibroid size.
Long-term treatments are associated with endometrial thickening on ultrasound and histological changes in
the endometrium. The endometrial change such as endometrial thickening seems to be connected to cystic
glandular dilatation (Spitz et al. Current Opinion in Obstetrics and Gynecology, 2009, 21:318-324.).
Progesterone receptor antagonists with a fluorinated 17 -side chain were published in WO 98/34947 and
Fuhrmann et al., J. Med. Chem. 43, 5010 - 5016 (2000).
In PEARL I and PEARL II trial (N Engl J Med. 2012;366:409-420) women with excessive uterine bleeding
due to the presence of fibroids were randomized to ulipristal acetate (5 mg vs. 10 mg orally once daily) vs.
placebo or intramuscular injections of leuprolide acetate for up to 13 weeks.
To conclude, endometrium changes were observed during treatment with most of the cited above
progesterone receptor antagonists.
It was surprisingly found that (11β,17β)Hydroxy[4-(methylsulphonyl)phenyl]
(pentafluoroethyl)estra-4,9-dienone is a potent competitive progesterone receptor antagonist creating
alternatives for the treatment of gynaecological diseases. Amenorrhea was observed in healthy subjects
treated with said compound. (11β,17β)Hydroxy[4-(methylsulphonyl)phenyl]
(pentafluoroethyl)estra-4,9-dienone was originally disclosed in WO2011/009531A1. Further, it was
surprisingly found that the dosage of about 0.5 to 5 mg and more particularly 2 mg of (11β,17β)
Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone that is a potent
progesterone receptor antagonist being useful for the treatment of certain gynaecological diseases wherein
the gynaecological disease is preferably characterized by excessive uterine bleeding. Indeed, it was
observed an amenorrhea (non-bleeding) of 92.5% in the healthy subjects to which said compound was
administered at a dosage of 2 mg. Amenorrhea corresponds to the major objective of the treatment i.e.
control of excessive uterine bleeding.
In the case of the present invention further improvements were observed in respect of the return of
bleeding after the end of treatment and the endometrium thickness.
Summary
The invention is directed to use of (11β,17β)Hydroxy[4-(methylsulphonyl)phenyl]
(pentafluoroethyl)estra-4,9-dienone or salts thereof in the manufacture of a medicament for treatment
and/or prophylaxis of a gynaecological disease, wherein the medicament comprises about 1 to 5 mg of
(11β,17β)Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone.
Described is a pharmaceutical composition comprising about 0.5 to 5 mg of (11β,17β)Hydroxy[4-
(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone and treatment and/or prophylaxis of
gynaecological diseases in patients in need wherein the gynaecological disease is preferably characterized
by excessive uterine bleeding.
Also described is a pharmaceutical composition comprising about 2 mg of (11β,17β)Hydroxy[4-
(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone and treatment and/or prophylaxis of
gynaecological diseases in patients in need wherein the gynaecological disease is preferably characterized
by excessive uterine bleeding.
Further, described is an oral dosage form comprising about 2 mg of (11β,17β)Hydroxy[4-
(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone and treatment and/or prophylaxis of
gynaecological diseases in patients in need wherein the gynaecological disease is preferably characterized
by excessive uterine bleeding.
Finally, described is a method for obtaining said pharmaceutical composition or oral dosage form.
The compound described herein is defined as a selective progesterone receptor modulator with well
confirmed antagonist property.
Description
In a first aspect, the invention is directed to use of (11β,17β)Hydroxy[4-(methylsulphonyl)phenyl]-
17-(pentafluoroethyl)estra-4,9-dienone or salts thereof in the manufacture of a medicament for treatment
and/or prophylaxis of a gynaecological disease, wherein the medicament comprises about 1 to 5 mg of
(11β,17β)Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone.
Also described is a pharmaceutical composition comprising about 0.5 to 5 mg of (11β,17β)Hydroxy
[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone
of formula
or salts thereof.
