EP2585435A1 - Dérivés de 6,7-dihydro-5h-benzo[7]annulène, leur procédé de préparation, préparations pharmaceutiques les contenant et leur utilisation pour la fabrication de produits pharmaceutiques - Google Patents

Dérivés de 6,7-dihydro-5h-benzo[7]annulène, leur procédé de préparation, préparations pharmaceutiques les contenant et leur utilisation pour la fabrication de produits pharmaceutiques

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Publication number
EP2585435A1
EP2585435A1 EP11729943.8A EP11729943A EP2585435A1 EP 2585435 A1 EP2585435 A1 EP 2585435A1 EP 11729943 A EP11729943 A EP 11729943A EP 2585435 A1 EP2585435 A1 EP 2585435A1
Authority
EP
European Patent Office
Prior art keywords
benzo
dihydro
sulfonyl
hexyl
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11729943.8A
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German (de)
English (en)
Inventor
Tim Wintermantel
Carsten Möller
Ulrich Bothe
Reinhard Nubbemeyer
Ludwig Zorn
Dirk Kosemund
Antonius Ter Laak
Rolf Bohlmann
Lars Wortmann
Donald Bierer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Intellectual Property GmbH
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Bayer Intellectual Property GmbH
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Application filed by Bayer Intellectual Property GmbH filed Critical Bayer Intellectual Property GmbH
Publication of EP2585435A1 publication Critical patent/EP2585435A1/fr
Withdrawn legal-status Critical Current

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    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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Definitions

  • the invention relates to Selective Estrogen Receptor Modulators (SERM) and process for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular bleeding disorders, osteoporosis, endometriosis, Fibroids, hormone-dependent tumors, hormone replacement therapy and contraception.
  • SERM Selective Estrogen Receptor Modulators
  • SERMs are compounds which have tissue-selective either an antiestrogenic / estrogen-inhibiting or an estrogenic or partial estrogenic action, for example, inhibit the action of the estrogen on the uterus, but have a neutral or estrogen-like action on the bone. Examples of such compounds include tamoxifen, raloxifene and apeledoxifene.
  • SERM and pure anti-estrogens which have a purely antagonistic, estrogen-inhibiting effect in all tissues and show no estrogens or partial estrogenic effects in a tissue.
  • SERDs Selective Estrogen Receptor Downregulators
  • SERDs belong to the anti-estrogenic genres and lead on Protei side to a complete depletion of the estrogen receptor in the target cells.
  • the compound fulvestrant is called.
  • SERM or the use of certain SERM in the treatment of certain diseases can be found, for example, in EP 0584952, WO 96/21656; J. Endocrinol. 1994, 141, 335; EP 0124369; US 6645951; Bioorg. Med. Chem. Lett.
  • Object of the present invention is to provide alternative acting as SERM substances with improved physico-chemical properties.
  • the present invention relates to compounds of the formula (I):
  • ⁇ is selected from the group comprising hydrogen, CrC 6 - alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CC 6 - alkyl-S (0) 2 -, C 1 -C 6 -alkylcarbonyl, phenyl-C 6 -alkyl-, which may be mono-, di- or polysubstituted by -OH, halogen, - CN, -NR 8 R 9 , -C (O) NR 10 R 11 , -N (R 10 ) C (O) NR 10 R 11 , -C 1 -C 6 -haloalkoxy, -CC 6 -alkoxy, -C (O) OH, -C (O) OC C 6 -alkyl or - C (0) may be substituted by benzyl, optionally also hydrogen atoms can be exchanged for deuterium atoms
  • Y is a perfluorinated or partially fluorinated -CrC 4 -alkyl or perfluorinated or partially fluorinated C 3 -C 8 -cycloalkyl
  • n 4, 5, 6 or 7,
  • n 2, 3, 4, 5 or 6
  • p 0, 1 or 2
  • q 0, 1, 2, 3, 4, 5 or 6
  • 6,7-dihydro-5H-benzo [7] annulene derivatives (I) which are linked at the 8-position to a fluorinated aromatic substituent and which are linked at position 9 to an optionally substituted aliphatic chain to act as SERM.
  • a large proportion of the claimed 6,7-dihydro-5H-benzo [7] annulene derivatives shows - in contrast to previously known SERMs such as tamoxifen, raloxifene or similar compounds - additionally a destabilizing effect on the ERa content (remaining relative ERA content). Content of less than or equal to 30%).
  • these compounds show a high antiestrogenic effect in vitro (IC 50 values less than 0.6 micromolar) and predominantly even two- or single-digit nanomolar IC 50 values for the inhibition of estradiol-induced luciferase activity).
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the enantiomers and / or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • Enantiomerically pure in the context of the present invention is a compound with an enantiomeric excess of more than 90% (> 90% ee) before. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, acetic, formic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic acetic, formic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).
  • Alkyl per se and "Alk” and "alkyl” in alkoxy, alkylcarbonyl, alkylamino, alkylamino carbonyl, alkoxycarbonyl, alkoxycarbonylamino and alkylcarbonylamino are a linear or branched alkyl radical having usually 1 to 6, preferably 1 to 4, especially preferably 1 to 3 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • Alkoxy is, by way of example and by way of preference, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Alkylcarbonyl is exemplary and preferably formyl, acetyl and propanoyl.
  • Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents.
  • (C 1 -C 3 ) -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, ⁇ /, / V-dimethylamino, ⁇ /, / V-diethylamino, / V-ethyl / V-methylamino, N-methyl / Vn-propylamino, / V-isopropyl / Vn-propylamino, / Vt-butyl / V-methylamino, / V-ethyl / Vn-pentylamino and / Vn-hexyl / V-methylamino.
  • Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents.
  • (C 1 -C 3 ) -Alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Alkoxycarbonylamino is by way of example and by way of preference methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino, n-hexoxycarbonylamino, methoxycarbonyl-N-methylamino, ethoxycarbonyl-N-methylamino, n-propoxycarbonyl-N-methylamino,
  • Alkylcarbonylamino is by way of example and preferably acetylamino, acetyl-N-methylamino, ethylcarbonylamino and ethylcarbonyl-N-methylamino
  • Cycloalkyl represents a cycloalkyl group having usually 3 to 8, preferably 5 to 7 carbon atoms, wherein the ring may also be partially unsaturated, by way of example and preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Aryl is a mono- to tricyclic aromatic, carbocyclic radical of usually 6 to 14 carbon atoms; by way of example and preferably phenyl, naphthyl and phenanthrenyl.
  • Heteroaryl is an aromatic, mono- or bicyclic radical having usually 5 to 10, preferably 5 to 6 Ri ngatomen u nd up to 5, preferably up to 4 heteroatoms from the series S, O and N, by way of example and preferably Thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.
  • Heterocvclyl is a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic heterocyclic radical having usually 4 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups of the Row N, O, S, SO, S0 2 .
  • the heterocyclyl radicals may be saturated or partially unsaturated. Preference is given to 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S. Examples include, and are preferably: tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, piperidinyl, morpholinyl, thiomorpholinyl, perhydroazepinyl.
  • Halogen is fluorine, chlorine, bromine and iodine.
  • Deuterium or D is used when circumscribing substances in which the deuterium content is greatly increased in relation to the naturally occurring isotope ratio at the respective position, eg compounds with an isotopic purity of 10-100%, in particular with an isotopic purity of 50.60, 70, 80, 90% or higher.
  • Perfluorinated C 1 -C 5 -alkyl is a fully fluorinated straight-chain or branched alkyl radical having generally 1 to 4, preferably 1 to 3, carbon atoms, by way of example and preferably trifluoromethyl, pentafluoroethyl, heptafluoropropyl and heptafluoroisopropyl.
  • Partially fluorinated C 1 -C 6 -alkyl is a partially fluorinated straight or branched chain alkyl radical of generally 1 to 4 carbon atoms - selected but not limited to 1, 2,2,2-tetrafluoroethyl, 1,1,2,2-tetrafluoroethyl , 2,2,2-trifluoro-1 - (trifluoromethyl) ethyl, 1, 1, 3,3,3-pentafluoropropyl, 1,1,3,3,3,3-hexafluoropropyl, 1, 1, 2,2, 3,3,4,4-octafluorobutyl, 1, 2,2,3,3,3-hexafluoro-1-methylpropyl, 1, 1, 3,3,3-pentafluoro-2
  • cycloalkyl group having usually 3-7, preferably 5-6 carbon atoms, by way of example and preferably perfluorocyclopentyl and perfluorocyclohexyl.
  • 4,4-difluorocyclohexyl 4-fluorocyclohexyl, 3,3-difluorocyclohexyl, 3,3-difluorocyclopentyl, 3,3-difluorocyclobutyl and 2,2-difluorocyclopropyl.
  • Particularly preferred is 4,4-difluorocyclohexyl.
  • a symbol * on a bond means the point of attachment in the molecule.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 are independently hydrogen or fluorine, wherein at least one substituent R 1 , R 2 , R 3 and R 4 is fluorine.
