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WO2012059594A1 - Antagonistes de récepteur de minéralocorticoïde pour le traitement de l'obésité induite par corticoïde - Google Patents

Antagonistes de récepteur de minéralocorticoïde pour le traitement de l'obésité induite par corticoïde Download PDF

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Publication number
WO2012059594A1
WO2012059594A1 PCT/EP2011/069464 EP2011069464W WO2012059594A1 WO 2012059594 A1 WO2012059594 A1 WO 2012059594A1 EP 2011069464 W EP2011069464 W EP 2011069464W WO 2012059594 A1 WO2012059594 A1 WO 2012059594A1
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WIPO (PCT)
Prior art keywords
syndrome
antagonist
glucocorticoid
drospirenone
endogenous
Prior art date
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Ceased
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PCT/EP2011/069464
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English (en)
Inventor
Vladimir Patchev
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Bayer Pharma AG
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Bayer Pharma AG
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Publication of WO2012059594A1 publication Critical patent/WO2012059594A1/fr
Priority to CN201280054180.0A priority Critical patent/CN103957921A/zh
Priority to ARP120104105A priority patent/AR088622A1/es
Priority to CA2854215A priority patent/CA2854215A1/fr
Priority to EP12783197.2A priority patent/EP2773356A1/fr
Priority to HK15100197.4A priority patent/HK1199712A1/xx
Priority to EA201400537A priority patent/EA201400537A1/ru
Priority to US14/356,165 priority patent/US20140288035A1/en
Priority to IN3307CHN2014 priority patent/IN2014CN03307A/en
Priority to PCT/EP2012/071700 priority patent/WO2013064620A1/fr
Priority to AU2012331089A priority patent/AU2012331089A1/en
Priority to JP2014539339A priority patent/JP2014532685A/ja
Priority to TW101140872A priority patent/TW201322986A/zh
Priority to KR1020147014686A priority patent/KR20140088197A/ko
Priority to MX2014005367A priority patent/MX2014005367A/es
Priority to BR112014010590A priority patent/BR112014010590A2/pt
Anticipated expiration legal-status Critical
Priority to IL232325A priority patent/IL232325A0/en
Ceased legal-status Critical Current

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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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • 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
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids
    • 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
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/46—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of glucocorticosteroids

Definitions

  • the present invention is on the field of prevention, and/or attenuation of adipo- genesis and obesity.
  • mineralcorticoid receptor antagonists are used as a therapeutically active principle, such as a therapeutically active ingredient (API).
  • the mineralcorticoid receptor antagonists used in this invention are capable of displacing the endogenous glucocorticoid Cortisol from the antimin- eralcorticoid receptor.
  • mineralocorticoid receptor (MR) antagonists are used for the prevention, treatment and/or attenuation of adiposity and obesity resulting from general, local or iatrogenic glucocorticoid excess.
  • Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances.
  • the primary en- dogenous mineralocorticoid is aldosterone, although a number of other endogenous hormones (including progesterone and deoxycorticosterone) have mineralocorticoid function.
  • Mineralocorticoids cause their effects by binding to the mineralocorticoid receptor (MR) and mineralocorticoids may be natural (cognate) or synthetic ligands.
  • MR mineralocorticoid receptor
  • mineralocorticoids may be natural (cognate) or synthetic ligands.
  • Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. GC are distinguished from mineralocorticoids and sex steroids by their specific receptors, target cells, and effects. Cortisol (or hydrocortisone) is the most important human glucocorticoid. GC cause their effects by binding to the glucocorticoid receptor (GR) and GC may be natural (cognate) or synthetic ligands. GC also show affinity of the MR indistinguishable from that of the cognate ligand of MR, see further below.
  • GR glucocorticoid receptor
  • MR mineralocorticoid receptors
  • Glucocorticoid elevation and resultant glucocorticoid receptor (GR) occupa- tion may have several endogenous pathogenic causes, among which Cushing's syndrome, Cushing's disease, chronic stress, major depression and alcohol abuse should be mentioned [7, 8, 9].