Preferably, the pharmaceutical composition comprises a range of about 0.7 to 5 mg, 0.7 to 4.5 mg, 1 to 4.5
mg, 1 to 4 mg, 1.5 to 3.5 mg or 1.5 to 3 mg of above mentioned compound or salt thereof independently
from each other. More preferably, the pharmaceutical composition comprises a range of about 0.7 to 5 mg,
1 to 4 mg or 1.5 to 3 mg of above mentioned compound or salt thereof independently from each other.
Even more preferably, the pharmaceutical composition comprises a range of about 1 to 4 mg of above
mentioned compound or salt thereof.
Preferably, the pharmaceutical composition comprises 0.5 mg, 0.7 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg of
above mentioned compound or salt thereof. More preferably, the pharmaceutical composition comprises 2
mg, 3 mg or 4 mg of above mentioned compound or salt thereof.
Even more preferably, described is a pharmaceutical composition comprising about 2 mg of (11β,17β)
Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone
of formula
or salts thereof.
In a first embodiment, the pharmaceutical composition comprises additionally a pharmaceutically
acceptable excipient.
Pharmaceutically acceptable excipient is defined as a filler (such as sugars, such as lactose, sucrose,
dextrose and dextrates; sugar alcohols, such as mannitol, sorbitol and xylitol); carbonates and phosphates
of alkaline earth metals, such as calcium carbonate and calcium phosphate; celluloses, such as powdered
cellulose and microcrystalline cellulose; colloidal silica; titanium dioxide; kaolin; talc), or lubricants (such as
magnesium stearate).
In a second embodiment, the pharmaceutical composition comprises additionally a pharmaceutically
acceptable excipient and/or at least one or more other active substances, in particular active substances
known for the treatment and/or prophylaxis of the aforementioned diseases.
For the treatment of fibroids of the uterus or endometriosis, the compound described herein can be
combined simultaneously or sequentially with gestagens or combinations of oestrogens and gestagens.
Progesterone receptor antagonists/gestagen regimens are disclosed in WO 96/15794 (Spicer et al.,
Balance Pharm. Inc.), WO 96/03130 (Stöckemann et al., Schering AG) and (Möller et
al., Bayer Schering Pharma AG). Regimens – optionally repeated – in which the progesterone receptor
antagonist is administered over a period of two to four months, followed by the administration of the
gestagen for a period of one to four weeks, are very suitable for the treatment of fibroids of the uterus and
endometriosis. Administration of the progesterone receptor antagonist for 84 days, followed by
administration of the gestagen for 14 days – optionally repeated – is especially suitable.
Simultaneous or sequential administration of the compounds described herein e.g. with SERMs, SERDs
and oestrogens can be considered for the treatment of complaints associated with the menopause.
SERMs (selective estrogen receptor modulators) are compounds that are tissue selective and have either
an anti-oestrogenic or oestrogenic action, for example on the uterus they inhibit the action of oestrogen, but
on bone they have a neutral or oestrogen-like action. Examples are clomifene, raloxifene, tamoxifen,
torimifene, bazedoxifene, lasofoxifene and ormeloxifene.
Selective estrogen receptor destabilizers (SERD) are pharmaceuticals which completely antagonize the
oestrogen receptor ('pure anti-oestrogens' without oestrogenic active component) and lead to down-
regulation of the receptor (for example fulvestrant, ZK-703 and ZK-253 (Hoffmann J et al., J Natl Cancer
Inst 2004, 96:210-218) and compounds described in WO 98/007740, WO 99/33855 and WO 03/045972.
Anti-oestrogens are compounds that completely antagonize the oestrogen receptor, for example
fulvestrant.
Gestagens are, in the sense of the present invention, either the natural progesterone itself or synthetic
derivatives, which like progesterone itself bind to the progesterone receptor and, at dosages above the
ovulation inhibiting dose, inhibit ovulation. As examples of the synthetic derivatives, we may mention
drospirenone, gestodene, levonorgestrel, cyproterone acetate, desogestrel and 3-ketodesogestrel,
norethisterone, norethisterone acetate and dienogest.