  • X is selected from the group comprising hydrogen, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkyl-S (O) 2 -, C 6 -alkylcarbonyl-, phenyl-CIC 6 Alkyl, which may be mono-, di- or polysubstituted by -OH, halogen, deuterium, -CN, -NR 8 R 9 , -C (O) NR 10 R 11 , - N (R 10 ) C (O) NR 10 R 11 , alkoxy, -C (O) OH, -C (O) OC C 6 -alkyl or -C (O) -benzyl may be substituted,
  • R 8 and R 9 are C 1 -C 6 -alkyl or benzyl
  • R 10 and R 11 are hydrogen, C 1 -C 6 -alkyl or benzyl, Y is -CF 3 , -C 2 F 5 , -C 3 F 7 , -C 4 F 9 or -C 3 -C 7 cycloalkyl
  • n 4, 5 or 6
  • n 2, 3, 4, 5 or 6
  • p 0, 1 or 2
  • q 0, 1, 2, 3, 4, 5 or 6
  • R 1 , R 2 , R 3 , R 4 independently of one another represent hydrogen or fluorine, where at least one and at most two
  • Fluorine atoms should be included,
  • R 5 and R 6 independently of one another represent hydrogen or fluorine
  • R 7 is hydrogen
  • X is selected from the group comprising hydrogen
  • -dC 4 alkyl cyclopropyl, which may be mono- or polysubstituted by -O-C, -CN, methoxy, -C (O) OH, -C (O) OCH 3 or -C (O), or optionally C 1-8 or Deuterium can be substituted, or X is selected from methyl-S (0) 2 - or methylcarbonyl
  • Y is -CF 3 , -C 2 F 5 , -CF 2 CF 2 CF 3 , -CF (CF 3 ) 2 or
  • n 3, 4 or 5
  • p 0, 1 or 2
  • q 0, 1, 2, 3, 4 or 5
  • R 1 , R 2 , R 3 and R 4 independently represent hydrogen or fluorine, wherein at least one and at most two
  • R 5 and R 6 independently of one another represent hydrogen or fluorine, limited by the fact that R 5 and R 6 do not simultaneously denote fluorine,
  • X represents C 1 -C 4 -alkyl, substituted by naphthyl, which is substituted by
  • Y is -CF 3, -C 2 F 5 , 4,4-difluorocyclohexyl,
  • n 3 or 4
  • p stands for 1 or 2
  • Y is 4,4-difluorocyclohexyl
  • R 5 and R 6 independently of one another represent hydrogen or fluorine, where R 5 and R 6 do not simultaneously denote fluorine,
  • X is C 1 -C 4 -alkyl optionally substituted by deuterium
  • Y is -CF 3, -C 2 F 5, 4,4-difluorocyclohexyl
  • n stands for 3 or 4
  • p stands for 1 or 2
  • Y is 4,4-difluorocyclohexyl
  • Another object of the invention relates to compounds of formula (I) wherein
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen or fluorine, wherein at least one substituent R 1 , R 2 , R 3 and R 4 are fluorine.
  • Another object of the invention relates to compounds of formula (I) wherein
  • R 5 , R 6 and R 7 independently of one another represent hydrogen, fluorine, chlorine, bromine,
  • a further subject of the invention relates to compounds of the formula (I) in which X is selected from the group comprising H, C 1 -C 6 -alkyl-, C 3 -
  • C (0) may be substituted by benzyl, optionally also hydrogen atoms may be substituted by deuterium atoms.
  • Another object of the invention relates to compounds of formula (I) wherein
  • R 8 and R 9 are optionally substituted with halogen and / or Deu teri substituted C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, phenyl or benzyl.
  • Another object of the invention relates to compounds of formula (I) wherein
  • R 10 and R 11 are hydrogen or optionally with halogen and / or
  • Another object of the invention relates to compounds of formula (I) wherein Y is a perfluorinated or partially fluorinated -CrC 4 alkyl or perfluorinated or partially fluorinated C 3 -C 8 - cycloalkyl.
  • Another object of the invention relates to compounds of formula (I) wherein m is 4, 5, 6 or 7.
  • Another object of the invention relates to compounds of formula (I) wherein n is 2, 3, 4, 5 or 6.
  • Another object of the invention relates to compounds of formula (I) wherein p is 0, 1 or 2.
  • Another object of the invention relates to compounds of formula (I) wherein q is 0, 1, 2, 3, 4, 5 or 6.
  • Another object of the invention relates to compounds of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 are independently hydrogen or fluorine, wherein at least one substituent R 1 , R 2 , R 3 and R 4 is fluorine.
  • a further subject of the invention relates to compounds of the formula (I) in which X is selected from the group comprising H, C 1 -C 6 -alkyl-, C 3 -
  • C 8 cycloalkyl Ci-C 6 alkyl-S (0) 2 -, CC 6 alkylcarbonyl, phenyl-CrC 6 alkyl, optionally mono-, di- or polysubstituted by -OH, halogen, deuterium , -CN, -NR 8 R 9 , -C (O) NR 10 R 11 , -N (R 10 ) C (O) NR 10 R 11 , alkoxy, -C (O) OH, -C (O) OC C 6 alkyl or -C (O) -benzyl may be substituted.
  • Another object of the invention relates to compounds of formula (I) wherein
  • R 8 and R 9 are CC 6 alkyl or benzyl.
  • Another object of the invention relates to compounds of formula (I) wherein
  • R 10 and R 11 are hydrogen, CC 6 alkyl or benzyl.
  • Another object of the invention relates to compounds of formula (I) wherein Y is -CF 3 , -C 2 F 5 , -C 3 F 7 , -C4F 9 or -C 3 -C 7 cycloalkyl 2-4 Fluorine atoms stands.
  • Another object of the invention relates to compounds of formula (I) wherein m is 4, 5 or 6.
  • Another object of the invention relates to compounds of formula (I) wherein n is 2, 3, 4, 5 or 6.
  • Another object of the invention relates to compounds of formula (I) wherein
  • R 1 , R 2 , R 3 , R 4 independently of one another are hydrogen or fluorine, it being said that at least two fluorochromes are to be present at least once.
  • Another object of the invention relates to compounds of formula (I) wherein R 5 and R 6 are independently hydrogen or fluorine.
