WO2011009532A2 - 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-benzyliden-derivate, verfahren zu deren herstellung und deren verwendung zur behandlung von krankheiten - Google Patents
17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-benzyliden-derivate, verfahren zu deren herstellung und deren verwendung zur behandlung von krankheiten Download PDFInfo
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- WO2011009532A2 WO2011009532A2 PCT/EP2010/004150 EP2010004150W WO2011009532A2 WO 2011009532 A2 WO2011009532 A2 WO 2011009532A2 EP 2010004150 W EP2010004150 W EP 2010004150W WO 2011009532 A2 WO2011009532 A2 WO 2011009532A2
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- pentafluoroethyl
- methyl
- hydroxy
- phenyl
- dodecahydro
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- 0 C[C@](C[C@@]1c2cccc(C=CC3=CC=CI=C3)c2)(C(CC2)C(CC3)C1=C(CCC1(C4)OCC(C)(C)CO1)[C@@]34O)[C@@]2(*)O Chemical compound C[C@](C[C@@]1c2cccc(C=CC3=CC=CI=C3)c2)(C(CC2)C(CC3)C1=C(CCC1(C4)OCC(C)(C)CO1)[C@@]34O)[C@@]2(*)O 0.000 description 6
- HCXZYMBXXXHRFY-FACVUMESSA-N C[C@](C[C@@H]1c2ccc(C=C)cc2)(C(CC2)C(CC3)C1=C(CCC1(C4)OCC(C)(C)CO1)[C@@]34O)C2(CC1C=S=C1)O Chemical compound C[C@](C[C@@H]1c2ccc(C=C)cc2)(C(CC2)C(CC3)C1=C(CCC1(C4)OCC(C)(C)CO1)[C@@]34O)C2(CC1C=S=C1)O HCXZYMBXXXHRFY-FACVUMESSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
-
- 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
-
- 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
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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
-
- 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
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0085—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being a saturated hydrocarbon group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
- C07J21/006—Ketals at position 3
-
- 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
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Definitions
- Object of the present invention is highly potent competitive
- R 1 is hydrogen or a C 1 -C 8 -alkyl radical
- R 3 is a C 1 -C 10 alkyl, O-alkyl, O- (CH 2 ) n -COOR 4 , O-CH 2 aryl, aryl, C 7 -C 20 aralkyl or a CH 2 CO 2 R 4 radical in which
- R 4 is hydrogen or a C-
- R 5 is a C 1 -C 8 -j-alkyl, C 2 -C 18 -alkenyl-I, aryl-,
- R 6 is hydrogen, a C-
- -Cio-alkyl, aryl or C7-C 2 o-aralkyl radical. If R 5 stands for ⁇ ⁇ ⁇ - ', the arrow marks the position at which
- X is oxygen
- Also preferred according to the invention are the compounds of the formula (I) in which the substituent (radical) Y is bonded in the para position to the phenyl ring.
- Alkyl in R 1, R 2, R 3, R 4, R 5 and R 6 as well as in other cases, are straight or branched chain alkyl groups having the indicated number of carbon atoms, or, where appropriate, to be understood 1-10 carbon atoms, such as methyl, ethyl , Propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl or decyl.
- alkyl groups R 1, R 2, R 3, R 4, R 5 and R 6 may also be perfluorinated or substituted with 1-5 halogen atoms, hydroxy, C-
- 2-aryl groups (which in turn may be substituted by 1-3 halogen atoms) may be substituted.
- alkyl may therefore also be hydroxymethylene (HO-CH 2), hydroxyethylene (HO-C2H 4), hydroxypropylene (HO-C 3 H 6) and hydroxybutylene (HO-C 4 H 8) and their isomers.
- Alkenyl in R 4 and R 1 are straight or branched chain alkenyl groups having 2-10 carbon atoms, such as vinyl, propenyl, butenyl, pentenyl, isobutenyl or isopentenyl.
- the alkenyl groups R 4 and R 5 may be substituted by 1-5 halogen atoms, hydroxy groups, C 1 -C 3 alkoxy groups, or C 3 -C 8 aryl groups (which in turn may be substituted by 1-3 halogen atoms).
- Aryl in R 2 , R 3 , R 5 and R 6 and in other cases are to be understood as meaning substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms, for example phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl , Oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl or tetrazolyl, which are mono- or polysubstituted by halogen, OH, O-alkyl, S-alkyl, S (O) alkyl and SO 2 alkyl, CO 2 H, CO 2 alkyl , NH 2 , NO 2 , N 3 , CN, CiC ⁇ alkyl, C 1 -C 10 acyl, C 1 - C ⁇ acyloxy groups may be substituted.
