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WO2015028409A1 - Dérivés de 6,7-dihydro-5h-benzo[7]annulène, procédé pour les préparer, préparations pharmaceutiques les contenant et leur utilisation pour fabriquer des médicaments - Google Patents

Dérivés de 6,7-dihydro-5h-benzo[7]annulène, procédé pour les préparer, préparations pharmaceutiques les contenant et leur utilisation pour fabriquer des médicaments Download PDF

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Publication number
WO2015028409A1
WO2015028409A1 PCT/EP2014/067957 EP2014067957W WO2015028409A1 WO 2015028409 A1 WO2015028409 A1 WO 2015028409A1 EP 2014067957 W EP2014067957 W EP 2014067957W WO 2015028409 A1 WO2015028409 A1 WO 2015028409A1
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WIPO (PCT)
Prior art keywords
sulfonyl
benzo
dihydro
annulen
pyrrolidin
Prior art date
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Ceased
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PCT/EP2014/067957
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German (de)
English (en)
Inventor
Ludwig Zorn
Dirk Kosemund
Carsten Möller
Horst Irlbacher
Reinhard Nubbemeyer
Antonius Ter Laak
Ulrich Bothe
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Bayer Pharma AG
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Bayer Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings

Definitions

  • the invention relates to "Selective Estrogen Receptor Modulators” (SERM) and processes 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
  • the estrogen receptor (ER) or its two subtypes of ERa and ER ⁇ belong to the family of nuclear hormone receptors.
  • the ER is responsible for mediating a variety of female sex or fertility functions (Handb.Exp. Pharmacol., 2012; (214): 543-87, doi: 10.1007 / 978-3-642-30726-3 24; Pharmacology and Clinical use of sex steroid hormone receptor modulators, Cleve A, Fritzemeier KH, Haendler B, Heinrich N, Moeller C, Swede W, Winter Coat T.).
  • Influencing the function of the ER by synthetic ligands may alleviate the symptoms and / or the course of various diseases (especially bleeding disorders, osteoporosis, endometriosis, fibroids, hormone-dependent tumors, hormone replacement therapy and contraception) (Handb. Exp. Pharmacol. 2012; (214): 543-87 Pharmacology and clinical use of sex Steroid hormone receptor modulators Cleve A, Fritzemeier KH, Haendler B, Heinrich N, Moeller C, Swede W, Winter coat T.).
  • Endometriosis is an estrogen-dependent disease (Serdar E. Bulun, N Engl J Med 2009; 360: 268-79.). Compounds which inhibit the action of the hormone estrogen at its receptors and which moreover destabilize the estrogen receptor are therefore suitable for the treatment of this disease, since this central mechanism of action is blocked. It is important that the degradation of the receptor is not complete, as such compounds could lead to increased hypoestrogenic side effects (Aman U Buzdar, John FR Robertson, Ann Pharmacother 2006; 40: 1572-83.).
  • SERMs are compounds which have tissue-selective either an anti-estrogen / estrogen-inhibiting or estrogenic or partial estrogenic action, for example, inhibit the action of the estrogen on the uterus, but have a neutral or estrogen-like effect on the bone. Examples of such compounds include tamoxifen, raloxifene and apeledoxifene. To distinguish are SERM of pure antiestrogens, which in All tissues have a purely antagonistic, the effect of estrogens inhibitory effect and show no estrogens or partial estrogenic activity in a tissue.
  • SERD Selective Estrogen Receptor Downregulators
  • anti-inflammatory genes influence the level of expression of the ER in the target tissues by stimulating the proteolytic degradation of the ER (see above, definition of SERD).
  • SERD the proteolytic degradation of the ER
  • the ER bound in complex with the pure antiestrogen fulvestrant has a substantially shorter half-life.
  • the ER stability is enhanced by the Tamoxifen SERM, resulting in overall ER stabilization.