  • Another object of the invention relates to compounds of formula (I) wherein is hydrogen.
  • Another object of the invention relates to compounds of formula (I) wherein X is selected from the group comprising hydrogen, -CrC 4 alkyl, cyclopropyl, optionally simply with -OH, -CN, methoxy, -C (0 ) OH, -C (O) OCH 3 or -C (O) OBn or mono- or polysubstituted by -F or deuterium, methyl-S (O) 2 - or methylcarbonyk
  • the invention further relates to compounds of the formula (I) in which Y is -CF 3 , -C 2 F 5 , -CF 2 CF 2 CF 3 , -CF (CF 3 ) 2 or TEHT.
  • Another object of the invention relates to compounds of formula (I) wherein m is 5 or 6.
  • Another object of the invention relates to compounds of formula (I) wherein n is 3, 4 or 5.
  • Another object of the invention relates to compounds of formula (I) wherein q is 0, 1, 2, 3, 4 or 5.
  • Another object of the invention relates to compounds of formula (I) wherein R 5 and R 6 are independently hydrogen or fluorine, limited in that R 5 and R 6 are not fluorine at the same time.
  • Another object of the invention relates to compounds of formula (I) wherein X is CC 4 alkyl.
  • Another object of the invention relates to compounds of formula (I) wherein Y is -CF 3, -C 2 F 5 , 4,4-difluorocyclohexyl.
  • Another object of the invention relates to compounds of formula (I) wherein m is 5 or 6.
  • Another object of the invention relates to compounds of formula (I) wherein n is 3 or 4.
  • Another object of the invention relates to compounds of formula (I) wherein p is 1 or 2.
  • Another object of the invention relates to compounds of formula (I) wherein q is 2, 3, 4 or 5.
  • Another object of the invention relates to compounds of formula (I) wherein in the particular case that Y is 4,4-difluorocyclohexyl, q is 0 or 1.
  • Another object of the invention relates to compounds of formula (II), wherein
  • R 12 is 3,5-difluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 4-
  • Another object of the invention relates to compounds of formula (II) wherein R 5 and R 6 are independently hydrogen or fluorine, limited in that R 5 and R 6 are not fluorine simultaneously.
  • Another object of the invention relates to compounds of formula (II) wherein X is CC 4 alkyl.
  • Another object of the invention relates to compounds of formula (II) wherein Y is -CF 3, -C 2 F 5 , 4,4-difluorocyclohexyl.
  • Another object of the invention relates to compounds of formula (II) wherein m is 6.
  • Another object of the invention relates to compounds of formula (II) wherein n is 3 or 4.
  • Another object of the invention relates to compounds of formula (II) wherein p is 1 or 2.
  • Another object of the invention relates to compounds of formula (II) wherein q is 2, 3, 4 or 5.
  • Another object of the invention relates to compounds of formula (II), wherein in the particular case that Y is 4,4-difluorocyclohexyl, q is 0 or 1.
  • 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.
  • Another object of the invention is a process for the preparation of the compounds of the invention.
  • the preparation of the compounds (I) or the compounds (II) according to the invention as a subset of the formula (I) can be illustrated by the following synthesis scheme Intermediate 5, which were prepared analogously to the patent WO 03/033461 A1, are shown in the following general formula scheme (synthesis scheme 1), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7, the in of formula (I) have the meaning given.
  • Synthesis of the intermediates 2 is carried out according to the condensation reactions of acetaldehyde known to one skilled in the art with one of the intermediates 1 (commercially available, for example, from Aldrich, ABCR) with base catalysis in water with or without the addition of an organic solvent which is stable under these conditions (Organic Reactions 1968 , 16, 1; Justus Liebigs Ann. Chem. 1917, 412, 322; J. Org. Chem. 1951, 16, 1519; Helv. Chim. Acta 1993, 76, 1901). Particularly preferred here is the reaction with potassium hydroxide with the addition of dichloromethane between 1 - 30 ° C.
  • the intermediates 3 are then reacted according to the Knoevenagel conditions known to those skilled in the art with an arylacetic acid (commercially available from eg Aldrich, ABCR) (Organic Reactions 1967, 15, 204, Tetrahedron Lett. 1998, 39, 8013). Particularly preferred is the reaction with acetic anhydride and triethylamine at a temperature of 90 ° C to reflux.
  • an arylacetic acid commercially available from eg Aldrich, ABCR
  • acetic anhydride and triethylamine at a temperature of 90 ° C to reflux.
  • the intermediates 4 are synthesized (Houben Weyl, "Methods of Organic Chemistry", Bd. 4/1 c Part 1, p 14 ff.
  • the intermediates 5 are prepared according to those familiar to the person skilled in the art Rev. 1970, 70, 553, J. Org. Chem. 1958, 23, 789, J. Org. Chem. 1981, 46, 2974; J. Med. Chem. 1986, 29, 29; 1615). Particularly preferred is the use of phosphorus pentoxide in methanesulfonic acid or trifluoromethanesulfonic mentioned in the temperature range of 0 - 30 ° C.
  • intermediates 5 can be prepared according to Scheme 2, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the meaning given in the formula (I).