- Aralkyl in R 2 , R 3 , R 5 and R 6 is to be understood as meaning aralkyl groups which contain up to 14 carbon atoms, preferably 6 to 10 C atoms, in the ring and 1 to 8, preferably 1 to 4, carbon atoms in the alkyl chain can.
- Suitable aralkyl radicals are, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl or pyridylpropyl.
- the rings may be mono- or polysubstituted by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, NO 2 , N 3 , CN, C-
- j -C2r acyloxy groups may be substituted as heteroatoms of sulfur, oxygen or nitrogen are suitable, with nitrogen being preferred
- An example is the pyridylpropyl radical...
- alkoxy (O-alkyl)
- Alkoxy may in particular be methoxy, ethoxy and propoxy.
- acyl (CO-alkyl) is mentioned, it is acyl groups with 1-20
- Acyl may in particular be formyl, acetyl, propionyl and butyryl.
- acyloxy (O-CO-alkyl)
- it concerns acyloxy groups with 1-20 carbon atoms.
- Acyloxy may in particular be formyloxy, acetyloxy, propionyloxy and butyryloxy.
- Halogen is fluorine, chlorine or bromine. Among these, fluorine and chlorine are preferable.
- Diastereomers exist.
- the invention therefore also encompasses the enantiomers or diastereomers and their respective mixtures including the racemates. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
- Each of said substituents on the steroid backbone may be present in both an ⁇ and a ⁇ position.
- the substituents on the steroid skeleton which contain a double bond and in which the
- Double bond on each atom carries at least one substituent that is not hydrogen, both E- and Z-configured. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms
- novel compounds of the general formula I can also be present as solvates, hydrates and salts, where also different
- Solvates in the context of the invention are those forms of the compounds according to the invention which show adduct formation with solvent molecules in the solid or liquid state. If the derivatives of the formula I are present as solvates, the solvent present may be present in a stoichiometric or non-stochiometric ratio Stochiomet ⁇ schen Solvaten, one speaks also of Herrn, (Semi-), Mono-, Sesqui-, Di-, Tri-, Tetra-, Penta, etc. Solvaten
- Hydrates are a special form of solvates in which coordination takes place with water.
- sovates the hydrates are preferred, ie coordination compounds with water
- Suitable salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, they also include salts which are not suitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds according to the invention
- Physiologically acceptable salts of the compounds according to the invention comprise, if a basic function is present, salts with inorganic or organic acids, in particular mineral acids, carboxylic acids and sulfonic acids, eg salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid,
- Physiologically acceptable salts of the compounds according to the invention comprise - if an acidic function is present - alkali metal salts, alkaline earth metal salts or ammonium salts, as may be obtained by reaction with corresponding inorganic or organic bases, by way of example and preferably called alkali metal salts (eg, sodium and potassium salts), alkaline earth salts (eg, calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, for example, and preferably ethylamine,
- alkali metal salts eg, sodium and potassium salts
- alkaline earth salts eg, calcium and magnesium salts
- ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms such as, for example, and preferably ethylamine
- the present invention also includes prodrugs of the compounds of the invention.
- prodrugs encompasses compounds which, during their residence time in the body, are converted into compounds according to the invention, for example by enzymatic or hydrolytic processes.
- radical definitions given in detail in the respective combinations or preferred combinations of radicals are also replaced, irrespective of the particular combinations of the radicals indicated, by radical definitions of other combinations.
- These compounds are valuable pharmaceutical agents. Among other things, they can be used to manufacture pharmaceutical preparations for the treatment of
- the treatment of uterine fibroids or endometriosis the
- compounds according to the invention can be combined simultaneously or sequentially with gestagens or combinations of estrogens and gestagens.
- WO 96/15794 (Spicer et al., Balance Pharm. Inc.), WO 96/03130 (Stöckemann et al., Schering AG) and PCT / EP2009 / 003249 (Moller et al., Bayer Schering Pharma AG) are progesterone receptor antagonists / Gestagen regime revealed.
- Treatment of uterine fibroids and endometriosis are well suited - optionally repeating - regimens in which the progesterone receptor antagonist is given over a period of two to four months, followed by the administration of the progestogen over a period of one to four weeks.
- Particularly suitable is the - possibly repeating - 84-day dose of
- Progesterone receptor antagonists followed by the 14-day administration of the progestin.