  • the ability of pure anti-estrogens and certain SERMs to induce ER degradation contributes significantly to the overall effect of the compounds.
  • Compounds which show a destabilizing property but at the same time have the desired tissue-specific agonistic qualities, e.g.
  • ligands may be particularly useful for their use in certain indications, e.g. Tamoxifen Resistant Breast Cancer (Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: Wardell SE, Nelson ER, Chao CA, McDonnell DP, Clin Cancer Res., 2013 May 1, 19 (9 ): 2420-31, doi: 10.1158 / 1078-0432.CCR-12-3771, Epub 2013 Mar 27), endometriosis, relieving bleeding disorders, osteoporosis or uterine fibroids.
  • WO2012 / 084711 describes a new series of N-substituted azetidine derivatives which are suitable as selective estrogen receptor modulator (SERM).
  • SERM selective estrogen receptor modulator
  • WO 2011/161101 and WO 2013/083568 describe 6,7-dihydro-5H-benzo [7] annulen derivatives which are linked at the 8-position to an aromatic substituent and which at position 9 are aliphatic Chain substituted with an acyclic amino group.
  • the compounds described in WO 2011/161101 and in WO 2013/083568 act as
  • SERM 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%). Over the entire structural region, these compounds show high antiestrogenic activity in vitro.
  • the claimed compounds are also active as SERM.
  • the claimed compounds, as well as the 6,7-dihydro-5H-benzo [7] annulene derivatives described in WO 2011/161101 and WO 2013/083568, have a destabilizing effect on the ER ⁇ content (remaining relative ER ⁇ content of less than or equal to 30%) and show a high anti-estrogenic activity in vitro (IC 50 values less than 0.6 micromolar for the inhibition of estradiol-induced luciferase activity).
  • the present invention relates to compounds of the formula (I):
  • R 5, R 6 and R 7 independently represent hydrogen, halogen, Ci-Ci alkyl or nitrile
  • R 8 , R 9 are hydrogen, hydroxy or fluorine, but R 8 and R 9 are not simultaneously hydroxy or not simultaneously hydroxy and fluoro;
  • Xi is -O-CH2-, -CH2- or -CH2-CH2-;
  • X 2 is nitrogen or -CH-;
  • Ci-C / i-alkyl per- or partially fluorinated Ci-C / i-alkyl or per- or partially fluorinated Cs-Cs-cycloalkyl;
  • Q is -SO 2 -, -SO-, -S- or -O-;
  • n 4, 5, 6 or 7;
  • q 1, 2, 3 or 4;
  • t 0, 1, 2, 3 or 4
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts and the compounds of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, insofar as the compounds mentioned below of formula (I) are not already salts, solvates and solvates of the salts, including all crystal modifications.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore encompasses the enantiomers and / or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform constituents can be isolated in a manner known to those skilled in the art.
  • 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 are themselves biologically active or may be inactive, but during their residence time in the body to be converted into compounds of the invention (for example, metabolically or hydrolytically).
  • alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
  • Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, neopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3 Methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 2-ethylbutyl.
  • Preference is given to methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylbutyl and neopentyl.
  • Hydroxy-C 1 -C 6 -alkyl in the context of the invention is a linear or branched alkyl radical having 1 to 6 carbon atoms, which carries in the chain or terminal hydroxy group as a substituent.
  • Examples which may be mentioned are: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1, 1-dimethyl-2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyethyl 2-methylpropyl, 2-hydroxy-1-methylpropyl, 2-hydroxy-2-methylpropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl and 4-hydroxybutyl. Preference is given to hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl.
  • Halogen-C 1 -C 6 -alkyl in the context of the invention represents a linear or branched alkyl radical having 1 to 6 carbon atoms, which carries one or more halogen atoms as substituents in the chain or terminally. Fluorine is preferred as the halogen atom. Examples include: -CF3, -CHF 2 , -CH 2 F, -CF 2 CF 3, or -CH 2 CF 3.
  • Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, 1-ethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy and n-hexoxy. Preference is given to a linear or branched alkoxy radical having 1 to 4 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy, 1-methylpropoxy, n-butoxy and iso-butoxy. Preference is given to methoxy.
  • Hydroxy-C2-C6-alkoxy in the context of the invention is a linear or branched alkoxy radical having 2 to 6 carbon atoms, which carries in the chain or terminal hydroxy group as a substituent. Examples include: 2-hydroxyethoxy and 2-hydroxypropoxy. Preference is given to 2-hydroxyethoxy.
  • Halogen-C 1 -C 6 -alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 carbon atoms which carries one or more halogen atoms as substituents in the chain or terminally. Fluorine is preferred as the halogen atom. Examples include: -OCF3, -OCHF 2 , -OCH2F, -OCF2CF3, or -OCH2CF3
  • Cycloalkyl is a mono- or bicyclic, saturated, monovalent hydrocarbon radical having generally 3 to 10, preferably 3 to 8, and particularly preferably 3 to 7 carbon atoms.
  • Particularly preferred is a cyclopropyl, cylopentyl or cyclohexyl radical.
  • bicyclic cycloalkyl radicals are:
  • Halogen is fluorine, chlorine, bromine and iodine. Preference is given to fluorine and chlorine. Particularly preferred is fluorine.
  • Ci-C i-alkyl is a fully fluorinated straight-chain or branched alkyl radical having usually 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 18 -alkyl represents a partially fluorinated straight-chain or branched alkyl radical, generally having 1 to 4 carbon atoms, selected from 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- (trifluoromethyl) propyl, 2, 2,2-trifluoro-1-methyl-1 -
  • Perfluorinated Cs-Cs-cycloalkyl is a fully fluorinated cycloalkyl group having usually 3-8, preferably 5-6 carbon atoms, by way of example and preferably perfluorocyclopentyl and perfluorocyclohexyl.
  • Partially fluorinated C3-C8-cycloalkyl is a partially fluorinated cycloalkyl group having usually 3 to 8 carbon atoms - selected but not limited to: 2,2-difluorocycloheptyl,
  • Heterocycloalkyl in the context of the invention is a saturated heterocycle having a total of 5 or 6 ring atoms which contains one to three ring heteroatoms from the series N or O.
  • the sequence -X 1 -X 2 -N- is inserted into a ring structure representing a heterocycloalkyl group.
  • Examples include: pyrrolidine, tetrahydro-lH-pyrazole, morpholine, 1,3,4-oxadiazinane, piperidine and hexahydropyridazine. Preference is given to pyrrolidine, piperidine and morpholine.
  • 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.
  • treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restricting, reducing, depressing, restraining or curing a disease, a disease, a disease, a disease Injury or a health-related disorder, the unfolding, the course or the progression of such States and / or symptoms of such conditions.
  • therapy is hereby understood to be synonymous with the term “treatment”.
  • prevention means prevention or prevention.
  • prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health Disruption, development, or progression of such conditions, and / or to experience, experience, suffer, or have the symptoms of such conditions.
  • Another object of the invention relates to compounds of formula (I) wherein
  • Another object of the invention relates to compounds of formula (I) wherein R 5 , R 6 and R 7 are independently hydrogen, halogen, Ci-C3-alkyl or nitrile.
  • Another object of the invention relates to compounds of formula (I) wherein X 2 is -CH-.
  • Another object of the invention relates to compounds of formula (I) wherein Q is -SO 2 -, -SO- or -S-.
  • 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
  • R 1 , R 2 , R 3 and R 4 independently of one another are hydrogen, C 1 -C -alkyl, C 1 -C -alkoxy, halogen, hydroxyl, nitrile or C 1 -C 3 -alkyl-SC> 2-.
