Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
• • 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
• • 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
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • 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
• • 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
  • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
• • 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
• • 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
  • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
• • 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
  • A61P15/18—Feminine contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
• • 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
• • 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
  • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
  • C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings

Definitions

• the invention relates to 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl derivatives of Formula I with progesterone antagonizing action and method of production thereof, use thereof for the treatment and/or prophylaxis of diseases and use thereof for the production of medicinal products for the treatment and/or prophylaxis of diseases, in particular of fibroids of the uterus (myomas, uterine leiomyoma), endometriosis, heavy menstrual bleeds, meningiomas, hormone-dependent breast cancers and complaints associated with the menopause or for fertility control and emergency contraception.
• these compounds are valuable pharmaceutical active substances. They can be used among other things for the production of pharmaceutical preparations for the treatment of fibroids of the uterus or endometriosis, heavy menstrual bleeds, meningiomas, hormone-dependent breast cancers and of complaints associated with the menopause or for fertility control and emergency contraception.
• the compounds according to the invention can also be administered sequentially in combination with gestagens. In such a treatment regimen the compounds according to the invention could be administered over a period of 1-6 months, followed by a pause in treatment or sequential treatment with a gestagen over a period of 2-6 weeks or followed by treatment with an oral contraceptive (OC-combinations) over the same period.
• the compounds with fluorinated 17 ⁇ -side chain described in WO 98/34947 generally have a very strong antagonistic activity on the progesterone receptor.
• Compounds that are very potent and therefore preferred in WO 98/34947 are 11 ⁇ -(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17 ⁇ -pregna-4,9-dien-3-one, 11 ⁇ -(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17 ⁇ -pregna-4-en-3-one and 6′-acetyl-9,11 ⁇ -dihydro-17 ⁇ -hydroxy-17 ⁇ -(1,1,2,2,2-pentafluoroethyl)-4′H-naphth[3′,2′,1:10,9,11]ester-4-en-3-one.
• the problem to be solved by the present invention is to make highly potent competitive progesterone receptor antagonists available and thus create alternatives for the treatment of gynaecological diseases.
• compounds according to the invention are especially suitable for solving this problem.
• compounds with alkylsulphanyl and alkylsulphonyl groups show very strong antagonistic activity on the progesterone receptor, i.e. they inhibit the action of progesterone on its receptor.
• the compounds with alkylsulphonyl groups compared e.g. with alkanoyl groups, have a far higher metabolic as well as chemical stability against temperature, light and oxidative stress.
• the compound (11 ⁇ ,17 ⁇ )-17-hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one displays, compared with the respective analogue with an alkanoyl or hydroxyalkanoyl group (11 ⁇ -(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17 ⁇ -pregna-4,9-dien-3-one or 20,20,21,21,21-pentafluoro-17-hydroxy-11 ⁇ -[4-(hydroxyacatyl)phenyl]-19-nor-17 ⁇ -pregna-4,9-dien-3-one), a surprisingly high
• the present invention relates to 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl derivatives with the general chemical formula I:
• R 9 , R 10 independently of one another are selected from the group comprising hydrogen, C 1 -C 10 -alkyl or aryl or alternatively represent, together with the nitrogen atom, a 3- to 8-membered, saturated or unsaturated heterocyclic ring
• the compounds according to the invention of general formula I can exist in stereoisomeric forms (enantiomers, diastereomers).
• the invention therefore comprises the enantiomers or diastereomers and their respective mixtures including racemates.
• the stereoisomerically uniform constituents can be isolated in a known way from said mixtures of enantiomers and/or diastereomers.
• Each of the stated substituents on the steroid backbone chain can be both in an ⁇ -position and in a ⁇ -position.
• the substituents on the steroid backbone chain which contain a double bond and in which the double bond on each atom bears at least one substituent, which is not hydrogen, can be both E- and Z-configured.
• the present invention comprises all tautomeric forms.
• Physiologically harmless salts of the compounds according to the invention are preferred as salts within the scope of the present invention.
• salts that are not suitable in themselves for pharmaceutical uses, but can for example be used for the isolation or purification of the compounds according to the invention are also covered.
• Physiologically harmless salts of the compounds according to the invention 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.
• 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,
• Physiologically harmless salts of the compounds according to the invention 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.
• alkali metal salts e.g. sodium and potassium salts
• alkaline earth metal salts e.g.
• 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.