- tumor diseases e.g. the following
- Active ingredients / classes of drugs can be administered either simultaneously or sequentially: SERMs, SERDs, antiestrogens, aromatase inhibitors, kinase inhibitors,
- Angiogenesis inhibitors and / or cytostatic agents.
- compounds according to the invention can be combined simultaneously or sequentially with gestagens or combinations of estrogens and gestagens.
- simultaneous or sequential administration of the compounds of the invention e.g. with SERMs, SERDs and estrogens.
- SERMs Selective Estrogen Receptor Modulators
- SERMs are compounds which either have an antiestrogenic or estrogenic effect on the tissue, for example inhibit the action of the estrogen on the uterus but have a neutral or estrogen-like effect on the bone. Examples are
- SESD Selective Estrogen Receptor Stabilizers
- Anti-estrogens are compounds which completely antagonize the estrogen receptor, for example fulvestrant.
- Aromatase inhibitors inhibit the enzyme aromatase and thus the aromatization of androgens in estrogens. These include, but are not limited to, anastrozole, letrozole, exemestane,
- Kinase inhibitors inhibit enzymes which transfer a phosphate residue from ATP to other substrates, especially to hydroxy groups, e.g. sorafenib
- Angiogenesis inhibitors e.g. Avastin, reduce or block the neovascularization and thus the circulation of a tumor.
- Cytotoxic agents such as cis-platin, taxol, taxotere, sagopilone, ixabepilone are natural or synthetic substances that drive tumor cells into apoptosis.
- progestins are understood to be either the natural progesterone itself or synthetic derivatives which, like the progesterone itself, bind to the progesterone receptor and in dosages which exceed the progesterone receptor
- Ovulation inhibitor dose inhibit ovulation.
- Active ingredient combinations contained in the conventional oral contraceptives 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 administered in a suitable manner, such as, for example, orally, intrauterine,
- intravaginal parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.
- Intrauterine means in particular the application by means of IUS (intrauterine system) or IUD (intrauterine device).
- IUS intrauterine system
- IUD intrauterine device
- the intravaginal application can i.a. by IVR (vaginalng).
- Intrauterine or intravaginal forms of aphcation can thereby the compounds of the invention and
- Non-hindered 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 administration forms.
- Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
- a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
- absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
- Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
- Inhalation medicines including powder inhalers, nebulizers
- nasal drops solutions, sprays
- lingual, sublingual or buccal tablets to be applied
- films / wafers or capsules to be applied
- suppositories ear or eye preparations
- vaginal capsules aqueous suspensions (lotions, shake mixtures)
- lipophilic suspensions ointments, creams, transdermal
- therapeutic systems such as patches
- milk pastes, foams, scattering powders, implants or stents.
- the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. To this
- Excipients include u.a. Excipients (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers, and
- Dispersing or wetting agents for example, sodium dodecylsulfate,
- Polyoxysorbitan oleate binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxides), and flavor and / or odoriferous agents.
- binders e.g., polyvinylpyrrolidone
- synthetic and natural polymers e.g., albumin
- stabilizers e.g., antioxidants such as ascorbic acid
- dyes e.g., inorganic pigments such as iron oxides
- flavor and / or odoriferous agents e.g., inorganic pigments such as iron oxides
- compositions containing at least one compound of the invention usually together with one or several inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
- the invention further relates to a process for the preparation of the derivatives of the formula I.
- Such derivatives can be prepared as shown in Scheme 1, by reacting an epoxide of the general formula II, wherein
- X ' is an oxygen atom, two alkoxy groups OR 7 , a C2-Cin- A
- R7 C 1 -C 4 -AlkVl represent by organometallic coupling reactions, preferably copper-catalyzed Grignard reactions, into a compound of general formula IM, wherein R 1 and X 'have the meanings given above, and R 8 is hydrogen,
- R 9 is a hydroxyl group
- reaction of compounds of the general formula III to give compounds of the general formula IV is carried out by metal-catalyzed coupling reactions with olefins according to the methods known in the art.
- Preferred catalysts are complexes with ruthenium.
- Typical embodiments are found in Examples 2a, 3a, 4a and 27a
- Reaction of compounds of the general formula III to give compounds of the general formula V is carried out by oxidative cleavage of the double bond by the methods known to the person skilled in the art. Typical embodiments are to be found in Examples 21b and 28b
- reaction of compounds of the general formula V to give compounds of the general formula VI is carried out by reaction with oximes or oximethem the methods known to those skilled in the art. Typical embodiments can be found in Examples 34a-38a.