  • Another object of the invention relates to compounds of formula (I), wherein is -SO2- or -S-. Another object of the invention relates to compounds of formula (I) wherein t is 1, 2, 3 or 4.
  • Another object of the invention relates to compounds of formula (I) wherein Xi is -O-CH 2 - or -CH 2 -.
  • Another object of the invention relates to compounds of formula (I) wherein
  • Y is -Ci-C i-alkyl or per- or partially fluorinated -Ci-C i-alkyl.
  • Another object of the invention relates to compounds of formula (I) wherein Q is -SO 2 -.
  • Another object of the invention relates to compounds of formula (I) wherein q is 2, 3 or 4.
  • Another object of the invention relates to compounds of formula (I) wherein t is 2, 3 or 4.
  • Another object of the invention relates to compounds of formula (I) wherein R 1, R 2, R 3 and R 4 are independently hydrogen, fluorine or hydroxy.
  • Another object of the invention relates to compounds of formula (I) wherein R 5 , R 6 and R 7 are independently hydrogen or fluorine.
  • Another object of the invention relates to compounds of formula (I) wherein
  • Y represents a tert-butyl group, CF 3 or C 2 F 5.
  • the 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.
  • R 1 , R 2 , R 3 and R 4 independently of one another are hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen
  • R 5, R 6 and R 7 are independently hydrogen, halogen, Ci-C3-alkyl or nitrile;
  • R 8 , R 9 are hydrogen, hydroxy or fluorine, but R 8 and R 9 are not simultaneously hydroxy or not simultaneously hydroxy and fluoro;
  • Xi is -O-CH2-, -CH2- or -CH2-CH2-;
  • X 2 is -CH-
  • Y is -Ci-C i-alkyl, per- or partially fluorinated -Ci-C i-alkyl or per- or partially fluorinated C3-C8-cycloalkyl;
  • Q is -SO 2 -, -SO- or -S-;
  • n 5 or 6;
  • q 1, 2, 3 or 4;
  • t 0, 1, 2, 3 or 4
  • R 1 , R 2 , R 3 and R 4 independently of one another represent hydrogen, C 1 -C -alkyl, C 1 -C -alkoxy, halogen,
  • R 5 , R 6 and R 7 independently of one another are hydrogen, halogen, C 1 -C 3 -alkyl or nitrile;
  • R 8 , R 9 are hydrogen, hydroxy or fluorine, but R 8 and R 9 are not simultaneously hydroxy or not simultaneously hydroxy and fluoro;
  • Xi is -O-CH2-, -CH2- or -CH2-CH2-;
  • X 2 is -CH-
  • Y is -Ci-C i-alkyl, per- or partially fluorinated -Ci-C i-alkyl or per- or partially fluorinated Cs-Cs-cycloalkyl;
  • Q is -SO 2 - or -S-;
  • n 5 or 6;
  • q 1, 2, 3 or 4;
  • t stands for 1, 2, 3 or 4
  • R 1 , R 2 , R 3 and R 4 independently represent hydrogen, halogen or hydroxy
  • R 5 , R 6 and R 7 are independently hydrogen or halogen
  • R 8 , R 9 are hydrogen, hydroxy or fluorine, but R 8 and R 9 are not simultaneously hydroxy or not simultaneously hydroxy and fluoro;
  • Xi is -O-CH 2 - or -CH 2 -;
  • X 2 is -CH-
  • Y is -Ci-C / i-alkyl or perfluorinated or partially fluorinated -Ci-C / i-alkyl;
  • n 5 or 6;
  • q 2, 3 or 4;
  • R 1 , R 2 , R 3 and R 4 independently represent hydrogen, fluorine or hydroxy
  • R 5 , R 6 and R 7 are independently hydrogen or fluorine
  • R 8 , R 9 are hydrogen, hydroxy or fluorine, but R 8 and R 9 are not simultaneously hydroxy or not simultaneously hydroxy and fluoro;
  • Xi is -O-CH 2 - or -CH 2 -;
  • x 2 is -CH-;
  • Y is a tert-butyl group, CF 3 or C 2 F 5;
  • the compounds according to the invention are potent SERMs which have a destabilizing effect on the ER ⁇ content (remaining relative ER ⁇ content of less than or equal to 30%) and show a high anti-estrogenic activity in vitro (IC50 values of less than 0.6 micromolar for the inhibition of ER Estradiol-induced luciferase activity).