  • the intermediates 5 can be prepared by arylation of the intermediates K as known to the person skilled in the art (J. Am.Chem.Soc.1997, 119, 11108, J. Am.Chem.Soc.2002, 124, 15168; Chem. Soc.1997, 119, 12382; J. Am. Chem. Soc. 1999, 121, 1473; J. Am. Chem. Soc. 2000, 122, 1360; Tetrahedron 2001, 57, 5967; Chem., 2001, 66, 3284; J. Org. Chem.2006, 71, 3816; Org. Lett.2002, 4, 4053; J. Organomet. Chem. 2005, 690, 5832; Org.
  • a palladium compound eg Pd (OAc) 2 , Pd 2 (dba) 3
  • a ligand eg BINAP, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, xantphos, triphenylphosphine, DTPF, 1 , 1'-bis (di-o-tolylphosphino) ferrocene, 1, 3-di-tert-butyl-2-chloro-1, 3,2-diazaphospholidine, 2 '- (dicyclohexylphosphino) -N, N-dimethylbiphenyl-2 amine) in a solvent (for example toluene, xylene, tetrahydrofuran, dioxane, dimethoxyethane, tert-butyl methyl ether) with a base (for example sodium tert-butoxide, potassium ter
  • the set temperature is also dependent on the solvent.
  • the palladium compound used can also be previously bonded to corresponding ligands such as (ltBu) Pd (allyl) Cl, (IPr) Pd (acaac) Cl, Pd (dppf) Cl, [PdBrPtBu] 2 .
  • Particularly preferred for the reactions palladium (II) acetate with BINAP or Xantphos or allylchlor (1, 3-bis (2,6-di-isopropylphenyl) imidazol-2-ylidene) palladium used.
  • an alkali metal salt of an alcohol as base in THF at 60-80 ° C is particularly preferred.
  • the synthesis of the intermediates 10 can be carried out according to the synthesis scheme 3, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 and m have the meaning given in the formula (I).
  • Intermediate 6 can be prepared according to the conditions known to those skilled in the art (Tetrahedron: Asymmetry 1990, 1, 97, J. Org. Chem. 1996, 61, 8536, Synthesis 2002, 2064). It is also possible to prepare analogous perfluorinated sulfonylol ethers, with the remainder of nonafluorobutyl being replaced by, for example, trifluoromethyl. Particularly preferred for the preparation of the intermediate 6, the reaction in the presence of organic Amines in ethers or halogenated solvents.
  • the methyl ether has to be cleaved by methods known to those skilled in the art ("Protective Groups in Organic Synthesis” 3rd ed., Pp. 250 ff. (1999), John Wiley & Sons New York), most preferably cleavage with boron tribromide, and most preferably methyl ether cleavage with boron tribromide with addition of a pyridine derivative (eg, lutidine) with cooling in an inert solvent (eg, dichloromethane) at 0-10 ° C.
  • a pyridine derivative eg, lutidine
  • the intermediate 10 in the side chain is converted into an activated form as known to those skilled in the art (J.Am.Chem.Soc. 1964, 86, 964; Tetrahedron Lett., 1973, 3937; Angew. Chem. Int. Ed 1975, 14, 801; J. Org. Chem. 1969, 34, 212; J. Am. Chem. Soc. 1970, 92, 2139; J. Chem. Soc., Perkin Trans. 1, 1980, 2866; Chem., 1986, 51, 5291, J. Org.
  • halogen is chlorine, bromine or iodine
  • n has the meaning given in the formula (I)
  • X 1 is selected from the group comprising H, C 1 -C 6 -alkyl-, C 3 -C 8 -cycloalkyl, phenyl-C 1 -C 6 -alkyl, which may optionally be mono-, di- or poly-substituted by -OH, halogen, - CN, alkoxy.
  • the intermediates 11 can be prepared according to the conditions known to the person skilled in the art (J. Chem. Soc., 1950, 579, J. Am. Chem. Soc., 1953, 75, 3700).
  • Intermediates 16 can be prepared according to synthesis scheme 5, where Y, q, n have the meaning given in the formula (I), X 2 is selected from the group comprising H, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl , Phenyl-C 1 -C 6 -alkyl-, which may optionally be monosubstituted, disubstituted or polysubstituted by -OH, deuterium, halogen, -CN, alkoxy.
  • intermediates 12 for example Aldrich are converted into intermediates 13 by methods known to the skilled person (J. Chem Soc 1939, 1248, Synthesis 1996, 594, Helv. Chim. Acta 1946, 29, 671).
  • the intermediates 14 can be synthesized by the methods known to those skilled in the art (J. Chem. Soc., 1950, 579, J. Am. Chem. Soc., 1 953, 75, 3700).
  • the intermediates 15 are prepared by the synthesis methods known to the person skilled in the art (Pharm. Chem. J. 1989, 23, 998).
  • the intermediates 16 are synthesized by the methods known to those skilled in the art (Org. Synth. Coli. Vol. 1, 102, 1941; Org. Synth.