- R1 or R ⁇ contained functional groups in compounds of the general formulas III, IV, V, VI and I 'can be further modified by the methods known in the art.
- the ester cleavage such as these in the
- Examples 5, 13, 17, 50, 52 and 56 the esterification of carboxylic acids as exemplified in Examples 30 and 31, the conversion of a hydroxyl group into an azide group, their reduction to an amino group as exemplified in the examples 39b and 39a, as well as their further functional transformation, for example, to ureas, as described by way of example in Examples 39, 40-48, 49a, 51a, 53, 54, 55a, 57 and 58.
- Example 1 (5R, 8S, 11R, 13S, 14S f 17S) -11- (4-ethenylphenyl) -5 I, 5 l 13-t ⁇ methyl-17- (pentafluoroethyl) - 1, 2,3,4,6, 7, 8, 11, 12, 13, 14, IS.ie.-tetradecahydro-spirotcyclopentata-phenanthrene-3,2 '- [1,3-diolan] -5,17-d ⁇ ol
- Example 2a 50 mg (84 ⁇ mol) of the compound prepared according to Example 1a were reacted and, after working up and purification, 15 mg (25%) of the title compound were isolated as a colorless foam.
- Example 2a 200 mg (340 ⁇ mol) of the compound prepared according to Example 1a were reacted and isolated after work-up and purification 42 mg (20%) of the title compound as a colorless foam.
- Lithium hydroxide solution and stirred for 3 hours at 23 0 C.
- the mixture was acidified by adding a 1 molar hydrochloric acid, saturated with sodium chloride and extracted several times with
- Example 28b 250 mg (0.42 mmol) of the compound prepared according to Example 28b were reacted using diethyl pyridin-3-ylmethylphosphonate and, after work-up and purification, 170 mg (60%) of a mixture of the two title compounds were isolated colorless foam.
- Example 8a (5R.8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-trimethyl-17- (pentafluoroethyl) -11 - ⁇ 4 - [(E / Z) -2- (pyridine) 4-yl) ethenyl] phenyl ⁇ -1, 2,3,4,6,7,8, 11, 12, 13, 14, 15, 16,17-tetradecahydro- spiro [cyclopenta [a] phenanthrene-3,2 '- [1,3] dioxane] -5,17-diol
- Example 9a (5R.8S, 11R, 13S, 14S, 17S) -5 ⁇ 5 ', 13-trimethyl-11 - ⁇ 4 - [(E / Z) -2- (2-methyl-1,3-thiazole 4-yl) ethenyl] phenyl ⁇ -17- (pentafluoroethyl) -1,3,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydro-spiro-cyclopentalalphenanthrene-S, n-2-sulfonic acid.
- Example 10a In analogy to Example 1, 84 mg (0.11 mmol) of the compound prepared according to Example 10a were reacted and isolated after working up and purification 44 mg (61%) of the title compound as a colorless foam.
- Example 10a (SR. ⁇ S.H R.ISS.MS. ⁇ SJ-S'.S'.IS-trimethyl-1-methyl-1-S-benzothiazol-S-y-ethyl-phenyl-1-yl-1-yl) pentafluoroethyl O-1-silane, 12,13,14,15,16,17-tetradecahydro-spiro-cyclopentatalphenanthrene-S, 3'-fi-sialioxan-6-diol
- Example 12a 50 mg (75 ⁇ mol) of the compound prepared according to Example 12a were reacted and, after working up and purification, 25.2 mg (60%) of the title compound were isolated as a colorless foam.
- Example 28b 250 mg (0.42 mmol) of the compound prepared according to Example 28b were reacted using (diethoxy-phosphoryl) -acetic acid ethyl ester and isolated after work-up and purification 230 mg (82%) of the title compound as a colorless foam.
- Example 14a (2E / Z) -3- ⁇ 4 - [(5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-5 ', 5 ⁇ 13-trimethyl-17- (pentafluoroethyl-I ⁇ . S.ej. ⁇ .H.I ⁇ .IS.M.IS.ie. ⁇ - tetradecahydro- spirotcyclopentafalphenanthren-S ⁇ '- ti.Sldioxanl-H-yllphenylJprop ⁇ -enonitrile
- Example 28b 1.0 g (1.67 mmol) of the compound prepared according to Example 28b was reacted using diethyl cyanomethylphosphonate and, after work-up and purification, isolated 961 mg (93%) of the title compound as a colorless foam.