  • the present invention relates to compounds of the formula (I) for the treatment and / or prophylaxis of diseases.
  • the compounds of the invention unpredictably show a valuable pharmacological and pharmacokinetic activity spectrum. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in 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 As shown in Tables 1-3, the compounds according to the invention are potent SERMs, making them able are those which show a high anti-estrogenic activity in vitro and at the same time destabilize the ER ⁇ .
  • the compounds according to the invention are therefore particularly suitable for the treatment and / or prophylaxis of endometriosis.
  • the compounds according to the invention are suitable for inhibiting ovulation, for inhibiting sperm maturation, for alleviating the symptoms of andropause and menopause, ie for male and female hormone replacement therapy, for the prevention or prophylaxis and for the treatment of disorders associated with dysmenorrhea, dysfunctional uterines Bleeding, acne, cardiovascular diseases, hypercholesterolemia and hyperlipidemia, atherosclerosis, smooth muscle cell proliferation, neonatal respiratory distress syndrome, primary pulmonary hypertension, osteoporosis, bone loss in postmenopausal women, hysterectomized women, or women who have been treated with LHRH agonists or antagonists, rheumatoid arthritis, Alzheimer's disease, endometriosis, fibroids, hormone-dependent tumors, such as mammary or endometrial carcinoma, infertility, prostatic diseases, benign diseases of the breast such as mastopathy , stroke, Alzheimer's and other diseases of the central nervous system that are associated with the cell death of neurons.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned 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 aforementioned diseases.
  • Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or Pro ⁇ phylaxe of the aforementioned diseases.
  • compositions containing at least one compound of the invention and at least one or more other active ingredients 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: aromatase inhibitors, 17beta HSD1 inhibitors, steroid sulfatase (STS) inhibitors, LHRH analogs, LHRH antagonists, GnRH agonists and antagonists, Kisspeptin receptor (KISSR) antagonists, selective androgen receptor modulators ( SARMs), androgens, selective progesterone receptor modulators (SPRMs), progestins, progesterone receptor antagonists, oral contraceptives, estrogens, inhibitors of mitogen-activated protein (MAP) kinases and inhibitors of MAP kinases, kinases (Mkk3 / 6, Mekl / 2 , Expl / 2) inhibitors of protein kina
  • the invention also relates to pharmaceutical compositions containing 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.
  • compositions and pharmaceutical compositions may preferably be used for oral, but also for rectal, vaginal, subcutaneous, percutaneous, intravenous, buccal, transdermal or intramuscular administration.
  • conventional carriers and / or diluents they contain at least one compound of the general formula (I) or salts thereof.
  • the medicaments of the invention are prepared in a known manner with the usual solid or liquid carriers or diluents and the pharmaceutically-technical auxiliaries customarily used in accordance with the desired mode of administration with a suitable dosage.
  • the preferred preparations are in a dosage form suitable for oral administration.
  • dosage forms are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or else depot forms.
  • parenteral preparations such as injection solutions come into consideration.
  • preparations for example, Supposi ⁇ and called agents for vaginal application are tories as preparations for example, Supposi ⁇ and called agents for vaginal application.
  • Corresponding tablets can be prepared, for example, by mixing the active compound with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or or means for obtaining a depot effect such as carboxylpolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinylacetate.
  • the tablets can also consist of several layers.
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
  • the dragee wrapper can also consist of several layers, wherein the auxiliaries mentioned above in the case of the tablets can be used.