  • GR glucocorticoid receptor
  • chronic treatment with synthetic glucocorticoids or adrenocorticotropic hormone might produce iatrogenic consequences which emulate several metabolic consequences of glucocorticoid hyper- secretion.
  • visceral obesity and insulin resistance can result from abnormally high generation of glucocorticoids in the fat tissue, due to aberrant activity of 11 ⁇ hydroxysteroid dehydrogenase type 1 [10].
  • adipocyte maturation and adipogenesis can be disrupted by MR blockade using selective MR antagonists, whose affinity for the MR is comparable to, or higher than that, of endogenous glucocorticoids (e.g. Cortisol) and, thus, capable of displacing the en- dogenous glucocorticoids from their binding to the MR.
  • endogenous glucocorticoids e.g. Cortisol
  • the present invention therefore relates to the use of antagonists of the mineralo- corticoid receptor which display an affinity for the mineralocorticoid receptor, which exceeds that of endogenous or exogenously administered glucocorticoids for the manufacture of a medicament for the prevention or attenuation of adipo- genesis and/or obesity resulting from supraphysiological mineralcorticoid and/or glucocorticoid level.
  • antagonists of the mineralocorticoid receptor which display an affinity for the mineralocorticoid receptor, which exceeds that of endogenous or exogenously administered glucocorticoids are used for prevention or attenuation of adipogenesis and/or obesity resulting from supraphysiological mineralcorticoid and/or glucocorticoid level.
  • one aspect of the invention relates to an antagonist of the mineralocorticoid receptor (MR) which displays an affinity for the mineralocorticoid receptor, which exceeds that of endogenous or exogenously administered glucocorticoids for the prevention or attenuation of adipogenesis and/or obesity resulting from a supra- physiological mineralcorticoid and/or glucocorticoid level.
  • MR mineralocorticoid receptor
  • Another aspect of the present invention relates to an antagonist of the mineralocorticoid receptor (MR) which displays an affinity for the mineralocorticoid recep- tor, which exceeds that of endogenous or exogenously administered glucocorticoids for the prevention or attenuation of a disease selected from the group consisting of Cushing's disease, primary hyperaldosteronism, ectopic ACTH syndrome, ectopic CRH syndrome, macronodular or diffuse adrenal hyperplasia, adrenal adenoma, apparent mineralocorticoid excess syndrome, primary pigmented nodular adrenal hyperplasia, McCune-Albright syndrome, iatrogenic Cushing's syndrome (chronic ACTH or glucocorticoid therapy), alcohol abuse-related pseudo-Cushing's syndrome, major depression, diabetes mellitus Type 2, HIV-associated lipodystrophy and Chronic glucocorticoid therapy resulting from a supraphysiological mineralcorticoid and/or glucocortico
  • the antagonists of the MR have a higher affinity to the MR than the endogenous glucocorticoid Cortisol.
  • the MR antagonist has a competition factor (CF), as defined in example IV, of less that 1.85.
  • the mineralcorticoid antagonists to be used according to the invention could also be termed as being selective MR antagonists in a sense that the MR antagonistic potency clearly supersedes the interaction potential with other hormone receptors.
  • the ability of a MR antagonist to displace Cortisol from the MR can be evaluated according to the procedure given in Example IV according to the invention by simultaneously comparing the respective MR antagonist to Cortisol in a receptor protein affinity assay.
  • Figure 1 Effect of the mineralocorticoid Aldosterone (Aldo) on the formation of the marker of pre-adipocyte differentiation and antagonization of the Aldo effect by the MR antagonist Drospirenone (DRSP).
  • Aldo mineralocorticoid Aldosterone
  • DRSP Drospirenone
  • Figure 2 DRSP treatment is shown to attenuate Cortisol-induced lipid accumulation in pre-adipocytes (Figure 2a).
  • Figure 2b shows quantification of the experiment in Figure 2a :
  • Figure 4 Molecular structure of an MR antagonist.
  • Figure 5 Molecular structure of an MR antagonist.
  • Figure 6 Molecular structure of an MR antagonist.