  • X 3 is selected from the group comprising H, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl , Phenyl-C 1 -C 6 -alkyl-, which may optionally be monosubstituted, disubstituted or polysubstituted by -OH, deuterium, halogen, -CN, alkoxy.
  • Intermediates 17 can be prepared by the methods known to those skilled in the art (Org., Prep., Proced., Int, 1982, 14, 45, J. Org. Chem., 1962, 27, 282). In this case, the oxidation with metaperiodate is particularly preferred. Very particular preference is given to oxidation with sodium metaperiodate.
  • the intermediates 18 can be prepared as described in Intermediate 16.
  • Y, q, n have the meaning given in the formula (I)
  • X 4 is selected from the group comprising H, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl , Phenyl-C 1 -C 6 -alkyl-, which may optionally be monosubstituted, disubstituted or polysubstituted by -OH, deuterium, halogen, -CN, alkoxy.
  • Y II
  • the intermediates 19 can be prepared by the methods known to those skilled in the art (J. Org. Chem. 1957, 22, 241; J. Org. Chem. 2004, 69, 3824; J. Am. Chem. Soc. 1941, 63, 2939 Org. Lett. 1999, 1, 189). In this case, the oxidation with peracids is particularly preferred.
  • the intermediates 20 can be produced as described for the intermediates 16.
  • the intermediates 14 can also be prepared from the corresponding halogen compounds by the methods known to those skilled in the art (J. Am Chem Chem 1953, 75, 3700, J. Org. Chem. 1984, 49, 3231).
  • intermediates 16, 18 and 20 may also be prepared via Synthetic Scheme 9, wherein Y, p, q, n are as defined in formula (I), X5 is selected from the group comprising H, C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, phenyl-C 1 -C 6 -alkyl, which may optionally be monosubstituted, disubstituted or polysubstituted by -OH, deuterium, halogen, -CN, alkoxy.
  • the synthesis of the intermediates 21 is carried out by reacting the tosylate 13 or the corresponding halogen compounds with an intermediate 1 1 by the methods known to the person skilled in the art, as described for the intermediates 15.
  • the conversion into the intermediates 22 is analogous to the methods for the preparation of the intermediates 17 and 19.
  • the conversion into the intermediates 16, 18 and 20 starting from the intermediates 21 or 22 can be carried out according to the methods known to the person skilled in the art (eg "Protective Groups in Organic Synthesis 3rd Ed., Pp. 520 et seq., (1999), John Wiley & Sons New York), particularly preferred is cleavage with acids, and most preferably cleavage with trifluoroacetic acid.
  • Synthesis of the example compounds can be carried out according to synthesis scheme 10 by reacting the intermediates 16, 18 or 20 with the intermediate 10, where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n, p , q, Y are as in formula (I) defined above,
  • X6 is selected from the group consisting of H, -C 6 alkyl, C 3 -C 8 cycloalkyl, phenyl-CrC 6 - alkyl, which optionally one, two or more times with -OH, deuterium, halogen, -CN, alkoxy may be substituted.
  • Synthesis of the example compounds was carried out according to synthesis scheme 10 by reacting the intermediates 16, 18 or 20 with the intermediate 10.
  • the reactions can be carried out by the methods known to the person skilled in the art as described in the reaction of intermediate 15 to intermediate 16.
  • the reaction in the presence of an alkali metal iodide and a carbonate of the alkali metals in an aprotic solvent, e.g. DMF or NMP is preferred.
  • X7 selected from the group comprising C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkyl -S (0) 2 -, CC 6 al
  • Cycloalkyl, -C 6 alkylcarbonyl, phenyl-CrC 6 alkyl which mono-, di- or polysubstituted by -C (0) OCRC 6 alkyl substituted, for example, compounds having the meaning X8 -C 6 - alkyl , C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, phenyl-C 1 -C 6 -alkyl- which are mono-, di- or poly-substituted by -C (O) OH, can be prepared by methods known to the person skilled in the art (Protective Groups in Organic Synthesis 3rd Ed., p 250 ff., 1999; John Wiley & Sons New York; J.
  • the compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic activity spectrum. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases Humans and animals.
  • treatment in the context of the present invention includes the prophylaxis
  • the pharmaceutical activity of the compounds according to the invention can be explained by their action as SERM.
  • Another object of the present invention is the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, preferably of gynecological diseases, for the relief of the symptoms of andropause and menopause, i. male and female hormone replacement therapy (HRT) for both prevention and treatment; for the treatment of disorders associated with dysmenorrhoea; Treatment of dysfunctional uterine bleeding; Treatment of acne; Prevention and treatment of cardiovascular diseases; Treatment of hypercholesterolemia and hyperlipidemia; Prevention and treatment of atherosclerosis; for the inhibition of the proliferation of arterial smooth muscle cells; for the treatment of respiratory distress syndrome in newborns; Treatment of primary pulmonary hypertension; for the prevention and treatment of osteoporosis (Black, LJ, Sato, M., Rowley, ER, Magee, DE, Bekele, A., Williams, DC, Cullinan, GJ, Bendele, R., Kauffman, RF, Bensch, WR, Frolik, CA, Dates, JD and Bryant,
  • the compounds of the invention are suitable for both male and female contraception.