Combinations of gestagens and oestrogens are the combinations of active substances that are contained
in the oral contraceptives that are known per se, for example Yasmin, Femovan, Triquilar, Marvelon, YAZ
etc.
The description encompasses all salts, solvates or solvates of the salts, including all crystal modifications of
(11β,17β)Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone.
The pharmaceutical composition is in an appropriate form for intravenous (i.v.), intramuscular (i.m.) or oral
administration. Preferably, oral form for administration is a dosage form such as tablet capsule or solution.
Nevertheless, it may optionally be necessary to deviate from the stated amounts, namely depending on
body weight, route of administration, individual response to the active substance, type of preparation and
point of time or interval when application takes place. Thus, in some cases it may be sufficient to use less
than the aforementioned minimum amount, whereas in other cases the stated upper limit must be exceeded. In
the case of the administration of larger amounts it may be advisable to distribute these in several individual
doses throughout the day.
(11β,17β)Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone is
referenced as compound 1 within the whole specification.
It shall be understood that the dosage “about 2 mg” means any dosage from 1.5 to 2.5 mg of compound 1.
Preferably, the dosage is of 2 mg of compound 1.
The compound 1 described herein displays an unforeseeable, valuable pharmacological, pharmacokinetic
and pharmacodynamic profile of action.
Also described is a pharmaceutical composition useful for the treatment and/or prophylaxis of
gynaecological diseases. The gynaecological disease is preferably characterized by excessive uterine
bleeding. More preferably, the gynaecological disease is fibroids of the uterus (myomas, uterine
leiomyoma), endometriosis or excessive menstrual bleeds. Even more preferably, the gynaecological
disease is fibroids of the uterus (myomas, uterine leiomyoma).
In other word described is a method for the treatment and/or prophylaxis of gynaecological diseases with
the administration to a patient in need of a pharmaceutical composition comprising about 0.5 to 5 mg of
(11β,17β)Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone or salts
thereof. The gynaecological disease is preferably characterized by excessive uterine bleeding. More
preferably, the gynaecological disease is fibroids of the uterus (myomas, uterine leiomyoma),
endometriosis or excessive menstrual bleeds. Even more preferably, the gynaecological disease is fibroids
of the uterus (myomas, uterine leiomyoma).
Preferably, the pharmaceutical composition comprises a range of about 0.7 to 5 mg, 0.7 to 4.5 mg, 1 to 4.5
mg, 1 to 4 mg, 1.5 to 3.5 mg or 1.5 to 3 mg of above mentioned compound or salt thereof independently
from each other. More preferably, the pharmaceutical composition comprises a range of about about 0.7 to
mg, 1 to 4 mg or 1.5 to 3 mg of above mentioned compound or salt thereof independently from each
other. Even more preferably, the pharmaceutical composition comprises a range of about 1 to 4 mg of
above mentioned compound or salt thereof.
Preferably, the pharmaceutical composition comprises 0.5 mg, 0.7 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg of
above mentioned compound or salt thereof. More preferably, the pharmaceutical composition comprises 2
mg, 3 mg or 4 mg of above mentioned compound or salt thereof.
More particularly, described is a method for the treatment and/or prophylaxis of gynaecological diseases
with the administration to a patient in need of a pharmaceutical composition comprising about 2 mg of
(11β,17β)Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone or salts
thereof. The gynaecological disease is preferably characterized by excessive uterine bleeding. More
preferably, the gynaecological disease is fibroids of the uterus (myomas, uterine leiomyoma),
endometriosis or excessive menstrual bleeds. Even more preferably, the gynaecological disease is fibroids
of the uterus (myomas, uterine leiomyoma).
Also described is an oral dosage form comprising about 0.5 to 5 mg of (11β,17β)Hydroxy[4-
(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone
of formula
or salts thereof.