  • Figure 7 Molecular structure of an MR antagonist.
  • Figure 8 Molecular structure of an MR antagonist.
  • the essential and decisive advantage of the claimed specific mineralocorticoid receptor antagonists for the manufacture of a medicament for the prevention or attenuation of adipogenesis and/or obesity resulting from supraphysiological miner- alcorticoid and/or glucocorticoid levels over existing treatments consists in their exceptional affinity for the MR, which exceeds that of endogenous or exogenously administered glucocorticoids, thus permitting efficient displacement of said glucocorticoids from their interaction with the MR.
  • Attenuation of adipogenesis and/or obesity is defined as a reduction in the occurrence of the symptoms related with these diseases.
  • Adipogenesis is generation of fat tissue by the maturation and accumulation of fat droplets in preadipocytes.
  • Obesity is the manifested medical condition consisting in the accumulation of excess body fat.
  • Adipocyte differentiation of preadipocytes is the process which transforms preadipocytes into adipocytes which accumulate fat droplets.
  • the claimed therapeutics are exemplified by, but not restricted to, the chemical compound drospirenone.
  • Any compound of the class of MR antagonists which will fulfil the requirement to display an affinity for the mineralocorticoid receptor which exceeds that of endogenous or exogenously administered glucocorticoids can be used according to the invention.
  • Such further MR antagonists which display an affinity for the mineralocorticoid receptor which exceeds that of endogenous or exogenously administered glucocorticoids are disclosed for example in the following international patent applications WO 2006/072467, WO 2008/000521, WO 2008/152112, WO 2008/151746, WO 2008/151745, WO 2009/083266, WO 2009/083267, WO 2009/083268, WO 2009/083269, WO 2009/083270, WO 2009/083271, WO 2009/083272 and espe- daily WO 2009/146811 (especially 6 ,7 ; 15 ,16 -Dimethylen-3-oxo-17-pregna- 4,9(ll)-dien-21,17 -carbolacton).
  • pathological conditions are all connected to an elevated supra- physiological glucocorticoid level and are thus within the claimed use of selective high-affinity MR antagonists according to the invention. These pathological conditions are only by way of example and the present invention is by no way limited thereto: Cushing's disease
  • diabetes mellitus Type 2 diabetes mellitus Type 2
  • Elevated glucocorticoid level means that the glucocorticoid level is elevated longer than the normally fluctuating glucocorticoid level, i.e. the level is elevated for several hours (L. Thomas, Labor und Diagnose, Medizinische Verlagsgesellschaft, 1992, S. 1323).
  • supra-physiological glucocorticoid level means that the glucocorticoid level is elevated above a normal physio- logical level.
  • the mean average serum Cortisol level is above 50 pg/dl blood (above 0.30 ⁇ ).
  • the Cortisol serum level is fluctuating between day and night, i.e. it displays circadian rhythm.
  • the daily dosage of a mineralcorticoid receptor antagonist to be used according to the invention depends on its affinity to the mineralcorticoid receptor in order to compete with Cortisol for the binding site of the receptor.
  • the daily dosage should be selected such that the Cortisol will be displaced from the mineralcorticoid re- ceptor effectively (the test is performed as described in Example IV).
  • supraphysiological mineralcorticoid level means that the mineralcorticoid level is elevated compared to the normal mineralcorticoid level.
  • the daily dosage of drospirenone to be used according to the invention is 2 to 10 mg, preferably 2 to 5 mg.
  • the daily dosage can be administered in one dosage unit or may be divided into two separate dosage units which can be administered simultaneously or consecutively, i.e. which a time distance of up to 12 hours.
  • an embodiment of the invention relates to the antagonist according to the invention, wherein said antagonist is Drospirenone.
  • a further embodiment of the invention relates to a dosage unit comprising the antagonist according to the invention.
  • Astill further embodiment of the invention relates to the dosage unit according to the invention, wherein the daily dosage of Drospirenone is 2 to 10 mg, preferably 2 to 5 mg.
  • the MR receptor antagonist may be one of the compounds shown in Figures 4-8.