  • Solutions or suspensions with the compounds of the general formula (I) according to the invention may additionally taste-improving agents such as saccharin, CyclaTnat or sugar and, for example Flavorings such as vanillin or orange extract contain. They may also contain suspensions-such as sodium car-boxymethylcellulose or preservatives such as p-hydroxybenzoates.
  • Capsules containing the compounds of general formula (I) can be prepared, for example, by mixing the compound (s) of general formula (I) with an inert carrier such as lactose or sorbitol and encapsulating it in gelatin capsules.
  • an inert carrier such as lactose or sorbitol
  • Suitable suppositories can be prepared, for example, by mixing with suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.
  • the compounds according to the invention are partial estrogen stabilizers and have anti-estrogenic activity.
  • Compounds of the invention are particularly suitable for oral administration.
  • the starting materials 11 can be obtained commercially (eg CAS 73365-02-3, CAS 69610-41-9, CAS 192320-50-6) or synthesized according to the conditions known to the person skilled in the art (US 2011/105520 A1, WO 2011/53706 AI, US 2007/191361 A1, WO 2004/76407 A2, Tetrahedron 1991, 47, 5051).
  • PG stands for a protecting group and can be selected according to the conditions of the synthesis suitable for the person skilled in the art, as it is suitable for the synthesis and the final deprotection of PG (Theodora W.
  • the intermediates 13 can be activated by the methods known to those skilled in the art (Helv. Chim. Acta 1951, 34, 2202; J. Org. Chem. 1991, 56, 1393; J. Am. Chem. Soc., 1993, 115, 7045; Helv. Chim. Acta 1990, 73, 122), preference being given to conversion into the mesylate.
  • the intermediates 14 may be prepared by the methods known to those skilled in the art (Tetrahedron Lett., 1987, 28, 535, Tetrahedron Lett., 1995, 36, 1223, J.Med.Chem., 2004, 47, 3275, Pharm. Chem , 23, 998), the synthesis of the thioacetates used here being described in WO 2011/161101. Here, the release of the thiolate from the thioacetate with sodium methoxide and the subsequent reaction with the mesylate is preferred.
  • the intermediates 15 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.
  • the oxidation with peracids is particularly preferred.
  • the release of the intermediates 16 can be carried out according to the conditions known to the person skilled in the art (Theodora W. Greene and Peter GM Wuts in "Protective Groups in Organic Synthesis” 3rd Editing, (1999), John Wiley & Sons New York) Buutyloxycarbonyl protective group is the acidic cleavage favors, wherein the cleavage with trifluoroacetic acid is particularly preferred.
  • the starting materials ST 17 can be prepared by the methods known to the person skilled in the art (WO 2011/161101 A1, WO 2005/77968 A2).
  • the intermediates 17 can according to the Chem. 1975, 40, 284; Tetrahedron 2010, 66, 2642). Here, the method with acetonitrile is particularly preferred.
  • the intermediates 18 can be prepared by the methods known to those skilled in the art using the Wittig reagent 17 (J. Org. Chem. 1975, 40, 284; Tetrahedron 2010, 66, 2642; Bioorg. Med. Chem. 2002, 10, 1399; Tetrahedron 1994, 50, 7093), wherein the reaction with potassium tert-butoxide at initial -30 to -40 ° C is performed.
  • the intermediates 19 can be prepared by the methods known to those skilled in the art (Houben Weyl, "Methods of Organic Chemistry", Vol. 4 / 1c Part 1, p. 14 ff. (1980), Georg Thieme Verlag Stuttgart, New York) If the reaction with palladium on activated carbon under a hydrogen atmosphere is preferred, the release of the intermediates 20 can be carried out according to the conditions known to the person skilled in the art, as described for the intermediates 16. Particular preference is given to cleavage with trifluoroacetic acid.