  • Another object of the present invention is the use of the compounds of the invention for the treatment of infertility and the induction of ovulation.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and prophylaxis of stroke and Alzheimer's and other diseases of the central nervous system, which is associated with the cell death of neurons.
  • Another object of the invention is the use of the compounds according to the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the afore-mentioned diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of the compounds of the invention.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the afore-mentioned diseases.
  • Another object of the present invention are the inventive
  • Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention and at least one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • suitable combination active ingredients are: estrogens, progestins and progesterone receptor antagonists.
  • Estrogens are compounds (naturally occurring or synthetic, steroidal and non-steroidal compounds) which exhibit estrogenic activity. Such compounds include: ethinylestradiol, estradiol, estradiols, estradiolvalerate, estradiol, estrones, mestranol, estriol, estriolsuccinate and conjugated estrogens, including conjugated equine estrogens such as estrone sulfate, 17 ⁇ -estradiol sulfate, 17 ⁇ -estradiol sulfate, equilin sulfate, 17 ⁇ -dihydroequilin sulfate, 17a Dihydroequilin sulfate, equilin sulfate, 17 ⁇ -dihydroequilenin sulfate and 17 ⁇ -dihydroequilenin sulfate.
  • conjugated equine estrogens such as estrone sulfate, 17 ⁇ -estradio
  • estrogens are ethinylestradiol, estradiol, estradiolsulfamates, estradiol valerate, estradiol-15-benzoate, strontium, estrone and estrone sulfate.
  • Preferred estrogens are ethinylestradiol, estradiol and mestranol, particularly preferred is ethinyl estradiol.
  • progestins are understood to be either the natural progesterone itself or synthetic (steroidal and non-steroidal) derivatives which, like progesterone itself, bind to the progesterone receptor and inhibit ovulation in dosages above the ovulation inhibitory dose.
  • Progesterone receptor antagonists bind compounds that inhibit the growth of progesterone at its receptor.
  • RU 486, onapristone, lonaprisan (1-1 ⁇ - (4-acetylphenyl) -17 ⁇ -hydroxy-17 ⁇ - (1,1,2,2,2,2-pentafluoroethyl) estra-4,9-dien-3-one see WO 98/34947
  • the compounds claimed in WO 08/58767 see WO 08/58767.
  • the invention also relates to pharmaceutical preparations which contain at least one compound of general formula I (or physiologically acceptable addition salts with organic and inorganic acids thereof) and the use of these compounds for the preparation of medicaments, in particular for the indications mentioned above.
  • the compounds both after oral and parenteral administration, can be used for the aforementioned indications.
  • the compounds may also be used in combination with the natural vitamin D3 or with calcitriol analogs for bone augmentation or as supportive therapy for therapies that cause bone mass loss (for example, glucocorticoid therapy, chemotherapy).
  • the compounds of general formula I can also be used in conjunction with progesterone receptor antagonists or in conjunction with pure estrogens, in particular for use in hormone replacement therapy and for the treatment of gynecological disorders and for female fertility control.
  • a therapeutic product containing an estrogen and a pure antiestrogen for simultaneous, sequential or separate use for the selective estrogen therapy of perimenopausal or postmenopausal states has already been described in EP-A 0 346 014.
  • the compounds of general formula I can also be given in conjunction with progestogens, gestagenic substances or COCs (combined oral contraceptives), in particular for use in premenopausal women for the treatment of gynecological diseases such as endometriosis, myomas or disorders of menstrual bleeding such as dysmenorrhoea or hypermenorrhea or for the treatment of hormone-dependent tumors such as breast cancer.
  • progestogens such as endometriosis, myomas or disorders of menstrual bleeding such as dysmenorrhoea or hypermenorrhea
  • COCs combined oral contraceptives
  • the compounds of the general formula I can be administered both continuously (by way of example once daily) and in intermittent regimens.
  • treatment regimens such as once a week, once a month, daily over a period of several days, on certain days of the female menstrual cycle (e.g., on 14 consecutive days of the secretory phase or several days in the middle of the menstrual cycle) are exemplified.
  • the compounds of general formula I may be given continuously over a longer treatment period (e.g., 14-168 consecutive days) followed by a treatment break which is either fixed (e.g., 14-84 days) or flexibly lasting until the next menstrual period.
  • the compounds of general formula I can be administered in these intermittent treatment regimes alone or in combination with combination therapies already mentioned, wherein these can be administered continuously but also intermittently.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms
  • the prior art functional shells and / or modifying agents are the application forms which are suitable according to the invention and which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form such as tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (e.g. - or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be carried out with the use of a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or with involvement of absorption (eg intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • a resorption step eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly
  • absorption eg intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops, solutions, sprays including lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, Pastes, foams, scattering powders, implants, intrauterine substance delivery systems IUS (eg intrauterine spirals), vaginal rings or stents.
  • IUS intrauterine substance delivery systems
  • 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.
  • These adjuvants include, among others. Carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides), and flavor and / or odor remedies.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents eg liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dodecyl
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the amount per day is about 0.01 to 100 mg / kg of body weight.