  • the MR antagonists can be administered to human fe- males as well as males for prevention or attenuation of adipogenesis and/or obe- sity resulting from supraphysiological mineralcorticoid and/or glucocorticoid levels.
  • the progestogenic activity the MR antagonist may display as well can be ignored.
  • An aspect of the invention relates to an antagonist of the mineralocorticoid receptor (MR) which displays an affinity for the mineralocorticoid receptor, which exceeds that of endogenous or exogenously administered glucocorticoids for the prevention or attenuation of adipogenesis and/or obesity resulting from a supraphysiological mineralcorticoid and/or glucocorticoid level.
  • MR mineralocorticoid receptor
  • Another aspect of the invention relates to an antagonist of the mineralocorticoid receptor (MR) which displays an affinity for the mineralocorticoid receptor, which exceeds that of endogenous or exogenously administered glucocorticoids for the prevention or attenuation of a disease selected from the group consisting of Cush- ing's disease, primary hyperaldosteronism, ectopic ACTH syndrome, ectopic CRH syndrome, macronodular or diffuse adrenal hyperplasia, adrenal adenoma, apparent mineralocorticoid excess syndrome, primary pigmented nodular adrenal hyperplasia, McCune-Albright syndrome, iatrogenic Cushing's syndrome (chronic ACTH or glucocorticoid therapy), alcohol abuse-related pseudo-Cushing's syn- drome, major depression, diabetes mellitus Type 2, HIV-associated lipodystrophy and Chronic glucocorticoid therapy resulting from a supraphysiological mineralcorticoid and/or glucocor
  • An embodiment the invention relates to the antagonist according to the invention, wherein the antagonist of the MR has a higher affinity to the MR than the endogenous glucocorticoid Cortisol.
  • Drospirenone is a preferred antagonist of the MR.
  • An embodiment of the invention relates to an antagonist of the mineralocorticoid receptor according to the invention, wherein said antagonist has a competition factor of preferably less than 1.85, such as less than 1.50, such as less than 1.0, such as less than 0.50 when computed as the ratio between IC 50 test compound (antagonist) and IC50 Aldosterone-
  • an antagonist of the mineralocorticoid receptor displays a lower competition factor for the mineralocorticoid receptor, than that of exogenously administered glucocorticoids.
  • An exogenously administered glucocorticoid has a competition factor of more than 2.0, such as more than 2.5, such as more than 3.0 when computed as the ratio between IC 50 test compound (antagonist) and IC 50 Aldosterone on the MR.
  • an antagonist of the mineralocorti ⁇ coid receptor (MR) displays a competition factor of less than 2.0, such as preferably less than 1.50, such as more preferably less than 1, such as most preferably less than 0.50 when compared to the competition factor of an exogenously admin- istered glucocorticoid.
  • An exogenously administered glucocorticoid may be dexa- methasone, as summarized in Table 1.
  • Yet another embodiment of the invention relates to an antagonist of the mineralocorticoid receptor according to the invention, wherein said antagonist has an IC 50 value of less than 27.4 nM, such as preferably less than about 25 nM, such as more preferably less than about 20 nM, such as even more preferably less than about 15 nM, such as yet more preferably less than about 10 nM, such as most preferably about 7.22 nM on the mineralocorticoid receptor.
  • Exogenously administered glucocorticoids have IC 50 values of preferably about 30 nM, such as more preferably more than about 30 nM.
  • An exogenously administered glucocorticoid having an IC 50 value of 30 nM to the mineralocorticoid receptor may be dexa- methasone, as summarized in Table 1.
  • Example I Drospirenone antagonizes aldosterone-induced 3T3-L1 pre- adipocyte differentiation, and this effect is not abolished by a glucocorti- coid receptor antagonist
  • Preadipocytes 3T3-L1 (ATCC, Manassas, Virg., USA) were cultured to confluence in Dulbecco's Essential Medium /// Dulbecco ' s modified Eagle ' s medium (DMEM) containing 10% dextran-coated charcoal-pretreated foetal calf serum (DCC), de- void of endogenous steroids.