  • the intermediates 21 can be prepared according to the conditions known to those skilled in the art (J. Med. Chem. 1991, 34, 2547; Org. Lett. 2000, 2, 3765; Synth. Commun. 2006, 36, 3001; Org. Lett , 9, 2477; Angew. Chem. Int. Ed. 2002, 41, 3284).
  • the method is preferred with organic bases, and most preferably with trialkylamines.
  • the intermediates 22 can be prepared by the methods known to those skilled in the art (Houben Weyl, "Methods of Organic Chemistry", Vol. 4 / 1c Part 1, p. 14 ff.
  • the intermediates 25 can be prepared by the methods known to the person skilled in the art, analogously to the synthesis of the intermediates 14.
  • the intermediates 26 can be prepared by the methods known to the person skilled in the art, analogously to the synthesis of the intermediates 15, preference being given to peracids.
  • the cleavage of the amino protecting group to the intermediate 27 is carried out as described in Intermediate 16, while trifluoroacetic acid or hydrochloric acid is preferred for the cleavage of the tert-butoxycarbonyl group.
  • the protective group can be cleaved off at the stages of intermediates 25, 26 or 27, as is known to the person skilled in the art (Theodora W. Greene and Peter GM Wuts in "Protective Groups in Organic Synthesis 3rd Ed., (1999), John Wiley & Sons, Inc., New York) .
  • the protective group for the hydroxy group may be different groups, with preference given to ether protecting groups, most preferably silyl ether groups, especially the The silyl protecting groups may be cleaved acidic or with tetrabutylammonium fluoride, the latter being preferred
  • the deprotection is preferred after oxidation to intermediate 26.
  • 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 with additions of ammonia, ammonium acetate, trifluoroacetic acid or formic acid.
  • acetonitrile for example, methanol could also be used.
  • the flow in the purification was 50 ml / min.
  • the compounds of the invention could be purified by chromatography on silica gel.
  • silica gel for example, pre-packed silica gel cartridges (for example from Separtis, Isolute® Flash silica gel) in combination with the Flashmaster II chromatographic apparatus (Argonaut / Biotage) and solvents or solvent mixtures such as hexane, hexane / ethyl acetate or dichloromethane, for example Dichloromethane / methanol used, wherein also aqueous ammonia solution could be added.
  • pre-packed silica gel cartridges for example from Separtis, Isolute® Flash silica gel
  • the Flashmaster II chromatographic apparatus Arnaut / Biotage
  • solvents or solvent mixtures such as hexane, hexane / ethyl acetate or dichloromethane, for example Dichloromethane / methanol used, wherein also aqueous ammonia solution could be added.
  • Rotational values were determined as follows: Instrument: JASCO P2000 Polarimeter; Wavelength 589 nm; Temperature: 20 ° C; Integration time 10 s; Layer thickness 100 mm.
  • the mixture was concentrated, combined with water and ethyl acetate, and the organic phase was separated and extracted three times with ethyl acetate.
  • the combined organic phases were washed with water (addition of dilute hydrochloric acid solution for phase separation), saturated sodium bicarbonate solution and sodium chloride solution, dried over sodium sulfate and concentrated. After purification by column chromatography on silica gel (hexane / ethyl acetate), 0.84 g of the title compound was obtained.
  • Step 1

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Abstract

L'invention concerne des modulateurs sélectifs des récepteurs aux œstrogènes (SERM), un procédé pour les préparer, leur utilisation pour le traitement et/ou la prévention de maladies ainsi que leur utilisation pour fabriquer des médicaments destinés au traitement et/ou à la prévention de maladies, en particulier les troubles hémorragiques, l'ostéoporose, l'endométriose, les myomes, les tumeurs hormonodépendantes, ainsi qu'à l'hormonothérapie substitutive et à la contraception.