Preferably, the pharmaceutical composition comprises a range of about 0.7 to 5 mg, 0.7 to 4.5 mg, 1 to 4.5
mg, 1 to 4 mg, 1.5 to 3.5 mg or 1.5 to 3 mg of above mentioned compound or salt thereof independently
from each other. More preferably, the pharmaceutical composition comprises a range of about 0.7 to 5 mg,
1 to 4 mg or 1.5 to 3 mg of above mentioned compound or salt thereof independently from each other.
Even more preferably, the pharmaceutical composition comprises a range of about 1 to 4 mg of above
mentioned compound or salt thereof.
Preferably, the pharmaceutical composition comprises 0.5 mg, 0.7 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg of
above mentioned compound or salt thereof. More preferably, the pharmaceutical composition comprises 2
mg, 3 mg or 4 mg of above mentioned compound or salt thereof.
More particularly, described is an oral dosage form comprising about 2 mg of (11β,17β)Hydroxy[4-
(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone
of formula
or salts thereof.
In a first embodiment, the oral dosage form comprises additionally a pharmaceutically acceptable excipient.
In a second embodiment, the oral dosage form comprises additionally a pharmaceutically acceptable
excipient and/or at least one or more other active substances, in particular active substances known for the
treatment and/or prophylaxis of the aforementioned diseases.
Embodiment and preferred features as described above are herein included.
Further, described is an oral dosage form as described in third aspect for the treatment and/or prophylaxis
of gynaecological diseases. The gynaecological disease is preferably characterized by excessive uterine
bleeding. More preferably, the gynaecological disease is fibroids of the uterus (myomas, uterine
leiomyoma), endometriosis or excessive menstrual bleeds. Even more preferably, the gynaecological
disease is fibroids of the uterus (myomas, uterine leiomyoma).
Embodiment and preferred features as described above are herein included.
Finally, described is a method for obtaining said pharmaceutical composition or oral dosage form as
described above.
Embodiment and preferred features as described above are herein included.
Definitions and Preferred features applicable to first to fourth aspect:
Physiologically harmless salts of the compounds described herein are preferred as salts within the scope of the
present invention. However, salts that are not suitable in themselves for pharmaceutical uses, but can for
example be used for the isolation or purification of the compounds described herein, are also covered.
Physiologically harmless salts of the compounds described herein comprise – when they contain a basic
function – salts with inorganic or organic acids, in particular of mineral acids, carboxylic acids and sulphonic
acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid,
ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalene-disulphonic acid, acetic
acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid
and benzoic acid.
Physiologically harmless salts of the compounds described herein comprise – when they contain an acid
function – alkali metal salts, alkaline earth metal salts or ammonium salts, such as can be obtained by reaction
with corresponding inorganic or organic bases. We may mention, for example and preferably, alkali metal salts
(e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and
ammonium salts, derived from ammonia or organic amines with 1 to 16 carbon atoms, such as, for example
and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine,
diethanolamine, triethanolamine, bicyclo-hexylamine, dimethylamino-ethanol, procaine, dibenzylamine, N-
methylmorpholine, arginine, lysine, ethylenediamine, N-methyl piperidine, N-methyl glucamine, D-methyl
glucamine, ethyl glucamine, 1,6-hexadiamine, glucosamine, N-methylglycine, 2-amino-1,3-propandiol, tris-
hydroxymethyl-aminomethane and 1-amino-2,3,4-butanetriol.
Those forms of the compounds described herein that display, in the solid or liquid state, adduct formation with
solvent molecules, are designated as solvates. The solvent can be present in stoichiometric or even non-
stoichiometric proportions. In the case of stoichiometric solvates, they are also called hemi-, (semi-), mono-
, sesqui-, di-, tri-, tetra-, penta-, etc. solvates. Hydrates are a special form of solvates, in which the
coordination takes place with water.
The pharmaceutical efficacy of the compound described herein can be explained by their action as
progesterone receptor antagonists, and thus by their antagonizing action on the progesterone receptor.