- Example 16 In analogy to Example 6a, 180 mg (0.3 mmol) of the compound prepared according to Example 28b were reacted using ethyl (E) -4- (diethoxy-phosphoryl) -but-2-enoate and, after working up and purification, isolated 170 mg (81%) of the title compound as a colorless foam.
- E ethyl
- E diethoxy-phosphoryl
- Example 16a In analogy to Example 1 was reacted 33 mg (52 .mu.mol) of a mixture of the compounds shown in Example 16a and isolated after work-up and purification, 6.7 mg (24%) of the title compound as a pale yellow foam.
- Example 17 In analogy to Example 6a, 180 mg (0.3 mmol) of the compound prepared according to Example 28b were reacted using (2-oxopropyl) phosphonic acid dimethyl ester and, after working up and purification, isolated 33 mg (17%) of the title compounds as a colorless foam.
- Example 17 In analogy to Example 6a, 180 mg (0.3 mmol) of the compound prepared according to Example 28b were reacted using (2-oxopropyl) phosphonic acid dimethyl ester and, after working up and purification, isolated 33 mg (17%) of the title compounds as a colorless foam.
- Example 22 (8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-17-pentafluoroethyl-11- [3 - ((E) -2-pyridin-3-yl-vinyl) -phenyl] - 1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-cyclopenta [a] phenanthren-3-one
- Example 25a In analogy to Example 1, 51 mg (69 ⁇ mol) of the Example 25a were used
- Example 21b 120 mg (0.2 mmol) of the compound prepared according to Example 21b were reacted using (2-methyl-benzothiazol-5-ylmethyl) -phosphonic acid diethyl ester and isolated after working-up and purification 70 mg (50%). the title compound as a pale yellow foam.
- Example 2a 500 mg (0.84 mmol) of the compound prepared according to Example 1a were reacted using allylmalonitrile and, after working up and purification, 93 mg (16%) of the title compound were isolated as a colorless foam.
- Example 30 In analogy to Example 30 were reacted 13 mg (21 .mu.mol) of the compound prepared according to Example 29 and isolated after work-up and purification, 12 mg (90%) of the title compound as a colorless foam.
- Example 33a (5R, 8S, 11R, 13S, 14S, 17S) -11- ⁇ 4 - [(E) -2- (4-methylsulfanyl-phenyl) -vinyl] -phenyl ⁇ -5 ', 5', 13- trimethyl-17-pentafluoroethyl-1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydro spiro [cyclopenta [a] phenanthrene-3,2 '- [ 1, 3] dioxane] -5,17-diol
- Example 34 In analogy to Example 6a, 200 mg (0.33 mmol) of the compound prepared according to Example 28b were reacted using (4-methylsulfanyl-benzyl) -phosphonic acid diethyl ester and isolated after working up and purification 175 mg (73%) of the title compound as colorless Foam.
- Example 34
- Example 34a In analogy to Example 1 were reacted to 59.6 mg (89 .mu.mol) of the compound according to Example 34a shown and isolated after work-up and purification 39 mg (77%) of the title compound as a colorless foam.
- Tetrahydrofuran was added at 23 ° C with 230 .mu.l of a 2.5 molar solution of n-butyl in hexane and after 20 minutes with the solution of 100 mg (0.17 mmol) of the compound prepared according to Example 28b in 1 ml of tetrahydrofuran Man warmed 2.5 Hours to 55 ° C and allowed to react for a further 16 hours at 23 ° C. It was poured into water, acidified by addition of a 1 molar hydrochloric acid and extracted several times with ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride solution, saturated sodium bicarbonate solution and dried over sodium sulfate. The residue obtained after filtration and solvent removal was purified by chromatography. Isolated 60 mg (53%) of the title compound as a colorless foam.
- Example 34a 100 mg (0.17 mmol) of the compound prepared according to Example 28b were reacted using O-benzylhydroxylamine hydrochloride and, after working up and purification, isolated 87 mg (94%) of the title compound as a colorless foam.
- Example 34a 100 mg (0.17 mmol) of the compound prepared according to Example 28b were reacted using O-ethylhydroxylamine hydrochloride and, after working up and purification, isolated 40 mg (37%) of the title compound as a colorless foam.
- Example 34a 100 mg (0.17 mmol) of the compound prepared according to Example 28b were reacted using 0- (3,4-dichlorobenzyl) -hydroxylamine hydrochloride and, after working up and purification, isolated 105 mg (81%). ) of the title compound as a colorless foam.