  • DCC foetal calf serum
  • Differentiation of 3T3-L1 cells to adipocytes was in- prised by exposure to 100 ⁇ 3-isobutyl-l-methylxanthine (IBMX) and 170 nM insulin for 2 days and subsequent incubation for 5 days in 10% DCC and 1 nM insulin.
  • IBMX 3-isobutyl-l-methylxanthine
  • triglyceride content and G3PDH activity were washed twice with cold phosphate-buffered saline (PBS), harvested, and homogenized in Tris-HCI 25 mM, pH 7.5, Ethylene Diamine Tetra Acidicacid (EDTA) 1 mM. A fraction of the homogenate was stored at -80°C. The remaining fraction was centri- fuged at 10,000 x g for 10 min at 4°C, and the supernatant was kept at -80°C until use. Aliquots of the homogenates and supernatants were used to determine protein content (BC Assay Uptima kit, Interchim, Montlugon, France), using bovine serum albumin as a standard.
  • PBS cold phosphate-buffered saline
  • EDTA Ethylene Diamine Tetra Acidicacid
  • Triglyceride content was determined on homogenates with PAP150 triglyceride kit (Biomerieux, Marcy L ' Etoile, France). G3PDH activity was assayed by recording the initial rate of oxidation of Nicotine Amide Adenine Dinucleotide (NADH) at 25°C (Sigma Aldrich, Saint Quentin Fallavier, France).
  • NADH Nicotine Amide Adenine Dinucleotide
  • Aldosterone is able to promote adipocyte differentiation of 3T3-L1 preadipocytes, as indicated by the changes in G3PDH activity and this effect was completely abolished in the presence of Drospirenone.
  • Figure 1 shows the effect of the mineralocorticoid Aldosterone (Aldo) on the formation of the marker of pre-adipocyte differentiation G3PDH in steroid-free (DCC, Figure la) and steroid-containing medium (FCS, Figure lb) and antagonization of the aldosterone effect by the mineralocorticoid receptor antagonist Drospirenone (DRSP).
  • UT is Untreated Control.
  • Example II The mineralocorticoid receptor antagonist Drospirenone an- tagonizes pre-adipocyte differentiation induced by the endogenous glucocorticoid Cortisol
  • Preadipocytes 3T3-L1 were grown to confluence at 37°C in Dulbecco ' s modified Eagle ' s medium (DMEM) (Invitrogen, Paisley, Scotland) containing 4.5 g/liter D- glucose, 10 % fetal calf serum (FCS) (Invitrogen), 100 units/ml penicillin, and 100 Mg/ml streptomycin.
  • DMEM Dulbecco ' s modified Eagle ' s medium
  • FCS fetal calf serum
  • 3T3-L1 adipocyte differentiation was initiated by the addition to the medium of a cocktail containing 100 ⁇ 3-isobutyl-l-methylxanthine (IBMX), 100 nM Cortisol and 175 nM insulin for 48 hours.
  • IBMX 3-isobutyl-l-methylxanthine
  • Cells were then incubated for 2-3 days with DMEM containing 10 % FCS and 175 nM insulin. From the beginning of the differentiation protocol, cells were exposed to increasing doses of Drospirenone (10 ⁇ 8 - 3 x 10 "5 M). Cells were examined daily, and analyzed under light microscopy; treatment-induced changes were documented by microphotog- raphy. For a morphological determination of cell lipid content, cells were fixed in 5% formaldehyde in phosphate-buffered saline (PBS), washed, then stained with Oil Red O. In some experiments, cells were permeabilized with 10% sodium dode- cyl sulphate (SDS) and Red Oil staining was spectrophotometrically quantified at 520 nM, upon normalization for cell numbers.
  • Drospirenone 10 ⁇ 8 - 3 x 10 "5 M
  • PBS phosphate-buffered saline
  • Oil Red O Oil staining was spectrophotometric
  • Figure 2a shows that Drospirenone (DRSP) treatment dose-dependently attenuates Cortisol-induced lipid accumulation in pre-adipocytes, as revealed by Oil Red O accumulation.