Also described is the use of the compound described herein for the treatment and/or prophylaxis of
diseases based on hormone-dependent hyperproliferative processes, preferably of gynaecological
diseases, in particular of fibroids of the uterus, endometriosis or hormone-dependent breast cancers.
The compounds described herein can act systemically and/or locally. For this purpose they can be applied
in a suitable way, e.g. by the oral, intrauterine, intravaginal, parenteral, pulmonary, nasal, sublingual,
lingual, buccal, rectal, dermal, transdermal, conjunctival, or otic route or as an implant or stent.
Intrauterine means in particular application by means of an IUS (intrauterine system) or IUD (intrauterine
device). Intravaginal application can be effected by means of, among others, IVR/VRS (intravaginal
ring/vaginal ring system).
Forms for intrauterine or intravaginal application (cf. e.g. WO 01/47490, especially page 1, line 10 to line 5,
line 13 and line 7, line 19 to line 58, line 6, or for vaginal rings: WO 06/010097, especially page 10, line 22
to page 14, line 28) can contain the compounds described herein and non-silicone and/or silicone polymers,
in particular also siloxane-based elastomers (cf. WO 01/47490, especially page 7, line 19 – page 15, line
15).
For these routes of administration, the compounds described herein can be administered in suitable dosage
forms.
Quick-release and/or modified-release dosage forms functioning according to the prior art are suitable for
oral administration, containing the compounds described herein in crystalline and/or amorphous and/or
dissolved form, e.g. tablets (uncoated or coated tablets, for example with enteric coatings or delayed-
dissolving or insoluble coatings, which control the release of the compound described herein), tablets or
films/wafers that quickly disintegrate in the oral cavity, films/lyophilizates, capsules (for example hard-
gelatin or soft-gelatin capsules), coated tablets, granules, pellets, powders, emulsions, suspensions,
aerosols or solutions.
Parenteral application can take place while avoiding an absorption step (e.g. intravenous, intraarterial,
intracardial, intraspinal or intralumbar) or with inclusion of absorption (e.g. intramuscular, subcutaneous,
intradermal, percutaneous or intraperitoneal). Injection and infusion preparations in the form of solutions,
suspensions, emulsions, lyophilizates or sterile powders, among others, are suitable as dosage forms for
parenteral administration.
For the other routes of administration, the following are suitable, e.g. inhalation dosage forms (including
powder inhalers, nebulizers), nasal drops, solutions, and sprays; tablets for lingual, sublingual or buccal
administration, films/wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous
suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal
therapeutic systems (for example patches), milk, pastes, foams, dusting powders, implants or stents.
The compounds described herein can be converted to the aforementioned dosage forms. This can be
carried out in a manner that is known per se, by mixing with inert, non-toxic, pharmaceutically suitable
excipients. These excipients include, among others, carrier substances (for example microcrystalline
cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or
wetting agents (for example sodium dodecylsulphate, polyoxysorbitan oleate), binders (for example
polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants,
for example ascorbic acid), colouring matter (e.g. inorganic pigments, for example iron oxides) and taste
and/or odour correctants.
Experimental part
The percentages in the following tests and examples are, unless stated otherwise, percentages by weight;
parts are parts by weight. Proportions of solvents, dilution ratios and concentration figures for liquid/liquid
solutions always refer to volume.
The following examples serve to explain the invention without limiting it in any way.
Example 1: Synthesis path of compound 1
(11β,17β)Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone
OH S
O OH
g of the compound described in example 1b) was dissolved in a mixture of 140 ml THF and 140 ml
methanol. A solution of 20 g Oxone in 94 ml water was slowly added dropwise at 0°C. Then it was stirred
for a further 3.5 hours at 0°C. Then a mixture of water and dichloromethane was added to the reaction
mixture. The phases were separated and the aqueous phase was extracted several times with
dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride
solution, dried over sodium sulphate and concentrated under vacuum. The raw product was purified by
silica gel chromatography. This gave 3.8 g of the title compound.