- Example 38a In analogy to Example 1, 58 mg (86 ⁇ mol) of the Example 38a were used
- Example 38a 4 - ((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-5 ', 5 ⁇ 13-trimethyl-17-pentafluoroethyl
- Example 34a 100 mg (0.17 mmol) of the compound prepared according to Example 28b were reacted using O-isobutyl-hydroxylamine hydrochloride and, after working up and purification, isolated 58 mg (52%) of the title compound as a colorless foam.
- Example 39 40 mg (53 ⁇ mol) of the compound prepared according to Example 39a were reacted using phenyl isocyanate and, after working up and purification, isolated 10.2 mg (30%) of the title compound as a colorless foam.
- Example 44 4-Fluoro-phenyl) -3 - ⁇ (E) -3- [4 - ((8S > 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo ⁇ -pentafluoroethyl- ⁇ .S.ej. ⁇ .ii. ⁇ . iS.U.IS.I ⁇ .iZ-dodecahydro-IH-cyclopenta [a] phenanthrene-11-yl) -phenyl] allyl-urea
- Example 39 40 mg (53 ⁇ mol) of the compound prepared according to Example 39a were reacted using 4-fluorophenyl isocyanate and isolated after working up and purification 21 mg (60%) of the title compound as a colorless foam.
- Example 46 1-Benzyl-3 - ⁇ (E) -3- [4 - ((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3 , 6,7,8,11,12,13,14,15,16,17-dodecahydro-1 / y-cyclopenta [a] phenanthrene-11-yl) -phenyl] allyl-urea
- Example 39 40 mg (53 ⁇ mol) of the compound prepared according to Example 39a were reacted using benzyl isocyanate and, after working up and purification, isolated 18.2 mg (52%) of the title compound as a colorless foam.
- Example 39 40 mg (53 ⁇ mol) of the compound prepared according to Example 39a were reacted using 3,5-dimethyl-isoxazol-4-yl isocyanate and, after working up and purification, isolated 9.1 mg (26%). the title compound as a colorless foam.
- Example 49a In analogy to Example 1 was reacted 40 mg of the crude product shown in Example 49a and isolated after work-up and purification 16 mg (47%) of the title compound as a colorless foam.
- Example 51a In analogy to Example 50 were reacted 60 mg (79 .mu.mol) of the compound according to Example 51a shown compound and isolated after workup and purification 21 mg (42%) of the title compound as a colorless foam.
- Example 39 40 mg (53 ⁇ mol) of the compound prepared according to Example 39a were reacted using 4-chlorophenyl isocyanate and, after working up and purification, isolated 23.5 mg (66%) of the title compound as a colorless foam
- Example 49a 120 mg (0.16 mmol) of the compound prepared according to Example 39a were reacted using 4-isocyanato-benzoic acid ethyl ester and, after work-up, 121 mg of the title compound were isolated as crude product.
- Example 55a 80 mg of the compound prepared according to Example 55a were reacted and isolated after working up and purification 35 mg (52%) of the title compound as a colorless foam.
- Example 39 20 mg (27 ⁇ mol) of the compound prepared according to Example 39a were reacted using allyl isocyanate and isolated after working up and purification 10 mg (62%) of the title compound as a colorless foam.
- Example 39 40 mg (53 ⁇ mol) of the compound prepared according to Example 39a were reacted using 4-piperidinephenyl isocyanate and, after working up and purification, isolated 17 mg (43%) of the title compound as a colorless foam.
- Reporter construct SK-N-MC cells (human neuroblastoma cells) stably transfected with plasmids containing human progesterone receptor B (pRChPR-B-neo) or human progesterone receptor A (pRChPR-A-neo) and a reporter construct (pMMTV - LUC) were incubated for 24 hours either in the absence (negative control) or in the presence of increasing amounts of the respective test compound (0.01 ⁇ mol / l, 0.1 nmol / l, 1 nmol / l, 10 nmol / l, 100 nmol / l and 1 pmol / l) to determine agonist activity.
- the cells were treated with the synthetic progestin Promegeston (0.01 nmol / l, 0.1 nmol / l, 1 nmol / l, 10 nmol / l, 100 nmol / l and 1 pmol / l).
- the cells were incubated 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 pmol / l).
- the activity of the reporter gene LUC (LUC luciferase) was determined in the cell lysates and measured as RLU (relative light units). All measured values are given as% efficiency and as EC50 or IC50
- the comparative compound (reference substance) used is the compound described in Example 10 of WO 1998/34947 (8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [4- (hydroxymethyl) -phenyl] -13-methyl-17-pentafluoroethyl-1, 2,6,7,8,11,12,13,14,15,16,17-dodecahydro-cyclopenta [a] -phenanthren-3-one.