  • UT is untreated pre-adipocytes.
  • Figure 2b shows the quantification by Oil Red O accumulation of the experiment in Fig. 2a.
  • Figure 2b shows that Drospirenone dose-dependently inhibits cortisol-induced 3T3-L1 red oil accumulation.
  • UT is untreated i.e. the control level (100%).
  • Example III Drospirenone antagonized Cortisol-induced differentiation and lipid accumulation in primary human pre-adipocytes
  • Primary human visceral pre-adipocytes were purchased from Lonza (Basel, Switzerland) and grown and differentiated according to the manufacturer ' s instruc- tions in the presence of 100 nM Cortisol.
  • primary human visceral and subcutaneous pre-adipocytes were isolated from epicardial and subcutaneous adipose tissue obtained from patients undergoing coronary artery bypass.
  • Human adipose stromal vascular fraction was isolated by enzymatic digestion and selective culturing techniques.
  • Pre-adipocytes were induced to differ- entiate into mature adipocytes by incubation in an adipogenic medium containing DMEM/Ham F12 (Invitrogen) supplemented with troglitazone (1 mg/ml), IMBX (0.2 mM), Cortisol (100 nM), insulin (80 nM) and triiodothyronine (0.2 nM) for 3 days.
  • Cells were exposed to Drospirenone or vehicle during the entire process of adipocyte differentiation, in order to examine the effect of mineralocorticoid re- ceptor blockade. Subsequently, cells were cultivated in the same adipogenic medium lacking IBMX and troglitazone for further 7 days. Medium was changed every 3 days.
  • Drospirenone has higher affinity for the mineraiocorticoid receptor than the principal human endogenous glucocorticoid Cortisol and the prototypic synthetic glucocorticoids Dexamethasone and Predni- solone
  • IC 50 half maximal inhibitory concentration
  • a competition factor CF was computed as the ratio between IC 50 test compound and
  • affinity relates to how tightly a ligand binds to a particular protein e.g. how tightly Drospirenone binds to the mineraiocorticoid receptor.

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Abstract

La présente invention concerne le domaine de la prévention et/ou du traitement de l'adipogenèse et de l'obésité. Selon l'invention, des antagonistes de récepteur de minéralocorticoïde sont utilisés en tant que substance thérapeutiquement active. Les antagonistes de récepteur de minéralocorticoïde utilisés dans cette invention sont capables de déplacer le glucocorticoïde cortisol endogène du récepteur antiminéralocorticoïde.
PCT/EP2011/069464 2010-11-04 2011-11-04 Antagonistes de récepteur de minéralocorticoïde pour le traitement de l'obésité induite par corticoïde Ceased WO2012059594A1 (fr)

Priority Applications (16)

Application Number Priority Date Filing Date Title
BR112014010590A BR112014010590A2 (pt) 2011-11-04 2012-11-02 18-metil-6,7-metilen-3-oxo-17-pregn-4-eno-21,17?-carbolactonas, preparações farmacêuticas contendo os compostos mencionados e seu uso na terapia da endometriose
PCT/EP2012/071700 WO2013064620A1 (fr) 2011-11-04 2012-11-02 18-méthyl-6,7-méthylène-3-oxo-17-prégn-4-ène-21,17β-carbolactones, préparations pharmaceutiques contenant ces composés et leur utilisation dans le traitement de l'endométriose