H-NMR (300 MHz, CDCl ): δ= 7.86 d (2H); 7.40 d (2H); 5.81 sbr (1H); 4.50 dbr (1H); 3.07 s (3H); 0.51 s
(3H).
Example 2: Dose-effect of 84 days treatment with compound 1
Randomized Study population:
1. Healthy female subjects, sterilized by tubal ligation
2. Age at screening: 18 - 45 years
3. Body mass index (BMI) at screening: ≥ 18 and ≤ 32 kg/m²
4. At least 3 consecutive regular menstrual cycles with a cycle length of 24 – 35 days before first
screening examination according to the subject’s history
. Absence of clinically relevant abnormal findings in the pre-treatment endometrial biopsy
6. Adequate venous access (frequent blood sampling)
Protocol:
Table 1: Treatment dosage with compound 1
Dose Treatment (Dose Amount / route of administration Cumulative dose No. of
level compound 1) for per subject subjects
84 days treated
A 0.1 mg 1 tablet 0.1 mg compound 1and 3 8.4 mg 10
tablets placebo once daily per os
B 0.5 mg 1 tablet 0.5 mg compound 1and 3 42 mg 10
tablets placebo once daily per os
C 1 mg 2 tablets 0.5 mg compound 1and 2 84 mg 10
tablets placebo once daily per os
D 2 mg 4 tablets 0.5 mg compound 1once 168 mg 10
daily per os
E 5 mg 1 tablet 5 mg compound 1and 3 420 mg 10
tablets placebo once daily per os
P Placebo 4 tablets placebo once daily per os 0 mg 10
The subject had to start the intake of the study drugs on the first or second day of menstrual bleeding after
the pre-treatment cycle. The pre-treatment cycle started on the first day of the subject’s menstrual bleeding
after screening examinations had shown that the subject was eligible for further participation. After the pre-
treatment cycle treatment was started. The treatment period started with the first and ended with the last
intake of compound 1. For each intake day the subject received one bottle containing 4 tablets. The
number of tablets taken and the intake time had to be documented in the diary.
The evaluation of bleeding pattern was based on a daily self-assessment of the bleeding intensity by the
subject. These assessments were categorized as defined below. The subjects were provided with an
explanation of the categories in local language, and were asked to document the bleeding intensity in their
diaries accordingly (one entry per day).
Administration of compound 1 occurred during 84 days (multiple doses administration).
Table 2: Bleeding pattern categories
Results:
Results of the bleeding pattern is shown in figure 1 (posterior of non-blrrding (per protocol set).
It was observed that compound 1 caused a marked and dose-dependent reduction in the number of days
of bleeding during the treatment period. After administration of 0.5 mg of compound 1, three (3) out of
eleven (11) subjects (27 %) had no further bleeding during the treatment period of 84 days. 50% of dose-
dependent reduction of bleeding is obseverd with a dosage of 0.7 mg. Clear stagnation appears around 2
mg and from 2 mg up to 5 mg a saturation is observed around 95%.
Example 3: Return of bleeding after end of treatment (84 days) with compound 1
Randomized Study population:
As described in example 2.
Protocol:
The first day of bleeding after the end of the treatment was marked.
Results
Subjects of the study treated with 2 mg of compound 1 during 84 days show a delayed return of bleeding
with a mean of 25 days. A delayed return of bleeding after treatment leads to longer free bleeding periods
per year for the subject. One subject showed a delayed return of bleeding after treatment of about 52
days.
All results are in table 3 below.
Table 3: Number of days until onset of bleeding after end of treatment (mean ± SD, min – max; PPS, n =
67).
Plac 0.1 mg 0.5 mg 1 mg 2 mg 5 mg
(n = 12) (n = 11) (n = 11) (n = 10) (n = 12) (n = 11)
Number of days until
9.8 ± 8 12.2 ± 9.9 14.8 ± 10.2 20.3 ± 6.2 25.8 ± 11.1 20.9 ± 10.9
first bleeding after end
(1 – 23) (3 – 35) ( 1 – 28) (8 – 28) (9 – 52) (1 – 38)
of treatment
Plac: Placebo
Example 4: Measurement of endometrial thickness during and after treatment with compound 1
Randomized Study population
As described in example 2.