• ethylamine diethylamine
• triethylamine ethyldiis
• solvates Those forms of the compounds according to the invention that display, in the solid or liquid state, adduct formation with solvent molecules, are designated as solvates within the scope of the invention.
• the solvent can be present in stoichiometric or even non-stoichiometric proportions.
• 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 present invention also comprises prodrugs of the compounds according to the invention.
• prodrugs comprises compounds which, while they are in the body, are converted to compounds according to the invention, for example by enzymatic or hydrolytic processes.
• Alkyl stands for linear or branched alkyl groups with 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl.
• Aryl stands for a mono- to tricyclic aromatic, substituted or unsubstituted carbocyclic residue, for example phenyl, naphthyl, which can be substituted one or more times with halogen (F, CI, Br, I), OH, O-alkyl, CO 2 H, CO 2 -alkyl, NH 2 , NH(C 1 -C 10 -alkyl), N(C 1 -C 10 -alkyl) 2 , in particular N(CH 3 ) 2 , NO 2 , N 3 , CN, C 1 -C 10 -alkyl, C 1 -C 10 -perfluoro-alkyl, C 1 -C 10 -acyl, C 1 -C 10 -acyloxy groups.
• halogen F, CI, Br, I
• Heteroaryl stands for an aromatic, mono- or bicyclic residue with as a rule 5 to 10, preferably 5 to 6 ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and N, for example and preferably for benzofuranyl, benzothiophenyl, quinolinyl, furyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, oxazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, pyrazolyl, isoxazolyl, pyrazinyl, quinolyl or tetrazolyl.
• Aralkyl stands for aralkyl groups that can contain up to 14 carbon atoms, preferably 6-10 carbon atoms, in the ring, and 1-8, preferably 1-4, carbon atoms in the alkyl chain.
• Aralkyl residues that may be considered are for example benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl.
• the rings can be substituted one or more times with halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, NH 2 , NH(C 1 -C 10 -alkyl), N(C 1 -C 10 -alkyl) 2 , NO 2 , N 3 , CN, C 1 -C 20 -alkyl, C 1 -C 10 -perfluoro-alkyl, C 1 -C 20 -acyl, C 1 -C 20 -acyloxy groups.
• residues in the compounds according to the invention are substituted, unless otherwise specified, the residues can be substituted one or more times.
• the residues that occur more than once their meaning is independent of one another.
• a substitution with one, two or three identical or different substituents is preferred.
• Substitution with one substituent is quite especially preferred.
• R 1 S(O) 2 R 3 , X: O and R 3 : C 1 -C 6 -alkyl, in particular those in which R 3 denotes methyl.
• R 1 S(O)(NH)R 3 , X: O and R 3 : C 1 -C 6 -alkyl, in particular those in which R 3 denotes methyl.
• the preferred residue R 1 can be both in the R- and in the S-configuration, and in any mixture ratio.
• the compounds according to the invention and/or derivatives display good progesterone-antagonizing action. It was found in several clinical studies that treatment with progesterone receptor antagonists (mifepristone, asoprisnil, Proellex) can lead to significant shrinking of fibroids of the uterus and a significant reduction of the symptoms associated with said fibroids of the uterus. Moreover, it was shown in clinical studies that during treatment with the stated progesterone receptor antagonists, the symptoms caused by endometriosis (especially pains) can also be reduced considerably.
• the compounds with the general chemical formula I are prepared starting from (5′R,8′S,10′R,13′S,14′S,17′S)-5,5,13′-trimethyl-1′,2′,7′,8′,12′,13′,14′,15′,16′,17′-decahydro-6′H-spiro[1,3-dioxane-2,3′-[5,10]epoxycyclopenta[a]phenanthren]-17′-ol (for production see Tetrahedron Lett. 26, 2069-2072 (1985) by analogy with the method described in WO 98/34947 and in WO 2008/058767.
• ketal protecting groups we may for example mention the ethylenedioxy or 2,2-dimethylpropylene-1,2-dioxy group.
• Hydroxyl groups are for example protected in the form of methoxymethyl, methoxyethyl, tetrahydropyranyl, benzyl, or silyl ethers.
• the protecting groups are then split off by methods known by a person skilled in the art.
• cleavage of the 3-ketal to the 3-keto group of the steroid backbone a 5 ⁇ -hydroxyl group optionally still present is eliminated, so that compounds of general formula 1 are formed.
• the production of the salts takes place in the usual way, by adding the equivalent amount or an excess of a base or acid, which is optionally in solution, to a solution of the compound with the general chemical formula I, optionally separating the precipitate or processing the solution in the usual way.