AU2012331089A AU2012331089A1 (en) 2011-11-04 2012-11-02 18-methyl-6,7-methylene-3-oxo-17-pregn-4-ene-21,17beta-carbolactones, pharmaceutical preparations comprising said compounds and use thereof in the treatment of endometriosis
CA2854215A CA2854215A1 (fr) 2011-11-04 2012-11-02 18-methyl-6,7-methylene-3-oxo-17-pregn-4-ene-21,17?-carbolactones, preparations pharmaceutiques contenant ces composes et leur utilisation dans le traitement de l'endometriose
EP12783197.2A EP2773356A1 (fr) 2011-11-04 2012-11-02 18-méthyl-6,7-méthylène-3-oxo-17-prégn-4-ène-21,17 -carbolactones, préparations pharmaceutiques contenant ces composés et leur utilisation dans le traitement de l'endométriose
HK15100197.4A HK1199712A1 (en) 2011-11-04 2012-11-02 18-methyl-6,7-methylene-3-oxo-17-pregn-4-ene-21,17β-carbolactones, pharmaceutical preparations comprising said compounds and use thereof in the treatment of endometriosis
EA201400537A EA201400537A1 (ru) 2011-11-04 2012-11-02 18-МЕТИЛ-6,7-МЕТИЛЕН-3-ОКСО-17-ПРЕГН-4-ЕН-21,17β-КАРБОЛАКТОНЫ, ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ, СОДЕРЖАЩИЕ УКАЗАННЫЕ СОЕДИНЕНИЯ, И ИХ ПРИМЕНЕНИЕ В ЛЕЧЕНИИ ЭНДОМЕТРИОЗА
US14/356,165 US20140288035A1 (en) 2011-11-04 2012-11-02 18-methyl-6,7-methylene-3-oxo-17-pregn-4-ene-21,17b-carbolactones, pharmaceutical preparations comprising said compounds and use thereof in the treatment of endometriosis
IN3307CHN2014 IN2014CN03307A (fr) 2011-11-04 2012-11-02
CN201280054180.0A CN103957921A (zh) 2011-11-04 2012-11-02 18-甲基-6，7-亚甲基-3-氧代-17-孕甾-4-烯-21，17β-碳内酯、包含所述化合物的药物制剂及其在治疗子宫内膜异位症中的用途
ARP120104105A AR088622A1 (es) 2011-11-04 2012-11-02 18-METIL-6,7-METILEN-3-OXO-17-PREGN-4-EN-21,17b-CARBOLACTONA, PREPARADOS FARMACEUTICOS QUE CONTIENEN LOS COMPUESTOS MENCIONADOS Y SU USO EN LA TERAPIA DE LA ENDOMETRIOSIS
JP2014539339A JP2014532685A (ja) 2011-11-04 2012-11-02 １８−メチル−６，７−メチレン−３−オキソ−１７−プレグナ−４−エン−２１，１７β−カルボラクトン、該化合物を含有する医薬製剤、および子宮内膜症の治療におけるその使用
TW101140872A TW201322986A (zh) 2011-11-04 2012-11-02 １８－甲基－６，７－亞甲基－３－氧基－１７－妊－４－烯－２１，１７β－羧內酯、包含該化合物之醫療製劑及其於治療子宮內膜異位症之用途
KR1020147014686A KR20140088197A (ko) 2011-11-04 2012-11-02 18-메틸-6,7-메틸렌-3-옥소-17-프레그느-4-엔-21,17β-카르보락톤, 상기 화합물을 함유하는 약제학적 제제 및 자궁내막증 치료에 있어서 이들의 용도
MX2014005367A MX2014005367A (es) 2011-11-04 2012-11-02 18-metil-6,7-metilen-3-oxo-17-pregn-4-en-21,17b-carbolactona, preparados farmaceuticos que contienen los compuestos mencionados y su uso en la terapia de la endometriosis.
IL232325A IL232325A0 (en) 2011-11-04 2014-04-29 18-methyl-7,6-methylene-3-oxo-17-paragan-4-en-21, 17b-carbolactones, pharmaceutical preparations containing these compounds and their use for the treatment of endometrial disease

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WO2013064620A1 (fr) 2011-11-04 2013-05-10 Bayer Pharma Aktiengesellschaft 18-méthyl-6,7-méthylène-3-oxo-17-prégn-4-ène-21,17β-carbolactones, préparations pharmaceutiques contenant ces composés et leur utilisation dans le traitement de l'endométriose
CN103957921A (zh) * 2011-11-04 2014-07-30 拜耳医药股份有限公司 18-甲基-6，7-亚甲基-3-氧代-17-孕甾-4-烯-21，17β-碳内酯、包含所述化合物的药物制剂及其在治疗子宫内膜异位症中的用途

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