Protocol:
The endometrial thickness was measured in the medio-sagittal section as double-layer in millimeters using
transvaginal ultrasound.
Results:
Subjects of the study treated with 2 mg of compound 1 during 84 days show a lower maximum thickness
of the endometrium compared to other dosages of compound 1. Further, the observed results of the
subjects of said group are more consistent than other dosage groups.
See figure 2 (Box plot for maximum endometrial thickness within treatment epoch).
Bay means compound 1.
Example 5: Ovulation inhibition: Follicle size, Estradiol (E2), Progesterone (P)
Protocol: Randomized Study population of healthy female subjects as described in example 2 above.
Blood samples were obtained from healthy female subjects for the determination of Estradiol (E2),
Progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) in serum and taken at
the same time points as listed below during the pre-treatment cycle, the treatment and follow-up cycle.
Transvaginal ultrasound (TVU) was used to monitor ovarian follicular growth during pretreatment (days 9
and 21), treatment (days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84) and follow-up cycle (days 9 and 21).
Results:
Table 4 shows the number and percentage of subjects, classified according to the maximum follicle size
and Estradiol (E2) and Progesterone (P) values during the treatment period (number of subjects n = 69)
During treatment, maximum diameters of Follicle-like structures (FLS) were between 13 and 30 mm in the
majority of subjects of all treatment groups (including placebo).
No ovulation occurred in most of the subjects receiving dosages ≥ 0.5 mg of compound 1 during subject
treatment of 84 days (i.e. progesterone value < 1.57 µg/L).
Table 4
Claims (11)
1. Use of (11β,17β)Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dien- 3-one or salts thereof in the manufacture of a medicament for treatment and/or prophylaxis of a gynaecological disease, wherein the medicament comprises about 1 to 5 mg of (11β,17β) 5 Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone.
2. The use according to claim 1, wherein the medicament comprises about 1 to 4 mg of (11β,17β)- 17-Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone.
3. The use according to claim 1 or 2, wherein the medicament comprises about 2 to 4 mg of (11β,17β)Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone. 10
4. The use according to any one of claims 1 to 3, wherein the medicament comprises about 2 mg of (11β,17β)Hydroxy[4-(methylsulphonyl)phenyl](pentafluoroethyl)estra-4,9-dienone.
5. The use according to any one of claims 1 to 4, wherein the medicament additionally comprises a pharmaceutically acceptable carrier.
6. The use according to any one of claims 1 to 5, wherein the medicament is in a form of an oral 15 dosage.
7. The use according to claim 6, wherein the dosage form is a tablet or a capsule.
8. The use according to any one of claims 1 to 7, wherein the gynaecological disease is characterized by excessive uterine bleeding.
9. The use according to any one of claims 1 to 8, wherein the gynaecological disease is selected 20 from the group consisting of fibroids of the uterus (myomas, uterine leiomyoma), endometriosis and excessive menstrual bleeds.
10. The use according to any one of of claims 1 to 9, wherein the gynaecological disease is fibroids of the uterus (myomas, uterine leiomyoma).
11. The use according to any one of claims 1 to 10, substantially as herein described with reference to 25 any example thereof .
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ750686A NZ750686B2 (en) | 2013-04-11 | 2014-04-09 | Progesterone receptor antagonist dosage form |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13163417.2 | 2013-04-11 | ||
EP13163417 | 2013-04-11 | ||
PCT/EP2014/057101 WO2014166971A1 (en) | 2013-04-11 | 2014-04-09 | Progesterone receptor antagonist dosage form |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ712670A NZ712670A (en) | 2020-10-30 |
NZ712670B2 true NZ712670B2 (en) | 2021-02-02 |
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