• the resulting compounds of formula (I) are optionally converted, with the corresponding (i) solvents and/or (ii) bases or acids to their solvates, salts and/or solvates of the salts.
• the compounds according to the invention display an unforeseeable, valuable pharmacological, pharmacokinetic and pharmacodynamic profile of action.
• the pharmaceutical efficacy of the compounds according to the invention can be explained by their action as progesterone receptor antagonists, and thus by their antagonizing action on the progesterone receptor.
• Another object of the present invention is the use of the compounds according to the invention 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.
• Another object of the present invention is the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, in particular the aforementioned diseases.
• Another object of the present invention comprises the compounds according to the invention for use in a method of treatment and/or prophylaxis of fibroids of the uterus, endometriosis and hormone-dependent breast cancers.
• Another object of the present invention is the use of the compounds according to the invention for the production of a medicinal product for the treatment and/or prophylaxis of diseases, in particular the aforementioned diseases.
• Another object of the present invention is a method of treatment and/or prophylaxis of diseases, in particular the aforementioned diseases, using 0.1-100 mg of the compounds according to the invention per day per patient in the treatment of fibroids of the uterus or endometriosis and for contraceptive use or of 0.1-500 mg of the compounds according to the invention per day per patient in tumour diseases (e.g.
• meningioma or hormone-dependent tumours e.g. breast cancer
• for emergency contraception meningioma or hormone-dependent tumours, e.g. breast cancer
• Another object of the present invention comprises medicinal products containing at least one compound according to the invention and at least one or more other active substances, in particular for the treatment and/or prophylaxis of the aforementioned diseases.
• active substances/classes of active substances can be administered either simultaneously or sequentially: SERMs, SERDs, anti-oestrogens, aromatase inhibitors, kinase inhibitors, angiogenesis inhibitors and/or cytostatics.
• the compounds according to the invention 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 (Stockemann et al., Schering AG) and PCT/EP2009/003249 (Moller et al., Bayer Schering Pharma AG).
• Simultaneous or sequential administration of the compounds according to the invention e.g. with SERMs, SERDs and oestrogens can be considered for the treatment of complaints associated with the menopause.
• SERMs selective estrogen receptor modulators
• SERMs 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, apeledoxifene, lasofoxifene and ormeloxifene.
• SESD selective estrogen receptor destabilizers
• 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.
• Aromatase inhibitors inhibit the enzyme aromatase and therefore the aromatization of androgens to oestrogens. These include, among others, anastrozole, letrozole, exemestane, vorozole, formestans and fadrozole.
• Kinase inhibitors are enzymes that transfer a phosphate residue from ATP to other substrates, and in particular to hydroxyl groups there, e.g. sorafenib (Nexavar) or imatinib (Gleevec).
• Angiogenesis inhibitors e.g. Avastin, reduce or block the supply of vessels and therefore the blood supply to a tumour.
• Cytostatics e.g. cisplatin, taxol, Taxotere are natural or synthetic substances that inhibit cell growth or cell division.
• 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.
• 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 compounds according to the invention 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, IVRNRS (intravaginal ring/vaginal ring system).
• Forms for intrauterine or intravaginal application can contain the compounds according to the invention 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).
• the compounds according to the invention 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 according to the invention 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 according to the invention), 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.
• tablets uncoated or coated tablets, for example with enteric coatings or delayed-dissolving or insoluble coatings, which control the release of the compound according to the invention
• tablets or films/wafers that quickly disintegrate in the oral cavity films/lyophilizates, capsules (for example hard-gelatin or soft-gelatin capsules), coated tablets,
• 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).
• absorption step e.g. intravenous, intraarterial, intracardial, intraspinal or intralumbar
• 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.
• 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.
• 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
• the compounds according to the invention 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.
• 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.
• carrier substances for example microcrystalline cellulose, lactose, mannitol
• solvents e.g. liquid polyethylene glycols
• Another object of the present invention comprises medicinal products that contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and use thereof for the aforementioned purposes.
• 125 mg of the title compound was prepared from 200 mg of the compound prepared in 2a) by reaction with semi-concentrated sulphuric acid in methanol.
• 256 mg of the title compound was prepared from 500 mg of the compound described in example 9c) and (4-methylsulphonylphenyl)boronic acid in the presence of tetrakis(triphenylphosphine)palladium, lithium chloride, 2-molar aqueous sodium carbonate solution in a mixture of toluene and ethanol.