PCT/EP2014/067957 2013-08-27 2014-08-25 Dérivés de 6,7-dihydro-5h-benzo[7]annulène, procédé pour les préparer, préparations pharmaceutiques les contenant et leur utilisation pour fabriquer des médicaments Ceased WO2015028409A1 (fr)

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WO2017186140A1 (fr) * 2016-04-28 2017-11-02 江苏恒瑞医药股份有限公司 Procédé de préparation d'un inhibiteur de tyrosine kinase et d'un dérivé correspondant
US10118910B2 (en) 2015-12-09 2018-11-06 The Board Of Trustees Of The University Of Illinois Benzothiophene-based selective estrogen receptor downregulators
CN108884079A (zh) * 2016-02-15 2018-11-23 赛诺菲 作为雌激素受体调节剂的6,7-二氢-5h-苯并[7]轮烯衍生物
US10208011B2 (en) 2017-02-10 2019-02-19 G1 Therapeutics, Inc. Benzothiophene estrogen receptor modulators
US10695333B2 (en) 2017-12-01 2020-06-30 Novartis Ag Pharmaceutical combination comprising LSZ102 and alpelisib
US10703747B2 (en) 2016-10-24 2020-07-07 The Board of Directors of the University of Illinois Benzothiophene-based selective mixed estrogen receptor downregulators
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WO2022084298A1 (fr) * 2020-10-19 2022-04-28 Sanofi Composés de 6,7-dihydro-5h-benzo[7]annulène substitués, leurs dérivés, procédés permettant leur préparation et utilisations thérapeutiques associées
WO2022084280A1 (fr) * 2020-10-19 2022-04-28 Sanofi Composés 6,7-dihydro-5h-benzo[7]annulène substitués et leurs dérivés, processus permettant leur préparation et utilisations thérapeutiques associées
US11364222B2 (en) 2017-01-06 2022-06-21 G1 Therapeutics, Inc. Combination therapy for treatment of cancer
US11713296B2 (en) 2018-09-07 2023-08-01 Sanofi Salts of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-l-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate and preparation process thereof
CN116615414A (zh) * 2020-10-19 2023-08-18 赛诺菲 经取代的6,7-二氢-5h-苯并[7]轮烯化合物及其衍生物、其制备方法及其治疗用途
US12427142B2 (en) 2020-02-27 2025-09-30 Sanofi Combination comprising alpelisib and 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl[oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid
US12528768B2 (en) 2019-12-09 2026-01-20 Sanofi Crystalline form of a 7H-benzo[7]annulene-2-carboxylic acid derivative
JP7808602B2 (ja) 2020-10-19 2026-01-29 サノフイ 置換６，７－ジヒドロ－５ｈ－ベンゾ［７］アヌレン化合物およびそれらの誘導体、それらの製造のための方法ならびにそれらの治療的使用

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WO2003033461A1 (fr) * 2001-10-12 2003-04-24 Schering Aktiengesellschaft Synthese de benzocycloheptenes substitues par des atomes d'oxygene, servant d'intermediaires importants pour produire des oestrogenes a selectivite tissulaire
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US11072595B2 (en) 2015-12-09 2021-07-27 The Board of Trustees of lhe University of Illinois Benzothiophene-based selective estrogen receptor downregulator compounds
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US12054469B2 (en) 2015-12-09 2024-08-06 The Board Of Trustees Of The University Of Illinois Benzothiophene-based selective estrogen receptor downregulator compounds
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US10570090B2 (en) 2016-02-15 2020-02-25 Sanofi Substituted 6,7-dihydro-5H-benzo[7]annulene compounds, processes for their preparation and therapeutic uses thereof
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JP2019520305A (ja) * 2016-04-28 2019-07-18 ジエンス ヘンルイ メデイシンカンパニー リミテッドＪｉａｎｇｓｕ Ｈｅｎｇｒｕｉ Ｍｅｄｉｃｉｎｅ Ｃｏ．，Ｌｔｄ． チロシンキナーゼ阻害剤及びその誘導体を製造する方法
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