- HBM human liver microsomes
- Liver blood flow 1 3 L * kg / h, specific liver weight (per kg body weight) 21g / kg, microsomal protein content 40mg / g liver) according to the well-stirred model
- the comparative compound (reference substance) is the compound described in Example 10 of WO 1998/34947 (8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [4- (hydroxymethyl) -phenyl ] -13-methyl-17-pentafluoroethyl- ⁇ S-on. This compound has a good predicted maximum bioavailability in the rat, but not in humans.
- progesterone and the progesterone receptor are essential for successful pregnancy or gestation in mammals.
- the progesterone antagonist activity of the compounds of the invention was confirmed on pregnant rats (6 rats per group) on day 5 to 7 post coitum
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Toxicology (AREA)
- Diabetes (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201080032886.8A CN102471366B (zh) | 2009-07-20 | 2010-07-07 | 17-羟基-17-五氟乙基雌-4,9(10)-二烯11-苯亚甲基衍生物、其制备方法及其用于治疗疾病的用途 |
ES10731477T ES2552789T3 (es) | 2009-07-20 | 2010-07-07 | Derivados de 17-hidroxi-17-pentafluoroetil-estra-4,9(10)-dien-11-bencilideno, procedimiento para su preparación y su uso para el tratamiento de enfermedades |
US13/386,031 US9156877B2 (en) | 2009-07-20 | 2010-07-07 | 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-benzylidene derivatives, methods for the production thereof and use thereof for treating diseases |
CA 2768433 CA2768433A1 (en) | 2009-07-20 | 2010-07-07 | 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-benzylidene derivatives, methods for the production thereof and use thereof for treating diseases |
EP10731477.5A EP2456782B1 (de) | 2009-07-20 | 2010-07-07 | 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-benzyliden-derivate, verfahren zu deren herstellung und deren verwendung zur behandlung von krankheiten |
JP2012520922A JP5781070B2 (ja) | 2009-07-20 | 2010-07-07 | 17−ヒドロキシ−17−ペンタフルオロエチルエストラ−4,9(10)−ジエン11−ベンジリデン誘導体、その製造方法、及び疾患治療のためのその使用 |
Applications Claiming Priority (2)
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DE102009034367A DE102009034367A1 (de) | 2009-07-20 | 2009-07-20 | 17-Hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-benzyliden-Derivate, Verfahren zu deren Herstellung und deren Verwendung zur Behandlung von Krankheiten |
DE102009034367.9 | 2009-07-20 |
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WO2011009532A2 true WO2011009532A2 (de) | 2011-01-27 |
WO2011009532A3 WO2011009532A3 (de) | 2011-04-21 |
Family
ID=43332859
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PCT/EP2010/004150 WO2011009532A2 (de) | 2009-07-20 | 2010-07-07 | 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-benzyliden-derivate, verfahren zu deren herstellung und deren verwendung zur behandlung von krankheiten |
Country Status (8)
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US (1) | US9156877B2 (de) |
EP (1) | EP2456782B1 (de) |
JP (1) | JP5781070B2 (de) |
CN (1) | CN102471366B (de) |
CA (1) | CA2768433A1 (de) |
DE (1) | DE102009034367A1 (de) |
ES (1) | ES2552789T3 (de) |
WO (1) | WO2011009532A2 (de) |
Families Citing this family (6)
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DE102009034366A1 (de) | 2009-07-20 | 2011-01-27 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-methylenoxyalkylenaryl-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung zur Behandlung von Krankheiten |
DE102009034368A1 (de) | 2009-07-20 | 2011-01-27 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-acyloxyalkylenphenyl-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung zur Behandlung von Krankheiten |
DE102009034526A1 (de) | 2009-07-21 | 2011-02-10 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-ethinylphenyl-Derivate, Verfahren zu deren Herstellung und deren Verwendung zur Behandlung von Krankheiten |
DE102009034525A1 (de) | 2009-07-21 | 2011-01-27 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-aryl-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung zur Behandlung von Krankheiten |
DE102010007722A1 (de) | 2010-02-10 | 2011-08-11 | Bayer Schering Pharma Aktiengesellschaft, 13353 | Progesteronrezeptorantagonisten |