• 715 mg of the title compound was prepared from 800 mg of the compound prepared in example 9d) with Chloramine-T-Trihydrate® in acetonitrile.
• 235 mg of the title compound was prepared from 300 mg of the compound described in example 9c) and [4-[(dimethylamino)sulphonyl]phenyl]boronic acid in the presence of tetrakis(triphenylphosphine)palladium, lithium chloride, 2-molar aqueous sodium carbonate solution in a mixture of toluene and ethanol.
• 113 mg of the title compound was prepared from 230 mg of the compound prepared in 14a) by reaction with semi-concentrated sulphuric acid in methanol.
• SK-N-MC cells human neuroblastoma cells
• plasmids which express the human progesterone receptor B (pRChPR-B-neo) or the human progesterone receptor A (pRChPR-A-neo) and a reporter construct (pMMTV-LUC)
• pRChPR-B-neo human progesterone receptor B
• pRChPR-A-neo human progesterone receptor A
• pMMTV-LUC reporter construct
• the cells were treated with the synthetic gestagen promegestone (0.01 nmol/l, 0.1 nmol/l, 1 nmol/l, 10 nmol/l, 100 nmol/l and 1 ⁇ mol/l).
• the cells were treated with 0.1 nmol/l promegestone and additionally with increasing amounts of the respective test compound (0.01 nmol/l, 0.1 nmol/l, 1 nmol/l, 10 nmol/l, 100 nmol/l and 1 ⁇ mol/l).
• Progesterone Progesterone receptor A (PR-A) receptor B (PR-B) Potency Effi- Potency Effi- IC 50 cacy IC 50 cacy Compound [nmol/l] [%] [nmol/l] [%] 11 ⁇ -(4-Acetylphenyl)- 0.014 100 0.02 100 20,20,21,21,21- pentafluoro-17-hydroxy- 19-nor-17 ⁇ -pregna-4,9- dien-3-one 20,20,21,21,21- 0.18 100 0.28 100 Pentafluoro-17-hydroxy- 11 ⁇ -[4-(hydroxyacatyl) phenyl]-19-nor-17 ⁇ -pregna- 4,9-dien-3-one dien-3-one
• Example 1 0.011 100 0.012 100
• Example 2 0.01 100 0.01 100
• Example 3 0.11 100 0.12 100
• Example 5 0.1 100 0.09 100
• Example 6 0.2 100 0.23 100
• progesterone and of the progesterone receptor are fundamental precondition for successful pregnancy or gestation in mammals.
• the progesterone-antagonistic action of the compounds according to the invention was tested on pregnant rats (6 rats per group) on day 5 to 7 post coitum with conventional housing and feeding conditions.
• the pregnant animals pre-d7 p.c.
• the animals then each received subcutaneously or orally 0.15; 0.5; 1.5 or 5 mg/kg of the test compound or 1.0 ml/kg of vehicle (benzyl benzoate/castor oil: 1+4 [v/v]) daily from day 5 to day 7 (d5-d7 p.c.).
• HLM human liver microsomes
• the (metabolic) in vivo clearance in humans predicted correspondingly for the test compounds (11 ⁇ ,17 ⁇ )-17-hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one and (11 ⁇ ,17 ⁇ )-17-hydroxy-11-[4′-(methylsulphonyl)biphenyl-4-yl]-17-(pentafluoroethyl)-estra-4,9-dien-3-one was very low: 0.1 L/h/kg and ⁇ 0.01 L/h/kg, respectively.
• the permeability test was performed in duplicate at a substance concentration of 2 ⁇ M.
• 100 ⁇ l (Ap0 min) was taken from the apical compartment and 100 ⁇ l of ice-cold stopping solution was added to it immediately.
• the filters were then incubated at 37° C. with gentle shaking for 90 min, then 100 ⁇ l was taken again from the apical side (Ap90 min) and 400 ⁇ l from the basolateral side (Bas90 min) and in each case the same volume of stopping solution was added.
• After further dilution of the samples with 4 times the volume of stopping solution/transport buffer (1+1) they were sedimented overnight at ⁇ 20° C. and the supernatant was analysed by LCMS/MS.
• the Papp value of the substances was calculated from the following formula.
• V res buffer volume on the receptor side
• C t0, don concentration of substance on the donor side
• ⁇ C res / ⁇ t change in concentration of substance over time on the receptor side

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