  • the amount of a compound of general formula I to be administered will vary within a wide range and may cover any effective amount. Depending on the condition to be treated and the mode of administration, the amount of compound administered may be 0.01-100 mg / kg of body weight per day.
  • the compounds according to the invention could be prepared by preparative HPLC, for example by an autopurifier from Waters (detection of the compounds by UV detection and electrospray ionization) in combination with commercially available, pre-packed HPLC columns (for example column XBridge (Waters ), C18, 5 ⁇ , 30 x 100mm) are cleaned.
  • the solvent system used was acetonitrile / water + 0.1% TFA or 0.1%> formic acid.
  • acetonitrile for example, methanol could also be used.
  • the flow during the purification was 50 mL / min.
  • the compounds according to the invention were purified by the following method (HPLC method 1):
  • the compounds according to the invention were purified by the following method (HPLC method 2): XBridge C18, 5 ⁇ , 100 x 30 mm, 50 mL / min, eluent: water with 0.1% formic acid-methanol 70:30, 0-1 minute; 70:30 -> 1: 99, 1-7.5 minutes; 1:99, 7.5-10 minutes, other conditions were analogous to Method 1. Freeze-drying or vacuum centrifugation was used to remove the HPLC solvent mixture.
  • the compounds thus obtained could be present as TFA salts or formate salts and could be converted into the respective free bases by the standard laboratory procedures known to the person skilled in the art.
  • the compounds of the invention could be purified by chromatography on silica gel.
  • pre-packed silica gel cartridges e.g., Separtis, Isolute® Flash silica gel
  • Flashmaster II Chromatograph Arnaut / Biotage
  • chromatography solvents or mixtures such as hexane, ethyl acetate, and dichloromethane and methanol into consideration, whereby additions of aqueous ammonia solution could be added.
  • System Waters Aqcuity UPLC-MS Binary Solvent Manager, Sample Manager / Organizer, Column Manager, PDA, ELSD, SQD 3001, Column: Acquity BEH C18, 1.7 ⁇ , 50x2.1 mm.
  • solvent A water with 0.1%> TFA or with 0.1%> formic acid was used.
  • Solvent B was acetonitrile.
  • a Waters ZQ4000 device or a single quadrupole API (Atomic Pressure Ionization) mass detector (Waters) was used to acquire a mass spectrum.
  • reaction mixture was diluted with dichloromethane or methyl tert-butyl ether, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate or sodium sulfate and concentrated. The mixture was then chromatographed on silica gel 60.
  • Step b Preparation of S- ⁇ 4 - [(tert-butoxycarbonyl) (methyl) amino] butyl ⁇ ethanethioate
  • N-methyl-4 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] butane-1-amine 4.5 g (14.9 mmol) of 4 - [(4-chlorobutyl) sulfonyl] -1,1,1,2,2-pentafluorobutane were dissolved in 150 ml of 33% methylamine solution in ethanol in accordance with general procedure 16-18-20-D24 Stirred and worked up for hours. 3.67 g (83% of theory) of product were obtained.
  • the residue was purified on silica gel 60 (eluent: dichloromethane, dichloromethane-methanol 98: 2, 95: 5 and 90:10).
  • the crude product was mixed with diisopropyl ether, sonicated in an ultrasonic bath, filtered off and dried at 40 ° C in a drying oven. There was 455.5 mg (29% of theory) of product.
  • reaction mixture was diluted with tert-butyl methyl ether and water, the phases were separated, extracted twice with tert-butyl methyl ether and the combined organic phases were washed with brine and dried over sodium sulfate. After purification by column chromatography on silica gel (hexane / ethyl acetate), 464 mg of the title compound were obtained.

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Abstract

L'invention concerne des modulateurs sélectifs des récepteurs aux oestrogènes (SERM) et leur procédé de préparation, leur utilisation pour le traitement et/ou la prophylaxie de maladies ainsi que leur utilisation pour la fabrication de produits pharmaceutiques servant au traitement et/ou à la prophylaxie de maladies, notamment les troubles hémorragiques, l'ostéoporose, l'endométriose, les myomes, les tumeurs hormonodépendantes, à l'hormonothérapie substitutive et à la contraception.
EP11729943.8A 2010-06-25 2011-06-21 Dérivés de 6,7-dihydro-5h-benzo[7]annulène, leur procédé de préparation, préparations pharmaceutiques les contenant et leur utilisation pour la fabrication de produits pharmaceutiques Withdrawn EP2585435A1 (fr)

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DE102010030538A DE102010030538A1 (de) 2010-06-25 2010-06-25 6,7-Dihydro-5H-benzo[7]annulen-Derivate, Verfahren zu ihrer Herstellung, pharmazeutische Präparate die diese enthalten, sowie deren Verwendung zur Herstellung von Arzneimitteln
PCT/EP2011/060335 WO2011161101A1 (fr) 2010-06-25 2011-06-21 Dérivés de 6,7-dihydro-5h-benzo[7]annulène, leur procédé de préparation, préparations pharmaceutiques les contenant et leur utilisation pour la fabrication de produits pharmaceutiques

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DOP2012000325A (es) 2013-02-28
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