DE102010007719A1 (de) | 2010-02-10 | 2011-08-11 | Bayer Schering Pharma Aktiengesellschaft, 13353 | Progesteronrezeptorantagonisten |
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DE102009034368A1 (de) | 2009-07-20 | 2011-01-27 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-acyloxyalkylenphenyl-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung zur Behandlung von Krankheiten |
DE102009034362A1 (de) | 2009-07-20 | 2011-01-27 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-aryl-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung zur Behandlung von Krankheiten |
DE102009034366A1 (de) | 2009-07-20 | 2011-01-27 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-methylenoxyalkylenaryl-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung zur Behandlung von Krankheiten |
DE102009034525A1 (de) | 2009-07-21 | 2011-01-27 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-aryl-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung zur Behandlung von Krankheiten |
DE102009034526A1 (de) | 2009-07-21 | 2011-02-10 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-ethinylphenyl-Derivate, Verfahren zu deren Herstellung und deren Verwendung zur Behandlung von Krankheiten |
DE102010007719A1 (de) | 2010-02-10 | 2011-08-11 | Bayer Schering Pharma Aktiengesellschaft, 13353 | Progesteronrezeptorantagonisten |
DE102010007722A1 (de) | 2010-02-10 | 2011-08-11 | Bayer Schering Pharma Aktiengesellschaft, 13353 | Progesteronrezeptorantagonisten |
-
2009
- 2009-07-20 DE DE102009034367A patent/DE102009034367A1/de not_active Withdrawn
-
2010
- 2010-07-07 EP EP10731477.5A patent/EP2456782B1/de not_active Not-in-force
- 2010-07-07 ES ES10731477T patent/ES2552789T3/es active Active
- 2010-07-07 CN CN201080032886.8A patent/CN102471366B/zh not_active Expired - Fee Related
- 2010-07-07 WO PCT/EP2010/004150 patent/WO2011009532A2/de active Application Filing
- 2010-07-07 JP JP2012520922A patent/JP5781070B2/ja not_active Expired - Fee Related
- 2010-07-07 CA CA 2768433 patent/CA2768433A1/en not_active Abandoned
- 2010-07-07 US US13/386,031 patent/US9156877B2/en not_active Expired - Fee Related
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EP0057115A2 (de) | 1981-01-09 | 1982-08-04 | Roussel-Uclaf | In Stellung 11-beta substituierte Steroidderivate, Verfahren zu ihrer Herstellung, ihre Anwendung als Arzneimittel und Zusammensetzungen, die sie enthalten |
WO1996003130A1 (de) | 1994-07-27 | 1996-02-08 | Schering Aktiengesellschaft | Progesteronantagonist und gestagen zur behandlung der endometriose und leiomyomata uteri |
WO1996015794A1 (en) | 1994-11-22 | 1996-05-30 | Balance Pharmaceuticals, Inc. | Compositions and methods for contraception and for treatment of benign gynecological disorders |
WO1998034947A1 (de) | 1997-02-07 | 1998-08-13 | Schering Aktiengesellschaft | ANTIGESTAGEN WIRKSAME STEROIDE MIT FLUORIERTER 17α-ALKYLKETTE |
WO2001047490A1 (en) | 1999-12-23 | 2001-07-05 | Leiras Oy | Devices for the delivery of drugs having antiprogestinic properties |
WO2003093292A1 (de) | 2002-05-03 | 2003-11-13 | Schering Ag | 17α-FLUORALKYL-11β-BENZALDOXIM-STEROIDE, VERFAHREN ZU DEREN HERSTELLUNG, DIESE STEROIDE ENTHALTENDE PHARMAZEUTISCHE PRÄPARATE SOWIE DEREN VERWENDUNG ZUR HERSTELLUNG VON ARZNEIMITTELN |
WO2006010097A2 (en) | 2004-07-09 | 2006-01-26 | The Population Council, Inc. | Sustained release compositions containing progesterone receptor modulators |
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Title |
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U. FUHRMANN ET AL., J. MED. CHEM., vol. 43, 2000, pages 5010 - 5016 |
Also Published As
Publication number | Publication date |
---|---|
CN102471366B (zh) | 2015-12-16 |
ES2552789T3 (es) | 2015-12-02 |
DE102009034367A1 (de) | 2011-01-27 |
CN102471366A (zh) | 2012-05-23 |
CA2768433A1 (en) | 2011-01-27 |
JP5781070B2 (ja) | 2015-09-16 |
EP2456782B1 (de) | 2015-08-19 |
EP2456782A2 (de) | 2012-05-30 |
JP2012533576A (ja) | 2012-12-27 |
US20120316145A1 (en) | 2012-12-13 |
US9156877B2 (en) | 2015-10-13 |
WO2011009532A3 (de) | 2011-04-21 |
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